Vol. 31 (2026)



No.  01DOI: 10.1186/s11658-025-00827-2 Volume 31 (2026) - 30:01
Title LOSS OF ALPHA-KINASE 1 CONTRIBUTES TO THE FORMATION OF CONGENITAL CATARACTS IN MICE
Authors Hui-Shan Wang1†, Yu-Xin Yang1†, Shang-Shang Duan1†, Fang-Yi Long2, Ting Wu1, Nai-Hong Yan1, Xiao-Hong Li1* and Jun-Rong Du1*
Abstract Background: Alpha-kinase 1 (ALPK1), a cytosolic receptor involved in innate immune activation, promotes apical trafficking in epithelial cells. While its role in autoinflammatory disorders is known, its function in epithelial homeostasis remains unexplored. This study investigates ALPK1’s role in murine lens development and its pathological relevance to congenital cataracts (CCs).
Methods: We utilized ALPK1-deficient (ALPK1−/−) C57BL/6 mice and primary lens epithelial cells (LECs) with ALPK1 knockout (via lentiviral sgRNA) to analyze lens histo-morphological alterations and cellular and molecular pathologies, including apical protein transport and localization, endoplasmic reticulum (ER) stress, apoptosis, and LEC differentiation.
Results: We observed strong ALPK1 immunoreactivity in the LECs of C57BL/6 mice. ALPK1−/− mice developed CCs with combined Y-suture and cortical opacities, disrupted lens cell architecture, and vacuolar degeneration. Molecular dysregulation included reduced phosphorylation of myosin Ia, mislocalization of zonula occludens-1 (ZO-1) from apical tight junctions to cytoplasmic aggregates, upregulation of the endoplasmic reticulum (ER) stress marker C/EBP-homologous protein (CHOP), increased apoptosis (evidenced by TUNEL-positive cells), and disorganized interlocking patterns in lens fiber cells. Lentiviral ALPK1 re-expression in ALPK1−/− mice significantly restored lens transparency and ZO-1 apical localization, reduced CHOP expression, and suppressed apoptosis.
Conclusions: This study first demonstrates that ALPK1 is critical for maintaining LEC homeostasis by regulating myosin Ia phosphorylation-dependent apical trafficking and tight junction integrity. ALPK1 deficiency disrupts these processes, leading to loss of apical polarity, ER stress-induced apoptosis, and ultimately CC formation.
Keywords ALPK1, Apical transport, Congenital cataracts, Lens epithelial cells, Myosin Ia
Address and Contact Information 1 West China School of Pharmacy, West China School of Public Health, Research Laboratory of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
2 Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610032, Sichuan, China
*Corresponding author: Xiao-Hong Li li_xiaohong@scu.edu.cn Jun-Rong Du dujunrong@scu.edu.cn
† Hui-Shan Wang, Yu-Xin Yang and Shang-Shang Duan have contributed equally to this work.
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No.  03DOI: 10.1186/s11658-025-00831-6 Volume 31 (2026) - 30:03
Title TRIGEMINAL NERVE ROOT COMPRESSION INDUCED NEUROINFLAMMATORY RESPONSE PROMOTES MECHANICAL ALLODYNIA THROUGH THE CGRP/SP-Piezo2 AXIS VIA Ca2+ SIGNALING
Authors Xinyue Liao1†, Zhaoke Luo1†, Feng Huang1†, Yiqian Wang1, Zhangying Zeng1, Weihang Liao1, Yating Ou1, Xuemei Wu1, Feng Wang1,2* and Daoshu Luo1,2*
Abstract Trigeminal neuralgia (TN) is one of the most severe types of neuropathic pain, but its pathological mechanisms remain unknown. In this study, we identified a unique neuroinflammatory response induced by chronic compression of trigeminal root entry zone (TREZ) in a TN rat model, establishing a connection between ATP-driven intracellular pathways and Piezo2-mediated mechanotransduction. Piezo2, the pain-related neuropeptide calcitonin gene-related peptide (CGRP) receptor complex CRLR-RAMP1 and the neuropeptide substance-P (SP) receptor NK1R are co-expressed on rat Merkel cells. Protein kinase C (PKC) plays a crucial role in upregulating Piezo2 and CGRP/SP expression in both the trigeminal ganglion (TG) and whisker pad, thereby facilitating orofacial mechanical allodynia in TN rats. Furthermore, the inhibition of cAMP signaling in the whisker pads effectively alleviated mechanical allodynia, while Piezo2 knockdown in both the TG and whisker pads significantly reversed db cAMP-induced allodynia. In vitro studies demonstrated that extracellular ATP not only enhances CGRP and SP expression but also induces Piezo2 expression through Ca2+-dependent activation of ERK1/2 and p38 MAPK cascades, mediated by specific transcription factors. These findings reveal that peripheral sensitization in TN is mediated through a Ca2+-CGRP/SP-Piezo2 positive feedback loop, dependent on the neuroinflammatory response along the TG neuron–Merkel cell axis as a prerequisite condition. This discovery provides a novel insight into the pathogenesis of TN.
Keywords Piezo2, CGRP/SP, Neuroinflammation, Trigeminal neuralgia, Ca2+-PKC
Address and Contact Information 1 Laboratory of Clinical Applied Anatomy, School of Basic Medical Sciences, Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fujian Medical University, 350122 Fuzhou, China 2 Department of Human Anatomy, The School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town 350122, Fuzhou, China *Corresponding author: Feng Wang fjwf95168@163.com Daoshu Luo luods2004@fjmu.edu.cn † Xinyue Liao, Zhaoke Luo and Feng Huang contributed equally to this work.
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No.  04DOI: 10.1186/s11658-025-00816-5 Volume 31 (2026) - 30:04
Title tsRNA-3040b ACCUMULATES R-LOOP TO REGULATe Trim35 TRANSCRIPTION, WHICH LEADS TO DISORDERED GLYCOLYSIS AND PROMOTES PAECS PROLIFERATION
Authors Xu Wang1†, Songyue Li1†, Jianli Hou1, Shukun Cao2, Yibin Zhang1, Jingya Zhang1, Xinru Wang1, Xinyue Song3, Ya Xu3, Jing Qi1, Yan Xing1,4* and Xiaodong Zheng2,4*
Abstract Background: Hypoxia significantly influences the development of pulmonary hypertension (PH). However, the role of transfer RNA-derived small RNAs (tsRNAs) produced by nuclease cleavage on PH, particularly their impact on the proliferation of pulmonary artery endothelial cells (PAECs), remains unclear.
Methods: To detect tsRNA expression, panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq) sequencing analysis and quantitative polymerase chain reaction (qPCR) were employed. The formation of R-loops between tsRNA and genomic DNA was confirmed through chromatin immunoprecipitation followed by polymerase chain reaction (ChIP-PCR) and Dot-blot analyses. Mouse PAECs and lung tissue were manipulated to either overexpress or inhibit tsRNA-3040b, followed by assessments of cell proliferation, RT-qPCR, and enzyme activity assays on three key glycolytic rate-limiting enzymes. Molecular docking, immunofluorescence and endogenous coprecipitation were used to demonstrate the colocalization of Trim35 and Wnt3a.
Results: The expression of tsRNA-Asp-GTC-3040b (termed tsRNA-3040b) was significantly increased in the lung tissue of a hypoxia-induced PH mouse model. By integrating database prediction with RNA sequencing, Trim35 was identified as a downstream target of tsRNA-3040b. ChIP-PCR and Dot-blot analyses using S9.6 indicated that tsRNA-3040b promoted R-loops in the genomic DNA of Trim35, thus inhibiting its transcription. Further investigation revealed that the Trim35 affected glucose metabolism levels through ubiquitinated substrate Wnt3a. Ultimately, it was elucidated that the tsRNA-3040b–Trim35–Wnt3a–glucose metabolism signaling pathway exacerbated the progression of PH.
Conclusions: This study highlights the role of tsRNA-3040b in promoting PH by influencing glucose metabolism processes. These results offer a new approach to treating PH and suggest that tsRNA-3040b could serve as a potential target for diagnosing PH and related conditions.
Keywords Pulmonary hypertension, Glucose metabolism reprogramming, tRNA-derived small RNAs, R-loops, Trim35, Wnt3A, Cell proliferation
Address and Contact Information 1 Department of Pharmacology, Harbin Medical University-Daqing, Daqing 163319, Heilongjiang, People’s Republic of China
2 Department of Medical Genetics, Harbin Medical University-Daqing, Daqing 163319, Heilongjiang, People’s Republic of China
3 Central Laboratory, Harbin Medical University-Daqing, Daqing 163319, Heilongjiang, People’s Republic of China
4 Engineering Technology Research Center for Precision Diagnosis and Treatment of Frigid Zone-Related Diseases in Heilongjiang Province, Daqing, Heilongjiang 163319, People’s Republic of China
*Corresponding author: Yan Xing xingyan@hmudq.edu.cn Xiaodong Zheng zhengxiaodong@hmudq.edu.cn
† Xu Wang and Songyue Li contributed equally to this work.
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No.  06DOI: 10.1186/s11658-025-00835-2 Volume 31 (2026) - 30:06
Title A NOVEL tRF-Gly IS ASSOCIATED WITH OBESITY DEVELOPMENT THROUGH POST-TRANSCRIPTIONAL REGULATION OF LIPID METABOLISM
Authors Yuhang Lei1,2,3†, Mailin Gan1,2,3†, Kai Wang1,2,3†, Tianci Liao1,2,3, Yiting Yang1,2,3, Xue Zhao1,2,4, Xin Zhang1,2,3, Dujun Chen1,2,3, Xinyi Wang1,2,3, Jianfeng Ma1,2,3, Lili Niu1,2,3, Ye Zhao1,2,3, Lei Chen1,2,3, Xiaofeng Zhou1,2,3, Yan Wang1,2,3, Mingzhou Li1,2,3, Li Zhu1,2,3* and Linyuan Shen1,2,3*
Abstract Background: Obesity, characterized by excessive fat accumulation, represents a global health crisis closely linked to metabolic disorders such as type 2 diabetes, hypertension, and atherosclerosis. tRNA-derived small RNAs (tsRNAs) have recently emerged as important epigenetic regulators, yet their roles in fat deposition remain poorly characterized. This study aims to identify tsRNAs that influence fat accumulation and to elucidate their molecular mechanisms, with a focus on tRF‑Gly‑GCC‑037 (tRF‑Gly) as a candidate regulator of adipocyte differentiation.
Methods: Visceral adipose tissue was collected from obese and lean pigs for comprehensive tRF and tiRNA sequencing. Differential expression analysis identified tRF‑Gly as a highly abundant candidate in obese samples. Functional assays in 3T3‑L1 preadipocytes included both overexpression and knockdown of tRF‑Gly, followed by lipid accumulation measurements and assessment of key adipogenic markers (CEBPα and PPARγ) by quantitative real-time PCR (qRT‑PCR) and western blot. Mechanistically, dual‑luciferase reporter assays, RNA immunoprecipitation (RIP), and nuclear–cytoplasmic protein fractionation were performed to examine how tRF‑Gly modulates the RAC1/JNK2/β‑catenin signaling axis.
Results: tRF‑Gly was significantly upregulated in visceral adipose tissue from obese pigs and ranked among the most abundant tsRNAs. Overexpression of tRF‑Gly in 3T3‑L1 cells and in C57BL/6 mice promoted lipid accumulation and increased CEBPα and PPARγ expression, whereas tRF‑Gly knockdown reduced lipid deposition. Mechanistically, tRF-Gly was suggested to bind RAC1 mRNA with AGO3 involvement, leading to RAC1 silencing. Consistently, RAC1 knockdown phenocopied the adipogenic effects of tRF-Gly, whereas RAC1 overexpression reversed these effects. Furthermore, RAC1 deficiency disrupted the RAC1/JNK2/β‑catenin complex, impaired β‑catenin nuclear translocation, and suppressed Wnt/β‑catenin signaling.
Conclusions: Our findings demonstrate that tRF‑Gly functions as a key regulator of fat accumulation. By silencing RAC1 via AGO3, tRF‑Gly disrupts RAC1/JNK2/β‑catenin complex assembly, prevents β‑catenin nuclear translocation, and downregulates Wnt/β‑catenin signaling, thereby promoting lipid deposition. This study uncovers a novel epigenetic mechanism by which tRF‑Gly controls fat accumulation and suggests that targeting tRF‑Gly may represent a therapeutic strategy for obesity and related metabolic disorders.
Keywords tRF-Gly, RAC1, RAC1/JNK2/β-catenin transport complex, Wnt/β-catenin signaling pathway, Fat deposition
Address and Contact Information 1 Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
2 State Key Laboratory of Swine and Poultry Breeding Industry, Sichuan Agricultural University, Chengdu 611130, China
3 Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
4 Animal Disease Prevention and Green Development Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, 610065 Chengdu, China
*Corresponding author: Li Zhu zhuli@sicau.edu.cn Linyuan Shen shenlinyuan@sicau.edu.cn
† Yuhang Lei, Mailin Gan and Kai Wang have contributed equally to this work.
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No.  07DOI: 10.1186/s11658-025-00832-5 Volume 31 (2026) - 30:07
Title CDCP1 ALLOSTERICALLY REGULATES THE AMPK α1 SUBUNIT TO ENHANCE FATTY ACID OXIDATION IN OSTEOBLASTS
Authors Xiang Li1,2†, Weichun Zhu3,4†, Jinlong Ma1,2, Zhenqian Sun1,2, Limin Wang5, Guangjun Jiao1,2*† and Yunzhen Chen1,2*†
Abstract Background: Lipid metabolism disorders in osteoblasts may lead to osteoporosis. CUB domain-containing protein 1 (CDCP1) is associated with various intracellular signaling pathways. We investigated how CDCP1 regulates lipid metabolism and osteoblast function.
Methods: This study utilized gene overexpression (via lentivirus) and loss-of-function (CRISPR/Cas9-mediated knockout) techniques to investigate the involvement of CDCP1 in lipid metabolism and osteogenesis. Transcriptomic and metabolomic analyses were performed to examine the mechanism of action of CDCP1. Furthermore, proximity ligation assays, GST pull-down, and molecular docking were employed to identify the interaction between CDCP1 and AMP-activated protein kinase (AMPK).
Results: CDCP1 alleviated bone loss in mice. In vitro, CDCP1 promoted the phosphorylation of AMPK. Phosphorylated AMPK can enhance the activity of carnitine palmitoyltransferase, leading to increased fatty acid oxidation and promoting osteogenesis. Mechanistically, CDCP1 prevents the formation of the autoinhibitory conformation of the autoinhibitory domain by binding to the α3 helix, thereby protecting AMPK phosphorylation from self-inhibition.
Conclusions: Our research revealed a new molecular mechanism linking CDCP1 and allosteric control of AMPK. These findings reveal for the first time the mechanism by which CDCP1 affects osteogenesis through lipid metabolism regulation, suggesting its potential as a therapeutic target for osteoporosis.
Keywords CDCP1, AMPK, Allosteric control, Fatty acid oxidation, Osteoblastic function
Address and Contact Information 1 Department of Orthopedics, Qilu Hospital of Shandong University, No.107, Wenhuaxi Road, Lixia District, Jinan 250000, China
2 The First Clinical College of Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
3 State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Jinan, Shandong, China
4 Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
5 Department of Human Anatomy, Binzhou Medical University, Yantai, Shandong, China
*Corresponding author: Guangjun Jiao jiaoguangjun@sdu.edu.cn Yunzhen Chen qilucyz@yeah.net † Guangjun Jiao and Yunzhen Chen have contributed equally as corresponding authors. † Xiang Li and Weichun Zhu have contributed equally as first authors.
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No.  14DOI: 10.1186/s11658-025-00840-5 Volume 31 (2026) - 30:14
Title THE CANCER-TESTIS lncRNA LINC01940 PROMOTES GASTRIC CANCER MALIGNANT PROGRESSION AND CHEMORESISTANCE BY ENHANCING RIBOSOME BIOGENESIS VIA TAF15-MEDIATED NOL11 SUMOYLATION
Authors Weijie Zang1,2,3, Debiao Fan1,2,3, Zhuang Lu1,2,3,5, Xian Gao1,2,3, Danjie Xing1,2,3,6, Guangze Zhang1,2,3, Lei Liu2,4, Jianfeng Yi1,2,3, Junjie Chen2,3*, Yilin Hu1,2,3* and Wanjiang Xue1,2,3*
Abstract Background: Aberrant ribosome biogenesis promotes gastric cancer (GC) progression and contributes to chemoresistance by sustaining protein synthesis, upon which GC cell survival depends. However, the regulatory role of cancer-testis-associated long noncoding RNAs (CT-lncRNAs) in modulating ribosome biogenesis in GC remains largely unexplored.
Methods: First, we performed a screening of lncRNAs and identified CT-lncRNA LINC01940 on the basis of integrated expression and survival analyses using The Cancer Genome Atlas (TCGA) data. Subsequently, the impact of LINC01940 on GC progression and chemosensitivity was evaluated using in vitro cell functional assays, patient-derived organoid models, and in vivo subcutaneous tumor xenograft experiments. To further elucidate the underlying mechanisms, we employed a comprehensive approach combining bioinformatics analyses, RNA sequencing, fluorescence in situ hybridization, translation assays, ribosomal DNA (rDNA) transcription assays, methylated RNA immunoprecipitation, co-immunoprecipitation mass spectrometry, fluorescence multiplex immunohistochemistry, and RNA pull-down mass spectrometry.
Results: Normally, testis-specific LINC01940 is aberrantly upregulated in GC and associated with poor prognosis. Functional assays demonstrated that LINC01940 promotes GC cell proliferation and invasion and confers resistance to cisplatin. Mechanistically, LINC01940 is stabilized by methyltransferase 16 (METTL16)/ insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m6A) modification, which enhances its ability to act as a scaffold promoting the interaction between the small ubiquitin-like modifier 2 (SUMO2) E3 ligase TATA-box binding protein associated factor 15 (TAF15) and Nucleolar protein 11 (NOL11), promoting the SUMOylation of NOL11 and enhancing its protein stability. This, in turn, increases ribosomal DNA transcription and ribosome biogenesis, thereby promoting GC progression and chemoresistance.
Conclusions: LINC01940 is a cancer-testis lncRNA that promotes GC progression and cisplatin resistance by enhancing ribosome biogenesis via the METTL16/IGF2BP3–TAF15–NOL11 axis. These findings suggest its potential as a prognostic biomarker and therapeutic target in GC.
Keywords LINC01940, SUMOylation, Gastric cancer, Ribosome biogenesis, Cancer drug resistance
Address and Contact Information 1 Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, 20 Xisi Street, Nantong 226001, Jiangsu, China
2 Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong 226001, Jiangsu, China
3 Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
4 Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226001, China
5 Department of Graduate School, Dalian Medical University, Dalian 116000, China
6 Department of General Surgery, Qidong People’s Hospital/Qidong Liver Cancer Institute/Affiliated Qidong Hospital of Nantong University, Nantong 226200, China
*Corresponding author: Junjie Chen ntfyCJJ@ntu.edu.cn Yilin Hu hyl510@ntu.edu.cn Wanjiang Xue xuewanjiang@ntu.edu.cn
† Weijie Zang, Debiao Fan, and Zhuang Lu contributed equally to this work.
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No.  09DOI: 10.1186/s11658-025-00838-z Volume 31 (2026) - 30:09
Title PCSK9 INHIBITION AMELIORATES MICROPLASTIC-INDUCED ENDOTHELIAL REDOX IMBALANCE VIA SIRT6 MODULATION
Authors Nunzia D’Onofrio1,5†, Isabella Donisi1†, Vitale Del Vecchio2, Francesco Prattichizzo3, Valeria Pellegrini3, Michelangela Barbieri4,5, Antonio Ceriello3, Raffaele Marfella4,5, Giuseppe Paolisso4,5† and Maria Luisa Balestrieri1,5*†
Abstract Background: Microplastics (MPs) have emerged as significant environmental pollutants, posing a threat to ecosystems and humans. The presence of MPs in atherosclerotic plaques, exacerbating cardiovascular risk, has been recently reported. However, the molecular mechanism underlying the effects of MPs on the vascular endothelium are still undefined. In this regard, this study aims to investigate the effects of MPs on endothelial cell function and redox state and the underlying mechanisms.
Methods: Immortalized human aortic endothelial cells (teloHAEC), human umbilical vein endothelial cells (HUVEC), and human coronary artery endothelial cells (HCAEC) were treated with MPs in the form of polyethylene (PE) and polyvinyl chloride (PVC) alone (70 µg/mL) or combined PE (30 µg/mL) + PVC (30 µg/mL) (PE + PVC) for up to 48 h. The effects of MPs on cell viability were evaluated using CCK-8, and its role in endothelial function was evaluated by flow cytometric analyses, enzyme-linked immunosorbent assays (ELISA), and XF HS Seahorse bioanalyzer. Proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. Molecular involvement of sirtuin 6 (SIRT6) was investigated through gene silencing.
Results: Our study demonstrated that PE and PVC, alone or in combination, upregulated inflammatory mediators monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) (p < 0.001), modulated the expression of autophagy markers anti-autophagy related 5 (ATG5) and p62, impaired mitochondrial metabolism by reducing maximal and basal respiration and adenosine triphosphate (ATP) production (p < 0.001), promoted reactive oxygen species (ROS) accumulation (p < 0.001) and cell cycle perturbations (p < 0.01), and increased apoptosis cell death (p < 0.001). These events were accompanied by a downregulation of sirtuin 6 (SIRT6) expression (p < 0.01) and an upregulation of PCSK9, at protein and messenger RNA (mRNA) levels (p < 0.01). Treatment with the PCSK9 inhibitor (iPCSK9) evolocumab ameliorated MP-induced cellular redox state imbalance, mitochondrial metabolism alteration, and SIRT6 downregulated levels (p < 0.01). SIRT6 transient silencing experiments denied the beneficial effects of iPCSK9 treatment, indicating that the pleiotropic functions of iPCSK9 may occur, at least in part, via modulation of SIRT6 and Forkhead box O3 (FOXO3A) expression levels.
Conclusions: Overall, the results indicate that PCSK9 inhibition via evolocumab exhibits substantial promise in the prevention of MP-induced endothelial dysfunction, suggesting the PCSK9–SIRT6 axis as a new promising pathway to target in preventive strategies for cardiovascular risk caused by plastic pollution.
Keywords Microplastics, PCSK9 inhibition, Endothelial dysfunction, SIRT6, Inflammation
Address and Contact Information 1 Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. De Crecchio 7, 80138 Naples, Italy
2 Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Via Luciano Armanni 5, 80138 Naples, Italy
3 IRCCS MultiMedica, Via Fantoli 16/15, 20138 Milan, Italy
4 Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Miraglia, 80138 Naples, Italy
5 Research Center for Environmental Pollution and Cardiovascular Diseases, University of Campania Luigi Vanvitelli, Piazza Miraglia, 80138 Naples, Italy
*Corresponding author: Maria Luisa Balestrieri marialuisa.balestrieri@unicampania.it
† Nunzia D’Onofrio and Isabella Donisi share first authorship.
† Giuseppe Paolisso and Maria Luisa Balestrieri contributed equally to this work and share last authorship.
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No.  10DOI: 10.1186/s11658-025-00836-1 Volume 31 (2026) - 30:10
Title BEYOND THE MUTATIONS: SPATIOTEMPORAL REGULATION OF CFTR BY cAMP AND CALCIUM SIGNALING IN EPITHELIAL PHYSIOLOGY AND CYSTIC FIBROSIS
Authors Arpad Varga1,2,3, Aletta Kiss1,2,3, Tim Crul1,2,3, Tamara Madácsy1,2,3, Petra Pallagi1,2,3 and József Maléth1,2,3*
Abstract Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the CFTR gene, but the functional expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl−/HCO3− channel is determined by more than its genetic sequence. Beyond the well-known folding defect of the common F508del mutation, CFTR activity is dynamically modulated by a network of intracellular signaling pathways that control the channel’s gating, trafficking to, and retention at the apical membrane. Foremost is the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, which drives CFTR opening via phosphorylation of its regulatory (R) domain and coordination by scaffolding proteins (e.g., A-kinase anchoring proteins (AKAPs) and Na+/H+ exchanger regulatory factor 1 (NHERF1)). Equally important, Ca2+-dependent signaling cascades provide complementary fine-tuning: Ca2+-bound calmodulin can directly bind and increase the CFTR open probability, Ca2+-activated kinases such as Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the tyrosine kinase Pyk2 (with Src) can phosphorylate CFTR through noncanonical routes, and signaling intermediates such as IP3 receptor binding protein released with IP3(IRBIT) connect Ca2+ release to CFTR activation. These cAMP- and Ca2+-driven pathways intersect in specialized subcellular nanodomains, enabling precise spatiotemporal regulation of CFTR function. Clinically, although new CFTR modulator drugs have greatly improved outcomes, their effectiveness is limited by mutation-specific responses and incomplete restoration of channel activity. Understanding how cAMP–Ca2+ crosstalk governs CFTR in context can reveal novel therapeutic strategies targeting the channel’s regulatory microenvironment. This review highlights how compartmentalized cAMP and Ca2+ signals orchestrate CFTR function and discusses emerging approaches to harness this insight for better therapies across CF-affected organs.
Keywords Cystic fibrosis, CFTR regulation, cAMP signaling, Calcium signaling
Address and Contact Information 1 First Department of Medicine, University of Szeged, Szeged 6720, Hungary
2 HAS-USZ Momentum Epithelial Cell Signaling and Secretion Research Group, University of Szeged, Szeged 6720, Hungary
3 HCEMM-USZ Molecular Gastroenterology Research Group, University of Szeged, Szeged 6720, Hungary
*Corresponding author: József Maléth jozsefmaleth1@gmail.com; maleth.jozsef@med.u-szeged.hu
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No.  12DOI: 10.1186/s11658-025-00833-4 Volume 31 (2026) - 30:12
Title GPR43 DEFICIENCY AGGRAVATES SEPSIS BY PROMOTING GUT MICROBIOTA–DEPENDENT BARRIER DISRUPTION AND HIF-1α–ENO1 AXIS–MEDIATED M1 POLARIZATION OF MACROPHAGES
Authors Mingyang Tang1,2†, Hongru Li3†, Fei Tang4†, Yuanlong Shu1,2†, Bao Meng1,2, Qingyue Zhang1,2, Chengcheng Li1,2, Yuexin Xu1,2, Ying Xu1,2, Jingjing Pan1,2, Yanyan Liu1,2, Lifen Hu1,2, Cui Wang5*, Ting Wu1,2* and Jiabin Li1,2*
Abstract Background: GPR43, a receptor for short-chain fatty acids (SCFAs), is broadly expressed in intestinal epithelial and immune cells and is essential for preserving barrier integrity and immune homeostasis. Nevertheless, how GPR43 influences gut microbiota composition and intestinal barrier integrity while also regulating macrophage immunometabolism in the context of sepsis remains poorly understood.
Methods: A cecal ligation and puncture model was used to induce sepsis in mice. Survival, histopathology, and immune responses were compared between Gpr43−/− and wild-type mice; 16S ribosomal RNA (rRNA) sequencing and untargeted metabolomics were performed to evaluate gut microbiota composition and metabolic profiles. Antibiotic-mediated microbiota depletion and fecal microbiota transplantation were used to assess functional impacts. Bone marrow-derived macrophages were employed to investigate the effects of GPR43 deficiency on macrophage polarization. RNA sequencing, metabolic flux analysis, and Western blotting were conducted to explore the molecular mechanisms involved. Peripheral blood mononuclear cell samples from patients with sepsis were analyzed for clinical correlation.
Results: Gpr43−/− mice exhibited significantly reduced survival following CLP, along with impaired intestinal barrier function and elevated proinflammatory cytokine levels. Microbiota diversity and SCFA-producing bacteria were markedly decreased, accompanied by reduced SCFA levels in fecal metabolites. Fecal microbiota transplantation (FMT) partially restored gut function and survival in Gpr43−/− mice. GPR43-deficient macrophages displayed a strong M1-polarized phenotype with the upregulation of the glycolytic enzyme ENO1 and its upstream regulator HIF-1α. The inhibition of either ENO1 or HIF-1α reversed the proinflammatory phenotype. A clinical data analysis revealed that GPR43 expression was negatively correlated with IL-6, ENO1, and lactate levels.
Conclusions: GPR43 exerts a dual protective role in sepsis by maintaining gut microbiota homeostasis and barrier integrity and by modulating macrophage metabolism and polarization via the HIF-1α–ENO1 axis. This study provides novel insights into the GPR43 in pathogenesis of sepsis and suggests potential therapeutic targets for intervention.
Keywords GPR43, Macrophage, Sepsis, Glycolysis, ENO1
Address and Contact Information 1 Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
2 Anhui Province Key Laboratory of Infectious Diseases, Anhui Medical University, Hefei 230022, China
3 Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
4 Department of Interventional Pulmonology and Endoscopic Diagnosis and Treatment Center, Anhui Chest Hospital, Hefei 230022, China
5 Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
*Corresponding author: Cui Wang colorfulday23@126.com Ting Wu wutingf88945@163.com Jiabin Li lijiabin@ahmu.edu.cn
† Mingyang Tang, Hongru Li, Fei Tang, and Yuanlong Shu contributed equally to this work.
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No.  02DOI: 10.1186/s11658-025-00825-4 Volume 31 (2026) - 30:02
Title MPP7 INHIBITS TUMOR METASTASIS THROUGH PROMOTING SNAIL DEGRADATION IN CLEAR CELL RENAL CELL CARCINOMA
Authors Mi Zhang1, Juan Zhang1, Yan Zhou1, Andi Zhao2, Hui Wang3, Bo Wang4, Juan Li4, Peijun Liu4* and Jin Yang1,3,5,6*
Abstract Background: Tumor metastasis is a major factor of high recurrence and mortality in clear cell renal cell carcinoma (ccRCC), but its underlying mechanism remains elusive. This study focuses on investigating the impact and underlying molecular mechanisms of MAGUK p55 subfamily member 7 (MPP7) on the metastasis of ccRCC.
Methods: The clinical significance of MPP7 in patients with ccRCC was investigated based on The Cancer Genome Atlas (TCGA), Genotype Tissue Expression Project (GTEx) databases and clinical tissue samples. Slow aggregation, microscopic photography and immunofluorescence (IF) assay were applied to assess the effect of MPP7 on intercellular adhesion, cell morphology, and cytoskeletal F-actin, respectively. Transwell and wound-healing assays were used to detect cell migration and invasion. The quantitative real-time polymerase chain reaction (qRT-PCR), western blot, IF, co-immunoprecipitation (Co-IP), and immunoprecipitation-mass spectrometry (IP-MS) were applied to elucidate the underlying molecular mechanism.
Conclusions: Our work elucidated the role and molecular mechanism of MPP7 in migration and invasion regulation of ccRCC.
Keywords Clear cell renal cell carcinoma, Ubiquitin–proteasome system, Epithelial–mesenchymal transition, MPP7, Snail
Address and Contact Information 1 Phase I Clinical Trial Ward, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
2 Department of General Practice, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
3 Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
4 Translational Medicine Center, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
5 Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
6 Precision Medicine Center, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
*Corresponding author: Peijun Liu liupeijun@xjtu.edu.cn Jin Yang yangjin@xjtu.edu.cn
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No.  15DOI: 10.1186/s11658-025-00839-y Volume 31 (2026) - 30:15
Title G-QUADRUPLEX STRUCTURES ARE KEY REGULATORS OF MAMMALIAN SPERMATOGENESIS
Authors Shuo Li1, Yixiao Ma1, Haoxin Shi1, Ruoyu Wang1, Chen Li1, Tian Zhang1, Chunyu Zhu3, Yanan Gu4, Ziyao Song1, Haoran Guo1, Mohan Dong2, Yu Li3, Zhen Li5, Ming-Qi Wang6, Weihong Wen7*, Fa Yang1* and Weijun Qin1*
Abstract Background: Male infertility, impacting 8–12% of couples globally, often lacks clear etiology. G-quadruplexes (G4s), noncanonical DNA structures, are implicated in genomic regulation but remain underexplored in spermatogenesis. This study investigates G4 dynamics and their roles in male fertility.
Methods: We employed antibody-based staining, cleavage under targets and tagmentation (CUT&Tag) sequencing, and a novel nanobody-based proximity labeling system (nanoG4BPL) to map G4 distribution and interacting proteins in mouse testicular cells. In vivo G4 stabilization with pyridostatin and clinical analysis of testicular tissues from patients with nonobstructive azoospermia (NOA) were conducted.
Results: G4 structures are enriched in testicular tissues, displaying stage-specific dynamics during spermatogonial differentiation, meiosis, and spermiogenesis. Genome-wide profiling revealed the dual roles of G4s in coordinating gene expression with active epigenetic marks and facilitating genome architecture via CTCF interactions. G4 stabilization disrupted double-strand break repair during meiosis, with nanoG4BPL identifying Nijmegen breakage syndrome 1 (NBS1) as a G4-interacting protein promoting phase separation for homologous recombination. Clinically, patients with NOA exhibited significantly elevated G4 levels in spermatocytes.
Conclusion: G4 structures are critical regulators of spermatogenesis, orchestrating gene expression, chromatin remodeling, and meiotic fidelity. Their dysregulation, particularly in patients with NOA, suggests a mechanistic link to male infertility, providing novel insights into its pathogenesis and highlighting potential avenues for future diagnostic or therapeutic exploration.
Keywords G-quadruplex, Spermatogenesis, DSB, HR, Male Infertility
Address and Contact Information 1 Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China
2 Department of Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China
3 Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi, China
4 Assisted Reproduction Center, Northwest Women and Children’s Hospital, Xi’an 710061, Shaanxi, China
5 Department of Human Anatomy, Histology and Embryology, Air Force Medical University, Xi’an 710032, Shaanxi, China
6 School of Pharmacy, Jiangsu University, Zhenjiang 212013, Jiangsu, China
7 Xi’an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi, China
*Corresponding author: Weihong Wen weihongwen@nwpu.edu.cn Fa Yang yangfa@fmmu.edu.cn Weijun Qin qinwj@fmmu.edu.cn
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No.  16DOI: 10.1186/s11658-025-00848-x Volume 31 (2026) - 30:16
Title MANY FACES OF MAMMALIAN NSD METHYLTRANSFERASES
Authors Eugenia A. Tiukacheva1,2, Yegor Vassetzky2,3*, Sergey V. Razin1,4, Dong Fang5 and Sergey V. Ulianov1,4*
Abstract Nuclear receptor-binding SET domain (NSD) proteins have been initially described as methyltransferases specific to lysine-36 in histone H3 and associated with active chromatin. However, their role in the regulation of transcription and in overall cellular physiology is much more complex, especially in mammals. The emerging diversity of their targets and, accordingly, the processes in which NSD proteins are involved, shows the importance of their noncanonical functions. A wide functionality apparently requires a complicated control system ensuring proper spatial and temporal activation of NSD methyltransferases. In this review, we discuss the role of NSD proteins in transcription, genome topology, mitosis, oncogenesis, immunity, DSB repair, and known mechanisms regulating their activity.

    Highlights
  • NSD proteins initially described as H3K36-specific methyltransferases methylate a wide range of nonhistone targets.
  • NSD proteins promote gene transcription by affecting RNA polymerase through elongation and transcription factors.
  • NSD1 promotes the spread of DNA methylation, preventing CTCF binding and, as a result, weakening TAD boundaries, while NSD2 strengthens existing TAD boundaries.
  • NSD1–3 affect oncogenesis, inflammation, immune response, and double-stranded breaks response through methylation of nonhistone proteins.
  • NSD proteins participate in the histone code and may also be involved in a universal post-translational modification (PTM) protein code.
Keywords NSD1, NSD2, NSD3, Histone methylation, H3K36me2, Chromatin structure
Address and Contact Information 1 Institute of Gene Biology, Moscow 119334, Russia
2 Koltzov Institute of Developmental Biology, Moscow 119334, Russia
3 CNRS UMR9018, Institut Gustave Roussy, 94805 Villejuif, France
4 Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Moscow 119991, Russia
5 Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
*Corresponding author: Yegor Vassetzky yegor.vassetzky@gustaveroussy.fr Sergey V. Ulianov sergey.v.ulyanov@gmail.com
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No.  17DOI: 10.1186/s11658-025-00842-3 Volume 31 (2026) - 30:17
Title TARGETING INTEGRIN αVβ3–Ptgs2–mTOR SIGNALING RESCUES BONE FORMATION IN OSTEOPOROSIS: FROM MOLECULAR MECHANISM TOWARD THERAPY
Authors Changshun Chen1,2,3†, Jinyi Gu4†, Chenhui Yang1,2†, Fei Yang1,2, Zirui Liu1,2, Lei Wen1,2,3, Rongjing Chen1,2, Bin Geng1,2* and Yayi Xia1,2*
Abstract Background: Integrin αVβ3, a key ECM receptor, is essential for bone metabolism, yet its role in postmenopausal osteoporosis (PMOP) remains unclear. This study investigates the molecular mechanisms by which integrin αVβ3 regulates osteoblast function and bone homeostasis in PMOP.
Methods: Using clinical samples, OVX mice, and in vitro models, we analyzed integrin αVβ3 expression and its impact on osteogenesis. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated knockout, multi-omics profiling, and protein interaction assays (Co-IP, BLI, and structural modeling) were employed to dissect the underlying pathway. An AAV9-based in vivo overexpression system was developed to evaluate therapeutic potential.
Results: Integrin αVβ3 was downregulated in PMOP patients and OVX mice, correlating with osteoblast dysfunction and reduced bone formation. Mechanistically, integrin αVβ3 deficiency upregulated Ptgs2, which directly bound to mammalian target of rapamycin (mTOR) via a hydrogen bond between Ptgs2-Glu52 and mTOR-Ser2159, inhibiting mTOR phosphorylation. This suppression disrupted mTORC1-S6K/4EBP1 signaling, impairing osteoblast proliferation and survival. Notably, AAV9-mediated integrin αVβ3 overexpression rescued bone loss in OVX mice.
Conclusions: Our findings unveil a novel integrin αVβ3–Ptgs2–mTOR axis in PMOP pathogenesis: estrogen deficiency reduces integrin αVβ3, enabling Ptgs2-mediated mTOR inhibition and osteogenic decline. This study identifies integrin αVβ3 as a potential therapeutic target to restore bone formation in osteoporosis.
Keywords Integrin αVβ3, Ptgs2, MTOR signaling, Postmenopausal osteoporosis, Osteoblast dysfunction
Address and Contact Information 1 Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China
2 Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China
3 Department of Orthopedics and Trauma Surgery, Affiliated Hospital of Yunnan University, Kunming 650032, China
4 Institute of Pathogen Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730030, China
*Corresponding author: Bin Geng gengbing2024@163.com Yayi Xia xiayay@163.com
† Changshun Chen, Jinyi Gu, Chenhui Yang contributed equally to this work and shared the first authorship.
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No.  18DOI: 10.1186/s11658-025-00834-3 Volume 31 (2026) - 30:18
Title THE NEURO-IMMUNE INSIGHTS OF ITCH: PERIPHERAL MECHANISMS AND CENTRAL GLIAL CONTRIBUTIONS
Authors Zhe Li1,2†, Ning Yu3,4†, Sidi Feng5†, Xinrui Wang6†, Yu-Xia Chu7* and Xiaowen Liu1*
Abstract Itch is a common symptom of inflammatory, systemic, and neurological conditions and is often driven by persistent neuroinflammatory processes. This review explores the intricate mechanisms underlying itch, focusing on interactions among sensory neurons, immune mediators, and glial cells. Key peripheral pathways include activation of pruriceptors by histamine, interleukins, and chemokines, as well as inflammatory pathways dependent on Toll-like receptors (TLRs). These pathways promote the release of mediators such as interleukin-6 (IL-6) and C–C motif chemokine ligand 2 (CCL2). In the spinal cord, astrocytes and microglia contribute to itch amplification by releasing proinflammatory cytokines and activating signaling pathways such as signal transducer and activator of transcription 3 (STAT3) and TLR4. These processes drive central sensitization and facilitate the transition from acute to chronic itch in conditions such as atopic dermatitis, psoriasis, and allergic contact dermatitis. By summarizing advances in neuroimmune crosstalk and glial–neuronal interactions, this review identifies potential molecular targets for therapeutic strategies aimed at alleviating itch and improving patient outcomes.
Keywords Itch, Pruriceptors, Immune receptors, Glial cells
Address and Contact Information 1 Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China
2 Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
3 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Human Anatomy, Histology and Embryology, Joint Laboratory of Anesthesia and Pain, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Neuroscience Center, Union Medical College, Beijing, China
4 Department of Neurology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
5 Dalian Medical University, Dalian, China
6 Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
7 Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institute of Acupuncture Research, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Shanghai Medical College, Fudan University, Shanghai 200032, China
*Corresponding author: Yu-Xia Chu yuxiachu@fudan.edu.cn Xiaowen Liu liuxiaowen@cjfh.org.cn
† Zhe Li, Ning Yu, Sidi Feng, and Xinrui Wang have contributed equally to this work.
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No.  19DOI: 10.1186/s11658-025-00844-1 Volume 31 (2026) - 30:19
Title THE MULTIPLE ROLES OF gt1-Cre IN THE GENERATION OF TRANSGENIC MICE
Authors Ze-Sen Feng1†, Jie Luo1†, Xiao-Cui Chen1†, Ping-Ping Zhao1, Shi-Tong Qiu1, Chun-Yu Wu1, Xiao-Rong Huang1, Bing-Chun Sun2, Xiao-Jun Guo1, Zhen-Nan Ye1*, Chen Yang1*, Hua-Feng Liu1* and Ji-Xin Tang1*
Abstract The Cre/loxP system continues to serve as a well-established and widely adopted strategy for generating conditional gene knockout or knock-in mouse models, facilitating precise genetic manipulations. The Ggt1 gene, which exhibits specific expression in proximal tubular epithelial cells (TECs) of the kidney, has been extensively employed as a Cre driver for tissue-specific gene targeting within these cells. In this study, to achieve conditional Fam134b knockout in proximal TECs, we generated Fam134b floxed mice and crossed them with Ggt1-Cre transgenic mice. After several generations of selective breeding, we successfully obtained conditional Fam134b knockout mice, which displayed specific deletion of the target gene in proximal TECs. This was confirmed by western blot analysis, which demonstrated a marked deficiency of the FAM134B protein in the renal cortex of these mice. During the mating experiments, we unexpectedly found that we could obtain systematic Fam134b knockout mice, suggesting that Ggt1-Cre might be expressed and functional in germ cells. Genomic and transcriptomic sequencing analysis unequivocally confirmed the deletion of exon 4, while western blot analysis revealed complete absence of FAM134B protein in both heart and kidney tissues of these knockout mice. Through the implementation of different mating strategies, we determined that Ggt1-Cre mediated gene knockout occurs in germ cells that have completed the first meiotic division, rather than in germ cells prior to this developmental stage. Furthermore, qPCR and western blot analyses demonstrated the expression of Cre driven by the Ggt1 promoter in both testes and ovaries, providing additional evidence for its germline activity. Lineage tracing experiments revealed that Ggt1-Cre is expressed in both the kidneys and testes of B6-G/R f/+; Ggt1-Cre transgenic mice, where it effectively catalyzes Cre recombinase activity, leading to the conversion of green fluorescent protein-expressing cells to red fluorescent protein-expressing cells. These findings collectively highlight that Ggt1-Cre is not only a reliable proximal TEC-specific Cre driver but also an effective germline-specific Cre driver. Consequently, it can be utilized to achieve gene knockout or overexpression in both proximal TECs and post-first meiotic division germ cells, thereby enabling in-depth in vivo functional studies of genes in these distinct cell types.
Keywords Cre/loxP system, CRISPR/Cas9, FAM134B, Gene knockout, Gene knock-in, Ggt1-Cre
Address and Contact Information 1 Department of Nephrology, National Clinical Key Specialty Construction Program (2023), Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
2 Department of Gynecology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
*Corresponding author: Zhen-Nan Ye yezhennan12@mails.ucas.ac.cn Chen Yang yangchen307@126.com Hua-Feng Liu liuhf@gdmu.edu.cn Ji-Xin Tang tangjixin@gdmu.edu.cn
† Ze-Sen Feng, Jie Luo and Xiao-Cui Chen have contributed equally to this work.
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No.  37DOI: 10.1186/s11658-025-00843-2 Volume 31 (2026) - 30:37
Title SLC25A11-MEDIATED REPROGRAMMING OF MITOCHONDRIAL REDOX STATE AND LIPID PEROXIDATION CONFERS NRF2-DEPENDENT FERROPTOSIS RESISTANCE IN BILIARY TRACT CANCER
Authors Yu-Yu Lin1†, Han-Hsi Kuo1†, Zhao-Jing He1, Hsin-Yi Chung2, Cheorl-Ho Kim3, Yi-Ru Pan4, Meng-Ju Wu5, Ming-Hsien Chan1, Chun-Nan Yeh4, Nai-Jung Chiang2,6,7, Ming-Huang Chen2,6* and Yu-Chan Chang1*
Abstract Background: Biliary tract cancer is a group of highly heterogeneous and metastatic malignancies of the biliary tract. Current clinical treatment strategies and diagnostic methods need further improvement to effectively manage this disease.
Methods: We performed multiomics integrative and in silico analyses of selected SLC25 family members. Cell models with SLC25A11 overexpression or knockdown can be used for various biological function assays and cell imaging. Animal models and clinical specimens can be used to evaluate prognosis and treatment.
Results: SLC25A11 inhibition significantly reduced cell migration and proliferation both in vitro and in vivo. In addition, loss of SLC25A11 leads to accumulation of TCA-related metabolites, alters mitochondrial homeostasis, and reduces mitochondrial membrane potential. In addition, we confirmed that lipid peroxidation and lipid ROS aggregation in mitochondria by SLC25A11-knockdown model. Based on our RNA sequencing data, inhibition of SLC25A11 reduces NRF2 expression and translocation, resulting in loss of interaction affinity with the ferroptosis suppressor FSP1 and subsequent reactivation of the ferroptosis machinery. We also showed that low levels of SLC25A11 and knockdown models can activate lipid peroxidation and related molecules ACSL4, LPCAT3, and PEBP1, further inducing ferroptosis. Furthermore, recruitment of ferrostatin-1 (Fer-1) antagonizes the ferroptosis state by reducing lipid peroxidation and blocking the expression levels of these related molecules.
Conclusions: Bringing all the evidence together, we added several important insights between ferroptosis and biliary tract cancer. We raised that SLC25A11 will serve as a novel prognostic factor and treatment strategy for biliary tract cancer.
Keywords Biliary tract cancer, SLC25A11, Mitochondrial homeostasis, NRF2, Ferroptosis
Address and Contact Information 1 Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
2 Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, 201 Shipai Road, Section 2, Taipei 112, Taiwan
3 Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Suwon, Gyunggi-Do 16419, Republic of Korea
4 Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
5 Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
6 School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
7 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
*Corresponding author: Ming-Huang Chen mhchen9@vghtpe.gov.tw Yu-Chan Chang yuchanchang@nycu.edu.tw
† Yu-Yu Lin and Han-Hsi Kuo contributed equally to this work.
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No.  13DOI: 10.1186/s11658-025-00809-4 Volume 31 (2026) - 30:13
Title MITOCHONDRIA–ENDOPLASMIC RETICULUM CONTACT SITES IN HEPATOCYTIC SENESCENCE
Authors Pavitra Kumar1, Mohsin Hassan1, Frank Tacke1 and Cornelius Engelmann1,2*
Abstract Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metabolic profiles. Among these interactions, mitochondria–endoplasmic reticulum (ER) contacts (MERCs) are particularly significant, encompassing about 5% of the mitochondrial surface. Key proteins involved in MERCs include inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), glucose-regulated protein 75 (GRP75), Sigma1 receptor (Sig-1R), vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), protein deglycase DJ-1, and protein tyrosine phosphatase interacting protein 51 (PTPIP51), with new proteins continually being identified for their roles in these structures. At these contact sites, metabolic exchanges involve calcium (Ca2+), lipids, reactive oxygen species (ROS), and proteins. MERCs enable efficient molecular exchanges through temporary bridges mainly formed by the ER, the organelle with the largest surface area. These contacts are crucial for maintaining mitochondrial dynamics, which is essential for cellular homeostasis, and they are notably impacted in pathological states such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver diseases (ALD), and viral hepatitis. Dysfunctional MERCs can lead to mitochondrial fragmentation, increased ROS production, impaired autophagy, and disrupted protein trafficking, thereby exacerbating senescence and cellular aging. Senescence is a cell fate initiated by stress, characterized by stable cell-cycle arrest and a hypersecretory state, and is an underlying cause of aging and many chronic conditions, including liver diseases. The hallmarks of senescence—such as macromolecular damage, cell cycle withdrawal, deregulated metabolism, and a secretory phenotype—are well established. However, recent studies have demonstrated that senescence is a heterogeneous process, with molecular markers varying according to the stressors that induce it. This review focuses on the functional aspects of MERCs in hepatic senescence and their impact on liver diseases, and explores the potential of targeting MERCs to address hepatocytic senescence.
Keywords Mitochondria, ER, Contact sites, MERCs, Calcium, Hepatocyte, Senescence
Address and Contact Information 1 Department of Hepatology and Gastroenterology, Medizinische Klinik M. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
2 Berlin Institute of Health (BIH), 10178 Berlin, Germany
*Corresponding author: cornelius.engelmann@charite.de
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No.  05DOI: 10.1186/s11658-025-00818-3 Volume 31 (2026) - 30:05
Title METHYLATION-INDUCED SILENCING OF AZGP1 ENHANCES PROSTATE CANCER METASTASIS BY STIMULATING TUMORAL GLYCOLYSIS
Authors Lu Li1†, Jinguang Luo2†, Linyue Zhao1†, Lu Tian3†, Jianfeng Wang4*, Yifei Cheng5* and Xiao Li6,7*
Abstract Background: Metastasis is the primary cause of mortality in patients with prostate cancer (PCa), yet effective treatments remain scarce. Identifying reliable biomarkers and understanding their underlying mechanisms is crucial for advancing clinical management.
Methods: Firstly, we integrated single-cell and bulk transcriptomic data and employed the Scissor tool to characterize tumor cells with metastatic advantages (termed metastatic cells). Then, independent predictive genes for metastasis were identified through univariate and multivariate regression analyses. The role of hub genes in PCa metastasis was further validated using multiple large datasets, malignant phenotype experiments, in vivo metastatic models, and a clinical-sample-based immunohistochemical cohort. Further, we explored the metabolic characteristics related to hub genes through unbiased functional annotation, and validated the upregulated glycolysis by measuring l-lactic acid production, extracellular acidification rates (ECAR), and oxygen consumption rates (OCR). Finally, multi-omics data were employed to investigate the promoter-methylation-dependent regulation of alpha-2-glycoprotein 1 (AZGP1) transcription, with methylation confirmed through PCa cell-based methylation-specific PCR (MSP) assays.
Results: AZGP1 was identified as an independent protective predictor of metastasis, which was validated in vitro and in vivo. Metabolic functional annotation revealed that glycolysis was upregulated in AZGP1-positive luminal cells. Consistently, overexpression of AZGP1 in PCa cells was associated with lower l-lactic acid levels, reduced ECAR, and increased OCR. In addition, DNA methylation at the cg26429636 region was linked to decreased transcriptional expression of AZGP1. MSP assays revealed an unmethylated pattern in PCa cells with high AZGP1 expression, and higher methylation levels in AZGP1-low cells.
Conclusions: Promoter methylation of AZGP1 leads to reduced transcriptional expression, thereby promoting glycolysis in tumor cells and facilitating metastasis. The detection of AZGP1 methylation levels offers a valuable reference for dynamic surveillance of PCa metastasis.
Keywords Prostate cancer, Metastasis, AZGP1, Glycolysis
Address and Contact Information 1 Department of Pathology, Nanjing Drum Tower Hospital, Affliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
2 Department of Urology, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
3 State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau 999078, China
4 Department of Urology, China–Japan Friendship Hospital, Beijing 100029, China
5 Department of Urology, Southeast University Zhongda Hospital, Nanjing 210009, China
6 Department of Urologic Surgery, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
7 Department of Scientific Research, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
*Corresponding author: Jianfeng Wang zryhyy1@126.com Yifei Cheng yifei_cheng@163.com Xiao Li leex91@163.com
† Lu Li, Jinguang Luo, Linyue Zhao, Lu Tian contributed equally to this work.
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No.  21DOI: 10.1186/s11658-025-00853-0 Volume 31 (2026) - 30:21
Title TGFβ PATHWAY REPRESSES HEPATIC RIBOSOME BIOGENESIS AND PROTEIN SYNTHESIS BY REGULATING p70S6K–S6RP PROTEINS
Authors Athanasios Stavropoulos1*, Vassiliki Stamatopoulou2, Eleftherios Pavlos1,3, Maria Manioudaki1, Stratigoula Sakellariou4, Constantinos Stathopoulos2 and Maria Xilouri1
Abstract Background: Transforming growth factor-beta (TGFβ)-superfamily signaling has been implicated in the regulation of hepatocyte growth and regeneration after acute or chronic liver injury. However, the precise mechanisms underlying TGFβ signaling in the distinct hepatic cell types during the progression of liver fibrosis remain largely unknown. We aim to identify the downstream molecular mechanisms of TGFβ-signaling modulation on hepatocytes.
Methods: To modulate TGFβ-superfamily signaling in vivo, Smad3 or Smad7 were adenovirally overexpressed in mouse liver. Parallelly, hepatosphere cultures were treated with recombinant TGFβ1 and subjected to transcriptomic analysis. These data were compared with transcriptomes from Smad7-overexpressing livers. To broaden the analysis, publicly available RNA-seq datasets from TGFβ-treated hepatic stellate cells and hepatocellular carcinoma lines were meta-analyzed. Finally, human liver tissues from cirrhotic and healthy individuals were examined for fibrosis and ribosome biogenesis markers to validate murine findings.
Results: Acute hepatic overexpression of Smad3 induced a transient fibrotic phenotype in the mouse liver. In hepatosphere cultures, TGFβ1 treatment suppressed key components of ribosomal assembly, whereas Smad7 overexpression exerted the opposite effect in the mouse liver, thus highlighting ribosome biogenesis as a major cellular process negatively regulated by the TGFβ superfamily. Inhibition of TGFβ signaling via Smad7 increased hepatic protein content (a critical parameter for restoring hepatic homeostasis upon liver damage), activated the nucleolus, and prompted the production of ribosomal pre-mRNAs without affecting p53 levels. Mechanistically, SMAD7-mediated inactivation of TGFβ signaling triggered selectively the p70S6K–S6RP regulatory axis, independently of cellular myelocytomatosis oncogene (c-MYC), mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) pathways. Importantly, analysis of hepatic tissue from cirrhotic patients and controls unveiled a negative association between TGFβ signaling and ribosome biogenesis in fibrotic livers. Complementary meta-analysis of RNA-seq data demonstrated that TGFβ regulates ribosome biogenesis in a cell type-specific manner, suppressing it in hepatocytes while enhancing it in hepatic stellate cells, consistent with their distinct functional states and transcriptional landscapes.
Conclusions: Collectively, our data reveal a SMAD-dependent regulatory role of TGFβ-superfamily signaling on hepatocytes that is tightly connected with hepatic growth to ensure proper energy homeostasis and metabolism. This is a critical regeneration parameter, which is closely related to the restoration of hepatic mass, especially following liver injury and fibrosis.
Keywords Cell signaling, Cirrhosis, Liver growth, Regeneration, Ribosome, Smads, Translation
Address and Contact Information 1 Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
2 Department of Biochemistry, School of Medicine, University of Patras, Patras, Greece
3 Division of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece
4 First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
*Corresponding author: Athanasios Stavropoulos astavrop@bioacademy.gr
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No.  08DOI: 10.1186/s11658-025-00837-0 Volume 31 (2026) - 30:08
Title HETEROGENEITY OF GLUCOSE METABOLISM AND UPTAKE IDENTIFIES DISTINCT CANCER CELL AND CANCER STEM CELL PHENOTYPES
Authors Zuzana Tylichova1*, Martin Krkoska1, Vaclav Hrabal1, Michaela Stenckova1, Borivoj Vojtesek1 and Philip J. Coates1*
Abstract Background: Tumor cells show phenotypic heterogeneity, including a small subpopulation of cancer stem-like cells (CSCs) that are responsible for maintaining tumor growth and metastasis. Altered glucose metabolism is a characteristic feature of cancer cells, which often display increased aerobic glycolysis alongside mitochondrial oxidative respiration (the Warburg effect). However, there is evidence that CSCs exhibit distinct glucose metabolism compared with the tumor cell bulk, with increased mitochondrial activity and oxidative respiration. Thus, identifying individual cells with different modes of glucose metabolism may serve as a common identifier of CSCs, and these metabolic differences would allow selective therapeutic targeting.
Methods: We investigated the levels of enzymes involved in glycolysis and oxidative respiration, together with glucose uptake and mitochondrial membrane potential in individual cancer cells. These parameters were correlated with each other and with CSC markers.
Results: We show considerable heterogeneity of metabolic markers in individual tumor cells. Surprisingly, high glucose uptake correlates with high mitochondrial membrane potential, indicating that increased oxidative respiration and aerobic glycolysis coexist rather than showing an inverse correlation. We also show that colonies derived from cells with high mitochondrial membrane potential exhibit heterogeneous metabolic parameters, demonstrating that metabolic profiles are not hard-wired. Public gene expression profiling data indicated similar inconsistent metabolic features of CSCs.
Conclusions: The data reveal inherent heterogeneity and plasticity of glucose metabolism and mitochondrial membrane potential in tumor cells, with evidence for a subpopulation that possesses both increased glucose uptake and increased mitochondrial membrane potential, with implications for therapeutic targeting of metabolism in cancer.
Keywords Glucose metabolism, Cancer stem cells, Mitochondria, ALDH, LDH, SDH, GLUT1
Address and Contact Information 1 RECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, Brno 656 53, Czech Republic
*Corresponding author: Zuzana Tylichova zuzana.tylichova@mou.cz Philip J. Coates philip.coates@mou.cz
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No.  27DOI: 10.1186/s11658-025-00845-0 Volume 31 (2026) - 30:27
Title HNF4A P2 ISOFORM ALLEVIATES KIDNEY FIBROSIS BY INHIBITING DEDIFFERENTIATION OF PROXIMAL TUBULAR CELLS THROUGH JAG1/NOTCH SIGNALING
Authors Guiya Jiang1†, Xun Lu3†, Rui Cao1†, Houliang Zhang1†, Yue Gao4, Kai Lu2, Lei Zhang2, Guangyuan Zhang2, Jianping Wu2, Bin Xu2, Jian Zhong5*, Jin Sun6*, Ming Chen2 and Shuqiu Chen2*
Abstract Background: Tubulointerstitial fibrosis is a critical and irreversible process of chronic kidney disease. Dedifferentiated proximal tubular cells (PTCs) after injury are important for tubulointerstitial fibrosis. Hepatocyte nuclear factor 4 alpha (HNF4A) is the main regulatory factor for PTC differentiation. However, its role in PTC dedifferentiation and kidney fibrosis remains unclear.
Methods: To investigate the role of HNF4A in kidney fibrosis, bioinformatics analysis and in vivo models were used to evaluate its expression in kidney tissues. The mechanisms through which the HNF4A P2 isoform inhibits kidney fibrosis were examined by using both in vivo and in vitro models.
Results: In this study, we revealed that the sustained downregulation of HNF4A expression was a key characteristic of abnormally repaired PTCs after injury and was associated with cell dedifferentiation. It was confirmed that the HNF4A P2 isoform, rather than the P1 isoform, inhibited TGF-β1-induced PTC dedifferentiation. The activation of fibroblasts, which was induced by dedifferentiated PTCs through paracrine signalling, was also inhibited. In vivo experiments confirmed that HNF4A P2 was more effective than HNF4A P1 was in alleviating kidney fibrosis. Mechanistically, on one hand, HNF4A P2 antagonized the TGF-β1-induced dedifferentiation of PTCs by inhibiting the JAG1/NOTCH pathway. On the other hand, the distinct structure of HNF4A P2 from that of P1 made it unaffected by TGF-β1-activated SRC, allowing HNF4A P2 to perform transcriptional regulatory functions.
Conclusions: These findings suggest that targeting the HNF4A P2 isoform could serve as a novel therapeutic strategy to alleviate kidney fibrosis.
Keywords HNF4A, Isoform, Kidney fibrosis, Tubular dedifferentiation
Address and Contact Information 1 Urology Department, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
2 Urology Department, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China
3 Department of Urology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, China
4 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
5 Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine/Zhangjiagang Traditional Chinese Medicine Hospital, Zhangjiagang 215000, Suzhou, China
6 Department of Urology, Xuyi County People’s Hospital, No.28 Hongwu Avenue, Xuyi County, Huaian 223001, China
*Corresponding author: Jian Zhong zhongjie_218@163.com Jin Sun 1261516421@qq.com Shuqiu Chen chenshuqiuzdyy@163.com
† Guiya Jiang, Xun Lu, Rui Cao and Houliang Zhang contributed equally to this work.
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No.  23DOI: 10.1186/s11658-025-00856-x Volume 31 (2026) - 30:23
Title TARGETING THE SIRTUIN 6–NF-κB p65 AXIS BY 6-HYDROXYHYOSCYAMINE HYDROBROMIDE: A DEACETYLATION-DRIVEN NEW THERAPY FOR DIABETIC WOUNDS
Authors Junren Chen1†, Siqi Qin1†, Ziwei Xing1, Feng Wan1, Jie Yin1, Cheng Peng1* and Dan Li1*
Abstract Background: Diabetic wounds are a debilitating complication of diabetes mellitus with a high rate of amputation and mortality. 6-Hydroxyhyoscyamine hydrobromide (6-HH) is a belladonna alkaloid with smooth-muscle-relaxing and microcirculation-enhancing properties, yet its role in diabetic wounds remains unknown.
Methods: In vivo, diabetic wounds were established in streptozotocin (STZ)-induced type 1 diabetic mice, high fat diet (HFD)/STZ-induced type 2 diabetic mice, and db/db diabetic mice to investigate the therapeutic effects of 6-HH, and skin samples were collected for hematoxylin and eosin (H&E) and Masson’s trichrome staining, immunofluorescence, RNA-seq analysis, and western blotting. In vitro, the mechanism of action of 6-HH on cytokines, nuclear factor kappa B (NF-κB) signals, and the interaction between sirtuin 6 (SIRT6) and p65 in lipopolysaccharide (LPS)-induced macrophages were detected by using enzyme-linked immunosorbent assay (ELISA), western blotting, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, and immunoprecipitation, while molecular docking was used to evaluate the binding energy between 6-HH and SIRT6 protein. Coculture systems of THP-1 cells–human umbilical vein endothelial cells (HUVECs)/immortalized human keratinocytes (HaCaTs) were established to investigate the effects of 6-HH on cross-talk between macrophages and endothelial cells/keratinocytes. SIRT6-specific inhibitor Oss_128167 was applied in vitro and in vivo to verify the mechanism of 6-HH in diabetic wound healing.
Results: 6-HH exhibited excellent pro-healing effect in the three types of diabetic mouse model. RNA-seq analysis found that 6-HH recovered diabetic-induced aberrant expression changes of genes in the local wounds, especially those related to M1 macrophage polarization with downregulation of Toll-like receptor (TLR) signals and nicotinamide adenine dinucleotide phosphate (NADP+) nucleosidase activity. Molecular docking analysis found that 6-HH could effectively bind to the active site of the SIRT6 protein. Remarkably, decline of SIRT6 in M1 macrophages resulted in lysine hyperacetylation, while activation and stabilization of SIRT6 by 6-HH suppressed M1 macrophage polarization and hyperacetylation through inhibiting p65 transcription with deacetylation of p65Lys310 and H3K9, contributing to improve angiogenesis and re-epithelization through interaction between macrophages and endothelial cells/keratinocytes. However, pharmacological inhibition of SIRT6 reversed the action of 6-HH in macrophages and diabetic wounds.
Conclusions: Collectively, deacetylase SIRT6 might be a direct pharmacological target of 6-HH that downregulates the hyperacetylated state of macrophages, thus contributing to diabetic wound healing.
Keywords SIRT6, Deacetylation, Macrophage polarization, 6-Hydroxyhyoscyamine hydrobromide, Diabetic wound
Address and Contact Information 1 Key Laboratory of Standardization of Chinese Medicine (Ministry of Education), Chinese Medicine Germplasm Resources Innovation and Effective Uses Key Laboratory of Sichuan Province, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Road, Wenjiang District, Chengdu 611137, China
*Corresponding author: Cheng Peng pengcheng_cd@126.com Dan Li lidan@cdutcm.edu.cn
† Junren Chen and Siqi Qin have contributed equally to this manuscript.
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No.  32DOI: 10.1186/s11658-026-00860-9 Volume 31 (2026) - 30:32
Title COGNITIVE–EXERCISE DUAL-TASK TRAINING DELAYS NATURAL AGING/D-GALACTOSE-INDUCED COGNITIVE DECLINE IN MICE
Authors Zi-Man Zhu1,2, Teng-Teng Dai3, Rong Zhang3, Pei-Ling Huang4, Ji-Lin Wu1,2, Li Song1,2 and Wei-Jun Gong4*
Abstract Background: Cognitive–exercise dual-task training has been shown to enhance cognitive function through mechanisms such as suppression of chronic inflammation, reduction of oxidative stress, and enhancement of synaptic plasticity. However, the precise mechanisms underlying the ability of dual-task training to delay aging-related cognitive decline remain incompletely understood.
Methods: Aged male C57BL/6J mice were subjected to a 12-week intervention program consisting of cognitive training, exercise, or cognitive–exercise dual-task training. Cognitive and physical function were assessed using a battery of behavioral tests, including the open field test, elevated plus maze test, inverted grid test, wire hanging test, rotarod test, novel object recognition test, novel object localization test, eight-arm maze test, and Morris water maze test. Hippocampal aging and associated molecular changes were assessed using multiple techniques, including terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Nissl staining, immunohistochemistry, immunofluorescence, flow cytometry, quantitative polymerase chain reaction, Western blotting, co-immunoprecipitation, and dual-luciferase reporter assays. In addition, we established in vitro models of cellular senescence using d-galactose, RNA overexpression/silencing models utilizing siRNA, and Ephrin type-B receptor 2 (EphB2) inducer/inhibitor models to explore specific molecular mechanisms.
Results: Age-related upregulation in microRNA (miR)-204 and downregulation in long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) were observed to disrupt Ephrin-B1 (EFNB1)/EphB2 interactions, leading to reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway activation. These alterations were implicated in the pathogenesis of aging-related cognitive decline. Timely interventions, especially cognitive–exercise dual-task, were found to attenuate these phenomena, thereby delaying the progression of aging-related cognitive decline.
Conclusions: Timely intervention during the aging process can effectively delay the progression of cognitive decline. The effects of cognitive–exercise dual-task training may surpass those of single-task interventions with either cognitive training or exercise alone.
Keywords Aging, Cognitive decline, Dual-task, microRNA
Address and Contact Information 1 Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
2 School of Beijing Rehabilitation Medicine, Capital Medical University, Beijing, China
3 The Second Clinical Medical College of Yunnan University of Chinese Traditional Medicine, Yunnan, China
4 Department of Neurological Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China
*Corresponding author: Wei-Jun Gong gwj197104@ccmu.edu.cn
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No.  11DOI: 10.1186/s11658-025-00846-z Volume 31 (2026) - 30:11
Title INHIBITION OF THE RORC/GPX4 MEDIATED FERROPTOSIS REGULATORY AXIS SUPPRESSES TUMOR GROWTH AND ALLEVIATES ENZALUTAMIDE RESISTANCE IN PROSTATE CANCER
Authors Yan Li1,2†, Bingqi Zhang2†, Zhongmin Zhang1,2, Wei Yan1,2, Haoyu Wang1,2, Xun Xu1,2, Anqi Lv2, Zhengming Liao1,2* and Lang Guo1,2*
Abstract Background: Patients with castration-resistant prostate cancer (CRPC) often develop resistance following long-term enzalutamide treatment. Building upon previous research, we aims to further explore the effect of ilicicolin A (ili-A) on enzalutamide resistance and to elucidate the underlying resistance mechanisms.
Methods: Proliferation, migration, and invasion of prostate cancer (PCa) cells were evaluated by 5-ethynyl-2′-deoxyuridine (EdU) assays, colony formation, scratch, and Transwell. Cell Counting Kit 8 (CCK-8) was used to assess the efficacy of drug inhibition in CRPC cells. The expression of tumor cell apoptotic proteins and ferroptosis was assessed using western blot (WB) analysis. Coimmunoprecipitation (Co-IP) and proximity ligation assay (PLA) were used to identify the mechanism of interaction between ilicicolin A and ferroptosis. Tumor transplantation experiments with mice were conducted to confirm findings.
Results: Ili-A showed dose-dependent inhibition of PCa cells including C4-2B and 22Rv1 cell lines. The overexpression of the RORC gene activated the expression of ferroptosis-related proteins, such as FTH1, GPX4 and SLC7A11, and enhanced proliferation of PCa cells. WB experiments indicated that RORC upregulated AR and AR-V7. An enzalutamide-resistant C4-2B cell line revealed that RORC serves as a gene target for enzalutamide resistance. Finally, it was observed that ili-A could suppress CRPC cells proliferation by downregulating RORC expression, thereby promoting ferroptosis and enhancing the sensitivity to enzalutamide.
Conclusions: Ili-A inhibited RORC expression, increased malondialdehyde (MDA) content, suppressed glutathione (GSH) production, released free Fe2+, increased reactive oxygen species (ROS), activated the ferroptosis pathway, enhanced enzalutamide sensitivity, and inhibited CRPC cell proliferation. Furthermore, ili-A enhances the interaction between ROR-γ and GPX4.
    Highlights:
  • On the basis of previous studies, we further explored the relationship between the enhancement of enzalutamide drug sensitivity by ilicicolin A and the ferroptosis phenotype.
  • Lentivirus-transfected cells were used for subcutaneous tumor transplantation in nude mice.
  • Erastin, an iron death inducer, was used as a drug control in animal experiments to explore the mechanism of enzalutamide resistance.
  • Co-IP and PLA experiments were used to deeply explore the relationship between RORC, a potential drug resistance target of enzalutamide, and ferroptosis.
  • Tightly combine ilicicolin A with the enzalutamide resistance target RORC.
Keywords Castration-resistant prostate cancer, Ilicicolin A, Ferroptosis, Enzalutamide, Drug resistance, Orphan nuclear receptor
Address and Contact Information 1 Department of Urology, Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Chinese Medicine, Hubei Sizhen Laboratory, Hubei University of Chinese Medicine, Wuhan 430000, Hubei, China
2 Hubei University of Chinese Medicine, No.1, Tanhualin, Wuchang District, Wuhan 430000, Hubei, China
*Corresponding author: Zhengming Liao lzmwhu@163.com Lang Guo guol199110@163.com
† Yan Li and Bingqi Zhang contributed equally to this work and are co-first authors for this paper.
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No.  24DOI: 10.1186/s11658-025-00841-4 Volume 31 (2026) - 30:24
Title VPS34-IN1 POTENTIATES STING-DEPENDENT ACTIVATION IN HUMAN CAL-1 CELLS
Authors Paulo Antas1, Mariana D. Machado1, Fátima Leite-Pinheiro1,2, Daniela Barros1,2, Carlota Ramalhinho1,3, Andreia Mendes1,2, Beatriz H. Ferreira1,3, Daniela Carvoeiro1, Luís F. Mendes1,4, Marisa Reverendo1,2, Iola F. Duarte3,4, Miwako Narita5, Bing Su6, Rafael J. Argüello2, Beatrice Nal2, Philippe Pierre1,2,6*, Catarina R. Almeida1* and Evelina Gatti1,2*
Abstract Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been previously suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on the leukemic blastic plasmacytoid dendritic cell neoplasm (BPDCN) CAL-1. However, we also found that VPS34-IN1 interferes with the function of this plasmacytoid dendritic cell (pDC) line, by inhibiting Toll-like receptor (TLR)7 signaling. In contrast, VPS34-IN1 triggers activation of the stimulator of interferon genes (STING) and significantly enhances cellular response to the STING agonist 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (2′3′-cGAMP) with increased expression of type I interferons (IFNs). Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation. Thus, despite their limited toxicity toward different cancer lines, VPS34-IN1 may represent a promising compound to promote expression of type I IFNs and thus antitumoral immunity.
Keywords BPDCN, Chemotherapy, CL307, Immunotherapy, STING, Type I interferon, PtdIns 3-kinase
Address and Contact Information 1 Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
2 Aix Marseille Université, CNRS, INSERM, CIML, 13288 Marseille Cedex 9, France
3 Department of Chemistry, CICECO, Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
4 LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
5 Faculty of Medicine, School of Health Sciences, Niigata University, Niigata 951-8518, Japan
6 Department of Microbiology and Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China
*Corresponding author: Philippe Pierre pierre@ciml.univ-mrs.fr Catarina R. Almeida cra@ua.pt Evelina Gatti gatti@ciml.univ-mrs.fr
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No.  26DOI: 10.1186/s11658-025-00855-y Volume 31 (2026) - 30:26
Title KERATINIZATION-RELATED GENE SIGNATURE PREDICTING SURVIVAL AND RESPONSE TO RADIATION IN PATIENTS WITH HPV-NEGATIVE HEAD AND NECK SQUAMOUS CELL CARCINOMA VIA REGULATION OF CORNIFICATION AND INTEGRIN SIGNALING
Authors Min Kyeong Lee1, Harim Joo1, Minji Bae1, Yeonseo Lee1, Joo-Kyung Noh1, Young Chan Lee2, Jung Woo Lee3, Soonki Min4, Moonkyoo Kong4, Seong-Gyu Ko5 and Young-Gyu Eun1,2*
Abstract Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy associated with poor prognostic outcomes. Despite ongoing efforts to identify reliable biomarkers for prognosis, the clinical utility of these markers remains limited owing to the need for further validation and deeper mechanistic insights. In this study, we developed and validated a novel keratinization-related gene signature (KRGS) to predict prognosis and radiation therapy (RT) response in human papillomavirus (HPV)-negative HNSCC using data from The Cancer Genome Atlas (TCGA). The 16-gene KRGS effectively stratified patients with HNSCC into two subgroups with significantly differing survival outcomes. KRGSlow, characterized by low KRGS expression, exhibited poorer survival and reduced sensitivity to RT, while KRGShigh, with high KRGS expression, was associated with more favorable survival outcomes and enhanced RT responsiveness. Functional validation, both in vitro and in vivo, demonstrated that keratinization activation through all-trans retinoic acid (ATRA) treatment upregulated the cornified envelope and sensitized HNSCC cells to RT. The enhanced response to RT was further associated with the upregulation of eight KRGS-related genes and increased expression of involucrin (IVL), a key regulator of terminal differentiation during cornification. Notably, the combination of ATRA and IR reduced radioresistance in HNSCC cells, which was linked to the downregulation of integrin alpha-1 (ITGA1) expression. These findings provide new insights into the role of keratinization in modulating radioresistance and suggest that KRGS-driven activation of keratinization, in combination with RT, may represent a promising therapeutic strategy to overcome resistance in HNSCC.
Keywords HPV-negative HNSCC, KRGS, Radiation therapy, Keratinization
Address and Contact Information 1 Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, Republic of Korea
2 Department of Otolaryngology-Head and Neck Surgery, Kyung Hee University School of Medicine, Kyung Hee University Medical Center, #23 Kyungheedae-Ro, Dongdaemun-Gu, Seoul 02447, Republic of Korea
3 Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung Hee University, Seoul, Korea
4 Department of Radiation Oncology, Kyung Hee University School of Medicine Kyung Hee University Medical Center, Seoul, Republic of Korea
5 Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
*Corresponding author: Young-Gyu Eun ygeun@khu.ac.kr
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No.  28DOI: 10.1186/s11658-026-00858-3 Volume 31 (2026) - 30:28
Title ROLE OF LONP1 IN HUMAN DISEASES: MOLECULAR MECHANISMS AND THERAPEUTIC POTENTIAL
Authors Mingkang Li1*, Anguo Wang2, Chengchun Tang3, Yong Qiao3, Wenkang Zhang3* and Yamei Wu2*
Abstract Mitochondria, the primary energy producers in eukaryotic cells, depend on an intricate protein quality control (PQC) system to preserve their functional integrity. Lon protease 1 (LONP1), an adenosine triphosphate (ATP)-dependent serine protease localized in the mitochondrial matrix, maintains mitochondrial proteostasis through selective degradation of misfolded and oxidatively modified proteins. Beyond its proteolytic activity, LONP1 not only acts as a molecular chaperone facilitating protein folding but also directly binds to mitochondrial DNA (mtDNA), suggesting a multifunctional role in mitochondrial genome regulation. LONP1 is tightly regulated through multilayered mechanisms spanning transcriptional control, epigenetic modulation, and post-translational modifications. Emerging evidence establishes mechanistic links between LONP1 and the pathogenesis of various human diseases. In this review, we comprehensively summarize the structural features and multifunctional roles of LONP1, with particular emphasis on its disease-associated molecular mechanisms. We further evaluate existing pharmacological modulators of LONP1 activity, providing a theoretical basis for the development of new therapeutic strategies for related diseases.
Keywords Lon protease 1, Mitochondrial homeostasis, Cell death and proliferation, Human diseases, Therapeutic targets
Address and Contact Information 1 Department of Cardiology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, No. 19 Xiuhua Road, Haikou 570311, Hainan, People’s Republic of China
2 Reproductive Medical Center, Hainan Women and Children’s Medical Center, No. 75 Longkun South Road, 570206 Haikou, Hainan, People’s Republic of China
3 Department of Cardiology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Nanjing 210009, Jiangsu, People’s Republic of China
*Corresponding author: Mingkang Li limingkang0611@hotmail.com Wenkang Zhang zwk96@126.com Yamei Wu 15595799860@163.com
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No.  20DOI: 10.1186/s11658-026-00859-2 Volume 31 (2026) - 30:20
Title TSP50 ATTENUATES METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE VIA SCD1 DEGRADATION-MEDIATED SUPPRESSION OF HEPATOCYTE LIPOGENESIS
Authors Jiujia Liang1,2,3, Zhihui Luan4, Rong Jin2, Rina Su1, Jiarong Ge4, Xiao Tian1, Chunxue Niu1, Jiawei Li1, Xiaoli Li2, Feng Gao3, Zhenbo Song1, Luguo Sun1, Guannan Wang3, Lihua Zheng3, Ying Sun2, Lei Liu3, Yongli Bao3, Shuyue Wang1 & Xiaoguang Yang2
Abstract Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to chronic liver disease worldwide, yet the molecular mechanisms driving its pathogenesis remain incompletely defined. Although dysregulated hepatic lipogenesis is a well-established driver of MASLD progression, the role of testes-specific protease 50 (TSP50)—an enzyme with demonstrated oncogenic functions in multiple cancers—in hepatic lipid metabolism and its potential involvement in the development of MASLD remains unexplored.
Methods: The study utilized the STelic Animal Model (STAM) along with high-fat/high-cholesterol plus fructose (HFF) and methionine-choline deficient (HFMCD) dietary models to evaluate the functional role of TSP50 in MASLD progression. Hepatocyte-specific knockout and AAV-mediated TSP50 reconstitution were performed to assess cell-autonomous effects. Mechanistic insights were gained through biochemical analyses of lipid metabolism pathways and protein interaction studies.
Results: TSP50 deficiency markedly accelerated MASLD progression across all experimental models, promoting hepatic steatosis, inflammation and fibrosis while increasing susceptibility to hepatocellular carcinoma (HCC). Conversely, TSP50 supplementation exerted protective effects against MASLD development. Furthermore, we identified a novel regulatory mechanism whereby TSP50 directly interacts with and degrades stearoyl-CoA desaturase 1 (SCD1) through its catalytic hydrolase activity, thereby suppressing de novo lipogenesis. The inhibitor of SCD1 rescued hepatic TSP50 knockout induced lipid accumulation and liver injury during MASLD.
Conclusions: Our study reveals the role of TSP50 in hepatic lipid metabolism, identifying it as a novel regulator of hepatic de novo lipogenesis that exerts protective effects against MASLD through catalytic degradation of SCD1. These findings not only advance our understanding of MASLD pathogenesis but also offer novel insights for developing therapeutic strategies.
Keywords TSP50, SCD1, Protease, MASLD, Hepatocyte lipid accumulation
Address and Contact Information 1 National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
2 China International Joint Research Center for Human Stem Cell Bank, Northeast Normal University, Changchun 130024, China
3 Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Ministry of Education, Northeast Normal University, Changchun 130024, China
4 School of Life Sciences, Changchun Normal University, Changchun 130032, China
*Corresponding author: Shuyue Wang wangsy171@nenu.edu.cn Xiaoguang Yang yangxg168@nenu.edu.cn
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No.  29DOI: 10.1186/s11658-025-00851-2 Volume 31 (2026) - 30:29
Title SEPSIS ALTERS NK CELL TRANSCRIPTIONAL PROGRAMS FOR STRESS, ACTIN REMODELING, AND INTRACELLULAR TRAFFICKING
Authors Holger A. Lindner1*, Carolina de la Torre2, Sonia Y. Velásquez1, Jutta Schulte1, Carsten Sticht2, Manfred Thiel1 and Anna Coulibaly1*
Abstract Background: Natural killer (NK) cells exert cytotoxicity against transformed and infected cells. In human sepsis, a suppressive NK cell receptor signature and defective effector molecule expression have been described. However, the transcriptional mechanisms underlying this phenotype remain poorly defined.
Methods: We analyzed microarray-based transcriptomic profiles of isolated peripheral NK cells from patients with sepsis, patients with systemic inflammatory response syndrome (SIRS), and presurgical controls. Enrichment analyses of canonical pathways, biological processes, and cellular compartments were performed. Differential gene expression was validated in an independent cohort using a multiplex branched-DNA assay. Functional signal transducer and activator of transcription (STAT) phosphorylation responses ex vivo and proliferation marker expression were assessed by flow cytometry in independent patient samples.
Results: NK cells from patients with sepsis displayed transcriptional signatures indicative of DNA replication stress, endoplasmic reticulum (ER) stress, altered cytoskeletal dynamics, and vesicle trafficking. Despite enrichment of proliferation-associated transcriptional programs, NK cells showed no increase in Ki-67 expression, indicating impaired proliferative activity. In contrast, NK cells from patients with SIRS exhibited downregulation of immune signaling pathways.
Conclusion: This study identifies early stress-associated transcriptional programs and impaired subcellular organization in circulating NK cells during sepsis. Dysregulated DNA replication and ER stress responses, along with altered vesicle trafficking linked to impaired small guanosine triphosphatase (GTPase) signaling, may contribute to NK cell dysfunction in sepsis and may inform the development of NK cell-based immunotherapeutic strategies in critical illness.
Keywords Gene expression profiling, Natural killer cells, Pathway analysis, Sepsis, Systemic inflammatory response syndrome
Address and Contact Information 1 Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
2 NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
*Correspondence: Holger A. Lindner Holger.Lindner@medma.uni-heidelberg.de Anna Coulibaly Anna.Coulibaly@medma.uni-heidelberg.de
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No.  33DOI: 10.1186/s11658-026-00863-6 Volume 31 (2026) - 30:33
Title TRMT6/TRMT61A-MEDIATED tRNA m1A MODIFICATION ENHANCES PROTEIN TRANSLATION AND ACTIVATES THE IRE1α–XBP1s PATHWAY TO PROMOTE ANAPLASTIC THYROID CANCER PROGRESSION
Authors Ying Ding1,2, Ziyang Feng2,3, Guanjun Chen3, Yunqing Liu3, Yuxing Zhu3 and Ke Cao3*
Abstract Background: Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with rapid progression and poor prognosis. Although N1-methyladenosine (m1A) modification has been implicated in cancer development, the specific role of tRNA m1A modification in ATC remains unclear.
Methods: An integrated multi-omics approach is employed, including m1A-MAP-tRNA-seq, tRNA-seq, RNA-seq, and Ribo-seq, complemented by functional assays such as tRNA aminoacylation assay, puromycin intake assay, and L-HPG staining. Additional experiments involved polysome profiling qRT-PCR, codon-switch assay, endoplasmic reticulum (ER)-tracker and TPE-MI staining, transmission electron microscopy, ChIP-qPCR, dual-luciferase reporter assay, and BODIPY staining to elucidate the underlying mechanism.
Results: TRMT6/TRMT61A is significantly upregulated in ATC. The complex promotes tumor cell proliferation and metastasis by enhancing the aminoacylation of specific tRNAs, thereby facilitating global protein translation. Elevated translation led to the accumulation of unfolded proteins in the ER, which activates the IRE1α–XBP1s pathway. Notably, m1A modification also increased IRE1α translation, further amplifying the pathway. Activation of the IRE1α–XBP1s pathway upregulates DGAT1 expression, which promotes triglyceride synthesis.
Conclusions: Together, these findings reveal a previously unrecognized mechanism by which TRMT6/TRMT61A drives ATC progression through translational and metabolic reprogramming, identifying TRMT6/TRMT61A as a promising therapeutic target in ATC.
Keywords TRMT6/TRMT61A, tRNA, m1A modification, Translation, IRE1α–XBP1s
Address and Contact Information 1 Department of Breast Thyroid Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
2 Postdoctoral Station of Medical Aspects of Specific Environments, the Third Xiangya Hospital, Central South University, Changsha, China
3 Department of Oncology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
*Correspondence: Ke Cao csucaoke@163.com
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No.  22DOI: 10.1186/s11658-026-00867-2 Volume 31 (2026) - 30:22
Title THE PROMOTING ROLES OF GLP1R AND GIPR IN STEMNESS MAINTENANCE AND MULTIPLE LINEAGE-SPECIFIC DIFFERENTIATION OF PDLSCs
Authors Yifen Shen1†, Mengjie Zhang3†, Tao Yang4, Yuxiang Wu5, Yinfeng Qiu6, Le Zhang2,7, Fei Li8, Minjie Chen3, Qili Chen9*, Wenbin Wei3*, Hua Li2,7* and Yihang Shen1*
Abstract Background: Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse factors in the periodontal microenvironment. Therefore, identifying novel therapeutic targets and elucidating the underlying molecular mechanisms to protect the proliferative and differentiation potential of PDLSCs is of significant importance.
Methods: PDLSCs were exposed to electronic cigarette extract and various common oral stressors to evaluate the expression of glucagon such as peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR). PDLSCs isolated from patients with periodontitis and PDLSCs from a mouse periodontitis model were also analyzed. Functional studies were performed by GLP1R or GIPR knockdown, overexpression, and treatment with single or dual receptor agonists, followed by assessment of cell proliferation and multilineage differentiation capacities. Transcriptome (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA immunoprecipitation sequencing (RIP-seq) were applied to delineate downstream signaling pathways and RNA–protein interactions. Protein synthesis regulation was further investigated by immunoprecipitation of interferon induced protein with tetratricopeptide repeats (IFIT)-associated translation initiation factors. For in vivo validation, wild-type and GLP1R/GIPR double-knockout periodontitis mice were transplanted with CRISPR-Cas9 mCherry-labeled PDLSCs and treated with receptor agonists. Disease severity and PDLSC fate were evaluated by histology and lineage tracing. Finally, a questionnaire-based survey was conducted in 150 patients with periodontitis, including 74 individuals with long-term use (> 1 month) of GLP1R or GLP1R/GIPR dual agonists (e.g., semaglutide, liraglutide, tirzepatide), to assess their periodontal outcomes.
Results: GLP1R and GIPR expression were markedly downregulated in PDLSCs exposed to multiple stressors and in PDLSCs isolated from periodontitis specimens. RNA-seq, ChIP-seq, and RIP-seq identified downstream pathways and RNA–protein interactions implicated in receptor-mediated regulation. Functionally, GIPR agonism promoted PDLSC proliferation via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, whereas GLP1R agonist enhanced multilineage differentiation capacity in vitro. Mechanistically, GLP1R knockdown induced robust upregulation of IFIT1/2/3, while GLP1R agonist suppressed IFIT expression. IFIT1/2/3 were shown to interact with eIF3C and to inhibit translation of differentiation-related mRNAs, linking GLP1R signaling to translational control of PDLSC fate. In vivo, transplantation experiments in both wild-type and GLP1R/GIPR double-knockout periodontitis mice demonstrated that single and dual receptor agonists significantly improved endogenous and exogenous PDLSC-mediated periodontal regeneration. Consistently, a clinical survey of 150 patients with periodontitis (74 receiving GLP1R or dual agonists) revealed significantly better periodontal staging and grading in treated individuals, with longer agonist exposure associated with greater improvement.
Conclusions: Our findings uncover the different molecular roles of GIPR and GLP1R in self-renewal capacity and multipotency of PDLSCs, and open new avenues for developing therapeutic targets and strategies in oral tissue engineering and regenerative medicine.
Keywords PDLSC, GLP1R, GIPR, MAPK/ERK, IFIT
Address and Contact Information Central Laboratory, Suzhou Ninth People’s Hospital, Soochow University, 2666 Ludang Road, Suzhou 215200, Jiangsu, China
2 Jiangsu Province Engineering Research Center of Development and Translation of Key Technologies for Chronic Disease Prevention and Control, Suzhou Vocational Health College, 28 Kehua Road, Suzhou 215009, Jiangsu, China
3 Department of Oral Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital; National Center for Stomatology, and National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Shanghai 200023, China
4 Department of Medical Cosmetology, Suzhou Ninth People’s Hospital, Soochow University, Suzhou 215200, Jiangsu, China
5 Department of Pathology, Suzhou Ninth People’s Hospital, Soochow University, Suzhou 215200, Jiangsu, China
6 Department of Stomatology, Suzhou Ninth People’s Hospital, Soochow University, Suzhou 215200, Jiangsu, China
7 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
8 Department of Preventive Dentistry, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital; National Center for Stomatology, and National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Shanghai 200023, China
9 School of Pharmacy, China Medical University, 77 Puhe Road, Shenyang 110122, Liaoning, China
*Corresponding author: Qili Chen qlchen@cmu.edu.cn Wenbin Wei tian_qian_cool@126.com Hua Li kaikaixinxin@sjtu.edu.cn Yihang Shen devbrother@sjtu.edu.cn
† Yifen Shen and Mengjie Zhang have contributed equally to this work.
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No.  34DOI: 10.1186/s11658-026-00875-2 Volume 31 (2026) - 30:34
Title BIP ORCHESTRATES BIDIRECTIONAL ER PROTEIN TRAFFICKING VIA CO-CHAPERONE COMPLEXES
Authors Suma Biadsy1, Ayelet Gilad1, Laila Abu Madegam1 and Aeid Igbaria1*
Abstract Background: Interorganellar protein redistribution is an emerging but underexplored aspect of proteostasis and cellular adaptation. Beyond canonical transcriptional and translational regulation, cells dynamically reprogram the spatial distribution of proteins to rapidly respond to environmental stress. This spatial plasticity enables single gene products to acquire novel, context-dependent functions on the basis of subcellular localization. Such relocalization is particularly pronounced in pathological conditions, such as cancer and viral infections, where proteome remodeling enhances cellular survival and adaptability. We previously defined endoplasmic reticulum (ER)-to-cytosol signaling (ERCYS) as a stress-responsive mechanism that alleviates ER burden by redistributing proteins into the cytosol. Despite growing interest, the molecular mechanisms driving ERCYS and related forms of spatial proteome remodeling remain poorly defined. Methods: To investigate these mechanisms, we employed siRNA- and CRISPR-based depletion of BIP, SGTA, and DNAJB12/14, coupled with subcellular fractionation and immunoblotting to assess protein localization under stress. Co-immunoprecipitation was used to examine protein–protein interactions, and unfolded protein response (UPR) activation was quantified via quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results: Our results reveal a previously unrecognized role for the UPR in mediating ER protein reflux. Specifically, we show that ATF6 and IRE1, but not PERK, are essential for initiating ERCYS. Notably, IRE1 simultaneously promotes ERCYS while suppressing BAX/BAK-mediated ER membrane permeabilization. Furthermore, we uncover a noncanonical, signaling-independent function of the ER-resident chaperone BIP in protein reflux. BIP forms a complex with membrane-bound DNAJB12/14 and cytosolic SGTA, facilitating chaperone-guided export of proteins from the ER lumen. This process depends on an intact DNAJB12 J-domain and requires BIP to originate within the ER, supporting a directional, regulated export mechanism. These findings challenge the classical view of BIP as solely mediating inward translocation and reveal a bidirectional role in protein trafficking. Our work uncovers a novel layer of UPR-regulated spatial proteome remodeling with potential relevance in cancer biology.
Keywords Spatial proteome, UPR, ER stress, Cancer, DNAJB12, ERCYS
Address and Contact Information 1 Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
*Corresponding author: Aeid Igbaria aigbaria@bgu.ac.il
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No.  35DOI: 10.1186/s11658-026-00865-4 Volume 31 (2026) - 30:35
Title EXTRACHROMOSOMAL CIRCULAR DNA: A POTENTIAL CLINICAL THERAPEUTIC TARGET IN MALIGNANT TUMORS
Authors Hao Zhang1,2, Enqing Zhuo4, Meng Li1, Junxiao Feng3, Xingjuan Shi3* and Xiaoou Sun1*
Abstract Malignant tumors, commonly referred to as cancer, are pathological conditions distinguished by the unregulated growth and infiltration of malignant cells into adjacent tissues or remote organs. This uncontrolled cell proliferation results in continuous tumor cell division and proliferation in the body. The tumor invades surrounding tissues and spreads to other body parts through the bloodstream or lymphatic system. This forms distant metastases that can influence several systems and organs, seriously affecting the health and life of patients. Effective treatment methods are still lacking owing to their complex mechanism of action. With the continuous development of precision medicine, research on the correlation between extrachromosomal circular DNA (eccDNA) and malignant tumors has become a hot topic. The eccDNA is a circular DNA molecule independent of chromosomes, more stable, and less susceptible to nuclease degradation. Increasing evidence has shown that eccDNA has a function in malignant tumor heterogeneity, invasiveness, evolution, and chemical resistance. It drives tumor heterogeneity so that cancer cells can quickly adapt to treatment plans and environmental changes. Compared with linear chromosomal DNA, eccDNA has an open structure, carries active histone modifications, and can facilitate long-range gene interactions, significantly improving the transcriptional activity of genes and playing an essential regulatory role in disease progression. It also serves as a biological marker for diagnosing and predicting malignant tumors, thus attracting increasing attention. This article reviews its role, mechanism, and value in malignant tumors, providing a new perspective for diagnosing and treating this disease.
Keywords Extrachromosomal circular DNA, Malignant tumor, Regulatory effect, Biomarker
Address and Contact Information 1 Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
2 Guangzhou Huateng Bioscience Corporation, Guangzhou 510530, China
3 School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China
4 Department of 2nd Oncology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
*Corresponding author: Xingjuan Shi xingjuanshi@seu.edu.cn Xiaoou Sun xiaoousun@gdut.edu.cn
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No.  36DOI: 10.1186/s11658-025-00849-w Volume 31 (2026) - 30:36
Title SPATIOTEMPORAL DYNAMICS OF REACTIVE OXYGEN SPECIES: IMPLICATIONS FOR CELLULAR HOMEOSTASIS AND REDOX THERAPIES
Authors Yucen Li1,2, Qiao Zhao3, Hanyu Hu1 and Jian-Fei Pei1*
Abstract Reactive oxygen species (ROS) are endogenously generated during cellular metabolism but can also be induced by environmental stressors, such as radiation, pollutants, and inflammation. While ROS are essential for cellular function, excessive levels of ROS can inflict damage on DNA, proteins, and lipids, resulting in cellular impairment and, in severe cases, cell death. Notably, both basal ROS levels and homeostatic set point of ROS vary markedly among various subcellular compartments, with each organelle exhibiting distinct pathological consequences when its oxidative homeostasis is disrupted. Furthermore, ROS levels exhibit significant diurnal oscillations in many species, resulting in dynamic changes in cellular redox homeostasis over the 24-h cycle. Regrettably, these spatiotemporal dimensions of ROS regulation have often been overlooked in previous studies and are rarely considered in current antioxidant therapeutic strategies. This review provides a comprehensive overview of the major sites of ROS and the enzymes responsible for ROS generation and scavenging in different subcellular locations, along with their temporal variations. Additionally, the driving forces and biological functions of redox rhythms are also discussed. By integrating these insights, we aim to advance the understanding of spatiotemporal ROS regulation and provide a foundation for developing precision redox-based therapies with enhanced clinical translation.
Keywords Oxidative stress, Circadian rhythms, Redox precision therapies, ROS spatiotemporal regulation
Address and Contact Information 1 Department of Medical Genetics, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
2 Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, China
3 Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
*Corresponding author: Jian-Fei Pei jamffypei@163.com
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No.  25DOI: 10.1186/s11658-026-00878-z Volume 31 (2026) - 30:25
Title CORRECTION: THE DIRECT BINDING OF BIOACTIVE PEPTIDE ANDERSONIN‐W1 TO TLR4 EXPEDITES THE HEALING OF DIABETIC SKIN WOUNDS
Authors Chao Li3†, Yuxin Xiong1,4†, Zhe Fu1†, Yuxin Ji1, Jiayi Yan1, Yan Kong1, Ying Peng1, Zeqiong Ru1, Yubing Huang3, Yilin Li1, Ying Yang4*, Li He5*, Jing Tang3*, Ying Wang2* and Xinwang Yang1*
Abstract Correction: Cellular & Molecular Biology Letters (2024) 29:24
https://doi.org/10.1186/s11658-024-00542-4

In this article [1], the wrong figure appeared as Fig. 1, S5 and S6; the correct figures should have appeared as shown below.
Keywords
Address and Contact Information 1 Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Yunnan 650500, Kunming, China
2 Key Laboratory of Chemistry in Ethnic Medicinal Resources & Key Laboratory of Natural Products Synthetic Biology of Ethnic Medicinal Endophytes, State Ethnic Affairs Commission & Ministry of Education, School of Ethnic Medicine, Yunnan Minzu University, Yunnan 650504, Kunming, China
3 Department of Biochemistry and Molecular Biology, Faculty of Basic Medical Science, Kunming Medical University, Yunnan 650500, Kunming, China
4 Department of Endocrinology, Affiliated Hospital of Yunnan University, Yunnan 650021, Kunming, China
5 Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Yunnan 650032, Kunming, China
*Corresponding author: Ying Yang yangying2072@126.com Li He drheli2662@126.com Jing Tang gracett916@163.com Ying Wang wangying_814@163.com Xinwang Yang yangxinwanghp@163.com; yangxinwang@kmmu.edu.cn
† Chao Li, Yuxin Xiong and Zhe Fu contributed equally to this manuscript.
The original article can be found online at https://doi.org/10.1186/s11658-024-00542-4.
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No.  38DOI: 10.1186/s11658-026-00862-7 Volume 31 (2026) - 30:38
Title BANNAKUNIN: A DUAL-TARGET KUNITZ INHIBITOR BRIDGING ANTICOAGULATION (FXa/XIIa) AND ANTI-PLATELET (α2β1/P2Y12) PATHWAYS
Authors Miao He1†, Yanmei He1†, Xiaoli Feng1†, Zhuorui Li1, Ting Lin1, Jiayi Yang1, Haiyan Luo1, Lixian Mu1*, Hailong Yang1,2* and Jing Wu1*
Abstract Background: Thrombosis is a major cause of morbidity and mortality worldwide. Consequently, there is an ongoing search for efficacious and safe anti-thrombotic drugs. Haematophagous animals have developed a large variety of salivary bioactive components to counteract host haemostatic responses. We aim to discover anti-thrombotic agents with dual anti-platelet and anticoagulant activities.
Methods: A novel single Kunitz domain inhibitor (Bannakunin) precursor cloned from the salivary glands complementary DNA (cDNA) library of blood-sucking black fly Simulium bannaense was expressed in Escherichia coli. Recombinant Bannakunin was purified by Immobilised Metal Affinity Chromatography and High-Performance Liquid Chromatography. The secondary structure was determined by circular dichroism spectroscopy. The anti-thrombotic activity was evaluated through carotid artery thrombosis and tail vein thrombosis models. The inhibitory activity was evaluated using serine protease inhibition assays, SPR and molecular docking. The regulation on platelets was assessed by platelet aggregation, clot retraction and platelet spreading assays. Subsequently, its target receptors and signalling pathways were investigated through western blotting, enzyme-linked immunosorbent assay (ELISA) and flow cytometry.
Results: Recombinant Bannakunin demonstrated significant anti-thrombotic efficacy in murine FeCl3-induced carotid artery and carrageenan-induced tail vein thrombosis models and did not induce bleeding complications. Simultaneously, Bannakunin markedly prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) in human plasma. Further investigation revealed that Bannakunin could inhibit the activity of the coagulation factors FXa and FXIIa, as well as the activities of elastase, trypsin, and plasma kallikrein, but it did not inhibit thrombin and FXIa. Surface plasmon resonance studies have shown that Bannakunin binds to the active sites of human elastase (KD: 1.95 nM) and human FXa (KD: 42.9 nM) with the highest affinity. Intriguingly, we observed that Bannakunin significantly inhibited clot retraction, as well as platelet aggregation and spreading. Mechanistically, Bannakunin inhibited collagen-induced platelet activation by downregulating the integrin α2β1-mediated Src/Syk/PLCγ2 signalling pathway and the release of Ca2+, TXB2 and ATP. Furthermore, Bannakunin could effectively inhibit ADP-induced platelet activation through blocking P2Y12 receptor, decreasing the activation of PI3K/Akt signalling pathways and upregulating the level of cAMP.
Conclusions: These findings enrich our understanding of the anti-platelet functions of Kunitz-type inhibitors and position Bannakunin as a promising molecular template for the development of novel anti-thrombotic drugs.
Keywords Kunitz-type inhibitor, Anti-thrombotic, Anticoagulation, Anti-platelet
Address and Contact Information 1 School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming 650500, Yunnan, China
2 Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, School of Rehabilitation, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming 650500 Yunnan, China
*Corresponding author: Lixian Mu mulixian77@163.com Hailong Yang jxauyhl@163.com Jing Wu wujing_205@163.com
† Miao He, Yanmei He, Xiaoli Feng contributed equally to this work.
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No.  39DOI: 10.1186/s11658-026-00866-3 Volume 31 (2026) - 30:39
Title GUT LACHNOSPIRACEAE IMPROVES WHITE MATTER INJURY-RELATED COGNITIVE DECLINE BY INCREASING L-ARGININE
Authors Yuhao Xu1,2,3,4,5†, Lili Huang1,2,3,4,5†, Liang Sun1,2,3,4,5, Chenggang Li1,2,3,4,5, Chao Zhou1,2,3,4,5, Pinyi Liu1,2,3,4,5, Zhi Zhang1,2,3,4,5, Shiji Deng1,2,3,4,5, Chenglu Mao1,2,3,4,5, Zheqi Hu1,2,3,4,5, Xinyu Bao1,2,3,4,5, Shengnan Xia1,2,3,4,5 and Yun Xu1,2,3,4*
Abstract Background: White matter injury (WMI) is the most prevalent lesion in cerebral small vessel disease and a major contributor to cognitive decline. Recent studies have highlighted the critical role of gut microbiota in regulating brain disorders. However, the role of gut microbiota in WMI-related cognitive decline remains unclear.
Methods: A bilateral carotid artery stenosis (BCAS) mouse model was established to mimic WMI and related cognitive decline. Fecal microbiota transplantation was employed to verify the causal relationship between gut microbiota dysbiosis and WMI. 16 S rRNA gene sequencing was used to analyze gut microbiota and its potential functions. Untargeted metabolomics was applied to identify differential metabolites. Cognitive function was assessed through Y-maze, novel object recognition, and fear conditioning tests. WMI was assessed using in vivo imaging, immunostaining, and electron microscopy. The changes in oligodendrocyte lineage cells, microglia, and blood-brain barrier were investigated using immunofluorescence staining, EdU cell proliferation assays, and Western blotting. Patients with ischemic WMI were included to examine the correlation between serum L-arginine (L-Arg) levels, brain imaging, and cognition.
Results: We discovered that BCAS mice exhibited gut microbiota dysbiosis and reduced arginine biosynthesis, with decreased L-Arg levels in serum and white matter. Fecal microbiota from BCAS mice resulted in WMI and related cognitive decline in normal mice. Serum L-Arg levels were reduced in patients with ischemic WMI and were closely associated with WMI and cognitive decline. Importantly, L-Arg supplementation improved WMI-related cognitive decline in BCAS mice. Mechanistically, L-Arg promoted oligodendrocyte precursor cell proliferation and differentiation, enhanced the anti-inflammatory activity of microglia, and reduced blood-brain barrier leakage, thereby mitigating WMI-related cognitive decline. Furthermore, Lachnospiraceae was identified as the main source of gut-to-brain L-Arg. Supplementation with Lachnospiraceae alleviates WMI-related cognitive decline.
Conclusion: Overall, our study revealed the critical role of gut microbiota, particularly Lachnospiraceae, and L-Arg in improving WMI-related cognitive decline, providing novel strategies for understanding and treating WMI-related cognitive decline.
Keywords Cognitive decline, White matter injury, L-arginine, Gut microbiota, Lachnospiraceae
Address and Contact Information 1 Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China
2 Jiangsu Key Laboratory for Molecular Medicine, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China
3 Nanjing Neurology Clinical Medical Center, 321 Zhongshan Road, Nanjing 210008, China
4 The Brain Disease and Brain Science Center of Nanjing Drum Tower Hospital, 321 Zhongshan Road, Nanjing 210008, China
5 Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine, 321 Zhongshan Road, Nanjing 210008, China
*Corresponding author: Yun Xu xuyun208@163.com
† Yuhao Xu and Lili Huang contributed equally to this work.
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No.  40DOI: 10.1186/s11658-026-00871-6 Volume 31 (2026) - 30:40
Title ROLE OF AUTOPHAGY IN ANTIVIRAL INNATE IMMUNITY
Authors Jiufeng Xie1†, Pengtao Jiao2†, Dong Wang1, Manyu Shi1, Cui Yuan1, Lijuan Su1, Guozhi Zhang1, Yuhe Wang3, Zhenling Ma1*, Liqing Li4* and Wei Liu1*
Abstract Autophagy exerts an important effect on preserving homeostasis of cellular metabolism through degrading superfluous intracellular components. In addition, it serves as the defense mechanism for eliminating invading pathogens, such as viruses, by the host. The onset of a viral infection triggers autophagy, thereby initiating the innate immunity via the pattern recognition receptor pathways. As a result, interferons and other proinflammatory factors are produced. Furthermore, autophagy specifically targets immune components linked to viral particles for degradation. Through presenting virus-derived antigens to T lymphocytes, this process supports adaptive immunity. Nonetheless, certain viruses evolve mechanisms for inhibiting autophagy, enabling evasion of degradation and immune detection, since autophagy is frequently related to inflammatory diseases, including infections, autoimmune disorders, cancer, metabolic syndromes, neurodegenerative conditions, and cardiovascular and liver diseases. This review aims to summarize the current knowledge regarding the key molecules and specific molecular mechanisms that underlie the pattern recognition receptor signaling where autophagy is implicated during viral infections.
Keywords Autophagy, Virus, Viral infection, Innate immune response, Pattern recognition receptor
Address and Contact Information 1 College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
2 Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
3 Department of Genomic and Computational Biology, University of Massachusetts Chan Medical School, Worcester 01605, USA
4 No.984 Hospital, PLA Joint Logistics Support Force, Beijing 100094, China
*Corresponding author: Zhenling Ma xmzl@henau.edu.cn Liqing Li liliqing028@163.com Wei Liu liuv@henau.edu.cn
† Jiufeng Xie and Pengtao Jiao have contributed equally to this work.
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No.  41DOI: 10.1186/s11658-026-00885-0 Volume 31 (2026) - 30:41
Title DNA TOPOLOGICAL REGULATION IN RNA POLYMERASE II TRANSCRIPTION
Authors Heeyoun Bunch1*
Abstract RNA polymerase II (Pol II) is the main enzyme that synthesizes protein-coding messenger RNA and a subset of nonprotein coding RNA molecules based on the DNA sequences harboring genetic information in eukaryotes. Pol II engagement with and dissociation from genes and its catalytic rate and polymerization processivity are modulated by diverse transcriptional elements. These factors control Pol II directly or modulate transcriptional microenvironments, chromatin, and nucleic acid structures. Classical and recent studies have reported multifaceted, important functions of DNA topology and structure and DNA topological regulators including DNA topoisomerases (TOPs), for controlled Pol II transcription. Furthermore, recent studies have indicated intriguing crosstalk among transcriptional factors, TOP2, and DNA damage response/repair factors in transcription, in particular, in the transcriptional initiation and elongation steps. This review updates and discusses these important findings regarding DNA topological modulations and the molecular mechanisms of TOP2 regulation in Pol II transcription.
Keywords DNA topology, Transcription, RNA polymerase II, Topoisomerase II, DNA repair factors, Pol II promoter-proximal pausing, Stress-inducible genes
Address and Contact Information 1 Department of Applied Biosciences, Kyungpook National University, 80 Daehak-ro, Agricultural and Life Sciences Building 1, Room 303, Daegu 41566, Republic of Korea
*Corresponding author: Heeyoun Bunch heeyounbunch@gmail.com
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No.  42DOI: 10.1186/s11658-026-00869-0 Volume 31 (2026) - 30:42
Title ASTRAGALOSIDE IV REPRESSES THE IMMUNE EVASION AND ACIDIC MICROENVIRONMENT OF ORAL SQUAMOUS CELL CARCINOMA
Authors Wei Zhao1,2†, Haowen Zheng1,2†, Yunhan Chang1,2†, Tingting Shang1†, Lixuan Wang3, Jingwen Liu1,2, Jiayin Deng1,2, Zhanyu Pan4*, Xin Hu1,2*, Xin Huang1,2* and Yameng Cui4*
Abstract Immune evasion and immunosuppression are important hallmarks of human malignancies. Astragaloside IV (AST) is one of the effective ingredients in Astragalus, which has been confirmed to enhance antitumor immunity. However, the functions and underlying mechanism of AST on oral squamous cell carcinoma (OSCC) tumorigenesis remain undetermined. Our present work tried to test whether and how AST inhibited OSCC immune evasion and ameliorated CD8+ T cell-mediated antitumor response in immune microenvironment. The results of the present work indicated that AST repressed OSCC cells’ proliferation and migration in dosage-dependent manner. In a co-culture system analysis of CD8+ T and OSCC cells, AST enhanced the antitumor activity of CD8+ T cells to impair the OSCC immune evasion. Moreover, AST also repressed the lactate secretion and extracellular acidification. Furthermore, excess lactate accumulation triggered the PD-L1 enrichment on OSCC cells in acidic microenvironment. Mechanistically, AST targeted MCT1 to degrade its mRNA stability, thereby mitigating the extracellular acidification and inhibiting the escape of OSCC from CD8+ T cells’ killing. This study indicates that AST could ameliorate the acidic microenvironment in OSCC to improve CD8+ T cell-mediated antitumor immune response. Our finding might offer novel insights for the anti-tumor effect of AST and provide a potential therapeutic strategy for OSCC.
Keywords Astragaloside IV, Oral squamous cell carcinoma, MCT1, Antitumor immunity, Lactate
Address and Contact Information 1 Tianjin Medical University School and Hospital of Stomatology and Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, No.12 Qixiangtai Road, Heping District, Tianjin 300070, People’s Republic of China
2 Tianjin Medical University Institute of Stomatology, No.12 Qixiangtai Road, Heping District, Tianjin 300070, People’s Republic of China
3 Stomatological Hospital of Chongqing Medical University, No. 426, Songshibei Road, Yubei District 401147 Chongqing, People’s Republic of China
4 Department of Integrated Traditional and Western Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, No. 1 Huanhu West Road, 300060 Tianjin, China
*Corresponding author: Zhanyu Pan pzytg1@126.com Xin Hu huxin90@126.com Xin Huang xinhuang@tmu.edu.cn Yameng Cui cuiyameng@tmu.edu.cn
† Wei Zhao, Haowen Zheng, Yunhan Chang and Tingting Shang contributed equally to this work.
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No.  43DOI: 10.1186/s11658-026-00886-z Volume 31 (2026) - 30:43
Title FROM HPSCS TO MSCS: DIFFERENTIATION STRATEGIES, PATHWAYS, AND THE EMERGENCE OF COMMON REGULATORY NETWORKS
Authors Shengxian Liang1*, Zhuang Qian1, Yichen Wang2, Jingjing Huangfu3 and Wenjie Ren1,2,3*
Abstract Mesenchymal stem/stromal cells (MSCs) derived from human pluripotent stem cells (hPSCs) represent a scalable and homogeneous source for regenerative medicine. To date, multiple differentiation protocols have been developed to direct hPSCs toward an MSC fate, with intermediate cell states arising from diverse lineages, including trophoblast, neural crest, mesoderm, and endoderm. Despite these divergent differentiation strategies, the induced MSCs exhibit similar phenotypes and biological functions, suggesting convergent molecular programs underlying MSC specification. In this review, we discuss current strategies for differentiating hPSCs into MSCs and summarize the key signaling pathways, with a focus on the transcriptional regulators that govern these lineage-specific differentiation routes. To identify common regulatory nodes across different lineages, we analyzed publicly available transcriptomic datasets from representative hPSC-to-MSC protocols deposited in the Gene Expression Omnibus (GEO) database. Comparative analysis revealed a core set of consistently dysregulated genes and enriched pathways, particularly those involved in extracellular matrix (ECM)-receptor interaction, focal adhesion, and the PI3K–Akt signaling pathway. Notably, SMAD3, along with AP-1 family members (JUN, JUND, FOSL1, FOSL2) and the associated regulatory targets (FN1 and COL1A1) emerged as recurrent hubs in mesenchymal commitment. These findings highlight both the plasticity and convergence in the induction of MSCs from hPSCs and provide a molecular framework for optimizing differentiation strategies and ensuring product consistency in regenerative applications.
Keywords Human pluripotent stem cells, Mesenchymal stem/stromal cells, Differentiation protocols, Molecular mechanisms, Transcriptomic analysis, Regulatory networks
Address and Contact Information 1 Clinical Medical Center of Tissue Engineering and Regeneration, Institutes of Health Central Plain, Henan Medical University, Xinxiang 453003, China
2 The First Affiliated Hospital, Henan Medical University, Xinxiang 453199, China
3 Henan Medical Key Laboratory for Research of Trauma and Orthopedics, The Third Affiliated Hospital, Henan Medical University, Xinxiang 453003, China
*Corresponding author: Shengxian Liang lsx@xxmu.edu.cn Wenjie Ren 171001@xxmu.edu.cn
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No.  44DOI: 10.1186/s11658-026-00873-4 Volume 31 (2026) - 30:44
Title GUT MICROBIOTA-DERIVED TRIMETHYLAMINE N-OXIDE CONTRIBUTES TO CARDIOMYOCYTE PYROPTOSIS AND CARDIAC INJURY VIA THE tRF-Glu–ANT1–GSDMD axis
Authors Tao Wang1†, Weibin Ren1†, Xinzhe Chen2†, Xueyao Wang1, Miaomiao Liu1, Yanhui Zhang1, Zhaoshui Li3, Yanbo Wang1, Zhiqiang Song1 and Hongyan Diao1,4*
Abstract Aims: Recent research has shown that the gut microbiota arrests the progression of myocardial infarction (MI) by modulating immune inflammation, oxidative stress, and metabolism. However, the mechanism by which gut-derived trimethylamine N-oxide (TMAO) promotes cardiomyocyte pyroptosis following MI remains unclear.
Methods and results: We found that a high-choline diet exacerbated cardiac injury in mice by disrupting the intestinal barrier. Under high-choline conditions, the expression levels of tRF-1:31-Glu-TTC-2 (tRF-Glu) derived from tRF and tiRNAs (tsRNAs) were elevated, serving as a key target for intervention in cardiomyocyte pyroptosis. Loss of tRF-Glu significantly ameliorated TMAO-induced deterioration of myocardial fibrosis and cardiac function. Mechanistically, tRF-Glu directly binds to the mitochondrial inner membrane protein ANT1 and stabilizes its expression by inhibiting ubiquitination. Cardiomyocyte knockdown of ANT1 significantly blocked the generation of TMAO-induced cardiomyocyte mitochondrial reactive oxygen species, restored cardiomyocyte membrane potential, and reduced mitochondrial DNA (mtDNA) leakage.
Conclusions: Our findings indicate that tRF-Glu inhibits the ubiquitination of ANT1 under the induction of TMAO, which in turn activates gasdermin D (GSDMD) and mtDNA release, accelerating cardiac remodeling. In conclusion, our study provides new insights into the role of the gut microbial metabolite-driven tRF-Glu–ANT1–GSDMD pathway in blocking cardiomyocyte pyroptosis and cardiac injury.
Keywords Trimethylamine N-oxide (TMAO), tRF-1:31-Glu-TTC-2 (tRF-Glu), ANT1, Mitochondrial DNA, Cardiomyocyte pyroptosis
Address and Contact Information 1 Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China
2 Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266021, China
3 Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwu Road, Jinan 250021, Shandong, China
4 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
*Correspondence: Hongyan Diao diao.hy@163.com
† Tao Wang, Weibin Ren and Xinzhe Chen have contributed equally to this work.
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No.  45DOI: 10.1186/s11658-026-00872-5 Volume 31 (2026) - 30:45
Title GENE EXPRESSION REGULATION BY Ca2+ SIGNALING: AN UPDATED SYSTEMATIC REVIEW
Authors Meng Zou1, Hongyu Wang1, Xuhui Zeng1,2* and Xiaoning Zhang1*
Abstract All life processes depend on the precise spatiotemporal expression of genes, which involves orderly processes including transcription, posttranscriptional processing, translation, and posttranslational modification. Accumulating evidence demonstrates that Ca2+ is the most critical second messenger that orchestrates nearly all fundamental biological processes vital for maintaining normal physiological functions. Ca2+ homeostasis/signaling is primarily maintained through Ca2+ influx, cytoplasmic Ca2+ release, Ca2+ store cycling, and binding and release of Ca2+ buffers. Their coordinated interactions ensure that Ca2+ concentrations remain within the physiologically appropriate range. Ca2+ signaling must be appropriately activated or suppressed during cellular signal transduction to support specific functions, and its dysregulation can trigger various pathological conditions. This review summarizes recent progress in Ca2+ signaling regulatory networks, including the roles of key regulatory elements/toolkits, the functional significance of Ca2+ signals in different microdomains, and the influence of Ca2+ signaling on gene expression, along with the underlying mechanisms at various stages of gene expression. The involvement of Ca2+, both independently and collaboratively, in the nucleus, cytoplasm, subcellular microdomains such as mitochondria, and the extracellular space, in the multi-level regulation of gene expression, has been extensively studied. This information is essential for understanding the mechanisms underlying gene expression and for advancing the diagnosis and treatment of diseases. Finally, we propose forward-looking recommendations to address current research gaps, aiming to provide valuable references for researchers in this field.
Keywords Ca2+ signaling, Ca2+ homeostasis, Gene expression, Transcription, Translation, Posttranslation modification, Ca2+-dependent transcription factor
Address and Contact Information 1 Institute of Reproductive Medicine, Medical School, Nantong University, Nantong 226001, China
2 Jiangsu Province Key Laboratory in University for Inflammation and Molecular Drug Target, Nantong University, Nantong 226019, China
*Corresponding author: Xuhui Zeng zengxuhui@ntu.edu.cn Xiaoning Zhang zhangxn@ntu.edu.cn
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No.  46DOI: 10.1186/s11658-026-00876-1 Volume 31 (2026) - 30:46
Title PDIA6 PROMOTES THE CELL PROLIFERATION OF ESCC BY ENHANCING THE DISULFIDE BOND FORMATION IN TRAF4
Authors Yingying Chen1,2,3†, Weizhe Zhang1,2,3†, Yurong Chen1,2, Xiaoyu Li1,2, Yunshu Shi1,2, Qiang Yuan1,2, Ruixian Han1,2, Yuhan Zhang1,2, Xiaokun Zhao1,2, Yamei Hu2,3, Chenjuan Zhang7, Ziming Dong1,2,3,4, Mee-Hyun Lee5, Myoung Ok Kim6, Zigang Dong1,2,3,4, Yanan Jiang1,2,3,4* and Kangdong Liu1,2,3,4,7*
Abstract Background: Protein disulfide isomerase A6 (PDIA6), a member of the PDI family, catalyzes disulfide bond formation and assists protein folding. However, its function in esophageal squamous cell carcinoma (ESCC) remains largely unknown.
Methods: Functional experiments, including CRISPR/Cas9 knockout, overexpression, rescue assays, and patient-derived xenograft (PDX) models, were performed to evaluate the role of PDIA6 in ESCC proliferation and tumor growth. Pull down-mass spectrometry assays, co-immunoprecipitation, and protein-protein docking assays were used to investigate PDIA6–tumor necrosis factor receptor-associated factor 4 (TRAF4) interactions and disulfide bond formation. Ubiquitination and cycloheximide chase assays were applied to assess the stability of TRAF4. Antisense oligonucleotides (ASOs) targeting PDIA6 were tested for therapeutic efficacy in vitro and in vivo.
Results: We found PDIA6 was markedly upregulated in ESCC tissues, with a positive correlation to a poor prognosis. Functional assays demonstrated that PDIA6 significantly promoted the proliferation of ESCC cells both in vitro and in vivo. A pull down–mass spectrometry assay identified TRAF4 as a direct binding partner of PDIA6. Protein-protein docking revealed that PDIA6 interacted with the N-terminal (1-277) domain of TRAF4, enhancing disulfide bond formation at Cys39/Cys42 and Cys83/Cys106. These bonds were indispensable for TRAF4’s E3 ubiquitin ligase activity in facilitating the ubiquitination of AKT. PDIA6 further stabilized TRAF4 by competing with SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1), thereby preventing TRAF4 ubiquitination and proteasomal degradation. The absence of PDIA6 led to the destabilization of TRAF4, resulting in the inactivation of the AKT/mTOR pathway. Rescue experiments using TRAF4 C42A or C83A mutants failed to restore AKT signaling or tumor growth. Notably, ASOs targeting PDIA6 suppressed ESCC growth in vitro and in patient-derived xenografts.
Conclusions: PDIA6 drives ESCC progression by stabilizing TRAF4 and sustaining AKT/mTOR signaling. Targeting PDIA6 with ASOs offers a promising therapeutic strategy for ESCC.
Keywords PDIA6 drives ESCC progression by stabilizing TRAF4 and sustaining AKT/mTOR signaling. Targeting PDIA6 with ASOs offers a promising therapeutic strategy for ESCC.
Address and Contact Information 1 State Key Laboratory of Metabolic Dysregulation and the Prevention and Treatment of Esophageal Cancer, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China
2 Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou 450000, Henan, China
3 China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, Henan, China
4 Henan International Joint Laboratory of Cancer Chemoprevention, Zhengzhou University, Zhengzhou 450000, Henan, China
5 College of Korean Medicine, Dongshin University, Naju, Republic of Korea
6 Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Republic of Korea
7 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou 450000, Henan, China
*Corresponding author: Yanan Jiang yananjiang@zzu.edu.cn Kangdong Liu kdliu@zzu.edu.cn
† Yingying Chen and Weizhe Zhang have contributed equally to this work.
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No.  48DOI: 10.1186/s11658-026-00864-5 Volume 31 (2026) - 30:48
Title METTL3–m6A–STAT1/NF-κB AXIS: A KEY SWITCH FOR THE IMMUNOSUPPRESSIVE CAPACITY OF MESENCHYMAL STEM CELLS
Authors Keke Tang1,5†, Hong Han1,5†, Ruizheng Sun1,5, Yi Xu4,5, Shengdi Zhang1,3,5, Chen Lai2,4,5* and Yu Peng1,3,5*
Abstract Background: Owing to their immunosuppressive nature, mesenchymal stem cells (MSCs)—a type of multipotent stem cell—hold considerable promise for therapeutic applications. Functioning as the primary catalytic subunit of the RNA N6-methyladenosine (m6A) methyltransferase complex, methyltransferase-like 3 (METTL3) plays extensive roles in numerous biological processes. It is hypothesized that METTL3 participates in governing the immunomodulatory functions inherent to MSCs. However, the exact mechanisms governing METTL3’s control over MSCs’ immunosuppressive capacity are poorly defined.
Methods: MSCs extracted from bone marrow were transfected with lentivirus to knockdown or overexpress METTL3, while METTL3 enzyme activity was inhibited using the METTL3 inhibitor STM2457. In vitro co-culture assays and in vivo tumor models revealed that knocking down METTL3 or inhibiting its enzyme activity in MSCs weakened its inhibitory ability on T cells, while overexpressing METTL3 increased its inhibitory ability. in both concanavalin A (ConA)-induced liver injury and dextran sulfate sodium (DSS)-induced colitis models, the therapeutic benefits of MSCs against inflammatory diseases were shown to be dependent on METTL3
Results: Our findings establish METTL3 as a critical regulator of the immunosuppressive capacity of MSCs, mediated through inducible nitric oxide synthase (iNOS) expression. Mechanistic investigations revealed that METTL3 targets JAK1, STAT1, TAB1, and NFKB1 in an IGF2BP1/2-dependent fashion. This regulatory influence stems from METTL3’s ability to potentiate STAT1 and NF-κB signaling pathways. Supporting this, overexpression of METTL3 enhanced NF-κB and STAT1 activation, which consequently elevated iNOS expression.
Conclusions: METTL3 enhances MSC immunosuppression via the m6A–STAT1/NF-κB–iNOS axis, presenting a dual role: it potentiates therapeutic efficacy in inflammatory diseases but exacerbates tumor progression by impairing T-cell infiltration. Targeting METTL3 offers a strategy to optimize MSC-based therapies, though context-specific modulation is essential to balance benefits and risks.
Keywords Mesenchymal stem cells, METTL3, Immunosuppressive capacity, iNOS, Immunotherapy
Address and Contact Information 1 Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
2 Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
3 Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Changsha 410008, Hunan, China
4 Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
5 Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
*Corresponding author: Chen Lai 4011333@csu.edu.cn Yu Peng pengyu918@csu.edu.cn
† Keke Tang and Hong Han have contributed equally.
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No.  49DOI: 10.1186/s11658-026-00861-8 Volume 31 (2026) - 30:49
Title PSEUDOURIDINE SYNTHASES UPREGULATE 5′-tRF-Lys TO INHIBIT YPEL3 AND DRIVE MALIGNANT PROGRESSION IN NASOPHARYNGEAL CARCINOMA
Authors Daixi Ren1,2, Mei Yang1,2, Yongzhen Mo3, Qijia Yan3, Lei Shi4, Shanshan Zhang3, Zhaojian Gong4, Can Guo2, Ming Zhou1,2, Bo Xiang1,2,5, Ming Tan6, Guiyuan Li1,2, Pan Chen1,2,5*, Wei Xiong1,2,5* and Zhaoyang Zeng1,2,5*
Abstract Transfer RNA-derived fragments (tRFs) are a recently discovered class of short noncoding RNAs widely distributed in various tissues and cell types. They are involved in the regulation of gene expression and play important roles in both physiological and pathological processes, garnering growing attention. However, the functions and underlying mechanisms of most tRFs in tumorigenesis and progression remain largely unclear. Through small RNA sequencing of nasopharyngeal carcinoma (NPC) and adjacent tissues, we found that among the top 30 highly expressed tRFs in NPC tissues, 13 were derived from lysine tRNAs, forming the 5′-tRF-Lys cluster. This cluster was found to promote NPC cell proliferation, invasion, and migration. Mechanistically, 5′-tRF-Lys binds to the 3′-untranslated region (3′-UTR) of YPEL3 messenger RNA (mRNA), suppressing its expression and thereby activating the Hippo/YAP signaling pathway to drive tumor progression. The elevated expression of pseudouridine synthases PUS1 and PUS7 in NPC tissues catalyzes pseudouridine modification of tRNA-Lys, facilitating its cleavage into 5′-tRF-Lys and accounting for its upregulation. Notably, the PUS1-targeting small-molecule inhibitor mogroside IV-e effectively reversed malignant phenotypes in both in vitro and in vivo NPC models. This study uncovers a novel mechanism in which pseudouridine synthases PUS1 and PUS7 drive the biogenesis of the tRF-Lys cluster, promoting NPC malignancy by suppressing YPEL3 and activating the Hippo/YAP signaling pathway. These findings highlight the therapeutic potential of targeting pseudouridine synthases to reduce tRF-Lys production as a novel strategy for NPC treatment.
Keywords Pseudouridine synthase, TRF, YPEL3, Nasopharyngeal carcinoma, Hippo/YAP signaling pathway, Mogroside IV-e
Address and Contact Information 1 NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410078, Hunan, China
2 Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and Xiangya School of Basic Medicine Sciences, Central South University, Changsha 410078, Hunan, China
3 Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
4 Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
5 FuRong Laboratory, Changsha 410078, Hunan, China
6 Institute of Biochemistry and Molecular Biology, and Research Center for Cancer Biology, China Medical University, Taichung 406040, Taiwan
*Corresponding author: Pan Chen chenpan08@csu.edu.cn Wei Xiong xiongwei@csu.edu.cn Zhaoyang Zeng zengzhaoyang@csu.edu.cn
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No.  30DOI:10.1186/s11658-026-00877-0 Volume 31 (2026) - 30:30
Title CORRECTION: A FROG PEPTIDE PROVIDES NEW STRATEGIES FOR THE INTERVENTION AGAINST SKIN WOUND HEALING
Authors Chao Li3†, Zhe Fu1†, Tao Jin5†, Yixiang Liu2, Naixin Liu1, Saige Yin1, Zhuo Wang3, Yubing Huang3, Yinglei Wang1, Yingxuan Zhang1, Jiayi Li1, Yutong Wu1, Li He4*, Jing Tang3*, Ying Wang2* and Xinwang Yang1*
Abstract Correction: Cellular & Molecular Biology Letters (2023) 28:61

https://doi.org/10.1186/s11658-023-00468-3

In this article [1], the wrong figure appeared as Figs. 1, 3 and 5, S3, S5, S8, and S14; the correct figures should have appeared as shown below.
Keywords
Address and Contact Information 1 Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Yunnan 650500, Kunming, China
2 Key Laboratory of Chemistry in Ethnic Medicinal Resources & Key Laboratory of Natural Products Synthetic Biology of Ethnic Medicinal Endophytes, State Ethnic Affairs Commission & Ministry of Education, School of Ethnic Medicine, Yunnan Minzu University, Yunnan 650504, Kunming, China
3 Department of Biochemistry and Molecular Biology, Faculty of Basic Medical Science, Kunming Medical University, Yunnan 650500, Kunming, China
4 Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Yunnan 650032, Kunming, China
5 Department of Orthopedics, 920th Hospital of Joint Logistics Support Force of PLA, Yunnan 650032, Kunming, China
*Corresponding author: Li He drheli2662@126.com Jing Tang gracett916@163.com Ying Wang wangying_814@163.com Xinwang Yang yangxinwanghp@163.com; yangxinwang@kmmu.edu.cn
† Chao Li, Zhe Fu and Tao Jin contributed equally to this work.

The original article can be found online at https://doi.org/10.1186/s11658-023- 00468-3.
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No.  50DOI: 10.1186/s11658-026-00881-4 Volume 31 (2026) - 30:50
Title TOLL-LIKE RECEPTOR 2 DRIVES LIVER SENESCENCE AND FIBROSIS IN AGING THROUGH GUT-DERIVED MICROBIAL SIGNALING
Authors Annette Brandt1, Raphaela Staltner1, Anja Baumann1, Katharina Burger1, Julia Jelleschitz2, Patricia Oliveira Prada1, Annika Höhn2,3, Florian Kopp4, Jordi Mayneris-Perxachs5,6, José Manuel Fernández-Real7,8 and Ina Bergheim1*
Abstract Background: While the role of endotoxins from Gram-negative bacteria has been studied extensively, the contribution of Gram-positive bacterial components—particularly those activating toll-like receptor 2 (TLR2), such as lipoteichoic acid (LTA)—to liver aging, inflammation, and fibrosis remains poorly understood. Here, we investigated the role of TLR2 and its ligand LTA in liver aging by using murine models, in vitro experiments, and human samples from young and elderly individuals.
Methods: TLR2 ligands were evaluated in serum samples from young (aged 21–33 years) and elderly (aged 65–77 years) healthy individuals. Markers of liver damage, senescence, and inflammation were assessed in 4- and 20-month-old male C57BL/6 and TLR2 knockout (TLR2−/−) mice. In addition, 17-month-old male C57BL/6 mice were treated either with the TLR2 inhibitor ortho-vanillin (60 mg/kg BW in drinking water) or plain water for 4 months and markers as determined above were assessed. The presence of markers of senescence was measured in J774A.1 cells and human peripheral blood mononuclear cells stimulated with LTA.
Results: In humans and mice, aging was associated with significantly elevated circulating levels of TLR2 ligands. In aging mice, this was accompanied by increased hepatic Tlr2 mRNA expression. Strikingly, 20-month-old male TLR2−/− mice exhibited reduced markers of senescence (e.g., plasma plasminogen activator inhibitor-1 and liver p16 expression), inflammation (e.g., hepatic neutrophil infiltration, Il1b mRNA expression), and fibrosis (e.g., α-smooth muscle actin expression, Sirius Red staining), compared with age-matched wild-type controls. Similarly, in aged male C57BL/6 J mice showing first signs of impaired intestinal barrier function i.e., rising peripheral TLR2 ligand levels in plasma, treatment with the TLR2 inhibitor ortho-vanillin for 4 months attenuated the progression of liver aging as indicated by attenuated senescence, liver inflammation, and fibrosis. In vitro, stimulation of J774A.1 macrophages and human peripheral blood mononuclear cells with LTA induced the expression of senescence-associated genes p16 and p21.
Conclusions: Collectively, these findings suggest that increased translocation of TLR2 ligands and subsequent activation of TLR2-dependent pathways play a critical role in age-associated liver degeneration. Targeting TLR2 signaling may therefore represent a promising therapeutic approach to mitigate hepatic aging and associated pathologies.
Keywords Aging, Lipoteichoic acid, Hepatic inflammation, Fibrosis, TLR2, Senescence
Address and Contact Information 1 Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
2 German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
3 German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
4 Clinical Pharmacy Group, Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria
5 Integrative Systems Medicine and Biology Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Salt, Spain
6 CIBER Fisiopatología de La Obesidad y Nutrición (CIBERobn), Madrid, Spain
7 Department of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomèdica de Girona (IDIBGI), Girona, Spain
8 CIBERobn Fisiopatología de la Obesidad y Nutrición; and Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain
*Corresponding author: Ina Bergheim ina.bergheim@univie.ac.at
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No.  52DOI: 10.1186/s11658-026-00891-2 Volume 31 (2026) - 30:52
Title HIGH-FAT DIET LEADS TO MALE REPRODUCTIVE DYSFUNCTION BY DISRUPTING LIPID-DROPLET-MEDIATED ORGANELLE CROSSTALK
Authors Lu Sun1†, Ao Wang1†, Yi Zhang2†, Jinsi Chen3†, Peng Huang4, Kaixuan Zeng5, Shuai Huang5, Jiayu Huang1,6, Jin Luo2* and Jiancheng Wang1*
Abstract Background: The incidence of reproductive system disorders has been steadily rising in recent years. Moreover, with the rising standard of living, the incidence of metabolic diseases also has been gradually increasing. However, the connection and mechanisms linking reproductive and metabolic diseases are poorly defined.
Methods: For organelle connectivity analysis, we analyzed mitochondria–endoplasmic reticulum (ER) contacts (MERCs) gene expression using a published single-cell RNA sequencing data. The link between lipid droplets (LDs) and actin cytoskeleton was analyzed by mass-spectrometry-based proteomics. By flow-cytometry-based cell sorting coupled with transmission electron microscopy, we explored the LD-mediated mitochondria–endoplasmic reticulum contacts.
Results: We found decreased expression of numerous MERC-associated genes, along with a reduction in Leydig cells (LCs), in high-fat diet (HFD) mice. Mechanistically, LDs downregulated the expression of G-actin, leading to the separation of mitochondria from the ER. From a functional perspective, Firsocostat, a lipogenesis enzyme acetyl-CoA carboxylase (ACC) inhibitor, inhibited LD synthesis, which shortened the distance between mitochondria and the ER, improved their functions, and promoted testosterone synthesis. Finally, targeting the LDs offered a promising therapeutic strategy to improve LC function under high-fat conditions, thereby protecting testicular endocrine function.
Conclusions: HFD leads to reproductive dysfunction by disrupting lipid-droplet-mediated Mito–ER contacts.
Keywords Endocrine reproductive disorders, Testosterone, High-fat diet, Lipid droplets, Mitochondria-endoplasmic reticulum contacts
Address and Contact Information 1 Center of Scientific Research, Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-Sen University, ZhenYuan Road 628, Shenzhen 518107, Guangdong, China
2 Reproductive Medicine Center, Renmin Hospital of Wuhan University, JieFang Road 238, Wuhan 430060, Hubei, China
3 National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
4 Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, Guangdong, China
5 School of Medicine, Sun Yat-Sen University, Shenzhen 518107, Guangdong, China
6 Department of Urology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, Guangdong, China
*Corresponding author: Jin Luo lj8974@126.com Jiancheng Wang wangjch38@mail.sysu.edu.cn
† Lu Sun, Ao Wang, Yi Zhang, and Jinsi Chen have contributed equally to this work.
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No.  53DOI: 10.1186/s11658-026-00894-z Volume 31 (2026) - 30:53
Title OPTIMIZED GENETIC TRACERS FOR VIRAL MEDIATED NEURONAL PROJECTION MAPPING
Authors Jennifer N. Dulin1,2,3, Li Ye4, Teresa Grider1, Anael Rizzo1, Ephron S. Rosenzweig1, Janet Weber1, Charu Ramakrishnan5,6, Brian Hsueh5,6, Karl Deisseroth5,6, Mark H. Tuszynski1, Daniel Gibbs1 and Gunnar H. D. Poplawski1,7*
Abstract Mapping fine axonal projections with high sensitivity remains a major challenge in neuroanatomy. Here, we developed Codon Optimized Membrane Embedded Tracers (COMET), a family of genetically encoded, membrane-anchored fluorescent proteins optimized for adeno-associated virus (AAV) delivery. COMET tracers—based on codon-optimized SuperFolder GFP (gCOMET) and TdTomato (rCOMET) fused to an H-RAS CaaX prenylation motif—enable robust plasma membrane targeting and enhance fluorescent signal localization to fine-caliber axons. In vivo, COMET tracers significantly outperformed conventional soluble fluorophores and chemical tracers in detecting corticospinal tract (CST) projections, revealing previously underappreciated collateralization and fine arborizations. Following spinal cord injury, COMET provided superior sensitivity for detecting regenerating and sprouting axons compared with biotinylated dextran amine (BDA). Importantly, COMET tracers retained bright native fluorescence after tissue clearing by CLARITY, enabling volumetric imaging of long-range projections without antibody amplification. COMET expands the available toolkit for high-resolution connectomics and regeneration studies, offering a versatile platform for sensitive, scalable, and cell-type-specific neuronal tracing in intact and injured mammalian nervous systems.
Keywords Adeno-associated virus (AAV), Corticospinal tract (CST), COMET tracers, Membrane targeting, Fluorescent proteins, Axon regeneration, Neural progenitor grafts, Tissue clearing, CLARITY, Neuroanatomical tracing
Address and Contact Information 1 Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
2 Department of Biology, Texas A&M University, College Station, TX, USA
3 Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, USA
4 Present address: Department of Neuroscience and Dorris Neuroscience Center, Scripps Research, San Diego, CA, USA
5 Department of Bioengineering and Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
6 Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
7 Present address: Poplawski Laboratory, Cancer Science, Cleveland Clinic, Cleveland, OH, USA
*Corresponding author: Gunnar H. D. Poplawski poplawg@ccf.org
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No.  54DOI: 10.1186/s11658-026-00887-y Volume 31 (2026) - 30:54
Title THE SPATIOTEMPORAL DYNAMICS OF MAMS: MECHANISMS, PATHOLOGIES, AND THERAPEUTIC REWIRING
Authors Dongxue Xu1†, Yinye Huang1†, Xiaoyu Zhang1, Benzheng Liu1, Mingying Wang1, Yiming Li1* and Zhiyong Peng1,2,3*
Abstract Mitochondria-associated endoplasmic reticulum membranes (MAMs) constitute highly dynamic signaling hubs that coordinate a spatiotemporal network regulating calcium flux, lipid trafficking, and innate immune activation. Beyond functioning as physical organelle tethers, the plasticity of MAMs is essential for cellular resilience. Notably, maladaptive remodeling of these contacts, which presents a spatiotemporal paradox in that both pathological tightening and excessive dissociation can precipitate dysfunction, underlies the pathogenesis of diverse complex diseases, including neurodegeneration, cardiovascular failure, and kidney injury. In this review, we provide an integrated synthesis of the molecular architecture of MAMs and highlight the indispensable role of endoplasmic reticulum (ER)–mitochondria coupling in sustaining physiological homeostasis. We further dissect how MAM dysregulation operates as a central convergence point for metabolic stress and inflammatory signaling. Additionally, we summarize technological advances such as super-resolution imaging and multi-omics frameworks that increasingly resolve the structural and functional heterogeneity of MAMs. Importantly, emerging evidence indicates a therapeutic paradigm shift: several widely used clinical agents, including sodium-glucose cotransporter 2 (SGLT2) inhibitors and metformin, appear to exert their renoprotective and metabolic benefits by restoring or stabilizing MAM integrity. Together, these insights reposition MAMs not as passive structural bystanders but as actionable, high-value therapeutic targets for next-generation precision medicine and drug repurposing strategies.
Keywords Mitochondria-associated membranes, ER stress, Neurodegenerative disease, Cancer, Diabetes, Kidney disease, Therapeutics
Address and Contact Information 1 Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
2 Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
3 Department of Critical Care Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
*Corresponding author: Yiming Li lym-fly@whu.edu.cn Zhiyong Peng zn001590@whu.edu.cn
† Dongxue Xu and Yinye Huang have contributed equally to this work.
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No.  31DOI: 10.1186/s11658-026-00879-y Volume 31 (2026) - 30:31
Title HK2-DRIVEN HISTONE H3K18 LACTYLATION PROMOTES STROMAL CELL SENESCENCE AND DECIDUALIZATION DEFICIENCY IN URSA VIA CUX1-MEDIATED SASP FACTOR TRANSCRIPTION
Authors Xiaoxuan Zhao1,2, Yang Zhao3, Yuepeng Jiang4, Yiming Ma5, Jing Ma1, Hongli Zhao1* and Xiaoling Feng6*
Abstract Background: Unexplained recurrent spontaneous abortion (URSA) is characterized by defective endometrial stromal cell decidualization, with cellular senescence emerging as a key contributor. However, the metabolic–epigenetic mechanisms linking glycolysis to senescence-driven decidualization failure remain unclear. This study elucidates how hexokinase 2 (HK2)-mediated glycolytic reprogramming promotes histone lactylation-dependent stromal senescence and decidualization impairment in URSA.
Methods: We employed multi-omics profiling (RNA-seq, metabolomics, and CUT&Tag) of primary stromal cells from patients with URSA and controls to map the histone H3K18 lactylation (H3K18la)–cut-like homeobox 1 (CUX1)–senescence-associated secretory phenotype (SASP) axis. Subsequently, this axis was validated both in vitro decidualization models and URSA murine models.
Results: Decidual tissues from patients with URSA exhibited stromal cell senescence and impaired decidualization. Mechanistically, HK2-driven glycolysis elevated lactate production, which in turn promoted H3K18la at the CUX1 promoter. CUX1 then directly activated the transcription of key SASP factors, thereby propagating the senescence state. Critically, CUX1 depletion or glycolysis inhibition rescued these senescence and decidualization deficiency in vitro. Furthermore, CUX1 knockdown in the URSA murine model reduced stromal senescence and improved decidualization.
Conclusions: Our findings define a novel HK2–H3K18la–CUX1–SASP signaling axis that drives URSA pathogenesis by linking metabolic reprogramming with epigenetic regulation. This work highlights CUX1 as a potential therapeutic target for correcting decidualization deficiency in URSA.
Keywords Unexplained recurrent spontaneous abortion, Decidualization deficiency, Cell senescence, Histone lactylation, CUX1, SASP
Address and Contact Information 1 Department of Traditional Chinese Medicine (TCM) Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310007, China
2 Research Institute of Women’s Reproductive Health Zhejiang Chinese Medical University, Hangzhou 310007, China
3 The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
4 Zhejiang Chinese Medical University, Hangzhou 310053, China
5 Macau University of Science and Technology, Macau 999078, China
6 Department of Gynecology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150040, China
*Corresponding author: Hongli Zhao z6hl@163.com Xiaoling Feng fengxiaoling@hljucm.edu.cn
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No.  55DOI: 10.1186/s11658-026-00874-3 Volume 31 (2026) - 30:55
Title miR-223-3p IMPROVES MACROPHAGE POLARIZATION BALANCE AND MITOCHONDRIAL METABOLISM TO AMELIORATE UVEITIS BY ORCHESTRATING P65Lys310 ACETYLATION THROUGH RBPJ/HDAC1 AXIS
Authors Yuan Peng1†, Bin Liu1†, Shuqin Xu1, Ruyi Qu1, Ruixue Zhang1, Congling Wang1, Yunfeng Liu1, Huixia Wei2,3, Qingmei Tian2, Miao Zhang1, Hongsheng Bi2,3, Xuewei Yin2* and Dadong Guo3,4,5*
Abstract Background: Uveitis is an autoimmune disease characterized by iris, ciliary muscle, and choroid inflammation. miR-223-3p, an anti-inflammatory microRNA, can regulate the expression of inflammatory genes involved in the disease process. However, the role and potential mechanism of miR-223-3p against uveitis remain unclear.
Methods: STRING website prediction, molecular docking, and co-IP experiments were performed to verify whether there was an interaction between RBPJ-HDAC1, HDAC1-P65, and P65-ARG1. Based on ex vivo and in vivo experiments, we detected NF-κB P65lys310 acetylation, P65 nuclear translocation, and the level of M1/M2 macrophage polarization. In addition, we also determined the levels of mitochondrial pressure and calcium flux under different conditions. Regulation of NF-κB P65lys310 acetylation via the RBPJ/HDAC1 axis affects macrophage polarization and mitochondrial function.
Results: We first found reduced miR-223-3p expression, elevated RBPJ and total acetylation levels, and an imbalance in macrophage polarization in peripheral blood monocyte-derived macrophages from patients with uveitis. Co-IP experiments supported the interaction between RBPJ and HDAC1, and HDAC1, as a key deacetylase, could inhibit NF-κB P65lys310 acetylation. Notably, overactivation of NF-κB P65lys310 acetylation levels in uveitis leads to elevated polarization of M1 macrophages and mitochondrial dysfunction. miR-223-3p can attenuate NF-κB P65lys310 acetylation and P65 nuclear translocation levels through the RBPJ/HDAC1 axis in uveitis, effectively reducing pro-inflammatory macrophage levels and mitigating mitochondrial damage, thereby reducing ocular inflammation and positively regulating the intraocular microenvironment in uveitis.
Conclusion: miR-223-3p can inhibit P65lys310 acetylation and enhance mitochondrial function to improve M1/M2 macrophage polarization balance to ameliorate uveitis through RBPJ/HDAC1 axis.
Keywords Uveitis, miR-223-3p, Macrophage polarization, NF-κB P65lys310 acetylation, Mitochondria
Address and Contact Information 1 Shandong University of Traditional Chinese Medicine, No. 4655#, Daxue Road, Jinan 250355, China
2 Affiliated Eye Hospital of Shandong University of Traditional Chinese Medicine, No. 48, Yingxiongshan Road, Jinan 250002, Shandong, China
3 Shandong Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Therapy of Ocular Diseases, Jinan 250002, China
4 Medical College of Optometry and Ophthalmology, Shandong University of Traditional Chinese Medicine, Jinan 250002, China
5 Shandong Academy of Eye Disease Prevention and Therapy, No. 48#, Yingxiongshan Road, Jinan 250002, China
*Corresponding author: Xuewei Yin 854132981@qq.com Dadong Guo dadonggene@sdutcm.edu.cn
† Yuan Peng and Bin Liu contributed equally to this work and should be regarded as co-first authors.
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No.  56DOI: 10.1186/s11658-026-00870-7 Volume 31 (2026) - 30:56
Title THE miR-8/miR-200 FAMILY: FROM FUNCTIONAL DIVERSIFICATION TO TRANSLATIONAL APPLICATIONS
Authors Ximei Yuan1, Yiqing He1, Chen Wang1 and Yuejun Fu1*
Abstract The miR-8/miR-200 family is a phylogenetically ancient microRNA regulator conserved across bilaterian animals, originating as a single miR-8 isoform in invertebrates and expanding to miR-200a/b/c, miR-141, and miR-429 in vertebrates through gene duplication. This review summarizes the biogenesis, genealogical details, and regulatory roles of the miR-8/miR-200 family. Furthermore, it presents the first comprehensive analysis of its evolutionary trajectory from invertebrates to vertebrates, thereby establishing a foundational understanding that underscores its significant potential for translational applications. Phylogenetic analyses confirm its sequence conservation and lineage-specific distribution, indicating that miR-8 originated in Platyhelminthes, with subsequent isoforms emerging in chordates. Functionally, this family plays pleiotropic roles: in invertebrates, miR-8 regulates immune defense, reproduction, and biosynthesis; in vertebrates, miR-200 subtypes modulate stress responses, epithelial-mesenchymal transition (EMT), tumor suppression, and neurodevelopment via conserved pathways (e.g., Wnt, Notch, PI3K). Cross-species conservation underlies core functions in cell differentiation, apoptosis, and growth, while vertebrate-specific adaptations drive roles in cancer (e.g., targeting ZEB1 in metastasis) and metabolic diseases (e.g., diabetes via β-cell apoptosis). This work explores the translational potential of this family, including nucleic acid pesticides in agriculture (targeting insect miR-8) and diagnostic/therapeutic tools in medicine (miR-200 as cancer biomarkers). Key challenges remain in delivery specificity and addressing functional pleiotropy. Future research should elucidate regulatory networks in non-model species and refine targeted delivery systems for clinical and agricultural applications.
Keywords miR-8/miR-200 family, Biological function, Evolutionary analysis, Signal transduction pathway, Pest management, Molecular diagnosis, Disease treatment
Address and Contact Information 1 Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China
*Corresponding author: Yuejun Fu yjfu@sxu.edu.cn
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No.  57DOI: 10.1186/s11658-026-00857-4 Volume 31 (2026) - 30:57
Title REDUCED eccDNA CONTENT IN IDIOPATHIC ASTHENOZOOSPERMIA SPERM IS ASSOCIATED WITH COMPROMISED DNA REPAIR CAPACITY AND ELEVATED DNA DAMAGE
Authors Zilong Wang1,2†, Changze Song3†, Xiaoning Hong1†, Jiaying Yu1†, Zhen Xu3, Peng Han1,4, Chunxiao He1, Shuang Mao1, Zhenghao Li3, Huisheng Yuan3, Xinkun Wang3, Jiawen Zhai3, SenBao Tan3, Weiwen Fan5, Yuan Xu6, Tianzhi Zhang7, Zheng Yang7, Shengyun Lin8, Wenli Zhu8, Lei Huang8, Chengchao Chen9, Gang Zou9, Wenbin Chen10, Wei Lv11, Lars Bolund12, Lin Lin12, Yonglun Luo12, Feng Zhang13*, Fengbiao Mao14,15*, Jiang Li1* and Xi Xiang1*
Abstract Background: Despite representing approximately 30% of male infertility cases, idiopathic asthenozoospermia (iAZS) remains etiologically uncharacterized. Extrachromosomal circular DNA (eccDNA) is mobile and circular DNA outside of linear chromosomes. Although eccDNA has been identified in human sperm, its biogenesis and potential role in iAZS pathogenesis requires further study.
Methods: We enrolled 31 patients with idiopathic asthenozoospermia (iAZS) and 31 healthy controls (normozoospermia, NZS), collecting sperm samples with progressive motility (PR) ranging from 0.3% to 90.9%. Sperm eccDNAs were purified and characterized using Circle-seq. Outward PCR, Sanger sequencing, and Nanopore long-read sequencing were employed to investigate eccDNA biogenesis and its potential genomic effects. In addition, spermatozoa RNA sequencing (RNA-seq) and immunofluorescence staining were conducted to identify DNA repair-related candidate genes. A CRISPR/Cas9-mediated APLF knockout model was established to explore DNA repair mechanisms in eccDNA formation in vitro.
Results: Comprehensive analysis of eccDNAs derived from the sperm samples revealed a significant positive correlation between sperm motility and eccDNA abundance. Larger eccDNAs (≥ 3 kb) showed inverse associations with meiotic recombination rates and coding gene density, while smaller eccDNAs lacked these trends. Although eccDNA formation broadly aligned with transposable element (TE) densities, larger eccDNAs (≥ 3 kb) were negatively correlated with short interspersed nuclear elements (SINEs) (mainly Alu elements). Microhomology-mediated end joining (MMEJ) likely drove eccDNA biogenesis, as 58% of eccDNAs harbored 3 bp direct repeat (DR) pairs. Nanopore and variant analyses suggested eccDNAs may arise from genomic deletions and later reintegrate. Importantly, sperm motility and eccDNA abundance correlated positively with DNA repair capacity but negatively with DNA damage. Finally, we identified APLF, a downregulated DNA repair protein in low-motility sperm, as a key regulator of eccDNA formation in vitro.
Conclusions: These findings emphasize the potential interplay between genomic elements and sperm eccDNA formation, highlight that impaired DNA repair and elevated DNA damage level may be major causes of reduced sperm motility and pathogenesis of iAZS, and offer new insights into strategies for improving male fertility.
Keywords Extrachromosomal circular DNA, Idiopathic asthenozoospermia, Sperm motility, Male fertility, Transposable element, DNA repair
Address and Contact Information Scientific Research Center, Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, Guangdong, China
2 Department of Burns and Plastic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
3 Department of Andrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
4 Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
5 Department of Obstetrics and Gynecology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
6 Department of Medical Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
7 Diagnostic Pathology Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
8 School of Medicine, Sun Yat-sen University, Shenzhen 518107, China
9 MGI Tech Co., Ltd., Shenzhen 518000, China
10 VitaVitro Biotech Co., Ltd., Shenzhen 518118, China
11 Department of Urology & Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China
12 Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
13 Department of Breast Surgery, Breast Cancer Center, The Affiliated Taian City Central Hospital of Qingdao University, Taian 271000, China
14 Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
15 Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Beijing 100191, China
*Corresponding author: Feng Zhang zhangfenga885@163.com Fengbiao Mao fengbiaomao@bjmu.edu.cn Jiang Li lijiang29@mail.sysu.edu.cn Xi Xiang xiangx25@mail.sysu.edu.cn
† Zilong Wang, Changze Song, Xiaoning Hong and Jiaying Yu have contributed equally to this work.
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No.  58DOI: 10.1186/s11658-025-00852-1 Volume 31 (2026) - 30:58
Title GPA33 FORMS A DISTINCT DIAGNOSTIC TARGET CLASS TO CLAUDIN 18.2 IN OESOPHAGEAL ADENOCARCINOMA ENABLING THE DEVELOPMENT OF A NOVEL GPA33 ANTIBODY-BASED DETECTION PLATFORM
Authors Jack Brydon1†, Radovan Krejcir2†, Filip Zavadil-Kokas2, Ashita Singh2, Lenka Hernychova2, Skye Coleman1, Sofian Al Shboul3, Vaclav Hrabal2, Zuzana Kuncova2, Marcos Yébenes Mayordomo4, Łukasz Arcimowicz2, Kathryn L. Ball1, Monikaben Padariya4, Umesh Kalathiya4, Borivoj Vojtesek2,5*, Ted Hupp1,4* and J. R. O’Neill6,7*
Abstract Background: Oesophageal adenocarcinoma (OAC) is a cancer of high unmet clinical need. Because of tumour heterogeneity, it is likely that OAC will be stratified into several subtypes. Claudin 18.2 antibodies form emerging novel therapeutics in patients with a subtype of OAC. A large-scale proteogenomics screen in OAC identified glycoprotein A33 (GPA33) protein as a dominating cancer-specific target. We set out to determine whether GPA33 is distinct from or overlaps with Claudin 18.2 as a theranostic target in OAC.
Methods: A microarray from n = 106 patients, composed of cancer, normal squamous tissue, normal gastric tissue, and metastatic lymph nodes, was used to compare the expression of GPA33 and Claudin 18.2. A single-chain variable fragment (scFv)-phage display library was screened against recombinant GPA33 protein to isolate novel monoclonal antibodies. Next-generation complementarity-determining region 3 (CDR3) DNA sequencing (NGS) and enzyme-linked immunosorbent assay (ELISA) were both used to measure efficacy of antibody enrichment during biopanning.
Results: GPA33 exhibits superior tumour-specific expression compared with Claudin 18.2, the latter of which is expressed in normal gastric tissue. GPA33 and Claudin 18.2 exhibit statistically significant mutually exclusive expression in cancer tissue cores; 36% of cancers are GPA33+/Claudin 18.2−, whilst 22% are GPA33−/Claudin 18.2+. GPA33 therefore forms a novel target for theranostics in a significant number of patients. A monoclonal antibody (RSE-05) targeting GPA33 was isolated from a scFV-phage display library. The antibody required a di-sulphide bridge to maintain its epitope on the antigen. Epitope mapping was performed using di-sulphide bridge mutagenesis, peptide-phage display, and XL-MS. The dominant epitope resides in the V-type IgG domain of GPA33 at residues 27–29 and structural amino acids S17 and K65. This di-sulphide bridge-constrained epitope defines a novel monoclonal antibody binding interface. The RSE-05 monoclonal antibody can be adapted and used as a capture-sensor tool to measure GPA33 protein in liquid phase using a two-site sandwich ELISA format.
Conclusions: GPA33 exhibits elevated cancer-specific expression relative to Claudin 18.2, indicating that GPA33 can also form the basis for a cancer diagnostic. Claudin 18.2 and GPA33 generally exhibit mutually exclusive expression suggestive of two different OAC development pathways. Thus, GPA33 forms a novel target that captures the Claudin 18.2-negative patient class, and the monoclonal antibody we describe forms the basis for novel diagnostic and therapeutic tools for development in OAC.
Keywords scFV, Phage biopanning, Epitope mapping, Immunohistochemistry, Oesophageal adenocarcinoma
Address and Contact Information 1 Institute of Genetics and Cancer (IGC), University of Edinburgh, Edinburgh, UK
2 Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
3 Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan
4 International Center for Cancer Vaccine Science (ICCVS), University of Gdansk, Gdansk, Poland
5 Laboratory of Growth Regulators, Institute of Experimental Botany, The Czech Academy of Sciences, Olomouc, Czech Republic
6 Cambridge Oesophagogastric Centre, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK
7 Department of Surgery, University of Cambridge, Cambridge, UK
*Corresponding author: Borivoj Vojtesek vojtesek@mou.cz Ted Hupp ted.hupp@ed.ac.uk J. R. O’Neill robertoneill@nhs.net
† Jack Brydon and Radovan Krejcir are joint first authors.
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No.  59DOI: 10.1186/s11658-026-00896-x Volume 31 (2026) - 30:59
Title LncRNA MEG3 REGULATES THE DEVELOPMENT OF PORCINE SKELETAL MUSCLE SATELLITE CELLS BY ENHANCING HMGA1 STABILITY
Authors Quan Liu1, Honghong Zhou1, Chong Fu1, Su Xie1, Mengxun Li1 and Changchun Li1*
Abstract Background: Porcine skeletal muscle satellite cells (PSCs) are the core stem cell population for the development of porcine skeletal muscle. In postnatal piglets, PSCs can differentiate into myoblasts and fuse with existing muscle fibers, increasing muscle fiber volume. While the long noncoding RNA MEG3 (MEG3) has been shown to modulate PSC development, its mechanisms remain nebulous. Here, we aim to explore the mechanism whereby MEG3 modulates PSC development.
Methods: Core interaction regions between MEG3 and CDC23 were detected using truncated constructs combined with RNA pull-down and RNA immunoprecipitation (RIP). Potential CDC23 target proteins were analyzed using coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC). The potential mechanism of MEG3 modulation was then further explored by employing MG-132 and cycloheximide (CHX) treatment and ubiquitination assays. Finally, downstream signaling pathways associated with MEG3 were detected by transcriptome sequencing (RNA-seq) and western blot analysis.
Results: The 787–839 nt region of MEG3 and the 464–594aa region of CDC23 are necessary for binding, with MEG3 (Δ787–839 nt) showing a reduced inhibitory effect on proliferation and promoting effect on differentiation. Furthermore, CDC23 promotes HMGA1 ubiquitination via a K48 linkage at the K7 site, significantly shortening its half-life. MEG3 competitively binds CDC23, enhancing HMGA1 stability and protecting it from proteasome degradation. Functional detection and transcriptome sequencing further clarified that MEG3 acts through HMGA1-mediate inhibition of proliferation and promotion of differentiation. Furthermore, MEG3 knockdown, and subsequent HMGA1 downregulation, mediates the activation of ERK signaling, thereby promoting PSC proliferation and inhibiting differentiation.
Conclusions: This study demonstrates a novel mechanism of MEG3 regulation in PSC development, implicates potential genetic targets, and provides a theoretical basis for accelerated porcine skeletal muscle development.
Keywords MEG3, Ubiquitination, Porcine skeletal muscle satellite cells, Proliferation, Differentiation
Address and Contact Information 1 Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture, Huazhong Agricultural University, Wuhan 430070, Hubei, People’s Republic of China
*Corresponding author: Changchun Li lichangchun@mail.hzau.edu.cn
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No.  60DOI: 10.1186/s11658-026-00888-x Volume 31 (2026) - 30:60
Title mTORC1 AS A METABOLIC RHEOSTAT COORDINATES HORMONAL SIGNALS AND CELLULAR PROLIFERATION TO SUSTAIN ENDOMETRIAL COMPETENCE
Authors Yadong Sun1,2,3†, Shuo Wan4†, Mingyue Zhao1,2,3†, Kexin Chen5,6†, Yue Wu1, Yong Huang1, Jun He7, Feng Liu1,2,3, Hanlin Shuai1*, Jiacong Yan5,6* and Meixiang Yang1,2,3,7*
Abstract Background: Optimal endometrial thickness and receptivity, precisely regulated by steroid hormones, are critical determinants for successful embryo implantation. Thin endometrium is a major cause of female infertility, yet its pathogenesis requires further exploration. Cellular proliferation and differentiation are highly dependent on the activation status of intracellular metabolic signaling pathways, among which the mammalian target of rapamycin (mTOR) signaling pathway serves as a central metabolic integrator. However, the mechanistic links between mTOR dysregulation, metabolic reprogramming, and endometrial regenerative failure remain poorly understood, representing a critical knowledge gap in reproductive medicine.
Methods: Uterine-specific Raptor knockout mice (Rptorfl/flPgrcre/+) were generated using the Cre-LoxP system. Endometrial pathology was assessed through multi-dimensional analyses: (1) hematoxylin–eosin staining, immunofluorescence, and T2-weighted magnetic resonance imaging were used to quantify endometrial dimensions, glandular development, and vascularization; (2) Functional competence was evaluated via the Pollard experiment and artificial decidualization models to assess receptivity and decidualization; (3) Molecular mechanisms were dissected using high-throughput RNA sequencing and flow cytometry to profile mTORC1-mediated cholesterol synthesis signaling, endometrial renewal, and cell cycle progression.
Results: Rptorfl/flPgrcre/+ mice recapitulated key features of thin endometrium syndrome, exhibiting significantly reduced endometrial thickness, impaired glandular development, and defective vascularization. Despite having comparable estrogen and progesterone levels, these mice displayed profound endometrial receptivity defects and impaired decidual response. Raptor deficiency attenuated cell proliferation by disrupting lipid metabolism pathways, consequently impairing estrogen responsiveness and diminishing uterine regenerative capacity.
Conclusions: Our study establishes that mTORC1 signaling orchestrates hormone-responsive endometrial proliferation through metabolic regulation, fundamentally underpinning endometrial receptivity and decidualization. These findings provide mechanistic insights into the pathogenesis of thin endometrium and highlight potential therapeutic targets for infertility treatment.
Keywords Thin endometrium, mTORC1 signaling, Cholesterol biosynthesis, Endometrial proliferation and differentiation
Address and Contact Information 1 The Fifth Affiliated Hospital (Heyuan Shenhe People’s Hospital), Jinan University, Heyuan 517000, China
2 The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China
3 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Health Science Center (School of Medicine), The Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China
4 Key Laboratory of Regenerative Medicine of the Ministry of Education, International Joint Laboratory for Embryonic Development and Prenatal Medicine, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632, China
5 Department of Reproductive Medicine, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, First People’s Hospital of Yunnan Province, Kunming 650500, China
6 KUST-YPFPH Reproductive Medicine Joint Research Center, Kunming 650500, China
7 Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control (Jinan University). Guangzhou Key Laboratory for Germ-Free Animals and Microbiota Application, Institute of Laboratory Animal Science. School of Medicine, Jinan University. Guangzhou, Guangzhou 510632, China
*Corresponding author: Hanlin Shuai piaoshuai2003@126.com Jiacong Yan yan_jiacong@kust.edu.cn Meixiang Yang mxyang@jnu.edu.cn
† Yadong Sun, Shuo Wan, Mingyue Zhao and Kexin Chen have contributed equally to this work.
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No.  61DOI: 10.1186/s11658-026-00889-w Volume 31 (2026) - 30:61
Title PERSISTENT PI3K–AKT SIGNALING FORTIFIES CELLULAR DEFENSE AGAINST OXIDATIVE STRESS AND FERROPTOSIS THROUGH AUGMENTED MITOCHONDRIAL FITNESS
Authors Xin Xie1*, Shanshan Wang2, Wentao Zeng1, Xiaohang Long3, Daheng Zheng1, Jianping Ye1, Rachid Rezgui4 and Pu-Ste Liu5*
Abstract Background: Chronic oxidative stress is recognized as a hallmark of cancer and represents a potentially targetable vulnerability in malignant cells. Oncogenic mutations in phosphatidylinositol 3-kinase (PI3K) are frequently observed across diverse malignancies, playing a crucial role in cancer progression. However, the relationship between PI3K–AKT signaling, mitochondrial fitness, and ferroptosis resistance remains poorly understood.
Methods: We compared the sensitivity of MCF-7 cells (harboring oncogenic PI3K activation) and MDA-MB-231 cells with oxidative stress and ferroptosis inducers using high-content imaging analysis and flow cytometry. RNA-sequencing was performed to identify transcriptomic changes following PI3K inhibition. Mitochondrial fitness was assessed by measuring mitochondrial mass, membrane potential, ATP production, and glutathione levels. Functional validation was conducted through pharmacological manipulation using PI3K–AKT–mTOR pathway inhibitors and AKT activators, as well as genetic approaches involving ectopic expression of oncogenic PIK3CA-E542K in HeLa cells.
Results: Cancer cells with constitutive PI3K activation exhibited high resistance to oxidative stress and ferroptosis compared with cells without oncogenic PI3K mutations. Mechanistically, PI3K–AKT signaling orchestrated an augmented mitochondrial gene program, enhancing mitochondrial fitness and antioxidant capacity. Inhibition of the PI3K–AKT–mTOR pathway selectively increased reactive oxygen species levels, compromised mitochondrial fitness, induced mitophagy, and sensitized cells with oncogenic PI3K activation to ferroptosis. Conversely, ectopic expression of oncogenic PIK3CA or pharmacological activation of AKT conferred resistance to oxidative stress and ferroptosis in a mitochondria-dependent manner, as evidenced by the abrogation of protective effects upon mitochondrial uncoupling.
Conclusions: Our findings establish a novel link between enhanced mitochondrial fitness and ferroptosis resistance in cancer cells with hyperactive PI3K signaling. These results suggest that combining ferroptosis induction with PI3K inhibition and mitochondrial fitness impairment may offer a promising therapeutic strategy for cancers harboring oncogenic PI3K mutations. This approach provides new insights into potential treatment modalities that exploit the interplay between oncogenic signaling pathways and cellular redox homeostasis in cancer cells.
Keywords Oncogenic, PI3K–AKT signaling, Ferroptosis resistance, Mitochondrial fitness, Oxidative stress
Address and Contact Information 1 School of Life and Environmental Sciences, Shaoxing University, Shaoxing, Zhejiang, China
2 School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
3 School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
4 Core Technology Platform, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
5 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
*Corresponding author: Xin Xie 2022000032@usx.edu.cn Pu-Ste Liu z11302014@ncku.edu.tw
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No.  62DOI: https://link.springer.com/article/10.1186/s11658-026-00884-1 Volume 31 (2026) - 30:62
Title POST-TRANSLATIONAL MODIFICATIONS OF SELECTIVE AUTOPHAGY RECEPTORS: ORCHESTRATING CELLULAR HOMEOSTASIS, DISEASE PATHOGENESIS, AND THERAPEUTIC OPPORTUNITIES
Authors Wenyun Zhu1, Xiaohui Wang1, Qing Li2, Xiaogang Jiang1* and Guoqiang Xu1,2,3,4,5*
Abstract Selective autophagy, an evolutionarily conserved quality control process, preserves cellular homeostasis by degrading specific substrates or organelles. Autophagy receptors, which precisely recognize and target substrates through sophisticated molecular mechanisms, are central to this pathway. These receptors orchestrate diverse biological functions ranging from DNA damage response, protein degradation, proteostasis, neuronal health, to immune modulation. Increasing evidence suggests that posttranslational modifications (PTMs) critically regulate the biological functions of autophagy receptors, forming a complex regulatory network that remains incompletely characterized in disease pathogenesis. This review first summarizes current knowledge of mammalian autophagy, including the principal molecular machinery across diverse pathways. We then categorize autophagy receptors on the basis of cargo specificity, and highlight PTM-mediated regulatory mechanisms. Furthermore, we explore their pathophysiological roles and assess their therapeutic potential by integrating recent advances. Finally, we discuss emerging perspectives in the autophagy research field, especially for the discovery of pathology-associated PTMs that modulate the functions of autophagy receptors. A deeper understanding of autophagic regulation and its pathophysiological significance will advance innovative therapeutic strategies targeting diseases associated with autophagy dysfunction.
Keywords Autophagy receptor, Posttranslational modification, Selective autophagy, Proteostasis, Disease pathogenesis
Address and Contact Information 1 Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, The Fourth Affiliated Hospital of Soochow University, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-Communicable Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, 199 Ren’ai Road, Suzhou 215123, Jiangsu, China
2 Suzhou Key Laboratory of Geriatric Neurological Disorders, Department of Gastroenterology, The First People’s Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou 215400, Jiangsu, China
3 Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China
4 MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, Jiangsu, China
5 Biomedical Basic Research Center (BBRC) of Jiangsu Province, Jiangsu, China
*Corresponding author: Xiaogang Jiang jiangxiaogang@suda.edu.cn Guoqiang Xu gux2002@suda.edu.cn
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No.  63DOI:10.1186/s11658-026-00883-2 Volume 31 (2026) - 30:63
Title ENDOTHELIAL Ffar4 PROTECTS AGAINST DIABETIC KIDNEY DISEASE BY POTENTIATING ENDOGENOUS RETINOIC ACID METABOLISM
Authors Jiayu Li1,2†, Siyuan Cui1,5†, Wei Wang1,6†, Tingting Zhang2,7, Zhe Wang1, Xianlong Ye3, Yong Q. Chen1,2,4* and Shenglong Zhu1*
Abstract Background: Diabetic kidney disease (DKD) occurs in up to 40% of individuals with diabetes and remains the primary cause of kidney failure worldwide, and a complex interaction of genetic and environmental dietary factors may be involved. Free fatty acid receptor 4 (Ffar4) may serve as a link between the genetic and dietary aspects of DKD progression; however, its role in DKD remains unclear.
Methods: Ffar4-mediated DKD protection was evaluated using comprehensive genetic models. In addition, the effects of Ffar4 on glomerular inflammation and endothelial injury in mice were evaluated in vivo and in vitro, and the regulation of the Aldh1a1 gene by Ffar4 to maintain endogenous retinoic acid (RA) metabolic balance and related signaling pathways in the glomeruli was investigated.
Results: We found that Ffar4 expression was decreased in diabetes and was associated with renal complications. Conventional and endothelial-specific Ffar4 knockout exacerbated DKD, whereas endothelial-specific Ffar4 overexpression improved renal function. Mechanistically, Ffar4 regulated endogenous RA metabolism in the glomeruli through the Atf4–Aldh1a1 pathway. RA supplementation partially reversed DKD progression in endothelial-specific Ffar4 knockout mice.
Conclusions: Taken together, these findings revealed a novel role of Ffar4 in potentiating endogenous RA production and delaying the progression of DKD-related multi-dysfunction.
Keywords Ffar4, Endothelial cells, Diabetes kidney disease, Retinoic acid, Aldh1a1
Address and Contact Information 1 Wuxi School of Medicine, Jiangnan University, Wuxi 214122, Jiangsu, China
2 School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu, China
3 Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, Jiangxi, China
4 Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Ministry of Education, Wuxi 214122, Jiangsu, China
5 Endocrinology Department, Wuxi People’s Hospital, Wuxi 214122, Jiangsu, China
6 The Second Clinical Medical School, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
7 State Key Laboratory of Natural Medicines, School of Engineering, China Pharmaceutical University, Nanjing 211198, China
*Corresponding author: Yong Q. Chen yqc_lab@126.com Shenglong Zhu shenglongzhu@jiangnan.edu.cn
† Jiayu Li, Siyuan Cui and Wei Wang contributed equally.
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No.  51DOI: 10.1186/s11658-026-00899-8 Volume 31 (2026) - 30:51
Title DICHOTOMOUS SMAD2/3 REGULATION AND SELECTIVE ANTIHYPERTROPHIC ACTIVITY OF HEPARIN DURING IN VITRO CHONDROGENESIS OF MESENCHYMAL STROMAL CELLS
Authors Sven Schmidt1, Safak Chasan1, Helen F. Dietmar1, Felicia A. M. Klampfleuthner1, Eliane Hesse1, Tilman Walker2, Uwe Freudenberg3, Wiltrud Richter1 and Solvig Diederichs1*
Abstract Background: Endochondral instead of chondral differentiation hinders mesenchymal stromal cell (MSC) application for clinical cartilage regeneration. We previously showed that heparin–polyethylene glycol (PEG) hydrogels loaded with transforming growth factor TGF-β instructed stable chondral MSC development in vivo. Here, we assessed this approach in vitro, utilizing heparin–PEG hydrogels or the pellet culture system with soluble heparin supplementation of chondrogenic medium.
Methods: Human MSCs were cultured in heparin–PEG hydrogels (22.4 mg/mL crosslinked heparin, 120 ng TGF-β1) or as pellet cultures treated with soluble heparin (0, 10, 100, 700 μg/mL) in TGF-β1-containing (10 ng/mL) chondrogenic medium. Chondral and endochondral signaling (1–3 h, 4 weeks) and cartilage matrix formation (4 weeks) were analyzed using western blot, histology, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and enzyme activity.
Results: Unlike in vivo, human MSCs differentiated in heparin–PEG hydrogels into type X collagen and alkaline phosphatase-positive hypertrophic chondrocytes in vitro. Interestingly, treating MSC pellets with soluble heparin (10–700 µg/mL) revealed reduced TGF-β-SMAD3 but not SMAD2 activation at unaffected type II collagen and proteoglycan/DNA levels. We propose that the stimulation of the insulin-AKT pathway by heparin aided in maintaining SMAD2 activation, which apparently plays a more prominent role than SMAD3 for MSC chondrogenesis. Heparin treatment inhibited the pro-hypertrophic WNT/β-catenin pathway in vitro but insufficiently silenced TGF-β-SMAD1/5/9 activation and unfortunately reduced antihypertrophic prostaglandin PGE2 levels. Ultimately, treatment with 10 µg/mL heparin reduced the upregulation of several hypertrophy markers (MEF2C, IHH, IBSP messenger RNAs [mRNAs], alkaline phosphatase activity) below control levels, but type X collagen remained unresponsive. Thus, soluble heparin treatment was similarly selective and effective as previous antihypertrophic interventions (PTHrP pulses, WNT inhibition), while offering technical simplicity, reduced cost, and solvent-free formulation.
Conclusions: Taken together, heparin-TGF-β showed a novel dichotomous SMAD2/3 inhibition at maintained chondrogenic differentiation and context-dependent lineage-instructive properties—permitting endochondral commitment in vitro but chondral development in vivo. Thus, environmental contributions are mandatory to allow heparin–PEG-guided chondral versus endochondral lineage commitment of MSCs in vivo, potentially involving SMAD1/5/9 suppressors and PGE2 sources.
Keywords Heparin, Heparan sulfate, Endochondral development, Chondrocyte hypertrophy, TGF-β, WNT/β-catenin, SMAD, AKT, Prostaglandin, Stem cells
Address and Contact Information 1 Experimental Orthopaedics, Research Centre for Molecular and Regenerative Orthopaedics, Department for Orthopaedics, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany
2 Department for Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
3 Leibniz Institute of Polymer Research Dresden (IPF), Max Bergmann Centre of Biomaterials Dresden (MBC), Centre for Regenerative Therapies Dresden (CRTD), Dresden University of Technology, Dresden, Germany
*Corresponding author: Solvig Diederichs solvig.diederichs@med.uni-heidelberg.de
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No.  65DOI: 10.1186/s11658-026-00902-2 Volume 31 (2026) - 30:65
Title STUB1 DOWNREGULATES TOP2A THROUGH A DUAL MECHANISM OF UBIQUITINATION AND FOXM1-MEDIATED TRANSCRIPTION REPRESSION, SUPPRESSING BREAST CANCER GROWTH AND ENHANCING SENSITIVITY TO CHEMOTHERAPY
Authors Baohui Yue1, Qiaoling Xiang1, Huimin Qiu1, Mingxiang Huang1, Mengxin Qi1, Xianglan Yi1, Sheng Zhou1* and Jing Xiong1*
Abstract Background: DNA topoisomerase IIɑ (TOP2A) is crucial for maintaining genomic stability and is an important target for genotoxic chemotherapeutic drugs. STIP1 homology and U-box-containing protein 1 (STUB1) is a U-box containing E3 ubiquitin ligase that participates in the degradation of specific oncogenic proteins. This research examined the potential regulatory function of STUB1 in relation to TOP2A, and explored its functional implications.
Methods: To identify interactions between STUB1 and TOP2A, coimmunoprecipitation, Glutathione S-transferases (GST) pull-down, and immunofluorescence assays were performed. Cycloheximide (CHX) pulse-chase assay, in vivo and in vitro ubiquitination, quantitative RT-PCR, chromatin immunoprecipitation (CHIP), and luciferase assays were performed to determine how STUB1 interacts with TOP2A. In addition, TOP2A catalytic activity, colony formation, WST-1, and flow cytometry assays were performed and a xenograft model was further developed to explore whether STUB1 could downregulate the catalytic activity of TOP2A, reduce the growth of breast cancer, and increase its sensitivity to doxorubicin. Moreover, immunohistochemical staining was conducted to assess STUB1 and TOP2A expression levels, as well as their predictive roles in the efficacy of neoadjuvant chemotherapy in individuals diagnosed with breast cancer.
Results: STUB1 enhanced TOP2A translocation to the cytoplasm, downregulating its expression through increased ubiquitination and degradation. Forkhead box M1 (FOXM1), another substrate of STUB1, served as a transcription factor for TOP2A, playing a role in STUB1-mediated downregulation of TOP2A at the transcriptional level. STUB1 inhibited TOP2A’s activity, reduced cancer cell proliferation, increased doxorubicin-induced apoptosis, and promoted cell cycle arrest. In a breast cancer xenograft model, STUB1 suppressed tumor growth and improved doxorubicin sensitivity. A positive correlation between FOXM1 and TOP2A expression was found in patients with breast cancer undergoing EC-T chemotherapy, both negatively correlated with STUB1, whose higher expression levels were linked to increased pathologic complete response (pCR) rates. STUB1 was evaluated as an independent predictor of pCR through univariate and multivariate analyses.
Conclusions: This study proposes a novel function of STUB1 in the downregulation of TOP2A, which directly enhances sensitivity to chemotherapy.
Keywords Breast cancer, Chemosensitivity, STUB1, TOP2A, FOXM1
Address and Contact Information 1 Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
*Corresponding author: Sheng Zhou zhou71@163.com Jing Xiong xiongjingtj@126.com
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No.  66DOI: 10.1186/s11658-025-00850-3 Volume 31 (2026) - 30:66
Title COMBINATION OF TRIPTERYGIUM GLYCOSIDES AND Lactobacillus paracasei SENSITISES EPITHELIAL OVARIAN CANCER TO CISPLATIN VIA DOWNREGULATING Keap1-Nrf2-GPX4 sIGNALLING PATHWAY
Authors Meiyun Tian1,5, Xiangdi Zeng2, Yanying Zhong1, Bo Ma4, Ying Feng1, Xiaoyun Wu1, Yajie Liao2, Yunyun Xu1, Tingtao Chen1,2,3* and Buzhen Tan1*
Abstract Background: Epithelial ovarian cancer (EOC) is a highly heterogeneous malignancy with significant morbidity and mortality, and cisplatin (DDP) resistance remains a major obstacle in its treatment. Previous studies suggest that Tripterygium glycosides (TG), derived from Tripterygium wilfordii, may enhance EOC chemo-sensitivity to DDP, potentially involving gut microbiota, though the underlying mechanisms remain to be fully elucidated.
Purpose: This study sought to determine how TG enhanced chemotherapy sensitivity in EOC and to examine the involvement of gut microbiota in this process.
Study design: Experimental research in vivo models was conducted, including fecal microbiota transplantation (FMT) from healthy controls and validation assays with Lactobacillus paracasei.
Methods: TG were administered alone or combined with FMT to evaluate their impact on DDP sensitivity in EOC. Mechanistic studies focused on the Keap1–Nrf2–GPX4 signalling pathway and ferroptosis induction. L. paracasei was co-administered with TG to assess synergistic effects, while Nrf2 pathway activation was tested to confirm its regulatory role.
Results: TG significantly enhanced DDP sensitivity in EOC, either alone or synergistically with FMT. Mechanistically, TG inhibited the Keap1–Nrf2–GPX4 axis, inducing tumor ferroptosis. Gut microbiota, particularly the probiotic Lactobacillus, contributed to this effect: L. paracasei combined with TG amplified DDP cytotoxicity in EOC cells. Conversely, Nrf2 pathway activation attenuated the synergistic effect.
Conclusion: TG sensitises EOC to DDP by suppressing the Keap1–Nrf2–GPX4 pathway to trigger ferroptosis, with gut microbiota (e.g., L. paracasei) playing a synergistic role. Combining TG and probiotics may offer a promising and innovative method to improve chemotherapy efficacy in EOC, offering a foundation for future therapeutic development.
Keywords Epithelial ovarian cancer, Tripterygium glycosides, Gut microbiota, Lactobacillus paracasei, Ferroptosis
Address and Contact Information 1 Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
2 National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
3 Jiangxi Province Key Laboratory of Bioengineering Drugs, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
4 Department of Neurosurgery, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
5 Department of Obstetrics and Gynecology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
*Corresponding author: Tingtao Chen chentingtao1984@163.com Buzhen Tan tanbuzhen@sina.com
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No.  67DOI: 10.1186/s11658-026-00893-0 Volume 31 (2026) - 30:67
Title INTERMITTENT FASTING INHIBITS FERROPTOSIS BY MODULATING CD36 AND ITS PALMITOYLATION TO ALLEVIATE DIABETIC DRY EYE
Authors Wenhui Wang1†, Jianwen Xue1†, Bing Xiao1, Xiaobing Qian1, Jing Li1, Xingyan Lin1, Ziyan Chen1*, Wei Wang2,3* and Lingyi Liang1*
Abstract Background: Excessive lipid accumulation in the lacrimal glands under diabetic conditions can lead to lacrimal gland dysfunction and reduced tear secretion, subsequently resulting in ocular surface inflammation, dry eye syndrome, and corneal vulnerability, ultimately compromising the patient’s quality of life. There are limited and easily implemented intervention strategies to reduce excessive lipid accumulation. While intermittent fasting (IF) has emerged as a promising metabolic intervention, its mechanistic underpinnings and therapeutic potential in diabetes-associated lacrimal gland disorders require systematic elucidation.
Methods: Diabetic mice were divided into three groups for an 8-week dietary intervention: ad libitum, meal feeding, and every-other-day feeding. After dietary intervention, we assessed the damage to lacrimal glands and ocular surface, and elucidated lipid accumulation, ferroptosis, and functional changes in the lacrimal glands. Transcriptomic analysis was used to examine gene expression. CD36 and its palmitoylation were examined around three groups. In addition, damage to the ocular surface and lacrimal glands was assessed in vivo, after the mice were injected with the ferroptosis inhibitor Fer-1 and CD36 shRNA.
Results: In this study, we found that compared with caloric restriction, IF more effectively reduced lipid accumulation in the lacrimal glands of diabetic db/db mice, decreased lipid peroxidation and ferroptosis, and improved function. IF downregulated CD36 expression and its palmitoylation, potentially mediated by ZDHHC20. CD36 shRNA and ferroptosis inhibition (Fer-1) comparably restored lacrimal secretory function, yet only CD36 knockdown concurrently resolved lipidostasis and ferroptosis.
Conclusions: This analysis identifies CD36 as a key regulator bridging lipotoxic stress and ferroptotic execution in diabetic lacrimal gland dysfunction. Importantly, our findings suggest that ferroptosis may serve as the critical effector mechanism converting metabolic overload to glandular dysfunction, suggesting potential therapeutic value in dual targeting of lipidostasis and cell death pathways.
Significance: Intermittent fasting, which appears more effective than that of caloric restriction, may be associated with reduced lipid absorption resulting from decreased CD36 expression and its palmitoylation on lacrimal gland cell membranes. These findings uncover a potential novel treatment strategy for diabetic dry eye.
Keywords Intermittent fasting, Diabetic dry eye, Lacrimal gland, Ferroptosis, ZDHHC20, CD36
Address and Contact Information 1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University, 7 Jinsui Road, Guangzhou 510060, China
2 Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou 510120, China
3 Department of Endocrinology, Shenshan Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shanwei 516600, China
*Corresponding author: Ziyan Chen chenziyan@gzzoc.com Wei Wang wangw253@mail.sysu.edu.cn Lingyi Liang lianglingyi@gzzoc.com
† Wenhui Wang and Jianwen Xue have contributed equally to this work and share first authorship.
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No.  68DOI: 10.1186/s11658-026-00895-y Volume 31 (2026) - 30:68
Title TARGETING DORMANT CANCER CELLS: FERROPTOSIS AS A PRECISION THERAPEUTIC STRATEGY
Authors Sijia Hao1,2, Yulu Guo1,2, Qiaozhen Huang3, Lu Gan1,2, Cheng Chen4, Qiang Li1,2*, Cuixia Di1,2* and Jing Si1,2*
Abstract Dormant cancer cells are a significant source of cancer recurrence and metastasis and exhibit robust resistance to conventional therapies. Therefore, the exploration of novel therapeutic strategies to eliminate these cells has become a hot topic in cancer research. Ferroptosis, a newly identified form of regulated cell death, has garnered considerable attention in the field of cancer therapy in recent years. As a novel form of regulated cell death, the core mechanism of ferroptosis lies in the accumulation of intracellular iron and the induction of lipid peroxidation. Oxidative stress, the transforming growth factor-β (TGF-β) signaling pathway, autophagy, and lipid metabolism play dual roles in the survival of dormant cancer cells and the process of ferroptosis, influencing the response of dormant cancer cells to ferroptosis. These complex molecular mechanisms form a regulatory network between ferroptosis and dormant cancer cells, which holds significant implications for the development of future anti-tumor therapeutic strategies. This review synthesizes current evidence on targeting ferroptosis to eliminate dormant cancer cells, positions ferroptosis as a precision modality against dormant cancer cells, and discusses its therapeutic promise as a conceptual framework for developing next-generation anti-tumor strategies.
Keywords Cancer dormancy, Ferroptosis, Oxidative stress, TGF-β signaling, Lipid metabolism, Autophagy
Address and Contact Information 1 Department of Medical Physics Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
2 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
3 School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, China
4 Department of Breast, Gansu Wuwei Tumour Hospital, Wuwei, China
*Corresponding author: Qiang Li liqiang@impcas.ac.cn Cuixia Di dicx@impcas.ac.cn Jing Si sijing@impcas.ac.cn
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No.  47DOI: 10.1186/s11658-026-00892-1 Volume 31 (2026) - 30:47
Title Ash2l DEFICIENCY IMPAIRS ADIPOSE TISSUE THERMOGENESIS AND EXACERBATES OBESITY IN MICE
Authors Yajie Hu1, Jialin Zhao1, Chenxi Xiao1, Jiayao Liu1, Jie Xu1, Shenhan Xu1, Wen Zhong1, Ruoxue Chen1, Mengting He1, Chunxiang Fan1*, Jun Chang1* and Xinhua Liu1*
Abstract Background: Epigenetic regulation plays a pivotal role in adipocyte development and thermogenesis. Ash2l, a key component of the COMPASS (Complex of Proteins Associated with Set1) histone methyltransferase, regulates gene expression through epigenetic mechanisms. This study explored the role of Ash2l in adipose tissue thermogenesis and obesity-related metabolic dysfunction.
Methods: Ash2l was initially identified through transcriptomic analysis, and its expression was further validated in mouse models of high-fat diet (HFD), cold exposure, and CL316,243 stimulation. In vitro gain- and loss-of-function experiments were conducted to assess the role of Ash2l in adipogenesis and thermogenesis. To knockdown Ash2l in vivo, adeno-associated viruses carrying short hairpin RNA targeting Ash2l (AAV-shAsh2l) were injected into either the brown adipose tissue (BAT) or the inguinal white adipose tissue (iWAT). The functional consequences of Ash2l deficiency were evaluated in mice under room temperature, cold exposure, and HFD conditions. Finally, chromatin immunoprecipitation sequencing (ChIP-seq) was employed as an exploratory analysis to identify genomic regions associated with Ash2l during adipocyte development.
Results: Our findings demonstrate that Ash2l modulates the expression of both adipogenic and thermogenic genes in adipocytes. Mice with BAT- or iWAT-knockdown of Ash2l displayed defective cold-induced thermogenesis, aggravated diet-induced obesity, and systemic metabolic dysregulation. Moreover, Ash2l knockdown in BAT under cold exposure or HFD conditions also attenuated thermogenic activity in iWAT, an effect that may be mediated by reduced secretion of FABP4.
Conclusions: These findings establish Ash2l as a critical regulator of adipogenesis and thermogenesis. This study provides important insights into the epigenetic role of Ash2l in maintaining metabolic homeostasis under conditions of nutritional excess.
Keywords Ash2l, Adipogenesis, Thermogenesis, BAT, iWAT, Obesity
Address and Contact Information 1 Phenome Research Center of TCM, Department of Traditional Chinese Medicine, Shanghai Pudong Hospital, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China
*Corresponding author: Chunxiang Fan fanxiang1258@163.com Jun Chang jchang@fudan.edu.cn Xinhua Liu liuxinhua@fudan.edu.cn
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No.  69DOI: 10.1186/s11658-026-00901-3 Volume 31 (2026) - 30:69
Title MACROPHAGE-DERIVED LEGUMAIN AMELIORATES EXCESSIVE MECHANICAL STRESS-INDUCED FERROPTOSIS OF NUCLEUS PULPOSUS CELLS AND INTERVERTEBRAL DISC DEGENERATION VIA INTEGRIN αvβ3–HIPPO SIGNALING
Authors Peiyang Wang1†, Zhiyang Xie1†, Liting Deng2†, Yan Zhou1 na1, Zhengyuan Xu1, Jiawei Gao1, Rui Sun1, Lei Liu1, Zhiwei Wang1, Xiaotao Wu1, Guanrui Ren1*, Cong Zhang1* & Yuntao Wang1*
Abstract Background: Excessive mechanical stress is a major cause of intervertebral disc degeneration (IVDD). Macrophages can sense physical signals, but their role in responding to mechanical stress within the disc to maintain homeostasis is unclear. This study investigates the function of macrophage-derived legumain (LGMN) in IVDD.
Methods: Single-cell RNA sequencing data of human disc samples were analyzed. Macrophage-specific Lgmn knockout (LgmnF/F;LysMCre) and nucleus pulposus cell (NPC)-specific Yap1 knockin (Yap1LSL/LSL; Col2a1Cre) mice were generated to study IVDD progression in vivo using a lumbar spine instability model. In vitro, NPCs and macrophages were cultured under mechanical compression. Molecular interactions were predicted with AlphaFold3 and validated by coimmunoprecipitation and mass spectrometry. Signaling pathways were analyzed via RNA sequencing, western blot, and chromatin immunoprecipitation. Engineered LGMN-overexpressing small extracellular vesicles (sEVs) were tested therapeutically in a rat compression model.
Results: LGMN was significantly upregulated in human and animal degenerate discs, primarily in macrophages. Conditional knockout in macrophages accelerated IVDD in mice. Mechanistically, macrophage-derived LGMN bound to integrin αvβ3 on NPCs, inhibiting RhoA activity and activating the Hippo pathway. This led to phosphorylation and cytoplasmic retention of YAP1, which suppressed mechanical stress-induced ferroptosis in NPCs. Mechanical stress promoted STAT3 nuclear translocation in macrophages, directly enhancing LGMN transcription. Intradiscal delivery of LGMN-enriched sEVs alleviated IVDD in rats.
Conclusions: Macrophage-derived LGMN is a key mechanosensitive regulator that ameliorates IVDD by inhibiting NPC ferroptosis via the integrin αvβ3–Hippo pathway, revealing a novel endogenous protective mechanism and a potential therapeutic strategy.
Keywords Intervertebral disc degeneration, Mechanical stress, Macrophage, Nucleus pulposus cell, Ferroptosis
Address and Contact Information 1 Department of Spine Surgery, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
2 Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
*Corresponding author: Guanrui Ren renguanrui@163.com Cong Zhang zhangcong19@hotmail.com Yuntao Wang wangyttod@126.com
† Peiyang Wang, Zhiyang Xie, Liting Deng, Yan Zhou have contributed equally to this work.
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No.  70DOI: 10.1186/s11658-026-00880-5 Volume 31 (2026) - 30:70
Title THERAPEUTIC POTENTIAL OF 20-HYDROXYECDYSONE IN PULMONARY ARTERIAL HYPERTENSION: INVOLVEMENT OF MAS RECEPTOR AND PI3K–Akt PATHWAY
Authors Tong Lu1,2†, Weiwei Jia1†, Yuefei Wang1, Yong Ma1, Chengrun Song1, Fengxia Du2, Hengyu Gao1, Xiangguo Jin4, Hong Li3, Chen Liu3, Haifeng Jin1,5* and Yan Lin1*
Abstract Background: 20-Hydroxyecdysone (20E), a natural polyhydroxylated steroid found in various edible plants, exhibits diverse pharmacological effects. Pulmonary arterial hypertension (PAH) remains challenging to treat owing to its multifactorial pathogenesis. Although recent advances, including US Food and Drug Administration (FDA)-approved therapies such as sotatercept, have improved outcomes, no curative treatment is currently available. This study aims to investigate the preventive and therapeutic effects of 20E on PAH and elucidate its underlying molecular mechanisms.
Methods: A monocrotaline-induced PAH rat model was utilized to evaluate the efficacy of 20E. The Mas receptor antagonist A779 and agonist AVE0991 were used to investigate the role of Mas in PAH progression and 20E-mediated prevention. Molecular docking and pull-down assays were conducted to confirm the interaction between 20E and the Mas receptor. In vitro, the effects of 20E on Ang II-induced proliferation and migration of human pulmonary arterial smooth muscle cells (HPASMCs) were assessed. The PI3K–Akt signaling pathway was analyzed by western blot.
Results: 20E prevented PAH at 30 mg/kg and 90 mg/kg, while 90 mg/kg rescued preexisting PAH. The protective effects of 20E were attenuated by A779. 20E upregulated Mas receptor expression and directly bound to it. In vitro, 20E inhibited Ang II-induced HPASMC proliferation and migration. It also downregulated p-PI3K, p-Akt, and p-mTOR while restoring P27 and P21 expression. Furthermore, knockdown of the Mas in HPASMCs abolished the effects of 20E on these processes.
Conclusions: 20E inhibits PASMC proliferation and migration through Mas-dependent mechanisms and modulation of downstream PI3K–Akt signaling, thereby effectively preventing and rescuing PAH. It may be a promising pharmacological candidate for PAH treatment.
Keywords 20-Hydroxyecdysone, Pulmonary arterial hypertension, Mas receptor, Pulmonary arterial smooth muscle cells, ACE2/Ang-(1–7)/Mas axis, PI3K–Akt signaling pathway
Address and Contact Information 1 Heilongjiang Provincial Key Laboratory of Food & Medicine Homology and Metabolic Disease Prevention, Qiqihar Medical University, Qiqihar, China
2 College of Medical Technology, Qiqihar Medical University, Qiqihar, China
3 The Third Affiliated Hospital, Qiqihar Medical University, Qiqihar, China
4 School of Nursing, Qiqihar Medical University, Qiqihar, China
5 Key Discipline of Human Anatomy and Histoembryology, Qiqihar Medical University, Qiqihar, China
*Corresponding author: Haifeng Jin haifengjin10@hotmail.com Yan Lin linyan_qqhr@163.com
† Tong Lu and Weiwei Jia contributed equally to this work.
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No.  64DOI: 10.1186/s11658-026-00900-4 Volume 31 (2026) - 30:64
Title CDH4/UBA1/RBMX AXIS PROMOTES POLYCYSTIC OVARY SYNDROME PROGRESSION THROUGH YAP1 ACTIVATION
Authors Ning Xu1, Bo Yu2, Yingying Li1, Yuxi Yang1, Yalong Wang3, Lingling Fang3, Hongliang Wu3*, Yingyi Luan1* and Chenghong Yin1*
Abstract Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of childbearing age. In addition, it is a heterogeneous disease with numerous etiologies, multiple levels, and uneven manifestation. In patients with PCOS, the number of antral follicles is abnormally increased. Several studies indicate and preliminarily support that Hippo pathway abnormalities may contribute to PCOS development by promoting excessive antral follicle proliferation. Moreover, the key Hippo pathway effector, Yes-associated protein 1 (YAP1), contributes to PCOS susceptibility. Furthermore, dysfunction of ovaries in patients with PCOS leads to irregular granulosa cell (GC) growth, which can affect ovulation and cause infertility. Nevertheless, few studies have investigated the key mechanism regulating Hippo activation in PCOS.
Methods: Hippo-associated gene sets and publicly available sequencing databases were used to screen potential PCOS-driving genes, and cadherin 4 (CDH4, R-cadherin) was found to exhibit abnormally high expression in ovarian granulosa cells. Functional studies were conducted to investigate the effects of CDH4 inhibition on PCOS-related ovarian function.
Results: A lower CDH4 level ameliorated ovarian function in patients with PCOS by decreasing chronic inflammation and modulating mitochondrial function and apoptosis in GCs. Mechanistically, CDH4 interacts with UBA1 and RBMX, increasing the ubiquitin-dependent degradation of RBMX and finally resulting in the transcriptional activation of YAP1. These results highlight the pivotal role of CDH4 in PCOS, which is achieved through the regulation of the Hippo–YAP1 signaling axis.
Conclusions: This study demonstrates that CDH4 plays a pivotal role in PCOS pathogenesis by regulating the Hippo–YAP1 signaling axis. The finding that reduced CDH4 could enhance the prognosis of individuals with PCOS by regulating ovarian GC activity could potentially inform novel treatment strategies.
Keywords Polycystic ovary syndrome, Ovarian granulosa cell, CDH4, Hippo, YAP1
Address and Contact Information 1 Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, No. 251 Yaojiayuan Road, Chaoyang District, Beijing 100026, China
2 AMG Nephrology, Avera Mckennan Hospital, Sioux Falls 57110, USA
3 Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
*Corresponding author: Hongliang Wu wuhongliang2021@126.com Yingyi Luan luanyingyi@mail.ccmu.edu.cn Chenghong Yin yinchh@ccmu.edu.cn
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No.  71DOI: 10.1186/s11658-026-00898-9 Volume 31 (2026) - 30:71
Title TARGETING FIBROBLAST ACTIVATION PROTEIN-α TO TREAT RENAL FIBROSIS
Authors Li Gong1*†, Xinyu Lu2†, Na Ma4†, Tao Lu5†, Yuhong Gong1, Liwei Hao6, Weikang Xu7, Qianbing Zhang8, Xiaolan Chen2, Qinglin Mo9, Jiexing Tan1, Henrique de Paula Lemos10, Alexander Speechley10,12, Wenwei Tu13, Jianpiao Cai14, Lei Huang10,11, Wei Zhu2 and Sha Wu9
Abstract Background: Renal fibrosis is the common outcome of chronic renal disease. Currently, there are no effective therapies. Fibroblast activation and extracellular matrix accumulation are key processes driving renal fibrosis.
Methods and results: Fibroblast activation protein (FAP) is highly induced in injured kidneys, and immunofluorescence staining revealed that FAP is mainly expressed in Platelet-derived growth factor receptor-beta (PDGFRβ)+ and alpha-smooth muscle actin (α-SMA)+ myofibroblasts in kidney samples from mice with renal fibrosis and patients with chronic kidney diseases or post-acute kidney injury. In this study, targeting FAP as a strategy for treating renal fibrosis is tested using two preclinical animal models: the mouse models of unilateral ureteral obstruction and unilateral renal ischemia–reperfusion. Adoptive transfer of T cells expressing chimeric antigen receptor specific to FAP or administration of an FAP inhibitor (SP-13786) significantly alleviated kidney fibrosis in both mouse models. Eliminating FAP+ fibroblasts using chimeric antigen receptor T-cell (CAR-T) therapy or inhibiting the FAP prevented fibroblast overactivation, proliferation, and migration, promoted apoptosis, and effectively suppressed other myofibroblast populations.
Conclusions: Overall, we report herein that targeting FAP offers a novel promising treatment approach for renal fibrosis.
Keywords Fibroblast activation protein-α (FAP), Renal fibrosis, Chimeric antigen receptor (CAR) T-cell immunotherapy
Address and Contact Information 1 Experimental Animal Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
2 Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
3 State Key Laboratory of Multi-organ Injury Prevention and Treatment; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology; Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology., 510515 Guangzhou, China
4 Department of Pathology, The First People’s Hospital of Foshan (Foshan Hospital Affiliated to Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology, Guangdong 528000 Foshan, China
5 Changzhou Geriatric Hospital Affiliated to Soochow University, Changzhou no. 7 People’s Hospital, Changzhou 213011, China
6 The School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China
7 Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510220, China
8 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
9 Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangdong Provincial Key Laboratory of Proteomics, Guangzhou 510515, China
10 Translational and Clinical Research Institute, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle Upon Tyne NE4 5PL, UK
11 Zeal BioScience Group Limited, 999077 Hongkong, China
12 Present address: Barts and The London, School of Medicine and Dentistry, Queen Mary’s University of London, Garrod Building, London E1 2AD, UK
13< Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
14 State Key Laboratory for Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong 999077, China
*Corresponding author: Li Gong gongli009@126.com
† Li Gong, Xinyu Lu, Na Ma and Tao Lu contributed equally to this work.
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No.  87DOI: 10.1186/s11658-026-00907-x Volume 31 (2026) - 30:87
Title TARGETING MUTANT p53 IN CANCER: FROM MECHANISTIC INSIGHTS TO THERAPEUTIC STRATEGIES
Authors H. Helena Wu1*, Sarah Leng2, David D. Eisenstat3,4,5,6, Consolato Sergi2,7 and Roger Leng1*
Abstract The tumor suppressor p53, often referred to as the “guardian of the genome,” is mutated in more than half of human cancers. These mutations have a significant impact on cancer biology and response to therapy. p53 mutations involve a range of changes that interfere with DNA binding, eliminate tumor suppressor functions, and, in many cases, confer dominant-negative or gain-of-function characteristics that actively promote oncogenesis. These mutations are closely linked to poor clinical outcomes and resistance to standard treatments. This review examines the impact of p53 mutations on cancer therapy in various ways. In chemotherapy and radiotherapy, loss of wild-type p53 impairs DNA damage responses, whereas mutant forms often contribute to treatment resistance. Additionally, p53 status influences responses to targeted therapies and immunotherapies, thereby affecting patient outcomes and prognoses. Importantly, ongoing clinical trials are beginning to integrate p53 mutational status as a predictive biomarker for therapy selection. Strategies aimed at restoring p53 activity are gaining increasing popularity in the development of treatments. These approaches include gene therapy to reintroduce the wild-type gene, targeted degradation of mutant p53 proteins, and small molecules designed to refold or reactivate mutant p53. In addition, synthetic lethality frameworks are being utilized to exploit vulnerabilities specific to tumors with p53 mutations, as well as interventions that target downstream effectors of p53 pathway. Together, these strategies represent a significant shift in precision oncology.
Keywords p53 tumor suppressor, Mutation, Gain-of-function, Cancer progression, Cancer therapy
Address and Contact Information 1 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada
2 Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada
3 Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, AB T6G 1Z2, Canada
4 Department of Pediatrics, University of Alberta, 11405-87 Ave, Edmonton, AB T6G 1C9, Canada
5 Department of Medical Genetics, University of Alberta, 8613 114 Street, Edmonton, AB T6G 2H7, Canada
6 Department of Paediatrics, Murdoch Children’s Research Institute, University of Melbourne, 50 Flemington Road, Parkville, Melbourne, VIC 3052, Australia
7 Division of Anatomical Pathology, Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada
*Corresponding author: H. Helena Wu hwu8@ualberta.ca, Roger Leng rleng@ualberta.ca
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No.  72DOI: h10.1186/s11658-026-00903-1 Volume 31 (2026) - 30:72
Title RIBBON CONSTRAINS DENDRITIC PRUNING VIA ACTIN SCAFFOLDING AND EXOCYST COMPLEX
Authors Wanting Wang1†, Su Wang1†, Yuhao Yuan1 and Menglong Rui1*
Abstract Background: During animal development, neurons selectively remove superfluous synaptic connections, strengthen key synapses, and optimize neural circuits in the brain, which is a core mechanism for fine-tuning the development of the nervous system. Drosophila class IV dendritic arborization (C4da) sensory neurons undergo dendrite-specific pruning during development. Nevertheless, the cell-autonomous inhibitory mechanisms of dendritic pruning in C4da neurons are largely unknown.
Methods and results: Here, we discovered Ribbon (Rib), a nuclear BTB-domain protein, whose malfunction in C4da neurons causes a precocious occurrence of dendritic pruning. Our study further shows that the regulation of dendritic pruning by Rib is dependent on Akt/Tor signaling. Moreover, actin polymerization factors and exocyst complex subunits are also involved in repressing dendritic pruning and function as downstream effectors of Rib and Akt/Tor signaling.
Conclusions: Overall, the present study reveals a cell-autonomous inhibitory mechanism of Rib in dendritic pruning, with a perspective to provide new insights into neurodevelopment and the pathogenesis of relevant neurological disorders.
Keywords Neurite pruning, Actin scaffolding, Exocyst complex, Ribbon, Akt/Tor signaling
Address and Contact Information 1 School of Life Science and Technology, the Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
*Corresponding author: Menglong Rui ruimenglong@seu.edu.cn
† Wanting Wang and Su Wang have contributed equally to this work.
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No.  77DOI: 10.1186/s11658-026-00904-0 Volume 31 (2026) - 30:77
Title PALMITOYLATION-DEPENDENT REGULATION OF INNATE AND ADAPTIVE IMMUNITY: MOLECULAR INSIGHTS AND TRANSLATIONAL OPPORTUNITIES
Authors Binhui Zhou1,2,3*†, Bowen Zhang2†, Yingcheng Qi2†, Sainan Li3†, Tingting Liu2†, Tong Li2†, Ying Wang1,2,3†, Haifeng Wang1, Jiaqi Lu1, Fei Cao1, Xiaohong Kang1, Eryan Kong1,3 and Yinming Liang2*
Abstract Immune cells orchestrate organismal defense through pathogen surveillance, tissue homeostasis, and immune tolerance, with innate and adaptive subsets coordinating context-specific responses. The dynamic lipid modification, S-palmitoylation (often referred to simply as palmitoylation), regulates membrane trafficking, signal transduction, and protein–protein interactions by spatiotemporally controlling the localization, stability, and activity of immune mediators. Dysregulation of this process in immune cells contributes to pathologies including immunosuppression, chronic inflammation, and autoimmunity. This review synthesizes current knowledge on how palmitoylation governs immune cell development, subset-specific functions, and immune-mediated pathologies—encompassing metabolic disorders, infectious diseases, autoimmune disorders, and cancer. We further explore the diagnostic and therapeutic potential of targeting palmitoyltransferases, depalmitoylases, and palmitoylation-dependent immune checkpoints to restore immune equilibrium. By integrating mechanistic insights into palmitoylation-dependent immune regulation with translational applications, this work underscores the potential of palmitoylation-centric biomarkers and therapies to transform immunological diagnostics and treatment.
Keywords Protein palmitoylation, Immune cells, Immune-mediated diseases, Diagnostic biomarkers, Therapeutic targeting
Address and Contact Information 1 The First Affiliated Hospital of Henan Medical University, Xinxiang, Henan, China
2 Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Henan Medical University, Xinxiang, Henan, China
3 Institute of Psychiatry and Neuroscience of Henan Medical University, Xinxiang, Henan, China
*Corresponding author: Binhui Zhou zhoubinhui@gris.org.cn, Yinming Liang yinming.liang@gris.org.cn
† Binhui Zhou, Bowen Zhang, Yingcheng Qi, Sainan Li, Tingting Liu, Tong Li, and Ying Wang have contributed equally to the work.
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No.  73DOI: 10.1186/s11658-026-00917-9 Volume 31 (2026) - 30:73
Title DYRK2 DRIVES RENAL FIBROSIS THROUGH CDK1-DEPENDENT G2/M PHASE DYSREGULATION IN TUBULAR EPITHELIAL CELLS
Authors Fang Bai1,3, Chunjie Wang1,3, Sha Wang1, Yuxuan Zhao4, Feng Feng1, Kuipeng Yu1,2,3, Lei Liu1,2 and Xiangdong Yang1,2*
Abstract Background: Renal fibrosis is a common pathological characteristic of chronic kidney disease (CKD) and serves as the critical prognostic indicator for renal outcomes. However, current therapeutic strategies for managing renal fibrosis remain limited. Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2), an evolutionarily conserved kinase, is implicated in cell proliferation and apoptosis in various pathological contexts. However, its role in renal fibrosis is unclear.
Methods: The expression of DYRK2 and association with renal injury and fibrosis were assessed in pathological sections from various CKD subtypes. Two independent renal fibrosis models, namely unilateral ureteral obstruction-induced and aristolochic acid-induced mice, were used to investigate the role of DYRK2 in renal fibrosis. Integrated multi-omics approaches, including RNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC–MS/MS) interactomics, were employed to elucidate the underlying mechanisms.
Results: Clinically, DYRK2 expression was elevated in patients with CKD and strongly correlated with histopathological fibrosis, glomerular filtration rate (GFR) decline, and an increased urine albumin-to-creatine ratio (UACR) in patients. In experimental fibrosis models, DYRK2 expression was markedly upregulated, which was particularly observed in proximal tubules. Silencing DYRK2 attenuated tubular injury, collagen deposition, and fibroblast activation. RNA sequencing revealed significant enrichment of oxidative stress-related pathways upon DYRK2 silencing. Functional studies demonstrated that DYRK2 ablation restored redox homeostasis in renal tubular epithelial cells (RTECs). Moreover, Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment showed that DYRK2 ablation restored the G2/M phase of the cell cycle in RTECs, reflected by a decrease in the cyclin B1/cyclin D1 ratio, as well as reduced levels of p21 and phosphorylated histone H3 (P-H3). Mechanistically, mass spectrometry screening and co-immunoprecipitation assays revealed an interaction of DYRK2 and cyclin-dependent kinase 1 (CDK1). Notably, DYRK2 promoted phosphorylation of CDK1 at the Thr14 site, thereby inhibiting its activity. The increased Thr14 phosphorylation of CDK1 almost reversed the protective effects of DYRK2 loss on transforming growth factor (TGF)-β1-induced tubular cell injury and fibrosis.
Conclusion: These findings highlight the pivotal role of DYRK2 in driving G2/M dysregulation in RTECs under fibrotic conditions. Targeting DYRK2 may offer a promising and novel therapeutic strategy for renal fibrosis.
Keywords Renal fibrosis, Renal tubular epithelial cells, DYRK2, Cell cycle, CDK1
Address and Contact Information 1 Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
2 Department of Blood Purification, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
3 Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
4 Department of Radiology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
*Corresponding author: Xiangdong Yang yxd@email.sdu.edu.cn
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No.  74DOI: 10.1186/s11658-026-00910-2 Volume 31 (2026) - 30:74
Title ADAM9 IN TUMOR BIOLOGY: MOLECULAR FUNCTIONS, CLINICAL IMPLICATIONS, AND THERAPEUTIC TARGETING
Authors Kuo-Hao Ho1, Chao-Jung Wu2, Yi-Chieh Yang3* and Ming-Hsien Chien2,4,5,6,7*
Abstract A disintegrin and metalloproteinase 9 (ADAM9), a member of the ADAM family, is expressed across multiple organs and is crucial to multiple physiological processes. Increasing evidence implicates ADAM9 in cancer progression through extracellular matrix (ECM) remodeling, protein shedding, and tumor microenvironment modulation. This study comprehensively reviews the literature on the clinical significance of ADAM9 and the mechanistic roles of ADAM9 in cancer. The results of our pan-cancer analysis demonstrated that ADAM9 is frequently upregulated and consistently associated with poor prognosis across tumor types. The results of in silico analyses also revealed that increased ADAM9 expression is correlated with an immunosuppressive tumor microenvironment and the activation of cancer-promoting pathways, such as cell cycle progression, epithelial–mesenchymal transition (EMT), and metabolism. This study also reviewed therapeutic strategies targeting ADAM9 and evaluated their potential in cancer treatment. This review provides insights into ADAM9 as both a biomarker of malignancy and a promising therapeutic target.
Keywords A disintegrin and metalloproteinase 9 (ADAM9), Extracellular matrix (ECM) remodeling, Protein shedding, Tumor microenvironment (TME), Cancer progression
Address and Contact Information 1 Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
2 School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
3 School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan
4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan
5 TMU Research Center for Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
6 Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
7 Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan
*Corresponding author: Yi-Chieh Yang ycyang@tmu.edu.tw Ming-Hsien Chien mhchien1976@gmail.com
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No.  89DOI: 10.1186/s11658-026-00918-8 Volume 31 (2026) - 30:89
Title INTEGRATED ANALYSIS OF SINGLE-CELL RNA SEQUENCING, TRANSCRIPTOMICS, AND THERMAL PROTEOME PROFILING IDENTIFIES PLCG1 AS THE THERAPEUTIC TARGET OF ISOPIMPINELLIN IN TREATING RHEUMATOID ARTHRITIS
Authors Huantian Cui1†, Ning Wang1†, Feitian Min1†, Huan Pei2†, Yuming Wang2, Hanzhou Li2, Qianqian Wan1, Yan Meng3, Mingwei He1, Xiaoman Lv4, Liwei Xing1, Zixuan Li5, Tianze Pan2, Renlin Li6, Weibo Wen1*, Xiangying Kong7* and Yuhong Bian2*
Abstract Background: Isopimpinellin (ISOP), derived from Toddalia asiatica (L.) Lam, is thought to possess anti-inflammatory potential. However, the effects of ISOP on rheumatoid arthritis (RA) and corresponding mechanisms remain unclear.
Methods: We evaluated the therapeutic effect of ISOP on RA using the collagen-induced arthritis (CIA) rat model. Subsequently, we determined the potential mechanisms of ISOP by combining single-cell RNA sequencing of rat synovial tissue in vivo with transcriptome analysis of macrophages in vitro. Molecular docking, thermal proteome profiling, cellular thermal shift assays, and drug affinity responsive target stability were then employed to identify the molecular targets of ISOP. Finally, we validated this target and explored the interaction between macrophages and RA-fibroblast-like synoviocytes (FLS) in vitro.
Results: We found that ISOP improved pathological changes in CIA rats. Mechanistically, ISOP inhibited macrophage migration and M1 macrophage polarization, and downregulated Spp1 expression. Furthermore, ISOP restrained the RAS/ERK pathway in M1 macrophages. Importantly, PLCG1 is a direct target of ISOP. Silencing PLCG1 reduced the related inhibitory effects of ISOP on M1 macrophage polarization. In addition, the supernatant of macrophages treated with ISOP reduced the proliferation and activation of RA-FLS. Silencing PLCG1 eliminated the regulatory effects of ISOP in the macrophage-RA-FLS co-culture system.
Conclusions: ISOP exerts its anti-RA effects by targeting PLCG1 to inhibit the production of SPP1 in M1 macrophages.
Keywords Isopimpinellin, Rheumatoid arthritis, Macrophage polarization, SPP1, PLCG1, Fibroblast-like synoviocytes, scRNA-seq
Address and Contact Information 1 First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
2 School of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
3 Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi 830054, China
4 Science and Technology Department, Yunnan University of Chinese Medicine, Kunming 650500, China
5 Medical School, Xizang University, Lhasa 850000, China
6 Second School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
7 Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
*Corresponding author: Weibo Wen wenweibo2020@163.com, Xiangying Kong xykong@icmm.ac.cn, Yuhong Bian bianyuhong_2012@163.com
† Huantian Cui, Ning Wang, Feitian Min and Huan Pei have equal contributions to this work.
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No.  82DOI: 10.1186/s11658-026-00916-w Volume 31 (2026) - 30:82
Title A tRNA-DERIVED FRAGMENT tRF3019a PROMOTES LUAD METASTASIS BY STABILIZING hnRNPK AND ENHANCING MYH11 EXPRESSION
Authors Xin Li1,2,3,4, Weifang Cui1,2,3,4, Zhangjie Wang1,2,3,4, Danyao Chen1,2,3,4, Zhenyu Kuang1,2,3,4, Junjie Jiang1,2,3,4, Yuwei Lai1,2,3,4, Xiongzhou Zhang1,2,3,4, Chaojun Duan1,2,3,4,5*, Chunfang Zhang1,2,3,4* and Xizhe Li1,2,3,4*
Abstract Background: tRNA-derived fragments (tRFs) have been shown to play important regulatory roles in cancer biology. However, the impact of tRFs on lung adenocarcinoma (LUAD) remains largely unexplored.
Methods: The differential expression of tRF3019a, a tRNA fragment derived from tRNA-Ala (AGC), was identified through database mining and subsequently validated by quantitative reverse transcription PCR (qRT–PCR) in pathological tissues obtained from 100 patients with LUAD. The role of tRF3019a in LUAD metastasis was assessed through both in vitro and in vivo experiments. A comprehensive investigation of its regulatory function involved RNA pulldown assays, mass spectrometry, RNA immunoprecipitation (RIP), western blotting, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and rescue assays.
Results: tRF3019a expression was significantly elevated in LUAD tumor tissues and was associated with advanced disease stage and metastatic progression. Higher tRF3019a expression correlated with shorter overall survival and disease-free survival. Functionally, tRF3019a enhanced LUAD cell migration and invasion both in vitro and in vivo. Mechanistically, tRF3019a interacted with heterogeneous nuclear ribonucleoprotein K (hnRNPK) and inhibited its ubiquitin-mediated proteasomal degradation, leading to increased hnRNPK protein stability. This was accompanied by changes in epithelial–mesenchymal transition (EMT)-associated markers, including increased N-cadherin and vimentin and decreased E-cadherin. Furthermore, tRF3019a enhanced hnRNPK-associated transcriptional regulation of the myosin heavy chain 11 (MYH11) gene, contributing to the pro-metastatic phenotype of LUAD cells.
Conclusions: tRF3019a promotes LUAD progression and metastasis by stabilizing hnRNPK and enhancing hnRNPK-associated transcriptional regulation of MYH11. These findings identify a previously unrecognized tRF3019a–hnRNPK–MYH11 regulatory axis involved in LUAD metastasis.
Keywords tRNA-derived fragments, LUAD, hnRNPK, Ubiquitination, MYH11
Address and Contact Information 1 Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
2 Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha 410008, Hunan, China
3 National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha 410008, Hunan, China
4 Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
5 Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
*Corresponding author: Chaojun Duan duancjxy@csu.edu.cn Chunfang Zhang zhcf3801@csu.edu.cn Xizhe Li lixizhe@csu.edu.cn
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No.  83DOI: 10.1186/s11658-026-00912-0 Volume 31 (2026) - 30:83
Title EIF4A3-INDUCED CIRCUBAC2 PROMOTES LUNG CANCER PROGRESSION VIA REGULATION OF THE HIPPO SIGNALING PATHWAY
Authors Fan Meng1†, Xiaokang Zhang1†, Xinlin Wang2, Binqiang Qiu2, Dingcheng Zeng2, Xiao Huang2, Jianping Liu3, Haiwu Wu3, Kaiwang Cui3, Bin Zhong4, Weiyou Liu4, Xiangwen Gong3 and Xin He1,4*
Abstract Background: Circular RNAs (circRNAs) are stable noncoding RNAs involved in cancer, yet their mechanisms in lung adenocarcinoma (LUAD) remain unclear. This study explores the oncogenic role of circUBAC2 in LUAD progression.
Methods: Differentially expressed circRNAs were screened by microarray. circUBAC2 expression/location was analyzed via quantitative real-time PCR (qRT-PCR), RNA in situ hybridization (RNA-ISH), and fluorescence in situ hybridization. Functional impacts were evaluated through wound healing, Transwell, EdU, colony formation, and xenograft models. circUBAC2 targets were identified by RNA-sequencing/proteomics, with protein interactions assessed via western blotting, immunoprecipitation, and ubiquitination assays. Molecular interactions were examined using dual luciferase, chromatin Immunoprecipitation (ChIP), and RNA pull-down.
Results: circUBAC2 was upregulated in LUAD tissues and correlated with poor prognosis. It promoted LUAD cell proliferation, migration, and invasion in vitro, as well as tumor growth/metastasis in vivo. Mechanistically, circUBAC2 competitively bound 14-3-3 to release YAP for nuclear translocation while scaffolding OTUB1–YAP interactions to enhance YAP deubiquitination and stabilization, collectively activating TEAD-mediated oncogenic transcription. EIF4A3 facilitated circUBAC2 biogenesis by binding flanking intronic regions.
Conclusions: circUBAC2 drives LUAD progression via YAP signaling, positioning it as a therapeutic target and prognostic biomarker.
Keywords circUBAC2, EIF4A3, OTUB1–YAP axis, 14-3-3 proteins, Lung adenocarcinoma
Address and Contact Information 1 Jiangxi Provincial Branch of China Clinical Medical Research Center for Geriatric Diseases, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jangxi Province, People’s Republic of China
2 The First Clinical Medical College of Gannan Medical University, Ganzhou, People’s Republic of China
3 Department of Respiratory and Critical Care Medicine, Ganzhou Key Laboratory of Respiratory Diseases, Ganzhou Institute of Respiratory Diseases, The Fifth People’s Hospital of Ganzhou, Ganzhou, Jiangxi, China
4 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, People’s Republic of China
*Corresponding author: Xin He hexin@gmu.edu.cn
† Fan Meng and Xiaokang Zhang contributed equally to the study.
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No.  78DOI: 10.1186/s11658-026-00897-w Volume 31 (2026) - 30:78
Title RESTORATION OF LYSOSOMAL MEMBRANE INTEGRITY IN CELL MODELS OF POMPE DISEASE DEPENDS ON FATTY ACID SYNTHASE AND ITS PRODUCT PALMITIC ACID
Authors Edouard Le Guillou1,2,3,4, Arianna Segaloni1,2,3, Alexis Gadault1,2,3, Catia Oliveira Dias1,2,3, Nathaniel F. Henneman1,2,3, Min Su5, Ivan Nemazanyy6, Nesrine Hifdi7, Valérie Nivet-Antoine4, Michael Laemmerhofer5, Karim Hnia7, Catherine Caillaud1,2,3,4 and Ganna Panasyuk1,2,3*
Abstract Background: Lysosomal storage disorders (LSDs) are rare inherited diseases caused by mutations in genes encoding lysosomal proteins, leading to substrate accumulation and lysosomal dysfunction. Whether this build-up compromises lysosomal membrane integrity remains an open question. In this study, we aimed to investigate the presence of lysosomal membrane damage in LSD cells and to identify mechanisms that could reveal potential strategies for improvement of lysosomal function.
Methods: Primary skin fibroblasts from patients with LSDs were used to evaluate lysosomal integrity and function. Lysosomal immunopurification enabled lipidomic and proteomic profiling, complemented by viral transduction for targeted protein expression at lysosomal membranes. Pharmacologic and metabolite treatments were applied in loss-of-function and rescue analyses. Microscopy-based approaches were used to assess lysosomal activity, membrane damage, and integrity. As a complementary model, we employed conditional mouse embryonic fibroblasts (MEFs) lacking class 3 phosphoinositide 3-kinase (PI3K-3), which exhibit lysosomal dysfunction and autophagy defects characteristic of LSDs.
Results: In Pompe disease, caused by mutations in the acid alpha-glucosidase gene, glycogen accumulation aggravates persistent lysosomal membrane damage. Moreover, using loss- and gain-of-function models of PI3K-3, we showed that its product, phosphoinositide-3-phosphate (PI3P), was essential for preserving lysosomal membrane integrity. Notably, Pompe patient fibroblasts exhibited chronic lysosomal damage, marked by increased galectin-3 (GAL-3) recruitment and reduced levels of lysosome-associated PI3K-3. Targeted restoration of PI3K-3 at lysosomal membranes rescued this defect and stabilized membrane integrity. Proteomic analyses following genetic or pharmacologic inhibition of PI3K-3 revealed a striking downregulation of fatty acid metabolism, including depletion of fatty acid synthase (FASN). We further demonstrated that PI3K-3 and FASN functionally interacted to maintain lysosomal integrity in Pompe cells. Supplementation with the FASN product palmitate reproduced the protective effect of PI3K-3 targeting, enhancing lysosomal proteolysis and restoring autophagic flux. Importantly, palmitate treatment also improved lysosomal function in fibroblasts from patients with Gaucher disease and type 2 neuronal ceroid lipofuscinosis, extending the relevance of this mechanism across LSDs.
Conclusions: These findings in cell models of LSDs uncover a link between PI3K-3, fatty acid metabolism, and lysosomal membrane integrity. They provide a basis for future in vivo validation of PI3K-3 activation and metabolic modulation as adjuvant treatments to improve lysosomal function in LSDs.
Keywords Lysosomal storage disorders, Pompe disease, Lysosome, Lysosomal membrane damage, Class 3 PI3K, Fatty acid synthase, Palmitic acid
Address and Contact Information 1 Institut Necker-Enfants Malades (INEM), Paris 75015, France
2 INSERM U1151/CNRS UMR 8253, Paris 75015, France
3 Université Paris Cité, Paris 75006, France
4 Biochemistry Laboratory, Necker-Enfants Malades Hospital, APHP, Paris 75015, France
5 Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-) Analysis, University of Tübingen, Auf Der Morgenstelle 8, Tübingen 72076, Germany
6 Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR 3633, Paris 75015, France
7 Institute of Cardiovascular and Metabolic Diseases (I2MC), INSERM- UMR 1297, University Paul Sabatier, Toulouse, France
*Corresponding author: Ganna Panasyuk ganna.panasyuk@inserm.fr
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No.  91DOI: 10.1186/s11658-026-00915-x Volume 31 (2026) - 30:91
Title HEDGEHOG PATHWAY ACTIVITY DOWNSTREAM OF SMOOTHENED IS REGULATED SPECIFICALLY BY BASAL CILIARY PKA
Authors Hongyu Zhang1†, Shujing Chen1†, Zhuoya Huang1, Jin Ben2, Yanling Wei1, Guangxin Chen1, Changxin Wu1, Haibo Xie4, Philip W. Ingham3* and Zhonghua Zhao1*
Abstract Background: Effectors of the vertebrate Hedgehog (HH) signaling pathway are organized within primary cilia (PC). Protein kinase A (PKA), a ubiquitously distributed kinase in most cells, functions as a specific negative regulator of the HH pathway. Its functional specificity in the HH pathway has been suggested to be controlled by cyclic adenosine monophosphate (cAMP) in PC. However, the regulation of PKA and its roles in PC remain unclear, partly owing to the lack of observations regarding PKA localization in PC during the resting state of HH signaling, as well as conflicting reports on the dynamic changes in ciliary cAMP levels and HH pathway activity. Here, we clarify that PKA with basal activity in PC specifically regulates the HH pathway and confirm that Smoothened (SMO)-mediated HH pathway activation may not be fully dependent on its inhibition of ciliary PKA activity.
Methods: To investigate the role of PKA during HH pathway, we have developed an improved ciliary-localized Förster resonance energy transfer (FRET)-based A-kinase activity probe (Nphp3N-AKAR2-CR) for real-time monitoring of ciliary PKA activity in both cultured cells and living embryos. Additionally, by leveraging a highly efficient ciliary targeting peptide (Nphp3N), we specifically delivered PKA variants to either PC or cytoplasm, thereby dissecting the regulatory roles of PKA in the HH pathway across different subcellular compartments. Furthermore, we performed constitutively active SMO variant (SMOA1)–forskolin (FSK) titration assays to validate the dose-dependent relationship underlying SMO-mediated inhibition of PKA.
Results: Basal ciliary PKA activity in cells was detected by this probe, despite the absence of observable PKA catalytic subunits in PC. Only ciliary-targeted PKA can modulate the HH pathway, even when PC integrity is disrupted. Notably, ciliary PKA activity is barely changed by either inhibition or activation of the HH pathway at the level of SMO. Furthermore, even low concentrations of FSK efficiently inhibit the HH pathway in the presence of SMOA1.
Conclusions: A basal level of PKA localized in PC but not cytoplasm specifically regulates HH signal transduction, and SMO-mediated activation of the HH pathway may not be solely attributed to the direct regulation of ciliary PKA activity.
Keywords HH pathway, Primary cilia, Cilia targeted PKA, Nphp3N-AKAR2, Smoothened
Address and Contact Information 1 Biomedical and Health Laboratory in Shanxi Province, Institute of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, School of Life Science, Shanxi University, Taiyuan 030006, China
2 School of Life Science, Yunnan University, Kunming 650504, China
3 Department of Life Sciences, University of Bath, Bath BA2 7AY, UK
4 College of Marine Sciences, Ocean University of China, Qingdao 266000, China
*Corresponding author: Philip W. Ingham P.Ingham2@exeter.ac.uk Zhonghua Zhao zhzhao@sxu.edu.cn
† Hongyu Zhang and Shujing Chen have contributed equally to this work.
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No.  90DOI: 10.1186/s11658-026-00914-y Volume 31 (2026) - 30:90
Title NK-CELL-DERIVED EXOSOMES EXERT ANTITUMOR POTENCY VIA miR-140/XYLT1/HSPG2 AXIS
Authors Dingru Li5†, Zerui Chen4†, Herong Liang1†, Qiang Li3†, Xiaofan Mao3†, Beiying Zhang3, Weiquan Gu3, Ye Xiao3, Xing-dong Xiong1*, Dan Zhou3*, Yuhua Deng3* and Mengyun Cai1,2,3*
Abstract Non-small cell lung cancer (NSCLC) remains a leading cause of global mortality, necessitating novel therapies. This study investigated the therapeutic role of natural killer cell-derived exosomes (NK-Exo), whose antitumor mechanisms are incompletely understood. Exosomes were isolated from interleukin (IL)-2-independent NK-92MI cells via differential ultracentrifugation and characterized by nanoparticle tracking, electron microscopy, and western blotting. They exhibited cup-shaped morphology (50–150 nm), expressed CD81/TSG101, and demonstrated selective cytotoxicity against tumor cells (A549, A375) but not nontumor cells (293 T) in vitro; this effect was corroborated in patient-derived lung organoids. Small RNA sequencing revealed miR-140-3p as highly enriched in NK-Exo, and its expression correlated with improved survival in patients with NSCLC. Functional validation showed that overexpressing miR-140-3p enhanced NK-Exo cytotoxicity and directly inhibited cancer cell migration and invasion, whereas inhibiting miR-140-3p promoted tumor growth. Mechanistically, miR-140-3p directly targeted xylosyltransferase 1 (XYLT1), as confirmed by dual-luciferase assay, leading to reduced levels of heparan sulfate proteoglycan 2 (HSPG2). Knockdown of XYLT1 phenocopied the tumor-suppressive effects of miR-140-3p, while supplementation with heparan sulfate reversed them. In a Lewis lung carcinoma mouse model, intratumoral delivery of NK-Exo, miR-140-3p mimic, or XYLT1 Small interfering RNA (siRNA) significantly inhibited tumor growth and alleviated splenomegaly. In conclusion, NK-Exo deliver miR-140-3p to suppress tumors via the novel miR-140-3p/XYLT1/HSPG2 axis, presenting a promising therapeutic strategy for cancer.
Keywords NK-92MI, Exosomal miR-140-3p, XYLT1, Heparan sulfate
Address and Contact Information 1 Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
2 Department of Histology and Embryology, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, China
3 Southern University of Science and Technology Affiliated Foshan Hospital, Guangdong, China
4 General Surgery Department, Guangdong Provincial People’s Hospital’s Nanhai Hospital, Foshan, Guangdong, China
5 Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
*Corresponding author: Xing-dong Xiong xiongxingdong@gdmu.edu.cn Dan Zhou zhoudanms@hotmail.com Yuhua Deng dyhsmu@163.com Mengyun Cai cai_mengyun@163.com
† Dingru Li, Zerui Chen, Herong Liang, Qiang Li, and Xiaofan Mao have contributed equally to this work.
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No.  98DOI: 10.1186/s11658-026-00908-w Volume 31 (2026) - 30:98
Title THE ROLE OF THE cGAS/STING PATHWAY IN SKELETAL MUSCLE REGENERATION: MODULATION OF INFLAMMATION, MACROPHAGE POLARIZATION, AND OXIDATIVE STRESS
Authors Xiaoguang Liu1,2†, Hao Wang1†, Miaomiao Xu3†, Huan Wang1, Haozhe Wang1, Wenjun Fang1, Mengqian Li1, Jiongxing Huang1, Huiguo Wang1,2, Yang Yu1,2 and Lin Zhu1,4*
Abstract Background: Skeletal muscle regeneration is essential for restoring muscle structure and function following injury. This process is influenced by various signaling pathways. Recent studies suggest that cGAS/STING signaling, which is known for its role in innate immunity, may also play a crucial role in tissue regeneration. This study investigated the regulatory role of the cGAS/STING pathway in skeletal muscle regeneration.
Methods: Skeletal muscle injury was induced via intramuscular injection of cardiotoxin (CTX) into the tibialis anterior (TA) muscle of mice. Genetic knockout models of cGAS and STING, as well as treatment with a STING agonist (DMXAA), were used to explore the role of the pathway in muscle regeneration. Histological analysis, flow cytometry, RNA extraction, and gene expression analysis were performed to evaluate muscle tissue morphology, macrophage infiltration, and the expression of inflammatory and oxidative stress markers.
Results: STING expression was significantly increased following injury. Treatment with a STING agonist impaired muscle regeneration, characterized by reduced muscle fiber dimensions, elevated pro-inflammatory macrophage infiltration, and increased oxidative stress. In contrast, cGAS or STING knockout enhanced muscle regeneration and promoted the accumulation of anti-inflammatory macrophages.
Conclusions: The cGAS/STING pathway plays a critical role in skeletal muscle regeneration by influencing inflammation, macrophage polarization, and oxidative stress.
Keywords Skeletal muscle, Regeneration, cGAS, STING, Macrophages
Address and Contact Information 1 School of Sport and Health, Guangzhou Sport University, Guangzhou 510500, China
2 Research Center for Innovative Development of Sports and Healthcare Integration, Guangzhou Sport University, Guangzhou 510500, China
3 Department of Physical Education, Guangdong University of Education, Guangzhou 510303, China
4 Innovative Research Center for Sports Science in the Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou Sport University, Guangzhou 510500, China
*Corresponding author: Lin Zhu 11251@gzsport.edu.cn
† Xiaoguang Liu, Hao Wang and Miaomiao Xu contributed equally to this work.
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No.  92DOI: 10.1186/s11658-026-00926-8 Volume 31 (2026) - 30:92
Title HIGH-TEMPERATURE ssBP-LAMP BREAKS THE BARRIER OF NONSPECIFIC AMPLIFICATION AND UNLOCKS THE FULL POTENTIAL OF LAMP DIAGNOSTICS
Authors Rita S. Simões1,2,3, Pedro Bule2,3, Carlos M. G. A. Fontes1,2,3 and João S. Teodoro1*
Abstract Background: Loop-mediated isothermal amplification (LAMP) is a highly attractive nucleic acid detection method for decentralized molecular diagnostics, but its broader adoption has been limited by unpredictable nonspecific amplification (NSA). Here, we dissect the fundamental determinants of LAMP specificity and present a new high-temperature ssBP-LAMP technique to suppress NSA without compromising assay sensitivity or speed.
Methods: Ubiquitous bioinformatic tools for prediction and design of primer sets and their characteristics were employed to generate a panel of 21 primer sets targeting diverse bacterial, viral, fungal, and human targets. Fluorometric ssBP-LAMP was implemented with a series of coordinated modifications, from increased temperature (only possible owing to a novel, engineered thermostable strand displacement Bst polymerase enzyme) to fine-tuning of additives and auxiliary enzymes. Finally, proof-of-concept validation using both fluorometric and colorimetric approaches for ssBP-LAMP was performed, and their resistance to common inhibitors of molecular diagnostics was evaluated.
Results: We show for the first time that primer design alone is insufficient to ensure specificity, and bioinformatic predictions are insufficient predictors of efficiency and, more importantly, of specificity, even when using elevated reaction temperatures. This suggests that NSA frequently originates during the thermal ramp-up phase, before the assay reaches its operational temperature. To address this, we employed a thermolabile single-stranded DNA-binding protein (ssBP) from bacteriophage T7, which transiently sequesters primers during temperature ramp-up. When combined with conventional LAMP primers and elevated assay temperatures (≥ 68 °C), ssBP consistently suppressed NSA across all tested targets. This approach translated directly to both liquid and lyophilized master mixes, enabling highly specific ssBP-LAMP detection by real-time fluorescence and colorimetry. These formulations retained robust sensitivity (down to 10–100 copies/reaction for real-time detection), eliminated false positives, and exhibited tolerance to clinically relevant inhibitors such as plasma, hemoglobin, saliva, and urine, especially in real-time fluorescence detection.
Conclusions: Together, the results establish high-temperature ssBP-LAMP as a rapid (< 15 min), specific, inhibitor-tolerant, and highly adaptable molecular diagnostic technology that overcomes key limitations of conventional LAMP while achieving analytical performance comparable to qPCR, with broad relevance for both clinical and point-of-care testing.
Keywords Loop-mediated isothermal amplification, LAMP, Bst polymerases, Nonspecific amplification, Primer design, Colorimetric LAMP
Address and Contact Information 1 NZYtech—Genes and Enzymes, Campus do Lumiar, Building J, 1649-038 Lisbon, Portugal
2 CIISA—Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, 1300-477, Lisbon, Portugal
3 Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 1300-477, Lisbon, Portugal
*Corresponding author: João S. Teodoro joao.teodoro@nzytech.com
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No.  95DOI: 10.1186/s11658-026-00924-w Volume 31 (2026) - 30:95
Title ENDOTHELIAL JAML INHIBITS INFLAMMATION AND ATHEROSCLEROSIS THROUGH TRIM25-MEDIATED STAT1 UBIQUITINATION
Authors Qingmei Han1†, Fei Xue1†, Jingwei Li1, Zhenguo Wu1, Chenghu Guo1, Yujie Zhang1, Xiao Wu1, Jie Yan1, Dachuan Guo1, Xiaohan Zou1, Wencheng Zhang1, Meng Zhang1, Cheng Zhang1* and Jianmin Yang1*
Abstract Background: Atherosclerosis is a chronic inflammatory disease initiated by endothelial dysfunction. Junctional adhesion molecule-like protein (JAML) is known to regulate inflammatory responses; however, its function in vascular endothelial cells and atherosclerosis remains unclear. This study aimed to investigate the function of endothelial JAML in atherosclerosis and to uncover the molecular mechanisms involved.
Methods: We generated mice with specific deletion of JAML in endothelial cells and fed them a high-fat diet to induce atherosclerosis, then assessed plaque formation in the aortic root and entire aorta. In parallel, endothelial cells were treated with tumor necrosis factor alpha, and the effects of increasing or silencing JAML on adhesion molecule expression were evaluated, with protein interactions analyzed by co-immunoprecipitation and immunoblotting.
Results: JAML exhibited downregulation in endothelial cells within both atherosclerotic lesions and cultured cells subjected to inflammatory stimuli. In mice, the loss of JAML resulted in exacerbated atherosclerotic progression, characterized by larger plaque formation, increased vascular inflammation, and increased macrophage infiltration. Conversely, overexpression of JAML attenuated the expression of adhesion molecules. Mechanistically, JAML was found to promote the degradation of signal transducer and activator of transcription 1 (STAT1) by facilitating its interaction with the E3 ubiquitin ligase tripartite motif-containing 25. This interaction led to ubiquitin-mediated proteolysis of STAT1, independent of alterations in its gene expression levels.
Conclusions: These findings suggest that endothelial JAML holds significant promise as a novel therapeutic target for the prevention and intervention of atherosclerosis.
Keywords Atherosclerosis, Endothelial inflammation, Ubiquitination, Junctional adhesion molecule-like protein, Signal transducer and activator of transcription 1, Tripartite motif-containing 25
Address and Contact Information 1 State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
*Corresponding author: Cheng Zhang zhangc@sdu.edu.cn Jianmin Yang yangjianmin@sdu.edu.cn
† Qingmei Han and Fei Xue contribute equally to this article
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No.  81DOI: 10.1186/s11658-026-00923-x Volume 31 (2026) - 30:81
Title DDX17-MEDIATED RAPTOR-DEPENDENT mTORC1 ACTIVATION LINKS AUTOPHAGY INHIBITION AND METABOLIC COMPENSATION IN HCC DEVELOPMENT
Authors Chaoxiang Lv1*†, Na Luo1†, Chunli Wei1†, Qiqi Zhang1†, Kan Guo1, Xia Jiang1,2, Xiuhua Cao1,3, Maghsoudloo Mazaher1, Ali ElFar1 and Junjiang Fu1*
Abstract Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with an increasing global incidence and mortality. Dysregulated gene expression drives uncontrolled proliferation and metastasis, contributing to poor patient survival despite therapeutic advances. The DEAD-box RNA helicase DDX17 has been implicated in tumorigenesis, but its functional role and underlying mechanisms in HCC remain incompletely defined. Here, we found that DDX17 drives HCC tumorigenesis via a novel mechanism involving direct binding to Raptor, a core component of the mTORC1 complex, thereby activating mTORC1 signaling and inhibiting autophagy, as evidenced by reduced autophagosome formation and a decreased LC3-II/LC3-I ratio. Moreover, DDX17 unwinds the RNA G-quadruplex (rG4) structure in the Raptor 3′ untranslated region (3′ UTR), enhancing its translation and establishing Raptor as an rG4-dependent oncogenic target. Combined DDX17 knockdown and rapamycin treatment synergistically suppressed proliferation and induced autophagy. Additionally, DDX17 inhibition reshaped tumor cell metabolism by decreasing extracellular acidification and promoting lipid droplet accumulation following autophagy induction, highlighting its role in metabolic adaptation. These findings suggest that DDX17 promotes HCC progression by unwinding the rG4 motif in Raptor mRNA to enhance translation, activating mTORC1 signaling, and suppressing autophagy. Hence, co-targeting DDX17 and mTORC1 produces strong synergistic antitumor effects, revealing a promising therapeutic strategy for HCC.
Keywords Hepatocellular carcinoma (HCC), DEAD-box helicase, DDX17, Raptor, Autophagy, Tumor growth
Address and Contact Information 1 Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
2 Department of Reproductive Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
3 Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
*Corresponding author: Chaoxiang Lv lvchaoxiang@126.com Junjiang Fu fujunjiang@swmu.edu.cn
† Chaoxiang Lv, Na Luo, Chunli Wei and Qiqi Zhang have contributed equally to this work.
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No.  93DOI: 10.1186/s11658-026-00921-z Volume 31 (2026) - 30:93
Title CHEMOKINES AND CHEMOKINE RECEPTORS IN METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS: PATHOGENIC MECHANISMS AND CLINICAL IMPLICATIONS
Authors Min Yin1,2, Yan Zhang1, Shanshan Liu1,3,4* and Xia Li1*
Abstract Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by persistent hepatic inflammation and fibrosis and frequently progresses to cirrhosis or hepatocellular carcinoma. Chemokines and their receptors, which drive disease progression and complications by orchestrating immune cell recruitment, inflammatory responses, and fibrotic processes, are central to the pathophysiology of MASH. Emerging evidence also underscores their functions as active metabolic integrators, reciprocally linking systemic insulin resistance to hepatic inflammation. This review aims to elucidate the pathogenic contributions of key chemokines such as chemokine (C–C motif) ligand (CCL)2, CCL5, CCL20, and chemokine (C–X–C motif) ligand (CXCL)10 in MASH by assessing their dual potential as therapeutic targets and non-invasive biomarkers for early detection. We also survey the current landscape of chemokine-directed therapies to critically evaluate both their efficacy and limitations. Although early clinical trials targeting chemokine pathways have yielded mixed outcomes, emerging research underscores the complexity of chemokine signaling and highlights multiple opportunities for stage-tailored and sex-specific interventions. Therefore, a deeper understanding of chemokine function in MASH holds considerable promise for facilitating the development of targeted, multidimensional treatment strategies, paving the way for personalized management of this progressive liver disorder.
Keywords Chemokines, Chemokine receptors, Metabolic dysfunction-associated steatohepatitis, Hepatocytes, Inflammation, Fibrosis, Biomarkers
Address and Contact Information 1 National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
2 Department of Clinical Nutrition, The Second Xiangya Hospital of Central South University, Changsha, China
3 CSU-Sinocare Research Center for Nutrition and Metabolic Health, Xiangya School of Public Health, Central South University, Changsha, China
4 Furong Laboratory, Changsha, China
*Corresponding author: Shanshan Liu lss0625@csu.edu.cn Xia Li lixia@csu.edu.cn
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No.  96DOI: 10.1186/s11658-026-00925-9 Volume 31 (2026) - 30:96
Title LUCAT1 DRIVES ARECOLINE-INDUCED HEAD AND NECK CANCER PROGRESSION VIA STAT1-MEDIATED TRANSCRIPTIONAL REGULATION
Authors Hung-Han Huang1,2, Guo-Rung You2, Joseph T. Chang3,4 and Ann-Joy Cheng1,2,4*
Abstract Background: Areca nut chewing is a major environmental risk factor for head and neck cancer (HNC), particularly in Southeast Asia. However, the molecular mechanisms linking areca nut exposure to malignant progression remain poorly understood. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of oncogenesis, but their role in areca nut-associated HNC remains unexplored.
Methods: We performed functional assays, transcriptomic profiling, and bioinformatics analyses to investigate the role of the lncRNA LUCAT1 in arecoline-treated HNC cells. Cell motility, epithelial–mesenchymal transition (EMT), reactive oxygen species (ROS) levels, and therapeutic resistance were assessed following LUCAT1 knockdown or overexpression. We identified upstream regulators of LUCAT1 through promoter analysis, transcription factor knockdown, and pharmacological inhibition.
Results: LUCAT1 expression was significantly upregulated by arecoline exposure and promoted cell motility, EMT, ROS clearance, and resistance to radiotherapy and chemotherapy. Knockdown of LUCAT1 reversed these malignant phenotypes and suppressed antioxidant enzyme expression, partly through modulation of the p38 MAPK pathway. Transcriptomic and promoter analyses identified STAT1 as a key transcription factor activated by arecoline via muscarinic acetylcholine receptor (mAChR) signaling. Functional rescue experiments confirmed that LUCAT1 acts downstream of STAT1 to sustain arecoline-induced tumor aggressiveness.
Conclusions: Our findings define a novel mAChR–STAT1–LUCAT1 regulatory axis that mediates areca nut-induced malignant progression in HNC. This study not only reveals a critical molecular pathway linking environmental carcinogen exposure to oncogenic transcriptional reprogramming but also highlights LUCAT1 as a promising target for therapeutic intervention in high-risk patients with HNC.
Keywords Lung cancer associated transcript 1 (LUCAT1), Signal transducer and activator of transcription 1 (STAT1), Areca nut, Arecoline, Head and neck cancer, Epithelial–mesenchymal transition (EMT), Reactive oxygen species (ROS), Therapeutic resistance, p38 MAPK signaling, Muscarinic acetylcholine receptor (mAChR)
Address and Contact Information 1 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Guishan Dist., Taoyuan 33302, Taiwan
2 Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
3 School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
4 Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
*Corresponding author: Ann-Joy Cheng annjoycheng@gap.cgu.edu.tw
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No.  99DOI: 10.1186/s11658-026-00928-6 Volume 31 (2026) - 30:99
Title UPREGULATED CCN1 FROM PLEURAL MESOTHELIAL CELLS ALTERS COLLAGEN I CONFORMATION AND DRIVES FIBROSIS VIA ITGB1/MAPK SIGNALING
Authors Xiao-Lin Cui1†, Lin-Jie Song2†, Qian Li1, Zi-Heng Jia2, Xiyong Dai3, Meng Wang1, Yang-Ping Lv1, Shuai-Jun Chen1, He-De Zhang1, Pei-Pei Cheng1, Shu-Yi Ye2, Shi-He Hu1, Chen-Yue Lian2, Li-Mei Liang2, Fan Yu2, Xin-Liang He2, Liang Xiong2, Fei Xiang2, Xiaorong Wang2, Hong Ye1* and Wan-Li Ma2,4*
Abstract Background: Pleural mesothelial cells (PMCs) have been identified as key contributors to pleural fibrosis. Cellular communication network factor 1 (CCN1), a matricellular protein, regulates cell–matrix interactions and fibrotic signaling in multiple contexts. However, the specific role and mechanism of CCN1 in PMCs during pleural fibrosis remained unclear.
Methods: Expression of CCN1 was evaluated in human pleural fibrosis samples and bleomycin-induced mouse models. In vitro, PMCs were treated with recombinant CCN1 or fibrotic matrix. Mechanistic studies included gene knockdown, immunoprecipitation, mass spectrometry, and functional assays.
Results: CCN1 was significantly elevated in pleural fibrosis tissues. CCN1 expression was driven by YAP/TAZ activation and in turn promoted further YAP/TAZ activation, creating a feedback loop to produce more CCN1. Upregulated CCN1 directly altered conformation of type I collagen (collagen I) by binding vWC binding domain. Then, CCN1 with conformation-changed collagen I activated integrin β1 (ITGB1)/MAPK signaling, which induced remodeling of cytoskeleton as well as fibrosis. At last, it was confirmed that neutralization of CCN1 reduced pleural fibrosis in vitro and in vivo.
Conclusions: Upregulated CCN1 contributes to pleural fibrosis via changing collagen I conformation and ITGB1/MAPK pathway activation. Targeting CCN1 is a potential therapeutic strategy.
Keywords Pleural mesothelial cells, CCN1, Type I collagen, ITGB1, YAP/TAZ, MAPK
Address and Contact Information 1 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2 Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
3 Department of Thoracic Surgery, Wuhan Pulmonary Hospital, Wuhan 430030, China
4 Key Laboratory of Anesthesiology and Resuscitation, (Huazhong University of Science and Technology), Ministry of Education, China, Wuhan 430022, China
*Corresponding author: Hong Ye yehmwl@hust.edu.cn Wan-Li Ma whmawl@hust.edu.cn
† Xiao-Lin Cui and Lin-Jie Song have contributed equally to this work.
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No.  97DOI: 10.1186/s11658-026-00929-5 Volume 31 (2026) - 30:97
Title PLACENTAL EXOSOMAL miR-372-3p DRIVES PREECLAMPSIA PROGRESSION BY INDUCING MITOCHONDRIAL DAMAGE IN RVLM NEURONS
Authors Shuai Zhang1,2,3,9†, Linping Wang4†, Bingjie Zhao4†, Tengteng Dai4, Maolin Nie5, Lei Tong4, Qiangcheng Zeng7, Wei Guo6*, Yongmei Shen5* and Dongshu Du4,7,8,9*
Abstract Background: Preeclampsia (PE) is a pregnancy-specific disorder rooted in placental dysfunction, characterized by new-onset hypertension with proteinuria and/or end-organ dysfunction, often linked to sympathetic overactivation. The rostral ventrolateral medulla (RVLM) serves as a crucial hub for sympathetic and blood pressure (BP) control. Placental exosomes are implicated in PE, but their role in placenta–RVLM communication is unclear. Investigating this could reveal the neurogenic pathogenesis underlying cardiovascular dysregulation in PE.
Methods: Placental exosomes derived from patients with PE (PE-exo) and normal pregnancies (N-exo) were isolated by ultracentrifugation. Their roles in regulating RVLM neuronal excitability, sympathetic tone, and BP, along with the underlying mechanisms, were evaluated using various experiments.
Results: Tail vein injection of PE-exo significantly enhanced RVLM neuronal excitability, sympathetic tone, and BP in pregnant rats. miR-372-3p levels were significantly elevated in PE-exo compared with N-exo and were upregulated in the RVLM of pregnant rats following PE-exo administration. miR-372-3p knockdown reversed the PE-exo-induced increases in RVLM neuronal excitability, sympathetic tone, and BP in pregnant rats. Mechanistically, miR-372-3p markedly reduced MPC1 expression, leading to RVLM neuronal mitochondrial damage.
Conclusions: This study is the first to demonstrate that placental exosomes deliver miR-372-3p to the RVLM neurons, impairing neuronal mitochondrial function and thereby promoting neuronal hyperexcitability, sympathetic overactivity, and elevated BP in PE.
Keywords Placental exosomes, miR-372-3p, MPC1, Rostral ventrolateral medulla, Preeclampsia
Address and Contact Information 1 College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, Hubei, China
2 Hubei Shizhen Laboratory, Wuhan 430065, Hubei, China
3 International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
4 School of Life Sciences, Shanghai University, Shanghai 200444, China
5 Tianjin Key Laboratory of Human Development and Reproductive Regulation/Tianjin Institute of Obstetrics and Gynecology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin 300100, China
6 School of Management, Shanghai University, Shanghai 200444, China
7 College of Life Sciences, Dezhou University, Dezhou 253023, Shandong, China
8 Department of Preventive Medicine, Heze Medical College, Heze 274000, Shandong, China
9 College of Agriculture and Bioengineering, Heze University, Heze 274015, Shandong, China
*Corresponding author: Wei Guo weiguo@shu.edu.cn Yongmei Shen 5020202003@nankai.edu.cn Dongshu Du dsdulab@163.com; dsdu@shu. edu.cn
† Shuai Zhang, Linping Wang, and Bingjie Zhao have contributed equally to this work.
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No.  94DOI: 10.1186/s11658-026-00934-8 Volume 31 (2026) - 30:94
Title DIFFERENTIATION STATE AFFECTS PD-L1 EXPRESSION IN CUTANEOUS MELANOMA: A SYSTEMATIC REVIEW
Authors Teitur Sævarsson1, Hong Nhung Vu2, Eiríkur Steingrímsson2 and Berglind Ósk Einarsdóttir1*
Abstract Background: Programmed death ligand-1 (PD-L1) is a widely used biomarker for immunotherapy in melanoma. The expression of PD-L1 in melanoma cells is known to vary considerably among and within patients’ tumor samples. Recent studies suggest that there may be a link between PD-L1 expression and the differentiation status of melanoma cells which is known to fluctuate in response to external stimuli and to be influenced by a multitude of regulators. Here, we systematically review which differentiation regulators affect PD-L1 expression in melanoma.
Methods: A systematic review was performed on studies collected through PubMed, Scopus, and Web of Knowledge up until February 13th, 2026. Screening of abstracts and titles was performed independently by two reviewers. Screening of full-text articles, data extraction, and validity assessments were performed by one reviewer. Studies published in English reporting changes in PD-L1 expression associated with a known differentiation regulator in a melanocytic/melanoma model were included. Studies were assessed for risk of bias regarding imprecision in experimental reporting and model validity, using previously defined assessment tools. Synthesis of results was performed narratively.
Results: Out of 496 identified articles, 57 studies met the inclusion criteria. A total of 16 differentiation regulators were significantly associated with PD-L1 expression in melanoma cells. Most studies (45/57) reported a single regulator, while 12/57 reported multiple. STAT3 appeared in 20/57 studies; all other regulators were reported in eight or fewer. PD-L1 expression was positively associated with all dedifferentiation-linked regulators (9/9). Among differentiation-linked regulators, 3/4 (MITF, SOX10, IRF4) showed contrasting associations depending on the PD-L1 expression mode and study. In total, 120 human and 10 mouse melanoma cell lines were used. The A375, SK-MEL-28, and B16 cell lines were used in 20, 18, and 28 studies, respectively, suggesting lineage bias. Most studies had unclear risk of bias regarding imprecision (82%) and model validity (70%).
Conclusions: PD-L1 expression is commonly affected by differentiation regulators in melanoma cells, linking high PD-L1 expression to dedifferentiated cell states. The various regulators and inducible pathways that affect PD-L1 may in turn explain the heterogeneity observed in PD-L1 expression between and within patients with melanoma. Owing to the clinical significance of PD-L1 expression as a predictive biomarker for immunotherapy response, it is crucial to better understand the impact of various regulators on its expression.
Keywords Melanoma, Differentiation, PD-L1, MITF
Address and Contact Information 1 Department of Biomedical Science, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
2 Department of Biochemistry and Molecular Biology, Faculty of Medicine, BioMedical Center, University of Iceland, Reykjavík, Iceland
*Corresponding author: Berglind Ósk Einarsdóttir boe@hi.is
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No.  `05DOI: 10.1186/s11658-026-00930-y Volume 31 (2026) - 30:`05
Title CHICORIC ACID TARGETS PYGL TO NORMALIZE GLYCOGENOLYSIS-DRIVEN GLYCOLYSIS TO SUPPRESS NON-SMALL CELL LUNG CANCER
Authors Xingfa Huo1, Helei Hou2, Chuantao Zhang2, Xueqin Duan1, Hongwei Lan1, Yufeng Li1, Na Zhou1* and Xiaochun Zhang1*
Abstract Background: Chicoric acid (CA), a bioactive natural compound found in Chicory and Echinacea purpurea, exhibits antiinflammatory, antioxidant, and apoptosis-inducing properties. However, its therapeutic potential and underlying mechanisms in non-small cell lung cancer (NSCLC) remain unclear.
Methods: We utilized bioinformatics analysis to identify potential hub genes targeted by CA. The clinical relevance of glycogen phosphorylase liver form (PYGL) was assessed via immunohistochemistry in NSCLC tissues. Functional assays, including Cell Counting Kit-8, flow cytometry, and xenograft models, were employed to evaluate the impact of PYGL on tumor growth. Glycogen metabolism and glycolytic flux were monitored using PAS staining and Seahorse assays. Direct binding between CA and PYGL was confirmed through virtual screening, molecular docking, cellular thermal shift assay, and surface plasmon resonance. Binding specificity was further validated using site-directed mutagenesis.
Results: Here, we demonstrate that CA restores glucose metabolic homeostasis and inhibits the proliferation of NSCLC cells. We identified PYGL as a key driver of NSCLC, where its upregulation enhances glycogenolysis to fuel glycolytic flux and promote tumor growth. Mechanistically, CA allosterically inhibits PYGL by binding to specific residues (Glu162, Arg247, Glu273) and inducing conformational changes, thereby suppressing glycogenolysis and reducing glycolysis. Furthermore, CA disrupts the interaction between PYGL and lactate dehydrogenase A (LDHA), accelerating the proteasomal degradation of LDHA and further reshaping glucose metabolic homeostasis.
Conclusions: Our findings highlight PYGL as a metabolic vulnerability in NSCLC and establish CA as a promising lead compound that targets the PYGL–LDHA axis to reprogram glucose metabolism and inhibit tumor growth.
Keywords Chicoric acid, PYGL, LDHA, Metabolic reprogramming, NSCLC
Address and Contact Information 1 Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, No. 59 Haier Road, Qingdao 266035, Shandong, China
2 Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao 266031, Shandong, China
*Corresponding author: Na Zhou zhouna@qdu.edu.cn Xiaochun Zhang zxc9670@qdu.edu.cn
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No.  100DOI: 10.1186/s11658-026-00931-x Volume 31 (2026) - 30:100
Title IRE1–XBP1DRIVEN INDUCTION OF TMED9 STABILIZES ATF6 DURING ER STRESS TO PROMOTE CELL SURVIVAL
Authors Chen Lenchisky1†, Areen Muhammad Majadly1†, Irena Bronshtein Berger1†, Danielle Biton1, Alaa Daoud Sarsour1,2, Narkis Arbeli1, Tamar Cohen1, Naama Amos1,2, Sara Kinstlinger1, Ortal Cohen1, Elad Horwitz1 and Moran Dvela-Levitt1*
Abstract Background: The endoplasmic reticulum (ER) plays a central role in protein homeostasis by facilitating the folding, modification, and quality control of secretory and membrane proteins. Disruption of ER function results in protein misfolding and ER stress, which activate the unfolded protein response (UPR). While the three canonical UPR branches, inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6), have been extensively studied, the mechanisms that coordinate their activities and ultimately dictate survival or death remain poorly understood. Transmembrane P24 trafficking protein 9 (TMED9), a cargo receptor that cycles between the ER and Golgi, has been implicated in protein quality control under pathological conditions, but its physiological role in ER proteostasis and UPR signaling is unclear.
Methods: The ER stress response was studied in cellular human models including normal epithelial cells and patient-derived pediatric glioma cultures. To define the regulatory mechanisms dictating TMED9 expression, quantitative Reverse Transcription polymerase chain reaction (qRT-PCR), luciferase reporter assay, and western blotting were employed. To elucidate TMED9 function, loss-of-function approaches, including clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9-mediated knockout and small interfering RNA knockdown were used in combination with RNA-seq and live imaging. Protein stability was tested by pulse-chase experiments, ubiquitination, and degradation analyses. To study the implications of TMED9 activation, we screened curated gene expression datasets from the European Molecular Biology Laboratory- European Bioinformatics Institute (EMBL-EBI) Expression Atlas and employed live-cell imaging-based assays and functional assays (cell viability, apoptosis, migration, and self-renewal).
Results: Our study uncovers a physiological role for TMED9 in ER proteostasis and UPR signaling. We show that, under ER stress, TMED9 expression is transcriptionally induced by the IRE1–spliced X-box binding protein 1 (XBP1s) pathway via a conserved unfolded protein response element (UPRE)-like element in its promoter. Removal of TMED9 selectively impairs ATF6 activation without altering IRE1 or PERK signaling, resulting in increased sensitivity to ER stress-induced apoptosis. Mechanistically, we identify TMED9 as a stress-induced stabilizer of ATF6 that prevents its ubiquitin-dependent proteasomal degradation. Functionally, TMED9 regulation is exploited by tumor cells, which sustain IRE1–XBP1s activity to upregulate TMED9, thereby enhancing survival under ER stress conditions.
Conclusions: Collectively, our findings establish TMED9 as a critical regulator of ER stress adaptation. TMED9 emerges as a molecular mediator that links IRE1-dependent transcriptional response to ATF6 stabilization, ultimately supporting increased secretory demand under stress conditions and in cancer development.
Keywords TMED9, p24 proteins, Proteostasis, ER stress, UPR, IRE1–XBP1s pathway, ATF6, Glioma, DIPG
Address and Contact Information 1 The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
2 Institute of Nanotechnology and Advanced Materials (BINA), Bar-Ilan University, Ramat-Gan 52900, Israel
*Corresponding author: Moran Dvela-Levitt moran.dvela-levitt@biu.ac.il; dvelamo@gmail.com
† Chen Lenchisky, Areen Muhammad Majadly and Irena Bronshtein Berger contributed equally to this work.
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No.  106DOI: 10.1186/s11658-026-00922-y Volume 31 (2026) - 30:106
Title BRD2 UPREGULATION AS A PAN-CANCER ADAPTIVE RESISTANCE MECHANISM TO BET INHIBITION
Authors Suyakarn Archasappawat1,2, Juliette Jacques1, EunJung Lee1 and Chang-il Hwang1,2*
Abstract Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinical utility, necessitating a better understanding of adaptive mechanisms. We identified BRD2 upregulation as a conserved response to BET inhibition across multiple cancer types and hypothesized that BRD2 compensates for BRD4 loss, sustaining essential transcriptional programs upon treatment. Consistent with this, BRD2 knockdown sensitized cancer cells to BETi in vitro, and combining BRD2 depletion and JQ1 treatment significantly impaired tumor growth in vivo. At the chromatin level, BRD2 and BRD4 ChIP-seq analysis of pancreatic cancer cells showed consistent BRD4 loss from chromatin after JQ1 treatment, while BRD2 displacement differed by sensitivity. Resistant cells maintained higher BRD2 occupancy than sensitive cells, suggesting a link between BRD2 retention and drug response. Mechanistically, NFYA mediates BRD2 upregulation as NFYA depletion attenuated BRD2 upregulation upon BETi treatment. Collectively, our findings establish BRD2 as a critical mediator of pan-cancer adaptive resistance to BETi and identify NFYA as a novel transcriptional regulator of this process. Co-targeting BRD2 or its regulatory network offers a rational strategy to enhance the durability and efficacy of BET-based therapies.
Keywords BET inhibitor, Resistance, Pan-cancer, BRD2, BRD4
Address and Contact Information Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, Davis, CA, USA
2 University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
*Corresponding author: Chang-il Hwang cihwang@ucdavis.edu
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No.  108DOI: 10.1186/s11658-026-00909-9 Volume 31 (2026) - 30:108
Title BEYOND NEUROTRANSMISSION: THE ROLES OF SEROTONYLATION IN PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES
Authors Jia-Ming Wang1†, Feng-Hao Zhang1†, Yi-Ru Chen1†, Dan-Ni Chen2†, Xiao Wang1*, Hai-Yun Xie3*, Jiang-Feng Li1*, Jin-Dan Luo1* and Li-Ping Xie1
Abstract Serotonin, also known as 5-HT, is a classical neurotransmitter produced both in the nervous system and in non-nervous system. Its involvement in various fundamental physiological processes and pathogenic conditions is significant, as it binds to a diverse array of functionally distinct receptors. Apart from binding to 5-HT receptors and activating downstream signaling cascades, recent studies have revealed a novel posttranslational modification named serotonylation, where serotonin is re-taken up by serotonin transporter and is covalently attached to target proteins ranging from histone proteins to nonhistone proteins. Transglutaminases (TGMs), especially TGM2, catalyze serotonylation through the transfer of serotonin to the glutamine residues of target proteins. This review aims to investigate recent progresses in understanding the involvement of serotonylation in physiological and pathological processes. In addition, this review emphasizes how to target serotonylation as a therapeutic strategy for disease management.
Keywords Serotonin, Transglutaminase, Serotonin transporter, Intracellular processes, Targeted therapy
Address and Contact Information 1 Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
2 Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
3 Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
*Corresponding author: Xiao Wang zjuwangxiao@zju.edu.cn Hai-Yun Xie 12018518@zju.edu.cn Jiang-Feng Li lijf@zju.edu.cn Jin-Dan Luo luojindan@zju.edu.cn
† Jia-Ming Wang, Feng-Hao Zhang, Yi-Ru Chen, Dan-Ni Chen have contribute equally to this work.
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No.  84DOI: 10.1186/s11658-026-00936-6 Volume 31 (2026) - 30:84
Title CRISPR AND COMPOUND SCREENS IN A NOVEL EX VIVO TISSUE MODEL IDENTIFY DDR1 AND ETA AS REGULATORS OF CANCER CELL INVASION
Authors Junnan Liu1,5†, Wencheng Jiang1,6†, Xue Wang1,6,7†, Anca Azoitei1, Hengchuan Liu1, Gregoire Najjar1, Kuangzheng Liu1, Michael Karl Melzer1, Stephan Stilgenbauer2, Mohamed Elati3, Martin D. Burkhalter4, Melanie Philipp4, Felix Wezel1, Friedemann Zengerling1, Christian Bolenz1*† and Cagatay Günes1*†
Abstract Background: Bladder cancer (BC) can be characterized clinically as either non-muscle-invasive (NMIBC) or muscle-invasive (MIBC). While NMIBC generally has a favorable prognosis, MIBC is characterized by high morbidity and mortality. Understanding the molecular determinants of tumor invasion is critical, yet research is hampered by the limitations of current experimental models. Standard assays such as the Boyden chamber lack physiological complexity, while porcine bladder models suffer from tissue contamination and genetic variability. There is an urgent need for reliable models that mimic the intact tissue architecture.
Methods: We established a unique ex vivo tissue invasion model (EXTIM) to evaluate the invasive capacity of BC cells within a largely intact tissue context, using freshly prepared bladders from mice. The invasiveness of human BC cells (RT4, T24, UMUC3) and the immortal urothelial cell strain (Y235T) was comparably evaluated using EXTIM, the Boyden chamber, and porcine models. Gene knockdown or ectopic expression of GJB3 or ORP3 indicated the suitability of EXTIM to investigate the impact of specific factors on tumor cell invasion. To identify novel genetic regulators of cell invasion, we combined EXTIM with a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout screen. Additionally, we utilized the EXTIM to perform a pharmacological screen of a small molecule library comprising 90 substances to identify compounds capable of suppressing BC cell dissemination.
Results: Importantly, by combining EXTIM with genomewide CRISPR-Cas9 screening, we identified several candidate genes involved in BC progression. Notably, discoidin domain receptor tyrosine kinase 1 (DDR1) was identified as a functional inhibitor of tumor cell invasion. Furthermore, the small-molecule screen revealed that PD-156707, a selective antagonist of the endothelin receptor A (ETA), significantly suppresses cancer cell invasion within the EXTIM environment.
Conclusions: EXTIM serves as a robust and physiologically relevant tool for assessing tumor cell invasion and migration under ex vivo conditions. EXTIM can be used to identify factors involved in the progression of invasive BC by high-throughput genetic screenings in an ex vivo organ culture system, by culturing cells after transmigration through the bladder tissue. Moreover, the impact of specific genetic factors in the process of tumor cell dissemination can be assessed by placing bladders from genetically modified mice into the EXTIM.
Keywords Bladder cancer, NMIBC, MIBC, Invasion, Metastasis, Ex vivo tissue model, Small-compound library, CRISPR-Cas9 screening
Address and Contact Information Department of Urology, Ulm University Hospital, Ulm, Germany
2 Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany
3 CANTHER, ONCOLille Institute, University of Lille, CNRS UMR 1277, Inserm U9020, Lille, France
4 Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University Tübingen, Tübingen, Germany
5 Present address: Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
6 Present address: Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA
7 Mol. Pharmacology and Exp. Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
*Corresponding author: Christian Bolenz Christian.Bolenz@uniklinik-ulm.de Cagatay Günes Cagatay.Guenes@uni-ulm.de
† Junnan Liu, Wencheng Jiang and Xue Wang contributed equally.
† Cagatay Günes and Christian Bolenz contributed equally to this work.
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No.  107DOI: 10.1186/s11658-026-00911-1 Volume 31 (2026) - 30:107
Title DNASE1L3 FUNCTIONS AS A SIGNIFICANT METASTATIC SUPPRESSOR BY ATTENUATING MYH9/β-catenin/c-Jun/LncRNA-KDM4A-INDUCED E-cadherin UBIQUITINATION DEGRADATION IN NASOPHARYNGEAL CARCINOMA
Authors Xingyu Tao1,2,3†, Xiong Liu4†, Xiangdong Zhao5,6†, Beixian Zhou1†, Chao Cheng7†, Weiwei Yan1, Jingjing He3, Haolin Cao3, Yun Su2,3, Jianyang Xin3, Xiaoning Gan9, Hong Peng5,6*, Wanli Lin1*, Weiyi Fang1,2* and Zhen Liu3,8*
Abstract Background: Deoxyribonuclease 1 Like 3 (DNASE1L3) is a member of the deoxyribonuclease I family that is associated with some diseases, including systemic lupus erythematosus and hypocomplementemic urticarial vasculitis. Recently, abnormal DNASE1L3 was preliminarily shown to correlate with tumor pathogenesis. However, its role is still undetermined in nasopharyngeal carcinoma (NPC).
Methods: Multiple sets of Gene Expression Omnibus (GEO) high-throughput data were utilized to screen the differentially expressed genes. Signal pathway enrichment analysis analyzed the correlation between DNASE1L3 and epithelial-mesenchymal transition (EMT) and cytoskeleton reorganization. An immunohistochemistry assay for analysis of DNASE1L3 expression was used to detect the clinical samples. Woundhealing, migration, invasion assays, and mouse model of lung metastasis were used to assess the role of DNASE1L3 in NPC metastasis. The mechanism of DNASE1L3 inhibition of NPC metastasis by attenuating MYH9/β-catenin/c-Jun/LncRNA-KDM4A-induced E-cadherin ubiquitination degradation was demonstrated by protein stability evaluation, co-immunoprecipitation, immunofluorescence, chromatin immunoprecipitation, dual-luciferase reporter assay, and RNA immunoprecipitation.
Results: DNASE1L3 downregulation in patients with NPC was not only negatively related to lymph node metastasis and distant metastasis but was also positively associated with poor prognosis. Overexpression of DNASE1L3 in NPC cells suppresses migration, invasion, and metastasis in vitro and in vivo. Inversely, DNASE1L3 knockdown increased cell migration and invasion abilities. Mechanistically, DNASE1L3 recruited PARK2 to ubiquitinate and degrade MYH9 protein. MYH9 protein activated β-catenin/c-Jun signal and augmented c-Jun-induced LncRNA-KDM4A transcription. In the process of DNASE1L3-induced metastatic suppression, decreased LncRNA-KDM4A attenuated the recruitment of E3 ubiquitin ligase Hakai and thus impeded the degradation of E-cadherin, by which heightened E-cadherin protein stability and finally inactivated the EMT signal.
Conclusions: Our data firstly elucidated that DNASE1L3 acts as a metastatic suppressor by attenuating E-cadherin ubiquitination degradation via the MYH9/β-catenin/c-Jun/LncRNA-KDM4A axis in NPC. DNASE1L3 is a potential marker for predicting NPC prognosis.
Keywords DNASE1L3, Epithelial-mesenchymal transition, Metastasis suppression, MYH9/β-catenin/c-Jun/LncRNA-KDM4A axis, Nasopharyngeal carcinoma
Address and Contact Information 1 Gaozhou People’s Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China 2 Department of Respiratory Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 3 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China 4 Department of Otolaryngology, Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China 5 Department of Otorhinolaryngology, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China 6 Department of Otorhinolaryngology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China 7 Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital, Shenzhen, China 8 Department of pathology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China 9 Department of Medical Oncology, Guangzhou First People’s Hospital, Guangzhou, China
*Corresponding author: Hong Peng doctorpenghong@163.com Wanli Lin wanliLin2020@163.com Weiyi Fang fangweiyi1975@163.com Zhen Liu narcissus_jane@163.com
† Xingyu Tao, Xiong Liu, Xiangdong Zhao, Beixian Zhou and Chao Cheng have contributed equally to this work.
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No.  109DOI: 10.1186/s11658-026-00944-6 Volume 31 (2026) - 30:109
Title REGULATION OF MITOCHONDRIAL FUNCTION DURING SPERMATOGENESIS AND SPERM MATURATION
Authors Kai Meng1,2*†, Ziming Zhu1,3†, Haocheng Jia1,3, Yingying Feng1,3, Jingwen Feng1,4, Yanlin Shen1,4, Wenjia Jiang1,3, Chenyan Liu1,4, Qin Qin5*, Fei Gao1,6* and Jinxiang Yuan1,2*
Abstract With the recent increase in the incidence of male infertility, greater attention is being paid to male reproductive health. The causes of male infertility are complex, and damage occurring during any process from spermatogenesis to fertilization can affect sperm quantity and quality of the sperm. Mitochondria are the power sources of cells and help regulate cellular homeostasis and physiological function. Mitochondria play a crucial role in male reproduction. Mitochondria undergo dynamic changes during spermatogenesis, sperm maturation, and fertilization. Mitochondrial dynamics and mitophagy help regulate the structure and function of mitochondria by meeting the cellular energy requirements of sperm during reproduction and reducing levels of damaged mitochondrial DNA (mtDNA); the elimination of excess mtDNA during fertilization prevents the spread of genetic mutations. Stable mitochondrial function ensures the smooth occurrence and maturation of sperm, maintaining male fertility. Externally induced mitochondrial dysfunction can lead to an inadequate energy supply, oxidative stress, cellular apoptosis, and abnormal sperm structure formation, which can lead to male infertility. In this article, the mechanism through which mitochondrial dysfunction affects the entire process of male reproduction, from spermatogonial stem cell division to final fertilization, and leads to infertility is discussed in chronological order. This article explores potential therapeutic targets for improving male fertility through therapies targeting mitochondrial function to provide a reference for subsequent research and more precise treatment directions.
Keywords Energy metabolism, Quality control, Genomic, Spermatogenesis, Male infertility
Address and Contact Information 1 Lin He’s Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, Jining, China
2 Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China
3 College of Clinical Medicine, Jining Medical University, Jining, China
4 College of Medical Imaging and Laboratory, Jining Medical University, Jining, China
5 Reproductive Medical Department, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, China
6 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
*Corresponding author: Kai Meng mengkai521888@126.com Qin Qin qinqin@sxmu.edu.cn Fei Gao gaof@ioz.ac.cn Jinxiang Yuan yuanjinxiang18@163.com
† Kai Meng and Ziming Zhu have contributed equally to this work.
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No.  110DOI: 10.1186/s11658-026-00932-w Volume 31 (2026) - 30:110
Title ENDOPLASMIC RETICULUM AND GOLGI STRESS SIGNALING-MEDIATED REGULATION OF PROTEIN SECRETION
Authors Ketsia Bakambamba1, Manon Nivet1, Sophie Martin1,2, Elodie Lafont1, Eric Chevet1,2 and Tony Avril1,2*
Abstract The eukaryotic secretory pathway (SP) is essential to ensure cellular functions and multicellular communication. The early SP is constituted mostly of the endoplasmic reticulum (ER), the ER–Golgi intermediate compartment (ERGIC), and the Golgi apparatus. These intracellular organelles achieve proper folding and modification of newly synthesized transmembrane and secretory proteins, en route to their final destination, e.g., plasma membrane, endosomes, lysosomes, and the extracellular space. They also integrate quality control systems to ensure export of productively folded proteins and to trigger dysfunctional proteins to degradation. The ER as the first SP compartment is subjected to a precise control of its own homeostasis through signaling of the unfolded protein response. In this review, we provide an overview of the early SP and its regulatory mechanisms, focusing on the ER and Golgi stress-dependent signaling. We contextualize this information within physiological and pathological processes, and discuss how ER and Golgi stress responses might coordinate their regulatory effects across the entire SP.
Keywords Secretory pathway, Protein secretion machinery, Endoplasmic reticulum stress response, Golgi stress response
Address and Contact Information 1 UMR1242 Oncogenesis Stress Signaling, Proteostasis and Cancer Team, INSERM, University of Rennes, 35042 Rennes, France
2 Centre de Lutte Contre Le Cancer Eugène Marquis, Rennes, France
*Corresponding author: Tony Avril t.avril@rennes.unicancer.fr
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No.  111DOI: 10.1186/s11658-026-00940-w Volume 31 (2026) - 30:111
Title RING FINGER E3 UBIQUITIN LIGASES: NOVEL THERAPEUTIC OPPORTUNITIES IN MELANOMA
Authors Ji-fang Zhang1, Long-tian Li1, Yue-ying Yang1, Shi-chen Zhang1, Chao Gao1, Xu Zhu1*, He Xin2* and Xin-yang Li1*
Abstract Melanoma is an aggressive type of cancer that is prone to developing resistance to targeted therapies and immunotherapies, so it is necessary to seek novel therapeutic opportunities. RING finger E3 ubiquitin ligases (RNFs) play a crucial role in the ubiquitin–proteasome system and are important in regulating the development of melanoma by orchestrating various pathways. In this review, we analyze the structural and functional characteristics of the RNF subfamily to clarify their mechanisms of action in melanoma and to compare the functional differences among various RNFs. Additionally, we systematically evaluate potential therapeutic strategies targeting RNFs, including small-molecule drugs, proteolysis-targeting chimeras (PROTACs), and molecular glues, and further propose new directions for drug design by using computer-aided technology. Furthermore, this review suggests that RNF-targeted therapy should be combined with existing therapies, providing a novel approach for the precise treatment of melanoma, and is significant for clinical application and drug development.
Keywords Melanoma, Ubiquitination, RNFs, PROTAC
Address and Contact Information 1 Department of Pharmacy, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang 110004, People’s Republic of China
2 Department of Interventional Radiology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang 110004, People’s Republic of China
*Corresponding author: Xu Zhu 13898800527@163.com He Xin xinhe518518@126.com Xin-yang Li xinyanglicmu@163.com
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No.  112DOI: 10.1186/s11658-026-00942-8 Volume 31 (2026) - 30:112
Title Rv1983 PROMOTES MYCOBACTERIAL DISSEMINATION BY TRIGGERING FERROPTOSIS THROUGH GPX4 UBIQUITINATION
Authors Zilu Qu1,2†, Yuanyuan Zhou3†, Qinzhen Cai4†, Tian Chen4,5, Yun Xiang4,5*, Liuqing Chen1,2* and Chunhui Yuan6,7*
Abstract Background: Ferroptosis, a unique form of regulated cell death induced by iron-dependent lipid peroxidation, has been implicated in the pathogenesis of Mycobacterium tuberculosis (Mtb). However, the role of Mtb proteins, particularly those encoded by the genomic regions of deletion (RDs), involved in mediating macrophage ferroptosis has not been thoroughly investigated. This study aimed to screen for Mtb RD region-encoded proteins that induce macrophage ferroptosis and elucidate the underlying molecular mechanisms.
Methods: We identified the Rv1983 protein with cytotoxic activity against murine bone marrow-derived macrophages (BMDMs) through screening of prokaryotically expressed Mtb RDs proteins, and subsequently determined the specific cell death modality induced by Rv1983 in BMDMs through flow cytometry, western blotting, and cytotoxicity assays following Rv1983 stimulation. To investigate the role of Rv1983 in Mtb infection, we constructed an Rv1983-knockout Mtb H37Ra strain (H37RaΔRv1983) and compared its intracellular and extracellular bacterial loads with wild-type H37Ra strain in infected BMDMs. Using coimmunoprecipitation, immunofluorescence, and flow cytometry, we identified and validated the target protein of Rv1983 in macrophages and its functional role in Rv1983-mediated macrophage death. For in vivo validation, wild-type H37Ra and H37RaΔRv1983 strains were used to infect both wild-type and macrophage-specific Rv1983-binding protein knockout mice, and the role of Rv1983 during Mtb infection was assessed through bacterial colony counting, flow cytometry analysis, and histochemical staining.
Results: This study identifies Rv1983 (PE_PGRS35), an RD2-encoded secreted protein of Mtb that acts as a ferroptosis effector to promote mycobacterial dissemination. Mechanistically, Rv1983 binds to E3 ubiquitin ligase tripartite motif 25 (TRIM25) in macrophages through its PE domain, especially on the Y62 site. The Rv1983–TRIM25 complex interacts with glutathione peroxidase 4 (GPX4), and subsequently promotes K48-linked ubiquitination degradation of GPX4 at the K75 site, ultimately inducing ferroptosis to promote mycobacterial dissemination. An Rv1983-deficient Mtb strain (H37RaΔRv1983) displayed significant suppression of Mtb dissemination both in vitro and in vivo.
Conclusions: These findings provide a new insight into the molecular mechanism of Mtb-induced ferroptosis, and suggest that targeting ferroptosis mediated by the Rv1983–TRIM25–GPX4 signaling axis is a potential strategy for therapeutic control of tuberculosis.
Keywords Mycobacterium tuberculosis, Ferroptosis, Rv1983, TRIM25, GPX4 ubiquitination
Address and Contact Information 1 Hubei Province and Key Laboratory of Skin Infection and Immunity, Wuhan No. 1 Hospital, Wuhan 430022, China
2 Department of Dermatology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
3 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
4 Department of Laboratory Medicine, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, China
5 Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China
6 Department of Laboratory Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China
7 Institute of Clinical Molecular Diagnosis, Wuhan University, Wuhan 430060, China
*Corresponding author: Yun Xiang xiangyun5272008@163.com Liuqing Chen chlq35@126.com Chunhui Yuan chunhuii.yuen@whu.edu.cn
† Zilu Qu, Yuanyuan Zhou, and Qinzhen Cai contributed equally to this work.
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No.  113DOI: 10.1186/s11658-026-00913-z/span> Volume 31 (2026) - 30:113
Title NAT10-mediated ac4C MODIFICATION OF TNFRSF1A PROMOTES ACUTE KIDNEY INJURY BY ACTIVATING NF-κB PATHWAY
Authors Minjie Zhang1, Yankun Li1, Chunyu Wu1, Quanren Pan1, Peng Wang1* and Hua-Feng Liu1*
Abstract Background: Acute kidney injury (AKI) is closely linked to inflammatory responses driven by the NF-κB pathway, yet the epigenetic mechanisms underlying this association remain poorly understood. This study investigates the role of N-acetyltransferase 10 (NAT10)-mediated RNA N4-acetylcytidine (ac4C) modification in regulating NF-κB signaling during AKI.
Methods: Clinical AKI specimens and experimental models (in vivo and in vitro) were analyzed to assess NAT10 expression in renal tubular epithelial cells (RTECs). Genetic knockdown and overexpression of NAT10 (including the catalytically inactive NAT10-G641E mutant) were performed in vitro to evaluate NF-κB pathway activity and hypoxia/reoxygenation (H/R)-induced inflammatory responses. In murine ischemia/reperfusion (I/R)-induced AKI models, genetic ablation of NAT10 in RTECs and pharmacological inhibition using Remodelin were employed to study renal inflammation and injury. Mechanistic insights were derived from integrated ac4C acetylated RNA immunoprecipitation sequencing (acRIP-seq) and RNA sequencing (RNA-seq) analyses to identify NAT10-mediated ac4C modification targets and their effects on RNA stability, translation efficiency, and signaling pathways.
Results: NAT10 was significantly upregulated in RTECs of clinical AKI specimens and experimental models. In vitro, NAT10 knockdown suppressed NF-κB activation, mitigating H/R-induced inflammation and cellular damage, while NAT10 overexpression (but not the G641E mutant) activated NF-κB, exacerbating RTECs injury. In murine I/R-AKI models, genetic or pharmacological inhibition of NAT10 attenuated NF-κB-mediated renal inflammation and tubular damage. Mechanistically, NAT10-mediated ac4C modification enhanced RNA stability and translation efficiency of tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), leading to aberrant NF-κB activation and subsequent inflammatory cascades.
Conclusions: This study identifies the NAT10–ac4C–TNFRSF1A axis as a novel epigenetic regulator of NF-κB-driven renal inflammation in AKI. NAT10 promotes inflammatory signaling and tubular damage by enhancing TNFRSF1A mRNA stability and translation efficiency, highlighting its potential as a therapeutic target. These findings provide a theoretical foundation for developing AKI treatments targeting NAT10-mediated ac4C modification to mitigate NF-κB-dependent pathology.
Keywords N-acetyltransferase 10, N4-acetylcytidine, Acute kidney injury, Tumor necrosis factor receptor superfamily member 1A, NF-κB pathway
Address and Contact Information 1 Department of Nephrology, National Clinical Key Specialty Construction Program (2023); Institute of Nephrology; Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases; Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
*Corresponding author: Peng Wang wangpeng@gdmu.edu.cn Hua-Feng Liu liuhf@gdmu.edu.cn
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No.  102DOI: 10.1186/s11658-026-00941-9 Volume 31 (2026) - 30:102
Title IMPLICATIONS OF FERRITINOPHAGY IN CARDIOVASCULAR DISEASES AND ITS PHARMACOLOGICAL MODULATION: UNDERLYING MECHANISMS AND CLINICAL TRANSLATION STRATEGIES
Authors Yan-lin Wu1,2, Ling Xiao3, He-ning Li4 and Lin-xi Chen2,5*
Abstract Ferritinophagy is a crucial intracellular process mediated by the selective autophagy receptor nuclear receptor coactivator 4 (NCOA4), which plays a central role in maintaining iron homeostasis by regulating ferritin degradation. In recent years, its function as a key interface between autophagy and iron metabolism has attracted considerable attention owing to its pathophysiological relevance in cardiovascular diseases (CVDs). This review systematically delineates the molecular mechanisms of ferritinophagy, including the formation of the NCOA4–ferritin complex, lysosomal degradation pathways, and the multilayered regulatory networks involved. Particular focus is given to the dual role of ferritinophagy in cardiovascular pathology, encompassing myocardial ischemia–reperfusion injury (MIRI), atherosclerosis (AS), and diabetic cardiomyopathy (DCM). While moderate ferritinophagy activity is essential for maintaining adequate cardiac iron supply, its excessive activation leads to labile iron accumulation, oxidative stress via the Fenton reaction, and ferroptosis, thereby exacerbating myocardial injury and pathological remodeling. Consequently, this article provides a comprehensive overview of pharmacological strategies targeting ferritinophagy, including direct inhibition approaches (e.g., NCOA4 small interfering RNA (siRNA) and lysosomal inhibitors) and indirect modulation strategies (e.g., ferroptosis inhibitors and natural compounds). Finally, challenges to clinical translation are addressed, particularly regarding tissue specificity, drug delivery efficiency, and long-term safety. Future research directions are proposed, including the development of organ-specific targeting strategies and the exploration of combination therapies, with the aim of offering novel insights and potential therapeutic avenues for the prevention and treatment of CVDs.
Keywords Cardiovascular diseases, Ferritinophagy, NCOA4
Address and Contact Information 1 School of Basic Medical Sciences, University of South China, Hengyang 421001, Hunan, China
2 Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 421001, Hunan, China
3 School of Pharmaceutical Science, Yiyang Medical College, Yiyang 413000, Hunan, China
4 Yueyang Central Hospital, Yueyang 414000, Hunan, China
5 School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang 421001, Hunan, China
*Corresponding author: Lin-xi Chen 1995001765@usc.edu.cn
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No.  114DOI: 10.1186/s11658-026-00935-7 Volume 31 (2026) - 30:114
Title COMING TO LIGHT: THE TRANSCRIPTIONAL REGULATORY ROLES OF HISTONE LYSINE CROTONYLATION IN HEALTH AND DISEASE
Authors Shang-Kun Dai1*, Naixia Ren1, Chang-Mei Liu2* and Fengtang Yang1*
Abstract Research on histone lysine crotonylation has evolved from identifying its core regulatory factors and mapping its genome-wide landscape to dissecting its functions in physiological and pathological contexts. Since its discovery nearly 15 years ago, extensive biochemical, structural, and genetic studies have deepened our understanding of how this evolutionarily conserved modification is integrated into intricate epigenetic regulatory networks. In this review, we first summarize mechanistic insights into the molecular basis of transcriptional regulation mediated by histone crotonylation, and discuss competitive crosstalk between this modification and histone acetylation in local chromatin regions. We then present an updated integrative framework to systematically delineate the regulatory roles of histone crotonylation across genes with distinct transcriptional states, as well as its functional implications in health and disease. Finally, we propose a unifying context-dependent model for histone crotonylation-mediated transcriptional regulation, and outline key challenges and future directions in the field.
Keywords Histone crotonylation, Transcriptional regulation, Chromatin state, Development and disease
Address and Contact Information 1 School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255000, Shandong, China
2 Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
*Corresponding author: Shang-Kun Dai dsk19930907@163.com Chang-Mei Liu liuchm@ioz.ac.cn Fengtang Yang fengtangyang@163.com
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No.  115DOI: 10.1186/s11658-026-00945-5 Volume 31 (2026) - 30:115
Title H2S INDUCES APOPTOSIS OF TUMORS WITH HIGH IDO1 EXPRESSION VIA NR4A1-BCL-2 AND SOCS3 PATHWAYS
Authors Zhen Ning Tony He1†, Fangzhou Meng1†, Xiaoyang Qian1, Yuying Liu1, Xin Fang1, Dan Yang2* and Qing Yang1*
Abstract Background: Hydrogen sulfide (H2S) has been reported to exert both protumor and antitumor functions. It is worthy to clarify the condition under which H2S exerts antitumor effects and its underlying mechanism. Our previous study connected the immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1) and H2S by revealing that H2S downregulates IDO1 expression, leading to our hypothesis that antitumor effect of H2S is associated with IDO1 expression in tumor cells.
Methods: Apoptosis, cellular distribution of NR4A1, phosphorylation of IDO1, and the binding of phosphorylated IDO1 and SOCS3 are examined both in vitro and in vivo.
Results: In this study, we confirm our hypothesis by showing that H2S significantly reduces proliferation and induces apoptosis of tumor cells with high IDO1 expression. In tumor cells with high IDO1 expression, H2S promotes the translocation of NR4A1 out of nucleus and its binding with BCL-2, as well as the phosphorylation of IDO1 and the codegradation of phosphorylated IDO1 and SOCS3. Such mechanism by which H2S induces apoptosis of tumors with high IDO1 expression is also elucidated in tumor-bearing mice, where H2S shows great therapeutic effect against tumors with high IDO1 expression.
Conclusions: H2S induces apoptosis of tumor cells with high expression of IDO1 by promoting NR4A1-BCL-2 apoptotic pathway and the codegradation of phosphorylated IDO1 and SOCS3. Our study provides new theoretical and experimental evidence for a strategy for tumor therapy with H2S.
Keywords Hydrogen sulfide, Indoleamine 2,3-dioxygenase 1, Apoptosis, Tumor therapy
Address and Contact Information 1 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Songhu Road 2005, Shanghai 200438, China
2 Department of Orthopedics, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Luding Road 355, Shanghai 200062, China
*Corresponding author: Dan Yang yangdan@shchildren.com.cn Qing Yang yangqing68@fudan.edu.cn
† Zhen Ning Tony He and Fangzhou Meng contributed equally to this work.
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No.  116DOI: 10.1186/s11658-026-00938-4 Volume 31 (2026) - 30:116
Title QSOX1 CONFERS FERROPTOSIS RESISTANCE VIA REDOX MODIFICATION OF SLC7A11 IN COLORECTAL CANCER
Authors Mengqi Jia1*†, Hanxiang Chen2†, Yulin Liu4†, Jianzhuang Guo2, Xiaofei Wang2, Qiang Liu5, Zhiheng Liu6, Zhaoqing Meng7, Chunqing Wang2* and Yunqiu Wang2,3*
Abstract Background: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for colorectal cancer (CRC). However, the precise mechanisms by which CRC cells evade ferroptosis remain incompletely understood. Cysteine redox modification, typically catalyzed by cysteine oxidases, is a key regulatory factor governing protein structure and function. Quiescin sulfhydryl oxidase 1 (QSOX1), a Golgi-localized sulfhydryl oxidase known to promote various physiological functions, has an uncharacterized role in ferroptosis. Therefore, this study investigated the effects of QSOX1 on ferroptosis sensitivity in colorectal cancer.
Methods: We utilized a comprehensive set of analytical techniques to elucidate the mechanisms of QSOX1 in CRC ferroptosis resistance. We assessed cell proliferation, colony formation, and sensitivity to ferroptosis inducers (Erastin and RSL3) in CRC cells. Levels of reactive oxygen species (ROS), intracellular Fe2+, and redox metabolites were measured by biochemical assays and flow cytometry. RNA sequencing (RNA-seq) and untargeted metabolomics were performed using QSOX1-deficient HT-29 cells. The interaction between QSOX1 and SLC7A11 was confirmed via coimmunoprecipitation, immunofluorescence, and nonreducing gel electrophoresis. Cystine uptake and glutamate release assays were used to assess SLC7A11 function. Tumor xenografts were generated to assess the in vivo sensitivity of colon cancer cells to ferroptosis inducers.
Results: QSOX1 was significantly upregulated in CRC tissues and promoted CRC cell proliferation in vitro and in vivo. Knockdown of QSOX1 sensitized CRC cells to ferroptosis inducers, whereas QSOX1 overexpression conferred resistance. Mechanistically, QSOX1 enhanced redox homeostasis and GSH metabolism in CRC cells. QSOX1 interacted with and facilitated redox modification of SLC7A11 at cysteine 158 via its thioredoxin motif (C449-C452) in the ERV/ALR domain. This oxidative regulation enhanced SLC7A11 membrane localization, cystine uptake, and glutamate release, thereby boosting intracellular GSH synthesis and suppressing ferroptosis.
Conclusions: QSOX1 promotes ferroptosis resistance in CRC cells through redox-dependent post-translational modification of SLC7A11, enhancing its activity and promoting GSH synthesis. The QSOX1–SLC7A11 axis represents a potential therapeutic target to overcome ferroptosis resistance in CRC.
Keywords Colorectal cancer, Ferroptosis, Redox modification, QSOX1, SLC7A11
Address and Contact Information 1 Institute of Medical Sciences, The Second Qilu Hospital of Shandong University, Jinan, China
2 Department of Clinical Laboratory Medicine, Shandong Medicine and Health Key Laboratory of Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
3 Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, China
4 Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
5 Laboratory of Translational Medicine in Microvascular Regulation, Medical Research Center, Shandong Provincial Key Laboratory of Medicine in Microvascular Ageing, Laboratory of Future Industry of Gene Editing in Vascular Endothelial Cells of Universities in Shandong Province, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
6 Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
7< College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
*Corresponding author: Mengqi Jia jiamengqi@email.sdu.edu.cn Chunqing Wang wangchunqing@sdfmu.edu.cn Yunqiu Wang wangyunqiu@sdfmu.edu.cn
† Mengqi Jia, Hanxiang Chen and Yulin Liu contributed equally to this work.
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No.  117DOI: 10.1186/s11658-026-00939-3 Volume 31 (2026) - 30:117
Title DISCOVERY OF A NOVEL CANNABIDIOL-DERIVED TRANSIENT RECEPTOR POTENTIAL VANILLOID 4 INHIBITOR TO REDUCE PULMONARY EDEMA AND LUNG VASCULAR PERMEABILITY IN MICE
Authors Yassir Arfath1,2†, Pankaj Singh Cham2,3†, Tusharika Kotra1,2, Rahila Akhter1,2, Sumeer Ahmed3, Mandeep Kour3, Sheikh Tasduq Abdullah1,2, Parvinder Pal Singh2,3*, Sheikh Rayees1,2* and Zabeer Ahmed1,2*
Abstract Introduction: Activation of TRPV4 ion channel during acute lung injury (ALI) exacerbates lung dysfunction by promoting edema and inflammation. Pharmacological inhibition of TRPV4 signaling in the lungs offers protective benefits, reducing vascular leakage, enhancing blood oxygenation, and alleviating edema.
Objectives: We designed, synthesized, and preclinically evaluated cannabidiol-derived TRPV4 channel inhibitors for potential therapeutic application in ALI and future clinical translation.
Methods: We identified a lead cannabidiol-derived TRPV4 inhibitor through specific in vitro screening assays. The lead compound was then tested in a series of animal models of ALI. Initial evaluation employed the lipopolysaccharide (LPS) induced lung injury model, followed by models involving TRPV4 overexpression in alveolar macrophages, as well as models featuring TRPV4 hyperactivation. These models were strategically chosen to replicate key pathological features of clinical ALI.
Results: Our investigation revealed that administration of the lead derivative CS-85(4j) demonstrated significant protective effects in a mouse model of ALI. CS-85 effectively prevented lung edema and maintained the integrity of pulmonary vascular barrier. Notably, it inhibited neutrophil influx into the lung, reduced proinflammatory cytokine production, and mitigated associated pathological changes. In additional relevant preclinical in vivo models, we further investigated how TRPV4 hyperactivation via pharmacological stimulation and overexpression in alveolar macrophages through liposome-mediated gene delivery exacerbated key features of ALI. CS-85 effectively reduced this exaggerated lung inflammation and alleviated the ALI features. In exploring the downstream mechanisms of CS-85, we found that its pharmacological efficacy is mediated through modulation of the NLRP3-caspase-1, NFAT, and NF-ĸB signaling pathways, all of which are crucial inflammatory cascades.
Conclusions: We identified CS-85 as a potent and promising TRPV4 inhibitor that demonstrates strong preclinical efficacy in mitigating ALI by preserving vascular integrity and modulating key inflammatory signaling pathways. Its dual mechanism of action highlights its therapeutic potential for ALI and supports further clinical evaluation.
Keywords TRPV4, Inflammation, ALI, Ca2+, Cannabidiol, Edema, Vascular permeability, NLRP3
Address and Contact Information 1 Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
2 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
3 NPMC Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
*Corresponding author: Parvinder Pal Singh ppsingh.iiim@csir.res.in; ppsingh@iiim.ac.in Sheikh Rayees rayeesh.iiim@csir.res.in; rayees.sheikh@gmail.com Zabeer Ahmed zahmed.iiim@csir.res.in
† Yassir Arfath and Pankaj Singh Cham contributed equally.
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No.  118DOI: 10.1186/s11658-026-00937-5 Volume 31 (2026) - 30:118
Title m6A-MODIFICATED Linc00707 PROMOTES THE PROGRESSION OF TNBC VIA U2AF2-MEDIATED ALTERNATIVE SPLICING OF ATG4B
Authors Hongli Li1,2, Yong Li2, Qinghua Liu2, Chonggao Yin3, Yunxiang Zhang4* and Peng Gao1*
Abstract Background: Triple-negative breast cancer (TNBC) represents a clinically aggressive breast cancer subtype with limited therapeutic options. Emerging evidence suggests that long intergenic noncoding RNA 00707 (Linc00707) plays a role in TNBC; however, the upstream regulators governing Linc00707 expression and the mechanisms by which it contributes to tumor progression remain largely undefined.
Method: The FOXP3-mediated transcriptional regulation of Linc00707 was analyzed using chromatin immunoprecipitation and luciferase reporter assays. The post-transcriptional regulation of Linc00707 was examined by RNA immunoprecipitation (RIP), methylated RIP, and RNA pull-down assays to assess WTAP-dependent m6A modification, IGF2BP2-mediated stabilization, and U2AF2 interaction. RNA sequencing and biochemical analyses were used to identify downstream regulatory pathways. The binding of oligo-anti-Linc00707 to Linc00707 and its ability to disrupt U2AF2 association were confirmed by RIP and RNA fluorescence in situ hybridization (RNA-FISH). Cellular assays and nude mouse xenograft models were employed to evaluate functional and therapeutic effects.
Results: FOXP3 was found to transcriptionally activate Linc00707 through direct promoter binding. The WTAP-mediated m6A modification enhanced the IGF2BP2-dependent stabilization of Linc00707. In the nucleus, Linc00707 interacted with the splicing factor U2AF2, with nucleotides 1–593 identified as a critical interaction region. Building on this observation, we further showed that the Linc00707–U2AF2 interaction functionally controls U2AF2 expression and stability via FOXP3. The Linc00707–U2AF2 complex was associated with altered alternative splicing of the autophagy-related gene ATG4B, contributing to enhanced TNBC cell proliferation, invasion, and autophagy suppression. Importantly, oligonucleotides complementary to the U2AF2-binding region of Linc00707 (oligo-anti-Linc00707) disrupted this interaction, attenuated Linc00707-driven oncogenic phenotypes, and restored autophagic activity. In vivo, oligo-anti-Linc00707 treatment significantly reduced tumor growth, supporting its therapeutic potential in TNBC.
Conclusions: FOXP3 activates Linc00707 transcription in TNBC. WTAP-mediated m6A modification enhances Linc00707 stability via IGF2BP2. Linc00707 recruits U2AF2 to drive oncogenic ATG4B splicing, promoting tumor progression. Oligo-anti-Linc00707 specifically blocks Linc00707-U2AF2 complex formation, reversing its tumor-promoting and autophagy-suppressing functions. Thus, targeting Linc00707 represents a promising therapeutic strategy for TNBC.
Keywords TNBC, Linc00707, RNA splicing, Autophagy
Address and Contact Information 1 Department of Pathology, Qilu Hospital and School of Basic Medical Sciences, Shandong University, Jinan 250012, Shandong, China
2 Medicine Research Center, Shandong Second Medical University, Weifang 261053, Shandong, China
3 College of Nursing, Shandong Second Medical University, Weifang 261053, Shandong, China
4 Department of Molecular Pathology, Qingdao Central Hospital of University of Health and Rehabilitation Sciences, Qingdao 266114, Shandong, China
*Corresponding author: Yunxiang Zhang zhangyunxiang@uhrs.edu.cn Peng Gao gaopeng@sdu.edu.cn
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No.  127DOI: 10.1186/s11658-026-00933-9 Volume 31 (2026) - 30:127
Title GENOMIC CONTEXT OF MUTATIONS IN MIR142 IN BLOOD CANCERS: SUMMARY AND INTEGRATIVE ANALYSIS
Authors Wladyslaw Wegorek1†, Adrian Tire1†, Daniel Kuznicki1, Julia Richter2, Maciej Giefing3, Wolfram Klapper2, Piotr Kozlowski1* and Paulina Galka-Marciniak1*
Abstract MIR142 is the most frequently mutated microRNA (miRNA) gene in cancer, with recurrent alterations observed particularly in hematologic malignancies of lymphoid origin. It is expressed at very high levels in blood cells and plays an essential role in the development, differentiation, and maturation of various lymphopoietic and hematopoietic lineages. To gain a deeper understanding of MIR142 mutations, we summarize all data on these mutations, including their frequency in different cancers, their location within the miR-142 precursor, and their functional consequences. We also analyzed MIR142 mutations within a broader genomic context in thousands of cancers, including hundreds of blood neoplasms. Our results show that the most prevalent mutations in the MIR142 gene originate from a clearly distinct hotspot in hematologic malignancies, concentrated mainly within the sequence of the secondary miR-142 precursor. We found substantial differences in mutation frequency and distribution across cancer types. This indicates that MIR142 alterations are not random consequences of an increased mutational load but are likely subject to positive selection, underscoring their biological and clinical significance.
Keywords miR-142, DLBCL, AML, Lymphoma, miRNA mutations, CLL
Address and Contact Information 1 Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
2 Hematopathology Section, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
3 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
*Corresponding author: Piotr Kozlowski kozlowp@ibch.poznan.pl Paulina Galka-Marciniak pgalka@ibch.poznan.pl
† Wladyslaw Wegorek and Adrian Tire have contributed equally to this work.
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No.  101DOI: 10.1186/s11658-026-00920-0 Volume 31 (2026) - 30:101
Title NEUTROPHILS BLEND INNATE AND ADAPTIVE IMMUNITY IN EARLY BREAST MILK
Authors Gema Gomez-Casado1,2, Natalia Saldaña-García1,3, Antonio Cantarero-Cuenca4, Andrés Gonzalez-Jimenez4, Guillermo Paz-López4, Patricia Garcia-Hurtado5, Francisco J. Tinahones1,2,6,7*, Ernesto González-Mesa1,5,8† and Almudena Ortega-Gomez1,2,6,9*†
Abstract Background: Breast milk not only is the most optimal source of nutrition for newborns but also provides crucial immune support. While there is extensive evidence highlighting the health benefits of breastfeeding, the scientific understanding behind many of these advantages remains limited. The immune cell fraction of breast milk has been poorly studied, and characterization of this essential component may be crucial to shed light on the subject. Here, we investigate the population of neutrophils in breast milk to unveil their phenotype and functions.
Methods: Neutrophils in human breast milk were characterized by flow cytometry, and their phenotype was contrasted with that of their circulating counterparts using a paired approach. Transmission electron microscopy (TEM), intracellular granule immunocytochemistry, and Giemsa staining were employed to reveal their intracellular structure. In vitro neutrophil incubations were performed to assess the phenotypic modifications of circulating neutrophils in a breast milk environment. Functional assays were carried out to assess the activity of neutrophils and their potential impact on adaptive immunity. Finally, a proteomic approach was used on isolated neutrophils and their supernatant after cultivation to define the protein-based mechanisms involved in their biology. Paired t-tests and one- and two-way analysis of variance (ANOVA) were used for statistical analyses.
Results: In the breast milk from the first 5 days (known as colostrum), neutrophils represent most of the cellular compartment. Colostrum neutrophils present a cell surface signature markedly different from circulating neutrophils with a clear CXCR4+CD62L−CXCR2mid phenotype and important differences in other markers. These differences are partially phenocopied upon incubation of blood neutrophils with colostrum whey, implying that cell transition occurs owing to the niche environment. Additionally, colostrum neutrophils exhibit reduced cytoplasmic granule content and altered canonical functions. Proteomic analyses reveal that the most important processes in colostrum neutrophils are related to antigen binding and humoral response pathways.
Conclusions: This study provides evidence of a unique population of neutrophils in early breast milk connected to adaptive immunity, which may hold the key to understanding the mechanisms behind the immunological benefits of breastfeeding.
Keywords Neutrophil, Breast milk, Colostrum, Humoral response, Antigen, Proteomics
Address and Contact Information 1 Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma BIONAND), Universidad de Málaga, Málaga, Spain
2 Department of Endocrinology and Nutrition, Virgen de La Victoria University Hospital, Málaga, Spain
3 Department of Neonatology, Regional University Hospital of Málaga, Málaga, Spain
4 Bioinformatics Platform, Instituto de Investigación Biomédica de Málaga (IBIMA Plataforma BIONAND), Málaga, Spain
5 Department of Obstetrics and Gynecology, Regional University Hospital of Malaga, Málaga, Spain
6 CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
7 Department of Medicine and Dermatology, Faculty of Medicine, Universidad de Málaga, Málaga, Spain
8 Departmet of Surgical Specialties, Biochemistry and Immunology, Faculty of Medicine, Universidad de Málaga, Malaga, Spain
9 Department of Cardiology and Cardiovascular Surgery, Virgen de La Victoria University Hospital, Málaga, Spain
*Corresponding author: Francisco J. Tinahones fjtinahones@uma.es Almudena Ortega-Gomez almudena.ortega@ibima.eu
† Ernesto González-Mesa and Almudena Ortega-Gomez contributed equally to this work.
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No.  119DOI: 10.1186/s11658-026-00955-3 Volume 31 (2026) - 30:119
Title GPR161 CONTRIBUTES TO MACROPHAGE GLYCOLYTIC REPROGRAMMING VIA TARGETING C5aR1 IN ACUTE LUNG INJURY
Authors Yu-Huan Li1,2†, Xue Yang3†, Ying Chen3†, Miao Wang3, Han Shu3, Ke Wan3, Dan-Tong Sun3, Ning Yao3, Ying-Li Yang3, Fei Zhao2, Bo-Bo Han2, Chao Yao2, Biao Song4, Jing Bao5, Geng-Yun Sun1*†, Jun Li3*† and Xiao-Feng Li3,6*†
Abstract Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are severe respiratory disorders characterized by a dysregulated and excessive inflammatory response within the pulmonary system. Recent studies have underscored the pivotal role of macrophage activation in driving inflammatory processes, with glycolytic reprogramming emerging as a critical regulator of macrophage function. In this study, we observed significantly elevated expression levels of G protein-coupled receptor 161 (GPR161) in peripheral circulating monocytes from patients with ARDS, with GPR161 expression positively correlating with disease severity. Utilizing genetically engineered mouse models, including global and macrophage-specific conditional knockout mice, we demonstrated that GPR161 deficiency attenuated pulmonary inflammatory damage in lipopolysaccharide-induced and sepsis-associated ALI mice. In vitro experiments further elucidated the essential role of GPR161 in macrophage activation and glycolytic reprogramming. Mechanistic investigations, integrating RNA sequencing with co-immunoprecipitation and surface plasmon resonance assays, identified complement component 5a receptor 1 (C5aR1) as a downstream target of GPR161 and showed that GPR161 promotes glycolytic reprogramming in macrophages by suppressing C5aR1 expression. Collectively, these findings demonstrate that GPR161 enhances macrophage activation and glycolytic reprogramming in ALI/ARDS through a C5aR1-dependent mechanism. These results establish macrophage GPR161 as a promising therapeutic target for the treatment of ALI/ARDS.
Keywords Acute lung injury, Acute respiratory distress syndrome, Macrophage, Inflammatory response, G protein-coupled receptor 161, Glycolytic reprogramming
Address and Contact Information 1 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
2 Department of Tuberculosis, Anhui Chest Hospital, Hefei 230022, China
3 Inflammation and Immune Mediated Disease Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China
4 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
5 Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
6 Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
*Corresponding author: Geng-Yun Sun sungengy@126.com Jun Li lj@ahmu.edu.cn Xiao-Feng Li lixiaofeng@ahmu.edu.cn
† Yu-Huan Li, Xue Yang, Ying Chen have contributed equally to this work.
† Xiao-Feng Li, Jun Li and Geng-Yun Sun have contributed equally to this paper.
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No.  121DOI: 10.1186/s11658-026-00919-7 Volume 31 (2026) - 30:121
Title HucMSC-MEDIATED STROMAL METABOLIC REPROGRAMMING IN REACTIVATING AGED OVARIES: A SINGLE-CELL TRANSCRIPTOMIC PERSPECTIVE
Authors Ying-Yi Zhang1,2,3†, Yuqing Mei1,4†, Weijie Yang1,2,3†, Hanjing Zhou1,2,3, Yan Zhou1,2,3, Yingyan Chen1,2,3, Yi Zhang1,2,3, Jianmin Chen1,2,3, Jiamin Jin1,2,3, Xiaomei Tong1,2,3, Libing Shi1,2,3, Dong Huang1,2,3, Guoji Guo4*, Yin-Li Zhang1,2,3* and Songying Zhang1,2,3*
Abstract Background: Aging-induced decline in ovarian function and oocyte quality contributes to female infertility. However, the mechanisms underlying human umbilical cord-derived mesenchymal stem cell (HucMSC)-mediated rejuvenation of aged ovaries remain poorly understood. This study aimed to systematically investigate whether and how HucMSCs restore ovarian function and oocyte quality and elucidate the potential pathways involved.
Methods: Aged mice received in situ ovarian injections of HucMSCs. Ovarian follicular development and fertility outcomes were assessed. Low-input RNA-seq and single-cell RNA sequencing (scRNA-seq) were applied to evaluate transcriptomic heterogeneity in oocytes and somatic cells separately. Additionally, the molecular change and function of HucMSC-primed stromal cells (SCs) in aged ovaries were assessed to validate SCs’ functional roles in ovarian microenvironment improvement.
Results: HucMSC treatment enhanced follicular development, increased antral follicle numbers, and partially restored fertility in aged mice. Oocyte transcriptomes in HucMSC-treated mice resembled those of young mice, with 75% of aging-dysregulated genes (notably mitochondrial respiratory chain complex assembly-related genes) reverting to youthful expression patterns. scRNA-seq revealed upregulated transcription and glycolysis in granulosa cells (GCs), alongside stromal cell fate redirection toward steroidogenesis and folliculogenesis instead of fibrosis. Transplantation of HucMSC-primed SCs replicated these restorative effects. Mechanistically, HucMSCs promoted pregnenolone synthesis in stromal cells, facilitating follicular development.
Conclusions: HucMSCs reactivate aged ovaries by inducing metabolic reprogramming in both oocytes and somatic cells, enhancing mitochondrial function in oocytes, and redirecting stromal cells toward steroidogenic and folliculogenic pathways. These findings underscore stromal cell functional modulation as a critical mechanism in counteracting ovarian aging and revealing the potential of stromal cells as therapeutic targets.
Keywords Mesenchymal stem cells, Follicular microenvironment, Ovarian aging, Ovarian stroma, Metabolic reprogramming
Address and Contact Information 1 Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
2 Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou 310016, China
3 Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou 310016, China
4 Bone Marrow Transplantation Center of the First Affiliated Hospital, and Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China
*Corresponding author: Guoji Guo ggj@zju.edu.cn Yin-Li Zhang zhangyinli@zju.edu.cn Songying Zhang zhangsongying@zju.edu.cn
† Ying-Yi Zhang, Yuqing Mei, and Weijie Yang have contributed equally to this work and share first authorship.
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No.  123DOI: 10.1186/s11658-026-00960-6 Volume 31 (2026) - 30:123
Title Enolase 2-MEDIATED LACTYLATION-DEPENDENT DISRUPTION OF THE GNL3–MDM2–p53 AXIS IN AGE-RELATED OSTEOARTHRITIS
Authors Feng Hua1†, Jiangyu Nan1†, Rong Wu1, Bin Zhang1, Qimeng Liu1, Tianliang Ma1, Zheyu Zhang1, Yihe Hu1*, Jie Xie1* and Yute Yang1*
Abstract Background: Age-related osteoarthritis (OA) involves metabolic dysregulation and chondrocyte senescence. This study examined the nonmetabolic role of enolase 2 (ENO2) in OA pathogenesis and its therapeutic potential.
Methods: Human aged and OA cartilage (n= 3 per group) underwent 18F-FDG positron emission tomography (PET)–computed tomography (CT) imaging, proteomic profiling, and immunohistochemistry. In vitro chondrocyte senescence models were generated by inducing doxorubicin-induced stress and serial passaging. Protein–protein interactions (ENO2–GNL3–MDM2) were validated by co-immunoprecipitation (IP), GST pull-down, and site-directed mutagenesis (E4A-ENO2 and K5R-GNL3 mutants). Lactylation was assessed using lactylomics and immunoprecipitation. The therapeutic effect of the ENO2-specific inhibitor POMHEX was evaluated in C57BL/6 J mice (n = 6 per group) via intra-articular injection for 16 weeks. Outcomes included histology, micro-CT, pain behavior, and gait analysis.
Results: Proteomics revealed ENO2 upregulation in aged human cartilage. In vitro, ENO2 overexpression promoted extracellular matrix catabolism, senescence, and glycolysis, whereas ENO2 knockdown attenuated these processes. Mediated by its Glu-4 residue, nuclear ENO2 bound GNL3 lactylated at Lys-5. This interaction displaced MDM2 from GNL3, resulting in MDM2 destabilization, impaired ubiquitination, p53 accumulation, and persistent senescence. Moreover, p53 transcriptionally activated ENO2, establishing a pathological positive feedback loop. Pharmacological inhibition of ENO2 with POMHEX disrupted ENO2–GNL3 binding, restored p53 degradation, reduced senescence markers in vitro, and mitigated cartilage degradation, subchondral bone sclerosis, and pain in aged mice.
Conclusions: ENO2 promotes OA progression through a lactate-dependent, lactylation-mediated disruption of the GNL3–MDM2–p53 axis, leading to a senescent feedback loop. Targeting ENO2 may represent a novel disease-modifying therapeutic approach for age-related OA.
Keywords Osteoarthritis, Enolase-2, G protein nucleolar 3, Senescence, Lactylation
Address and Contact Information 1 Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
*Corresponding author: Yihe Hu xy_huyh@163.com Jie Xie dr_xiejie@zju.edu.cn Yute Yang yyyyyt@zju.edu.cn
† Feng Hua and Jiangyu Nan contributed equally to this work.
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No.  122DOI: 10.1186/s11658-026-00959-z Volume 31 (2026) - 30:122
Title MULTI-OMIC SCREENING IDENTIFIES RBMXL3 AS A PRIMATE-SPECIFIC RNA-BINDING PROTEIN AND CANDIDATE REGULATOR OF RNA METABOLISM IN HUMAN SPERMATOGENESIS
Authors Agata J. Barszcz1, Katarzyna Tutak1,2, Joanna Zyprych-Walczak3, Erik Dassi4, Erkut Ilaslan1,5, Małgorzata Dąbrowska1, Agnieszka Malcher1, Marta Olszewska1, Dominik Cysewski6, Agnieszka Nadel1, Tomasz Kolanowski1, Zofia E. Madeja7, Michał Hrab8, Alexander N. Yatsenko9,10,11, Maciej Kurpisz1, Zbigniew Warkocki12 and Natalia Rozwadowska1*
Abstract Background: RBMXL3 is a primate-specific gene localized on the X chromosome, of which the expression is detectable mainly in the male gonad. So far, very little is known about the RBMXL3 protein function and its molecular interactions. However, recent reports mention the RBMXL3 gene in the context of human spermatogenesis, cancer, and a breathing disorder that affects newborns. In this study, we investigate the RBMXL3’s molecular network on a genome-wide scale using the human seminoma cell line (TCam-2) as a male germline in vitro model.
Methods: By using transcriptomic (RNA sequencing [RNA-seq] and enhanced crosslinking and immunoprecipitation [eCLIP]) and proteomic (co-immunoprecipitation coupled with mass spectrometry, (Co-IP–MS)) approaches, we show RBMXL3’s importance in RNA metabolism. In addition, western blot, quantitative polymerase chain reaction with reverse transcription (qRT–PCR), immunostaining, and confocal imaging were used to investigate the function of RBMXL3. Finally, we used a plasmid-based L1 retrotransposition assay to demonstrate the suppressive effect of RBMXL3 on human Long Interspersed Nuclear Element-1 (LINE-1, L1) retrotransposition.
Results: Our RNA-seq data show that RBMXL3 expression drives gene expression changes and influence alternative splicing in human cells. Moreover, by performing eCLIP, we provide proof that RBMXL3 binds to a wide range of RNA transcripts. In addition, we confirmed the nuclear localization of RBMXL3 in TCam-2 cells and its presence in spermatogonia and spermatocytes within the human testis. Finally, we report for the first time that RBMXL3 restricts human LINE-1 retrotransposition.
Conclusions: Our findings for the first time identify primate-specific RBMXL3 protein as a new upstream regulator of RNA metabolism, characterized by broad RNA-binding activity in human TCam-2 cells. Finally, we show that RBMXL3 expression heavily reduces LINE-1 retrotransposition in human cells, underlying RBMXL3 importance in maintaining genome integrity. Our data suggest that RBMXL3 may contribute to the regulation of transcriptome dynamics in male germ cells, while its broader functional implications remain to be determined.
Keywords RNA-binding proteins, RNA metabolism, Splicing, Retrotransposition, Spermatogenesis, Infertility
Address and Contact Information Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
2 Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Poznan, Poland
3 Department of Mathematical and Statistical Methods, Poznan University of Life Sciences, Poznan, Poland
4 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
5 DNRF Center for Chromosome Stability, University of Copenhagen, 2200 Copenhagen, Denmark
6 Centre of Regenerative Medicine, Medical University of Bialystok, Bialystok, Poland
7 Department of Genetics and Animal Breeding, Faculty of Veterinary Medicine and Animal Sciences, Poznan University of Life Sciences, Poznan, Poland
8 Department of Urology, Poznan University of Medical Sciences, Poznan, Poland
9 Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
10 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
11 Department of Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA, United States
12 Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
*Corresponding author: Natalia Rozwadowska natalia.rozwadowska@igcz.poznan.pl
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No.  120DOI: 10.1186/s11658-026-00947-3 Volume 31 (2026) - 30:120
Title KRASG12V/A146T MUTATIONS ARE ASSOCIATED WITH NCRT RESISTANCE VIA ENHANCED DNA DOUBLE-STRAND BREAK REPAIR AND SUPPORT A DEEP LEARNING PREDICTION FRAMEWORK IN LARC
Authors Hengchang Liu1†, Dechao Bu2,3†, Guanhua Yu1†, Ran Wei4†, Hui Jin2,3, Yixiao Liu1, Xu Guan1, Zhixun Zhao1, Haipeng Chen1, Yi Zhao2,3* and Zheng Jiang1*
Abstract Background: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer (LARC), yet clinically validated biomarkers for predicting response remain lacking. This study aimed to identify candidate molecular events associated with nCRT response and to develop a pretreatment prediction framework integrating genomic and pathological information. Methods: Whole-exome sequencing (WES) was performed on pretreatment tumors from 67 patients with LARC, and an additional 22 published WES cases were integrated to compare genomic differences between responders (R) and nonresponders (NR). Using histopathological whole-slide images (WSIs; n = 106) and genome-derived features, a weakly supervised, multimodal deep learning fusion model was developed to predict nCRT response. Multiomics profiling was used for exploratory pathway characterization, and functional assays were conducted in colorectal cancer cell lines and mouse models harboring KRASG12V or KRASA146T. Results: WES identified 41 response-associated hotspot codon events. KRASG12V and KRASA146T were detected in the NR group in this cohort and were directionally aligned with poor response, indicating an association with nCRT resistance. Because these events are low-frequency alterations, and the study is a single-center retrospective cohort with limited numbers of carriers, multivariable adjustment for key covariates (including stage and T/N status) was not feasible; thus, these findings should be interpreted as exploratory candidate signals. The multimodal fusion model showed good discrimination within the cohort (AUC = 0.882). Mechanistically, exploratory multiomics analyses and orthogonal functional assays were consistent with KRAS variants being associated with altered DNA damage repair signaling and increased repair capacity, with the functional assays providing the main support for this interpretation. Conclusions: The proposed genome–pathology fusion model provides a research-oriented framework for pretreatment prediction and risk stratification of nCRT response in LARC. KRASG12V and KRASA146T are presented as candidate molecular events aligned with poor response, but their independent predictive value and the clinical usability of the model require validation in larger, multicenter prospective cohorts that include external WSI data, together with systematic evaluation of thresholding and calibration before clinical translation.
Keywords Locally advanced rectal cancer, Neoadjuvant chemoradiotherapy, KRAS mutations, DNA damage repair, Deep learning model, Multiomics analysis
Address and Contact Information 1 Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
2 Research Center for Ubiquitous Computing Systems, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China
3 University of Chinese Academy of Sciences, Beijing 100864, China
4 Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
*Corresponding author: Yi Zhao zhaoyi@ict.ac.cn Zheng Jiang jiangzheng@cicams.ac.cn
† Hengchang Liu, Dechao Bu, Guanhua Yu and Ran Wei are regarded as co-first authors.
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No.  124DOI: 10.1186/s11658-026-00953-5 Volume 31 (2026) - 30:124
Title AARS1 PROMOTES DIABETIC KIDNEY DISEASE THROUGH REWIRING Akt AND NF-κB SIGNALING TO SUPPRESS AUTOPHAGY AND SUSTAIN INFLAMMATION
Authors Lei Tian1,2,3, Yumeng Wang1, Chen Guan1,2, Ewud Agborbesong1,2, Julie Xia Zhou1,2, Shan Mou3 and Xiaogang Li1,2*
Abstract Background: Diabetic kidney disease (DKD) is characterized by metabolic reprogramming, autophagy impairment, and chronic inflammation, but the molecular mechanisms linking these processes are not fully understood. Lactylation has emerged as an important metabolic–epigenetic regulatory mechanism in diabetic tissues. Alanyl-tRNA synthetase 1 (AARS1) has recently been identified as a lactyltransferase, but whether and how AARS1-mediated lactylation contributes to tubular stress responses and DKD progression remains unclear.
Methods: Kidney-specific Aars1 knockout mice and β-alanine treatment were used in streptozotocin-induced and db/db diabetic mouse models. Human proximal tubular epithelial cells cultured under high-glucose conditions, including CRISPR/Cas9-mediated AARS1 knockout cells, were used for mechanistic studies. AARS1-dependent transcriptional programs were analyzed by CUT and Tag, ChIP assays, and luciferase reporter assays.
Results: AARS1 was upregulated in diabetic kidneys and directly lactylated Akt and the NF-κB subunit p65, enhancing their phosphorylation and activation. This modification promoted autophagy impairment, inflammatory cytokine expression, tubular injury, and macrophage accumulation. CUT and Tag analysis further revealed AARS1-dependent transcriptional control of HK2, PFKP, ZEB1, and PPP6C, linking AARS1 to glycolytic reprogramming and fibrotic signaling. Mechanistically, AARS1 operated within a glycolysis–lactate–NF-κB feedback circuit, in which glycolysis-driven lactate increased the lactylation and activation of NF-κB, promoting AARS1 transcription and reinforcing glycolytic reprogramming and chronic tubular stress. Genetic deletion of Aars1 or pharmacological inhibition with β-alanine reduced protein lactylation, restored autophagy, attenuated inflammation, and significantly slowed DKD progression in both diabetic mouse models.
Conclusions: These findings identify AARS1 as a metabolic–epigenetic amplifier that rewires Akt- and NF-κB-dependent signaling to sustain chronic tubular stress and fibrotic remodeling in DKD, highlighting the AARS1–lactylation axis as a potential therapeutic target.
Keywords Diabetic kidney disease, AARS1, Lactylaltion, Autophagy, Inflammation
Address and Contact Information 1 Department of Internal Medicine, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55905, USA
2 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
3 Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
*Corresponding author: Xiaogang Li li.xiaogang@mayo.edu
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No.  125DOI: 10.1186/s11658-026-00954-4 Volume 31 (2026) - 30:125
Title KAP1 SUMOYLATES AND STABILIZES SR-A TO FACILITATE GLYCATED LDL TRANSCYTOSIS AND ACCELERATE ATHEROSCLEROSIS
Authors Meng Shu1,2, Wenzhuo Cheng1, Fangyang Yu1, Liyin Zhang1, Li Wang1, Yan Shu1, Ruonan Wang1, Baorui Xue1 and Si Jin1*
Abstract Background: Atherosclerosis (AS)-associated cardiovascular disease is the main cause of global mortality. The excessive retention of glycated low-density lipoprotein (G-LDL) under the vascular endothelium promotes AS. In addition, G-LDL supports a role in promoting the expression of scavenger receptor A (SR-A), increasing SR-A-mediated transcytosis of G-LDL in endothelial cells (ECs), consequently accelerating the progression of atherosclerosis. However, the underlying mechanism used by G-LDL to promote SR-A expression has not been elucidated, thus representing the aim of this work.
Methods: The protein–protein interaction of the E3 SUMO ligase KRAB structural domain-associated protein 1 (KAP1) and SR-A were confirmed by co-immunoprecipitation (co-IP)-based immunoblotting and immunofluorescence in human umbilical vein endothelial cells (HUVECs). G-LDL uptake and transcytosis in KAP1-silencing or overexpressing HUVECs were assessed. The effect of KAP1 on de-ubiquitination and SUMOylation of SR-A was determined by co-IP-based immunoblotting. The role of KAP1 on G-LDL-induced atherosclerosis was tested by adenovirus-mediated knockdown in ApoE−/− mice.
Results: KAP1 was identified as an enhancer of SR-A, promoting its expression. KAP1 bound to SR-A and promoted SUMO1 modification of the SR-A lysine (K)22, which hampers K48-linked ubiquitination and proteasomal degradation of SR-A. KAP1 deficiency attenuated G-LDL-induced SR-A activation both in vitro and in vivo, reduced aortic G-LDL retention, and consequently, atherosclerotic vulnerable plaque formation in murine models.
Conclusions: This study identifies a SUMOylation–ubiquitination crosstalk that governs SR-A stability, revealing KAP1 as a key molecular switch controlling SR-A turnover in endothelial cells. These findings provide a mechanistic basis for how G-LDL accelerates atherosclerosis.
Keywords Atherosclerosis, Transcytosis, Glycated LDL, KAP1, SR-A, SUMOylation
Address and Contact Information 1 Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, 39 Lake Road, East Lake Ecological Scenic, Wuhan 430077, Hubei Province, China
2 Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
*Correspondence: Si Jin Jinsi@hust.edu.cn
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No.  126DOI: 10.1186/s11658-026-00946-4 Volume 31 (2026) - 30:126
Title OTULIN PROTECTS HYPEROXIA-INDUCED NEONATAL LUNG INJURY AND MODULATES MITOCHONDRIAL PROTEIN OPA1 IN ASSOCIATION WITH THE E3 UBIQUITIN LIGASE RNF31
Authors Li Huang1†, Qing Liu2,3†, Aimin Zhang1, Yanhan Liu1, Furong Huang1, Juanmei Wang1, Manting Tan1, Duane Wang1, Menghua Zhao1* and Xu Wu2,3*
Abstract The deubiquitinating enzyme OTULIN has been implicated in the development of lung injury, and regulating its expression may either exacerbate or alleviate pulmonary inflammatory damage. In this study, we aimed to investigate the role of deubiquitinating enzyme OTULIN in hyperoxia-induced lung injury and the underlying mechanisms involved. A bronchopulmonary dysplasia (BPD) model was established by exposing neonatal mice to a hyperoxic environment, and the effects of regulating OTULIN expression on mitochondrial homeostasis in pulmonary epithelial cells were further examined under hyperoxic conditions. In addition, we investigated the mechanisms through which OTULIN regulates mitochondrial-associated proteins and the ubiquitination mechanisms of differential mitochondrial protein OPA1. The results showed that hyperoxia induced significant lung injury in neonatal mice and was accompanied by upregulation of OTULIN expression. Additionally, hyperoxia disrupted mitochondrial homeostasis in neonatal mice lung tissue, as observed by a reduction in mitochondrial number and increased mitochondrial fusion and autophagy. After hyperoxia exposure, overexpression of OTULIN significantly reduced mitochondrial reactive oxygen species (ROS) levels in alveolar epithelial cells, maintained mitochondrial membrane potential, and promoted mitochondrial homeostasis. Mechanistically, OTULIN was found to directly interact with OPA1 and regulate its ubiquitination status. The E3 ubiquitin ligase RNF31 was identified as a key regulator of OPA1 stability, with knockdown of RNF31 reducing OPA1 levels. Moreover, OTULIN regulated the expression of both OPA1 and RNF31 and affected the stability of OPA1 and mitochondrial function through RNF31-dependent mechanisms. In vivo experiments further showed that knockdown of OTULIN aggravated hyperoxia-induced lung injury in neonatal mice, characterized by alveolar simplification, increased fibrosis, and further impairment of mitochondrial function, whereas overexpression of OTULIN alleviated these pathological changes. In conclusion, deubiquitinating enzyme OTULIN protected hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31. These findings provide new insights into the pathogenesis of BPD and highlight the therapeutic potential of targeting the OTULIN/RNF31–OPA1 axis.
Keywords Ubiquitination, Mitochondria, Hyperoxia, OTULIN, OPA1, Neonatal lung injury
Address and Contact Information 1 Department of Pediatrics, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, 61 Jie-Fang West Road, Fu-Rong District, Changsha 410005, China
2 Pulmonary and Critical Care Medicine, the Second Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
3 Hengyang Medical School, University of South China, No. 30, Jiefang Road, Shigu District, Hengyang 421001, Hunan, China
*Corresponding author: Menghua Zhao zhaomh705@hunnu.edu.cn Xu Wu wx1048946906@126.com
† Li Huang and Qing Liu are Co-first authors.
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No.  128DOI: 10.1186/s11658-026-00952-6 Volume 31 (2026) - 30:128
Title Exendin-4 AVERTS ALL-TRANS-RETINAL-DRIVEN DAMAGE TO PHOTORECEPTORS AND THE RETINA VIA THE GLP-1R/PKA/CREB1 SIGNALING AXIS
Authors Beiting He1,2, Yuling Chen1,2, Peixin Cai1,2, Ruitong Xi1,2, Xiaoqing Shen1,2, Shuting Guo1,2, Jingmeng Chen3, Shiying Li1* and Yalin Wu1,2,4*
Abstract Background: Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL. Methods: Cell and animal paradigms of STGD1 and dry AMD were generated by atRAL-loaded 661W cells and light-exposed Abca4−/−Rdh8−/− mice, respectively. RNA-sequencing, cell viability assays, morphometric analysis, annexin V/propidium-iodide staining using flow cytometry, quantitative polymerase chain reaction (qPCR), western blotting, immunofluorescence, electroretinography (ERG), fundus photography, hematoxylin and eosin (H&E) histology, and TUNEL staining were integrated to delineate the anti-apoptotic actions of EX-4 and to uncover its underlying protective mechanism. Results: GLP-1R/cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP response element–binding protein 1 (CREB1) signaling was markedly downregulated in atRAL-challenged 661W cells and in neural retina of light-exposed Abca4−/−Rdh8−/− mice. EX-4 reinstated this pathway, suppressed caspase-3 activation and DNA damage, and curtailed apoptosis in both cell and tissue contexts. Silencing of Glp1r or the PKA catalytic subunits by small interfering RNA (siRNA) abrogated EX-4-induced activation of the PKA/CREB1 axis in atRAL-loaded 661W cells. Pharmacologic blockade of CREB1 phosphorylation with the PKA inhibitor H-89 or the CREB1 inhibitor 666-15 largely nullified the DNA-protective and anti-apoptotic benefits conferred by EX-4 in 661W cells following atRAL exposure, suggesting that the GLP-1R/PKA/CREB1 signaling axis contributes to its cytoprotection action. More importantly, intraperitoneal injection of EX-4 significantly preserved retinal structure and function in Abca4−/−Rdh8−/− mice after exposure to light, and mitigated punctate lesions in the fundus. Conclusions: EX-4 exerted anti-apoptotic and DNA-protective effects against atRAL-induced photoreceptor loss and retinal degeneration at least partially through activating the GLP-1R/PKA/CREB1 pathway. These findings suggest that GLP-1R agonists could serve as potential preventive therapeutics for atrophic macular degeneration associated with atRAL toxicity, including dry AMD and STGD1.
Keywords Glucagon-like peptide-1 receptor (GLP-1R), Agonists, Atrophic macular degeneration, Retina, Exendin-4, Apoptosis
Address and Contact Information 1 Department of Ophthalmology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, Fujian, China
2 Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
3 School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
4 Shenzhen Research Institute of Xiamen University, Shenzhen 518057, Guangdong, China
*Corresponding author: Shiying Li shiying_li@126.com Yalin Wu yalinw@xmu.edu.cn
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No.  75DOI: 10.1186/s11658-026-00943-7 Volume 31 (2026) - 30:75
Title DEORPHANISATION AND FUNCTIONAL CHARACTERISATION OF OATP5A1 AS TRANSPORT PROTEIN FOR AMINO ACIDS AND VITAMINS
Authors Elena Kohlmann1,2, Nikola K. Schmid1,2, Arne Gessner1,2, Martin F. Fromm1,2 and Jörg König1,2*
Abstract Background: Transport proteins are important for the uptake, distribution and elimination of endogenous substances and drugs, and therefore essential for, e.g., cellular metabolism or drug effects. While the export of substrates out of cells is mediated by ATP-binding cassette (ABC) transporters, SLC (solute carrier) transporters are mainly responsible for the uptake into cells. In contrast to most well-characterised ABC transporters, many SLC transporters have been studied insufficiently. Such transporters are called orphan transporters. Despite the fact that the SLC21/SLCO family contains several important transporters for widely prescribed drugs, one of its family members, OATP5A1 (SLCO5A1), is such an orphan transporter. OATP5A1 is ubiquitously expressed throughout the body, including expression in the brain, heart, intestine and various cancerous tissues. However, no substrates have been characterised for this transporter to date.
Methods: Using stably-transfected HEK293 cells overexpressing human OATP5A1 (HEK-OATP5A1) and the respective control cells (HEK-VC), we investigated known substrates of other OATP family members as potential OATP5A1 substrates. Furthermore, an untargeted metabolomics analysis of both cell lines was performed after incubation with human plasma. Candidate substances were further characterised as substrates of OATP5A1.
Results: After characterisation of the stably-transfected HEK-OATP5A1 cells, uptake assays and untargeted metabolomics analysis identified the hormone conjugate estrone-3-sulfate, the amino acids glutamine, glycine and tyrosine, the vitamins pantothenic acid (vitamin B5) and thiamine (vitamin B1) and the nucleotide thymine as potential OATP5A1 substrates. While estrone-3-sulfate, tyrosine and thiamine were further characterised as uptake substrates, glutamine and glycine were exported by OATP5A1. Moreover, pantothenic acid and thymine inhibited OATP5A1-mediated tyrosine uptake. For estrone-3-sulfate, tyrosine and thiamine, kinetic transport parameters (Km values) of 102.2 µM, 169.9 µM and 15.6 µM were calculated, respectively.
Conclusions: In the present study, OATP5A1 was deorphanised by characterising amino acids and vitamins as substrates of this transport protein. Estrone-3-sulfate, tyrosine and thiamine were taken up by OATP5A1. Moreover, OATP5A1 mediated the efflux of the amino acids glutamine and glycine, which play essential roles in brain function.
Keywords Orphan transporter, Solute carrier, OATP, OATP5A1, Transport, Amino acids, Thiamine, Tyrosine, Glutamine, Glycine
Address and Contact Information 1 Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
2 FAU NeW–Research Center New Bioactive Compounds, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
*Corresponding author: Jörg König joerg.koenig@fau.de
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No.  129DOI: 10.1186/s11658-026-00948-2 Volume 31 (2026) - 30:129
Title PHOSPHOPROTEOMIC PROFILING REVEALS POST-TRANSLATIONAL DYSREGULATION IN HUNTINGTON’S DISEASE PATIENT-DERIVED NEURONS
Authors Lea Danics1,2,3†, Chandramouli Muralidharan2,4†, Ágnes Varga1,2,5, Melinda Rezeli6,7, Jeovanis Gil8, Anna A. Abbas1,2, Ádám Pap9,10, Andrew S. Park11,12, Marcell Cserhalmi13, Emilie M. Legault11,12, Ármin Sőth1,2, Dorina Jamniczky1,2, Roland Zsoldos1,2,5, Roger A. Barker14, Gergely Róna13,15, Janelle Drouin-Ouellet11,12, György Markó-Varga7, Zsuzsanna Darula9,10 and Karolina Pircs1,2,4,5*
Abstract Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene. Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, the contribution of post-translational modifications, such as phosphorylation, remains poorly understood. Here, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from HD patient fibroblasts. We identified 177 phosphopeptides with significantly altered abundance in HD-iNs, mapping to phosphoproteins associated with key signaling pathways known to be affected in HD, such as splicing and autophagy. By integrating P-MS data with previously published proteomic and transcriptomic data from the same donors, we identified distinct subsets of ON–OFF phosphopeptides that exhibited a complete loss of phosphorylation in either HD- or control-iNs, without corresponding changes at the RNA or protein level. An exception was MXRA8, previously described in glial cells as a mediator of blood–brain barrier integrity and astrocyte-mediated neuroinflammation. This protein showed increased protein abundance despite the absence of phosphorylation in HD-iNs, suggesting a compensatory mechanism. In addition, MXRA8 showed altered protein–protein interactions with lysosomal and metabolic regulators in HD-iNs, highlighting its potential role in autophagy impairment as well as in neurovascular dysfunction. These findings uncover a distinct layer of post-translational dysregulation in HD, suggesting that phospho-switch proteins such as MXRA8 may be candidate effectors of pathology, and thus, site-specific phosphorylation loss may contribute to impaired signaling and proteostasis in human HD neurons.
Keywords Huntington’s disease, Phosphorylation, Induced neurons, Post-translational modification, MXRA8, Autophagy
Address and Contact Information 1 Institute of Clinical Pathophysiology, Semmelweis University, Budapest, Hungary
2 Hungarian Centre of Excellence for Molecular Medicine—Semmelweis University (HCEMM-SU), Neurobiology and Neurodegenerative Diseases Research Group, Budapest, Hungary
3 HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, Budapest, Hungary
4 Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden
5 HUN-REN-SZTAKI-SU Rejuvenation Research Group, HUN-REN Office for Supported Research Groups (TKI), Budapest, Hungary
6 Division for Biomedical Engineering, Department of Biomedical Engineering, Lund University, Lund, Sweden
7 BioMS−Swedish National Infrastructure for Biological Mass Spectrometry, Lund University, Lund, Sweden
8 Clinical Chemistry, Department of Translational Medicine, Lund University, Lund, Sweden
9 Single Cell Omics Advanced Core Facility, Hungarian Centre of Excellence for Molecular Medicine, Szeged, Hungary
10 Laboratory of Proteomics, Complex Molecular and Cell Biology Service Centre, HUN-REN Biological Research Centre, Szeged, Hungary
11 Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada
12 Centre de Recherche Sur Le Cerveau Et L’apprentissage (CIRCA), University of Montreal, Montreal, QC, Canada
13 MTA-HUN-REN RCNS Lendület “Momentum” DNA Repair Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
14 Cambridge Stem Cell Institute and John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge, UK
15 Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
*Correspondence: Karolina Pircs pircs.karolina@semmelweis.hu
† Lea Danics and Chandramouli Muralidharan contributed equally to this work.
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No.  131DOI: 10.1186/s11658-026-00958-0 Volume 31 (2026) - 30:131
Title ZNF662 INHIBITS ONCOGENESIS THROUGH NUPR1/p53 SIGNALING PATHWAY IN EPITHELIAL OVARIAN CANCER AND IS REGULATED BY hsa-miR-429
Authors Zhen Huang1†, Hongxue Fu2†, Ling Li1, Wenjing Liao1, Jing Zhang1, Qin Tang1, Mao Huang1, Tingxiu Xiang3*† and Liangdan Tang1*†
Abstract Background: Epithelial ovarian cancer (EOC) represents the most lethal malignancy of the female reproductive system, though its etiology and pathogenesis remain incompletely characterized. The Krüppel-associated box domain zinc finger protein (KRAB-ZNF) family, the largest transcription factor family in mammals, plays critical roles in malignant tumor development and progression. This study aimed to investigate the clinical significance and molecular mechanisms of ZNF662 in EOC pathogenesis.
Methods: ZNF662 expression patterns and their association with clinicopathological features and prognosis were analyzed using integrated bioinformatics (The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), CSIOVDB, Kaplan–Meier Plotter) and clinical tissue specimens. Functional impacts on proliferation, migration, invasion, apoptosis, and cell cycle progression were assessed then. Mechanistic studies delineating upstream regulators and downstream effectors employed transcriptome sequencing, dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP), and functional validation experiments.
Results: ZNF662 expression was downregulated in ovarian cancer tissues, correlating with advanced tumor stage, ascites presence, and poor overall survival. Functional assays demonstrated that ZNF662 suppressed proliferation, migration, and invasion of ovarian cancer cells while promoting apoptosis and inducing G0/G1 cell cycle arrest. Bioinformatics analysis and dual-luciferase reporter assays confirmed that hsa-miR-429 directly binds to the 3ʹ-untranslated region (UTR) of ZNF662, downregulating its expression and promoting malignant behaviors. Transcriptomic and mechanistic validation revealed that ZNF662 transcriptionally represses NUPR1 and activates the p53 signaling pathway, thereby inhibiting the malignant phenotype of EOC.
Conclusions: The hsa-miR-429/ZNF662/NUPR1/p53 pathway axis critically regulates EOC pathogenesis. ZNF662 represents a promising diagnostic biomarker and therapeutic target for EOC.
Keywords ZNF662, NUPR1, p53, Hsa-miR-429, Epithelial ovarian cancer
Address and Contact Information 1 Department of Obstetrics and Gynecology, Chongqing Key Laboratory of Maternal and Fetal Medicine / Joint International Research Laboratory of Reproduction & Development, Ministry of Education / The Innovation and Talent Recruitment Base of Maternal-Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing 400016, China
2 Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, No.1 Youyi Road, Yuzhong District, Chongqing 400010, China
3 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
*Corresponding author: Tingxiu Xiang xiangtx@cqmu.edu.cn Liangdan Tang tangliangdan@hospital.cqmu.edu.cn
† Zhen Huang, Hongxue Fu have contributed equally to this work. Liangdan Tang and Tingxiu Xiang have contributed equally.
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No.  80DOI: 10.1186/s11658-026-00956-2 Volume 31 (2026) - 30:80
Title HETEROGENEITY OF MACROPHAGES IN PD-1/PD-L1 INHIBITOR THERAPY: A SINGLE-CELL PERSPECTIVE
Authors Jinjing Wu1,2,3, Dan Zhou3, Kunpeng Jiang3, Zhenkui Li3, Yudi Yao4, Shaqi Rao5, Xiaohong Yang1,2,3* and Daya Luo1,2,3*
Abstract Therapeutic blockade of the PD-1/PD-L1 signaling pathway is the focus of tumor immunotherapy. However, drug resistance and irAEs induced by PD-1/PD-L1 inhibitors have emerged as major limitations affecting survival outcomes in patients with cancer. Macrophages are not only the core immune cells that regulate tumor progression and metastasis, but also the key factors that affect the therapeutic effect of PD-1/PD-L1 inhibitors, thus showing significant clinical value in optimizing immunotherapy strategies. scRNA-seq technology has provided powerful analytical tools and precise biological insights to decipher macrophage heterogeneity, further elucidating disease-specific macrophage subpopulations with distinct gene signatures and functional plasticity during PD-1/PD-L1 blockade therapy. These advances have paved the way for better understanding the mechanisms underlying immunotherapy-induced toxicities and identifying novel predictive biomarkers. Herein, we comprehensively summarize the multifaceted functional roles of macrophages in PD-1/PD-L1 inhibitor-mediated antitumor efficacy, drug resistance and irAEs from a single-cell perspective, and the potential value of targeting macrophages to improve the accuracy of immunotherapy.
Keywords Macrophage, PD-1/PD-L1 inhibitor, irAEs, Drug resistance, Combination therapy
Address and Contact Information 1 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
2 Jiangxi Provincial Key Laboratory of Tumor Biology, Nanchang University, Nanchang 330031, China
3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
4 Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
5 Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
*Corresponding author: Xiaohong Yang xiaohongyang2007@ncu.edu.cn Daya Luo luodaya@ncu.edu.cn
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No.  86DOI: 10.1186/s11658-026-00905-z Volume 31 (2026) - 30:86
Title THE ROLE OF ECM MECHANICS IN CANCER MECHANOTRANSDUCTION THROUGH UNRAVELING THE MOLECULAR MACHINERY OF INTEGRINS, FAK, AND YAP SIGNALING
Authors Nourhan Hassan1,2*, Burkhard Greve3 and Martin Götte4
Abstract Mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, is fundamental for maintaining tissue homeostasis and regulating physiological functions. The extracellular matrix (ECM) serves as a critical mediator of mechanotransduction, with its mechanical properties influencing cellular behaviour and function through complex molecular machinery. This comprehensive review examines the role of ECM mechanics in disease mechanotransduction, focusing on the molecular machinery of integrins, focal adhesion kinase (FAK) and YAP signaling pathways. We explore the structure and composition of the ECM, including detailed analysis of key components such as collagens, elastin, glycoproteins, proteoglycans, hyaluronic acid and matrix metalloproteinases. The review elucidates how integrins function as key mediators of mechanotransduction, the role of FAK in signal transduction, and the mechanosensitive functions of YAP/TAZ signaling. We examine the intricate crosstalk between these mechanotransduction pathways and their dysregulation in cancer. Finally, we discuss emerging therapeutic strategies targeting mechanotransduction pathways and the challenges and opportunities for translating mechanotransduction research into clinical interventions. Understanding these complex mechanotransduction networks is crucial for developing novel therapeutic approaches to treat diseases characterized by altered tissue mechanics and dysregulated cellular responses to mechanical cues.
Keywords Mechanotransduction, Extracellular matrix, Integrins, Focal adhesion kinase, YAP signaling, Disease pathogenesis, Therapeutic targets
Address and Contact Information 1 Department of Biotechnology, Faculty of Science, Cairo University, Giza 12613, Egypt
2 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Straße 21, 50931 Cologne, Germany
3 Department of Radiotherapy-Radiooncology, Münster University Hospital, Albert-Schweitzer Campus 1, 48149 Münster, Germany
4 Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer Campus 1, 48149 Münster, Germany
*Corresponding author: Nourhan Hassan nourhan.hassan@uk-koeln.de; nyehia@sci.cu.edu.eg
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No.  85DOI: 10.1186/s11658-026-00966-0 Volume 31 (2026) - 30:85
Title OBITUARY: IN MEMORY OF WŁODZIMIERZ KOROHODA (1937–2026)
Authors Zbigniew Madeja1* and Aleksander F. Sikorski2*
Abstract Professor Włodzimierz Korohoda, an eminent Polish cell biologist and a long-standing member of the academic community of Jagiellonian University in Kraków, passed away in 2026 at the age of 89. He was a pioneer of modern cell biology in Poland and an internationally recognized authority on cell dynamics, whose scientific achievements, mentorship, and institutional leadership profoundly shaped generations of researchers.

Born in 1937, Professor Korohoda grew up in an intellectually vibrant environment that fostered his early interest in science. As he later recalled, a scientific career seemed almost inevitable, although his initial academic inclinations were not exclusively directed toward biology. A decisive moment came during his secondary education, when he visited laboratories at the Jagiellonian University where he witnessed pioneering microscopic research on living cells. This experience inspired him to pursue biological sciences, ultimately defining his lifelong research path.

Professor Korohoda remained affiliated with the Jagiellonian University throughout his entire academic career. He completed his master’s degree in 1957 and began his scientific work at the Department of Plant Physiology. In 1963, he obtained his PhD under the supervision of Professor Jan Zurzycki, becoming his first doctoral student. His doctoral research on the electrochemical properties of cell surfaces during differentiation anticipated themes that would remain central to his scientific work for decades.

Early in his career, he benefited from prestigious international fellowships, including support from the British Council (1965–1966), which enabled him to work at leading research institutions in London. There, he collaborated with prominent scientists and contributed to publications in high-impact journals such as Nature scientific journal. He later continued his international scientific development as a fellow of the Alexander von Humboldt Foundation (1972–1973), conducting research in Bonn on cytoskeletal function and cell motility.

Professor Korohoda’s scientific contributions focused on fundamental aspects of cell biology. He was a world-class expert on mechanisms of cell motility, including amoeboid movement, chemotaxis, and galvanotaxis. His work elucidated how the physicochemical properties of cell membranes and the organization of the cytoskeleton regulate cell shape, growth, and differentiation. These studies significantly advanced understanding of dynamic cellular processes.

In the 1990s, Professor Korohoda initiated pioneering efforts in cellular engineering in Kraków, particularly in the cultivation of human keratinocytes for applications in regenerative medicine and burn treatment. This work represented one of the earliest successful examples in Poland of translating in vitro cell culture techniques into clinical practice. In parallel, he and his collaborators developed innovative approaches in image analysis and cytometry, applying computational methods to the quantitative study of living cells.

His scientific output included more than 150 research and review articles published in leading international journals, as well as co-authorship of eight widely used academic textbooks. Beyond his publications, Professor Korohoda established a distinguished “Kraków school” of cell biology. He supervised over 100 master’s theses and 22 doctoral dissertations, mentoring numerous scientists who went on to successful academic careers in Poland and abroad.

Professor Korohoda also played a major organizational role in Polish science. He founded and led the Department of Cell Biology at the Jagiellonian University from 1979 to 2005 and served as Director of the Institute of Molecular Biology during a particularly challenging historical period. He was actively involved in multiple scientific committees and advisory boards of the Polish Academy of Sciences, including the Committee of Cytobiology, which he chaired from 1992 to 1995 and later served as its Honorary Chairman. He was one of the founders of the Polish Society of Cell Biology serving as a member of the Management Board in 1993–2005 and President in 1999–2001. He supported the initiative to establish our journal (Cellular and Molecular Biology Letters), was a member of the Editorial Board from the beginning of its operation, supporting CMBL in various institutions and organizations, Moreover, he was one of the most frequently publishing authors from Poland in our journal.

His contributions were widely recognized through numerous distinctions. Among the most notable were the Laur Jagielloński (2002) and the ceremonial renewal of his doctoral degree after 50 years (2013) by the Senate of the Jagiellonian University. He was elected a corresponding member of the Polish Academy of Arts and Sciences in 1991 and became a full member in 1995. He was also a recipient of prestigious international fellowships and multiple national and university awards.

Beyond his scientific and academic accomplishments, Professor Korohoda was remembered as an exceptionally dedicated mentor and an inspiring intellectual presence. He possessed a rare ability to stimulate independent thinking, often emphasizing that the essence of science lies not only in experimentation but also in critical reflection. His enthusiasm for research remained undiminished throughout his life, and his laboratory was a place of constant intellectual exchange and creativity.

Science always remained his primary focus, although— as he often admitted with a smile—there were moments when it had to yield to his passion for sport. Professor Korohoda was a talented competitive swimmer and, in 1955 in Wrocław, won the Polish Universities Championship. Fortunately for cell biology, sport did not ultimately take him away from science, although it undoubtedly instilled in him a spirit of competition, perseverance, and discipline that later became evident in his scientific work.

Professor Korohoda’s legacy extends far beyond his publications and institutional roles. He helped to build a strong and internationally visible community of cell biologists in Poland, fostering collaboration between basic science and medicine and promoting the practical application of biological research. In addition to all the above-mentioned merits and achievements, he was always an extremely cultured man, kind to older and younger colleagues, extremely friendly and cordial, and above all helpful, proud of the achievements of his former students and young colleagues.With his passing, the scientific community has lost an outstanding scholar, teacher, and organizer. He will be remembered not only for his pioneering contributions to cell biology but also for his unwavering commitment to academic excellence and for the generations of scientists he inspired.

Zbigniew Madeja, Aleksander F. Sikorski and friends.
Keywords
Address and Contact Information 1 Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Kraków, Poland
2 University of Wrocław, Wroclaw, Poland
*Corresponding author: Zbigniew Madeja z.madeja@uj.edu.pl Aleksander F. Sikorski afsikorskicmbl@gmail.com
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No.  132DOI: 10.1186/s11658-026-00973-1 Volume 31 (2026) - 30:132
Title HIF-1α ENHANCES FERROPTOSIS RESISTANCE IN ANAPLASTIC THYROID CARCINOMA BY SUPPRESSING ACSL4-MEDIATED LIPID METABOLIC HOMEOSTASIS
Authors Renjie Xie1, Ruixue Geng2,3,4, Yuchen Wang2,3,4, Chenyue Zhan2,3,4, Xinyue Deng2,3,4, Yanting Duan2,3,4, Juyong Liang2,3,4, Jiafeng Wang2,3,4,5, Ruimin Liang2,3,4, Jingyan Ge1,6, Minghua Ge2,3,4* and Xiaozheng Zhu2,3,4*
Abstract Background: Anaplastic thyroid carcinoma (ATC) exhibits extreme malignancy with a median survival of less than 6 months. Traditional therapeutic approaches yield limited efficacy, necessitating the urgent identification of novel treatment strategies. The tumor hypoxic microenvironment serves as a key driver of ATC progression and drug resistance, in which the transcription factor hypoxia-inducible factor 1α (HIF-1α) orchestrates key processes in regulating tumor metabolism, immune evasion, and resistance to cell death. Ferroptosis is a novel iron-dependent form of programmed death, defined by excessive peroxidation of polyunsaturated fatty acid phospholipids (PUFA-PL) within cellular membranes.
Methods: In this study, cellular and xenograft models were employed to demonstrate that hypoxia confers ferroptosis resistance to ATC cells. Lipid metabolomics analysis revealed HIF-1α regulates lipid metabolism, and acyl-CoA synthase 4 (ACSL4) was identified as key lipid metabolism-related candidate. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to assess the binding of HIF-1α to the hypoxia-response element (HRE) within the ACSL4 promoter region. Flow cytometric analysis was performed to investigate how HIF-1α inhibition augments the antitumor immunogenicity of PD-1 blockade, as evidenced by enhanced intratumoral CD8+ T-cell infiltration and cytokine secretion.
Results: This study identifies a key mechanism by which HIF-1α provides ferroptosis resistance in ATC under the intrinsically hypoxic tumor microenvironment. HIF-1α directly binds the HRE within the ACSL4 promoter, transcriptionally repressing ACSL4 and consequently curtailing PUFA-PL biosynthesis, thereby conferring ferroptosis resistance on ATC cells. In addition, combined treatment with HIF-1α inhibitor and PD-1 blockade effectively suppresses tumor progression and enhances intratumoral CD8+ T-cell infiltration.
Conclusions: This study elucidates the molecular mechanism by which HIF-1α mediates anti-ferroptosis in ATC through regulating lipid metabolism and proposes a promising therapeutic strategy in which HIF-1α inhibition acts synergistically with PD-1 blockade for the treatment of ATC.
Keywords ATC, HIF-1α, ACSL4, Ferroptosis, Lipid metabolism
Address and Contact Information 1 Zhejiang Key Laboratory of Bioorganic Synthesis, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
2 Otolaryngology and Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, China
3 Zhejiang Key Laboratory of Precision Medicine Research On Head and Neck Cancer, Zhejiang Provincial People’s Hospital, Hangzhou, China
4 Zhejiang Provincial Clinical Research Center for Head and Neck Cancer, Zhejiang Provincial People’s Hospital, Hangzhou, China
5 Department of Thyroid and Breast Surgery, Zhejiang Provincial People’s Hospital Bijie Hospital, Bijie, China
6 State Key Laboratory of Green Chemical Synthesis and Conversion, Zhejiang University of Technology, Hangzhou, China
*Corresponding author: Minghua Ge geminghua@hmc.edu.cn Xiaozheng Zhu zhuxiaozheng@hmc.edu.cn
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No.  103DOI: 10.1186/s11658-026-00967-z Volume 31 (2026) - 30:103
Title CORRECTION: TARGETING FIBROBLAST ACTIVATION PROTEIN-Α TO TREAT RENAL FIBROSIS
Authors Li Gong1*, Xinyu Lu2, Na Ma3, Tao Lu4, Yuhong Gong5, Liwei Hao6, Weikang Xu7, Qianbing Zhang8, Xiaolan Chen2, Qinglin Mo2,9,10, Jiexing Tan1, Henrique de Paula Lemos10, Alexander Speechley10,11, Wenwei Tu12, Jianpiao Cai13, Lei Huang10,14*, Wei Zhu2* and Sha Wu9*
Abstract Correction: Cellular & Molecular Biology Letters (2026) 31:71

https://doi.org/10.1186/s11658-026-00898-9

In this article [1] the author notice following corrections:

1. Corresponding Author Markings and Email Address

In the published version only one corresponding author is tagged, however there are three corresponding authors for this article, viz Sha Wu, Wei Zhu, and Lei Huang as corresponding authors.

The corresponding authors email address are given below:
  • Dr. Sha Wu: shawu99@outlook.com
  • Dr. Wei Zhu: zhuwei317@smu.edu.cn
  • Dr. Lei Huang: lei.huang@newcastle.ac.uk
  • Dr. Li Gong: gongli009@126.com

2. Affiliation Numbering

In the "Author Details" section of the manuscript, the affiliation numbering is currently disorganized, with the sequence being 1, 2, 4, 5, 6, and affiliation number 3 is missing. Please insert the missing affiliation number 3 in the correct position, and reassign all affiliation numbers in strict numerical order (1, 2, 3, 4, 5, 6) to ensure the affiliation numbering is complete and standardized.

3. Figure Placement

There is an error in the figure insertion of the manuscript: Figure 9 has not been included in the main text, and the position reserved for Figure 9 is mistakenly duplicated with Figure 7. Please remove the duplicated Figure 7 from this position, and insert the correct Figure 9 into the corresponding location of the main text.

The original article has been corrected.

4. Yuhong Gong is not corresponding author.
Keywords
Address and Contact Information 1 Experimental Animal Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
2 Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China; State Key Laboratory of Multi-organ Injury Prevention and Treatment; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology; Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou 510515, China
3 Department of Pathology, School of Medicine, The First People’s Hospital of Foshan (Foshan Hospital, Southern University of Science and Technology), Southern University of Science and Technology, Guangdong 528000, Foshan, China
4 Changzhou Geriatric Hospital Affiliated to Soochow University, Changzhou no. 7 People’s Hospital, Changzhou 213011, China
5 Experimental Animal Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
6 The School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China
7 Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510220, China
8 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
9 Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangdong Provincial Key Laboratory of Proteomics, Guangzhou 510515, China
10 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE4 5PL, UK
11 Barts and The London, School of Medicine and Dentistry, Queen Mary’s University of London, Garrod Building, London NE4 5PL, UK
12 Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
13 State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine, Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam 999077, Hong Kong, China
14 Zeal BioScience Group Limited, Hongkong 999077, China
*Corresponding author: Li Gong gongli009@126.com Lei Huang lei.huang@newcastle.ac.uk Wei Zhu zhuwei317@smu.edu.cn Sha Wu shawu99@outlook.com
The original article can be found online at https://doi.org/10.1186/s11658-026-00898-9.
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No.  130DOI: 10.1186/s11658-026-00995-9 Volume 31 (2026) - 30:130
Title ADAR-MEDIATED RNA EDITING IN CNS DISORDERS: FROM PATHOGENIC MECHANISMS TO THERAPEUTIC OPPORTUNITIES
Authors Fushuang Zheng1†, Rongli Guan2†, Xiaojin Yu2†, Jiaxin Yang2, Hai Zhao3* and Fan Yang2*
Abstract The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood–brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.
Keywords RNA editing, ADAR enzymes, Central nervous system, Neurodegeneration, Therapeutic targets
Address and Contact Information 1 Department of Thoracic Surgery, Shengjing Hospital of China Medical University, No.36 Sanhao Road, Shenyang 110004, China
2 Department of Anesthesiology, Shengjing Hospital of China Medical University, No.36 Sanhao Road, Shenyang 110004, China
3 Surgical Skills Training Laboratory, Clinical Practice Teaching Center, Shenyang Medical College, No.146 Huanghe North Road, Shenyang 110034, China
*Corresponding author: Hai Zhao 18940114758@189.cn Fan Yang yfysjx@126.com
† Fushuang Zheng, Rongli Guan, and Xiaojin Yu have contributed equally to this work.
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