Cellular signalling最新文献

{"title":"The binding of PCBP2 to IGF2 mRNA restores mitochondrial function in granulosa cells to ameliorate ovarian function in premature ovarian insufficiency mice","authors":"Yuanyuan Chen,&nbsp;Xiangyang Pan,&nbsp;Jun Tang,&nbsp;Zhaohua Liu,&nbsp;Man Luo,&nbsp;Yi Wen","doi":"10.1016/j.cellsig.2025.112103","DOIUrl":"10.1016/j.cellsig.2025.112103","url":null,"abstract":"<div><h3>Background</h3><div>Premature ovarian insufficiency (POI) is characterized by early ovarian dysfunction, which has a profound impact on female fertility. Insulin-like Growth Factor 2 (IGF2) is believed to maintain ovarian function, yet the mechanisms and specific roles of IGF2 in POI remain unclear. This study explores the roles of IGF2 and its binding protein PCBP2 in POI, with a particular focus on their effects on mitochondrial function in granulosa cells and ovarian function.</div></div><div><h3>Methods</h3><div>A POI mouse model was induced by cyclophosphamide (CTX), and ovarian function and IGF2 levels were evaluated using ELISA, RT-qPCR, Western blot, and histology. Human granulosa cells (KGN) were treated with CTX. IGF2 and PCBP2 were overexpressed or knocked down, and CCCP (a mitochondrial uncoupling agent) was applied to evaluate their effects on apoptosis, mitochondrial function, and mitochondrial fission proteins. RIP and RNA pull down assays were utilized to verify the binding of PCBP2 to IGF2 mRNA and IGF2 mRNA stability was assessed using actinomycin D. To further investigate the therapeutic potential of PCBP2 in POI, PCBP2 was overexpressed in the animal model to evaluate its effects on ameliorating ovarian function in POI mice.</div></div><div><h3>Results</h3><div>IGF2 expression was reduced in POI mouse ovaries, characterized by disrupted estrous cycles, hormonal imbalances, and decreased follicle numbers. IGF2 overexpression inhibited CTX-induced apoptosis in KGN cells, restored mitochondrial function, and downregulated mitochondrial fission proteins. These effects were reversed by CCCP pre-treatment. PCBP2 expression was downregulated in POI mice and CTX-treated KGN cells. PCBP2 stabilized IGF2 mRNA, thereby promoting its expression. Knocking down IGF2 reversed PCBP2's protective effects. In animal experiments, PCBP2 overexpression improved hormone levels, increased ovarian weight and follicle numbers, and significantly alleviated granulosa cell apoptosis and mitochondrial damage in POI mice.</div></div><div><h3>Conclusions</h3><div>PCBP2 promoted IGF2 expression by stabilizing IGF2 mRNA, thereby inhibiting granulosa cell apoptosis, restoring mitochondrial function, and ameliorating ovarian function in POI mice. This study highlights the significant function of the PCBP2/IGF2 axis in POI and suggests it as a promising potential therapeutic target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112103"},"PeriodicalIF":3.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926396","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":"UBE4B-driven suppression of megakaryocyte maturation by HBV: A novel mechanism linking viral infection to thrombocytopenia via p53-ERK1/2 crosstalk","authors":"Huinan Jiang ,&nbsp;Yanwei Li ,&nbsp;Xiaoguang Dou ,&nbsp;Chao Han ,&nbsp;Yaoxin Fan","doi":"10.1016/j.cellsig.2025.112089","DOIUrl":"10.1016/j.cellsig.2025.112089","url":null,"abstract":"<div><h3>Background and aim</h3><div>Hepatitis B virus (HBV) infection can lead to thrombocytopenia through its effects on hematopoiesis, although the underlying mechanisms have not been fully elucidated. Platelet production involves multiple stages, including the differentiation of mature megakaryocytes, which plays a pivotal role. In this study, we assessed the variances in megakaryocyte differentiation and maturation after HBV infection and investigated the molecular mechanism involved.</div></div><div><h3>Methods</h3><div>Different doses of HBV virus solution extracted from HepAD38 cells were co-cultured with hematopoietic stem cells that had been isolated from fresh, full-term healthy maternal cord blood through magnetic bead sorting. Label-free quantitative proteomics was employed to analyze the differential proteins during the mature megakaryocyte stages pre- and post-HBV infection, with a focus on elucidating their respective molecular mechanisms.</div></div><div><h3>Results</h3><div>A comparative analysis revealed that HBV impeded the differentiation of fully developed megakaryocytes. Its suppressive effect was more pronounced in the later stages of differentiation, consequently leading to impaired platelet production. Proteomic analysis revealed noteworthy disparities in UBE4B protein levels in mature megakaryocytes after HBV infection. Upon transfection with lentivirus and subsequent knockdown of UBE4B in mature megakaryocytes, a noticeable alleviation of HBV's inhibitory impact was observed, accompanied by regulation of p53 and ERK1/2 expression and phosphorylation.</div></div><div><h3>Conclusion</h3><div>HBV upregulates UBE4B expression, which inhibits p53 expression and phosphorylation while enhancing ERK1/2 expression and phosphorylation. This cascade suppresses mature megakaryocyte differentiation, resulting in impaired platelet production.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112089"},"PeriodicalIF":3.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944430","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":"Corrigendum to \"High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway\" [Cell Signal, 135 (2025), 112027].","authors":"Fadian Ding, Yikun Guo, Han Zhang, Yun Zhong, Denghan Zhang, Qiang Huang, Zhou Zheng, Guozhong Liu, Xiang Zhang, Shangeng Weng","doi":"10.1016/j.cellsig.2025.112087","DOIUrl":"10.1016/j.cellsig.2025.112087","url":null,"abstract":"","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112087"},"PeriodicalIF":3.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944819","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":"RNF11 confers chemotherapy sensitivity to tumor cells by regulating the ubiquitination of KU80 and the cell cycle","authors":"Cheng Wei ,&nbsp;Xiaojun Li ,&nbsp;Zhen Wei ,&nbsp;Boxiong Kang ,&nbsp;Jie Fu ,&nbsp;Xingang Wang ,&nbsp;Minxue Chen ,&nbsp;Xinyuan Zhou ,&nbsp;Qiuya Wei ,&nbsp;Chen Wang","doi":"10.1016/j.cellsig.2025.112088","DOIUrl":"10.1016/j.cellsig.2025.112088","url":null,"abstract":"<div><h3>Background</h3><div>Ring finger protein 11 (RNF11) is integral to cell signal transduction and transcription factor regulation and is strongly connected to the beginning and progression of malignant tumors. However, the core mechanisms of RNF11 remain unknown to date. This study highlights the significant function of RNF11 in the DNA damage response.</div></div><div><h3>Methods</h3><div>After the CRISPR-Cas9 gene knockout of RNF11, HCT116 cells were transfected, and cell viability assays were performed to evaluate the response of tumor cells to the chemotherapy drugs after RNF11 deletion. The interaction of RNF11 with its binding proteins and its ubiquitination mechanism, along with the recruitment of KU80 to chromatin, were subsequently evaluated. RNF11 was revealed to participate in the regulation of the cell cycle and apoptosis. An HCT116 xenograft tumor model was used to validate the <em>in vivo</em> sensitivity of tumors to 5-FU, revealing that RNF11 is essential for regulating the responsiveness of tumor cells to chemotherapy.</div></div><div><h3>Results</h3><div>RNF11 modulates KU80 expression and participates in cell cycle regulation. The elimination of RNF11 results in the accumulation of KU80 at the DNA damage sites, induces G1 phase cell cycle arrest, and increases sensitivity to the chemotherapy drugs. Mechanistically, RNF11 regulates KU80 expression through a direct interaction and facilitates its ubiquitination while modulating apoptosis and the cell cycle, thereby participating in the cellular damage response. Furthermore, high RNF11 expression is associated with poor prognosis in patients with cancer, while RNF11 deletion impedes tumor progression and enhances the sensitivity of the xenografts to 5-FU treatment. These findings demonstrate that RNF11 is involved in the clinical tumor treatment processes and could be a target for cancer treatment.</div></div><div><h3>Conclusion</h3><div>RNF11 binds with KU80, facilitates its ubiquitination, supports DNA damage repair, preserves genomic stability, and enhances the chemotherapy response in tumor cells.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112088"},"PeriodicalIF":3.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944877","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":"Notch4 but not Notch1 yin-yang dimerization correlates with condensate formation but not transcriptional activity","authors":"Tyler Lawton ,&nbsp;Jacob J. Crow ,&nbsp;David Oke ,&nbsp;Tana Gazdik ,&nbsp;Allan R. Albig","doi":"10.1016/j.cellsig.2025.112091","DOIUrl":"10.1016/j.cellsig.2025.112091","url":null,"abstract":"<div><div>Notch signaling facilitates direct communication between neighboring cells to largely coordinate cell differentiation mechanisms. Internal regulation of this pathway is far more complex than previously thought, including multiple dimerization states as well as formation of biomolecular condensates. Previous studies have focused on ankyrin mediated head-to-head dimerization in the regulation of Notch signaling. Herein, we focus on the less known DNA independent head-to-tail dimerization state which we refer to as yin-yang dimerization and its connection to the formation of Notch containing biomolecular condensates and transcriptional activity. We show that all four Notch paralogs participate in yin-yang homo and heterodimerization, and that N4ICD displays enhanced yin-yang dimerization compared to N1ICD. Through domain swap experiments, we Found that the N4ICD C-terminus mediates strong yin-yang dimerization, while the N1ICD C-terminus mediates weak yin-yang dimerization. We reveal that all four Notch paralogs form distinct condensates that are capable of colocalization in all combinations and assess the effects of the various domains within the NICD on condensate formation and transcriptional activity. Finally, through serial truncation of both the N4ICD and N1ICD C-termini we provide insight into the role that different amino acid sections within these domains plays in the ability to yin-yang dimerize, form condensates, and induce transcriptional effects. Though much remains to be learned about the specific contributions that the C-terminals of the NICDs has on yin-yang dimerization, condensate formation, and transcriptional output, the data we have laid out provides a framework to direct future research to further detail these properties.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112091"},"PeriodicalIF":3.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907682","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":"Ubiquitinome profiling identifies USP13-CMAS axis as critical regulator of hair follicular melanogenesis via K48-linked polyubiquitination","authors":"Yang Chen ,&nbsp;Shuaishuai Hu ,&nbsp;Sen Wang ,&nbsp;Zhiyuan Bao ,&nbsp;Jiawei Cai ,&nbsp;Bohao Zhao ,&nbsp;Xinsheng Wu","doi":"10.1016/j.cellsig.2025.112090","DOIUrl":"10.1016/j.cellsig.2025.112090","url":null,"abstract":"<div><div>The ubiquitin-proteasome system critically regulates melanogenesis through post-translational modifications. However, the specific deubiquitination substrates involved in this regulation remain poorly characterized. This study employed multi-omics integration and functional validation to decipher the role of USP13 in melanocyte (MC) biology. Through quantitative melanin assays and apoptosis/proliferation analyses, we established the dual functionality of USP13 in promoting MC pigmentation and survival. Systematic proteome-ubiquitinome analysis of USP13-overexpressing MCs identified 23 high-confidence substrates. Cytidine monophosphate <em>N</em>-acetylneuraminic acid synthetase (CMAS) was recognized as a key mediator. Mechanistically, <em>Co</em>-IP studies demonstratedthat USP13 stabilizes CMAS by specifically cleaving its K48-linked polyubiquitin chains, thereby enhancing melanogenic capacity. Furthermore, a novel transcriptional regulatory axis was identified, in which FOXO4 represses USP13 expression through direct promoter interaction, as demonstrated by luciferase reporter and EMSA assays. This study expands the substrate landscape of USP13 but also delineates a novel FOXO4-USP13-CMAS axis coordinating transcriptional and post-translational control of melanin biosynthesis. The results provide new therapeutic targets for pigmentary disorders.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112090"},"PeriodicalIF":3.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917449","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":"C20orf27 regulates colorectal cancer growth and metastasis based on different lipid levels","authors":"Peng Xu ,&nbsp;Haidi Guan ,&nbsp;Guangsheng Du ,&nbsp;Zhongwei Xu ,&nbsp;Dong Xiong ,&nbsp;Weidong Xiao ,&nbsp;Xiufei Liu ,&nbsp;Lihua Sun","doi":"10.1016/j.cellsig.2025.112082","DOIUrl":"10.1016/j.cellsig.2025.112082","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a high-incidence malignant tumor that lacks highly effective targeted treatments currently. Epidemiology studies have revealed a direct association between high-fat diet intake and CRC. C20orf27, a key factor controlling adipose thermogenesis and glucose homeostasis, is abnormally overexpressed in CRC. However, its roles in CRC remain unknown. Therefore, our study aimed to reveal the clinical significance and biological function of C20orf27 in human CRC. Here, C20orf27 expression showed a positive correlation with patient body mass index values. Furthemore, we have demonstrated that C20orf27 promotes tumor proliferation while suppressing metastasis in CRC cells. However, under high-lipid induction conditions, C20orf27 exhibits paradoxical effects-inhibiting proliferation but enhancing metastatic potential in CRC cells. Moreover, we revealed that C20orf27 mediated CRC cell proliferation and metastasis through different signaling pathways (XBP1 or MST1) in the presence or absence of hyperlipidemia. In conclusion, our study showed the unique tumorigenic properties of C20orf27 in regulating CRC development and delineated the underlying mechanism by which it is affected by the lipid environment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112082"},"PeriodicalIF":3.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917448","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":"Melatonin attenuates lipopolysaccharide-induced acute myocardial injury by regulating KLF4 expression","authors":"Zhangyong Dan ,&nbsp;Wanqing Liu ,&nbsp;Huanzhen Zhang ,&nbsp;Xiaorui Shi ,&nbsp;Rumeng Zhu ,&nbsp;Min Yang ,&nbsp;Yi Wang ,&nbsp;Huaqing Zhu","doi":"10.1016/j.cellsig.2025.112080","DOIUrl":"10.1016/j.cellsig.2025.112080","url":null,"abstract":"<div><div>Melatonin (MLT) has been reported to effectively reduce myocardial damage induced by lipopolysaccharide (LPS) in mice. MLT exerts its protective effects through multiple mechanisms, including antiferroptosis. This study investigated the relationship between MLT and ferroptosis in patients with sepsis-induced cardiomyopathy (SIC). We demonstrated that pretreatment with MLT improved cardiac contractile function and reduced myocardial injury in mice with sepsis. Furthermore, MLT attenuated the adverse effects of LPS on cardiac contractility in time- and concentration-dependent manners. MLT enhances the antioxidant capacity of tissues and alleviates LPS-induced mitochondrial damage in myocardial tissues. Following intraperitoneal LPS injection in mice, both protein and mRNA levels of KLF4 in myocardial tissue were significantly reduced. MLT pretreatment restored KLF4 protein expression in the myocardium of LPS-injured mice and increased that of antiferroptosis proteins. Notably, KLF4 overexpression stimulated via adeno-associated virus 9 (AAV9) through tail vein injection attenuated LPS-induced cardiac damage in mice. Similarly, in AC16 cells, LPS treatment reduced KLF4 expression, while MLT treatment upregulated it. However, this upregulation was inhibited by an melatonin receptor 1 (MT1) receptor antagonist, suggesting that MLT enhances KLF4 through MT1-dependent signaling. Pretreatment with MLT increased the antioxidant capacity of LPS-stimulated AC16 cells, reduced lipid peroxide levels, and increased the expression of antiferroptosis proteins. Furthermore, the knockdown or overexpression of KLF4 through lentiviral plasmid transfection altered the levels of p62 and YAP, which mirrored the changes in KLF4 expression. Taken together, these findings suggest that MLT protects against SIC through the KLF4-p62-Nrf2 signaling pathway and KLF4/YAP axis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112080"},"PeriodicalIF":3.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944856","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":"Β-Hydroxybutyrate inhibits centriole duplication and mitochondrial dysfunction through β-hydroxybutyrylation of ANXA11 in diabetic cardiomyopathy rats","authors":"Jingyu Liu ,&nbsp;Bin Wu ,&nbsp;Xin Nian ,&nbsp;Shiying Huang ,&nbsp;Yaxian Song ,&nbsp;Yaxin Guan ,&nbsp;Fang Sun ,&nbsp;Xiao Meng ,&nbsp;Shengting Huang","doi":"10.1016/j.cellsig.2025.112086","DOIUrl":"10.1016/j.cellsig.2025.112086","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial dysfunction is a major mechanism in the development of diabetic cardiomyopathy (DCM). However, the exact pathogenesis remains unclear, resulting in a lack of targeted clinical therapies. The aim of this study is to elucidate the mechanism by which ANXA11 affects DCM by inducing mitochondrial dysfunction through β-hydroxybutyrylation (kbhb).</div></div><div><h3>Methods</h3><div>Establishing a model through <em>in vivo</em> experiments to detect centrosome amplification, mitochondrial dysfunction, and ANXA11 expression. Co-IP was used to detect the Kbhb modification of ANXA11 and the binding between ANXA11 and Cep55. Western blot and immunofluorescence assay (IF) were used to detect the centrioles duplication related protein γ-Tubulin and polo-like kinase 4 (PLK4). Mitochondrial membrane potential (MMP) and ATP were also assessed.</div></div><div><h3>Results</h3><div><em>In vivo</em> and <em>in vitro</em> experiments have shown that centrosome amplification, mitochondrial dysfunction, and significant increase in ANXA11 expression occur in DCM. Co-IP showed that the Kbhb modification of ANXA11 was higher in 30.0 mmol/L glucose treated H9C2 cells and there exist the binding between ANXA11 and Cep55. ANXA11 overexpression increased the expression of γ-Tubulin and PLK4. ANXA11 overexpression also decreased the MMP and ATP level.</div></div><div><h3>Conclusion</h3><div>These results collectively provide mechanistic insight into the impact of ANXA11 on DCM severity through mitochondrial dysfunction and can be a useful therapeutic approach in patients with DCM.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112086"},"PeriodicalIF":3.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907681","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":"N2 neutrophils induce cell stemness reprogramming to promote gastric cancer progression via exosomal miRNAs","authors":"Haozhou Tang ,&nbsp;Yuan Zhong ,&nbsp;Jiayi Wang ,&nbsp;Shuting Meng ,&nbsp;Dan Yu ,&nbsp;Baiyuan Fan ,&nbsp;Xiaotong Dong ,&nbsp;Maoye Wang ,&nbsp;Min Fu ,&nbsp;Yu Qian ,&nbsp;Xiaoxin Zhang ,&nbsp;Runbi Ji ,&nbsp;Xu Zhang ,&nbsp;Xinjian Fang ,&nbsp;Jiahui Zhang","doi":"10.1016/j.cellsig.2025.112085","DOIUrl":"10.1016/j.cellsig.2025.112085","url":null,"abstract":"<div><div>Exosomes mediate cellular communications and have a profound impact on cancer progression. N2 neutrophils, which are polarized by factors from cancers, extensively infiltrate into tumor tissues and promote cancer progression <em>via</em> distinct mechanisms. However, the role and underlying mechanism of exosomes derived from N2 neutrophils (N2-EXO) in cancer remain to be investigated. Herein, we reported that N2-EXO enhanced the proliferation and metastasis of gastric cancer (GC) cells by promoting their stemness. In addition, miR-223-3p and miR-425-5p, which were highly expressed in N2-EXO from GC patients, promoted cancer metastasis and reduced cancer sensitivity to oxaliplatin. The cancer-promoting effect of N2-EXO was abolished by the addition of miRNA inhibitor both <em>in vitro and in vivo</em>. Mechanically, miR-223-3p and miR-425-5p directly targeted FOXO3 and PTEN genes, respectively, which synergistically promoted GC progression by regulating PI3K/AKT signaling pathway. Taken together, our results reveal a novel mechanism by which N2-EXO promotes GC progression, providing new insights into the function of exosomes from N2 neutrophils in cancer.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112085"},"PeriodicalIF":3.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907680","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}