Cellular and Molecular Life Sciences最新文献

{"title":"Irf7 aggravates prostatitis by promoting Hif-1α-mediated glycolysis to facilitate M1 polarization.","authors":"Tong Meng, Yi Zhang, Huihui Wang, Weikang Wu, Wei Peng, Jiabin Yue, Cong Huang, Wanqing Liu, Chaozhao Liang, Cheng Yang, Jing Chen","doi":"10.1007/s00018-025-05608-w","DOIUrl":"10.1007/s00018-025-05608-w","url":null,"abstract":"<p><strong>Background: </strong>Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder associated with voiding symptoms and pain in the pelvic or perineal area. Macrophages, particularly the pro-inflammatory M1 subtype, are crucial initiating of CP/CPPS. Interferon regulatory factor 7 (Irf7) has been implicated in promoting M1 polarization, contributing to the onset and progression of autoimmunity. However, the role of Irf7 in the etiology and progression of CP/CPPS remains unclear.</p><p><strong>Method: </strong>We established the experimental autoimmune prostatitis (EAP) mouse model by subcutaneous injection of prostate antigen combined with complete Freund's adjuvant. Six weeks after the first immunization, we analyzed the prostates, spleen, and blood to assess the degree of prostate inflammation, Irf7 expression levels, glycolysis, and M1 polarization to evaluate whether Irf7 could exacerbate the development of EAP by enhancing Hif-1α transcription, thereby increasing glycolysis and M1 polarization. Further investigations included sh-Irf7 intervention, Dimethyloxalylglycine (a Hif-1α agonist), and in vitro M1 polarization experiments. We also employed ChIP assays, dual-luciferase reporter assays, and q-PCR to explore if Irf7 could directly interact with the Hif-1α promoter in macrophages.</p><p><strong>Results: </strong>In the EAP mouse and cell models, elevated Irf7 expression was observed in inflamed tissues and cells. Reducing Irf7 expression decreased M1 cell glycolysis by inhibiting the nuclear translocation of Hif-1α, thus mitigating M1 cell polarization. Additionally, Irf7 was identified as a transcription factor that regulates Hif-1α transcription by interacting with its promoter in macrophages, confirmed through ChIP and dual-luciferase assays. Co-culturing macrophage cells with 3T3 fibroblasts with reduced Irf7 levels resulted in decreased fibrosis, and a significant reduction in prostate tissue fibrosis was noted in mice with Irf7 knockdown.</p><p><strong>Conclusion: </strong>Our findings indicate that Irf7 can contribute to the development and progression of CP/CPPS by promoting glycolysis, which can enhance both M1 polarization as well as interstitial fibrosis in the prostate. This process was found to be mediated by the upregulation of Hif-1α transcription, presenting new potential therapeutic targets for managing CP/CPPS.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"90"},"PeriodicalIF":6.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A double-edged sword in antiviral defence: ATG7 binding dicer to promote virus replication.","authors":"Yaotang Wu, Yang Wu, Chenlu Wang, Ningna Xiong, Wenxin Ji, Mei Fu, Junpeng Zhu, Zhixin Li, Jian Lin, Qian Yang","doi":"10.1007/s00018-025-05603-1","DOIUrl":"10.1007/s00018-025-05603-1","url":null,"abstract":"<p><p>RNA interference (RNAi) and autophagy are two pivotal biological processes that regulate virus replication. This study explored the complex relationship between autophagy and RNAi in controlling influenza virus replication. Initially, we reported that influenza virus (H9N2) infection increases the viral load and the expression of autophagy markers while inhibiting the RNAi pathway. Subsequent studies employing autophagy enhancer and inhibitor treatments confirmed that avian influenza virus (AIV, H9N2) promotes viral replication by enhancing autophagy pathways. Further analysis revealed that ATG7, an autophagy protein, can interact with dicer to affect its antiviral functions. Finally, we discovered that infection with other avian RNA viruses, including infectious bursal disease virus (IBDV) and infectious bronchitis virus (IBV), induced the upregulation of ATG7, which blocked the RNAi pathway to facilitate virus replication. Our findings suggested that virus infection might trigger the upregulation of autophagy and downregulation of the RNAi pathway, revealing a complex interaction between these two biological processes in the defence against viral replication.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"89"},"PeriodicalIF":6.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Class I PI3Ks activate stretch-induced autophagy in trabecular meshwork cells.","authors":"Myoung Sup Shim, Ethan J Sim, Kevin Betsch, Vaibhav Desikan, Chien-Chia Su, Diego Pastor-Valverde, Yang Sun, Paloma B Liton","doi":"10.1007/s00018-025-05615-x","DOIUrl":"10.1007/s00018-025-05615-x","url":null,"abstract":"<p><p>Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, a leading cause of irreversible blindness worldwide. IOP homeostasis is maintained through a balance between aqueous humor production and its drainage through the trabecular meshwork (TM)/Schlemm's Canal (SC) outflow pathway. Prior studies by our laboratory reported a key role of mechanical forces and primary cilia (PC)-dependent stretch-induced autophagy in IOP homeostasis. However, the precise mechanism regulating this process remains elusive. In this study, we investigated the upstream signaling pathway orchestrating autophagy activation during cyclic mechanical stretch (CMS) in primary cultured human TM cells, using biochemical and cell biological analyses. Our results indicate that TM cells express catalytic subunits of class IA PI3Ks (PIK3CA, B, and D), and that inhibition of class IA isoforms, but not class II and III, significantly prevent CMS-induced autophagy. Importantly, PIK3CA was found to localize in the PC. Furthermore, we identified a coordinated action of Class IA PI3Ks along INPP4A/B, a 4' inositol phosphatase, responsible for the formation of PI(3,4)P₂ and PI(3)P and stretch-induced autophagy in TM cells. These findings contribute to a deeper understanding of the molecular mechanisms underlying IOP homeostasis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"82"},"PeriodicalIF":6.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"37 kDa LRP::FLAG enhances telomerase activity and reduces ageing markers in vivo.","authors":"Tyrone C Otgaar, Martin Bernert, Gavin Morris, Pavan Baichan, Monique J Bignoux, Boitelo Letsolo, Stefan F T Weiss, Eloise Ferreira","doi":"10.1007/s00018-025-05593-0","DOIUrl":"10.1007/s00018-025-05593-0","url":null,"abstract":"<p><p>Ageing is a degenerative process characterised by a decline in physiological functioning of the organism. One of the core regulators of cellular ageing are telomeres, repetitive DNA sequences of TTAGGG that cap the ends of chromosomes and are maintained by the ribonucleoprotein complex, telomerase. Age-dependent progressive loss of the telomere ends eventually induces cell cycle arrest for the induction of either replicative senescence or apoptosis. It was previously established that overexpression of the 37 kDa/ 67 kDa laminin receptor (LRP/LR) increased telomerase activity and telomere length while concomitantly reducing senescence markers in aged normal cells in vitro. Therefore, it was hypothesized that elevating LRP/LR in vivo may increase telomerase activity and hinder the ageing process on an organism scale. To this end, aged C57BL/6J mice were treated/transfected to induce an overexpression of LRP::FLAG. Various physiological tests and histological analyses were performed to assess overall organism fitness as well as to discern the treatments' ability at reducing tissue degeneration and atrophy. It was found that mice overexpressing LRP::FLAG displayed improved physiological characteristics and markedly less tissue degeneration and atrophy when compared to control and non-treated mice. Alongside these improvements, certain organs displayed increased telomerase activity with a corresponding elongation in average telomere length. In addition the overexpression of LRP::FLAG significantly improved various proliferative and anti-ageing associated proteins while causing a concomitant decrease in senescence associated proteins. These findings are therefore indicative of a novel function of LRP/LR delaying the onset of senescence, while also promoting healthier ageing through elevating TERT and telomerase activity.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"83"},"PeriodicalIF":6.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NR4A1 deficiency promotes carotid plaque vulnerability by activating integrated stress response via targeting Bcat1.","authors":"Long Chen, Yiping Shi, Danrui Xiao, Yijie Huang, Yangjing Jiang, Min Liang, Feng Liang, Jieyuan Xue, Haiping Chen, Zhitong Liu, Xia Wang, Fei Zhuang, Guo Zhou, Huanhuan Huo, Zhaohua Cai, Qin Shao, Ben He","doi":"10.1007/s00018-025-05602-2","DOIUrl":"10.1007/s00018-025-05602-2","url":null,"abstract":"<p><p>Rupture of vulnerable carotid atherosclerotic plaque is one of the leading causes of ischemic stroke. However, the mechanisms driving the transition from stable to vulnerable plaques have not yet been elucidated. NR4A1 is an orphan nuclear receptor that functions in various inflammatory diseases. To explore the role of NR4A1 in vulnerable plaque formation, we generated a vulnerable plaque mouse model by combining partial ligation of the left common carotid artery and left renal artery in ApoE^-/- and ApoE^-/-;NR4A1^-/- mice. Our research revealed that NR4A1 deficiency significantly worsened the pathology of vulnerable plaque, increasing intraplaque hemorrhage, rupture with thrombus, and the occurrence of multilayer with discontinuity. Moreover, NR4A1 deficiency exacerbated macrophage infiltration, inflammation, and oxidative stress. Mechanistically, we identified Bcat1 as the target of NR4A1. NR4A1 modulated the integrated stress response (ISR) in macrophages by transcriptionally inhibiting Bcat1, thus influencing the progression of vulnerable plaque. ISR inhibitor GSK2606414 or Bcat1 inhibitor ERG240 significantly ameliorated atherosclerotic plaque formation and increased plaque stability. Notably, supplementation with Celastrol, an herbal extract, stabilized atherosclerotic plaques in mice. These findings suggest that NR4A1 deficiency exacerbates vulnerable plaque by activating ISR via targeting Bcat1. The NR4A1/Bcat1/ISR axis is therefore an important therapeutic target for stabilizing atherosclerotic plaque.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"91"},"PeriodicalIF":6.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The inhibition of ZC3H13 attenuates G2/M arrest and apoptosis by alleviating NABP1 m6A modification in cisplatin-induced acute kidney injury.","authors":"Qinghao Sheng, Qun Yu, Shangwei Lu, Meilin Yang, Xiaoting Fan, Hong Su, Zhijuan Kong, Ying Gao, Rong Wang, Zhimei Lv","doi":"10.1007/s00018-025-05596-x","DOIUrl":"10.1007/s00018-025-05596-x","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a clinical syndrome caused by various etiologies and causes a rapid decline in renal function in a short period of time. The most common internal modification of mRNAs is the N6-methyladenosine (m6A) modification, which is important for controlling gene expressions. However, the role of m6A modification in AKI is largely unknown. Here, we characterized the role of zinc finger CCCH-type containing 13 (ZC3H13), which is a type of m6A methyltransferases, in cisplatin-induced AKI mouse model and a cisplatin-treated human proximal tubular epithelial cell line (HK2 cells). The ZC3H13 knockdown attenuated the G2/M cell cycle arrest and apoptosis in HK2 cells. In the ZC3H13-overexpressed HK2 cells, the opposite was true. In the presence of cisplatin, mice with the AAV9-mediated silencing of ZC3H13 exhibited milder cell cycle arrest, apoptosis, and renal injury. In addition, we identified nucleic acid binding protein 1 (NABP1) as a target of ZC3H13, which was verified by knocking down and overexpressing ZC3H13 in HK2 cells. Moreover, we confirmed that the ZC3H13-mediated m6A modification stabilized NABP1 mRNA and was discriminated by insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1). In conclusion, ZC3H13 promoted the m6A modification of NABP1 and enhanced its mRNA stability through an IGF2BP1-dependent mechanism. The inhibition of ZC3H13 alleviated the G2/M cell cycle arrest, apoptosis and kidney injury by affecting the expression of NABP1. These results show that the ZC3H13/NABP1 axis is a promising AKI treatment target.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"86"},"PeriodicalIF":6.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXO regulation of TXNIP induces ferroptosis in satellite cells by inhibiting glutathione metabolism, promoting Sarcopenia.","authors":"Yasenjiang Maimaiti, Mukedasi Abulitifu, Zulifeiya Ajimu, Ting Su, Zhanying Zhang, Zhichao Yu, Hong Xu","doi":"10.1007/s00018-025-05592-1","DOIUrl":"10.1007/s00018-025-05592-1","url":null,"abstract":"<p><p>Aging-related sarcopenia represents a significant health concern due to its impact on the quality of life in the elderly. This study elucidates the molecular mechanisms underlying sarcopenia by employing single-cell sequencing and public transcriptome databases to compare young and aged mouse skeletal muscles. Cellular classification and pseudotime analyses differentiated cell types and their interrelationships, revealing a marked reduction in satellite cell numbers and a consistent upregulation of TXNIP (Thioredoxin interacting protein) across various muscle cell populations in aged mice. Further transcriptomic data integration and batch correction from the GEO (Gene Expression Omnibus) database highlighted key differentially expressed genes. The role of TXNIP and its transcriptional regulation by FOXO1 (Forkhead box O1) was confirmed through in vitro experiments, which demonstrated FOXO1's influence on TXNIP expression and its subsequent suppression of glutathione metabolism, leading to satellite cell ferroptosis. Additionally, in vivo studies showed that overexpression of TXNIP in young mice's muscle tissues significantly reduced muscle mass, suggesting its potential role in the initiation of sarcopenia. Our findings suggest that FOXO1-mediated regulation of TXNIP and the disruption of glutathione metabolism are central to the process of sarcopenia, offering new insights into its pathogenesis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"81"},"PeriodicalIF":6.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid condensates: a new barrier to loop extrusion?","authors":"Arseniy V Selivanovskiy, Maria N Molodova, Ekaterina E Khrameeva, Sergey V Ulianov, Sergey V Razin","doi":"10.1007/s00018-024-05559-8","DOIUrl":"10.1007/s00018-024-05559-8","url":null,"abstract":"<p><p>Liquid-liquid phase separation (LLPS), driven by dynamic, low-affinity multivalent interactions of proteins and RNA, results in the formation of macromolecular condensates on chromatin. These structures are likely to provide high local concentrations of effector factors responsible for various processes including transcriptional regulation and DNA repair. In particular, enhancers, super-enhancers, and promoters serve as platforms for condensate assembly. In the current paradigm, enhancer-promoter (EP) interaction could be interpreted as a result of enhancer- and promoter-based condensate contact/fusion. There is increasing evidence that the spatial juxtaposition of enhancers and promoters could be provided by loop extrusion (LE) by SMC complexes. Here, we propose that condensates may act as barriers to LE, thereby contributing to various nuclear processes including spatial contacts between regulatory genomic elements.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"80"},"PeriodicalIF":6.2,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"circ0066187 promotes pulmonary fibrogenesis through targeting STAT3-mediated metabolism signal pathway.","authors":"Bo Liu, Weili Liu, Hongbo Li, Nailiang Zhai, Changjun Lv, Xiaodong Song, Shuanying Yang","doi":"10.1007/s00018-025-05613-z","DOIUrl":"10.1007/s00018-025-05613-z","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial pneumonia, with increasing incidence and prevalence. One of the cellular characteristics is the differentiation of fibroblasts to myofibroblasts. However, the metabolic-related signaling pathway regulated by circular RNAs (circRNAs) during this process remains unclear. Here, we demonstrated that circ0066187 promoted fibroblast-to-myofibroblast differentiation by metabolic-related signaling pathway. Mechanism analysis research identified that circ0066187 directly targeted signal transducer and activator of transcription 3 (STAT3)-mediated metabolism signal pathway to enhance fibroblast-to-myofibroblast differentiation by sponging miR-29b-2-5p, resulting in pulmonary fibrosis. Integrative multi-omics analysis of metabolomics and proteomics revealed three pathways co-enriched in proteomics and metabolomics, namely, Protein digestion and absorption, PI3K-Akt signaling pathway, and FoxO signaling pathway. In these three signaling pathways, seven differentially expressed metabolites such as L-glutamine, L-proline, adenosine monophosphate (AMP), L-arginine, L-phenylalanine, L-lysine and L-tryptophan, and six differentially expressed proteins containing dipeptidyl peptidase-4 (DPP4), cyclin D1 (CCND1), cyclin-dependent kinase 2 (CDK2), fibroblast growth factor 2 (FGF2), collagen type VI alpha 1 (COL6A1) and superoxide dismutase 2 (SOD2) were co-enriched. Gain-and loss-of-function studies and rescue experiments were performed to verify that circ0066187 promoted STAT3 expression by inhibiting miR-29b-2-5p expression to control the above metabolites and proteins. As a result, these metabolites and proteins provided the material basis and energy requirements for the progression of pulmonary fibrosis. In conclusion, circ0066187 can function as a profibrotic metabolism-related factor, and interference with circ0066187 can prevent pulmonary fibrosis. The finding supported that circ0066187 can be a metabolism-related therapeutic target for IPF treatment.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"79"},"PeriodicalIF":6.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA binding protein Pumilio2 promotes chemoresistance of pancreatic cancer via focal adhesion pathway and interacting with transcription factor EGR1.","authors":"Zhao Bangbo, Qin Cheng, Li Zeru, Li Tianyu, Zhao Yutong, Wang Weibin, Zhao Yupei","doi":"10.1007/s00018-025-05599-8","DOIUrl":"10.1007/s00018-025-05599-8","url":null,"abstract":"<p><p>Pancreatic cancer (PCa) has insidious onset, high malignancy and poor prognosis. Gemcitabine (GEM) is one of the first-line chemotherapy drugs for PCa. However, GEM resistance has always been a bottleneck problem leading to recurrence and death of PCa patients. RNA-binding proteins (RBPs) are important proteins that regulate transportation, splicing, stability and translation of RNA. Abnormal expression of RBPs often lead to a series of abnormal accumulation or degradation of downstream RNA resulting in various diseases. In our study, we utilized RIP seq, RIP-qPCR, in vitro and in vivo experiments and found that pumilio2 (PUM2) was high expression in PCa, and promoted GEM resistance of PCa by regulating mRNA stability of integrin Alpha 3 (ITGA3) and other genes in focal adhesion pathway, and there was positive feedback regulation between PUM2 and transcription factor early growth response gene 1 (EGR1), that is PUM2 binding to 3'UTR region of EGR1 mRNA, and EGR1 binding to promoter region of PUM2 gene. The discovery of EGR1/PUM2/ITGA3 axis provided a solid experimental basis for the selection of chemotherapy regiments for PCa patients and exploration of combined regimens to reverse GEM resistance in the future.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"78"},"PeriodicalIF":6.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}