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.
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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
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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
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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
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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
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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
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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
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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.
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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
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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
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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
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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
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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
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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.
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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.
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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.
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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
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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
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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
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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
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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
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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.
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