Vol. 30 (2025)



No.  01DOI: 10.1186/s11658-024-00660-z Volume 30 (2025) - 30:01
Title EPIGENETIC MODIFICATION REGULATES THE LIGAMENTUM FLAVUM HYPERTROPHY THROUGH miR-335-3p/SERPINE2/β-CATENIN SIGNALING PATHWAY
Authors Yongzhao Zhao1,2,3†, Shuai Jiang1,2,3†, Longting Chen1,2,3†, Qian Xiang1,2,3, Jialiang Lin1,2,3 and Weishi Li1,2,3*
Abstract Background: Epigenetic modifications have been proved to play important roles in the spinal degenerative diseases. As a type of noncoding RNA, the microRNA (miRNA) is a vital class of regulatory factor in the epigenetic modifications, while the role of miRNAs in the regulation of epigenetic modifications in ligamentum flavum hypertrophy (LFH) has not been fully investigated.
Methods: The miRNA sequencing analysis was used to explore the change of miRNA expression during the fibrosis of ligamentum flavum (LF) cells caused by the TGF-β1 (10 ng/ml). The downregulated miRNA miR-335-3p was selected to investigate its effects on the fibrosis of LF cells and explored the accurate relevant mechanisms.
Results: A total of 21 miRNAs were differently expressed during the fibrosis of LF cells. The downregulated miR-335-3p was selected for further investigation. MiR-335-3p was distinctly downregulated in the LFH tissues compared to non-LFH tissues. Overexpression of miR-335-3p could inhibit the fibrosis of LF cells. Further research showed miR-335-3p prevented the fibrosis of LF cells via binding to the 3′-UTR of SERPINE2 to reduce the expression of SERPINE2. The increased SERPINE2 expression might promote the fibrosis of LF cells via the activation of β-catenin signaling pathway to promote the transcription of fibrosis-related genes (ACTA2 and COL3A1).
Conclusions: Our results revealed that miR-335-3p prevented the fibrosis of LF cells via the epigenetic regulation of SERPINE2/β-catenin signaling pathway. The epigenetic regulator miR-335-3p might be a promising potential target for the treatment of LFH.
Keywords Lumbar spinal stenosis, Ligamentum favum hypertrophy, Fibrosis, Epigenetic modifcation
Address and Contact Information 1 Department of Orthopaedics, Peking University Third Hospital, Peking University, No.49 NorthGarden Road, Haidian District, Beijing 100191, Beijing, China
2 Beijing Key Laboratory of Spinal Disease Research, Beijing, China
3 Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Beijing, China
*Corresponding author: puh3liweishi@bjmu.edu.cn
† Yongzhao Zhao, Shuai Jiang and Longting Chen contributed equally to this research, and were listed as the co-first authors.
Read full article at BMC

No.  02DOI: 10.1186/s11658-024-00682-7 Volume 30 (2025) - 30:02
Title SYSTEMATIC AND COMPREHENSIVE INSIGHTS INTO HIF-1 STABILIZATION UNDER NORMOXIC CONDITIONS: IMPLICATIONS FOR CELLULAR ADAPTATION AND THERAPEUTIC STRATEGIES IN CANCER
Authors Jiayi Zhang2,3, Mingxuan Yao1, Shiting Xia2, Fancai Zeng2* and Qiuyu Liu1*
Abstract Hypoxia-inducible factors (HIFs) are essential transcription factors that orchestrate cellular responses to oxygen deprivation. HIF-1α, as an unstable subunit of HIF-1, is usually hydroxylated by prolyl hydroxylase domain enzymes under normoxic conditions, leading to ubiquitination and proteasomal degradation, thereby keeping low levels. Instead of hypoxia, sometimes even in normoxia, HIF-1α translocates into the nucleus, dimerizes with HIF-1β to generate HIF-1, and then activates genes involved in adaptive responses such as angiogenesis, metabolic reprogramming, and cellular survival, which presents new challenges and insights into its role in cellular processes. Thus, the review delves into the mechanisms by which HIF-1 maintains its stability under normoxia including but not limited to giving insights into transcriptional, translational, as well as posttranslational regulation to underscore the pivotal role of HIF-1 in cellular adaptation and malignancy. Moreover, HIF-1 is extensively involved in cancer and cardiovascular diseases and potentially serves as a bridge between them. An overview of HIF-1-related drugs that are approved or in clinical trials is summarized, highlighting their potential capacity for targeting HIF-1 in cancer and cardiovascular toxicity related to cancer treatment. The review provides a comprehensive insight into HIF-1’s regulatory mechanism and paves the way for future research and therapeutic development.
Keywords HIF-1, Normoxia, Pseudohypoxia, Mechanisms, Cancer, Cellular response, Target therapy
Address and Contact Information 1 School of Pharmacy, Southwest Medical University, Luzhou 646000, China
2 Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
3 School of Clinical Medicine, Southwest Medical University, Luzhou 646000, China
*Corresponding author: zfcai@swmu.edu.cn; q.liu@swmu.edu.cn
Read full article at BMC

No.  03DOI: 10.1186/s11658-024-00681-8 Volume 30 (2025) - 30:03
Title FAILURE TO REPAIR DAMAGED NAD(P)H BLOCKS DE NOVO SERINE SYNTHESIS IN HUMAN CELLS
Authors Adhish S. Walvekar1, Marc Warmoes2, Dean Cheung1, Tim Sikora3, Najmesadat Seyedkatouli1, Gemma Gomez‐Giro4, Sebastian Perrone1, Lisa Dengler1, François Unger1, Bruno F. R. Santos5, Floriane Gavotto2, Xiangyi Dong2, Julia Becker‐Kettern1, Yong‐Jun Kwon5, Christian Jäger2, Jens C. Schwamborn4, Nicole J. Van Bergen3,6, John Christodoulou3,6,7 and Carole L. Linster1*
Abstract Background: Metabolism is error prone. For instance, the reduced forms of the central metabolic cofactors nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), can be converted into redox-inactive products, NADHX and NADPHX, through enzymatically catalyzed or spontaneous hydration. The metabolite repair enzymes NAXD and NAXE convert these damaged compounds back to the functional NAD(P)H cofactors. Pathogenic loss-of-function variants in NAXE and NAXD lead to development of the neurometabolic disorders progressive, early-onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL)1 and PEBEL2, respectively.
Methods: To gain insights into the molecular disease mechanisms, we investigated the metabolic impact of NAXD deficiency in human cell models. Control and NAXD-deficient cells were cultivated under different conditions, followed by cell viability and mitochondrial function assays as well as metabolomic analyses without or with stable isotope labeling. Enzymatic assays with purified recombinant proteins were performed to confirm molecular mechanisms suggested by the cell culture experiments.
Results: HAP1 NAXD knockout (NAXDko) cells showed growth impairment specifically in a basal medium containing galactose instead of glucose. Surprisingly, the galactose-grown NAXDko cells displayed only subtle signs of mitochondrial impairment, whereas metabolomic analyses revealed a strong inhibition of the cytosolic, de novo serine synthesis pathway in those cells as well as in NAXD patient-derived fibroblasts. We identified inhibition of 3-phosphoglycerate dehydrogenase as the root cause for this metabolic perturbation. The NAD precursor nicotinamide riboside (NR) and inosine exerted beneficial effects on HAP1 cell viability under galactose stress, with more pronounced effects in NAXDko cells. Metabolomic profiling in supplemented cells indicated that NR and inosine act via different mechanisms that at least partially involve the serine synthesis pathway.
Conclusions: Taken together, our study identifies a metabolic vulnerability in NAXD-deficient cells that can be targeted by small molecules such as NR or inosine, opening perspectives in the search for mechanism-based therapeutic interventions in PEBEL disorders.
Keywords Metabolite damage and repair, Inborn errors of metabolism, NAD(P)H hydration, NAXD, Serine biosynthesis, 3-Phosphoglycerate dehydrogenase, Inosine, Nicotinamide riboside
Address and Contact Information 1 Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L‐4367 Belvaux, Luxembourg
2 Metabolomics Platform, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L‐4367 Belvaux, Luxembourg
3 Brain and Mitochondrial Research Group, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3002, Australia
4 Developmental and Cellular Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L‐4367 Belvaux, Luxembourg
5 Disease Modeling and Screening Platform, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367, Belvaux and Luxembourg Institute of Health, L-1445, Strassen, Luxembourg
6 Department of Paediatrics, University of Melbourne, Melbourne, VIC 3002, Australia
7 Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3002, Australia
*Corresponding author: carole.linster@uni.lu
Read full article at BMC

No.  04DOI: 10.1186/s11658-024-00678-3 Volume 30 (2025) - 30:04
Title THE IQGAP-RELATED RASGAP IQGC REGULATES CELL–SUBSTRATUM ADHESION IN Dictyostelium discoideum
Authors Lucija Mijanović1, Darija Putar1, Lucija Mimica1, Sabina Klajn1, Vedrana Filić1 and Igor Weber1*
Abstract Proper adhesion of cells to their environment is essential for the normal functioning of single cells and multicellular organisms. To attach to the extracellular matrix (ECM), mammalian cells form integrin adhesion complexes consisting of many proteins that together link the ECM and the actin cytoskeleton. Similar to mammalian cells, the amoeboid cells of the protist Dictyostelium discoideum also use multiprotein adhesion complexes to control their attachment to the underlying surface. However, the exact composition of the multiprotein complexes and the signaling pathways involved in the regulation of adhesion in D. discoideum have not yet been elucidated. Here, we show that the IQGAP-related protein IqgC is important for normal attachment of D. discoideum cells to the substratum. Mutant iqgC-null cells have impaired adhesion, whereas overexpression of IqgC promotes directional migration. A RasGAP C-terminal (RGCt) domain of IqgC is sufficient for its localization in the ventral adhesion focal complexes, while RasGAP activity of a GAP-related domain (GRD) is additionally required for the proper function of IqgC in adhesion. We identify the small GTPase RapA as a novel direct IqgC interactor and show that IqgC participates in a RapA-regulated signaling pathway targeting the adhesion complexes that include talin A, myosin VII, and paxillin B. On the basis of our results, we propose that IqgC is a positive regulator of adhesion, responsible for the strengthening of ventral adhesion structures and for the temporal control of their subsequent degradation.
Keywords Cell attachment, DdIQGAP3, Amoeboid locomotion, RasG, Focal adhesions, Cell migration
Address and Contact Information 1 Department of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia
*Corresponding author: iweber@irb.hr
Read full article at BMC

No.  05DOI: 10.1186/s11658-024-00680-9 Volume 30 (2025) - 30:05
Title EFFECT OF SNORD113-3/ADAR2 ON GLYCOLIPID METABOLISM IN GLIOBLASTOMA VIA A-TO-I EDITING OF PHKA2
Authors Zheng Cui5,6,7, Xiaobai Liu1,2,3, Tiange E1,2,3, Hongda Lin1,2,3, Di Wang1,2,3, Yunhui Liu1,2,3, Xuelei Ruan2,4, Ping Wang2,4, Libo Liu2,4 and Yixue Xue2,4*
Abstract Background: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor, characterized by its poor prognosis. Glycolipid metabolism is strongly associated with GBM development and malignant behavior. However, the precise functions of snoRNAs and ADARs in glycolipid metabolism within GBM cells remain elusive. The objective of the present study is to delve into the underlying mechanisms through which snoRNAs and ADARs exert regulatory effects on glycolipid metabolism in GBM cells.
Methods: RNA immunoprecipitation and RNA pull-down experiments were conducted to verify the homodimerization of ADAR2 by SNORD113-3, and Sanger sequencing and Western blot experiments were used to detect the A-to-I RNA editing of PHKA2 mRNA by ADAR2. Furthermore, the phosphorylation of EBF1 was measured by in vitro kinase assay. Finally, in vivo studies using nude mice confirmed that SNORD113-3 and ADAR2 overexpression, along with PHKA2 knockdown, could suppress the formation of subcutaneous xenograft tumors and improve the outcome of tumor-bearing nude mice.
Results: We found that PHKA2 in GBM significantly promoted glycolipid metabolism, while SNORD113-3, ADAR2, and EBF1 significantly inhibited glycolipid metabolism. SNORD113-3 promotes ADAR2 protein expression by promoting ADAR2 homodimer formation. ADAR2 mediates the A-to-I RNA editing of PHKA2 mRNA. Mass spectrometry analysis and in vitro kinase testing revealed that PHKA2 phosphorylates EBF1 on Y256, reducing the stability and expression of EBF1. Furthermore, direct binding of EBF1 to PKM2 and ACLY promoters was observed, suggesting the inhibition of their expression by EBF1. These findings suggest the existence of a SNORD113-3/ADAR2/PHKA2/EBF1 pathway that collectively regulates the metabolism of glycolipid and the growth of GBM cells. Finally, in vivo studies using nude mice confirmed that knockdown of PHKA2, along with overexpression of SNORD113-3 and ADAR2, could obviously suppress GBM subcutaneous xenograft tumor formation and improve the outcome of those tumor-bearing nude mice.
Conclusions: Herein, we clarified the underlying mechanism involving the SNORD113-3/ADAR2/PHKA2/EBF1 pathway in the regulation of GBM cell growth and glycolipid metabolism. Our results provide a framework for the development of innovative therapeutic interventions to improve the prognosis of patients with GBM.
Keywords Glioma, Glycolipid metabolism, A-to-I RNA editing, Phosphorylation, ADAR2
Address and Contact Information 1 Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
2 Key Laboratory of Neuro-Oncology in Liaoning Province, Shenyang 110004, China
3 Liaoning Medical Surgery and Rehabilitation Robot Technology Engineering Research Center, Shenyang 110004, China
4 Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China
5 Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning, China
6 Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, China
7 Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, China
*Corresponding author: 15804086963@163.com
Read full article at BMC

No.  6DOI: 10.1186/s11658-024-00684-5 Volume 30 (2025) - 30:6
Title MOLECULAR SWITCH OF THE DENDRITE-TO-SPINE TRANSPORT OF TDP-43/FMRP-BOUND NEURONAL MRNAS AND ITS IMPAIRMENT IN ASD
Authors Pritha Majumder1,2*, Biswanath Chatterjee1, Khadiza Akter1, Asmar Ahsan1, Su Jie Tan2, Chi‐Chen Huang1, Jen‐Fei Chu1* and Che‐Kun James Shen1,3*
Abstract Background: Regulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity and learning/memory development. The trafficking of mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported into the spines upon glutamate-induced receptor activation. However, the molecular mechanism(s) behind the spine entry of dendritic mRNAs under metabotropic glutamate receptor (mGluR)-mediated neuroactivation and long-term depression (LTD) as well as the fate of these mRNAs inside the spines are still elusive.
Method: Different molecular and imaging techniques, e.g., immunoprecipitation (IP), RNA-IP, Immunofluorescence (IF)/fluorescence in situ hybridization (FISH), live cell imaging, live cell tracking of RNA using beacon, and mouse model study are used to elucidate a novel mechanism regulating dendritic spine transport of mRNAs in mammalian neurons.
Results: We demonstrate here that brief mGluR1 activation-mediated dephosphorylation of pFMRP (S499) results in the dissociation of FMRP from TDP-43 and handover of TDP-43/Rac1 mRNA complex from the dendritic transport track on microtubules to myosin V track on the spine actin filaments. Rac1 mRNA thus enters the spines for translational reactivation and increases the mature spine density. In contrast, during mGluR1-mediated neuronal LTD, FMRP (S499) remains phosphorylated and the TDP-43/Rac1 mRNA complex, being associated with kinesin 1-FMRP/cortactin/drebrin, enters the spines owing to Ca2+-dependent microtubule invasion into spines, but without translational reactivation. In a VPA-ASD mouse model, this regulation become anomalous.
Conclusions: This study, for the first time, highlights the importance of posttranslational modification of RBPs, such as the neurodevelopmental disease-related protein FMRP, as the molecular switch regulating the dendrite-to-spine transport of specific mRNAs under mGluR1-mediated neurotransmissions. The misregulation of this switch could contribute to the pathogenesis of FMRP-related neurodisorders including the autism spectrum disorder (ASD). It also could indicate a molecular connection between ASD and neurodegenerative disease-related protein TDP-43 and opens up a new perspective of research to elucidate TDP-43 proteinopathy among patients with ASD.
Keywords TDP-43, pFMRP (S499), mRNP granule, RNA binding protein (RBP), Posttranslational modifcation, Kinase, Phosphatase, DHPG, Potentiation, Long-term depression (LTD), Translation status, Immunofuorescence staining, Live cell imaging, High-resolution imaging
Address and Contact Information 1 PhD Program in Medical Neuroscience, Taipei Medical University, Taipei, Taiwan (R.O.C.)
2 Institute of Molecular Medicine, College of Medicine, National Chen Kung University, Tainan, Taiwan (R.O.C.)
3 Institute of Molecular Biology, Academia Sinica, Nangang, Taipei 115, Taiwan (R.O.C.)
*Corresponding author: pritham@tmu.edu.tw; mjaivc2010@gmail.com; ckshen@imb.sinica.edu.tw
Read full article at BMC

No.  7DOI: 10.1186/s11658-025-00685-y Volume 30 (2025) - 30:7
Title METABOLIC PATHWAYS OF EICOSANOIDS—DERIVATIVES OF ARACHIDONIC ACID AND THEIR SIGNIFICANCE IN SKIN
Authors Michał Biernacki1 and Elżbieta Skrzydlewska1*
Abstract The skin is a barrier that protects the human body against environmental factors (physical, including solar radiation, chemicals, and pathogens). The integrity and, consequently, the effective metabolic activity of skin cells is ensured by the cell membrane, the important structural and metabolic elements of which are phospholipids. Phospholipids are subject to continuous transformation, including enzymatic hydrolysis (with the participation of phospholipases A, C, and D) to free polyunsaturated fatty acids (PUFAs), which under the influence of cyclooxygenases (COX1/2), lipoxygenases (LOXs), and cytochrome P450 (CYPs P450) are metabolized to various classes of oxylipins, depending on the type of PUFA being metabolized and the enzyme acting. The most frequently analyzed oxylipins, especially in skin cells, are eicosanoids, which are derivatives of arachidonic acid (AA). Their level depends on both environmental factors and endogenous metabolic disorders. However, they play an important role in homeostasis mechanisms related to the structural and functional integrity of the skin, including maintaining redox balance, as well as regulating inflammatory processes arising in response to endogenous and exogenous factors reaching skin cells. Therefore, it is believed that dysregulation of eicosanoid levels may contribute to the development of skin diseases, such as psoriasis or atopic dermatitis, which in turn suggests that targeted control of the generation of specific eicosanoids may have diagnostic significance and beneficial therapeutic effects. This review is the first systemic and very detailed approach presenting both the causes and consequences of changes in phospholipid metabolism leading to the generation of eicosanoids, changes in the level of which result in specific metabolic disorders in skin cells leading to the development of various diseases. At the same time, existing literature data indicate that further detailed research is necessary to understand a clear relationship between changes in the level of specific eicosanoids and the pathomechanisms of specific skin diseases, as well as to develop an effective diagnostic and therapeutic approach.
Keywords Eicosanoids, Phospholipids metabolism, Phospholipases, Fatty acids, Cyclooxygenases, Lipoxygenases, Cytochrome P450, Prostaglandins, Leukotrienes
Address and Contact Information 1 Department of Analytical Chemistry, Medical University of Bialystok, Kilinskiego 1, 15‐069 Bialystok, Poland
*Corresponding author: elzbieta.skrzydlewska@umb.edu.pl
Read full article at BMC

No.  8DOI: 10.1186/s11658-025-00686-x Volume 30 (2025) - 30:8
Title FEEDBACK LOOP CENTERED ON MAF1 REDUCES BLOOD–BRAIN BARRIER DAMAGE IN SEPSIS-ASSOCIATED ENCEPHALOPATHY
Authors Xuebiao Wei1†, Wenqiang Jiang2†, Zhonghua Wang1†, Yichen Li2, Yuanwen Jing2, Yongli Han2, Linqiang Huang2 and Shenglong Chen2*
Abstract Background: A previous study found that MAF1 homolog, a negative regulator of RNA polymerase III (MAF1), protects the blood–brain barrier (BBB) in sepsis-associated encephalopathy (SAE); however, the related molecular mechanisms remain unclear.
Subjects and methods: In this study, a rat sepsis model was constructed using the cecum ligation and puncture (CLP) method. In vitro, rat brain microvascular endothelial cells and astrocytes were stimulated with serum from the sepsis model rats. The loss of MAF1 protein levels and the molecular mechanisms leading to cell damage were investigated.
Results: It was shown in the SAE models that MAF1 was expressed at low levels. Knockdown of Cullin 2 (CUL2) stimulated the accumulation of MAF1 protein, attenuated the RNA sensor RIG-I/interferon regulatory factor 3 (IRF3) signaling pathway, and reduced cell apoptosis. Furthermore, it increased phosphatase and tensin homolog (PTEN) expression and inactivated the serine/threonine kinase (AKT)/mechanistic target of the rapamycin kinase (mTOR) signaling pathway. Interference with forkhead box O1 (FOXO1) inhibited MAF1 expression and activated the RIG-I/IRF3 signaling pathway, while MAF1 overexpression promoted PTEN expression, decreased cell apoptosis, and normalized autophagy.
Conclusions: These findings demonstrate that CUL2 promoted MAF1 ubiquitination and caused BBB injury in SAE. Through the regulatory loop of PTEN/AKT/FOXO1/MAF1, CUL2 initiated the gradual downregulation of MAF1, which subsequently regulated polymerase III (Pol III)-dependent transcription and played essential roles in cell apoptosis in SAE. Clinical trial number: not applicable.
Keywords Sepsis, Blood–brain barrier, MAF1, Ubiquitination, Apoptosis
Address and Contact Information 1 Department of Geriatric Intensive Medicine, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 106, Zhongshan Er Road, Guangzhou 510080, Guangdong, China
2 Department of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
*Corresponding author: chenshenglong@gdph.org.cn
† Xuebiao Wei, Wenqiang Jiang, and Zhonghua Wang have contributed equally to this work.
Read full article at BMC

No.  9DOI: 10.1186/s11658-025-00693-y Volume 30 (2025) - 30:9
Title BEYOND DESTRUCTION: EMERGING ROLES OF THE E3 UBIQUITIN LIGASE HAKAI
Authors Juan‐José Escuder‐Rodríguez1, Andrea Rodríguez‐Alonso1, Lía Jove1, Macarena Quiroga1, Gloria Alfonsín1 and Angélica Figueroa1*
Abstract Hakai protein (CBLL1 gene) was identified as an E3 ubiquitin ligase of E-cadherin complex, inducing its ubiquitination and degradation, thus inducing epithelial-to-mesenchymal transition. Most of the knowledge about the protein was associated to its E3 ubiquitin ligase canonical role. However, important recent published research has highlighted the noncanonical role of Hakai, independent of its E3 ubiquitin ligase activity, underscoring its involvement in the N6-methyladenosine (m6A) writer complex and its impact on the methylation of RNA. The involvement of Hakai in this mRNA modification process has renewed the relevance of this protein as an important contributor in cancer. Moreover, Hakai potential as a cancer biomarker and its prognostic value in malignant disease also emphasize its untapped potential in precision medicine, which would also be discussed in detail in our review. The development of the first small-molecule inhibitor that targets its atypical substrate binding domain is a promising step that could eventually lead to patient benefit, and we would cover its discovery and ongoing efforts toward its use in clinic.
Keywords Hakai, CBLL1, E3 ubiquitin ligase, m6A methyltransferase complex, Cancer, Targeted therapy, Prognostic biomarker
Address and Contact Information 1 Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Xubias de Arriba 84, 15006 A Coruña, Spain
*Corresponding author: angelica.fgueroa.conde-valvis@sergas.es
Read full article at BMC

No.  10DOI: 10.1186/s11658-025-00692-z Volume 30 (2025) - 30:10
Title HETEROGENEOUS FOCAL ADHESION CYTOSKELETON NANOARCHITECTURES FROM MICROENGINEERED INTERFACIAL CURVATURE TO OVERSEE NUCLEAR REMODELING AND MECHANOTRANSDUCTION OF MESENCHYMAL STEM CELLS
Authors Huayu Fan1†, Hui Zhao2†, Yan Hou3†, Danni Meng3, Jizong Jiang3, Eon‐Bee Lee4, Yinzheng Fu2, Xiangdong Zhang1*, Rui Chen1,5* and Yongtao Wang3*
Abstract Background: Interfacial heterogeneity is widely explored to reveal molecular mechanisms of force-mediated pathways due to biased tension. However, the influence of cell density,, curvature, and interfacial heterogeneity on underlying pathways of mechanotransduction is obscure.
Methods: Polydimethylsiloxane (PDMS)-based stencils were micropatterned to prepare the micropores for cell culture. The colonies of human mesenchymal stem cells (hMSCs) were formed by controlling cell seeding density to investigate the influences of cell density, curvature and heterogeneity on mechanotransduction. Immunofluorescent staining of integrin, vinculin, and talin-1 was conducted to evaluate adhesion-related expression levels. Then, immunofluorescent staining of actin, actinin, and myosin was performed to detect cytoskeleton distribution, especially at the periphery. Nuclear force-sensing mechanotransduction was explained by yes-associated protein (YAP) and laminA/C analysis.
Results: The micropatterned colony of hMSCs demonstrated the coincident characters with engineered micropores of microstencils. The cell colony obviously developed the heterogeneous morphogenesis. Heterogeneous focal adhesion guided the development of actin, actinin, and myosin together to regulate cellular contractility and movement by integrin, vinculin, and talin-1. Cytoskeletal staining showed that actin, actinin, and myosin fibers were reorganized at the periphery of microstencils. YAP nuclear translocation and laminA/C nuclear remodeling were enhanced at the periphery by the regulation of heterogeneous focal adhesion (FA) and cytoskeleton arrangement.
Conclusions: The characters of the engineered clustering colony showed similar results with prepared microstencils, and colony curvature was also well adjusted to establish heterogeneous balance at the periphery of cell colony. The mechanism of curvature, spreading, and elongation was also investigated to disclose the compliance of FA and cytoskeleton along with curvature microarrays for increased nuclear force-sensing mechanotransduction. The results may provide helpful information for understanding interfacial heterogeneity and nuclear mechanotransduction of stem cells.
Keywords Cell colony, Interfacial heterogeneity, Focal adhesion, Cytoskeleton tension, Nuclear mechanotransduction
Address and Contact Information 1 Luoyang Orthopedic-Traumatological Hospital Of Henan Province (Henan Provincial Orthopedic Hospital), Zhengzhou 450008, Henan, China
2 Zhengzhou Revogene Technology Co., LTD, Airport District, Zhengzhou 451162, Henan, China
3 School of Medicine, Shanghai University, Shanghai 200444, China
4 Department of Aquatic Life Medicine, Pukyong National University, Busan 48513, Republic of Korea
5 School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, Fujian, China
*Corresponding author: 1058290809@qq.com; 41903878@qq.com; yongtao_wang@shu.edu.cn
† Huayu Fan, Hui Zhao, and Yan Hou have contributed equally to this paper.
Read full article at BMC

No.  11DOI: 10.1186/s11658-025-00694-x Volume 30 (2025) - 30:11
Title OMEGA-3 FATTY ACIDS: MOLECULAR WEAPONS AGAINST CHEMORESISTANCE IN BREAST CANCER
Authors Vittoria Marchio1†, Giuseppina Augimeri1†, Catia Morelli1,2, Adele Vivacqua1,2, Cinzia Giordano1,2, Stefania Catalano1,2, Diego Sisci1,2, Ines Barone1*† and Daniela Bonofglio1,2†
Abstract Breast cancer is the most commonly diagnosed type of cancer and the leading cause of cancer-related death in women worldwide. Highly targeted therapies have been developed for different subtypes of breast cancer, including hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, triple-negative breast cancer (TNBC) and metastatic breast cancer disease are primarily treated with chemotherapy, which improves disease-free and overall survival, but does not offer a curative solution for these aggressive forms of breast cancer. Moreover, the development of chemoresistance is a major cause of therapeutic failure in this neoplasia, leading to disease relapse and patient death. In addition, chemotherapy’s adverse side effects may substantially worsen health-related quality of life. Therefore, to improve the outcome of patients with breast cancer who are undergoing chemotherapy, several therapeutic options are under investigation, including the combination of chemotherapeutic drugs with natural compounds. Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), including docosahexaenoic and eicosapentaenoic acids, have drawn attention for their antitumoral properties and their preventive activities against chemotherapy-induced toxicities in breast cancer. A literature review was conducted on PubMed using keywords related to breast cancer, omega-3, chemoresistance, and chemotherapy. This review aims to provide an overview of the molecular mechanisms driving breast cancer chemoresistance, focusing on the role of ω-3 PUFAs in these recognized cellular paths and presenting current findings on the effects of ω-3 PUFAs combined with chemotherapeutic drugs in breast cancer management.
Keywords Breast cancer, Chemoresistance, Chemotherapy, Omega-3 polyunsaturated fatty acids, Natural compounds, Mediterranean diet
Address and Contact Information 1 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata Di Rende, 87036 Cosenza, Italy
2 Centro Sanitario, University of Calabria, Via P. Bucci, Arcavacata Di Rende (CS), 87036 Rende, Cosenza, Italy
*Corresponding author: ines.barone@unical.it
† Vittoria Marchio and Giuseppina Augimeri contributed equally to this work.
† Ines Barone and Daniela Bonofglio are joint senior authors.
Read full article at BMC

No.  12DOI: 10.1186/s11658-025-00691-0 Volume 30 (2025) - 30:12
Title VEXAS, CHEDIAK–HIGASHI SYNDROME AND DANON DISEASE: MYELOID CELL ENDO-LYSOSOMAL PATHWAY DYSFUNCTION AS A COMMON DENOMINATOR?
Authors Coline Savy1, Maxence Bourgoin1, Thomas Cluzeau1,2, Arnaud Jacquel1, Guillaume Robert1*† and Patrick Auberger1*†
Abstract Vacuolization of hematopoietic precursors cells is a common future of several otherwise non-related clinical settings such as VEXAS, Chediak–Higashi syndrome and Danon disease. Although these disorders have a priori nothing to do with one other from a clinical point of view, all share abnormal vacuolization in different cell types including cells of the erythroid/myeloid lineage that is likely the consequence of moderate to drastic dysfunctions in the ubiquitin proteasome system and/or the endo-lysosomal pathway. Indeed, the genes affected in these three diseases UBA1, LYST or LAMP2 are known to be direct or indirect regulators of lysosome trafficking and function and/or of different modes of autophagy. Furthermore, all three genes are highly expressed in the more mature myeloid cells pointing out their likely important function in these cells. LAMP2 deficiency for instance is known to be associated with alterations of lysosome architecture and function. It is thus well established that different cell types from Danon disease patients that harbor invalidating mutations in LAMP2 exhibit giant lysosomes containing undigested materials characteristic of defects in the fusion of lysosomes with autophagosomes, a feature also found in VEXAS and CHS. Other similarities regarding these three diseases include granulocyte and monocyte dysfunctions and a recurrent inflammatory climate. In the present review we discuss the possibility that some common clinical manifestations of these diseases, notably the hematopoietic ones are consecutive to a dysfunction of the endo-lysosomal pathway in myeloid/erythroid progenitors and in mature myeloid cells including neutrophiles, monocytes and macrophages. Finally, we propose reacidification as a way of reinducing lysosome functionalities and autophagy as a potential approach for a better management of these diseases.
Keywords VEXAS, Chediak–Higashi disease, Danon disease, Lysosomes, pH, Neutrophiles, Monocytes, Macrophages, Infammation
Address and Contact Information 1 University Cote d’Azur, Inserm, C3M, Nice, France
2 Clinical Hematology Department, Centre Hospitalier Universitaire, Nice, France
*Corresponding author: robertg@unice.fr; Patrick.auberger@inserm.fr
† Guillaume Robert and Patrick Auberger have contributed equally.
Read full article at BMC

No.  13DOI: 10.1186/s11658-025-00689-8 Volume 30 (2025) - 30:13
Title MONOCYTES SERVE AS SHIGA TOXIN CARRIERS DURING THE DEVELOPMENT OF HEMOLYTIC UREMIC SYNDROME
Authors Xinlei Sun1†, Shuang Qu2†, Fenglian Zhou1, Fujie Shi1, Yunfei Wu3, Lin Gu4, Minghui Liu3, Zhen Bian1, Lei Shi1, Zhihong Liu5*, Yuan Liu1* and Ke Zen1,6*
Abstract Shiga toxin (Stx)-induced hemolytic uremic syndrome (HUS) poses a life-threatening complication for which a definitive treatment remains elusive. To exert its cytotoxic effect on renal cells, Stx must be delivered from the infected intestines to the kidney. However, the mechanism underlying Stx delivery remains unclear. Here we pinpoint monocytes as the primary carriers responsible for transporting Stx2 to the renal region. Through single-cell sequencing analysis of Stx2-B-bound peripheral white blood cells sorted by flow cytometry, we observe that nearly all monocytes exhibit strong Stx2-B binding, whereas less than 10% of neutrophils are associated with Stx2-B, albeit with a lower affinity. Further examination of the single-cell dataset and cell binding assays suggest that monocytes likely bind to Stx2-B through the Toll-like receptor 4. Remarkably, Stx-laden monocytes demonstrate their ability to transport Stx2 to human renal glomerular endothelial cells (HRGEC), subsequently inducing apoptosis in HRGEC. In a mouse model of Stx1/2-positive EDL933 infection-induced HUS, the presence of Stx2-positive monocytes in peripheral blood and infiltrated kidney tissues was observed. Finally, depleting monocytes through the usage of a CD14 neutralizing antibody or blocking monocyte chemotaxis via inhibition of CCL2 notably mitigates kidney injury and dysfunction caused by lipopolysaccharide (LPS)/Stx2 treatment. Our findings unveil the pivotal role of monocytes in Stx delivery during STEC infection and offer a promising therapeutic approach for Stx-induced HUS.
Keywords Shiga toxin, Hemolytic uremic syndrome, Monocyte, Neutralizing antibody, Single-cell sequencing
Address and Contact Information 1 State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, Nanjing University Medical School, Nanjing University, Nanjing 210093, Jiangsu, China
2 Geriatric Hospital of Nanjing Medical University, Nanjing 210024, Jiangsu, China
3 School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, Jiangsu, China
4 Jiangsu Provincial Central for Disease Prevention and Control, Nanjing 210009, Jiangsu, China
5 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, Jiangsu, China
6 Department of Emergency Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210093, China
*Corresponding author: liuzhihong@nju.edu.cn; yliu@gsu.edu; kzen@nju.edu.cn
† Xinlei Sun and Shuang Qu have contributed equally to this work.
Read full article at BMC

No.  14DOI: 10.1186/s11658-025-00697-8 Volume 30 (2025) - 30:14
Title THE HISTONE DEMETHYLASE KDM5C ENHANCES THE SENSITIVITY OF ACUTE MYELOID LEUKEMIA CELLS TO LENALIDOMIDE BY STABILIZING CEREBLON
Authors Lu Zou1, Dan Cao1, Qing Sun1, Wenjun Yu1, Bingzong Li2, Guoqiang Xu1,3,4* and Liang Zhou1*
Abstract Background: The protein cereblon (CRBN) mediates the antileukemia effect of lenalidomide (Len). Len binds to CRBN, recruits IKZF1/IKZF3, and promotes their ubiquitination and degradation, through which Len exhibits its antileukemia and antimyeloma activity. Therefore, the protein level of CRBN might affect the antiproliferative effect of Len. In this study, we explored the interactome for CRBN using proximity labeling technique TurboID and quantitative proteomics, and then investigated the antileukemia effect of Len.
Methods: The primary acute myeloid leukemia (AML) cells and AML cell lines were used to explore the functions of histone demethylase KDM5C on the antileukemia effect of Len. The cell viability and CRBN protein levels were evaluated in these cell lines. In addition, the KDM5C inhibitors were used to determine the effects of KDM5C enzymatic activity on the viability of AML cell lines.
Results: We identified that histone demethylase KDM5C was a CRBN-interacting protein. Biochemical experiments found that the CRBN-interacting protein KDM5C could stabilize CRBN and enhance the antileukemia effect of Len in an enzyme activity-independent manner. Furthermore, our studies revealed that the small-molecule compound MLN4924 could increase CRBN by elevating KDM5C.The combination of MLN4924 and Len can further increase the sensitivity of primary AML cells and AML cell lines to Len.
Conclusions: This study provides a possible strategy for a combination treatment with MLN4924 and Len for leukemia.
Keywords Cereblon (CRBN), KDM5C, Leukemia, Lenalidomide, Cell viability
Address and Contact Information 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric 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 Department of Hematology, The Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou 215006, 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
*Corresponding author: gux2002@suda.edu.cn; liangzhou@suda.edu.cn
Read full article at BMC

No.  15DOI: 10.1186/s11658-025-00690-1 Volume 30 (2025) - 30:15
Title CircUCK2(2,3) PROMOTES CANCER PROGRESSION AND ENHANCES SYNERGISTIC CYTOTOXICITY OF LENVATINIB WITH EGFR INHIBITORS VIA ACTIVATING CNIH4–TGFα–EGFR SIGNALING
Authors Xindong Wei1,2,3†, Anfeng Si4†, Shuai Zhao5†, Yi Fu1,3, Jilei Li1,3, Kedeerya Aishanjiang1,5,6, Yujie Ma1,3, Chang Yu2, Bo Yu7, Chunhong Cui8, Hui Wang8, Xianming Kong3, Shibo Li9*, Xiaoni Kong2*, Ying Tong10* and Hailong Wu1,3,11*
Abstract Background: Circular (circ)RNAs have emerged as crucial contributors to cancer progression. Nonetheless, the expression regulation, biological functions, and underlying mechanisms of circRNAs in mediating hepatocellular carcinoma (HCC) progression remain insufficiently elucidated.
Methods: We identified circUCK2(2,3) through circRNA sequencing, RT–PCR, and Sanger sequencing. CircUCK2(2,3) levels were measured in two independent HCC cohorts using quantitative real-time PCR (qRT–PCR). We explored the functions of circUCK2(2,3) using gain- and loss-of-function assays. Techniques such as RNA-sequencing, RNA immunoprecipitation (RIP), polysome fractionation, RNA pulldown, dual luciferase reporter assay, inhibitors of EGFR downstream signaling, CRISPR–Cas9, and medium transfer assays were employed to investigate the regulatory mechanisms and the protumoral activities of circUCK2(2,3). Additionally, in vitro cytotoxic assays and patient-derived xenograft (PDX) models assessed the effects of circUCK2(2,3) on the cytotoxic synergy of lenvatinib and EGFR inhibitors.
Results: CircUCK2(2,3) is upregulated in HCC tissues and serves as an independent risk factor for poor recurrence-free survival. The expression of circUCK2(2,3) is independent on its host gene, UCK2, but is regulated by its upstream promoter and flanking inverted complementary sequences. Functionally, circUCK2(2,3) enhances HCC proliferation, migration, and invasion, both in vitro and in vivo. Mechanistically, by sponging miR-149-5p, circUCK2(2,3) increases CNIH4 levels, which in turn amplifies TGFα secretion, resulting in the activation of EGFR and downstream pAKT and pERK signaling pathways. Moreover, circUCK2(2,3) overexpression sensitizes HCC cells to EGFR inhibitors, and increases the synergistic cytotoxicity of combined lenvatinib and EGFR inhibitor treatment.
Conclusions: CircUCK2(2,3) regulates a novel oncogenic pathway, miR-149-5p–CNIH4–TGFα–EGFR, in HCC, presenting a viable therapeutic target and biomarker for the precision treatment of HCC.
Keywords Hepatocellular carcinoma, circRNA, CNIH4, TGFα–EGFR signaling, Lenvatinib, EGFR inhibitors
Address and Contact Information 1 Clinical Research Center, Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health Sciences, Shanghai 201800, China.
2 Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai 201203, China.
3 Collaborative Research Center for Biomedicines, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
4 Department of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210015, China.
5 Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
6 People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 831399, China.
7 School of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
8 Basic Medical College, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
9 Department of Infectious Disease, Zhoushan Hospital, Wenzhou Medical University, Zhoushan 316100, China.
10 Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai JiaoTong University, Shanghai 200003, China.
11 School of Pharmacy, Joint Innovation Laboratory for Cell Therapy Technology, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
*Corresponding author: lsb0398@126.com; xiaoni-kong@126.com; lilytongy@hotmail.com; wuhl@sumhs.edu.cn
† Xindong Wei, Anfeng Si, and Shuai Zhao have contributed equally to this study.
Read full article at BMC

No.  16DOI: 10.1186/s11658-025-00695-w Volume 30 (2025) - 30:16
Title BIOSYNTHESIS INHIBITION OF miR-142-5p in a N6-METHYLADENOSINE-DEPENDENT MANNER INDUCES NEUROPATHIC PAIN THROUGH CDK5/TRPV1 SIGNALING
Authors Jinshi Li1†, Yang Guo2†, Chen Zhu3, Dongxu Wang1, Yuan Li1, Xiaotong Hao1, Linyan Cao1, Yiting Fan1 and Bo Fang1*
Abstract Background: Neuropathic pain (NP) represents a debilitating and refractory condition. However, the understanding of NP and the current treatment approaches available for its management are limited. Therefore, there is a significant need to address the dearth of effective therapeutic interventions. This study aims to investigate the regulation of transient receptor potential vanilloid 1 (TRPV1) and cyclin-dependent kinase 5 (CDK5) expression levels by miR-142-5p as a common upstream molecule, and to delve into the mature process of miR-142-5p from the perspective of N6-methyladenosine (m6A) modification.
Methods: To assess the RNA levels of TRPV1, CDK5, miR-142-5p, pre-miR-142, and pri-miR-142, quantitative PCR with reverse transcription (RT–qPCR) was utilized. Western blot analysis was employed to determine changes in protein expression for TRPV1 and CDK5. For assessing the interaction mechanism and binding site between TRPV1 and CDK5, various techniques were applied, including mass spectrometry, coimmunoprecipitation (co-IP), and glutathione-S-transferase (GST)-pulldown assays. The subcellular localization of TRPV1 on the cell membrane was visualized through immunofluorescence, and the translocation was confirmed by western blot analysis after performing membrane-plasma separation in parallel. Moreover, intracellular calcium transport was monitored using calcium imaging as an indicator of cell excitability. The binding of miRNA-142-5p to the 3’UTR of TRPV1 and CDK5 was investigated using the dual-luciferase reporter assay. The overall level of m6A was first determined by RNA m6A methylation assay, and subsequently the methylation level of pri-miR-142 was assessed using the meRIP assay to detect m6A modification. In addition, an in vivo rat chronic constriction injury (CCI) model was established, and miR-142-5p agomir or antagomir was injected intrathecally. An enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of IL-6 and TNF. Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were examined.
Results: The expression levels of TRPV1 and CDK5 were found to be upregulated not only in the in vivo CCI model but also in the in vitro lipopolysaccharide (LPS) treatment cell model as well. CDK5 was observed to phosphorylate TRPV1 at T406, prompting the translocation of TRPV1 to the cell membrane and consequent augmentation of cellular excitability. Notably, CDK5 was found to directly bind to TRPV1, and the binding region was localized within the 1–390 amino acid sequence of TRPV1. According to database predictions, miR-142-5p, identified as a shared upstream molecule of TRPV1 and CDK5, exhibited downregulation following induction by NP. MiR-142-5p was shown to simultaneously bind to the mRNA of CDK5 and TRPV1, thereby inhibiting their expression. After LPS treatment, it was observed that pri-miR-142 expression increased, while pre-miR-142 and miR-142-5p expression decreased, suggesting inhibition of the maturation process of pri-miR-142. In addition, the overall level of m6A and in particular the pri-miR-142 m6A modification increased upon LPS treatment. Knockdown of METTL14 led to decreased pri-miR-124 expression, increased pre-miR-124 expression, and enhanced mature miR-142-5p expression, indicating the relief of miR-142-5p maturation repression. The in vivo results indicated that miR-142-5p negatively regulated the expression of CDK5 and TRPV1, suppressed the expression of inflammatory factors IL-6 and TNF, and improved the PWMT and PWTL.
Conclusions: In this study, we perform a thorough investigation to examine the effects of CDK5 and TRPV1 on NP, elucidating their binding relationship and the impact of CDK5 on the membrane transport of TRPV1. Notably, our findings reveal that miR-142-5p, acting as a crucial upstream molecule, exhibits inhibitory effects on the expression of both CDK5 and TRPV1. Moreover, we observe that METTL14 facilitates the m6A modification of pri-miR-142, thereby impeding the maturation transition of pri-miR-142 and ultimately leading to the downregulation of mature miR-142-5p.
Keywords Neuropathic pain, TRPV1, CDK5, N6-methyladenosine, Cell membrane transport, Phosphorylation
Address and Contact Information 1 Department of Anesthesiology, The First Hospital of China Medical University, NO.155, North Nanjing Street, Heping District, Shenyang 110001, Liaoning, China
2 Department of Surgical Oncology, Breast Surgery, General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China
3 Department of Neurosurgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China
*Corresponding author: bfang@cmu.edu.cn
† Jinshi Li, Yang Guo, and Chen Zhu contributed equally to this study.
Read full article at BMC

No.  17DOI: 10.1186/s11658-025-00688-9 Volume 30 (2025) - 30:17
Title CORRECTION: THE miR-1269a/PCDHGA9/CXCR4/β-CATENIN PATHWAY PROMOTES COLORECTAL CANCER INVASION AND METASTASIS
Authors Haitao Mei1,2,3†, Qingshan Luo2†, Junyong Weng3,5†, Jialing Hao2, Jinfeng Cai2, Runkai Zhou2, Ce Bian3, Yingzi Ye6*, Shengzheng Luo4* and Yugang Wen2*
Abstract Correction: Cellular & Molecular Biology Letters (2024) 29:144
https://doi.org/10.1186/s11658-024-00656-9

Following publication of the original article [1], the authors identifed an error in the *Correspondence section and in the author names of Yingzi Ye, Shengzheng Luo and Yugang Wen

The incorrect author names are: Ye Yingzi, Luo Shengzheng and Wen Yugang

The correct author names are: Yingzi Ye, Shengzheng Luo and Yugang Wen

The *Correspondence section and the author names have been updated above and the original article has been corrected.

Reference
1. Mei H, Luo Q, Weng J, Hao J, Cai J, Zhou R, Bian C, Ye Y, Luo S, Wen Y. The miR-1269a/PCDHGA9/CXCR4/β-catenin pathway promotes colorectal cancer invasion and metastasis. Cell Mol Biol Lett. 2024;29:144. https://doi.org/10.1186/s11658-024-00656-9.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional afliations.
Keywords
Address and Contact Information 1 Department of Gastrointestinal Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Shanghai 200071, China.
2 Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai 200080, China.
3 Department of Colorectal Surgery, Changzheng Hospital, Navy Medical University, 415 Fengyang Road, Shanghai 200003, China.
4 Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai 200080, China.
5 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China.
6 Department of Infectious Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China.
*Corresponding author: yeyingzi1502@sina.com; luoshengzheng2007@163.com; wenyg1502@hotmail.com
† Haitao Mei, Qingshan Luo, and Junyong Weng contributed equally to this work.
The original article can be found online at https://doi.org/10.1186/s11658-024-00656-9.
Read full article at BMC

No.  18DOI: 10.1186/s11658-024-00679-2 Volume 30 (2025) - 30:18
Title SPHINGOLIPID METABOLITES INVOLVED IN THE PATHOGENESIS OF ATHEROSCLEROSIS: PERSPECTIVES ON SPHINGOLIPIDS IN ATHEROSCLEROSIS
Authors Fufangyu Zhao1,2†, Mingyan Shao1†, Mingrui Li1, Tianxing Li1, Yanfei Zheng1*, Wenlong Sun3*, Cheng Ni2* and Lingru Li1*
Abstract Atherosclerosis, with its complex pathogenesis, is a leading underlying cause of many cardiovascular diseases, which are increasingly prevalent in the population. Sphingolipids play an important role in the development of atherosclerosis. Key metabolites and enzymes in sphingolipid metabolism influence the pathogenesis of atherosclerosis in a variety of ways, including inflammatory responses and oxidative stress. Thus, an investigation of sphingolipid metabolism-related metabolites and key enzymes may provide novel insights and treatment targets for atherosclerosis. This review discusses various mechanisms and research progress on the relationship between various sphingolipid metabolites, related enzymes, and atherosclerosis. Finally, we look into the future research direction of phytosphingolipids.
Keywords Sphingolipids, Phytosphingolipids, Atherosclerosis, Metabolites, Enzymes
Address and Contact Information 1 National Institute of Traditional Chinese Medicine Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
2 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
3 Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo 255000, Shandong, China
*Corresponding author: yanfei_z@163.com; 512649113@qq.com; nicheng@bucm.edu.cn; 700435@bucm.edu.cn
† Fufangyu Zhao and Mingyan Shao are equal contributors.
Read full article at BMC

No.  19DOI: 10.1186/s11658-025-00698-7 Volume 30 (2025) - 30:19
Title RETRACTION NOTE: DOWNREGULATION OF CDKL1 SUPPRESSES NEUROBLASTOMA CELL PROLIFERATION, MIGRATION AND INVASION
Authors Weiyi Li1, Jing Cao2, Jian Liu1, Wenli Chu1, Congqing Zhang1, Shuiling Chen1 and Zefeng Kang1*
Abstract Retraction Note: Cellular & Molecular Biology Letters (2019) 24:19
https://doi.org/10.1186/s11658-019-0139-z

The Editor-in-Chief has retracted this article because of concerns regarding the figures presented in this work. These concerns call into question the article's overall scientific soundness. An investigation conducted after its publication discovered the following issues:
  • The second GAPDH band in Fig. 1B appears to overlap with the GADPH band in Fig. 2E in [1];
  • The third CDKL1 band in Fig. 1B appears to overlap, when flipped and re-scaled, with the Ftl1, Duodenum band in Fig. 1A in [2];
  • The micrograph shown in Panel GFP, siCDKL1 of Fig. 2B appears to overlap with the micrograph shown in Panel GFP, shZFR of Fig. 2a in [3];
  • The GAPDH band in Fig. 2D appears to overlap, when flipped and re-scaled, with the GADPH, MG-63 band in Fig. 2C in [4];
  • The assay shown in Panel 0h, NC in Fig. 4A appears to overlap with the assay shown in Panel 0h, pcDNA in Fig. 4A in [5].


The Editor-in-Chief therefore no longer has confidence in the integrity of the research presented in this article.

The authors have not replied to correspondence from the Publisher.
Keywords
Address and Contact Information 1 Eye Hospital, China Academy of Chinese Medical Sciences, No 33 Lugu Road, Shijingshan District, Beijing 100040, China
2 Yinan Branch of Qilu Hospital of Shandong University, Linyi, Shandong, China
*Corresponding author: zefeng_K2016@126.com
The original article can be found online at https://doi.org/10.1186/s11658-019-0139-z.
Read full article at BMC

No.  20DOI: 10.1186/s11658-025-00687-w Volume 30 (2025) - 30:20
Title TUMOR-DERIVED EXOSOMAL KPNA2 ACTIVATES FIBROBLASTS AND INTERACTS WITH KIFC1 TO PROMOTE BLADDER CANCER PROGRESSION, A PROCESS INHIBITED BY miR-26b-5p
Authors Cong Yin1,4†, Cen Liufu2,3†, Shuai Ye1,4†, Tao Zhu2,3, Jiahao Jiang5,6, Mingxia Wang3, Liqun Zhou7,8, Lin Yao7,8*,Yan Wang3* and Bentao Shi1,4*
Abstract Background: Recent studies have illuminated the complexities of treating advanced bladder cancer (BCa), underscoring the importance of comprehending its molecular mechanisms for creating novel therapies. While the role of Karyopherin a2 (KPNA2) in promoting BCa growth is established, the precise mechanism remains elusive.
Methods: To investigate the regulatory role of KPNA2 in BCa, we employed a comprehensive approach integrating clinical case data and bioinformatics analysis to evaluate the expression of KPNA2 in BCa tissues. Mechanisms promoting cancer by KPNA2 were examined using both in vivo and in vitro models.
Results: Our research reveals that miR-26b-5p acts as an anticancer factor by targeting and inhibiting KPNA2 expression. Furthermore, we have observed that the interaction between KPNA2 and Kinesin Family Member C1 (KIFC1) facilitates the transition of BCa cells into the G2/M phase, thereby promoting tumor advancement via activation of the Phosphoinositide 3-kinase (PI3K)- Protein Kinase B (AKT) pathway. Importantly, this investigation is the first to identify KPNA2 expression in exosomes originating from BCa tissues. Plasma exosomes from patients with BCa exhibited notably increased levels of KPNA2 compared with healthy controls, suggesting KPNA2 as a potential new tumor indicator. Additionally, KPNA2 from BCa cells triggered the conversion of fibroblasts into cancer-associated fibroblasts (CAFs), which secreted elevated levels of interleukin-6 (IL-6), contributing to a tumor-supporting environment.
Conclusions: These findings suggest that KPNA2 is a key gene that promotes BCa progression, can potentially be a novel tumor marker, and may serve as a new therapeutic target for BCa.
Keywords BCa, Exosomes, KPNA2, Tumor microenvironment, Fibroblast activation, CAFs
Address and Contact Information 1 Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, No. 3002, Sungangxi Road, Shenzhen 518035, People’s Republic of China.
2 Present Address: Shantou University Medical College, Shantou 515041, China.
3 Department of Urology, Peking University Shenzhen Hospital, Institute of Urology, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
4 Shenzhen University Health Science Center, Shenzhen 518055, China.
5 Department of Urology, Shenzhen Second People’s Hospital, Clinical College of Anhui Medical University, Shenzhen 518035, China.
6 The Fifth Clinical Medical College of Anhui Medical University, Hefei 230032, Anhui, China.
7 Department of Urology, Peking University First Hospital, No. 8 Xishiku St., Xicheng District, Beijing 100034, People’s Republic of China.
8 Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, No. 8 Xishiku St., Xicheng District, Beijing 100034, China.
*Corresponding author: poparies@163.com; wangyan198614@163.com; shibentaopku@126.com
† Cong Yin, Cen Liufu and Shuai Ye contributed equally to this work.
Read full article at BMC

No.  21DOI: 10.1186/s11658-025-00701-1 Volume 30 (2025) - 30:21
Title HUMAN URINE STEM CELLS PROTECT AGAINST CYCLOPHOSPHAMIDE-INDUCED PREMATURE OVARIAN FAILURE BY INHIBITING SLC1A4-MEDIATED OUTFLUX OF INTRACELLULAR SERINE IN OVARIAN GRANULOSA CELLS
Authors Hao‐Cheng Gu1,2†, Ling‐Fang Wang1†, Yu‐Wei Zhang1,2, You‐Qiong Zhuo1,3, Zhou‐Hang Zhang1, Xing‐Yu Wei1, Quan‐Wen Liu1, Ke‐Yu Deng1,2* and Hong‐Bo Xin1,2,3*
Abstract Background: Cyclophosphamide (CTX) is the first-line medication for the treatment of breast cancer, although it potentially leads to severe ovarian dysfunction and even premature ovarian failure (POF). However, the mechanism of CTX-induced POF remains unclear. Mesenchymal stem cell-based therapy has been wildly used for treating numerous diseases. Therefore, our study aims to elucidate the underlying mechanism of CTX-induced POF and to explore the therapeutic effect of human urine stem cells (hUSCs) in POF.
Methods: CTX-induced POF or ovarian granulosa cell (GCs) apoptosis were treated with hUSCs and their exosomes in vitro and in vivo. Morphological, histological, and functional alternations were examined using multiple approaches. The effector molecules of hUSC-derived exosomes (hUSC-Exo) were determined by differential expression analysis in the ovaries. The target genes of miRNA were accessed by transcriptome sequencing in GCs, and the underlying mechanisms were further elucidated.
Results: hUSCs remarkably inhibited CTX-induced apoptosis and promoted the proliferation of GCs, respectively. In addition, we observed that miR-27b-3p was highly expressed in hUSC-Exo and markedly suppressed CTX-induced GC apoptosis by specifically inhibiting the expression of SLC1A4, a serine transporter, in ovarian GCs, which, in turn, elevated the concentration of the intracellular serine by inhibiting the outflux of cellular serine. More importantly, the knockdown of SLC1A4 or simple supplementation of serine suppressed CTX-induced apoptosis of GCs. Finally, we demonstrated that CTX-induced apoptosis of ovarian GCs was essential for POF by reducing the intracellular serine concentration via elevating the expression of SLC1A4, whereas hUSCs protected against CTX-induced POF via miR-27b-3p/SLC1A4/serine axis-mediated activation of the PI3K/AKT/mTOR signaling pathway.
Conclusions: Our study suggests that hUSC-based cell therapy or simple supplementation of serine may provide an efficient therapeutic approach for the prevention and treatment of CTX-induced POF clinically.
Keywords Premature ovarian failure, Human urine-derived stem cells, miR-27b-3p, SLC1A4, Ovarian granulosa cells, Cyclophosphamide
Address and Contact Information 1 The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang 330031, People’s Republic of China
2 School of Life and Science, Nanchang University, Nanchang 330031, People’s Republic of China
3 School of Food Science and Technology, Nanchang University, Nanchang 330031, People’s Republic of China
*Corresponding author: dky@ncu.edu.cn; xinhb@ncu. edu.cn
† Hao-Cheng Gu and Ling-Fang Wang contributed to this work equally.
Read full article at BMC

No.  22DOI: 10.1186/s11658-025-00700-2 Volume 30 (2025) - 30:22
Title EXPOSURE OF A2E TO BLUE LIGHT PROMOTES FERROPTOSIS IN THE RETINAL PIGMENT EPITHELIUM
Authors Bo Yang1,2, Kunhuan Yang1,2, Yuling Chen1,2, Qingjian Li2, Jingmeng Chen3,4, Shiying Li1* and Yalin Wu1,2,4*
Abstract Background: Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) is closely related to the etiology of autosomal recessive Stargardt’s disease (STGD1) and dry age-related macular degeneration (AMD). N-retinylidene-N-retinylethanolamine (A2E) is a leading component of RPE lipofuscin that is highly susceptible to blue light. Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by the accumulation of lipid peroxides to a lethal level, which plays an important role in retinal diseases. However, it remains unknown whether A2E functions as a physiological trigger for eliciting blue light-induced ferroptosis of RPE cells.
Methods: A2E-loaded RPE cells and Abca4−/−Rdh8−/− mice were exposed to blue light, respectively. Western blotting, immunofluorescence staining, reactive oxygen species (ROS) staining, intracellular iron staining, lipid peroxidation staining, fundus imaging, optical coherence tomography (OCT), hematoxylin–eosin (HE) staining, and electroretinography (ERG) were utilized to elucidate the role of blue light in A2E induced ferroptosis in the RPE and its potential mechanisms.
Results: Exposure of A2E to blue light promoted ferroptotic cell death in RPE cells by elevating ferrous ion (Fe2+) levels and inhibiting the solute carrier family 7 membrane 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis. GPX4 inactivation and ROS generated by Fe2+ overload and GSH depletion precipitated lipid peroxidation and subsequent ferroptosis in A2E-containing RPE cells upon exposure to blue light. In addition to GSH supplement, repressing either Fe2+ by deferiprone (DFP) or lipid peroxidation with ferrostatin-1 (Fer-1) significantly protected RPE cells against ferroptosis caused by blue light illumination of A2E. Abca4−/−Rdh8−/− mice featured by an accelerated deposition of A2E in the RPE is an animal model for STGD1 and dry AMD. It was observed that ferroptosis was indeed present in the RPE of Abca4−/−Rdh8−/− mice following exposure to blue light. Notably, alleviating ferroptosis by intraperitoneally injected Fer-1 effectively rescued retinal function and ameliorated RPE/photoreceptor degeneration in blue light-exposed Abca4−/−Rdh8−/− mice.
Conclusions: Our results suggest the importance of blue light in A2E-mediated ferroptosis in the RPE, and deeply broaden the understanding of mechanisms underlying RPE atrophy arising from lipofuscin accumulation in STGD1 and dry AMD.
Keywords Lipofuscin, A2E, Ferroptosis, Blue light, Macular degeneration, Retinal pigment epithelium
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@126.com; yalinw@xmu.edu.cn
Read full article at BMC

No.  23DOI: 10.1186/s11658-025-00696-9 Volume 30 (2025) - 30:23
Title REGULATING CHEMORESISTANCE AND CANCER STEMNESS: THE CDH17-YAP PATHWAY IN DISTINCT CELLULAR STATES OF LUNG CANCER CTC CLUSTERS
Authors Zujun Que1,2†, Dan Qi3,4†, Yun Yang2†, Wang Yao2, Jiajun Liu1, Yan Li2, Yuanyuan Yu5,6,7, Luyao Wang5,6,7, Fangfei Li5,6,7, Ge Zhang5,6,7*, Erxi Wu3,4,8,9,10* and Jianhui Tian1,2*
Abstract Background: Drug resistance in metastatic lung cancer significantly contributes to patient mortality. This study explores the role of circulating tumor cells (CTCs), the precursors to metastasis, in driving this resistance. We aim to delineate the unique biological traits of CTC clusters in lung cancer and elucidate the mechanisms underlying their resistance to chemotherapy.
Methods: We used an ultralow adsorption plate to establish a CTC suspension culture system. Comparisons between adherent and suspension cultures of CTC-TJH-01 cells were made via Cell Counting Kit-8 (CCK-8), western blot, immunofluorescence, and flow cytometry assays to evaluate cell proliferation, drug resistance, and cancer stemness. The tumorigenicity, tumor growth rate, and drug resistance of the CTC clusters were assessed in nude mice. Transcriptomic and proteomic analyses were subsequently conducted to identify differentially expressed genes and proteins in CTC-TJH-01 cells cultured under adherent and suspension conditions. CDH17 gene knockdown in CTC-TJH-01 cells was achieved through RNA interference, and hematoxylin and eosin (HE) staining, immunohistochemistry, and immunofluorescence assays were used to examine the pathological status of these cells.
Results: CTC-TJH-01 cells in suspension formed cell clusters and exhibited decreased proliferation, tumorigenicity, and tumor growth, but increased cancer stemness and drug resistance. CDH17 protein expression was significantly upregulated in these clusters, activating the YAP/TAZ pathway. Knocking down CDH17 not only inactivated this pathway but also significantly increased cell proliferation activity and cisplatin sensitivity in CTC-TJH-01 clusters. Additionally, the tumor growth rate was correlated with cisplatin sensitivity. CDH17 knockdown notably promoted the growth of CTC-TJH-01 xenografts and enhanced their sensitivity to cisplatin, although no significant difference was observed compared with those in the control group.
Conclusions: The results indicate that lung CTC clusters with stem cell-like properties exhibit chemoresistance, which is linked to an activated CDH17-YAP pathway. Additionally, the effectiveness of cisplatin is primarily observed in tumors with relatively high growth rates, highlighting the connection between tumor growth and sensitivity to chemotherapy.
Keywords Lung cancer, Circulating tumor cells, Cancer stemness, Chemoresistance, CDH17-YAP pathway
Address and Contact Information 1 Institute of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China.
2 Clinical Oncology Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China.
3 Department of Neurosurgery and Neuroscience Institute, Baylor Scott & White Health, Temple, TX 76508, USA.
4 Department of Neurosurgery, Baylor College of Medicine, Temple, TX 76508, USA.
5 Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, SAR, China.
6 Institute of Precision Medicine and Innovative Drug Discovery, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, SAR, China.
7 Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, SAR, China.
8 College of Medicine, Texas A&M University, College Station, TX 77843, USA.
9 Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX 77843, USA.
10 Department of Oncology, LIVESTRONG Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.
*Corresponding author: zhangge@hkbu.edu.hk; erxi.wu@bswhealth.org; tjhhawk@shutcm.edu.cn † Zujun Que, Dan Qi and Yun Yang have contributed equally to this work.
Read full article at BMC

No.  24DOI: 10.1186/s11658-025-00702-0 Volume 30 (2025) - 30:24
Title KLF5 ENHANCES CXCL12 TRANSCRIPTION IN ADIPOSE-DERIVED STEM CELLS TO PROMOTE ENDOTHELIAL PROGENITOR CELLS NEOVASCULARIZATION AND ACCELERATE DIABETIC WOUND HEALING
Authors Yunjia Xie1†, Xuejun Ni1,2†, Xiaofen Wan1†, Nating Xu3, Lu Chen1, Chensheng Lin4, Xi Zheng4, Beichen Cai1,2, Qian Lin1, Ruonan Ke1, Tao Huang1, Xuefeng Hu4*, Biao Wang1,2* and Xiuying Shan1,2*
Abstract Background: Adipose-derived stem cells (ADSCs) have been shown to accelerate diabetic wound healing by promoting neovascularization, though the underlying mechanisms are not fully understood. This study aims to explore whether ADSCs influence endothelial progenitor cells (EPCs) function to enhance diabetic wound healing.
Methods: Human adipose-derived stem cells (hADSCs) were isolated from patient adipose tissue and cultured under normal and high glucose (HG) conditions. RNA sequencing analyzed gene expression, while immunofluorescence validated findings in patient wound tissues. Mouse adipose-derived stem cells (ADSCs) from C57BL/6 mice were evaluated in vitro for their effects on EPCs under HG using EdU, Transwell, and tube formation assays. A diabetic mouse wound model was used to assess ADSCs therapeutic effects via digital imaging, histology, and immunofluorescence. Kruppel-like factor 5 (KLF5), identified via the JASPAR database, was confirmed by immunohistochemistry and immunofluorescence. KLF5 and C-X-C motif chemokine 12 (CXCL12) expression levels were measured by enzyme-linked immunosorbent assay (ELISA), western blot, and quantitative reverse transcription polymerase chain reaction (RT-qPCR), and their relationship was validated through dual-luciferase assays. Results:
We constructed a neovascularization-related signature (NRS) comprising 75 genes on the basis of differentially expressed genes (DEGs) linked to neovascularization. GO and KEGG analyses revealed that the NRS is primarily involved in vasculature development and receptor–ligand activity. Seven hub genes (CD34, CXCL12, FGF7, FGF18, FGF1, TEK, KIT) were identified and validated. In a diabetic mouse model, CXCL12 knockdown in ADSCs reduced their ability of promoting wound healing and neovascularization. KLF5 expression was lower in patients with diabetic ulcers and diabetic mice wound tissues compared with normal tissues, while ADSCs treatment significantly increased KLF5 expression in diabetic mice wounds. Dual-luciferase reporter assays confirmed KLF5 as an upstream transcription factor of CXCL12. Additionally, knocking down KLF5 in ADSCs impaired their therapeutic effects on diabetic wound healing. In vitro, the addition of exogenous CXCL12 recombinant protein restored EPCs proliferation, migration, and vasculogenic capacity in a high glucose environment after KLF5 silencing in ADSCs. Conclusions:
Our findings underscore the pivotal role of KLF5 in enhancing CXCL12 transcription within ADSCs, thereby facilitating EPC-mediated neovascularization and improving diabetic wound healing. Additionally, KLF5 emerges as a promising therapeutic target for accelerating tissue repair in diabetic wounds.
Keywords Adipose-derived stem cells, Endothelial progenitor cells, Diabetic wound, Neovascularization, Wound healing
Address and Contact Information 1 Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
2 Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
3 Department of Burn and Plastic Surgery, Fujian Provincial Hospital, Fuzhou 350001, China
4 Fujian Key Laboratory of Developmental and Neural Biology & Southern Center for Biomedical Research, College of Life Sciences, Fujian Normal University, Fuzhou 350117, Fujian, China
*Corresponding author: Bioxfh@fnu.edu.cn; biaowang@fmu.edu.cn; xiuyingshan@fmu.edu.cn
† Yunjia Xie, Xuejun Ni, and Xiaofen Wan contributed equally to this work.
Read full article at BMC

No.  25DOI: 10.1186/s11658-025-00703-z Volume 30 (2025) - 30:25
Title DNA-PKcs, A PLAYER WINDING AND DANCING WITH RNA METABOLISM AND DISEASES
Authors Jiabao Hou1, Mingjun Lu1, Jingwei Guo1, Jinghong Wu1, Chenyang Wang1, Ping‐Kun Zhou2* and Teng Ma1*
Abstract The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key kinase in the DNA repair process that responds to DNA damage caused by various factors and maintains genomic stability. However, DNA-PKcs is overexpressed in some solid tumors and is frequently associated with poor prognosis. DNA-PKcs was initially identified as a part of the transcription complex. In recent years, many studies have focused on its nonclassical functions, including transcriptional regulation, metabolism, innate immunity, and inflammatory response. Given the pleiotropic roles of DNA-PKcs in tumors, pharmacological inhibition of DNA-PK can exert antitumor effects and may serve as a potential target for tumor therapy in the future. This review summarizes several aspects of DNA-PKcs regulation of RNA metabolism, including its impact on transcriptional machinery, alternative splicing, and interaction with noncoding RNAs, and provides insights into DNA-PKcs beyond its DNA damage repair function.
Keywords DNA-PKcs, RNA metabolism, Transcriptional regulation, Alternative splicing, Noncoding RNAs
Address and Contact Information 1 Cancer Research Center, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing 101149, China
2 Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation Medicine, Beijing 100850, China
*Corresponding author: zhoupk@nic.bmi.ac.cn; mateng82913@163.com
Read full article at BMC

No.  26DOI: 10.1186/s11658-025-00699-6 Volume 30 (2025) - 30:26
Title SRSF3 AND hnRNP A1-MEDIATED m6A-MODIFIED circCDK14 REGULATES INTRAMUSCULAR FAT DEPOSITION BY ACTING AS miR-4492-z sPONGE
Authors Chunyu Qin1, Fang Xu1, Binglin Yue1, Jincheng Zhong1, Zhixin Chai1 and Hui Wang1*
Abstract The intramuscular fat (IMF) content of yak beef is critical for determining its quality. Circular RNAs (circRNAs) are a group of endogenous non-coding RNAs that have emerged as important factors in the regulation of IMF deposition. However, the molecular mechanisms through which circRNAs regulate IMF deposition, particularly in yaks, remain unclear. In the present study, a novel circRNA, circCDK14 (originating from the yak’s CDK14 gene), was identified by sequencing and RNase R treatment. In our previous study, we successfully established a ceRNA network map and identified miR-4492-z, which interacts with circCDK14. Furthermore, using methylation prediction software, we predicted two genes, SRSF3 and hnRNP A1, that have a strong binding relationship with circCDK14; existing research has confirmed their close association with m6A methylation modifications. On the basis of these findings, we comprehensively evaluated the effects of circCDK14, miR-4492-z, SRSF3 and hnRNP A1 on the proliferation and differentiation of yak intramuscular pre-adipocytes using EdU, CCK-8, BODIPY, Oil Red O and qRT-PCR analyses. Mechanistically, the interaction between circCDK14 and miR-4492-z was validated using a dual-luciferase reporter gene assay and rescue experiments. RIP assays revealed the binding interaction of circCDK14 with SRSF3 and hnRNP A1. The MeRIP experiments showed modification of circCDK14 methylation, with SRSF3 and hnRNP A1 promoting the methylation and translocation of circCDK14 from the nucleus to the cytoplasm. In summary, our results suggest that m6A-modified circCDK14 plays a crucial role as an miR-4492-z sponge in regulating IMF deposition in yaks and that the nuclear export of circCDK14 correlates with the expression levels of SRSF3 and hnRNP A1. This study provides a theoretical basis for the improvement of yak meat quality and promotes the development of molecular yak breeding.
Keywords circCDK14, m6A, SRSF3, hnRNP A1, Cell proliferation and diferentiation
Address and Contact Information 1 Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province and Ministry of Education, Southwest Minzu University, Chengdu 610225, China
*Corresponding author: wanghui892321@swun.edu.cn
Read full article at BMC

No.  27DOI: 10.1186/s11658-025-00710-0 Volume 30 (2025) - 30:27
Title OLD DRUGS, NEW CHALLENGES: REASSIGNING DRUGS FOR CANCER THERAPIES
Authors Paulina Czechowicz1, Anna Więch‐Walów1, Jakub Sławski1, James F. Collawn2 and Rafal Bartoszewski1*
Abstract The "War on Cancer" began with the National Cancer Act of 1971 and despite more than 50 years of effort and numerous successes, there still remains much more work to be done. The major challenge remains the complexity and intrinsic polygenicity of neoplastic diseases. Furthermore, the safety of the antitumor therapies still remains a concern given their often off-target effects. Although the amount of money invested in research and development required to introduce a novel FDA-approved drug has continuously increased, the likelihood for a new cancer drug’s approval remains limited. One interesting alternative approach, however, is the idea of repurposing of old drugs, which is both faster and less costly than developing new drugs. Repurposed drugs have the potential to address the shortage of new drugs with the added benefit that the safety concerns are already established. That being said, their interactions with other new drugs in combination therapies, however, should be tested. In this review, we discuss the history of repurposed drugs, some successes and failures, as well as the multiple challenges and obstacles that need to be addressed in order to enhance repurposed drugs’ potential for new cancer therapies.
Keywords Drug discovery, Drug repurposing, Cancer, Of-label use, Pharmaceutical development
Address and Contact Information 1 Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, F. Joliot‐Curie 14a Street, 50‐383 Wroclaw, Poland
2 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, USA
*Corresponding author: rafal.bartoszewski@uwr.edu.pl
Read full article at BMC

No.  28DOI: 10.1186/s11658-025-00706-w Volume 30 (2025) - 30:28
Title tRF-5028c DISRUPTS TROPHOBLAST FUNCTION IN RECURRENT SPONTANEOUS ABORTION BY INHIBITING CRKL-MEDIATED Rap1 SIGNALING PATHWAY
Authors Jialyu Huang1†, Jiawei Wang2†, Shuang Wang3†, Xiangpeng Xiong3, Ruiyin Jiang4, Chaoyi Xiong5, Lu Wang3, Lingling Huang1, Yan Zhao1, Zheng Fang6*, Xiaoyan Ai3* and Jiaying Lin7*
Abstract Background: Recurrent spontaneous abortion (RSA) affects approximately 1–5% of childbearing women and poses a significant threat to global reproductive health. Transfer RNA-derived small RNAs (tsRNAs) are a novel class of noncoding RNAs implicated in various human diseases. However, the role and mechanism of tsRNAs in regulating trophoblast function during RSA development remain unknown.
Methods: High-throughput sequencing was performed to analyze the differential tsRNAs in the villous tissues of patients with RSA and controls. CCK-8, transwell assay, and flow cytometry were performed to detect the effects of tRF-5028c on proliferation, migration, invasion, and apoptosis of human extravillous trophoblast cell line HTR-8/SVneo. The target genes of tRF-5028c were predicted via bioinformatic analysis and verified by dual luciferase reporter gene assay. Moreover, pregnant mice were injected with tRF-5028c mimics to confirm the findings in vivo.
Results: A total of 1907 tsRNAs were detected, of which 298 were differentially expressed in the villous tissues. tRF-5028c was significantly upregulated in the RSA group compared with control. Functionally, tRF-5028c overexpression inhibited HTR-8/SVneo cell proliferation, migration, and invasion and promoted apoptosis, whereas tRF-5028c knockdown showed opposite effects. Mechanically, tRF-5028c suppressed CRKL expression by directly binding to its 3′-untranslated region, thus inactivating the downstream C3G/Rap1 signaling pathway. Finally, tRF-5028c mimics injection increased embryo absorption rate in mice.
Conclusions: tRF-5028c upregulation impaired trophoblast function to facilitate RSA development by directly targeting CRKL-mediated Rap1 pathway. The findings provide the first evidence of tsRNA dysregulation in RSA pathogenesis and lay a foundation for potential targeted therapies.
Keywords Recurrent spontaneous abortion, Trophoblast, tRF-5028c, CRKL, Rap1
Address and Contact Information 1 Center for Reproductive Medicine, Jiangxi Key Laboratory of Reproductive Health, Jiangxi Maternal and Child Health Hospital, Jiangxi Branch of National Clinical Research Center for Obstetrics and Gynecology, Nanchang Medical College, Nanchang, China.
2 Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
3 Department of Gynecology, Jiangxi Mater-nal and Child Health Hospital, Nanchang Medical College, 318 Bayi Avenue, Nanchang 330006, China.
4 Department of Clinical Medicine, School of Queen Mary, Nanchang University, Nanchang, China.
5 Department of Pathology, Jiangxi Maternal and Child Health Hospital, Nanchang Medical College, Nanchang, China.
6 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, 569 Xinsi Road, Xi’an 710038, China.
7 Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
† Jialyu Huang, Jiawei Wang, and Shuang Wang have contributed equally to this work.
*Corresponding author: fangzheng_fmmu@outlook.com; axy_jmchh@126.com; lemon_1114@126.com
Read full article at BMC

No.  29DOI: 10.1186/s11658-025-00708-8 Volume 30 (2025) - 30:29
Title CDC20 PROTECTS THE HEART FROM DOXORUBICIN-INDUCED CARDIOTOXICITY BY MODULATING CCDC69 DEGRADATION
Authors Zhenyu Feng1†, Ningning Zhang2†, Liang Wang3†, Xumin Guan1, Yunpeng Xie1* and Yun‐long Xia1*
Abstract >Aims: Doxorubicin (DOX) is a potent anticancer drug; however, it is associated with significant cardiotoxicity. CDC20 is an E3 ubiquitin ligase that plays a role in cell cycle progression and apoptosis in various types of cancers. The involvement of CDC20 in DOX-induced cardiotoxicity (DIC) is poorly understood. Hence, this study aimed to explore the potential role of CDC20 in the development of DIC and assess whether CDC20 influences the antitumor effects of DOX.
Methods and results: H9C2 cells were treated with DOX, followed by transcriptomic analysis to identify differentially expressed genes. C57BL/6 mice were treated with DOX for 4 weeks after tail vein injection of CDC20 myocardial-specific knockout mice, AAV9-cTNT-(si) CDC20, or intraperitoneal injection of apcin. Cardiac function and pathological changes were evaluated by echocardiography and pathological staining, respectively. The influence of CDC20 on DOX-induced tumor inhibition was assessed in tumor-bearing mice. In vitro analysis involved treating cardiomyocytes with the Ad-CDC20 adenovirus and DOX, followed by proteomic and ubiquitination-related assays to identify potential downstream ubiquitinated CDC20 proteins. Additionally, we investigated the effect of CCDC69 on CDC20-mediated protection against DOX-induced apoptosis using CCDC69 shRNA. Transcriptome analysis revealed that DOX effectively suppressed the expression of CDC20. Cardiomyocyte-specific overexpression of CDC20 in a DOX-induced mouse model of myocardial injury effectively mitigated cardiomyocyte apoptosis, inflammation, fibrosis, and cell atrophy. Our mechanistic investigation revealed that CDC20 attenuates DOX-induced apoptosis by downregulating CCDC69 expression. Moreover, cardiomyocyte-specific overexpression of CDC20 had no effect on the therapeutic efficacy of DOX against tumors.
Conclusion: Our findings indicate that CDC20 safeguards the heart against DOX-induced cardiotoxicity by modulating CCDC69 degradation without compromising the antitumor efficacy of DOX.
Keywords Apoptosis, CDC20, CCDC69, Doxorubicin, Heart failure
Address and Contact Information 1 Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Lianhe Road 193, Dalian, Liaoning 116000, People’s Republic of China
2 Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
3 Department of Pharmacy, Liaoyang City Central Hospital, Liaoyang, People’s Republic of China
*Corresponding author: xieyunpeng@dmu.edu.cn; yunlong_xia@126.com
† Zhenyu Feng, Ningning Zhang, and Liang Wang have contributed equally to this work.
Read full article at BMC

No.  30DOI: 10.1186/s11658-025-00704-y Volume 30 (2025) - 30:30
Title SWI/SNF-TYPE COMPLEXES–TRANSCRIPTION FACTOR INTERPLAY: A KEY REGULATORY INTERACTION
Authors Anna Maassen1†, Jaroslaw Steciuk1†, Magdalena Wilga1, Jakub Szurmak1, Damian Garbicz2, Elzbieta Sarnowska2 and Tomasz J. Sarnowski1,3*
Abstract ATP-dependent switch/sucrose nonfermenting-type chromatin remodeling complexes (SWI/SNF CRCs) are multiprotein machineries altering chromatin structure, thus controlling the accessibility of genomic DNA to various regulatory proteins including transcription factors (TFs). SWI/SNF CRCs are highly evolutionarily conserved among eukaryotes. There are three main subtypes of SWI/SNF CRCs: canonical (cBAF), polybromo (pBAF), and noncanonical (ncBAF) in humans and their functional Arabidopsis counterparts SYD-associated SWI/SNF (SAS), MINU-associated SWI/SNF (MAS), and BRAHMA (BRM)-associated SWI/SNF (BAS). Here, we highlight the importance of interplay between SWI/SNF CRCs and TFs in human and Arabidopsi and summarize recent advances demonstrating their role in controlling important regulatory processes. We discuss possible mechanisms involved in TFs and SWI/SNF CRCs-dependent transcriptional control of gene expression. We indicate that Arabidopsis may serve as a valuable model for the identification of evolutionarily conserved SWI/SNF–TF interactions and postulate that further exploration of the TFs and SWI/SNF CRCs-interplay, especially in the context of the role of particular SWI/SNF CRC subtypes, TF type, as well as cell/tissue and conditions, among others, will help address important questions related to the specificity of SWI/SNF–TF interactions and the sequence of events occurring on their target genes.
Keywords SWI/SNF, Chromatin remodeling, Transcription factors, Human, Arabidopsis
Address and Contact Information 1 Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland
2 Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
3 Max Planck Institute for Plant Breeding Research, Cologne, Germany
*Corresponding author: tsarn@ibb.waw.pl
† Anna Maassen and Jaroslaw Steciuk have equally contributed to this work.
Read full article at BMC

No.  31DOI: 10.1186/s11658-025-00709-7 Volume 30 (2025) - 30:31
Title Deciphering distinct spatial alterations in N-glycan expression profiles in the spinal cord and brain of male rats in a neuropathic pain model
Authors Hyun Jun Jang1†, Juhee Shin1†, Sangkyu Lee1, Boyoung Lee1* and Dong Woon Kim2*
Abstract Background: Neuropathic pain is a complex condition resulting from damage or disease in the somatosensory nervous system, causing significant physical and emotional distress. Despite its profound impact, the underlying causes and treatment methods of neuropathic pain remain poorly understood.
Methods: To better understand this condition, we conducted the first study examining the spatial distribution and dynamic expression changes of N-glycan molecules that play a crucial role in nervous system function and sustainable pain signal transmission across multiple regions of the spinal cord and brain in an experimentally induced neuropathic pain model, using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI).
Results: Our findings revealed that neuropathic pain induces dynamic changes in N-glycan expression across various regions of the spinal cord and brain. Notably, we discovered distinct glycan profiles between the spinal cord and brain, with N-glycans downregulated in the spinal cord and upregulated in the brain at a time when mechanical allodynia is sustained following spinal nerve ligation (SNL). Significant changes in N-glycan expression were observed in the dorsal laminae IV/V/VI and the ventral horn of the spinal cord. Additionally, marked changes were detected in the contralateral regions of the primary sensory cortex (S1) and the primary sensory cortex hindlimb area (S1HL). Furthermore, we observed significant upregulation of N-glycan expression in the thalamus, anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC) in both ipsilateral and contralateral regions of the brain.
Conclusions: Given that N-glycans are implicated in pain processing yet their precise role remains unclear, our study highlights the need to explore N-glycosylation with a more nuanced focus on both the spinal cord and brain. This research provides new insights into the mechanisms of persistent neuropathic pain and lays the groundwork for future studies and the development of targeted therapeutic strategies.
Keywords Neuropathic pain, Spinal cord, Brain, N-glycan, MALDI MSI
Address and Contact Information 1 Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Republic of Korea
2 Department of Oral Anatomy & Developmental Biology, Kyung Hee University College of Dentistry, Seoul, Republic of Korea
*Corresponding author: blee@ibs.re.kr; visnu528@khu.ac.kr
† Hyun Jun Jang and Juhee Shin have contributed equally.
Read full article at BMC

No.  32DOI: 10.1186/s11658-025-00715-9 Volume 30 (2025) - 30:32
Title AFM REVEALS DIFFERENTIAL EFFECTS OF ACIDIFICATION ON LDL– AND OXIDIZED LDL–RECEPTOR INTERACTIONS: BIOMECHANICAL IMPLICATIONS IN ATHEROGENESIS
Authors Kun Wang1,2, Chenhan Sun2, Hongda Zhuang2,4, Xian‐Cheng Jiang3 and Yong Chen1,2,4*
Abstract The receptor recognition and interaction of plasma lipoproteins (e.g., native low-density lipoproteins (LDL)/oxidized low-density lipoproteins (oxLDL)), as well as the influence of microenvironmental/lysosomal acidification, play critical roles in lipoprotein metabolism and diseases (e.g., atherosclerosis) but have been less investigated. Here, the recognition/interaction of LDL or oxLDL with LDL receptor (LDLR) or CD36 (a scavenger receptor) or with living cells at various pHs was evaluated mainly via atomic force microscopy (AFM). To improve force measurement accuracy, a novel, micro-droplet-based method for AFM probe functionalization was developed. We found that solution acidification significantly reduced the LDL–LDLR binding at pH ≤ 6.4, whereas the oxLDL–CD36 binding had no significant change until pH ≤ 4.4. Compared with a traditional immersion method, our micro-droplet method for AFM probe functionalization produced more accurate interaction forces, and revealed that acidification significantly reduced the LDL–LDLR/cell interaction forces, instead of the oxLDL–CD36/cell-specific interaction forces and nonspecific interaction forces. The data imply that the LDL–LDLR/cell recognition and interaction are susceptible to acidification, whereas the oxLDL–CD36/cell recognition and interaction are tolerant of acidification. The results may provide important novel information and biomechanical/pathological implications for understanding lipoprotein metabolism and atherosclerosis.
Keywords Atomic force microscopy (AFM), Low-density lipoprotein (LDL), Atherosclerosis
Address and Contact Information 1 School of Life Sciences, Nanchang University, 999 Xuefu Ave., Honggutan District, Nanchang 330031, Jiangxi, People’s Republic of China
2 Institute for Advanced Study, Nanchang University, Nanchang 330031, Jiangxi, China
3 Department of Cell Biology, SUNY Health Science University, State University of New York, Brooklyn, NY 11203, USA
4 School of Pharmacy, Nanchang University, Nanchang 330031, Jiangxi, China
*Correspondence: tychen@ncu.edu.cn; dr_yongchen@hotmail.com
Read full article at BMC

No.  33DOI: 10.1186/s11658-025-00719-5 Volume 30 (2025) - 30:33
Title THE EXOSOME COLLECTION
Authors Steven R. Goodman1*
Abstract Cell and Molecular Biology Letters (CMBL) has assembled a Collection of its recently published primary research and review articles on the important topic of exosomes and their roles in disease etiology, diagnosis and monitoring of progression, therapeutics, and current and future applications in regenerative medicine. Extracellular vesicles are released from the surface of all cells and fall into two major categories that can be distinguished based on their mechanism of exit from the cell of origin; size distribution, and composition of constituents: ectosomes and exosomes. Ectosomes are formed by evagination of the plasma membrane resulting in blebbing and the release of vesicles ranging in size from 50 nm to 1 μm, including microvesicles, microparticles, and large vesicles. Exosomes are of endosomal origin and have a size range of 40 nm to 160 nm, with 100 nm being the average. The formation of exosomes occurs in multiple steps including invagination of the plasma membrane, formation of an early sorting endosome, maturation into a late-sorting endosome, invagination of the late sorting endosome to form multivesicular bodies (MVBs) containing intraluminal vesicles (ILVs). The multivesicular endosomes can fuse with lysosomes resulting in degradation, or with the plasma membrane where the ILVs are released as exosomes.

Exosomes, originally believed to function in excretion of intracellular and membrane unwanted functional molecules, are now known to undergo a complex cargo sorting process that leads to their specific final content. They can be isolated from all body fluids including blood plasma, urine, saliva, lymph, cerebrospinal fluid, semen, breast milk and bronchoalveolar lavage fluid (BALF); and their composition studied by multiomic stack approaches including proteomics, transcriptomics, microRNAomics, genomic analysis, metabolomics and lipidomics. Secreted exosomes contribute to both normal physiological homeostasis and pathological processes by entering the interstitial space and then the circulation and delivering specific cargo to target cells via local paracrine or distal systemic endocrine-like signaling. The exosome signaling molecules enclosed within the biologic membrane, include specific proteins, lipids, mRNAs, miRNAs (small noncoding RNAs with about 22 nucleotides involved in gene silencing by binding to mRNA and inhibiting translation or leading to mRNA degradation), long noncoding RNAs (lncRNA) (> 200 nucleotides lacking open reading frames and controlling gene expression at the transcriptional and post-transcriptional level), and circular RNA (circRNA) that bind to miRNA inhibiting its targeting of mRNA and sometimes directly interacting with specific proteins. The biologic effects demonstrated in several of the Collection articles are attributed to specific exosome cargo miRNAs. Exosomes also contain nuclear single and double stranded genomic DNA and mitochondrial DNA. Each individual exosome will have its own unique set of cargo molecules which are defined by the cell type of origin, protein cargo sorting by post translational modifications including ubiquitination/deubiquitination and binding to ESCRT complexes, miRNA sorting based on short sequence motifs and specific sorting proteins, and the metabolic influence of cell cycle events, cellular stress and inflammation due to specific disease status. Exosome targeting and uptake is based on the proteins and ligands on the surface of the exosome and its target cell membrane. Exosome uptake by endocytosis can be clathrin dependent or independent. Exosomes can also be internalized by the target cell via micropinocytosis, phagocytosis and fusion mechanisms. Due to their size and cell surface composition, exosomes can also cross the blood brain barrier making them useful in the diagnosis and treatment of neurodegenerative diseases.

Due to the noninvasive ease of obtaining exosomes from body fluids and the stability of its encapsulated cargo, they have proven valuable in preclinical studies for the identification of biomarkers for diagnosis, progression and therapeutic response for many diseases, including their use in liquid biopsies for cancer detection. The application of exosomes to produce anti-cancer vaccines also shows great promise. They are also being tested in early investigational and observational clinical trials for the usefulness of candidate biomarkers; as cell-free therapeutic agents; and as drug delivery agents. Clinical Trials.Gov indicates that there have been 444 investigational and observational clinical trial studies using exosomes of which I76 are currently looking for participants and 131 are actively recruiting. The advantages of MSC exosomes versus MSCs in clinical trials is that they are less likely to illicit an immune response in allogeneic trials, can more effectively reach their target because of their small size including crossing the blood brain barrier, and the lower likelihood of aggregating in the lungs upon IV administration. The primary disadvantage of MSC exosomes are the challenges of isolating pure and consistent lots in large enough quantities. Successful GMP production of exosomes for clinical trials requires large-scale production, uniformity and high quality, standard effective storage conditions that maintains the surface characteristics and cargo, enrichment of the therapeutic signaling molecules, and biodistribution testing and specificity of targeting.

Exosomes from mesenchymal stem cells or mesenchymal stromal cells (MSCs) are involved in tissue and organ rejuvenation and regeneration, as well as normal cellular physiology and homeostasis. But exosomes derived from infected, or disease associated cells tend to mediate pathogenesis. We find examples of both situations in this Exosome Collection of articles which the CMBL Editorial Board hopes you enjoy reading. I list several recent relevant comprehensive exosome reviews for interested readers
Keywords Editorial
Address and Contact Information 1 Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
*Corresponding author: sgoodma5@uthsc.edu
Read full article at BMC

No.  34DOI: 10.1186/s11658-025-00717-7 Volume 30 (2025) - 30:34
Title INSIGHTS INTO THE ROLES OF MACROPHAGES IN Klebsiella pneumoniae INFECTIONS: A COMPREHENSIVE REVIEW
Authors Yangguang Li1, Xuanheng Li1, Wenqi Wu1, Peizhao Liu1, Juanhan Liu1, Haiyang Jiang2, Liting Deng3, Chujun Ni2, Xiuwen Wu1*, Yun Zhao2,4* and Jianan Ren1*
Abstract Klebsiella pneumoniae (KP) infections represent a significant global health challenge, characterized by severe inflammatory sequelae and escalating antimicrobial resistance. This comprehensive review elucidates the complex interplay between macrophages and KP, encompassing pathogen recognition mechanisms, macrophage activation states, cellular death pathways, and emerging immunotherapeutic strategies. We critically analyze current literature on macrophage pattern recognition receptor engagement with KP-associated molecular patterns. The review examines the spectrum of macrophage responses to KP infection, including classical M1 polarization and the newly described M(Kp) phenotype, alongside metabolic reprogramming events such as glycolytic enhancement and immune responsive gene 1 (IRG1)–itaconate upregulation. We systematically evaluate macrophage fate decisions in response to KP, including autophagy, apoptosis, pyroptosis, and necroptosis. Furthermore, we provide a critical assessment of potential future therapeutic modalities. Given the limitations of current treatment paradigms, elucidating macrophage–KP interactions is imperative. Insights gained from this analysis may inform the development of novel immunomodulatory approaches to augment conventional antimicrobial therapies, potentially transforming the clinical management of KP infections.
Keywords Macrophage, Klebsiella pneumoniae, PAMPs, PRRs, Cell death, Immunotherapy
Address and Contact Information 1 Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
2 Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210009, China
3 School of Medicine, Southeast University, Nanjing 210000, China
4 Clinical Translational Research Center for Surgical Infection and Immunity of Nanjing Medical University, Nanjing, China
*Corresponding author: wuxiuwen@nju.edu.cn; zhaoyun056@gmail.com; jiananr@nju.edu.cn
Read full article at BMC

No.  35DOI: 10.1186/s11658-025-00714-w Volume 30 (2025) - 30:35
Title MAM KINASES: PHYSIOLOGICAL ROLES, RELATED DISEASES, AND THERAPEUTIC PERSPECTIVES—A SYSTEMATIC REVIEW
Authors A. Anjana Mohan1 and Priti Talwar1*
Abstract Mitochondria-associated membranes (MAMs) are tethering regions amid the membranes of the endoplasmic reticulum (ER) and mitochondria. They are a lipid raft-like structure occupied by various proteins that facilitates signal transduction between the two organelles. The MAM proteome participates in cellular functions such as calcium (Ca2+) homeostasis, lipid synthesis, ER stress, inflammation, autophagy, mitophagy, and apoptosis. The human kinome is a superfamily of homologous proteins consisting of 538 kinases. MAM-associated kinases participate in the aforementioned cellular functions and act as cell fate executors. Studies have proved the dysregulated kinase interactions in MAM as an etiology for various diseases including cancer, diabetes mellitus, neurodegenerative diseases, cardiovascular diseases (CVDs), and obesity. Several small kinase inhibitory molecules have been well explored as promising drug candidates in clinical trials with an accelerating impact in the field of precision medicine. This review narrates the physiological actions, pathophysiology, and therapeutic potential of MAM-associated kinases with recent updates in the field
Keywords MAM, Kinases, ER stress, Mitophagy, Neurodegenerative disease, Cancer, Diabetes, Therapeutics
Address and Contact Information 1 Apoptosis and Cell Survival Research Laboratory, 412G Pearl Research Park, Department of Biosciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India
*Corresponding author: priti.t@vit.ac.in; talwarpriti1@gmail.com
Read full article at BMC

No.  36DOI: 10.1186/s11658-025-00711-z Volume 30 (2025) - 30:36
Title Genetic and epigenetic regulation of Treg cell fitness by autism-related chromatin remodeler CHD8
Authors Jun‐Qi Yang1, Chen Wang1, Ramesh C. Nayak1, Manohar Kolla1, Mingjun Cai1, Mario Pujato2, Yi Zheng1, Q. Richard Lu1* and Fukun Guo1*
Abstract Background: Chromatin remodeler chromodomain helicase DNA-binding protein 8 (CHD8) defines a subtype of autism that is associated with immune disorders. It remains unknown whether CHD8 plays a cell-intrinsic role in immune cells such as regulatory T cells (Tregs) that maintain immune tolerance through suppressing CD4+ and CD8+ effector T cells.
Methods: Treg-specific conditional CHD8-deficient mice were generated by crossing Chd8Flox/Flox mice with Foxp3YFP−cre transgenic mice. Effects of CHD8 deficiency were investigated using hematoxylin and eosin (H&E) staining, flow cytometry, and multi-omics, including RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and chromatin immunoprecipitation sequencing (CHIP-seq).
Results: We found that Treg-specific CHD8 deletion led to early, fatal inflammation owing to increased CD4+ and CD8+ effector T cells. CHD8 deletion did not alter Treg homeostasis but increased their functional plasticity with elevated expression of effector T cell cytokines. CHIP-seq of Tregs uncovered that CHD8 binding genes were enriched in phosphatidylinositol-3 kinase (PI3K)–protein kinase B (Akt)–mammalian target of rapamycin (mTOR) signaling and several other pathways. RNA-seq and ATAC-seq revealed that CHD8 deletion upregulated a number of pathways, notably mammalian target of rapamycin complex 1 (mTORC1) signaling and its mediated glycolysis that have been reported to promote Treg plasticity. Integrating RNA-seq data with CHIP-seq and ATAC-seq data identified a number of CHD8 target genes whose expression depends on CHD8 direct binding-mediated chromatin remodeling.
Conclusions: Our findings suggest that CHD8 plays an important role in maintaining Treg fitness through genetic and epigenetic mechanisms to control autoimmunity, which may have important implications in immune changes in autism.
Keywords CHD8, Treg, Treg plasticity, Chromatin remodeling, Gene expression
Address and Contact Information 1 Division of Experimental Hematology and Cancer Biology, Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
2 Life Sciences Computational Services LLC, Huntingdon Valley, PA 19006, USA
*Corresponding author: richard.lu@cchmc.org; fukun.guo@cchmc.org
Read full article at BMC

No.  37DOI: 10.1186/s11658-025-00712-y Volume 30 (2025) - 30:37
Title CircNF1 MODULATES THE PROGRESSION AND IMMUNE EVASION OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA THROUGH DUAL REGULATION OF PD-L1
Authors Chang Wang1†, Chenxi Ju1†, Dan Du1†, Peiyu Zhu2†, Jie Yin3, Jinlin Jia1, Xue Wang1, Xinyu Xu1, Li Zhao4, Junhu Wan1, Ting Sun1, Lijun Yang1, Hongle Li5, Fucheng He1*, Mingxia Zhou6* and Jing He7*
Abstract Background: Tumor immune escape is a pivotal gateway for esophageal squamous cell carcinoma (ESCC) development. Immune checkpoint-blocking therapies, represented by programmed cell death receptor-1/ligand 1 (PD-1/PD-L1) inhibitors, have achieved remarkable breakthroughs in ESCC treatment. However, not all patients with ESCC receive satisfactory clinical benefit. Therefore, identifying novel biomarkers for predicting the efficacy of immunotherapy in ESCC is of great importance.
Methods: CircNF1 was screened from the circRNAs microarray, and its expression was measured by droplet digital polymerase chain reaction (ddPCR) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays in ESCC tissues and serum. Functional experiments were conducted to demonstrate the role of circNF1 in ESCC proliferation, metastasis, and tumor evasion. High-throughput RNA sequencing, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), and chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) were performed to clarify the underlying mechanisms of circNF1-mediated tumor progression.
Results: The upregulation of circNF1 was closely associated with the response of anti-PD-L1 immunotherapy. Functionally, circNF1 promoted ESCC cell malignant phenotypes and regulated CD8+ T-cell-mediated antitumor immunity. Mechanistically, circNF1 drove the IL-6-induced oncogenic activation of the JAK–STAT3 pathway, which stimulated p-STAT3 binding of the promoter regions of PD-L1. Furthermore, circNF1 physically interacted with annexin A1 (ANXA1), blocking the ANXA1 deubiquitination induced by ubiquitin-specific protease 7 (USP7), resulting in increased interaction between USP7 and PD-L1 and augmented PD-L1 stability.
Conclusions: Our findings provide novel insights into the specific regulatory mechanism of PD-L1 in ESCC cells, which offer a new strategy for synergizing with anti-PD-L1 therapy.
Keywords Esophageal squamous cell carcinoma (ESCC), circRNAs, STAT3, ANXA1, PD-L1
Address and Contact Information 1 Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
2 Key Laboratory of Carcinogenesis and Translational Research, Center of Gastrointestinal Cancer, Peking University Cancer Hospital and Institute, Beijing 100142, China.
3 Department of Oncology, The First Affiliated Hospital of Zheng-zhou University, Zhengzhou 450052, Henan, China.
4 Department of Research and Development, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
5 Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.
6 Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
7 Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
*Corresponding author: hefucheng@zzu.edu.cn; mingxiazhou@zzu.edu.cn; hejing921@zzu.edu.cn
† Chang Wang, Chenxi Ju, Dan Du and Peiyu Zhu have contributed equally.
Read full article at BMC

No.  38DOI: 10.1186/s11658-025-00707-9 Volume 30 (2025) - 30:38
Title NOVEL REGULATION MECHANISM OF HISTONE METHYLTRANSFERASE SMYD5 IN RHEUMATOID ARTHRITIS
Authors Chenxi Xiao1†, Zhenghua Su1†, Jialin Zhao1, Subei Tan1, Mengting He1, Yuhui Li1, Jiayao Liu1, Jie Xu1, Yajie Hu1, Zhongzheng Li2*, Chunxiang Fan1* and Xinhua Liu1*
Abstract Background: Fibroblast-like synoviocytes (FLS) are crucial for maintaining synovial homeostasis. SMYD5, a member of the histone lysine methyltransferase subfamily SMYDs, is involved in many pathological processes. This study aimed to investigate the role of SMYD5 in regulating synovial fibroblast homeostasis and the pathogenesis of rheumatoid arthritis (RA). Methods: Proteomic screening was conducted to assess SMYD5 expression in the synovium of patients with osteoarthritis (OA) and RA. In vitro, interleukin-1 beta (IL-1β) was used to induce proliferation and inflammation in FLS. Further, we performed loss-of-function and gain-of-function experiments to investigate the biological function of SMYD5. In vivo, adeno-associated virus (AAV) vectors carrying SMYD5 short-hairpin RNA (AAV-shSMYD5) were injected into the knee joints to knock down SMYD5 in a collagen-induced arthritis (CIA) mouse model to evaluate its role in joint damage. Results: We observed a significant elevation of SMYD5 expression in the synovial tissues of patients with RA and IL-1β-induced FLS. SMYD5 facilitated posttranslational modifications and activated downstream signaling pathways, thereby promoting proliferation and inflammation in FLS. Mechanistically, SMYD5 mediated the methylation of Forkhead box protein O1 (FoxO1), which accelerated its degradation through ubiquitination, resulting in substantial FLS proliferation. Additionally, SMYD5 promoted lactate release to activate NF-κB signaling pathways by upregulating hexokinases-2 (HK2) expression, a key glycolytic enzyme, thereby intensifying the inflammatory response in FLS. Supporting these findings, intraarticular delivery of AAV-mediated SMYD5 knockdown in the CIA mice model effectively alleviated joint swelling, bone erosion, and overall arthritis severity. Conclusions: Together, these findings suggest that SMYD5 is a dual target for regulating synovial fibroblast homeostasis and the pathogenesis of RA. Targeting SMYD5 through local treatment strategies may provide a novel therapeutic approach for RA, particularly when combined with immunotherapy.
Keywords Rheumatoid arthritis, Fibroblast-like synoviocytes, SMYD5, FoxO1, HK2, NF-κB
Address and Contact Information 1tment of Traditional Chinese Medicine, Shanghai Pudong Hospital, Pharmacophenomics Laboratory, Phenome Research Center of TCM, Human Phenome Institute, Fudan University, 825, Zhangheng Road, Pudong New District, Shanghai, China
2The 9th Hospital of Ningbo, 68, Xiangbei Road, Jiangbei District, Ningbo 315020, Zhejiang, China
*Corresponding author: nbnblzz@163.com; fanxiang1258@163.com; liuxinhua@fudan.edu.cn
† Chenxi Xiao and Zhenghua Su have contributed equally to this article.
Read full article at BMC

No.  39DOI: 10.1186/s11658-025-00721-x Volume 30 (2025) - 30:39
Title MAFF ALLEVIATES HEPATIC ISCHEMIA–REPERFUSION INJURY BY REGULATING THE CLCF1/STAT3 SIGNALING PATHWAY
Authors Dengliang Lei1†, Yihua Wang3†, Shanshan Li1†, Song Xiang1, Yunhai Luo1, Ping Yan1, Fang Luo1*, Zuotian Huang2* and ZhongJun Wu1*
Abstract Background: Although hepatic ischemia–reperfusion injury (IRI) frequently occurs during liver resection and transplantation, the underlying mechanisms remain incompletely understood. Through high-throughput sequencing, we found that v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) expression was significantly increased after hepatic IRI. The specific role of MAFF, a basic leucine zipper (bZIP) transcription factor, in hepatic IRI is unknown. In the present study, we aimed to explore the effect of MAFF on hepatic IRI injury.
Approach and results: Adenovirus vectors carrying the MAFF gene were administered to mice to explore the potential significance of MAFF. After ischemia–reperfusion, MAFF expression was significantly upregulated, suggesting a potential association between MAFF expression and hepatocyte apoptosis. A reduction in MAFF expression was demonstrated to worsen hepatic impairment and enhance the expression of proinflammatory cytokines in mice following ischemia–reperfusion. Conversely, MAFF overexpression had the opposite effect. Mechanistically, the combination of CUT&Tag and RNA sequencing technologies identified cardiotrophic factor-like cytokine 1 (CLCF1) as a direct transcriptional target for MAFF and BTB and CNC homology 1 (BACH1) heterodimers. This interaction subsequently triggers signal transducer and activator of transcription 3 (STAT3) signaling.
Conclusions: MAFF alleviates hepatic ischemia–reperfusion injury by reducing hepatocyte apoptosis and the inflammatory response through the activation of the CLCF1/STAT3 signaling pathway, offering valuable insights into the impact of MAFF on liver protection and potential therapeutic targets for liver treatment.
Keywords MAFF, Hepatic ischemia–reperfusion, BACH1, CLCF1, STAT3
Address and Contact Information 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
2 Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, China
3 Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guizhou, China
*Corresponding author: luofangdoctor19@163. com; 1351619201@qq.com; wzjtcy@126.com
† Dengliang Lei, Yihua Wang, and Shanshan Li contributed equally to this work.
Read full article at BMC

No.  40DOI: 10.1186/s11658-025-00718-6 Volume 30 (2025) - 30:40
Title A NOVEL MECHANISM FOR A-TO-I RNA-EDITED CYP1A1 IN PROMOTING CANCER PROGRESSION IN NSCLC
Authors Zhipeng Wang1†, Yan Wu3†, Ziqi Ding1, Xinru Xiao1, Yanhua Huang1, Zhiguang Liu1 and Qian Zhang1,2*
Abstract Background: Lung cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related mortality worldwide. Similar to other solid tumors, the development of non-small cell lung cancer (NSCLC) is believed to be a multistep process involving the accumulation of genetic and epigenetic alterations. A-to-I RNA editing is a widespread posttranscriptional epigenetic modification that confers specific nucleotide changes in selected RNA transcripts and plays a critical role in the pathogenesis of many human cancers. However, the mechanisms underlying A-to-I RNA editing that act as a potential driver in the pathogenesis of NSCLC progression remain incompletely elucidated.
Methods: Sanger sequencing was performed to validate the CYP1A1_I462V RNA editing event in NSCLC patients. In vitro and in vivo experiments were used to assess the effects of an ADAR1-regulated CYP1A1 and its editing on NSCLC cell growth and metastasis. The crosstalk between CYP1A1_I462V RNA editing and PI3K-AKT signaling was analyzed using RNA sequencing and molecular methods. The functional role of CYP1A1_I462V in the response to oxidative stress was verified through proteomics analysis, co-IP assay, and immunofluorescence assay.
Results: Sanger sequencing analysis identified an increased A-to-I RNA editing ratio of CYP1A1 in NSCLC specimens. This specific RNA editing, regulated by ADAR1, resulted in gain-of-function phenotypes characterized by enhanced tumor progression and more aggressive behavior. The edited form induced the expression of heme oxygenase-1 (HO-1) via PI3K/Akt-dependent activation compared with the wild-type CYP1A1, which led to an enhanced interaction with CYP1A1, thereby promoting the translocation of abundant HO-1 into the nucleus to resist oxidant stress in NSCLC cells.
Conclusions: Our findings highlight that the I462V A-to-I RNA editing event of CYP1A1 drives pulmonary carcinogenesis through inhibiting oxidative stress and suggest that the CYP1A1-HO-1-PI3K/Akt axis may be a potential therapeutic target for NSCLC.
Keywords A-to-I RNA editing, CYP1A1 gene, Non-small-cell lung cancer, Heme oxygenase-1
Address and Contact Information 1 Department of Respiratory and Critical Care Medicine, the Second People’s Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou 213164, China
2 Changzhou Medical Center, Nanjing Medical University, Changzhou 213164, China
3 State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
*Corresponding author: qianzhang@njmu.edu.cn
† Zhipeng Wang and Yan Wu have contributed equally to this work.
Read full article at BMC

No.  41DOI: 10.1186/s11658-025-00720-y Volume 30 (2025) - 30:41
Title FOLLICLE-STIMULATING HORMONE PROMOTES EndMT IN ENDOTHELIAL CELLS BY UPREGULATING ALKBH5 EXPRESSION
Authors Ping Li1,2†, Yixiao Xiang2†, Jinzhi Wei2†, Xingyan Xu2, Jiale Wang2, Haowei Yu2, Xiaosa Li2,3*, Huiping Lin2,3* and Xiaodong Fu1,2,3*
Abstract Background: The incidence of atherosclerosis markedly rises following menopause. Our previous findings demonstrated that elevated follicle-stimulating hormone (FSH) levels in postmenopausal women accelerate atherosclerosis progression. Plaque instability, the fundamental pathological factor in acute coronary syndrome, primarily results from vascular embolism due to plaque rupture. Recent evidence highlights that endothelial-to-mesenchymal transition (EndMT) exacerbates plaque instability, although the link between FSH and EndMT has not been fully established. This investigation sought to explore the possible influence of FSH in modulating EndMT.
Methods: In this study, apolipoprotein E-deficient (ApoE−/−) mice served as an atherosclerosis model, while human umbilical vascular endothelial cells (HUVECs) were used as cellular models. Protein levels were assessed through immunochemical techniques, gene expression was quantified via RT-qPCR, and nucleic acid–protein interactions were evaluated using immunoprecipitation. The m6A modification status was determined by MeRIP, and cellular behaviors were analyzed through standard biochemical assays.
Results: Our results indicate that FSH induces EndMT both in vitro and in vivo. Additional investigation suggested that FSH upregulates the transcription factor Forkhead box protein M1 (FOXM1) at both protein and mRNA levels by enhancing the expression of AlkB homolog 5, RNA demethylase (ALKBH5). FSH reduces m6A modifications on FOXM1 through ALKBH5, leading to increased nascent transcript levels and mRNA stability of FOXM1. Dual-luciferase reporter assays highlighted cAMP-response element binding protein (CREB)’s essential function in facilitating the FSH-induced upregulation of ALKBH5.
Conclusions: These findings suggest that FSH promotes ALKBH5 expression, facilitates N6-methyladenosine (m6A) demethylation on FOXM1, and consequently, induces EndMT. This study elucidates the impact of FSH on plaque instability and provides insights into potential strategies to prevent acute coronary syndrome in postmenopausal women.
Keywords Follicle-stimulating hormone (FSH), Endothelial to mesenchymal transition (EndMT), FOXM1, ALKBH5
Address and Contact Information 1 The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, Guangdong, People’s Republic of China
2 Key Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modifcation and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, Guangdong, People’s Republic of China
3 Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, Guangdong, People’s Republic of China
*Correspondding author: xiaosali@gzhmu.edu.cn; 2021390022@gzhmu.edu.cn; fuxiaod@gzhmu.edu.cn
† Ping Li, Yixiao Xiang, and Jinzhi Wei have contributed equally to this work.
Read full article at BMC

No.  42DOI: 10.1186/s11658-025-00713-x Volume 30 (2025) - 30:42
Title AUTOPHAGY: A DOUBLE-EDGED SWORD IN ISCHEMIA–REPERFUSION INJURY
Authors Lingxuan Tang3†, Wangzheqi Zhang2†, Yan Liao2†, Weijie Wang3, Xiaoming Deng1*, Changli Wang1* and Wenwen Shi4*
Abstract Ischemia–reperfusion (I/R) injury describes the pathological process wherein tissue damage, initially caused by insufficient blood supply (ischemia), is exacerbated upon the restoration of blood flow (reperfusion). This phenomenon can lead to irreversible tissue damage and is commonly observed in contexts such as cardiac surgery and stroke, where blood supply is temporarily obstructed. During ischemic conditions, the anaerobic metabolism of tissues and organs results in compromised enzyme activity. Subsequent reperfusion exacerbates mitochondrial dysfunction, leading to increased oxidative stress and the accumulation of reactive oxygen species (ROS). This cascade ultimately triggers cell death through mechanisms such as autophagy and mitophagy. Autophagy constitutes a crucial catabolic mechanism within eukaryotic cells, facilitating the degradation and recycling of damaged, aged, or superfluous organelles and proteins via the lysosomal pathway. This process is essential for maintaining cellular homeostasis and adapting to diverse stress conditions. As a cellular self-degradation and clearance mechanism, autophagy exhibits a dualistic function: it can confer protection during the initial phases of cellular injury, yet potentially exacerbate damage in the later stages. This paper aims to elucidate the fundamental mechanisms of autophagy in I/R injury, highlighting its dual role in regulation and its effects on both organ-specific and systemic responses. By comprehending the dual mechanisms of autophagy and their implications for organ function, this study seeks to explore the potential for therapeutic interventions through the modulation of autophagy within clinical settings.
Keywords I/R injury, Autophagy, Mitophagy, Apoptosis, Necroptosis
Address and Contact Information 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
2 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai 200433, China
3 Basic Medical University, Naval Medical University, Shanghai 200433, China
4 School of Nursing, Navy Military Medical University, Shanghai, China
*Corresponding author: dengphd@smmu.edu.cn; wangchangli1122@foxmail.com; xiaowenz@126.com
† Lingxuan Tang, Wangzheqi Zhang, and Yan Liao have contributed equally to this research.
Read full article at BMC

No.  43DOI: 10.1186/s11658-025-00723-9 Volume 30 (2025) - 30:43
Title IGF2BP2: AN m6A READER THAT AFFECTS CELLULAR FUNCTION AND DISEASE PROGRESSION
Authors Siyi Liu1,2, Shan Liao3, Junyu He4, Yanhong Zhou2* and Qian He1*
Abstract Insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 2 (IGF2BP2) is a widely studied N6-methyladenosine (m6A) modification reader, primarily functioning to recognize and bind to m6A modification sites on the mRNA of downstream target genes, thereby enhancing their stability. Previous studies have suggested that the IGF2BP2-m6A modification plays an essential role in cellular functions and the progression of various diseases. In this review, we focus on summarizing the molecular mechanisms by which IGF2BP2 enhances the mRNA stability of downstream target genes through m6A modification, thereby regulating cell ferroptosis, epithelial–mesenchymal transition (EMT), stemness, angiogenesis, inflammatory responses, and lipid metabolism, ultimately affecting disease progression. Additionally, we update the related research progress on IGF2BP2. This article aims to elucidate the effects of IGF2BP2 on cell ferroptosis, EMT, stemness, angiogenesis, inflammatory responses, and lipid metabolism, providing a new perspective for a comprehensive understanding of the relationship between IGF2BP2 and cell functions such as ferroptosis and EMT, as well as the potential for targeted IGF2BP2 therapy for tumors and other diseases.
Keywords IGF2BP2, Ferroptosis, Epithelial–mesenchymal transition, Cell stemness, Angiogenesis
Address and Contact Information 1 Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University/Hunan Cancer Hospital, Changsha 410013, Hunan, China
2 Cancer Research Institute, Basic School of Medicine, Central South University, Changsha 410011, Hunan, China
3 Department of Pathology, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China
4 Department of Clinical Laboratory, Brain Hospital of Hunan Province (The Second People’s Hospital of Hunan Province), Changsha 410007, Hunan, People’s Republic of China
*Corresponding author: zhouyanhong@csu.edu.cn; heqian1162@hnca.org.cn
Read full article at BMC

No.  44DOI: 10.1186/s11658-025-00705-x Volume 30 (2025) - 30:44
Title REPRESSION OF ZNFX1 BY LncRNA ZFAS1 MEDIATES TOBACCO-INDUCED PULMONARY CARCINOGENESIS
Authors Sichuan Xi1, Jigui Shan2, Xinwei Wu1, Haitao Wang1, Mary R. Zhang1, Shakirat Oyetunji1, Hong Xu3, Zuoxiang Xiao4, Tuana Tolunay1, Shamus R. Carr1, Chuong D. Hoang1 and David S. Schrump1*
Abstract Background: Despite exhaustive research efforts, integrated genetic and epigenetic mechanisms contributing to tobacco-induced initiation and progression of lung cancers have yet to be fully elucidated. In particular, limited information is available regarding dysregulation of noncoding RNAs during pulmonary carcinogenesis.
Methods: We examined correlations and interactions of long noncoding (lnc) RNAs and protein-coding genes in normal respiratory epithelial cells (NREC) and pulmonary tumor cells following exposure to cigarette smoke condensate (CSC) using gene expression arrays, qRT-PCR, western blot, growth assays, transwell assays, and murine xenograft models, as well as methylated DNA immunoprecipitation, RNA cross-link immunoprecipitation, and quantitative chromatin immunoprecipitation techniques with bioinformatics analyses.
Results: Among diverse alterations of lncRNA and coding gene expression profiles in NREC exposed to CSC, we observed upregulation of lncRNA ZFAS1 and repression of an adjacent protein-coding gene, ZNFX1, and confirmed these findings in primary lung cancers. Phenotypic experiments indicated that ZFAS1 is an oncogene, whereas ZNFX1 functions as a tumor suppressor in lung cancer cells. Mechanistically, CSC induces ZFAS1 expression via SP1 and NFĸB-associated activation of an enhancer linked to ZFAS1. Subsequently, ZFAS1 interacts with DNA methyltransferases and polycomb group proteins to silence ZNFX1. Mithramycin and methysticin repress ZFAS1 and upregulate ZNFX1 in lung cancer cells in vitro and in vivo.
Conclusion: These studies reveal a novel feedforward lncRNA circuit contributing to pulmonary carcinogenesis and suggest that pharmacologic targeting of SP1 and/or NFĸB may be useful strategies for restoring NFX1 expression for lung tumor therapy.
Keywords Lung cancer, Epigenetics, Noncoding RNA, ZNFX1, ZFAS1, Cigarette smoke, EZH2, BMI1, SUZ12, DNMT, SP1, NFĸB
Address and Contact Information 1 Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, Building 10; 4-3942, 10 Center Drive, Bethesda, MD 20892, USA
2 Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
3 Laboratory of Cancer Prevention, National Cancer Institute, Frederick, MD 21702, USA
4 Cancer and Infammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
*Corresponding author: David_Schrump@nih.gov
Read full article at BMC

No.  45DOI: 10.1186/s11658-025-00724-8 Volume 30 (2025) - 30:45
Title TROXERUTIN SUPPRESSES THE STEMNESS OF OSTEOSARCOMA VIA THE CD155/SRC/β-catenin SIGNALING AXIS
Authors Junkai Chen1,2†, Hongbo Li1,2†, Qinglin Jin3†, Xiaoguang Li4, Yiwen Zhang6, Jingnan Shen1,2, Gang Huang1,2, Junqiang Yin1,2, Changye Zou1,2, Xinyu Li5, Xin He6*, Xianbiao Xie1,2* and Tiao Lin1,2*
Abstract Background: Osteosarcoma is the most prevalent primary malignant bone tumor affecting pediatric and adolescent individuals. However, despite the passage of three decades, there has been no notable enhancement in the overall survival rate of patients with osteosarcoma. In recent years, CD155 has been reported to exhibit abnormal amplification in a range of tumors, yet the precise underlying mechanism remains elusive. The objective of this study is to investigate the role of CD155 in osteosarcoma, and to identify drugs that specifically target this molecule, thereby offering a novel direction for the treatment of osteosarcoma.
Methods: The prognosis of patients with osteosarcoma with high and low expression of CD155 was verified by immunohistochemistry. CCK-8 and colony formation assays were used to detect cell proliferation and drug resistance. Transwell experiments were used to detect cell migration and invasion. The sphere formation experiment was used to evaluate the stemness of tumor cells. Additionally, in vivo animal models were utilized to assess the functional role of CD155 in a biological context. RNA-seq and co-immunoprecipitation methods were used to search for downstream target molecules and signaling pathways of CD155. Finally, virtual screening was used to find drugs targeting CD155.
Results: In this study, we have established the significant amplification of CD155 in osteosarcoma. Utilizing a comprehensive array of experimental methods, including CCK-8 assay, colony formation assay, Transwell assay, and in vivo animal models, we unequivocally demonstrate that CD155 significantly potentiates the malignancy of osteosarcoma both in vitro and in vivo. Additionally, our findings reveal that CD155 promotes osteosarcoma stemness by modulating the Wnt/β-catenin signaling pathway. Advanced molecular techniques, such as RNA sequencing and co-immunoprecipitation, have been instrumental in elucidating the mechanism of CD155 in activating the Wnt/β-catenin pathway via the SRC/AKT/GSK3β signaling axis, thereby enhancing the stem-cell-like properties of osteosarcoma cells. To explore targeted therapeutic options, we conducted virtual screening and identified troxerutin as a promising CD155 inhibitor.
Conclusions: Our findings reveal that troxerutin effectively inhibits CD155, attenuates the SRC/AKT/GSK3β signaling cascade, diminishes the nuclear localization of β-catenin, and consequently mitigates osteosarcoma stemness. These discoveries position troxerutin as a promising candidate for targeted osteosarcoma therapy.
Keywords CD155, Osteosarcoma, β-catenin, Stemness, Troxerutin
Address and Contact Information 1 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
2 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
3 Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
4 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
5 Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
6 Institute of Human Virology, Department of Pathogen Biology and Biosecurity, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
*Corresponding author: hexin59@mail.sysu.edu.cn; xiexbiao@mail.sysu.edu.cn; lindiao@mail.sysu.edu.cn
† Junkai Chen, Hongbo Li and Qinglin Jin have contributed equally to this work.
Read full article at BMC

No.  46DOI: 10.1186/s11658-025-00730-w Volume 30 (2025) - 30:46
Title RETRACTION NOTE: PAK4, A TARGET OF miR-9-5p, PROMOTES CELL PROLIFERATION AND INHIBITS APOPTOSIS IN COLORECTAL CANCER
Authors Meihua Wang1*, Qianqian Gao1, Yufang Chen1, Ziyan Li1, Lingping Yue1 and Yun Cao1
Abstract Retraction Note: Cellular & Molecular Biology Letters (2019) 24:58
https://doi.org/10.1186/s11658-019-0182-9
The Editor-in-Chief has retracted this article because it contains data that overlaps with data from the following article, [1], also published by Cellular & Molecular Biology Letters. In addition, an investigation conducted after the publication of the two articles, which were under consideration by the journal at the same time, found additional signs which raise concerns about the authorship of the two manuscripts and the circumstances of the research presented in them. The Editor-in-Chief therefore no longer has confidence in the results and conclusions presented in this article.

The authors have not replied to correspondence from the Publisher.

Reference
Xu S, Zhang H, Wang A, et al. Silibinin suppresses epithelial–mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1. Cell Mol Biol Lett. 2020;25:36. https://doi.org/10.1186/s11658-020-00229-6
Keywords
Address and Contact Information 1 Department of Pathology, Changzhou Tumor Hospital Affiliated to Soochow University, 68 Honghe Road Changzhou, Changzhou 213032, Jiangsu, China
*Corresponding author: mei_huaW18@126.com
The original article can be found online at https://doi.org/10.1186/s11658-019-0182-9.
Read full article at BMC

No.  47DOI: 10.1186/s11658-025-00727-5 Volume 30 (2025) - 30:47
Title ROLE OF USP7 IN THE REGULATION OF TOLEROGENIC DENDRITIC CELL FUNCTION IN TYPE 1 DIABETES
Authors Farhan Ullah Khan1†, Puregmaa Khongorzul1†, Denis Gris2 and Abdelaziz Amrani1*
Abstract Background: Tolerogenic dendritic cells (toDCs) are critical for maintaining immune homeostasis and preventing autoimmune disease development, such as type 1 diabetes (T1D). We have previously shown that DCs of non-obese diabetic (NOD) mice expressing active Stat5b (Stat5b-CA.DCs) acquire toDCs signature and protect against diabetes. However, the mechanisms involved in reprogramming DCs to adopt tolerogenic or immunogenic signatures are not fully known. This study investigates for the first time the role of USP7 in DC-mediated immune regulation in T1D using a transgenic NOD mouse model expressing an active form of Stat5b (NOD.Stat5b-CA).
Methods: Splenic DCs were purified from diabetes-prone NOD mice and diabetes-resistant NOD.Stat5b-CA transgenic mice and their tolerogenic and immunogenic phenotypes were analyzed by FACS. Their pro-and anti-inflammatory cytokine patterns, IRF4, IRF8, de-ubiquitin ligase USP7, and methyltransferase Ezh2 expression were assessed by FACS and Western blot. Moreover, the impact of USP7 inhibition in DCs on Th1/Th2/Th17 and Treg and diabetes onset was assessed using an in vivo DC-based transfer model.
Results: In this study, we found that splenic Stat5b-CA.DCs expressed high levels of USP7, Ezh2, and PD-L-1/2 and contained a higher proportion of tolerogenic conventional DC2 (cDC2) subsets than immunogenic cDC1 compared to NOD mice DCs. We also found that the USP7 blockade increased Stat5b-CA.DCs maturation and proinflammatory cytokines production while decreasing anti-inflammatory cytokines and PD-L1 and PD-L2 expressions. Mechanistically, USP7 blockade in Stat5-CA.DCs promoted cDC1 over cDC2 subsets by increasing IRF8 expression in an Ezh2-dependent manner and decreasing IRF4 expression independently of Ezh2. USP7 blockade also increased Stat5b-CA.DC capacity to promote Th17 and to restrain Th2 and Treg cells. Importantly, the capacity of Stat5b-CA.DCs to protect NOD mice from diabetes were lost when treated with USP7 inhibitor.
Conclusions: Our findings underscore the role of the USP7/Ezh2 axis in maintaining tolerogenic DC functions that are required to tailor adaptive immune response and diabetes protection in NOD mice.
Keywords Type 1 diabetes, Dendritic cells, USP7, Ezh2, PD-L1/2, Immunotherapy
Address and Contact Information 1 Department of Pediatrics, Immunology Division, Université de Sherbrooke Faculté de Médecine et des Sciences de la Santé, 3001, 12 th Avenue North, Sherbrooke, QC J1H 5N4, Canada
2 Department of Phamacology-Physiology, Université de Sherbrooke Faculté de Médecine et des Sciences de la Santé, 3001, 12 th Avenue North, Sherbrooke, QC J1H 5N4, Canada *Corresponding author: abdelaziz.amrani@usherbrooke.ca † Farhan Ullah Khan and Puregmaa Khongorzul have contributed equally to this work.
Read full article at BMC

No.  48DOI: 10.1186/s11658-025-00725-7 Volume 30 (2025) - 30:48
Title CIRCULATING INNATE LYMPHOID CELLS ARE DYSREGULATED IN PATIENTS WITH PROSTATE CANCER
Authors Daniela Claudia Maresca1, Evelina La Civita2, Benedetta Romano1, Maria Rosaria Ambrosio3, Fabio Somma1, Tania Wyss4, Bernardo Rocco5, Valentina Rubino2, Luigi Cari6, Philippe Krebs7, Antonio Rodriguez‐Calero7, Matteo Ferro8, Sara Trabanelli9,10,11,12, Camilla Jandus9,10,11,12, Felice Crocetto13, Angela Ianaro1,14*, Daniela Terracciano2† and Giuseppe Ercolano1,14*†
Abstract Background: Prostate cancer (PCa) is the second most common cancer affecting men globally, especially those aged 50 years and above. Despite substantial progress in terms of both prognosis and therapy, PCa remains a significant health concern, necessitating the identification of novel therapeutic targets. Innate lymphoid cells (ILCs) have emerged as critical modulators of tumor immunity, exhibiting both pro- and antitumoral effects. However, little is known yet about their contribution in PCa. This study investigated the phenotypic and functional profiles of ILC subsets in the peripheral blood mononuclear cells (PBMCs) of patients with PCa stratified by Gleason score.
Methods: PBMCs were isolated by Lymphoprep. ILC frequency and activity were evaluated by flow cytometry. The levels of ILC-activating cytokines were analyzed by multiplex assay in the serum of healthy donors (HDs) and patients with PCa. To evaluate the crosstalk between ILC2s and cancer cells, PC3 and DU145 human PCa cell lines were used.
Results: We found a stage-dependent increase in the protumoral ILC2 frequency and a concurrent decrease in antitumoral ILC1s in patients with PCa compared with healthy controls. Interestingly, the frequency of ILC2s was higher in patients with elevated prostate-specific antigen (PSA) values, suggesting their potential as molecular predictor for defining the risk category of patients with PCa at diagnosis. Importantly, patients with PCa exhibited hyperactivated ILC2s, characterized by elevated interleukin (IL)-13 and IL-5 production, while ILC1s displayed reduced tumor necrosis factor (TNF)-α and interferon (IFN)-γ secretion. Furthermore, serum levels of ILC2-activating cytokines IL-33, IL-18, and prostaglandin D2 (PGD2) were elevated in patients with PCa. In vitro co-culture experiments demonstrated that PCa cell lines, capable of secreting these cytokines, could directly enhance ILC2 activity. Likewise, ILC2-derived IL-13 promoted PCa cell migration and invasion.
Conclusions: Collectively, our findings highlight a dysregulated ILC profile in PCa, characterized by ILC2 dominance and heightened activity at the expense of ILC1s, suggesting both ILC1s and ILC2s as potential therapeutic targets for PCa treatment.
Keywords Prostate cancer, Innate lymphoid cells, ILC1s, ILC2s, IL-33, IL-18, IL-13
Address and Contact Information 1 Department of Pharmacy, School of Medicine, University of Naples Federico II, 80138 Naples, Italy.
2 Department of Translational Medical Sciences, University of Naples “Federico II”, Naples, Italy.
3 Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy.
4 Translational Data Science‐Facility, AGORA Cancer Research Center, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
5 Department of Translational Medicine and Surgery, Gemelli IRCCS University Hospital Foundation in Rome, Università Cattolica del Sacro Cuore di Roma, Roma, Italy.
6 Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
7 Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland.
8 Unit of Urology, Department of Health Science, University of Milan, ASST Santi Paolo and Carlo, Via A. Di Rudini 8, 20142 Milan, Italy.
9 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
10 Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
11 Geneva Center for Infammation Research, Geneva, Switzerland.
12 Transla‐tional Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland.
13 Department of Neurosciences, Reproduc‐tive Sciences and Odontostomatology, University of Naples “Federico II”, Naples, Italy.
14 Department of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
*Corresponding author: ianaro@unina.it; giuseppe.ercolano@unina.it
† Daniela Terracciano and Giuseppe Ercolano have contributed equally.
Read full article at BMC

No.  49DOI: 10.1186/s11658-025-00716-8 Volume 30 (2025) - 30:49
Title EXPLORING THE ROLE OF GUT MICROBIOTA MODULATION IN THE LONG-TERM THERAPEUTIC BENEFITS OF EARLY MSC TRANSPLANTATION IN MRL/lpr MICE
Authors Quanren Pan1†, Fengbiao Guo1†, Jiaxuan Chen1†, Haimin Huang1, Yanyan Huang1, Shuzhen Liao1, Zengzhi Xiao1, Xi Wang1, Liuyong You2, Lawei Yang1, Xuemei Huang3, Haiyan Xiao4, Hua‐Feng Liu1* and Qingjun Pan1,2,5*
Abstract Background: Systemic lupus erythematosus (SLE), influenced by gut microbiota dysbiosis, is characterized by autoimmune and inflammatory responses. Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation is an effective and safe treatment for refractory or severe SLE; however, the long-term efficacy and mechanisms of early hUC-MSC therapeutic benefits in SLE need further investigation.
Methods: Here, lupus-prone MRL/MpJ-Faslpr (MRL/lpr) mice were divided into three groups: the control (Ctrl) group received saline injections, while the MSC and MSC-fecal microbiota transplantation (FMT) groups received early hUC-MSC transplants at weeks 6, 8, and 10. The MSC-FMT group also underwent FMT from the Ctrl group between weeks 9 and 13.
Results: Our results showed that early MSC treatment extended therapeutic effects up to 12 weeks, reducing autoantibodies, proinflammatory cytokines, B cells, and improving lupus nephritis. It also modulated the gut microbiota, increasing the abundance of beneficial bacteria, such as Lactobacillus johnsonii and Romboutsia ilealis, which led to higher levels of plasma tryptophan and butyrate metabolites. These metabolites activate the aryl hydrocarbon receptor (AHR), upregulate the Cyp1a1 and Cyp1b1 gene, enhance the zonula occludens 1 (ZO-1) protein, promote intestinal repair, and mitigate SLE progression. Notably, FMT from lupus mice significantly reversed hUC-MSC benefits, suggesting that the modulation of the gut microbiota plays a crucial role in the therapeutic response observed in MRL/lpr mice.
Conclusions: This research innovatively explores the early therapeutic window for MSCs in SLE, highlighting the partial mechanisms through which hUC-MSCs modulate the gut microbiota–tryptophan–AHR axis, thereby ameliorating SLE symptoms.
Keywords Mesenchymal stem cells, Systemic lupus erythematosus, Gut microbiota, Tryptophan metabolism, Butanoate metabolism, Aryl hydrocarbon receptor
Address and Contact Information 1 Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Noncommunicable Diseases, Department of Nephrology, Afliated Hospital of Guangdong Medical University, Zhanjiang, China
2 Department of Clinical Laboratory, State Key Laboratory of Respiratory Disease, The First Afliated Hospital of Guangzhou Medical University, Guangzhou, China
3 Department of Anesthesiology, First People’s Hospital of Foshan, Foshan, Guangdong, China
4 Department of Cellular Biology and Anatomy, James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, USA
5 Clinical Research and Experimental Center, Afliated Hospital of Guangdong Medical University, Zhanjiang, China
*Corresponding author: liuhf@gdmu.edu.cn; stilwapan@gmail.com
† Quanren Pan, Fengbiao Guo and Jiaxuan Chen contributed equally to this work.
Read full article at BMC

No.  50DOI: 10.1186/s11658-025-00728-4 Volume 30 (2025) - 30:50
Title RETRACTION NOTE: SILIBININ SUPPRESSES EPITHELIAL–MESENCHYMAL TRANSITION IN HUMAN NON-SMALL CELL LUNG CANCER CELLS BY RESTRAINING RHBDD1
Authors Suyan Xu1, Hongyan Zhang1, Aifeng Wang1, Yongcheng Ma1, Yuan Gan1 and Guofeng Li1*
Abstract Retraction Note: Cellular & Molecular Biology Letters (2020) 25:36
https://doi.org/10.1186/s11658-020-00229-6

The Editor-in-Chief has retracted this article because it contains data that overlaps with data from the following articles [1,2,3,4], the first of which was also published by Cellular & Molecular Biology Letters. In addition, an investigation conducted after the publication of these two articles, which were under consideration by the journal at the same time, found additional signs which raise concerns about the authorship of the two manuscripts and the circumstances of the research presented in them. The Editor-in-Chief therefore no longer has confidence in the results and conclusions presented in this article.

The authors have not replied to correspondence from the Publisher.

References 1. Wang M, Gao Q, Chen Y, et al. PAK4, a target of miR-9-5p, promotes cell proliferation and inhibits apoptosis in colorectal cancer. Cell Mol Biol Lett. 2019;24:58. https://doi.org/10.1186/s11658-019-0182-9.

2. Li Z, Wang F, Zhang S. Retracted: Knockdown of lncRNA MNX1-AS1 suppresses cell proliferation, migration, and invasion in prostate cancer. FEBS Open Bio. 2019;9:851–8. https://doi.org/10.1002/2211-5463.12611.

3. Sheng N, Tan G, You W, et al. MiR-145 inhibits human colorectal cancer cell migration and invasion via PAK4-dependent pathway. Cancer Med. 2017;6(6):1331–40. https://doi.org/10.1002/cam4.1029.

3. Wei Y, Dong J, Li F, Wei Z, Tian Y. Knockdown of SLC39A7 suppresses cell proliferation, migration and invasion in cervical cancer. EXCLI J. 2017;16:1165–76. https://doi.org/10.17179/excli2017-690.
Keywords
Address and Contact Information 1 Department of Pharmacy, Henan Provincial People Hospital, Department of Pharmacy of Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou 450003, Henan, China
*Corresponding author: guofeng_li245@163.com
The original article can be found online at https://doi.org/10.1186/s11658-020-00229-6.
Read full article at BMC

No.  51DOI: 10.1186/s11658-025-00729-3 Volume 30 (2025) - 30:51
Title RETRACTION NOTE: MicroRNA-582–3p NEGATIVELY REGULATES CELL PROLIFERATION AND CELL CYCLE PROGRESSION IN ACUTE MYELOID LEUKEMIA BY TARGETING CYCLIN B2
Authors Haixia Li1,2, Xuefei Tian3*, Paoqiu Wang1, Mao Huang4, Ronghua Xu5 and Tian Nie5*
Abstract Retraction Note: Cellular & Molecular Biology Letters (2019) 24:66
https://doi.org/10.1186/s11658-019-0184-7

The Editor-in-Chief has retracted this article because of concerns regarding the figures presented in this work. These concerns call into question the article's overall scientific soundness. An investigation conducted after its publication discovered the following issues:
  • the Cyclin B2 gel slice in Fig. 4A appears to overlap with the CDK1 gel slice in Fig. 5;
  • portions of the Cyclin B1 gel slice in Fig. 5 appear to overlap with portions of the Bad/MCF-7 and Bax/T-47D gel slices in Fig. 4B in [1];
  • the miR-582-3p mimics cell assay in Fig. 2C appears to overlap, when rotated, with the shNek7-1 cell assay in Fig. 3E in [2].
The Editor-in-Chief therefore no longer has confidence in the integrity of the research presented in this article.

The authors have not replied to correspondence from the Publisher.

References
1. Peng X, Yan B, Shen Y. MiR-1301-3p inhibits human breast cancer cell proliferation by regulating cell cycle progression and apoptosis through directly targeting ICT1. Breast Cancer. 2018;25:742–52. https://doi.org/10.1007/s12282-018-0881-5.

2. Zhang J, Wang L, Zhang Y. Downregulation of NIMA-related kinase-7 inhibits cell proliferation by inducing cell cycle arrest in human retinoblastoma cells. Exp Ther Med. 2018;15:1360–6. https://doi.org/10.3892/etm.2017.5558.
Keywords
Address and Contact Information 1 Department of Integrated Chinese and Western Medicine, Hunan Children’s Hospital, Changsha 410007, China
2 Hunan University of Chinese Medicine, Changsha 410208, China
3 College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
4 Department of Pediatric Rehabilitation, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050000, Hebei, China
5 Department of Hematology, The First Hospital of Hunan University of Chinese Medicine, 95 Shaoshan Middle Road, Changsha City 410007, Hunan Province, China
*Corresponding author: tian_Xf@outlook.com; nie_tian0607@126.com
The original article can be found online at https://doi.org/10.1186/s11658-019-0184-7.
Read full article at BMC

No.  52DOI: 10.1186/s11658-025-00726-6 Volume 30 (2025) - 30:52
Title ETOPOSIDE-INDUCED PROTEIN 2.4 HOMOLOG PROMOTES ARGININOSUCCINATE SYNTHASE 1 AND CANCER CELL SURVIVAL UPON ARGININE DEPRIVATION
Authors Vu T. A. Vo1,2,3†, Le Nhat Tran1,2,3†, Thu Thanh Bui1,2,3, Han‐Woong Lee4 and Yangsik Jeong1,2,3,5,6*
Abstract Background: Arginine auxotrophy has been reported in a subset of cancers with inherently defective de novo arginine synthesis. However, the use of arginine deprivation therapy seems to be unequally effective, partially owing to the resistance acquired by cancer cells. Study of underlying factors involved in this response thus becomes of utmost importance. Meanwhile, the function of etoposide-induced 2.4 homolog (EI24) in cancer metabolism, and specifically in arginine metabolism, remains unknown.
Methods: EI24 was overexpressed in cancer cells using a doxycycline-inducible system or adenovirus transduction, while siRNA was used to knockdown EI24. Amino acid(s) deprivation medium was exploited with a cell viability assay to check the reliance of cancer cell survival on arginine. Protein expression and activation were examined through western blot and co-immunoprecipitation blot. Furthermore, global and specific protein translation were assessed through the SUnSET assay and polysome fractionation analysis. Gene expression and arginine level were downloaded from public cancer datasets for in silico validation including gene set enrichment and survival analysis to objectively evaluate the association between EI24 and arginine metabolism.
Results: EI24 promoted cancer survival under arginine starvation. Mechanistically, EI24 replenished translation of argininosuccinate synthase 1 (ASS1) by inducing the inactive S-nitrosylated form of phosphatase and tensin homolog (PTEN), leading to release of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) axis. This tumor-promoting action of EI24 could be found in multiple ASS1-deficient cancer cells regardless of p53 status. Furthermore, expression of EI24 was linked to enrichment of arginine metabolism pathway as well as poor survival of patients with cancer across various cancer types, suggesting its role in cancer resistance to arginine deprivation.
Conclusions: This study is the first to report the role of EI24 in promoting cancer survival via translational regulation of the metabolic enzyme ASS1, thus paving a route for further investigation into the link between EI24 and cancer metabolism.
Keywords EI24, ASS1, Arginine, Cancer metabolism
Address and Contact Information 1 Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
2 Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
3 Organelle Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
4 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
5 Institute of Mitochondrial Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
6 ONCOin, Ltd., Startup cube #2 ‐ 204, 1 Kangwondaehakgil, Chuncheon, Republic of Korea
*Corresponding author: yjeong@yonsei.ac.kr
† Vu T. A. Vo and Le Nhat Tran have contributed equally to this work.
Read full article at BMC

No.  53DOI: 10.1186/s11658-025-00731-9 Volume 30 (2025) - 30:53
Title Cdkn1a SILENCING RESTORES MYOBLAST DIFFERENTIATION BY INDUCING SELECTIVE APOPTOSIS IN SENESCENT CELLS
Authors Sujin Kim1,2†, Bonsang Gu1,2,3†, Chan-Young So1,2,3, Keren Esther Kristina Mantik1,2,3, Seung-Hyun Jung4,5,6, Sohee Moon1,2, Dong-Ho Park3,7, Hyo-Bum Kwak3,7, Jinkyung Cho8, Eun-Jeong Cho3,7, Jae-Seon Lee2,3,9* and Ju-Hee Kang1,2,3*
Abstract Background: Sarcopenia, characterized by a progressive loss of skeletal muscle mass and function, is associated with the accumulation of senescent muscle stem cells, which impair muscle regeneration and contributes to the decline in muscle health. Cdkn1a, which encodes p21, is a well-known marker of cellular senescence. However, it remains unclear whether p21 inhibition eliminates senescent myoblasts and restores the differentiation capacity.
Methods: We performed transcriptomic analysis to identify genes related to aging-induced sarcopenia using 21 month-old Sprague–Dawley rats. To investigate the specific role of Cdkn1a gene in muscle aging, we used an in vitro model of ceramide-induced senescence in myoblasts, which was verified by the upregulation of p21 and increased senescence-associated beta-galactosidase (SA-β-gal) staining. To inhibit p21, we treated myoblasts with small interfering RNA (siRNA) targeting Cdkn1a. Using fluorescence-activated cell sorting, we separated subpopulations of cells with high or low caspase 3/7 activity. Protein expression related to myogenesis, muscle atrophy, protein synthesis, and apoptosis were quantified by western blotting.
Results: In our transcriptomic analysis, we identified Cdkn1a as an upregulated gene in both the soleus and white gastrocnemius muscles of aged rats, among 36 commonly upregulated genes. The upregulation of Cdkn1a appears to be linked to mitochondrial dysfunction and cellular senescence, underscoring its significance in sarcopenia pathogenesis. C2-ceramide treatment effectively induced senescence, as evidenced by increased p21 expression, enhanced SA-β-gal staining, decreased myogenesis, and increased apoptosis. Knockdown of p21 in ceramide-treated myoblasts significantly reduced SA-β-gal-positive cells, restored cell proliferation, reduced the expression of senescence-associated cytokines (i.e., interleukin (IL)-6 and tumor necrosis factor (TNF)-α), and selectively induced apoptosis in the senescent cell population, demonstrating a senolytic effect. Notably, p21 inhibition also improved differentiation of myoblasts into myotubes, as indicated by increased myosin heavy chain expression and improvements in myotube diameter and fusion index.
Conclusions: Our data suggest that p21 inhibition selectively eliminates senescent cells while simultaneously enhancing the regenerative capacity of healthy myoblasts, which may combine to improve muscle regeneration and promote myogenesis, ultimately improving muscle health and function in aged individuals.
Keywords p21, Cdkn1a, Senescence, Sarcopenia, Senolysis, Myogenesis
Address and Contact Information 1 Department of Pharmacology, Inha University College of Medicine, 100, Inha-Ro, Michuhol-Gu, Incheon 22212, Republic of Korea.
2 Research Center for Controlling Intercellular Communication, Inha University College of Medicine, Incheon 22212, Republic of Korea.
3 Program in Biomedical Science and Engineering, Inha University, Incheon, South Korea.
4 Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
5 Integrated Research Center for Genomic Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
6 Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, Republic of Korea.
7 Department of Kinesiology, Inha University, Incheon, Republic of Korea.
8 College of Sport Science, Sungk-yunkwan University, Suwon, Republic of Korea.
9 Department of Molecular Medicine, Inha University College of Medicine, 100, Inha-Ro, Michuhol-Gu, Incheon 22212, Republic of Korea.
*Corresponding author: jaseslee@inha.ac.kr; johykang@inha.ac.kr
† Sujin Kim and Bonsang Gu contributed equally to this study.
Read full article at BMC

No.  54DOI: 10.1186/s11658-025-00732-8 Volume 30 (2025) - 30:54
Title POTENTIAL OF AUTOPHAGY IN SUBRETINAL FIBROSIS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
Authors Janusz Blasiak1*, Elzbieta Pawlowska2, Hanna Helotera3, Maksim Ionov4, Marcin Derwich2 and Kai Kaarniranta3,5
Abstract Age-related macular degeneration (AMD) is an eye disease that can lead to legal blindness and vision loss. In its advanced stages, it is classified into dry and neovascular AMD. In neovascular AMD, the formation of new blood vessels disrupts the structure of the retina and induces an inflammatory response. Treatment for neovascular AMD involves antibodies and fusion proteins targeting vascular endothelial growth factor A (VEGFA) and its receptors to inhibit neovascularization and slow vision loss. However, a fraction of patients with neovascular AMD do not respond to therapy. Many of these patients exhibit a subretinal fibrotic scar. Thus, retinal fibrosis may contribute to resistance against anti-VEGFA therapy and the cause of irreversible vision loss in neovascular AMD patients. Retinal pigment epithelium cells, choroidal fibroblasts, and retinal glial cells are crucial in the development of the fibrotic scar as they can undergo a mesenchymal transition mediated by transforming growth factor beta and other molecules, leading to their transdifferentiation into myofibroblasts, which are key players in subretinal fibrosis. Autophagy, a process that removes cellular debris and contributes to the pathogenesis of AMD, regardless of its type, may be stimulated by epithelial–mesenchymal transition and later inhibited. The mesenchymal transition of retinal cells and the dysfunction of the extracellular matrix—the two main aspects of fibrotic scar formation—are associated with impaired autophagy. Nonetheless, the causal relationship between autophagy and subretinal fibrosis remains unknown. This narrative/perspective review presents information on neovascular AMD, subretinal fibrosis, and autophagy, arguing that impaired autophagy may be significant for fibrosis-related resistance to anti-VEGFA therapy in neovascular AMD.
Keywords Neovascular age-related macular degeneration, Subretinal fbrosis, Autophagy, Epithelial–mesenchymal transition, Endothelial–mesenchymal transition, Transforming growth factor beta 2, Extracellular matrix deposits
Address and Contact Information 1 Faculty of Medicine, Collegium Medicum, Mazovian Academy in Plock, 09-402 Plock, Poland
<2 Department of Pediatric Dentistry, Medical University of Lodz, 92-217 Lodz, Poland
3 Department of Ophthalmology, University of Eastern Finland, 70210 Kuopio, Finland
4 Faculty of Health Sciences, Mazovian Academy in Plock, 09-402 Plock, Poland
5 Department of Ophthalmology, Kuopio University Hospital, 70210 Kuopio, Finland
*Corresponding author: j.blasiak@mazowiecka.edu.pl
Read full article at BMC

No.  55DOI: 10.1186/s11658-025-00722-w Volume 30 (2025) - 30:55
Title Rho-GTPases sUBFAMILY: CELLULAR DEFECTORS ORCHESTRATING VIRAL INFECTION
Authors Beibei Zhang1†, Shuli Li1†, Juntao Ding1, Jingxia Guo2, Zhenghai Ma1, Hong Duan3*
Abstract Ras homolog gene family-guanosine triphosphatases (Rho-GTPases), key molecular switches regulating cytoskeletal dynamics and cellular signaling, play a pivotal role in viral infections by modulating critical processes such as viral entry, replication, and release. This review elucidates the intricate mechanisms through which Rho-GTPases, via interactions with guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and other signaling pathways, including the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), rat sarcoma (Ras), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, facilitate viral pathogenesis. Specific viruses, such as influenza A virus (IAV), herpesviruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), exploit Rho-GTPase-mediated cytoskeletal reorganization to enhance infectivity. For example, Rho-GTPases promote actin remodeling and membrane fusion, which are essential for viral entry and intracellular transport. Furthermore, Rho-GTPases modulate immune responses, often suppressing antiviral defenses to favor viral replication. Despite these insights, the molecular mechanisms underlying Rho-GTPase regulation during viral infections remain incompletely understood. Future research should focus on delineating the precise roles of Rho-GTPases in distinct viral life cycles, uncovering novel regulatory mechanisms, and developing targeted antiviral therapies that selectively inhibit Rho-GTPase signaling without compromising host cell functions. Such advancements could pave the way for broad-spectrum antiviral strategies, particularly against viruses that heavily rely on cytoskeletal manipulation for infection.
Keywords Rho-GTPases, Molecule switch, Viral infection, Regulatory mechanism, Therapeutic target
Address and Contact Information 1 Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
2 Disease Prevention and Control Center of Xinjiang Production and Construction Corps, Urumqi, Xinjiang, China
3 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
*Corresponding author: duanhong0924@126.com
† Beibei Zhang and Shuli Li have contributed equally to this work and share frst authorship.
Read full article at BMC

No.  56DOI: 10.1186/s11658-025-00733-7 Volume 30 (2025) - 30:56
Title YY1 INDUCED USP13 TRANSCRIPTIONAL ACTIVATION DRIVES THE MALIGNANT PROGRESSION OF HEPATOCELLULAR CARCINOMA BY DEUBIQUITINATING WWP1
Authors Qingwei Zhu1,2†, Zibo Yuan1,2†, Qiang Huo3†, Qiliang Lu4,5, Qingsong Wu2,6, Junwei Guo2,7, Wen Fu2,8, Ying Lu9, Lei Zhong10, Wenzhong Shang11, Di Cui2,12, Shuangshuang Li2, Xin Liu2*, Kangsheng Tu13, Dongsheng Huang2*, Qiuran Xu2* and Xiaoge Hu2,12*
Abstract Background: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer globally and the third leading cause of cancer-related mortality. Protein ubiquitination and deubiquitination play vital roles in human cancers. Ubiquitin-specific protease 13 (USP13) is a deubiquitinating enzyme (DUB) that is involved in many cellular processes. However, the mechanism by which USP13 regulates deubiquitination remains largely unknown.
Methods: Clinical data were analyzed via online databases. USP13 expression in HCC cell lines and tissues was analyzed via western blotting and immunohistochemistry. A lentivirus was used to established stable USP13-knockdown and USP13-overexpression cells. Cell Counting Kit-8, colony formation, wound healing, Transwell, and sphere formation assays were used to detect the malignant behaviors of HCC cells in vitro. A subcutaneous mouse model was used to investigate the function of USP13 in vivo. Co-immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter assays were conducted to explore the molecular regulation.
Results: USP13 was upregulated in HCC cell lines and tissues, which predicted a poor prognosis in patients with HCC. Functional experiments in which USP13 was overexpressed or depleted revealed the oncogenic role of USP13 in driving HCC progression both in vitro and in vivo. Mechanistically, WW domain–containing ubiquitin E3 ligase 1 (WWP1) was identified as a binding protein of USP13. Furthermore, USP13 can interact with WWP1 and then remove the K29- and K48-linked polyubiquitination chains from WWP1 to stabilize the WWP1 protein via the ubiquitin–proteasome pathway. Moreover, Yin Yang 1 (YY1) was explored as a new transcription factor of USP13, and YY1 could also upregulate WWP1 expression through USP13. Moreover, YY1 and WWP1 were shown to participate in the oncogenic role of USP13.
Conclusions: Our findings revealed the functional YY1/USP13/WWP1 signaling axis in HCC, identifying a promising therapeutic target for anti-HCC treatment.
Keywords HCC, USP13, WWP1, YY1, Deubiquitination
Address and Contact Information 1 The Qingdao Medical College of Qingdao University, Qingdao 266000, China.
2 Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China.
3 Department of General Surgery, Zhoushan Dinghai Central Hospital (Dinghai District of Zhejiang Provincial People’s Hospital), Zhoushan 316000, China.
4 General Surgery, Cancer Center, Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China.
5 The Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou 310014, China.
6 Department of Hepatobiliary, Shandong Provincial Third Hospital, Shandong University, Jinan 250031, China.
7 The Second Clinical Medical College of Zhejiang, Chinese Medical University, Hangzhou 310053, China.
8 Cancer Center, Department of Hematology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China.
9 Department of Haematology, Affiliated People’s Hospital of Ningbo University, Ningbo 315000, China.
10 Department of Laboratory Medicine, Tongxiang Traditional Chinese Medicine Hospital, Tongxiang 314500, China.
11 Department of Hematology, The frst People’s Hospital of Fuyang Hangzhou, Hangzhou 311400, China.
12 General Surgery, Cancer Center, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China.
13 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China.
*Corresponding author: liuxin@hmc.edu.cn; dshuang@hmc.edu.cn; xuqiuran@hmc.edu.cn; huxiaoge@hmc.edu.cn
† Qingwei Zhu, Zibo Yuan, Qiang Huo contribute equally to this study.
Read full article at BMC

No.  57DOI: 10.1186/s11658-025-00734-6 Volume 30 (2025) - 30:57
Title IMMUNODYNAMIC AXIS OF FIBROBLAST-DRIVEN NEUTROPHIL INFILTRATION IN ACUTE PANCREATITIS: NF-κB–HIF-1α–CXCL1
Authors Qiang Wang1,2†, Xiao Zhang1†, Chenglong Han1†, Zhenyi Lv2, Yi Zheng2, Xuxu Liu2, Zhiwei Du2, Tianming Liu2, Dongbo Xue2*, Tao Li1* and Liyi Wang2*
Abstract Background: Acute pancreatitis (AP) is a sterile inflammation, and 10–20% of cases can progress to severe acute pancreatitis (SAP), which seriously threatens human life and health. Neutrophils and their extracellular traps (NETs) play an important role in the progression of AP. However, the immunodynamic factors between the excessive infiltration of neutrophils during the occurrence of AP have not been fully elucidated.
Methods: Adult male C57BL/6 J mice were selected. An AP model was induced by cerulein, and a control group was set up. Single-cell sequencing technology was used to reveal the cell atlas of AP pancreatitis tissue. In vivo, the model mice were treated with anti-Ly6G antibody, DNase I, SC75741, PX-478, and SRT3109 respectively. In vitro, human pancreatic stellate cells were treated with hypoxia, H2O2, NAC, and JSH-2, and co-cultured with neutrophils in Transwell chambers. The severity of inflammation was evaluated, and the molecular mechanism by which fibroblasts exacerbate AP was revealed through techniques such as cell colony formation assay, cell migration assay, cell transfection, immunofluorescence, flow cytometry, Western blot, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), and co-immunoprecipitation (co-IP).
Results: The study showed that the elimination of neutrophils and NETs could significantly improve AP. Single-cell RNA sequencing (scRNA-seq) indicated that both neutrophils and fibroblasts in pancreatic tissue exhibited heterogeneity during AP. Among them, neutrophils highly expressed CXCR2, and fibroblasts highly expressed CXCL1. Further experimental results demonstrated that the infiltration of neutrophils in the early stage of AP was related to the activation of fibroblasts. The activation of fibroblasts depended on the nuclear factor kappa B (NF-κB) signaling pathway induced by hypoxia. NF-κB enhanced the activation of pancreatic stellate cells (PSCs) and the secretion of CXCL1 by directly promoting the transcription of HIF-1α and indirectly inhibiting PHD2, resulting in the accumulation of HIF-1α protein. The NF-κB–HIF-1α signal promoted the secretion of CXCL1 by fibroblasts through glycolysis and induced the infiltration of neutrophils. Finally, blocking the NF-κB–HIF-1α–CXCL1 signaling axis in vivo reduced the infiltration of neutrophils and improved AP.
Conclusions: This study, for the first time, demonstrated that activation of fibroblasts is one of the immunological driving factors for neutrophil infiltration and elucidated that glycolysis driven by the NF-κB–HIF-1α pathway is the intrinsic molecular mechanism by which fibroblasts secrete CXCL1 to chemotactically attract neutrophils. This finding provides a highly promising target for the treatment of AP.
Keywords Acute pancreatitis, Neutrophils, NETs, Fibroblasts
Address and Contact Information 1 Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
2 Department of General Surgery, The First Afliated Hospital of Harbin Medical University, Harbin, China
*Corresponding author: xuedongbo@hrbmu.edu.cn; litao7706@163.com; wangliyi@hrbmu.edu.cn
† Qiang Wang, Xiao Zhang, and Chenglong Han contributed equally.
Read full article at BMC

No.  58DOI: 10.1186/s11658-025-00737-3 Volume 30 (2025) - 30:58
Title MULTI-OMICS INTEGRATION REVEALS Vha68-3 AS A TESTICULAR AGING-SPECIFIC FACTOR THAT COORDINATES SPERMATID ELONGATION THROUGH MITOCHONDRIAL METABOLIC HOMEOSTASIS
Authors Jun Yu1*†, Qiuru Huang1†, Yangbo Fu1†, Lei He1, Cong Shen2, Xia Chen1,3, Zhiran Li4, Jiaxin Li1, Chenyu Wang1, Xinda Wang1, Binbin Yang1, Ziwen Lin1, Chen Qiao5, Xiaofang Tan6, Xiaoqing Yang7, Hao Chen8, Ying Zheng9, Bo Zheng2* and Fei Sun1,10*
Abstract Background: Testicular aging has profound effects on spermatogenesis, sperm function, and the spermatogenic microenvironment, contributing to reduced male fertility. However, the precise molecular mechanisms by which mitochondria influence spermiogenesis during aging still remain largely unclear.
Methods: Vha68-3 KO flies were generated using the CRISPR/Cas9 technique. Testicular phenotypes and functions were mainly observed through immunofluorescence staining and transmission electron microscopy. Multi-omics study was mainly conducted through single-cell RNA sequencing and transcriptome–metabolomics association analysis. Vha68-3 binding proteins were identified via liquid chromatography–tandem mass spectrometry. The therapeutic potential of modulating mitochondrial metabolism for testicular aging mainly relied on the dietary intake of related compounds in fruit flies.
Results: In this study, we identified Vha68-3, a testis-specific subunit of the V-type adenosine triphosphate (ATP) synthase, predominantly localized in the tails of elongated spermatids, as a key age-related regulator of male fertility and spermatid elongation in Drosophila testes. Crucially, Vha68-3 deficiency impaired mitochondrial homeostasis in elongated spermatids during testicular aging. Through a multi-omics approach, including single-cell transcriptomics, protein interaction mapping of Vha68-3, and transcriptome–metabolome integration, we identified pyruvate metabolism as a critical pathway disrupted by Vha68-3 deficiency. Moreover, dietary supplementation with pyruvate (PA), S-lactoylglutathione (SLG), and phosphoenolpyruvate (PEP) effectively alleviated mitochondrial dysfunction and testicular aging linked to Vha68-3 deficiency.
Conclusions: Our findings uncover novel mechanisms by which mitochondrial metabolism regulates spermatid elongation and propose potential therapeutic strategies to combat mitochondrial metabolic disorders in aging testes.
Keywords Spermiogenesis, Testicular aging, Mitochondrial homeostasis, Pyruvate metabolism, Multi-omics
Address and Contact Information 1 Institute of Reproductive Medicine, Medical School, Nantong University, Nantong 226001, China.
2 State Key Laboratory of Reproductive Medicine and Ofspring Health, Center for Reproduction and Genetics, Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou 215002, China.
3 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong 226001, China.
4 Department of Andrology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
5 Department of Clinical Pharmacy, The Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang 212001, China.
6 Reproductive Medicine Center, The Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong 226001, China.
7 Department of Obstetrics and Gynecology, The Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, China.
8 Guangzhou Women and Children’s Medical Center, GMU-GIBH Joint School of Life Science, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou 511495, China.
9 Department of Histology and Embryology, School of Medicine, Yangzhou University, Yangzhou 225009, China.
10 School of Basic Medical Sciences, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750004, China.
*Corresponding author: yujun9117@126.com; bozheng@njmu.edu.cn; sunfei@ntu.edu.cn
† Jun Yu, Qiuru Huang, Yangbo Fu, Lei He, and Cong Shen contributed equally.
Read full article at BMC

No.  59DOI: 10.1186/s11658-025-00735-5 Volume 30 (2025) - 30:59
Title NARCICLASINE ENHANCES CISPLATIN-INDUCED APOPTOTIC CELL DEATH BY INDUCING UNFOLDED PROTEIN RESPONSE-MEDIATED REGULATION OF NOXA AND MCL1
Authors Ji Hae Lee1,2, Seung Hee Seo1, Jaegal Shim1, Yong‐Nyun Kim1 and Kyungsil Yoon1*
Abstract Background: Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC); however, innate and acquired resistance is clinically seen in many patients. Hence, a combinatorial approach with novel therapeutic agents to overcome chemoresistance is a promising option for improving patient outcomes. We investigated the combinational anticancer efficacy of cisplatin and narciclasine in three-dimensional NSCLC tumor spheroids.
Methods: To assess the efficacy of cisplatin and narciclasine, cell viability assays, live/dead cell staining, cell death enzyme-linked immunosorbent assay (ELISA), western blot analysis for proteins related to apoptosis, and in vivo xenograft experiments were performed. The synergistic effects of cisplatin and narciclasine were elucidated through transcriptomic analysis and subsequent validation of candidate molecules by regulating their expression. To clarify the underlying molecular mechanisms, the activation of unfolded protein responses and kinetics of a candidate protein were assessed.
Results: Narciclasine inhibited viability of NSCLC tumor spheroids and augmented the sensitivity of cisplatin-resistant tumor spheroids to cisplatin by inducing apoptosis. After conducting bioinformatic analysis using RNA sequencing data and functional validation experiments, we identified NOXA as a key gene responsible for the enhanced apoptosis observed with the combination of cisplatin and narciclasine. This treatment dramatically increased NOXA while downregulating anti-apoptotic MCL1 levels. Silencing NOXA reversed the enhanced apoptosis and restored MCL1 levels, while MCL1 overexpression protected tumor spheroids from combination treatment-induced apoptosis. Interestingly, narciclasine alone and in combination with cisplatin induced unfolded protein response and inhibited general protein synthesis. Furthermore, the combination treatment increased NOXA expression through the IRE1α–JNK/p38 axis and the activation of p53. Cisplatin alone and in combination with narciclasine destabilized MCL1 via NOXA-mediated proteasomal degradation.
Conclusions: We identified a natural product, narciclasine, that synergizes with cisplatin. The combination of cisplatin and narciclasine induced NOXA expression, downregulated MCL1, and ultimately induced apoptosis in NSCLC tumor spheroids. Our findings suggest that narciclasine is a potential natural product for combination with cisplatin for treatment of NSCLC.
Keywords Narciclasine, Chemoresistance, Cisplatin, Apoptosis, Tumor spheroids, Nonsmall cell lung cancer
Address and Contact Information 1 Cancer Metastasis Branch, Research Institute, National Cancer Center, Goyang 10408, South Korea
2 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea
*Corresponding author: kyoon@ncc.re.kr
Read full article at BMC

No.  60DOI: 10.1186/s11658-025-00739-1 Volume 30 (2025) - 30:60
Title DNA DIOXYGENASE TET2 DEFICIENCY AGGRAVATES SEPSIS-INDUCED ACUTE LUNG INJURY BY TARGETING ITGA10 VIA THE PI3K/AKT SIGNALING PATHWAY
Authors Hongxue Fu1, Bin Gao1, Xin Zhou1, Yingting Hao1, Chang Liu1, Ailin Lan1, Jingyi Tang2,3* and Fachun Zhou1*
Abstract Background: Sepsis-induced acute lung injury (ALI) is a clinical condition with high morbidity and mortality, and impaired endothelial function is the main pathological characteristic. As a member of DNA demethylases, ten-eleven translocation protein 2 (TET2) is involved in a variety of biological processes. However, the role of TET2 in endothelial dysfunction of sepsis-induced ALI remains unclear.
Methods: We used cecal ligation and puncture (CLP) to establish a sepsis-induced acute lung injury mouse model and screened out Tet2 from TET family proteins. The results suggested that Tet2 was obviously declined. We used lipopolysaccharide (LPS) to stimulate human pulmonary microvascular endothelial cells (HPMECs) as an in vitro model, and we found the expression of TET2 was also decreased. Then we used small interfering RNAs and adenovirus to knockdown or overexpress TET2 to investigate the effect of TET2 on the function of HPMECs. The changes in sepsis-induced ALI symptoms were also analyzed in Tet2-deficient mice generated by adeno-associated virus 6 (AAV6). Next, RNA sequencing and KEGG analysis were used to find the TET2-regulated downstream target genes and signaling pathways under LPS stimulation. Finally, the rescue experiments were performed to analyze the role of target genes and signaling pathways modulated by TET2 in LPS-treated HPMECs.
Results: TET2 and 5-hmC levels were significantly decreased in both in vitro and in vivo models of sepsis-induced ALI. TET2 knockdown exacerbated the dysfunction and apoptosis of HPMECs induced by LPS. Conversely, TET2 overexpression significantly alleviated these dysfunctions and reduced apoptosis. Meanwhile, the lung injury of Tet2-deficient mice was aggravated by increased inflammation and apoptosis. RNA sequencing and subsequent experiments showed that TET2 overexpression could increase the expression of Integrin α10 (ITGA10) by reducing the methylation level of ITGA10 promoter. This, in turn, activated the PI3K-AKT signaling pathway. Knocking down ITGA10 weakened the beneficial effects of TET2 overexpression in LPS-stimulated endothelial cells.
Conclusions: In our study, we demonstrated that TET2 deficiency aggravates endothelial cell dysfunction and promotes acute lung injury by targeting ITGA10 via the PI3K-AKT pathway. These findings indicate that TET2 may be a promising therapeutic target for treating sepsis-induced ALI.
Keywords TET2, 5-hmC, Endothelial cell dysfunction, ITGA10, Sepsis-induced acute lung injury
Address and Contact Information 1 Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
2 School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
3 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
*Corresponding author: jingyitang@cqut.edu.cn; cyzfc1966@126.com
Read full article at BMC

No.  61DOI: 10.1186/s11658-025-00742-6 Volume 30 (2025) - 30:61
Title IL-6-INDUCED LONG NONCODING RNA MIR3142HG PROMOTES TUMORIGENESIS BY INTERACTING WITH THIOREDOXIN-1 AND STAT3 IN HUMAN COLORECTAL CANCER
Authors Daoquan Fang1†, Qian Feng2,3,4†, Baojian Zhou1†, Yangyang Liu1†, Yichu Lian1, Yihui Zhang5, Dichen Yang1, Xintong Liu1, Xiaomeng Shi1, Wuhua Ni5* and Lei Jiang1,6*
Abstract Background: Colorectal cancer (CRC) is a prevalent and highly malignant neoplasm on a global scale, ranking as the second most widespread cause of cancer-associated death. Long noncoding RNAs (lncRNAs) control tumorigenic processes in CRC by modulating inflammatory signals. However, the precise mechanisms remain unknown.
Methods: LncRNAs regulated by thioredoxin-1 (Trx-1) and interleukin (IL)-6 were identified by RNA sequencing (RNA-seq). The effect of MIR3142HG on CRC growth, migration, and invasion was assessed through methods of cell counting kit-8 (CCK-8), colony formation assay, Transwell assay, and animal experimentation, respectively. The regulation of signal transducer and activator of transcription 3 (STAT3) on the MIR3142HG promoter was verified using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The interaction of MIR3142HG with Trx-1 and STAT3 proteins was validated with RNA-binding protein immunoprecipitation (RIP) and RNA-pulldown experiments. Bioinformatics analysis and tissue microarray were utilized for evaluating the clinical value of MIR3142HG in CRC.
Results: We identified a lncRNA, MIR3142HG, regulated by Trx-1 knockdown and IL-6 treatment. Overexpression of MIR3142HG enhanced CRC cell proliferation, migration, and invasion, while its knockdown impaired these processes. STAT3 bound to the MIR3142HG promoter and activated its transcription. Upregulated MIR3142HG acted as a scaffold for the Trx-1/STAT3 complex to inhibit the degradation of Trx-1 and phosphorylated STAT3 (p-STAT3). In situ hybridization (ISH) results of CRC tissues indicated that MIR3142HG expression was significantly elevated during the early stages of CRC. Moreover, consistent with the Cancer Genome Atlas (TCGA) dataset, high MIR3142HG expression predicted better survival.
Conclusions: Our study identified a novel lncRNA MIR3142HG, which interacts with STAT3 and Trx-1 to promote CRC progression, providing a possible diagnostic target for CRC.
Keywords MIR3142HG, IL-6, STAT3, Trx-1, CRC
Address and Contact Information 1 Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
2 Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
3 Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
4 Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang, China
5 Reproductive Medicine Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
6 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
*Corresponding author: niwuhua228@163.com; lei.jiang@wmu.edu.cn
† Daoquan Fang, Qian Feng, Baojian Zhou, and Yangyang Liu have contributed equally to this work.
Read full article at BMC

No.  26DOI: 10.1186/s11658-025-00738-2 Volume 30 (2025) - 30:26
Title THE NOVEL tRNA-DERIVED FRAGMENT, tiRNA-Met, INHIBITS THE MALIGNANT PROGRESSION OF TRIPLE-NEGATIVE BREAST CANCER BY REGULATING RANBP3L VIA A TARGETED INTERACTION WITH SNRPA
Authors Jingjing Lu1,3†, Yangbai Sun4†, Xiufen Zhang1,7, Bujie Xu1, Ping Zhu5, Linzi Zeng1, Xue Wang6, Wei Zhu2* and Ping Zhou1*
Abstract Background: tRNA-derived fragments (tRFs) have emerged as significant noncoding RNAs in cancer biology; however, their roles and mechanisms in triple-negative breast cancer (TNBC) remain inadequately characterized.
Methods: tRF and tiRNA sequencing, real-time quantitative polymerase chain reaction (RT-qPCR), fluorescence in situ hybridization (FISH), and subcellular fractionation were used to explore the expression and characteristic of tiRNA-Met in TNBC. The biological functions of tiRNA-Met were assessed using CCK-8 assays, colony formation assays, and Transwell assays in vitro, alongside mouse xenograft models in vivo. RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), western blot, ubiquitination assays, RNA sequencing, actinomycin D assays, immunofluorescence, immunohistochemical staining, and rescue experiments were performed to explore the regulatory mechanisms of tiRNA-Met in TNBC.
Results: tiRNA-Met was an uncharacterized tRF that originated from mitochondrial tRNAMet−CAT and was primarily localized in the cytoplasm. Its expression was significantly downregulated in TNBC tumor tissues compared with adjacent normal tissues. Overexpression of tiRNA-Met markedly inhibited the proliferation, migration, and invasion of TNBC cells; whereas, its reduced expression elicited opposite effects. In addition, tiRNA-Met overexpression suppressed TNBC cell growth in vivo. Mechanistically, tiRNA-Met directly interacted with the RNA recognition motif 2 (RRM2) domain of small nuclear ribonucleoprotein A (SNRPA), promoting SNRPA protein degradation via the ubiquitin/proteasome pathway. This interaction enhanced the stability of Ran-binding protein 3-like (RANBP3L) mRNA, resulting in increased RANBP3L expression and subsequent inhibition of the mTORC1/RPS6 signaling pathway.
Conclusions: Our study identified tiRNA-Met as a novel anti-oncogenic tRF and elucidated its mechanism for inhibiting the malignancy of TNBC. tiRNA-Met directly bound to SNRPA, promoting its degradation and stabilizing RANBP3L mRNA, ultimately leading to the inhibition of the mTORC1 signaling pathway. These findings position tiRNA-Met as a promising candidate for diagnostic and therapeutic applications in TNBC.
Keywords tRNA-derived fragment, tiRNA-Met, SNRPA, RANBP3L, Triple-negative breast cancer
Address and Contact Information 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No.138 Yixueyuan Road, Shanghai 200032, China
2 Department of General Surgery, Zhongshan Hospital, Fudan University, No.111 Yixueyuan Road, Shanghai 200032, China
3 Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong 226019, Jiangsu, China
4 Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China
6 Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
7 Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu, China
*Corresponding author: zhu.wei1@zs-hospital.sh.cn; zping@shmu.edu.cn
† Jingjing Lu and Yangbai Sun have contributed equally to this work
Read full article at BMC

No.  63DOI: 10.1186/s11658-025-00736-4 Volume 30 (2025) - 30:63
Title YAP1 PROMOTER-ASSOCIATED NONCODING RNA AFFECTS EWING SARCOMA CELL TUMORIGENICITY BY REGULATING YAP1 EXPRESSION
Authors Lidia Chellini1*, Arianna Del Verme1, Veronica Riccioni1 and Maria Paola Paronetto1,2*
Abstract Background: Ewing sarcomas (ESs) are aggressive paediatric tumours of bone and soft tissues afflicting children and adolescents. Despite current therapies having improved the 5-year survival rate to 70% in patients with localized disease, 25% of patients relapse and most have metastasis at diagnosis. Resistance to chemotherapy, together with the high propensity to metastasize, remain the main causes of treatment failure. Thus, identifying novel targets for alternative therapeutic approaches is urgently needed.
Methods: Biochemical and functional analyses were carried out to elucidate the mechanism of regulation of YAP1 expression by pncRNA_YAP1-1 in ES cells.
Results: Here, we identified a novel promoter-associated noncoding RNA, pncRNA_YAP1-1, transcribed from the YAP1 promoter in ES cells. We found that pncRNA_YAP1-1 level exerts antitumour effects on ES by destabilizing YAP1 protein. The molecular mechanism relies on the interaction of pncRNA_YAP1-1 with the RNA binding protein FUS, which stabilizes the transcript. Furthermore, pncRNA_YAP1-1 binding to TEAD impairs its interaction with YAP1, thus determining YAP1 translocation into the cytoplasm, its phosphorylation and degradation.
Conclusions: Overall, our findings reveal a novel layer of regulation of YAP1 protein expression by pncRNA_YAP1-1 in Ewing sarcoma. Considering the role of YAP1 in therapy response and cell propensity to metastasize, our results indicate pncRNA_YAP1-1 as an actionable target that could be exploited to enhance chemotherapy efficacy in Ewing sarcoma.
Significance: PncRNA_YAP1-1 counteracts the YAP1 oncogenic transcriptional program in Ewing sarcoma cells by interfering with YAP1-TEAD interaction and impairing YAP1 protein stability. These findings uncover a novel treatment option for Ewing sarcoma.
Keywords Promoter-associated noncoding RNA, YAP1, Ewing sarcoma, FUS
Address and Contact Information 1 Laboratory of Cellular and Molecular Neurobiology, IRCCS Santa Lucia Foundation, Rome, Italy
2 Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy
*Corresponding author: chellinilidia@gmail.com
Read full article at BMC

No.  64DOI: https://cmbl.biomedcentral.com/articles/10.1186/s11658-025-00740-8 Volume 30 (2025) - 30:64
Title miR-196b STRICTLY REGULATES AND RELIABLY PREDICTS THE RESPONSE TO CETUXIMAB IN COLORECTAL CANCER
Authors Shiyun Chen1,2†, Zhaoli Tan2†, Yanli Lin1†, Fang Pang1,2,3, Xiaojie Wu1, Xiang Li1, Yumeng Cui1, Weiling Man1, Ying Li1, Yanghua Li1, Lu Han2, Miaomiao Gou2, Zhikuan Wang2*, Guanghai Dai2* and Youliang Wang1*
Abstract Background: Cetuximab resistance severely restricts its effectiveness in the treatment of patients with metastatic colorectal cancer (CRC). Previous studies have predominantly focused on the genetic level, with scant attention to the nongenetic aspects. This study aimed to identify the crucial microRNA (miRNA) that is responsible for cetuximab resistance.
Methods: Key miRNAs were identified using small RNA sequencing analysis. miR-196b’s role and mechanism in cetuximab resistance was explored by in vitro and in vivo experiments. Clinical blood samples were dynamically analyzed using droplet digital polymerase chain reaction (PCR) to assess the predictive value of miR-196b for efficacy.
Results: We initially discovered that the extracellular signal-regulated kinase (ERK) signaling pathway was progressively activated during the acquisition of cetuximab resistance in CRC cells. Further study determined that miR-196b can inhibit the activity of ERK and protein kinase B (AKT) signaling pathways by downregulating both NRAS and BRAF, which can kill two birds with one stone, thus enhancing the sensitivity of colorectal cancer cells to cetuximab. The expression of miR-196b was found to be significantly downregulated in both cetuximab-resistant cells and the tumor tissues of patients exhibiting resistance. In the presence of cetuximab, overexpression of miR-196b further inhibited the proliferation and migration and promoted the apoptosis of CRC cells, while miR-196b silencing had the opposite effects. Importantly, analysis of clinical blood samples confirmed that miR-196b can serve as a predictive and dynamic biomarker for monitoring the outcomes of patients with CRC treated with cetuximab.
Conclusions: This study supports that activation of the ERK signaling pathway is a key factor in cetuximab resistance. In addition, miR-196b can modulate and predict the CRC response to cetuximab, holding broad potential applications.
Keywords Cetuximab resistance, Microrna, Colorectal cancer, Prognosis
Address and Contact Information 1 Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing 100071, China
2 Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing 100071, China
3 School of Medicine, Nankai University, Tianjin 300071, China
*Corresponding author: wangzkme@sohu.com; daigh301@vip.sina.com; wang_you_liang@aliyun.com
† Shiyun Chen, Zhaoli Tan and Yanli Lin contributed equally to this work.
Read full article at BMC

No.  65DOI: 10.1186/s11658-025-00741-7 Volume 30 (2025) - 30:65
Title FNDC3B promotes gastric cancer metastasis via interacting with FAM83H and preventing its proteasomal degradation
Authors Yuying Zhang1, Lingyu Ran2, Yuying Liu3, Wei Li4, Ai Ran3, Haiping Li3,5, Bo Huang3, Junwu Ren3, Hao Ning3, Qiang Ma3, Xiaolin Wang3, Feifei Yang3, Xiaojuan Pan3, Ce Liang3, Shimin Wang3, Changhong Qin3, Yan Jiang3, Kun Qian6* and Bin Xiao1*
Abstract Background: Gastric cancer (GC) is one of the most prevalent digestive tract malignancies, with metastasis being a major contributor to poor prognosis in patients. Fibronectin type III domain-containing 3B (FNDC3B) plays pivotal roles in various tumors, yet its role in GC remains unknown.
Methods: We utilized a GC immunohistochemistry (IHC) chip and specimens to identify high expression of FNDC3B in GC. In vitro cellular experiments and in vivo nude mouse models were constructed to validate the biological functions of FNDC3B. Truncated mutants of FNDC3B and immunofluorescence (IF) assays were conducted to explore the critical domains of FNDC3B. Liquid chromatography-tandem mass spectrometry (LC–MS) and coimmunoprecipitation (Co-IP) were employed to screen and identify target proteins interacting with FNDC3B. Rescue experiments were performed to uncover interactions between FNDC3B and the binding protein.
Results: FNDC3B was found to function as an oncogene in GC. Clinically, FNDC3B was significantly upregulated in GC specimens and associated with poor survival in patients with GC. Functionally, elevated FNDC3B promoted GC metastasis both in vitro and in vivo. Structurally, the proline-rich N-terminus and a transmembrane (TM) domain at the C-terminus were crucial for maintaining the metastasis function of FNDC3B. Mechanistically, FNDC3B interacted with FAM83H, inhibiting the ubiquitin–proteasome degradation of FAM83H, which in turn enhanced GC progression through the FNDC3B/FAM83H/Snail/EMT axis.
Conclusions: Our results demonstrate that FNDC3B promotes GC metastasis and has the potential to serve as a therapeutic target for GC.
Keywords FNDC3B, FAM83H, Proteasomal degradation, TM domain, GC
Address and Contact Information 1 Department of Gastrointestinal Surgery of the First Affiliated Hospital and College of Pharmacy, Chongqing Medical University, Chongqing 400016, People’s Republic of China
2 Department of Kidney, Southwest Hospital, Army Medical University, Chongqing 400038, People’s Republic of China
3 College of Pharmacy, Chongqing Medical University, Chongqing 400016, People’s Republic of China
4 Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing 400030, People’s Republic of China
5 Shaanxi Coal Chemical Technology Research Institute Co., Ltd, Xi’an 710000, People’s Republic of China
6 Department of Gastrointestinal Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, People’s Republic of China
*Corresponding author: hxjsqk@hotmail.com; binxiaocqmu@cqmu.edu.cn
Read full article at BMC

No.  66DOI: 10.1186/s11658-025-00743-5 Volume 30 (2025) - 30:66
Title MOLECULAR SIGNATURES OF DISULFIDPTOSIS: INTERPLAY WITH PROGRAMMED CELL DEATH PATHWAYS AND THERAPEUTIC IMPLICATIONS IN ONCOLOGY
Authors Yingchao Liu1,4†, Sainan Li1†, Yunyi Wu1†, Ping Zhang5, Yanhua Yu1, Xi Chen1, Lingyan Yu1, Xinyi Yang1, Huanjuan Li1, Cuiyun Wu2*, Jing Du1* and Yanchun Li3*
Abstract Disulfidptosis represents a newly identified form of regulated cell death (RCD) distinct from other well-established RCD pathways. It occurs during periods of glucose starvation, specifically when intracellular NADPH is rapidly depleted and the expression of Solute Carrier Family 7 Member 11 (SLC7A11) is highly upregulated. Cancer cells utilize SLC7A11 to import cystine from the extracellular environment, and subsequently employ NADPH to convert it into cysteine. In the event of NADPH deficiency or an impairment in its utilization, cystine accumulates within the cells. This accumulation results in abnormal disulfide bond formation within actin cytoskeleton proteins, which in turn causes the collapse of the actin network and ultimately triggers disulfidptosis. This process uncovers a metabolic vulnerability within tumors, offering novel perspectives on the mechanisms that underlie cell death. In this paper, we provide a comprehensive review of the mechanism of disulfidptosis and compare its similarities and differences with other common programmed cell death mechanisms, such as apoptosis, autophagy, ferroptosis, and cuproptosis. The aim is to gain a more profound understanding of the characteristics and mechanisms of various cell death pathways. Understanding the correlation between disulfidptosis and tumors constitutes a crucial theoretical foundation for future research endeavors in cancer treatment. This review offers valuable insights that could pave the way for developing novel cancer treatment strategies and lead to groundbreaking advancements in cancer therapy.

Highlights
  1. Disulfidptosis is a novel type of cell death caused by disulfide stress from excessive cystine accumulation.
  2. High expression of SLC7A11 is a key factor distinguishing disulfidptosis from other cell deaths associated with NADPH depletion.
  3. Disulfidptosis can be modulated by regulating the expression levels of SLC7A11 and employing inhibitors of GLUT.
  4. Research on disulfidptosis holds promise for cancer therapy, offering novel insights for developing treatment strategies and potential avenues for creating new anti-cancer drugs.
Keywords Disulfidptosis, SLC7 A11, NADPH, Programmed cell death, Cancer therapy
Address and Contact Information 1 Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, China
2 Cancer Center, Department of Radiology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
3 Department of Clinical Laboratory, School of Medicine, Affiliated Hangzhou First People’s Hospital, Westlake University, Hangzhou, Zhejiang, China
4 School of Basic Medicine and Forensic Medicine, Hangzhou Medical College, Hangzhou 310063, Zhejiang, China
5 Department of Pharmacy, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
*Corresponding author: 2021110001@hmc.edu.cn; dujing1@hmc.edu.cn; lycmed@163.com
† Yingchao Liu, Sainan Li and Yunyi Wu are contributed equally to this work.
Read full article at BMC

No.  67DOI: 10.1186/s11658-025-00748-0 Volume 30 (2025) - 30:67
Title CIP2A PROMOTES INFLAMMATION AND EXACERBATES OSTEOARTHRITIS BY TARGETING CEMIP
Authors Jingyue Su1,2†, Xuying Sun3†, Xin Chen1,2, Kang Wei5, Danni Luo3, Shengwu Yang1,2, Chunwu Zhang1,2, Jian Xu4* and Zhenhan Deng1,2*
Abstract Background: Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degeneration with unclear pathogenic mechanism. This study aims to discuss the regulatory role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in OA pathogenesis and to elucidate the molecular mechanisms.
Methods: Mouse chondrocytes were induced by interleukin-1β (IL-1β) to mimic OA inflammation, and extracellular matrix (ECM) homeostasis and inflammatory factors were evaluated at mRNA and protein levels. A mouse model of OA was induced by destabilization of medial meniscus (DMM) surgery. Histopathological staining was used to assess the cartilage destruction of human and mouse. Osteophyte formation was observed using micro-computed tomography (CT). Downstream of CIP2A was screened by RNA sequencing and coimmunoprecipitation coupled with mass spectrometry in mouse chondrocytes.
Results: CIP2A was downregulated in cartilage of patients with OA and DMM mouse models, as well as in IL-1β-induced mouse chondrocytes. However, CIP2A overexpression promoted ECM degradation and inflammatory processes and exacerbated cartilage destruction and osteophyte formation. By contrast, knockdown or pharmacological inhibition of CIP2A alleviated cartilage degeneration to a certain extent, with no improvement in osteophytes formation caused by OA. Mechanistically, CIP2A interacted with its downstream cell migration-inducing protein (CEMIP) and activated the nuclear factor kappa B (NF-κB) signaling pathway, resulting in the imbalance of cartilage anabolic and catabolic factors and the activation of inflammation in the development of OA. In addition, CIP2A was ubiquitinated in mouse chondrocytes, causing it to be degraded, which could be a negative feedback of CIP2A expression in OA.
Conclusions: CIP2A targets CEMIP to activate NF-κB signaling pathway, which in turn aggravates cartilage destruction and inflammation and ultimately accelerates OA development. Our results suggest the potential role of the CIP2A/CEMIP axis as a therapeutic target for OA.
Keywords CIP2A, Osteoarthritis, Chondrocytes, CEMIP, NF-κB
Address and Contact Information 1 Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
2 Geriatrics Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
3 Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
4 Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China
5 Department of Plastic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
*Corresponding author: 0022029@zju.edu.cn; dengzhenhan@wmu.edu.cn
† Jingyue Su and Xuying Sun have contributed equally to this work.
Read full article at BMC

No.  68DOI: 10.1186/s11658-025-00751-5 Volume 30 (2025) - 30:68
Title BYPASSING THE GUARDIAN: REGULATED CELL DEATH PATHWAYS IN p53-MUTANT CANCERS
Authors Jonathan Y. Chung1* and Bruce A. Knutson1*
Abstract Approximately half of all cancers bear mutations in the tumor suppressor p53. Despite decades of research studying p53 function, treatment of p53-mutant cancers remains challenging owing to the effects of p53 mutations on many complex and interrelated signaling networks that promote tumor metastasis and chemoresistance. Mutations in p53 promote tumor survival by dysregulating cellular homeostasis and preventing activation of regulated cell death (RCD) pathways, which normally promote organismal health by eliminating dysregulated cells. Activation of RCD is a hallmark of effective cancer therapies, and p53-mutant cancers may be particularly susceptible to activation of certain RCD pathways. In this review, we discuss four RCD pathways that are the targets of emerging cancer therapeutics to treat p53-mutant cancers. These RCD pathways include E2F1-dependent apoptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and ferroptosis. We discuss mechanisms of RCD activation, effects of p53 mutation on RCD activation, and current pharmaceutical strategies for RCD activation in p53-mutant cancers.
Keywords P53, Cancer, Metastasis, Apoptosis, Necroptosis, Ferroptosis, Reactive oxygen species
Address and Contact Information 1 Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA
*Corresponding author: chungjo@upstate.edu; knutsonb@upstate.edu
Read full article at BMC

No.  69DOI: 10.1186/s11658-025-00750-6 Volume 30 (2025) - 30:69
Title TARGETING ALVEOLAR MACROPHAGES: A PROMISING INTERVENTION FOR PULMONARY INFECTION AND ACUTE LUNG INJURY
Authors Fei Hou1,2, Nan Shi1, Haoran Yuan1, Bingyi Li1, Junjie Xiao2,3, Kun Xiao2* and Lixin Xie2*
Abstract Pulmonary infections are common respiratory diseases caused by a variety of pathogens, some of which can lead to epidemics. When they progress to acute lung injury or acute respiratory distress syndrome, the mortality rate is high and effective treatment options are lacking. Macrophages play a crucial role in the development and progression of lung injury, and serve as core components of immune regulation in the lungs. Therefore, regulation of macrophages to intervene in the progression of infection-induced lung injury is a promising research direction. However, the existence of different macrophage subsets and their inherent heterogeneity has led to the failure of many studies to achieve effective results, thereby limiting their clinical applications. We believe that interventions targeting macrophages must consider factors, such as macrophage subsets, timing of interventions, patients’ varying immune states, and clinical stages, rather than simply focusing on regulating their phenotypes. This distinction is the key to the success of macrophage-targeted therapies. In this review, we summarize the characteristics of two distinct macrophage subpopulations, lung-tissue-resident alveolar macrophages and monocyte-derived macrophages, along with intervention strategies and research progress at various time points, with the aim of providing insights and directions for future research.
Keywords Alveolar macrophage, Pulmonary infection, Acute lung injury, Targeted therapy
Address and Contact Information 1 The 964th Hospital of PLA Joint Logistic Support Force, Changchun 130062, China
2 College of Pulmonary & Critical Care Medicine, 8th Medical Center, Chinese PLA General Hospital, Beijing 100091, China
3 Chinese PLA Medical School, Beijing 100853, China
*Corresponding author: 455957898@qq.com; xielx301@126.com
Read full article at BMC

No.  70DOI: 10.1186/s11658-025-00745-3 Volume 30 (2025) - 30:70
Title THE SPATIOTEMPORAL HETEROGENEITY OF REACTIVE OXYGEN SPECIES IN THE MALIGNANT TRANSFORMATION OF VIRAL HEPATITIS TO EPATOCELLULAR CARCINOMA: A NEW INSIGHT
Authors Huimin Yuan1, Jia Liu1, Ruochen Xu1, Keshan Yang1, Ruiyang Qu1, Shuai Liu2, Yonghui Zhang3* and Ming Xiang1*
Abstract During the transformation of viral hepatitis into hepatocellular carcinoma (HCC), oxidative stress levels increase significantly, leading to tissue damage and chronic inflammation. HCC is characterized by spatiotemporal heterogeneity, which influences oxidative stress patterns, with reactive oxygen species (ROS) as the primary representative molecules. ROS serve not only as critical biomarkers of cancer but also as potential therapeutic targets for HCC, given that their increased levels can either promote or inhibit disease progression. In this review, we systematically examine the temporal heterogeneity of ROS, emphasizing its role in different stages of HCC progression caused by viral hepatitis and in influencing cell fate. We further explore ROS spatial heterogeneity at three levels: cellular, organelle, and biomolecular. Next, we comprehensively review clinical applications and potential therapies designed to selectively modulate ROS on the basis of its spatiotemporal heterogeneity. Finally, we discuss potential future applications of novel therapies that target ROS spatiotemporal heterogeneity to prevent and manage HCC onset and progression. In conclusion, this review enhances understanding of ROS in the progression of viral hepatitis to HCC and offers insights into developing new therapeutic targets and strategies centered on ROS heterogeneity.
Keywords Reactive oxygen species, Spatiotemporal heterogeneity, Viral hepatitis, Hepatocellular carcinoma, Treatment strategy
Address and Contact Information 1 Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei, China
2 Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei, China
3 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei, China
*Corresponding author: zhangyh@tjmu.edu.cn; xiangming@tjmu.edu.cn
Read full article at BMC

No.  71DOI: https://cmbl.biomedcentral.com/articles/10.1186/s11658-025-00744-4 Volume 30 (2025) - 30:71
Title THE HETEROGENEOUS ROLES OF NEUTROPHILS IN GASTRIC CANCER: SCAFFOLD OR TARGET?
Authors Yansong Qin4†, Yunmei Liu1†, Peixin Dong2†, Wen‐Bin Zou3*, Zhaoshen Li4,5,6* and Lei Huang4,5,6*
Abstract Gastric cancer (GC) is a significant challenge for global health. Neutrophils, the predominant white blood cells in the innate immune system, are increasingly becoming known as potential contributors to either tumor-promoting or tumor-suppressive activities within different tumor biology settings. This review highlights such dual roles of neutrophils in GC, where complex interactions occur within the tumor microenvironment. Specifically, we focus on the formation and function of neutrophil extracellular traps (NETs), which have emerged as critical players in GC progression. NETs influence key processes such as inflammation, angiogenesis, and metastasis. This review offers a comprehensive analysis of the polarization of neutrophils into two of its distinct subtypes, namely N1 and N2, which exert opposing influences on tumor biology. While N1 neutrophils exert anti-tumor properties, N2 neutrophils are generally regarded as pro-tumor. We uniquely discuss how these subtypes interact with cancer cells, affecting epithelial–mesenchymal transition and immune evasion mechanisms. These interactions change the tumor microenvironment and impact overall GC progression. In addition, we underscore the potential of neutrophils and their associated molecules as biomarkers and therapeutic targets. Specific neutrophil-derived markers and neutrophil-associated signaling pathways, along with their perspectives in personalized medicine that would pave the way for neutrophil-based anti-GC therapy, have been discussed in this review. Through the integration of these perspectives, we aim to guide future research involving neutrophils and their therapeutic implications, thus establishing strategies to precisely and effectively treat GC and improve prognosis.
Keywords Gastric cancer, Neutrophil, Tumor microenvironment, Neutrophil extracellular trap (NET), Therapeutic target
Address and Contact Information 1 School of Cultural Heritage and Information Management, Shanghai University, Shanghai, China.
2 Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan.
3 Department of Gastroenterology, Shanghai Insitute of Pancreatic Diseases, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China.
4 Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, Shanghai 200433, China.
5 National Key Laboratory of Immunity and Inflammation, Changhai Clinical Research Unit, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, Shanghai 200433, China.
6 National Key Laboratory of Immunity and Inflammation, Changhai Clinical Research Unit, Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, Shanghai Institute of Pancreatic Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China.
*Corresponding author: dr.wenbinzou@hotmail.com; zhsl@vip.163.com; lei.huang@alumni.dkfz.de
† Yansong Qin, Yunmei Liu, and Peixin Dong have contributed equally to this work.
Read full article at BMC

No.  72DOI: 10.1186/s11658-025-00746-2 Volume 30 (2025) - 30:72
Title THE CRUCIAL ROLE OF METABOLIC REPROGRAMMING IN DRIVING MACROPHAGE CONVERSION IN KIDNEY DISEASE
Authors Na Gong1,3†, Wenjuan Wang3†, Yifei Fu1,3, Xumin Zheng1,3, Xinru Guo2,3, Yuhao Chen1,3, Yan Chen1,3, Shengchun Zheng1,3 and Guangyan Cai3*
Abstract Interstitial fibrosis after acute kidney injury is an ongoing pathological process of chronic inflammatory injury and repair. Macrophages participate in renal inflammation, repair and fibrosis by continuously changing their phenotype and function. The tissue microenvironment of kidney injury induces changes in key metabolic enzymes, pathways and metabolites in macrophages, leading to phenotypic and functional conversions, but the detailed mechanisms are unclear. However, in the early phase of acute kidney injury, macrophages shift to a pro-inflammatory role relying on glycolysis and pentose phosphate pathways. The tissue microenvironment regulates the suppression of glycolysis-related genes and the up-regulation of oxidative phosphorylation and tricarboxylic acid cycle genes in macrophages, resulting in a gradual shift to an anti-inflammatory phenotype, which is involved in tissue repair and remodelling. In the late stage of injury, if macrophages continue to be overactive, they will be involved in renal fibrosis. The concomitant enhancement of nucleotide and amino acid metabolism, especially arginine and glutamine metabolism, is critical for the macrophage function and phenotypic transition during the above injury process. Macrophage metabolic reprogramming therefore provides new therapeutic targets for intervention in inflammatory injury and interstitial fibrosis in kidney disease.
Keywords Inflammation, Injury and repair, Kidney fibrosis, Macrophages, Metabolic reprogramming
Address and Contact Information 1 Medical School of Chinese PLA, Beijing 100853, China
2 School of Medicine, Nankai University, Tianjin, China
3 Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-Vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(Zyyzdxk-2023310), Beijing 100853, China
*Corresponding author: caiguangyan@sina.com
† Na Gong and Wenjuan Wang contributed equally to this research.
Read full article at BMC

No.  73DOI: 10.1186/s11658-025-00749-z Volume 30 (2025) - 30:73/span>
Title IMMUNE CELL ABERRATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS: NAVIGATING THE TARGETED THERAPIES TOWARD PRECISION MANAGEMENT
Authors YuXian Wu1,2†, Wangzheqi Zhang3†, Yan Liao3†, Ting Sun1,5†, Yang Liu2* and Yaoyang Liu1,4*
Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by multilayered dysregulation of immune cell homeostasis, spanning B cell effector dysfunction, T follicular helper (Tfh) cell hyperactivity, and plasmacytoid dendritic cell (pDC) tolerance breakdown. Advances in high-parameter immunophenotyping, single-cell multiomics profiling, and spatial multiomics have redefined SLE pathogenesis, revealing stage-specific immune network perturbations. These discoveries have propelled mechanism-driven therapeutic strategies, including CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy for B cell depletion, disruption of T–B cell synaptic signaling (CD40L inhibitors), and restoration of pDC tolerance (anti-BDCA2 antibodies). While patient heterogeneity poses challenges for universal therapeutic efficacy, emerging strategies integrating molecular endotyping and cellular biomarkers hold promise for overcoming these limitations. By aligning targeted therapies with the immunophenotypic signatures of individual patients, precision medicine approaches are expected to optimize treatment efficacy, minimize off-target effects, and ultimately enhance long-term clinical outcomes in SLE. This review synthesizes current insights into how immune cell perturbations contribute to SLE pathogenesis, modulate disease flares, and determine therapeutic refractoriness, with a critical synthesis of recent clinical trial outcomes.
Keywords Systemic lupus erythematosus, Therapeutic targets, Immune dysregulation, Precise therapy, Immune cells
Address and Contact Information 1 Department of Clinic Genetics, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
2 Department of Critical Care Medicine, Naval Medical Center of PLA, Naval Medical University, Shanghai, China
3 School of Anesthesiology, Naval Medical University, Shanghai, China
4 Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
5 School of Medicine, Shanghai University, Shanghai, China
*Corresponding author: liuyaoyang000@163.com; liuyang3722@163.com
† YuXian Wu, Wangzheqi Zhang, Yan Liao and Ting Sun have contributed equally to this work.
Read full article at BMC

No.  74DOI: 10.1186/s11658-025-00747-1 Volume 30 (2025) - 30:74
Title IN-DEPTH ANALYSIS OF THE MODE OF ACTION OF RESVERATROL: GENOME-WIDE CHARACTERIZATION OF G-QUADRUPLEX BINDING PROPERTIES
Authors Ana Soriano‐Lerma1,2,3, Victoria Sánchez‐Martín4, Javier Murciano‐Calles5, Matilde Ortiz‐González6, María J. Tello‐López1,6, Virginia Pérez‐Carrasco1,3,7,8, Ángel Linde‐Rodríguez1,3,8, Inmaculada Ramírez‐Macías9, Irene Gómez‐Pìnto10, Inmaculada López‐Aliaga2, Miguel Soriano6† and Jose A. Garcia Salcedo1,3,8*†
Abstract Background: Resveratrol (RSV) is one of the most studied and used biomolecules, for which many pharmacological effects targeting multiple tissues have been described. However, a common underlying mechanism driving its full pharmacological activity has not been described in detail. G-quadruplexes (G4s) are non-canonical nucleic acid structures found in regulatory genomic locations and involved in controlling gene transcription, telomere maintenance, or genome stability, among others. This study provides a genome-wide characterization of RSV G4-binding properties, explaining its multi-target traits.
Methods: Immunofluorescence assays using a nucleolar and a G4-specific antibody were used to characterize RSV cellular effects on the nucleolus and G4 stabilization. DNA damage and cell cycle analyses were performed via western blot and flow cytometry. Breaks lLbeling In Situ and Sequencing (BLISS) was used to map double strand breaks (DSB) in response to treatment, and identify G4s targeted by RSV. mRNA sequencing was used to identify changes at the transcriptional level upon treatment and relate them to a direct targeting of G4s. Biophysical assays (circular dichroism, ultraviolet–visible [UV–Vis] titration, differential scanning calorimetry, and nuclear magnetic resonance) were used to characterize RSV–G4 interactions. Lastly, luciferase-based transcription assays were performed to confirm RSV–G4 interaction in vitro and its direct influence on gene expression.
Results: In a cellular context, RSV treatment showed classic G4-ligand effects, such as nucleolar disassembly, inhibition of RNA polymerase I, DNA damage, and cell cycle arrest. RSV was shown to stabilize cellular G4s, which accumulated around double strand breaks in the promoters of differentially expressed genes. Upon treatment, G4 stabilization triggered DNA damage and controlled gene expression. The interaction between RSV and target G4s was confirmed in vitro by biophysical assays and through luciferase-based transcription assays.
Conclusions: A G4-dependent mode of action was demonstrated as the main mechanism underlying RSV pleiotropic effects, along with the identification of target genes and G4s. This in-depth analysis of the mode of action of RSV will be helpful to improve its therapeutic potential in a wide variety of health scenarios.
Keywords Small molecule, DNA binding, G-quadruplex, Resveratrol, Secondary DNA structures
Address and Contact Information 1 GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain.
2 Department of Physiology (Faculty of Pharmacy), Institute of Nutrition and Food Technology “José Mataix”, University of Granada, 18071 Granada, Spain.
3 Instituto de Investigación Biosanitaria Ibs.GRANADA, Granada, Spain.
4 Department of Biochemistry, Molecular Biology III and Immunology, University of Granada, 18016 Granada, Spain.
5 Department of Physical Chemistry, Unit of Excellence for Chemistry Applied to Biomedicine and the Environment, and Institute of Biotechnology, University of Granada, 18071 Granada, Spain.
6 Center for Intensive Mediterranean Agrosystems and Agri‐Food Biotechnology (CIAIMBITAL), University of Almeria, 04001 Almería, Spain.
7 Department of Microbiology, University of Granada, 18016 Granada, Spain.
8 Microbiology Unit, University Hospital Virgen de Las Nieves, 18014 Granada, Spain.
9 Department of Parasitology, University of Granada, 18071 Granada, Spain.
10 Instituto de Química Física ‘Blas Cabrera’, (IQF-CSIC), 28006 Madrid, Spain.
*Corresponding author: jags@genyo.es
† Miguel Soriano and Jose A. Garcia Salcedo contributed equally to this work.
Read full article at BMC

No.  75DOI: 10.1186/s11658-025-00752-4 Volume 30 (2025) - 30:75
Title LONG-TERM TREATMENT WITH BENZODIAZEPINES AND RELATED Z-DRUGS EXACERBATES BREAST CANCER: CLINICAL EVIDENCE AND MOLECULAR MECHANISMS
Authors Wei‐Chung Vivian Yang1,2,3, Yen‐Yi Lin1,2, Jeak Ling Ding4, Chin‐Sheng Hung5,6, Phung‐Anh Nguyen7,8,9,10, Bo‐Xiang Zhang1,2,11, Tsung‐Han Hsieh12 and Shu‐Chun Chang1,2,13,14*
Abstract Background: Benzodiazepines (Diazepam) and related Z-drugs (Zolpidem), henceforth referred to as BZDRs, are widely used for clinical treatment of insomnia and anxiety disorders. BZDRs act on GABA type A receptors to inhibit neurotransmitters. We previously demonstrated that prolonged clinical use of BZDRs exacerbates the risk of breast cancer (BRCA).
Methods: By biomedical, health informatics platform analyses and in vivo studies, we explored clinical association between BZDR usage and BRCA development and advancement. Furthermore, by retrospective studies on patient clinical data and in vitro empirical analyses of the impact of BZDR on BRCA cells, and together with ingenuity pathway analysis (IPA) analyses, we validated the signaling pathways and identified potential intermolecular crosstalk involved.
Results: Clinical data showed that BRCA patients on long term treatment with BZDRs suffered increased mortality rate (p = 0.034). Studies on patient samples indicated that among 16 GABA receptors examined, GABRA3 (a pro-tumorigenic player) was significantly upregulated by BZDRs, which advanced BRCA disease. To support our clinical findings, we examined in vivo, the impact of BZDRs on BRCA advancement using MDA-MB231 cells to mediate metastasis in mice model. Our results show that BZDRs indeed promoted cancer advancement to the lungs and localized in the tibia. Using BRCA cell lines, we revealed the molecular-cellular effects of prolonged treatment with BZDRs in vitro. We showed significant metastasis indicated by increased cancer cell migration and invasion, which correlated well with our clinical observations. We discovered that BZDR-mediated GABRA3 stimulation was associated with downregulation of anti-tumorigenic extracellular matrix (ECM) molecules (S100B, COL6A6 and VIT) and upregulation of pro-tumorigenic FBN3 in BRCA cells. Notably, GABRA3-shRNA and GABRA3-CRISPR/Cas9 disrupted the abovementioned dynamics dramatically and suppressed BRCA cell invasion induced by BZDRs. Bioinformatics analyses highlighted molecular pathways showing interplay between GABRA3 and ECMs, which presumably exacerbated BZDR-induced BRCA progression via immune modulators.
Conclusions: Long-term clinical use of BZDRs significantly increased the mortality rate of BRCA patients. We provide in vivo and in vitro evidence confirming that BZDRs promote BRCA advancement. We revealed that BZDR-mediated BRCA signaling pathways through GABRA3-ECMs, which promotes metastasis, probably through immune modulation and changes in the tumor microenvironment.
Keywords Benzodiazepines and Z-drugs, Breast cancer, Extracellular matrix, GABA receptors, Clinical database informatics, Tumor microenvironment, CRISPR/Cas9 strategy
Address and Contact Information 1 The Ph.D. Program for Translational Medicine, College for Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
2 International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
3 Reproductive Medicine Center, Taipei Medical University Hospital, Taipei 110, Taiwan.
4 Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
5 Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan.
6 Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
7 Clinical Data Center, Office of Data Science, Taipei Medical University, Taipei 110, Taiwan.
8 Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
9 Research Center of Health Care Industry Data Science, College of Management, Taipei Medical University, Taipei 110, Taiwan.
10 Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei 110, Taiwan.
11 Ji Yan Biomedical (JY BioMed) Co., Ltd,Taipei 110, Taiwan.
12 Precision Health Center, Taipei Medical University, Taipei 110, Taiwan.
13 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan.
14 Yu Chun Biotech Co., Ltd, Taipei 110, Taiwan.
*Corresponding author: sc.chang@tmu.edu.tw
Read full article at BMC

No.  76DOI: 10.1186/s11658-025-00754-2 Volume 30 (2025) - 30:76
Title FRMD8 INHIBITS TUMOR METASTASIS IN BRCA1-ASSOCIATED TNBC BY NEGATIVELY REGULATING tmTNF-α
Authors Jun Xu1,2†, Xiaoyu Yang1†, Peng Shu3, Wei Wang1, Haibo Wu1* and Zhe Wang1,2*
Abstract Triple-negative breast cancer (TNBC), particularly in patients with metastasis, is associated with limited treatment options and shorter survival times. In this study, through library screening and animal experiments, we identified that the low expression of FERM domain-containing protein 8 (FRMD8) in breast cancer type 1 susceptibility protein (BRCA1)-mutant breast cancer cells (TNBC subtype), significantly enhances the metastatic potential of tumor cells to various organs. Further functional experiments revealed that FRMD8low inhibited the cleavage of tmTNF-α (transmembrane TNF-α) and promoted the expression of surface tmTNF-α. We also identified that the mechanism by which FRMD8 regulates tmTNF-α is related to the inhibition of inactive rhomboid protein 2 (iRHOM2) degradation, which acts mainly through the endocytic pathway. Furthermore, FRMD8low/iRHOM2low greatly facilitated the in vivo metastasis of TNBC. Finally, we found that combined treatment with paclitaxel and etanercept reversed the expression of FRMD8 and iRHOM2, concomitantly inhibiting the metastatic potential in vivo. This study explores how FRMD8 influences TNF-α processing and the metastatic behavior of breast cancer, providing insights into molecular dynamics that could guide future therapeutic strategies to improve outcomes in patients with breast cancer.
Keywords FRMD8 (FERM domain-containing protein 8), tmTNF-α (transmembrane TNF-α), Breast cancer metastasis, NF-κB (nuclear factor kappa B) pathways
Address and Contact Information 1 Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui, China
2 State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi’an 710032, China
3 Molecluar Laboratory, The People’s Hospital of Beilun District, Beilun Branch Hospital of The First Affiliated Hospital of Medical School Zhejiang University, 1288 Lushan East Road, Beilun District, Ningbo 315800, China
*Corresponding author: wuhaibo@ustc.edu.cn; zhwang@fmmu.edu.cn
† Jun Xu and Xiaoyu Yang contributed equally to this work.
Read full article at BMC

No.  77DOI: 10.1186/s11658-025-00753-3 Volume 30 (2025) - 30:77
Title AKT AND DUBs: A BIDIRECTIONAL RELATIONSHIP
Authors Valentina Serratore1, Maria Lucibello2, Donatella Malanga1,3, Giuseppe Viglietto1,3 and Carmela De Marco1,3*
Abstract The serine/threonine kinase Akt is crucial for cell physiology and can also contribute to pathology if its activation and regulation is disturbed. This kinase phosphorylates several substrates involved in mechanisms that are altered in human disease. AKT is regulated by several post-translational modifications (PTMs), including ubiquitination/deubiquitination. Ubiquitination can both target AKT to the proteasome and promote its activation. The interplay with the deubiquitination mechanism plays a crucial role in almost all biological activities of AKT. Information on the mechanisms of AKT deubiquitination and its key players has evolved rapidly in recent years along with the development of potential targeting strategies, although many of them are still unclear. Nevertheless, AKT in turn regulates various deubiquitinases (DUBs), suggesting further targeting strategies for human diseases. In this review, we aim to provide an up-to-date overview of the dual relationship between AKT and DUBs with respect to potential translational aim.

Highlights
  1. The Ser/Thr kinase AKT is subject to both activating and inactivating deubiquitination.
  2. Deubiquitination mediated by CYLD, USP1, and OTUD5 inactivates AKT.
  3. Deubiquitination mediated by USP7 activates AKT.
  4. OTUD1 inhibits AKT in a noncanonical manner.
  5. AKT phosphorylates USP4, USP14, USP35, and USP43, promoting cell growth and survival, cancer cell migration and invasion, and reducing autophagy.
Keywords AKT kinase, Post-translational modifications, Deubiquitinases, Phosphorylation
Address and Contact Information 1 Molecular Oncology Laboratory, Department of Experimental and Clinical Medicine, “Magna Graecia” University, 88100 Catanzaro, Italy
2 Department of Biomedical Sciences, Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR), 88100 Catanzaro, Italy
3 Interdepartmental Center of Services (CIS), Omics Sciences and Biobank, “Magna Græcia” University, 88100 Catanzaro, Italy
*Corresponding author: cdemarco@unicz.it
Read full article at BMC

No.  78DOI: 10.1186/s11658-025-00755-1 Volume 30 (2025) - 30:78
Title CORRECTION: A NOVEL MECHANISM FOR A‐to‐I RNA‐EDITED CYP1A1 IN PROMOTING CANCER PROGRESSION IN NSCLC
Authors Zhipeng Wang1†, Yan Wu3†, Ziqi Ding1, Xinru Xiao1, Yanhua Huang1, Zhiguang Liu1 and Qian Zhang1,2*
Abstract Correction to: Cellular & Molecular Biology Letters (2025) 30:40 https://doi.org/10.1186/s11658-025-00718-6

In this article [1], there was a minor error in Fig. 3. In Fig. 3F, the control vector of migration in A549 and H1299 were mixed up. For completeness and transparency, the old incorrect and correct versions are displayed in this correction.
Keywords
Address and Contact Information 1 Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou 213164, China
2 Changzhou Medical Center, Nanjing Medical University, Changzhou 213164, China
3 State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
*Correspondence: qianzhang@njmu.edu.cn
† Zhipeng Wang and Yan Wu have contributed equally to this work.
The original article can be found online at https://doi.org/10.1186/s11658-025-00718-6.
Read full article at BMC

No.  79DOI: 10.1186/s11658-025-00757-z Volume 30 (2025) - 30:79
Title MESENCHYMAL STEM CELL-SECRETED KGF AMELIORATES ACUTE LUNG INJURY VIA THE Gab1/ERK/NF-κB SIGNALING AXIS
Authors Shuning Xin1, Yan Ding1, Tong Yu1, Yunmei Fu1, Yong Cui2* and Hongguang Nie1*
Abstract Background: The epithelial sodium channel (ENaC) situated in the apical membrane of alveolar epithelial type 2 (AT2) cells is beneficial to edematous fluid reabsorption in acute lung injury (ALI). Recently, mesenchymal stem cells (MSCs), particularly their secretome, has emerged as a novel approach for treating pulmonary diseases. Among these secreted factors, keratinocyte growth factor (KGF) plays a critical role in mediating alveolar epithelial repair during ALI by enhancing epithelial cell proliferation, restoring epithelial integrity, and alleviating pulmonary edema, making it a promising candidate for therapeutic strategies. This study primarily focused on investigating the impact of KGF secreted from MSC on ALI, and clarifying its specific mechanism in regulating the expression of ENaC.
Methods: Lipopolysaccharide (LPS)-stimulated primary mouse AT2 cells were treated with KGF in vitro, and western blots along with immunofluorescence assays were performed to investigate the regulatory mechanism of KGF on ENaC protein expression. To further confirm the role of mouse bone marrow MSC-derived KGF, co-culture experiments with AT2 cells and either MSC or MSC with KGF knockdown (MSC-siKGF) were conducted. In vivo, an ALI model was established in mice by LPS-induced lung injury. The therapeutic effects of tail vein-injected MSC or MSC-siKGF were assessed using hematoxylin–eosin staining, lung wet/dry weight ratio, and alveolar fluid clearance.
Results: In primary mouse AT2 cells, KGF stimulation effectively restored the reduction of growth factor receptor-bound protein 2-associated binding protein 1 (Gab1) and α/γ-ENaC protein levels induced by LPS. KGF inhibited the activation of the LPS-induced extracellular regulated protein kinases (ERK) and nuclear factor-kappaB (NF-κB) signaling pathway. Treatment with the ERK pathway inhibitor PD98059 reversed the LPS-induced reduction in ENaC protein levels but had no effect on Gab1 levels. In addition, PD98059 suppressed LPS-induced activation of the NF-κB signaling pathway. Further analysis revealed that LPS stimulation weakened the interaction between the NF-κB p65 subunit and inhibitor kappaB (IκB), while KGF enhanced this interaction and inhibited the nuclear translocation of p65. Both KGF and the NF-κB inhibitor QNZ reversed the LPS-induced downregulation of ENaC protein levels and gene expression. Furthermore, both agents effectively restored the functional activity of ENaC channels. Co-culture with MSCs increased Gab1 protein levels, inhibited ERK/NF-κB signaling activation, and suppressed p65 nuclear translocation in LPS-treated AT2 cells, whereas these effects were attenuated in cells co-cultured with MSC-siKGF. In an ALI mouse model, tail-vein injection of MSCs alleviated lung injury and pulmonary edema, while the therapeutic effects of MSC-siKGF were weaker they were partly restored by the combination of QNZ.
Conclusions: Our study validated that the efficacy of MSCs in the treatment of edematous ALI was significantly associated with KGF, which potentially enhanced the upregulation of ENaC through the Gab1/ERK/NF-κB signaling pathway.
Keywords Acute lung injury, Epithelial sodium channel, Mesenchymal stem cell, Keratinocyte growth factor, Nuclear factor-kappaB
Address and Contact Information 1 Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
2 Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110122, China
*Corresponding author: ycui@cmu.edu.cn; hgnie@cmu.edu.cn
Read full article at BMC

No.  80DOI: 10.1186/s11658-025-00758-y Volume 30 (2025) - 30:80
Title THE SARS-COV-2 ENVELOPE PDZ BINDING MOTIF ACTS AS A VIRULENCE FACTOR DISRUPTING HOST’S EPITHELIAL CELL–CELL JUNCTIONS
Authors Flavio Alvarez1,2*, Guilherme Dias de Melo3†, Florence Larrous3†, Lauriane Kergoat3, Batiste Boëda4, Vincent Michel5, Danielle Seilhean6, Magali Tichit7, David Hing7, David Hardy7, Etienne Kornobis8, Hervé Bourhy3†, Nicolas Wolff1† and Célia Caillet‐Saguy9†
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), disrupts the alveolar epithelial barrier and exacerbates airway inflammation, leading to acute respiratory failure. The Envelope (E) protein is key to virulence, notably through its PDZ-binding motif (PBM), which interacts with host PDZ proteins, affecting signaling pathways and pathogenicity. This study investigates the PBM’s role in virulence by generating PBM-deficient mutant viruses and assessing their impact in vitro and in vivo. The mutants showed delayed replication and reduced cytopathic effects in vitro. In vivo, infected hamsters exhibited less weight loss, lower viral loads, and reduced inflammation, indicating attenuated pathogenicity. Histological analysis confirmed milder airway damage. Additionally, PBM-deficient viruses had impaired interactions with tight junction proteins like ZO-1, a PDZ-containing protein essential for epithelial integrity. Although the PBM played a key role in airway pathology, its impact on neuroinvasion was minimal during the acute phase of infection. Thus, the E protein PBM plays a critical role in SARS-CoV-2’s fitness, virulence, and pathogenicity, through the disruption of cell junctions and inflammation, underscoring its potential as a therapeutic target.
Keywords SARS-CoV-2, E protein, PDZ binding motif, Tight junctions, Virulence, Epithelial barrier, Inflammation, ZO-1, Viral pathogenesis
Address and Contact Information 1 Institut Pasteur, Signaling and Receptors Dynamics Unit, Université Paris Cité, 75015 Paris, France
2 Collège Doctoral, Sorbonne Université, 75005 Paris, France
3 Institut Pasteur, Lyssavirus Epidemiology and Neuropathology Unit, Université Paris Cité, 75015 Paris, France
4 Institut Pasteur, Cell Polarity Migration and Cancer Unit, 75015 Paris, France
5 Institut Pasteur, Pathogenesis of Vascular Infections Unit, Université Paris Cité, 75015 Paris, France
6 AP‐HP, Hôpital Pitié‐Salpêtrière, Département de Neuropathologie, Sorbonne Université, Paris, France
7 Institut Pasteur, Université Paris Cité, Histopathology Platform, 75015 Paris, France
8 Institut Pasteur, Université Paris Cité, Biomics C2RT, 75015 Paris, France
9 Institut Pasteur, Humoral Immunology Unit, Université Paris Cité, 75015 Paris, France
*Corresponding author: flavio.alvarez@pasteur.fr
† Guilherme Dias de Melo and Florence Larrous have contributed equally.
† Hervé Bourhy, Nicolas Wolff and Célia Caillet-Saguy have contributed equally.
Read full article at BMC

No.  81DOI: 10.1186/s11658-025-00756-0 Volume 30 (2025) - 30:81
Title FUNCTIONAL HUMANIZATION OF 15-LIPOXYGENASE-1 (Alox15) PROTECTS MICE FROM DEXTRAN SODIUM SULFATE INDUCED INTESTINAL INFLAMMATION
Authors Florian Reisch1,2, Marjann Schäfer1,2, Dominika Labuz3, Halina Machelska3, Sabine Stehling1, Gerhard P. Püschel2*, Michael Rothe4, Dagmar Heydeck1 and Hartmut Kuhn1*
Abstract Background: Mammalian arachidonic acid lipoxygenases (ALOXs) have previously been implicated in the pathogenesis of inflammatory disease, and pro- as well as anti-inflammatory activities have been reported. The human genome involves six functional ALOX genes and each of them encodes for a functionally distinct enzyme. ALOX15 is one of these isoforms and the majority of mammalian ALOX15 orthologs including mouse Alox15 convert arachidonic acid to its 12-hydroperoxy derivative. In contrast, human ALOX15 forms 15-hydroperoxy arachidonic acid instead. This difference in the catalytic properties of the two mammalian ALOX15 orthologs may be of biological relevance since arachidonic acid 15-lipoxygenating ALOX-isoforms exhibit an improved biosynthetic capacity for pro-resolving mediators. We recently generated Alox15 knock-in mice, which homozygously express a humanized Alox15 mutant (Leu353Phe) instead of the wildtype enzyme. These animals should be protected from the development of inflammatory symptoms in whole animal inflammation models if the biosynthesis of pro-resolving mediators plays a major role.
Methods: To explore whether functional humanization of mouse Alox15 might impact the pathogenesis of inflammatory diseases we tested Alox-KI mice in comparison with wildtype control animals in two whole animal inflammation models (dextran sodium sulfate induced colitis, Freund’s complete adjuvant induced paw edema). In these experiments we quantified the severity of inflammatory symptoms during the acute phase of inflammation and during the resolution period.
Results: We found that Alox15 knock-in mice are strongly protected from the development of inflammatory symptoms in the dextran sodium sulfate colitis model when the loss of body weight was used as major readout parameter. Quantification of the colon tissue oxylipidomes revealed that the colon concentrations of resolvin D5 were elevated in Alox15-KI mice and thus, this mediator might contribute to the protective effect induced by our genetic manipulation. However, other specialized pro-resolving mediators, such as maresin-2, neuroprotectin-1, and lipoxins, may not play a major role for the protective response. In the Freund’s complete adjuvant induced paw edema inflammation model no protective effect was observed.
Conclusions: Taken together, our data suggest that humanization of the reaction specificity of mouse Alox15 (Leu353Phe mutation) exhibits differential effects in two mouse inflammation models.
Keywords Eicosanoids, Lipid peroxidation, Oxylipidomes, Inflammation, Pain, Colitis, Paw edema
Address and Contact Information 1 Department of Biochemistry, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
2 Institute for Nutritional Sciences, University Potsdam, Arthur‐Scheunert‐Allee 114‐116, 14558 Nuthetal, Germany
3 Department of Experimental Anesthesiology, Charité˗Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Hindenburgdamm 30, D‐12203 Berlin, Germany
4 Lipidomix GmbH, Robert‐Roessle‐Str. 10, 1D‐3125 Berlin, Germany
*Corresponding author: gpuesche@uni-potsdam.de; hartmut.kuehn@charite.de
Read full article at BMC

No.  82DOI: 10.1186/s11658-025-00764-0 Volume 30 (2025) - 30:82
Title NON-MONOTONIC RESPONSE OF MACROPHAGES TO MECHANICAL STRETCH IMPACTS SKIN WOUND HEALING
Authors Qian Wei1,2, Fangzhou Du2, Jinjiang Cui2, Jiangen Xu2, Yuchen Xia1,2, Shikai Li1,2, Qiong Deng4, Xiaoyu Xu5, Jingzhong Zhang1,2,3* and Shuang Yu1,2,3*
Abstract Background: The skin is subjected to constant mechanical stress in both healthy and wounded states. Macrophages play crucial roles in skin homeostasis and in all stages of the wound healing process. However, the effects of static mechanical stretch (MS) on macrophages and the subsequent consequences on skin cells remain largely unclear.
Methods: We applied static MS at amplitudes of 7%, 15%, and 21% to macrophages derived from THP-1 using a customized cell-stretching device, thoroughly investigating its impacts on viability, polarization, secretome, and underlying signaling pathways. Recognizing the substantial influence of the macrophage secretome on neighboring cells, we collected conditioned medium from macrophages exposed to MS (MS-CM) and evaluated its effects on keratinocytes, fibroblasts, and endotheliocytes.
Results: Macrophages exhibited a non-monotonic biological response to MS across the range of 7–21%, resulting in similar non-monotonic effects of MS-CM on the behaviors skin cell behaviors. The most significant effects were observed when macrophages were subjected to 15% MS. The 15% MS promoted macrophage viability and polarization toward the M2 phenotype, leading to increased release of anti-inflammatory cytokines and growth factors, as well as activation of the mechanotransduction pathways Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Consistent with these findings, 15% MS-CM enhanced the migration of keratinocytes, endotheliocytes, and fibroblasts, and promoted in vitro tube formation and fibroblast activation. In contrast, both 7% and 21% MS showed a similar tendency but with less pronounced or insignificant effects. Additionally, in a full-thickness wound model, the application of concentrated 15% MS-CM demonstrated additional beneficial effects on wound healing by enhancing angiogenesis and dermal reconstitution.
Conclusions: Our observation of the non-monotonic macrophage response to MS provides a foundation for elucidating how macrophages may translate mechanical cues into paracrine signals that influence skin function and wound healing dynamics.
Keywords Macrophages, Mechanical stretch, YAP/TAZ, Skin cells, Wound healing
Address and Contact Information 1 School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
2 Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
3 Xuzhou Medical University, Xuzhou 221004, China
4 Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
5 Department of Radiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China
*Corresponding author: zhangjz@sibet.ac.cn; yush@sibet.ac.cn
Read full article at BMC

No.  83DOI:10.1186/s11658-025-00760-4 Volume 30 (2025) - 30:83
Title POSTTRANSLATIONAL MODIFICATIONS OF YAP/TAZ: MOLECULAR MECHANISMS AND THERAPEUTIC OPPORTUNITIES
Authors Zhenxiong Zhang1†, Peiheng He1,2†, Li Yang1,2†, Jun Gong1*, Renyi Qin1* and Min Wang1,3*
Abstract Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), are critical effectors of the Hippo pathway, as well as other biochemical and biophysical signals. Through their interaction with DNA-binding partners, YAP/TAZ can modulate the transcription of many genes critical for organ size regulation and tissue homeostasis maintenance. Aberrant expression or activation of YAP/TAZ is implicated in the pathogenesis of many cancers and noncancerous diseases. Notably, their functional outputs demonstrate remarkable diversity, with context-dependent roles emerging across distinct disease models and tissue microenvironments. Posttranslational modifications (PTMs) exert profound impacts on the stability, subcellular localization, and function of YAP/TAZ. The canonical Hippo pathway-mediated phosphorylation and ubiquitination have been well characterized as mechanisms that downregulate YAP/TAZ stability and transcriptional activity. Recent studies have identified novel phosphorylation sites, atypical ubiquitination patterns, along with ubiquitin-like modifications, glycosylation, methylation, acetylation, and lactylation on YAP/TAZ. These PTMs exhibit dynamic regulation in response to microenvironmental stimuli, providing molecular insights into the context-dependent functional versatility of YAP/TAZ. This review systematically synthesizes current understanding of YAP/TAZ PTM networks and discusses their therapeutic implications.
Keywords Hippo, YAP, TAZ, Posttranslational modifications, Pathogenesis
Address and Contact Information 1 Department of Biliary‐Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2 The Second Clinical School, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
3 State Key Lab of Molecular Oncology and Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
*Corresponding author: gjun@hust.edu.cn; ryqin@tjh.tjmu.edu.cn; wangmin0013128@aliyun.com
† Zhenxiong Zhang, Peiheng He, and Li Yang contributed equally to this work.
Read full article at BMC

No.  84DOI: 10.1186/s11658-025-00759-x Volume 30 (2025) - 30:84
Title GPD2 INHIBITION IMPAIRS COAGULATION FUNCTION VIA ROS/NF-κB/P2Y12 PATHWAY
Authors Jiajie Chen1,2,3, Guifeng Xu4, Zhipeng Xie5, Shaoxia Xie1,2,3, Wenwei Luo1,2*, Shilong Zhong1,2,3* and Weihua Lai1,2,3*
Abstract Background: Coronary heart disease (CHD) remains a global health threat. As antiplatelet therapy constitutes the cornerstone of CHD management, ticagrelor has been universally endorsed as a first-line agent in major clinical guidelines. However, the therapeutic efficacy of ticagrelor is compromised by interindividual variability in bleeding risk. Notably, while inherited genetic variations account for part of this heterogeneity, the dynamic regulatory role of modifiable epigenetic mechanisms—particularly DNA methylation in mediating platelet reactivity—remains inadequately characterized, presenting a critical knowledge gap in optimizing precision antiplatelet strategies.
Methods: We utilized the 850k methylation array to measure DNA methylation levels in blood samples from 47 healthy controls and 93 patients with CHD. Subsequently, epigenome-wide association study (EWAS), summary data-based Mendelian randomization (SMR), and heterogeneity in dependent instruments (HEIDI) analyses were applied to pinpoint critical methylation sites that influence gene expression, platelet function recovery, and bleeding risk. After developing a targeted cellular model using the CRISPR-dCas9-DNMT3A/Tet1CD-U6-sgRNA system and integrating with transcriptomic sequencing data, we conducted mechanistic cellular experiments to elucidate how these methylation sites affect platelet function recovery and bleeding risk. The findings were further validated through animal studies.
Results: Integrated analysis of EWAS and SMR-HEIDI revealed that hypermethylation at CpG site cg03230175 within the GPD2 gene promoter region was significantly associated with decreased GPD2 gene expression (P = 1.76E-18), delayed platelet functional recovery (P = 9.02 × 10–3), and elevated hemorrhagic risk (P = 2.71 × 10–2). Transcriptomic studies indicated that GPD2 gene (cg03230175) methylation affects mitochondrial function, nuclear factor kappa B (NF-κB) signaling pathway, reactive oxygen species metabolic process, and G protein-coupled receptor (GPCR) ligand binding. Cellular experiments demonstrated that the GPD2 gene (cg03230175) methylation inhibits coagulation function by suppressing reactive oxygen species (ROS) production, NF-κB activation, and P2Y12 gene expression (P2Y12 receptor plays a pivotal role in platelet activation, thrombus formation, and the pathogenesis of thrombotic disorders). The animal study results confirmed that GPD2 enzyme inhibition can indeed prolong the clotting time in mice.
Conclusions: GPD2 gene (cg03230175) methylation resulted in reduced gene expression levels, inhibited mitochondrial energy metabolism, decreased ROS levels, and affected P2Y12 gene expression through the NF-κB pathway, ultimately leading to inhibition of coagulation function.
Registry: The Impact of Genotype on Pharmacokinetics and Antiplatelet Effects of Ticagrelor in Healthy Chinese (IGPPT). Trial registration number: NCT03092076. Date of Registration: 09 March 2017, retrospectively registered. URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT03092076.
Keywords GPD2, DNA methylation, Epigenetic mechanism, ROS, NF-κB, P2Y12
Address and Contact Information 1 Department of Pharmacy, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
2 Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
3 School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
4 Department of Pharmacy of The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
5 Department of Pharmacy, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
*Corresponding author: luowenwei@gdph.org.cn; shz2020@qq.com; laiweihuax@163.com
Read full article at BMC

No.  85DOI: 10.1186/s11658-025-00767-x Volume 30 (2025) - 30:85
Title CORRECTION: CDC20 PROTECTS THE HEART FROM DOXORUBICIN-INDUCED CARDIOTOXICITY BY MODULATING CCDC69 DEGRADATION
Authors Zhenyu Feng1†, Ningning Zhang2†, Liang Wang3†, Xumin Guan1, Yunpeng Xie1* and Yun‐long Xia1*
Abstract Correction: Cellular & Molecular Biology Letters (2025) 30:29 https://doi.org/10.1186/s11658-025-00708-8

Following publication of the original article [1], the authors regret that the original version of this paper unfortunately contained an incorrect image in Figure S10B. The Figures used in the DOX  + Tumor groups were repeated. We have double checked the original data and found that the inadvertent errors occurred during figure compilation, and this correction does not affect the scientific conclusions of the article.
Keywords
Address and Contact Information 1 Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Lianhe Road 193, Dalian 116000, Liaoning, People’s Republic of China
2 Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
3 Department of Pharmacy, Liaoyang City Central Hospital, Liaoyang, People’s Republic of China
*Corresponding author: xieyunpeng@dmu.edu.cn; yunlong_xia@126.com
† Zhenyu Feng, Ningning Zhang and Liang Wang have contributed equally to this work.
The original article can be found online at https://doi.org/10.1186/s11658-​025-​00708-8.
Read full article at BMC

No.  86DOI: 10.1186/s11658-025-00770-2 Volume 30 (2025) - 30:86
Title TARGETING LINC02320 PREVENTS COLORECTAL CANCER GROWTH VIA GRB7-DEPENDENT INHIBITION OF MAPK SIGNALING PATHWAY
Authors Lingwei Zhang1†, Hong Chen1†, Yangmei Yang1†, Liangbo Zhao1, Huimin Xie1, Peixian Li1, Xinrui Lv2*, Luyun He3, Nian Liu1* and Benyu Liu1*
Abstract Background: It is estimated that over 85% of human transcripts are non-coding RNAs, which play an important role in the regulation of numerous biological processes and are closely associated with the development of human cancers. Nevertheless, the functions of the vast majority of non-coding RNAs are yet to be clearly elucidated.
Methods: Long non-coding RNA (lncRNA) LINC02320 was screened out by RNA-sequencing using paired CRC samples. The level of LINC02320 in colorectal cancer (CRC) tissues and cell lines was validated by qRT-PCR and in situ hybridization (ISH). CCK8, colony formation, transwell, wound healing and xenograft experiments were carried out to investigate the function of LINC02320. Antisense oligonucleotide (ASO) was used to target LINC02320. Mass spectrometry, pull-down, western blot and CUT&Tag assays were conducted to investigate the molecular mechanism of LINC02320, ILF2, GRB7, MAPK and FOS.
Results: LINC02320 was highly expressed in metastatic colorectal cancer (CRC) tissues based on RNA-sequencing. ISH staining using tissue microarray (TMA) indicated that LINC02320 is associated with the clinical stage and survival rate of patients with CRC. The results of loss-of-function and gain-of-function experiments demonstrated that LINC02320 facilitates cancer cell proliferation and metastasis in vitro and in vivo while simultaneously inhibiting apoptosis. LINC02320 is present in both the nucleus and cytoplasm, with a nuclear function. Mechanistically, LINC02320 recruits the transcriptional regulator ILF2 to the GRB7 promoter, thereby initiating its transcription. GRB7 then activates the mitogen-activated protein kinase (MAPK) signaling pathway, which contributes to CRC progression and leads to increased phosphorylation of the transcription factor FOS. Phosphorylated FOS directly promotes LINC02320 transcription, forming a positive feedback loop and amplifies this pro-cancer signal. Notably, LINC02320-targeted ASO therapy significantly blocked tumor growth in vivo.
Conclusion: In summary, our findings demonstrate the essential role of LINC02320 involved in CRC progression, which provides novel insights into the importance of lncRNA as a therapeutic target in cancer treatment.
Keywords LINC02320 therapy, GRB7, MAPK, Colorectal cancer
Address and Contact Information 1 State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
2 Kaifeng Key Laboratory for Infectious Diseases and Biosafety, The First Affiliated Hospital of Henan University, Kaifeng, Henan, China
3 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
*Corresponding author: lvxinrui@henu.edu. cn; nianliu@zzu.edu.cn; benyuliu@zzu.edu.cn
† Lingwei Zhang, Hong Chen, and Yangmei Yang have contributed equally to this work.
Read full article at BMC

No.  87DOI: 10.1186/s11658-025-00772-0 Volume 30 (2025) - 30:87
Title INTEGRATED TRANSCRIPTOMICS AND METABOLOMICS CONFIRMS THE OXIDATIVE STRESS MECHANISM OF HYPOTHERMIA-INDUCED NEURONAL NECROPTOSIS
Authors Song‐Jun Wang1*, Chao‐Long Lu1, Fu Zhang2, Xue‐Tong Dong1, Xiao‐Rui Su1, Jing‐Jing Sha1, Bin Cong1,3* and Xia Liu1*
Abstract Abnormal climate change seriously endangers the safety of outdoor work and life, often causing hypothermia-induced coma or death. As the underlying mechanism has not been fully elucidated, a targeted treatment for hypothermia-triggered neuronal injury and forensic pathology indicators of fatal hypothermia are lacking. Herein, we aimed to explore hypothermia-induced changes in gene expression and metabolite profiles of cerebral cortical tissues to elucidate the mechanism of hypothermia-promoted necroptosis of cerebral cortical neurons. Flow cytometry and fluoro-jade C staining showed that low temperature caused necroptosis of cerebral cortical neurons. Transcriptomics identified 244 differential genes between hypothermia-exposed cortical tissue and control tissue. These genes were enriched in tumor necrosis factor (TNF)-α and nuclear factor (NF)-kappa B signaling pathways, as revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Broadly targeted metabolomics identified 49 differential metabolites with significant differences. N-alpha-acetyl-L-arginine, argininosuccinic acid, glutaric acid, and other ornithine cycle-associated metabolites were significantly reduced in the hypothermia-exposed cortical tissue, driving fumaric acid reduction in the tricarboxylic acid (TCA) cycle. In addition, KEGG enrichment analysis showed significant changes in the TCA cycle pathway. A combined transcriptomic and metabolomic analysis uncovered that hypothermia induced oxidative stress through NF-κB activation, caused mitochondrial damage, impaired the ornithine cycle, and, ultimately, induced neuronal necroptosis. Pharmacological inhibition of NF-κB by the SC75741 inhibitor effectively ameliorated hypothermia-triggered necroptosis. In conclusion, our results suggest that the NF-κB transcription factor is a potential marker of hypothermia-induced neuronal necroptosis in the mouse cerebral cortex. In addition, our findings indicate the mechanism of necroptosis in cerebral cortical neurons caused by low temperature, which is beneficial for our understanding of hypothermia-induced coma and death.

Highlights
  1. Combined transcriptomic and metabolomic analysis reveal key mechanisms by which hypothermia-induced neuronal necroptosis occurs in cerebral cortical tissue.
  2. Necroptosis is the main type of hypothermia-induced neuronal death in cerebral cortical tissue.
  3. Oxidative stress is the main mechanism by which hypothermia induces neuronal necroptosis in cerebral cortical tissue.
  4. NF-κB–inducible nitric oxide synthase (iNOS) signaling pathways are key targets of hypothermia-induced neuronal necroptosis in cerebral cortical tissue.
Keywords Hypothermia, Death from cold, Cryoinjury, Oxidative stress, Necroptosis, Environmental stress
Address and Contact Information 1 Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, College of Forensic Medicine, Hebei Medical University, No. 361 Zhong Shan Road, Shijiazhuang, Hebei, China
2 Forensic Pathology Lab, Guangdong Public Security Department, No. 97 Huanghua Road, Guangzhou 510050, China
3 Hainan Tropical Forensic Medicine Academician Workstation, Haikou 571199, Hainan, China
*Corresponding author: 17800584@hebmu.edu.cn; cong6406@hebmu.edu.cn; 17800586@hebmu.edu.cn
Read full article at BMC

No.  88DOI: 10.1186/s11658-025-00763-1 Volume 30 (2025) - 30:88
Title COMPREHENSIVE ANALYSIS OF KELOID SUPER-ENHANCER NETWORKS REVEALS FOXP1-MEDIATED ANTI-SENESCENCE MECHANISMS IN FIBROSIS
Authors Hao Yang1†, Dongming Lv1†, Xiaohui Li1, Yongfei Chen1, Hailin Xu4, Honglin Wu1, Zhiyong Wang5, Xiaoling Cao1, Bing Tang1, Wuguo Deng2,3*, Jiayuan Zhu1* and Zhicheng Hu1*
Abstract There is a significant gap in multi-omics studies on keloids, especially concerning the interaction between fibroblasts and super-enhancers (SEs). Identifying novel biomarkers within the epigenetic landscape could greatly improve keloid management. In this study, we investigated gene expression at both transcriptional and translational levels to identify potential biomarkers and employed CUT&Tag technology to validate SE-associated genes and upstream transcription factors (TFs). Through integrated analyses of transcriptomics and proteomics, 10 hub genes that associated with ECM, immune, and metabolic pathways were found. Given the crucial role of fibroblasts in keloid pathogenesis, we further identified five SE-associated genes (SERPINH1 SE, MMP14 SE, COL5A1 SE, COL16A1 SE, and SPARC SE) that exhibit characteristic upregulation in keloids. Analysis of upstream TFs and core transcription regulatory circuitry (CRC) revealed potential master TFs (FOSL2, BACH2, and FOXP1), with FOXP1 emerging as the core TF likely driving pro-fibrotic development through its anti-senescence function. In summary, we anticipate that the outcomes of the integrative omics analysis will facilitate further investigation into the underlying molecular mechanisms of keloid formation and lead to novel strategies for its prevention and management. Specifically inhibiting the anti-senescence function of FOXP1 brings new promise for the treatment of fibrosis-related diseases.
Keywords Integrative omics analysis, Keloid, Super-enhancers (SEs), Transcription factors (TFs), Anti-senescence, Fibrosis
Address and Contact Information 1 Department of Burn and Wound Repair, Sun Yat-Sen University First Affiliated Hospital, Guangzhou 510080, China
2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
3 Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan 528200, China
4 Guangdong Provincial Dermatology Hospital, Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou 510091, China
5 Department of Joint Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
*Correspondinga author: dengwg@sysucc.org.cn; zhujiay@mail.sysu.edu.cn; huzhch5@mail.sysu.edu.cn
† Hao Yang, Dongming Lv, Xiaohui Li, Yongfei Chen, and Hailin Xu contributed equally to this work.
Read full article at BMC

No.  89DOI: 10.1186/s11658-025-00769-9 Volume 30 (2025) - 30:89
Title IMMUNE FACTORS AND THEIR ROLE IN TUMOR AGGRESSIVENESS IN GLIOBLASTOMA: ATYPICAL CADHERIN FAT1 AS A PROMISING TARGET FOR COMBATING IMMUNE EVASION
Authors Manvi Arora1†, Archismita Kundu1†, Subrata Sinha1 and Kunzang Chosdol1*
Abstract Immune evasion is one of the hallmarks of cancers, including glioblastoma, the most aggressive form of primary brain tumors. Multiple mechanisms are employed by tumor cells and its microenvironment to evade immune detection and foster tumor growth and progression. The secretion of immunosuppressive molecules such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), the expression of checkpoint proteins such programmed death-ligand 1 (PD-L1), and the recruitment of T-regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) leads to suppressed immune cell activity, favoring unchecked tumor growth. The FAT atypical cadherin 1 (FAT1) has shown context/tissue-dependent effects in cancers of different tissue origins, with either oncogenic or tumor suppressor roles. Our laboratory has reported FAT1 to have an oncogenic function in glioblastoma. In addition, FAT1 promotes an immunosuppressive microenvironment in glioblastoma, reducing T-cell and monocyte infiltration while increasing immunosuppressive cells such as MDSCs. It also upregulates pro-inflammatory mediators [cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and interleukin-6 (IL-6)], fostering tumor-promoting signaling. This dual role in immune evasion and pro-tumorigenic inflammatory processes makes FAT1 a key driver of glioblastoma progression. This highlights the potential of FAT1 as a compelling therapeutic target. This article provides a concise overview of immune tolerance mechanisms in glioblastoma, and the crucial role of FAT1 in promoting immune tolerance and tumor advancement. In addition, this review highlights currently available immunotherapies in clinical use or undergoing trials, and the potential of FAT1 as a promising target for combinatorial therapeutic interventions.
Keywords Glioblastoma, Tumor microenvironment, FAT1, Immunosuppression, Inflammation
Address and Contact Information 1 Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
*Corresponding author: kunzangchosdol@yahoo.com
† Manvi Arora and Archismita Kundu shares first authors.
Read full article at BMC

No.  90DOI: 10.1186/s11658-025-00765-z Volume 30 (2025) - 30:90
Title NT2-DERIVED ASTROCYTE–NEURON CO-CULTURE REFLECTS PHYSIOLOGICAL RELEVANCE AND OFFERS RESEARCH VALIDITY
Authors Sylwia Kedracka‐Krok1*, Ewelina Fic1, Zuzanna Cepil1, Piotr Rybczyński1, Agata Szlaga2, Radosław Cacała1, Sławomir Lasota3, Anna Blasiak2 and Marta Dziedzicka‐Wasylewska1
Abstract Background: Obtaining human neurons and astrocytes for in vitro studies presents a significant challenge owing to the complexity of replicating their development and functionality outside the human brain. The Ntera-2 cell line is a valuable source of human neurons and astrocytes in neuroscience research. However, differentiating Ntera-2 cells into neurons and astrocytes with all-trans retinoic acid is complicated by the lack of reliable markers to monitor differentiation stages effectively. This study aimed to characterize neuron-enriched and pure astrocyte cultures at two maturation stages and to compare these with the original Ntera-2 cells. Ntera-2 cells and NT2 cells are used interchangeably in this publication.
Methods: Using an advanced proteomic approach, we assessed the protein composition and abundance of neuron and astrocyte co-cultures and discovered that the astrocytic protein profile in co-culture with neurons was more representative compared with that in pure astrocyte cultures. Additionally, electrophysiological studies were conducted to investigate the best astrocyte content for neuronal functionality.
Results: Mass spectrometry-based analysis provided insights into over 9000 proteins, covering well-known protein markers, proteins unique to specific cell types, and differentially expressed proteins. Notably, differences in transcription factors, regulatory proteins, intermediate filaments, and proteins unique to early and mature astrocytes highlighted the distinct maturation, activation, and functional profiles of the various cells. These findings offer a straightforward tool for characterization and monitoring the differentiation process. Three weeks of maturation in pure culture yielded immature astrocytes; however, extending the maturation period to 6 weeks significantly altered the composition of the cellular proteome, indicating increased astrocyte maturity. Studies revealed a broader repertoire of astrocytic proteins in co-culture with neurons. Meanwhile, electrophysiological analyses demonstrated that a high content of astrocytes is essential for neuronal functional maturity.
Conclusions: Astrocyte–neuron co-cultures offer a more accurate model of neural tissue than pure cultures, highlighting the complexity of cell maturation and providing insights for improving in vitro modeling of human neural development.
Keywords Ntera-2, NT2, Human neurons, Human astrocytes, Co-culture, Proteome, Markers, Electrophysiology
Address and Contact Information 1 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Physical Biochemistry, Jagiellonian University, Kraków, Poland
2 Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland
3 Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
*Corresponding author: sylwia.kedracka-krok@uj.edu.pl
Read full article at BMC

No.  91DOI: 10.1186/s11658-025-00773-z Volume 30 (2025) - 30:91
Title MOLECULAR MECHANISMS AND FUNCTIONS OF PROTEIN ACETYLATION IN SEPSIS AND SEPSIS-ASSOCIATED ORGAN DYSFUNCTION
Authors Yang‐Fan Xu1, Ni Yang1, Peng‐Hui Hao1, Ri Wen1* and Tie‐Ning Zhang1*
Abstract Sepsis, a life-threatening condition characterized by organ dysfunction due to dysregulated host response to infection, remains a global health challenge with high morbidity, mortality, and long-term sequelae. The development of sepsis-associated organ dysfunction (SAODs) substantially worsens prognosis. Despite extensive studies, the pathophysiological mechanisms underlying sepsis and SAODs remain unclear. Protein acetylation is a widespread and reversible post-translational modification regulated by acetyltransferases and deacetylases that occurs on both histone and non-histone proteins. This modification plays a critical role in modulating various cellular processes by modifying target proteins. Emerging evidence indicates that acetylation is involved in sepsis and SAODs through regulation of key biological processes. In this review, we discuss the regulatory enzymes and mechanisms of acetylation, highlight their roles in sepsis and associated organ dysfunction, and explore the potential of acetylation modulators as therapeutic agents, offering new insights into understanding sepsis and developing novel therapeutic strategies.
Keywords Acetylation, Sepsis, Sepsis-associated organ dysfunction, Histone deacetylase, SIRTs
Address and Contact Information 1 Department of Pediatrics, Shengjing Hospital of China Medical University, No.36, SanHao Street, Shenyang 110004, Liaoning, China
*Corresponding author: wenri0801@hotmail.com; cmuztn@vip.qq.com
Read full article at BMC

No.  92DOI: 10.1186/s11658-025-00761-3 Volume 30 (2025) - 30:92
Title FLNA, A DISULFIDPTOSIS-RELATED GENE, MODULATES TUMOR IMMUNITY AND PROGRESSION IN COLORECTAL CANCER
Authors Qiong Li1,2*†, Renhong Huang3†, Lingling Lv2, Haifeng Ying2, Yuan Wu2, YuQing Huang2, Yuxi Li2, Wen Ma4, Xiaoshuang Liu5, Qinghui Meng6*, Fengying Xing7*, Yan Shen8* and Lan Zheng4*
Abstract Background: Disulfidptosis represents a novel type of regulated cell death induced by excessively high intracellular levels of cystine. Targeting disulfide imbalance is considered a promising treatment approach for colorectal cancer (CRC). However, the involvement of disulfidptosis in CRC immunotherapy is undefined.
Methods: Unsupervised clustering was applied to The Cancer Genome Atlas (TCGA) datasets to classify disulfidptosis-related phenotypes. The tumor microenvironment (TME) was characterized using diverse bioinformatics algorithms, including gene set variation analysis (GSVA) for pathway enrichment analysis and CIBERSORT for immune cell profiling. A disulfidptosis-related gene (DRG) signature was generated for stratifying CRC cases, and univariate Cox regression was utilized for identifying prognostic DRGs. Filamin A (FLNA) was pinpointed as a pivotal regulator of disulfidptosis, and its functional impacts on tumor progression and immunotherapy response were further investigated.
Results: Two different groups were determined on the basis of the built disulfidptosis-related signature (DRS), showing distinct clinical outcomes, as well as different pathway activation, drug sensitivity, and immune infiltration patterns. The high-DRS subgroup correlated with poorer prognosis, elevated immunosuppressive cell activity, and reduced cytotoxic immune cell infiltration. FLNA emerged as a critical mediator of disulfidptosis in CRC, with its knockdown suppressing tumor cell migration and invasion in vitro. The FLNA inhibitor PTI-125 attenuated tumor growth and epithelial–mesenchymal transition (EMT), while FLNA depletion reversed glucose-driven metastasis. Notably, combined glucose transporter 1 (GLUT1) inhibition and anti-programmed cell death protein 1 (PD-1) therapy enhanced CD8+ T cell recruitment and suppressed EMT.
Conclusions: This study elucidates the interplay between disulfidptosis and the CRC immune landscape, highlighting FLNA as a therapeutic target. These findings suggest that modulating disulfidptosis in conjunction with immunotherapy may offer a novel treatment paradigm for CRC.
Keywords Disulfidptosis, Filamin A, Epithelial mesenchymal transition, Glucose transporter 1, Immunotherapy, Colorectal cancer
Address and Contact Information 1 Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200120, China.
2 Department of Traditional Chinese Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
3 Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4 Department of Acupuncture, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200120, China.
5 Department of General Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200120, China.
6 Beijing Research Institute of Science and Technology, Beijing Milu Ecological Research Center, Beijing 100076, China.
7 Experimental Animal Center, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China.
8 State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
*Corresponding author: Liqiong427@163.com; mengqinghui2006@163.com; xingfengying@163.com; sy40685@rjh.com.cn; windy9453@126.com
† Qiong Li and Renhong Huang have contributed equally.
Read full article at BMC

No.  93DOI: 10.1186/s11658-025-00766-y Volume 30 (2025) - 30:93
Title XANTHOSINE ALLEVIATES MYOCARDIAL ISCHEMIA–REPERFUSION INJURY THROUGH ATTENUATION OF CARDIOMYOCYTE FERROPTOSIS
Authors Yang Xu1†, Wenfeng Zhou1†, Zhongguo Fan1†, Yiwei Cheng2,3†, Yujia Xiao1, Yu Liu4, Xinxin Li1, Zhenjun Ji1, Yi Fan1,5* and Genshan Ma1*
Abstract Background: Ischemic heart disease remains a leading cause of morbidity and mortality worldwide, with myocardial ischemia–reperfusion (I/R) injury significantly contributing to cardiomyocyte death and poor outcomes post-acute myocardial infarction (AMI). Emerging evidence highlights metabolic changes during myocardial injury, particularly in purine metabolism. This study investigates the protective role of xanthosine (XTS), a purine metabolism intermediate, in alleviating I/R injury.
Methods: Neonatal and adult mouse myocardial tissues post-myocardial infarction (MI) were analyzed using untargeted and targeted metabolomics to explore metabolic profiles. The effects of XTS on I/R injury were evaluated in vivo using a murine I/R model and in vitro with hypoxia/reoxygenation-treated neonatal rat cardiomyocytes (NRCMs). Cardiac function, fibrosis, apoptosis, oxidative stress markers, and ferroptosis-related pathways were assessed via echocardiography, biochemical assays, western blotting, and electron microscopy. Integrated drug affinity responsive target stability (DARTS)-based drug target screening and RNA-seq transcriptomic profiling elucidate XTS-mediated mechanisms against I/R injury.
Results: Metabolomics revealed distinct differences in purine metabolism between neonatal and adult mice post-MI, with significant XTS accumulation observed in neonatal hearts. In vivo, XTS treatment in adult mice enhanced left ventricular function, reduced fibrosis, and alleviated lipid peroxidation and mitochondrial damage post-I/R injury. In vitro, XTS significantly improved cardiomyocyte viability, reduced oxidative stress, and mitigated ferroptosis by restoring glutathione peroxidase 4 (GPX4) levels and reducing acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Mechanistically, XTS stabilized metabolic enzymes, upregulated l-arginine and glutathione (GSH) to mitigate reactive oxygen species(ROS), and inhibited ferroptosis.
Conclusions: XTS, a key purine metabolism intermediate, improves cardiac remodeling and function following I/R injury by suppressing ferroptosis and reducing mitochondrial ROS production. These findings provide novel insights into the therapeutic potential of XTS as an adjunctive treatment for patients with AMI undergoing revascularization.
Keywords Xanthosine (XTS), Ischemia–reperfusion (I/R) Injury, Ferroptosis, Purine metabolism, Reactive oxygen species (ROS)
Address and Contact Information 1 Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
2 State Key Laboratory of Reproductive Medicine and Ofspring Health, Nanjing Medical University, Nanjing, China
3 Innovation Center of Suzhou, Nanjing Medical University, Suzhou, China
4 Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
5 Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53705, USA
*Corresponding author: yfan246@wisc.edu; magenshan@hotmail.com
† Yang Xu, Wenfeng Zhou, Zhongguo Fan, and Yiwei Cheng contributed equally to this work.
Read full article at BMC

No.  94DOI: 10.1186/s11658-025-00771-1 Volume 30 (2025) - 30:94
Title PERSPECTIVES ON MITOCHONDRIAL DYSFUNCTION IN THE REGENERATION OF AGING SKELETAL MUSCLE
Authors Kai Wang1,2,3†, Mailin Gan1,2,3†, Yuhang Lei1,2,3, Tianci Liao1,2,3, Jiaxin Li1,2,3, Lili Niu1,2,3, Ye Zhao1,2,3, Lei Chen1,2,3, Yan Wang1,2,3, Li Zhu1,2,3* and Linyuan Shen1,2,3*
Abstract As the global population trends toward aging, the number of individuals suffering from age-related debilitating diseases is increasing. With advancing age, skeletal muscle undergoes progressive oxidative stress infiltration, coupled with detrimental factors such as impaired protein synthesis and mitochondrial DNA (mtDNA) mutations, culminating in mitochondrial dysfunction. Muscle stem cells (MuSCs), essential for skeletal muscle regeneration, also experience functional decline during this process, leading to irreversible damage to muscle integrity in older adults. A critical contributing factor is the loss of mitochondrial metabolism and function in MuSCs within skeletal muscle. The mitochondrial quality control system plays a pivotal role as a modulator, counteracting aging-associated abnormalities in energy metabolism and redox imbalance. Mitochondria meet functional demands through processes such as fission, fusion, and mitophagy. The significance of mitochondrial morphology and dynamics in the mechanisms of muscle regeneration has been consistently emphasized. In this review, we provide a comprehensive summary of recent advances in understanding the mechanisms of aging-related mitochondrial dysfunction and its role in hindering skeletal muscle regeneration. Additionally, we present novel insights into therapeutic approaches for treating aging-related myopathies.
Keywords Aging, Mitochondrial dynamics, Mitophagy, Oxidative stress, Skeletal muscle regeneration
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 Afairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
*Corresponding author: zhuli@sicau.edu.cn; shenlinyuan@sicau.edu.cn
† Kai Wang and Mailin Gan have contributed equally to this work.
Read full article at BMC

No.  95DOI: 10.1186/s11658-025-00775-x Volume 30 (2025) - 30:95
Title HYPOXIA-INDUCED GENOME-WIDE DNA DEMETHYLATION BY DNMT3A AND EMT OF CANCER CELLS
Authors Biswanath Chatterjee1,2†, Pritha Majumder1†, Chun‑Chang Chen2, Jing‑Ping Wang2,3, Po‑Hsuan Su4, Hung‑Cheng Lai4, Ching‑Chen Liu2, Hsin‑Nan Lin2, Chen‑Hsin A. Yu2, Hanna S. Yuan2 and Che‑Kun James Shen1,2*
Abstract Background: Despite the comprehensive advancement in the field of cancer therapeutics, there remains an urgent need to identify new pathophysiological mechanisms that can be targeted in isolation or in combination with existing therapeutic regimens. The epithelial-to-mesenchymal transitions (EMT) induced by hypoxia, cytokines, and growth factors involves acquisition of invasive and migratory properties by cancer cells. Epigenetic alterations of DNA methylations and/or histone modifications cause substantial transcriptomic reprogramming in cancer cells during EMT and metastasis, which can be therapeutically targeted by a thorough understanding of the mutual interactions among the epigenetic processes. Previously, the mammalian DNA methyltransferases (DNMTs) have been shown to possess redox- and Ca++- dependent active DNA 5mC demethylation activities in addition to the cytosine methylation activity.
Methods: In this study, we have carried out experiments using a range of molecular, cellular, and genome editing approaches including cell culturing, CRISPR/Cas9-editing, si- or sh-RNA-mediated knockdown, quantitative RT-PCR, western blotting, ChIP-qPCR, Na-bisulfite sequencing, EMT and lung colonization assays in conjunction with DNA methylome and DNMT3A ChIP-Seq analyses,
Results: We found that active DNA demethylation activity of DNMT3A is essential for hypoxia-induced EMT of the SW480 colon cancer cells, its global genomic DNA demethylation, and promoter DNA demethylation/transcriptional activation of EMT-associated genes including TWIST1 and SNAIL1. DNMT3A also regulates hypoxia-induced HIF-1α binding to and transcriptional activation of the TWIST1 promoter as well as genome-wide DNA demethylation and EMT of breast cancer and liver cancer cells. Mechanistic analysis supports a regulatory model where hypoxia-induced H3K36me3 mark recruits DNMT3A to demethylate CpG in the hypoxia-responsive element (HRE), thereby facilitating HIF-1α binding and activation of the promoters of EMT genes.
Conclusions: Altogether, this study has provided the first demonstration of a physiological function of the active DNA demethylation activity of the DNMTs. Equally important, our findings have revealed a missing link between the HIF-1α pathway and the O2-sensing KDM pathway both of which are known to be essential for a wide set of normal and disease-associated cellular processes. Finally, the active DNA demethylation activity of DNMT3A has now emerged as a new potential target for therapeutic development to prevent EMT and metastasis of cancer cells.
Keywords Hypoxia, EMT of cancer cells, Epigenetic regulation, DNA demethylation, DNMT3A, Histone modifcations
Address and Contact Information 1 The PhD Program in Medical Neuroscience, Taipei Medical University, 12F, Education & Research Building, Shuang‑Ho Campus, No. 301, Yuantong Road, Zhonghe District, New Taipei City 235, Taiwan
2 Institute of Molecular Biology, Academia Sinica, No. 128, Section 2, Academia Rd, Nangang District, Taipei City 115, Taiwan
3 National Applied Research Laboratories, National Laboratory Animal Center, Building G, No. 111, Lane 130, Section 1, Academia Road, Nangang District, Taipei City 115021, Taiwan
4 Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
*Corresponding author: ckshen@gate.sinica.edu.tw
† Biswanath Chatterjee and Pritha Majumder have contributed equally.
Read full article at BMC

No.  96DOI: 10.1186/s11658-025-00768-w Volume 30 (2025) - 30:96
Title M2 MACROPHAGE-DERIVED EXTRACELLULAR VESICLES PROTECT AGAINST ABDOMINAL AORTIC ANEURYSM BY MODULATING MACROPHAGE POLARIZATION THROUGH miR221-5p
Authors Yang Ma1,2†, Xiang‑jiu Ding3,4†, Si‑yu Lu1,2†, Xiao‑fang Huang1, Yuan‑yuan Hu1,2, Han Liu1,2, Bin Liu5, Ke‑yin Liu6, Ming‑xiang Zhang7,8, Hao Wang1,2*, Feng Xu5* and Wei‑dong Qin1,2,8*
Abstract Background: Extracellular vesicles (EVs) derived from M2 macrophages (M2-EVs) play a protective role in the pathogenesis of acute lung injury. However, their roles and mechanisms in abdominal aortic aneurysm (AAA) are unknown.
Methods: The effects of M2-EVs in AAA were examined in ApoE−/− mice with angiotensin II infusion. After M2 macrophages were stimulated with antisense oligonucleotides of miR221-5p (miR221-5p-ASOs), EVs were extracted and administered to mice via the tail vein. In vitro, the primary bone marrow-derived monocytes (BMDMs) were isolated and co-cultured with human aortic endothelial cells (HAECs) in Transwell chambers.
Results: M2-EVs significantly reduced AAA incidence and maximal aortic diameters, improved fiber continuity, increased α-SMA, and reduced macrophage infiltration in AAA mice. RNA sequencing revealed that miR221-5p was upregulated in M2-EVs and downregulated in AAA. miR221-5p-ASOs reduced the protection of M2-EVs in AAA mice. M2-EVs induced M2 macrophage polarization, while miR221-5p-ASOs had no effect. Moreover, M2-EVs alleviated oxidative stress and inflammatory responses in HAECs. Mechanistically, miR221-5p bound to poly(ADP-ribose) polymerase 1 (PARP-1) mRNA and reduced PARP-1 expression; PARP-1 was bound to protein phosphatase 1ɑ (PP-1ɑ) and negatively regulated its expression. In vitro experiments showed miR221-5p modulated macrophage polarization through the PARP-1/PP-1ɑ/JNK/c-Jun pathway. Macrophage deletion of PARP-1 inhibited AAA formation and phosphorylation of JNK/c-Jun in mice.
Conclusions: miR221-5p in M2-EVs plays a critical role in AAA pathophysiology by modulating macrophage polarization through PARP-1/PP-1ɑ/JNK/c-Jun signaling. M2-EVs and miR221-5p represent promising therapeutic options for AAA.
Keywords Abdominal aortic aneurysm, M2 macrophages, Extracellular vesicles, microRNA 221-5p, Macrophage polarization
Address and Contact Information 1 Department of Critical Care Medicine, Qilu Hospital of Shandong University, No. 107, Wen Hua Xi Road, Jinan 250012, Shandong, China.
2 Innovation Research Center for Sepsis and Multiple Organ Injury, Shandong University, Jinan, China.
3 Department of Vascular Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China.
4 Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
5 Department of Emergency Medicine, Qilu Hospital of Shandong University, No. 107, Wen Hua Xi Road, Jinan 250012, Shandong, China.
6 State Key Laboratory of Biobased Material and Green Paper Making, Key Laboratory of Pulp & Paper Science and Technology of Shandong Province/Ministry of Education, Qilu University of Technology, Shandong Academy of Sciences, Jinan, China.
7 Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
8 National Key Laboratory for Innovation and Transformation of Luobing Theory; the Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, No. 107, Wen Hua Xi Road, Jinan 250012, Shandong, China.
*Corresponding author: wanghao34@126.com; xufengsdu@email.sdu.edu.cn; icuqwd@163.com
† Yang Ma, Xiang-jiu Ding, and Si-yu Lu contributed equally to the work.
Read full article at BMC

No.  97DOI: 10.1186/s11658-025-00774-y Volume 30 (2025) - 30:97
Title MODELING THE EFFECTS OF RADIATION ON THE BONE TUMOR MICROENVIRONMENT: OPPORTUNITIES FOR EXPLORING COMBINATION THERAPIES IN MICROPHYSIOLOGIC SYSTEMS
Authors Kailey N. Jackett1, Devin L. DaPonte2, Pranav Soman3 and Jason A. Horton4*
Abstract Primary bone tumors and bone metastases represent significant challenges in oncology. Radiotherapy is an important adjuvant treatment for several primary bone and musculoskeletal tumors, as well as for palliative care for metastatic bone lesions. While effective in these applications, patients receiving skeletal radiation face a lifelong risk of fragility fracture at the irradiated sites, among other complications. Damage to bone could be reduced by development of tumor-selective radiosensitizers that would enhance the efficacy of radiotherapy, resulting in reducing the radiation dose delivered to the normal tissues. The creation of bone-selective radioprotection and radio-mitigant strategies that could respectively reduce the magnitude of off-target damage and stimulate functional recovery of the healthy bone microenvironment are warranted. Key barriers to progress in this field include the paucity and inconsistency of data on the skeletal effects of radiotherapy, low throughput and high cost of animal models, reproducibility challenges with in vitro experiments, and poor translational relevance of these models, which may not accurately replicate the human bone-tumor microenvironment. Microphysiological systems (MPS) will accelerate progress in this field by enabling rapid and cost-effective investigation while recapitulating the complexity of the bone-tumor microenvironment to more accurately model the collective response to therapy. Here, we summarize the current knowledge on the transient and long-lasting impacts of radiotherapy and explore opportunities for MPS to streamline and expand our knowledge base. We critically evaluate contemporary model systems, including MPS, and offer suggestions for how these systems can be used to efficiently model the intersection of skeletal radiobiology and bone cancer, and accelerate development of combination therapies.
Keywords Bone-tumor microenvironment, Radiation, Combination therapy, Microphysiological systems
Address and Contact Information 1 Norton College of Medicine and College of Graduate Studies, SUNY Upstate Medical University, Syracuse, NY, USA
2 Department of Cancer Biology, University of Central Florida, Orlando, FL, USA
3 Department of Chemical and Biomedical Engineering, L.C. Smith College of Engineering Syracuse University, Syracuse, NY, USA
4 Departments of Neuroscience & Physiology, Cell & Developmental Biology and Radiation Oncology, SUNY Upstate Medical University, 4706 Institute for Human Performance, Syracuse, NY 13210, USA
*Corresponding author: hortonj@upstate.edu
Read full article at BMC

No.  98DOI: 10.1186/s11658-025-00776-w Volume 30 (2025) - 30:98
Title PALMITOYLATION: AN EMERGING THERAPEUTIC TARGET BRIDGING PHYSIOLOGY AND DISEASE
Authors Weini Li7†, Jie Shen2†, Aojia Zhuang7, Ruiheng Wang3, Quanqi Li4, Anas Rabata5, Yanan Zhang6 and DuoYao Cao1,7*
Abstract Palmitoylation is a reversible post-translational lipid modification of proteins, catalyzed by the Zinc finger DHHC domain-containing (ZDHHC) family of palmitoyltransferases. Palmitoylation plays a pivotal role in regulating localization, stability, trafficking, and interactions, thereby contributing to a wide range of cellular processes. Dysregulation of palmitoylation has been implicated in numerous pathological conditions, including metabolic disorders, muscular diseases, mitochondrial disorders, cancer, and neurodegeneration. In this review, we summarize recent advances in understanding S-palmitoylation, emphasizing its critical roles in protein regulation, cellular and physiological processes, and its implications in both health and disease. Additionally, we highlight emerging therapeutic opportunities and novel strategies in therapeutic applications targeting this lipid modification.
Keywords Palmitoylation, Depalmitoylation, Disease pathogenesis, Targeted therapy
Address and Contact Information 1 International Center for Aging and Cancer, Department of Hematology of The First Afliated Hospital, Hainan Medical University, Haikou 571199, China
2 Department of GI Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
3 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA
4 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, Guangdong, China
5 Pulmonary Division in the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90067, USA
6 Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing 100850, China
7 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90067, USA
*Corresponding author: DuoYao.Cao@cshs.org
† Weini Li and Jie Shen Equal contribution of this work.
Read full article at BMC

No.  99DOI: 10.1186/s11658-025-00784-w Volume 30 (2025) - 30:99
Title CELL DEATH SIGNALING AND IMMUNE REGULATION: NEW PERSPECTIVES ON TARGETED THERAPY FOR SEPSIS
Authors Huang Wu1,2†, Jiale Cui1,2†, Jie Huang1†, Yuqi Feng1,2†, Jiaxin Zhao1,3, Yalin Zhu1,4, Xiaoming Deng1, Xinyu Li5*, Wangzheqi Zhang1,3* and Changli Wang1*
Abstract Cell death is essential for the preservation of tissue homeostasis, regulating inflammatory responses, and shaping immune status. The mechanism of cell death includes apoptosis, pyroptosis, necroptosis, ferroptosis and autophagy. The onset, progression, and unfavorable prognosis of sepsis are closely associated with these pathways. Here, the mechanisms associated with these five major cell death pathways in sepsis are reviewed, emphasizing two core aspects of the condition: excessive inflammation and immune suppression. These pathways play a fundamental role in modulating these characteristics and offer novel therapeutic prospects. The study provides valuable insights and detailed analyses, making a significant contribution to ongoing research in this domain. The interconnected nature of cell death is highlighted, not only by examining the distinct roles of individual pathways but also by exploring the interactions between different pathways and the crosstalk among key signaling molecules or pathways, including the caspase family, gasdermin family, and NF-κB pathway. Further research should continue to investigate well-established cell death mechanisms while also identifying previously unknown pathways. Therapeutic strategies targeting cell death pathways hold broad application potential. However, during the transition from preclinical research to clinical application, several challenges remain, including limitations of experimental models, as well as the safety and efficacy of treatments. Additionally, the development of personalized treatment approaches tailored to the unique immune profiles of patients is crucial for advancing precision medicine. In conclusion, the present review offers an extensive analysis of the diverse roles of cell death in sepsis, with novel insights into disease mechanisms and guiding therapeutic developments.
Keywords Cell death, Sepsis, Infammation, Immunosuppresion, Immune regulation, Signaling
Address and Contact Information 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
2 Basic Medical University, Naval Medical University, Shanghai 200433, China
3 School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai 200433, China
4 Department of Anesthesiology, Naval Hospital of Eastern Theater, Zhoushan 316004, China
5 Department of Burn Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China
*Corresponding author: 419894777@qq.com; 1198717503@qq.com; wangchangli1122@foxmail.com
† Huang Wu, Jiale Cui, Jie Huang and Yuqi Feng have contributed equally to this research.
Read full article at BMC