Cellular signalling最新文献

{"title":"STAT5/VCAN/PI3K signaling pathway promotes fibroblast activation and lung fibrosis","authors":"Jianjun Wang ,&nbsp;Guozheng Lv ,&nbsp;Wenjie Hou ,&nbsp;Guihong Chen ,&nbsp;Xianfu Cai ,&nbsp;Yuan cao ,&nbsp;Yaodong Wang ,&nbsp;Huiwen Luo ,&nbsp;Decai Wang","doi":"10.1016/j.cellsig.2025.111970","DOIUrl":"10.1016/j.cellsig.2025.111970","url":null,"abstract":"<div><h3>Rationale</h3><div>Pulmonary fibrosis (PF) is a progressive and debilitating disease characterized by the excessive deposition of extracellular matrix (ECM) components. The activation of fibroblasts and the production of large amounts of ECM are important factors in the development of PF. This study aimed to elucidate the role and mechanism of versican (VCAN) in promoting PF and to identify therapeutic targets for PF.</div></div><div><h3>Methods</h3><div>A mouse lung fibrosis model was constructed by tracheal instillation of bleomycin or ray-induced fibrosis in mice, and the expression level of VCAN was evaluated. The cellular localization of VCAN was determined using tissue immunofluorescence and the extraction of primary mouse cells. Using mice with specific VCAN knockout in fibroblasts, we analyzed the effects of VCAN on the degree of lung fibrosis and fibroblast activation via immunohistochemistry and immunofluorescence. Primary mouse fibroblasts were extracted, and human/mouse-derived fibroblast cell lines were used to assess the effect of the VCAN/PI3K pathway on fibroblast activation and its specific mechanism through immunofluorescence, Transwell, scratch, and western blotting assays. STAT5/VCAN signaling was investigated using protein blotting, chromatin immunoprecipitation, luciferase reporter gene analysis, and real-time quantitative polymerase chain reaction. Further, the pathogenesis of PF was evaluated in vivo in mice treated with a VCAN-specific knockdown virus or PI3K inhibitors.</div></div><div><h3>Results</h3><div>VCAN expression was significantly elevated in the fibroblasts of mice with PF. After the specific knockout of VCAN in fibroblasts, the activation level of lung fibroblasts and the level of lung fibrosis were significantly decreased in PF mice. Mechanistically, STAT5 acted as a transcription factor that promoted VCAN expression upon bleomycin induction. High VCAN expression promoted fibroblast activation through the PI3K pathway, and suppressing VCAN using an specific knockdown adeno-associated virus or the PI3K inhibitors significantly alleviated lung fibrosis in PF mice.</div></div><div><h3>Conclusion</h3><div>STAT5 is a transcription factor that enhances VCAN expression; VCAN promotes fibroblast activation through the PI3K signaling pathway in response to the transcription factor STAT5, thereby promoting lung fibrosis. The STAT5/VCAN/PI3K signaling pathway may serve as a potential target for lung fibrosis treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111970"},"PeriodicalIF":4.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative splicing as a novel pathogenic mechanism in chronic kidney disease.","authors":"Jiaying Qiu, Rong Wang, Li Li, Pei Wu, Haibo Zhang, Shengnan Gong, XiaoYan Ren, Yumei Tao, Xingxing Fang","doi":"10.1016/j.cellsig.2025.111972","DOIUrl":"https://doi.org/10.1016/j.cellsig.2025.111972","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a progressive condition with incompletely understood pathogenesis, affecting over 10 % of the global population. The poor understanding of these mechanisms impedes therapeutic development, leaving current treatments largely ineffective at halting or reversing disease progression. The balance between damage and repair in renal tubular epithelial cells, the primary renal parenchymal cells, is pivotal to CKD progression, and excessive damage to these cells significantly contributing to tubular atrophy and renal fibrosis. Recent studies leveraging single-cell sequencing reveal disease-associated dynamics and molecular drivers in renal tubular epithelial cells, with findings suggesting that alternative splicing (AS) represents a novel pathogenic mechanism in CKD. This review focuses on the regulatory mechanisms of AS and its documented and emerging roles in CKD pathogenesis. Certain CKD driver molecules can globally regulate AS, while key CKD marker genes are prone to generating functionally distinct splice isoforms. In addition, the pathogenic mechanism of many familial kidney disease patients is gene mutation leading to abnormal splicing. This review aims to elucidate the functional link between AS and CKD, highlighting AS-targeting approaches as a potential therapeutic strategy. However, future research should further investigate the dynamics of AS and its regulators in CKD, and delineate their functional contributions.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"111972"},"PeriodicalIF":4.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-throughput screening of E3 ubiquitin ligases identifies TRIM48 as a novel negative regulator of RIG-I signaling","authors":"Guandi Wu ,&nbsp;Jamie Frankish ,&nbsp;Joschka Willemsen ,&nbsp;Dominik Ricken ,&nbsp;Jonas Becker ,&nbsp;Darius Schweinoch ,&nbsp;Jürgen Beneke ,&nbsp;Sandra Wüst ,&nbsp;Nina Beil ,&nbsp;Petr Matula ,&nbsp;Karl Rohr ,&nbsp;Holger Erfle ,&nbsp;Lars Kaderali ,&nbsp;Marco Binder","doi":"10.1016/j.cellsig.2025.111973","DOIUrl":"10.1016/j.cellsig.2025.111973","url":null,"abstract":"<div><div>The retinoic acid-inducible gene-I (RIG-I) signaling is crucial for cell-intrinsic innate antiviral immunity. Upon cytosolic detection of virus-associated RNA, it triggers a cascade inducing production of potent cytokines, mainly type I and III interferons (IFNs). While effective, dysregulated responses can harm the host, requiring tight pathway control. Here, we performed a comprehensive, systematic siRNA-based high-throughput screen across 616 established and putative E3 ubiquitin ligases for their impact on RIG-I signaling. We employed a fluorescence-based live-cell imaging assay in A549 cells to monitor nuclear translocation of IRF3 and NF-κB, two key transcription factors downstream of RIG-I. Candidate genes were validated in an orthogonal secondary screen, assessing their impact on the functional antiviral response to a Rift Valley Fever reporter virus. Fourteen hits showed consistent effects on RIG-I signaling across both screens. These genes were further validated and characterized by assessing IFN-β promoter reporter activity and <em>IFNB1</em> mRNA levels upon dsRNA transfection. TRIM48 emerged as a highly robust negative regulator. Overexpression of TRIM48 suppressed RIG-I-mediated activation of IRF3 and NF-κB, reduced IFN and IFN-stimulated gene expression, and enhanced viral replication. Conversely, TRIM48 deficiency enhanced RIG-I signaling and inhibited viral replication. Notably, TRIM48 acts as an induced feedback regulator upon infection, and its effect depended on its enzymatic ubiquitin ligase activity. Our high-throughput screen provides an unbiased assessment of close to all E3 ubiquitin ligases for their regulatory effect in RIG-I signaling, and identified several interesting candidates for further investigation. TRIM48 was established as a negative feedback regulator of the RIG-I pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111973"},"PeriodicalIF":4.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling roles of NGLY1 in cellular homeostasis and related diseases","authors":"Chenxi Zhan ,&nbsp;Xuye Zhao ,&nbsp;Yaoxin Wei ,&nbsp;Renqiang Yang ,&nbsp;Nianlong Yan","doi":"10.1016/j.cellsig.2025.111971","DOIUrl":"10.1016/j.cellsig.2025.111971","url":null,"abstract":"<div><div>NGLY1, a cytoplasmic enzyme, removes N-glycans from misfolded glycoproteins during endoplasmic reticulum-associated degradation (ERAD), a critical protein quality control mechanism. ERAD coordinates with the ubiquitin-proteasome system (UPS), working synergistically to maintain cellular proteostasis and mitigate protein toxicity. Emerging evidence highlights the multifaceted roles of NGLY1 in proteostasis activity, autophagy, endoplasmic reticulum stress, and related areas, all of which are connected to numerous diseases, including neurodegenerative disorders and cancer, among others. To fully understand the function of NGLY1 in cellular homeostasis, this review comprehensively discusses recent research progress and the related molecular mechanisms of NGLY1 in cellular homeostasis and associated diseases, as well as the therapeutic approaches.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111971"},"PeriodicalIF":4.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-elicited exosomal HIF-1α promotes drug resistance of melanoma through modulating SLC7A11 ubiquitination","authors":"Jiaoquan Chen,&nbsp;Hui Zou,&nbsp;Bihua Liang,&nbsp;Yeqing Gong,&nbsp;Shaoyin Ma,&nbsp;Runxiang Li,&nbsp;Jiacong Zeng,&nbsp;Chao Bi,&nbsp;Huilan Zhu","doi":"10.1016/j.cellsig.2025.111939","DOIUrl":"10.1016/j.cellsig.2025.111939","url":null,"abstract":"<div><div>Drug resistance poses a significant challenge in the clinical management of melanoma, primarily driven by the hypoxic tumor microenvironment. This study aims to elucidate the molecular mechanisms underlying drug resistance in melanoma under hypoxic conditions. Exosomes were isolated from melanoma cells cultured under normoxic (Nor-exos) and hypoxic (Hypo-exos) environments. The proliferative capacity of tumor cells was assessed using CCK-8 and colony formation assays, while relevant molecular expressions were evaluated through qPCR, Western blotting, immunofluorescence, and immunohistochemistry. Additionally, mitochondrial damage was examined via transmission electron microscopy, and reactive oxygen species (ROS) levels were quantified using flow cytometry. Xenograft models further facilitated the investigation into the molecular mechanisms of drug resistance. Hypo-exos promote drug resistance in melanoma cells by inhibiting ferroptosis; mechanistically, Hypo-exos inhibiting p53 and OTUB1 expression through HIF-1α transfer. Furthermore, OTUB1 enhances SLC7A11 stability, thereby reducing ferroptosis levels and fostering drug resistance in melanoma. Our findings indicate that Hypo-exos inhibit ferroptosis to augment drug resistance in melanoma by delivering HIF-1α to modulate the p53/OTUB1/SLC7A11 axis. Exosomal HIF-1α may represent a promising biomarker and therapeutic target for addressing drug resistance in melanoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111939"},"PeriodicalIF":4.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM59 deficiency aggravates HFD-induced obesity in mice associated with increased adipose tissue inflammation, lipid accumulation, and apoptosis","authors":"Yinni Chen ,&nbsp;Xiangnuo Han ,&nbsp;Tongzhan Liu ,&nbsp;Yuqi Ni ,&nbsp;Xinxin Deng ,&nbsp;Wenhan Wei ,&nbsp;Meixiu Jiang","doi":"10.1016/j.cellsig.2025.111954","DOIUrl":"10.1016/j.cellsig.2025.111954","url":null,"abstract":"<div><div>TRIM59 (tripartite motif-containing 59) is involved in many pathological processes including inflammation and tumorigenesis. However, the effect of TRIM59 on obesity remains unknown. In this study, we aimed to investigate the role of TRIM59 in obesity and clarify the involved mechanisms. Our results showed that TRIM59 expression was significantly decreased in fat from high-fat diet (HFD)-induced obese mice. The TRIM59^+/− mice with HFD showed increased body weight and white adipose tissue (WAT) weight, larger adipocyte sizes, and increased adipose tissue inflammation with the elevated expression of pro-inflammatory cytokines including TNF-α, IL-1β and IL-6 accompanied by an increased macrophage infiltration. Moreover, TRIM59 knockdown increased the serum levels of triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Mechanistically, TRIM59 knockdown is associated with heightened activation of TLR4/JNK-p38/NF-κB signaling pathways to promote inflammation, increase adipogenesis and lipogenesis related genes while decreased lipolysis and β-oxidation related genes expression to increase lipid accumulation, simultaneously increased Bax and caspase 3 while decreased Bcl-2 expression to induce apoptosis, thereby leading to obesity. Taken together, our findings define a new critical biological role of TRIM59 in the regulation of diet-induced obesity through attenuating inflammation, improving lipid metabolism and apoptosis, and we conclude that TRIM59 may provide a novel insight in therapeutic target research for treatment of obesity-associated metabolic diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111954"},"PeriodicalIF":4.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKM2: A novel helmsman of lipid metabolism","authors":"Zhijun Liu,&nbsp;Yifei Le,&nbsp;Dezhao Lu","doi":"10.1016/j.cellsig.2025.111967","DOIUrl":"10.1016/j.cellsig.2025.111967","url":null,"abstract":"<div><div>PKM2 is an isoform of pyruvate kinase, which has low catalytic activity and is abundantly present in rapidly proliferating cells. Numerous studies have demonstrated the important role of PKM2 in diseases such as cancer, non-alcoholic fatty liver disease, atherosclerosis and other abnormalities of lipid metabolism. In this paper, we review the roles played by PKM2 in different pathways of lipid metabolism, and suggest that PKM2 may be a potential therapeutic target in disorders of lipid metabolism. In addition, this review introduces common PKM2 intervention modalities, aiming to provide new possibilities for targeting PKM2 in the treatment of lipid metabolism disorders-related diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111967"},"PeriodicalIF":4.4,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of EZH2 in regulating c-Myc stability through the E3 ubiquitin ligase HUWE1 in heart failure and its mechanisms.","authors":"Licheng Yan, Deng Xie, Tingfeng Huang, Haotian Zheng, Jie Huang, Haiyu Chen, Qi Xie, Guoxing Weng, Fuzhen Zheng","doi":"10.1016/j.cellsig.2025.111968","DOIUrl":"https://doi.org/10.1016/j.cellsig.2025.111968","url":null,"abstract":"<p><strong>Objective: </strong>Heart failure (HF) is a leading cause of mortality and morbidity. Respecting the role of enhancer of zeste homolog 2 (EZH2) in HF, we examined how EZH2 regulated c-Myc stability through HUWE1 and its mechanism.</p><p><strong>Methods: </strong>Gain- and loss-of-function assays were performed to investigate the role of EZH2 in HF. Cardiac function and histopathological changes in mice were assessed. EZH2, HUWE1, and c-Myc mRNA levels were determined by RT-qPCR. Cell viability was assessed using CCK-8 assay. HUWE1, EZH2, H3K27me3, c-Myc, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC) expression were detected, followed by immunofluorescence to determine cardiomyocyte size. Inflammatory cytokines, TNF-α, IL-6, and IL-1β promoter luciferase activity, and c-Myc enrichment in their promoter regions were evaluated. H3K27me3 enrichment in the HUWE1 promoter region, HUWE1-mediated c-Myc ubiquitination, and c-Myc protein stability were assessed.</p><p><strong>Results: </strong>EZH2 was up-regulated in myocardial tissues of HF mice. Angiotensin II reduced cell viability, increased cell size, elevated EZH2 and c-Myc expression and ANP, BNP, and β-MHC protein levels, and enhanced TNF-α, IL-6, and IL-1β levels in cells. EZH2 knockdown down-regulated c-Myc, ameliorating cardiomyocyte hypertrophy (CH); this effect was verified by in vivo experiments and partially averted by c-Myc overexpression. EZH2 reduced HUWE1 expression and c-Myc ubiquitination by enhancing H3K27me3 modification, improving c-Myc protein stability. HUWE1 overexpression reduced c-Myc protein stability and partially negated the improvement effect of EZH2 knockdown on CH.</p><p><strong>Conclusion: </strong>EZH2 curbs HUWE1 transcriptional expression by promoting H3K27me3 modification to enhance c-Myc protein stability, thereby contributing to HF.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"111968"},"PeriodicalIF":4.4,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RLIG1 promotes triple-negative breast cancer proliferation by activating mTORC1 signal pathway by interacting with ERK","authors":"Qingqing Wang ,&nbsp;Fengxia Chen ,&nbsp;Bo Pei ,&nbsp;Guojun Jiang ,&nbsp;Qianqian Yang ,&nbsp;Lu Xu ,&nbsp;Yu Gao ,&nbsp;Jing Su ,&nbsp;Guojin Huang ,&nbsp;Fuxiang Zhou ,&nbsp;Zeming Li","doi":"10.1016/j.cellsig.2025.111969","DOIUrl":"10.1016/j.cellsig.2025.111969","url":null,"abstract":"<div><h3>Background</h3><div>The prognosis of triple-negative breast cancer (TNBC) is notably unfavorable, necessitating the development of novel treatments to enhance therapeutic outcomes. The underlying mechanisms contributing to the pathogenesis of TNBC remain incompletely understood. RNA 5′-phosphate and 3’-OH ligase 1 (RLIG1) was found to be the first RNA ligase in humans and may be related to cancer development, but no reports have been reported. We observe RLIG1 elevated expression levels in TNBC tissues compared to adjacent non-cancerous tissues, with high RLIG1 expression correlating with reduced overall survival in TNBC patients.</div></div><div><h3>Methods</h3><div>We investigated RLIG1 in TNBC using bioinformatics tools, cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), colony formation, flow cytometry, and western blotting. Mechanistic insights were gained via mass spectrometry, co-immunoprecipitation, and immunofluorescence.</div></div><div><h3>Results</h3><div>Here, we found that interfering with RLIG1 can effectively hinder tumor cell cycle progression and proliferation in vitro, as well as inhibit tumor growth in vivo. Mechanistically, RLIG1 was identified as an oncogene that stimulates the mTORC1 signaling pathway in TNBC cells. Furthermore, the interaction between RLIG1 and ERK was confirmed, with RLIG1 promoting cell cycle transition and proliferation through mediating ERK phosphorylation.</div></div><div><h3>Conclusions</h3><div>Our research offers novel insights into the biological role of RLIG1, indicating its potential as a therapeutic target for TNBC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111969"},"PeriodicalIF":4.4,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rab27a+CAF exosomal miR-9-5p promotes osteosarcoma progression via CREBRF/MAPK signaling pathway","authors":"Xiaoying Niu ,&nbsp;Wen Tian ,&nbsp;Zhongyi Li ,&nbsp;Guorui Zhang ,&nbsp;Peng Zhang","doi":"10.1016/j.cellsig.2025.111964","DOIUrl":"10.1016/j.cellsig.2025.111964","url":null,"abstract":"<div><div>Osteosarcoma is the most common primary malignant bone tumor in adolescents, characterized by high rates of recurrence and chemotherapy resistance. Exosomes, as key mediators of intercellular communication, have emerged as potential biomarkers and therapeutic targets in cancer. However, the mechanisms by which cancer-associated fibroblasts (CAFs) exosomal miRNAs regulate osteosarcoma progression remain unclear. This study investigates the role of exosomal miR-9-5p derived from Rab27a⁺CAF in promoting osteosarcoma malignancy <em>via</em> CREBRF/MAPK (Mitogen-Activated Protein Kinase) signaling axis. Serum and tissue derived exosomes were isolated, followed by small RNA sequencing and validation of miR-9-5p expression using qRT-PCR (quantitative RT-PCR). Single-cell RNA sequencing was performed on osteosarcoma and adjacent tissues to characterize the tumor microenvironment. The interaction between exosomal miR-9-5p and CREBRF was confirmed using dual-luciferase reporter assays. CCK8 (Cell Counting Kit 8), Edu (5-Ethynyl-2′-deoxyuridine), cell cycle, and cell apoptosis <em>in vitro</em> were conducted to explore the function of exosomal miR-9-5p/CREBRF/MAPK signaling pathway on osteosarcoma. The tumorigenicity of CAF exosomal miR-9-5p was assessed using a subcutaneous osteosarcoma mouse model. Exosomal miR-9-5p was significantly upregulated in serum and tissue from osteosarcoma patients and was associated with poor prognosis. Single-cell RNA sequencing revealed that Rab27a⁺CAF were major contributors in the tumor microenvironment. Functional assays demonstrated that exosomal miR-9-5p promoted proliferation, cisplatin resistance, cell cycle progression, and inhibited apoptosis in osteosarcoma cells. Mechanistically, miR-9-5p targeted and downregulated CREBRF, thereby activating the MAPK signaling pathway. Experiments <em>in vivo</em> confirmed that high levels of exosomal miR-9-5p enhanced tumor growth and MAPK pathway activity. This study identifies Rab27a⁺CAF exosomal miR-9-5p as a key oncogenic factor in osteosarcoma, which promotes tumor progression and chemoresistance by suppressing CREBRF and activating the MAPK pathway. These findings highlight exosomal miR-9-5p as a promising biomarker and therapeutic target for precision treatment of osteosarcoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111964"},"PeriodicalIF":4.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}