Cellular signalling最新文献

{"title":"RNF126 suppresses amino acid-mediated mTORC1 signaling pathway by ubiquitinating ILF3 in HEK293T cells","authors":"Bin Hu ,&nbsp;Meng-Di Shang ,&nbsp;Xi Wang ,&nbsp;Xiao-Gang Zhang ,&nbsp;Meng-Hua Dong ,&nbsp;Qi Cao ,&nbsp;Xiao-Dan Wei ,&nbsp;Yan-Chun Han ,&nbsp;Fan Li ,&nbsp;Zhen-Lin Yang ,&nbsp;Lu-Ying Liu ,&nbsp;Jiu-Qiang Wang","doi":"10.1016/j.cellsig.2025.112110","DOIUrl":"10.1016/j.cellsig.2025.112110","url":null,"abstract":"<div><div>The mammalian Target of Rapamycin Complex 1 (mTORC1) serves as a metabolic hub that integrates external nutrients to promote cell growth and metabolism, with its activation closely associated with accelerated cancer progression. Interleukin enhancer-binding factor 3 (ILF3) has been identified as a negative regulator of mTORC1 by tethering GATOR1/2 to the lysosomal membrane during amino acid sensing. However, the regulatory mechanisms of the ILF3-mediated mTORC1 signaling pathway remain unclear. In this study, we demonstrate that RNF126 negatively regulates mTORC1 signaling by promoting the K63-linked ubiquitination of ILF3 in HEK293T cells. Silencing RNF126 significantly attenuated the interaction between ILF3 and the GATOR2 complex. Notably, RNF126 depletion in MCF7 cells suppressed breast cancer progression in preclinical models, highlighting its potential as a therapeutic target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112110"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989283","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":"Dimethyl fumarate is an inhibitor of pathological angiogenesis","authors":"Pei Qin Ng ,&nbsp;Kelvin Huang ,&nbsp;Fergus C. McLellan ,&nbsp;Menglu Yang ,&nbsp;Anton Lennikov ,&nbsp;Zhengping Hu ,&nbsp;Suman Chaudhary ,&nbsp;Alena C. Appiah ,&nbsp;Mong Linh Vuong ,&nbsp;Daisy Y. Shu","doi":"10.1016/j.cellsig.2025.112106","DOIUrl":"10.1016/j.cellsig.2025.112106","url":null,"abstract":"<div><div>Vascular endothelial growth factor (VEGF), a pro-angiogenic molecule, supports blood vessel growth during wound healing but also drives pathological neovascularization in blinding eye diseases such as neovascular age-related macular degeneration (nAMD). Dimethyl fumarate (DMFu), an FDA-approved drug for multiple sclerosis, has shown promising anti-inflammatory properties in the retinal pigment epithelium, a crucial structure disrupted in nAMD. Here, we extend the therapeutic potential of DMFu by discerning the anti-angiogenic capabilities of DMFu in choroidal and retinal endothelial cells. Choroidal endothelial cell proliferation was significantly attenuated by DMFu in the mouse choroidal sprouting assay. Even in the presence of VEGF, DMFu disrupted cell migration and tube formation in human microvascular retinal endothelial cells (HRECs). Bulk RNA sequencing highlighted that DMFu successfully ameliorated the expression of VEGF-controlled gene expression. Weighted gene co-expression network and gene set enrichment analyses confirmed downregulation of pathways involved in branching blood vessel morphogenesis but also revealed novel transcriptional mechanisms of action, including control of microtubule transport and ATP synthesis coupled electron transport. DMFu induced a decrease in maximal mitochondrial respiration, an increase in glycolysis and glycolytic capacity and reduced Complex II protein expression of the SDHB subunit on western blot. Such metabolic rewiring may limit the bioenergetic demands required to support angiogenic growth. With therapies available for nAMD being both limited and invasive, DMFu is a contender to be rapidly repurposed as an oral, patient-friendly therapeutic alternative.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112106"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999786","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":"Targeting YES1 enhances the efficacy of chemotherapy, targeted therapy and onco-immunotherapy","authors":"Dayong Zheng ,&nbsp;Yiran Wang ,&nbsp;Jun Li ,&nbsp;Gang Zhang ,&nbsp;Edward Chu ,&nbsp;Ning Wei","doi":"10.1016/j.cellsig.2025.112108","DOIUrl":"10.1016/j.cellsig.2025.112108","url":null,"abstract":"<div><div>YES1 (Yamaguchi sarcoma virus homolog 1), a non-receptor tyrosine kinase of the SRC family (SFK), has been abnormally amplified or mutated in several types of solid tumors. The alteration of YES1 impacted multiple biological processes, including promoting tumor progression and metastasis, especially, producing cancer therapy resistance <em>via</em> bypass pathways. Thus, YES1 can serve as a druggable target to overcome drug resistance and suppress tumor growth. Due to toxicity and lack of selectivity, several SFK-targeted agents in clinical trials were limited for further investigation. Recently, the emerging role of YES1-selective inhibitors and the promising approach of combinational therapy have exhibited synergistic anti-tumor effects. Herein, we summarize the multiple mechanisms of YES1-driving tumor progression and resistance, focusing on YES1 inhibitors in combination with other therapies. We also discuss the oncogenic mechanism of the YES1-YAP1 pathway, EGFR-YES1 crosstalk, the roles of YES1 in the tumor microenvironment, and the synthetic lethal effect of YES1 inhibitors. Taken together, available evidences strongly suggest that targeting YES1 could be a promising sensitization strategy for cancer treatment and improve the patient's quality of life.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112108"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999693","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":"The role and behavior of voltage-gated calcium channels in ischemia/reperfusion","authors":"Yusuf Anil Ay ,&nbsp;Emir Enis Yurdgulu ,&nbsp;Yasin Bayir ,&nbsp;Zekai Halici","doi":"10.1016/j.cellsig.2025.112107","DOIUrl":"10.1016/j.cellsig.2025.112107","url":null,"abstract":"<div><div>Ischemia/reperfusion (I/R) injury is a pathological condition that arises from the complex interplay of multifaceted mechanisms such as calcium imbalance, oxidative stress, mitochondrial dysfunction, and inflammatory processes. Voltage-gated calcium channels (VGCCs) play a critical role in this pathogenesis by regulating calcium influx into the cell, thereby initiating a cascade of detrimental intracellular events. During the ischemic phase, depletion of ATP reserves leads to the dysfunction of calcium transport systems; in the reperfusion phase, the stimulation of VGCCs by reactive oxygen species (ROS) intensifies intracellular calcium overload. This accumulation triggers the opening of mitochondrial permeability transition pores, amplifies ROS production, and activates cell death pathways such as apoptosis, necrosis, and ferroptosis.</div><div>This comprehensive review explores the structural subtypes and physiological functions of VGCCs in detail while broadly investigating their behavior under I/R conditions across various organ systems, including the cardiovascular, neurological, renal, and reproductive systems. The review focuses on the distinct roles of L-, T-, N-, and R-type VGCCs and examines current findings on tissue- and isoform-specific pharmacological blockade strategies. Experimental studies demonstrating the protective effects of VGCC inhibitors—such as nimodipine, mibefradil, and SNX-111—are critically evaluated along with their translational limitations.</div><div>By integrating up-to-date mechanistic insights with preclinical and early clinical data, this review highlights VGCCs as promising molecular targets for preventing I/R injury. Future therapeutic strategies should focus on isoform-specific targeting, time-dependent administration, and organ-directed formulations to enhance efficacy and safety.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112107"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989282","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":"Gut microbiota dysbiosis amplifies thiram hepatotoxicity via a mitochondrial-autophagy-apoptosis nexus orchestrated by the gut-liver axis","authors":"Junhong Hou ,&nbsp;Ping Wu ,&nbsp;Junjie Cai ,&nbsp;Bangjun Xia ,&nbsp;Yinghua Lei ,&nbsp;Chenqi Huang ,&nbsp;Ying Li ,&nbsp;Muhammad Immad Tareen ,&nbsp;Zhaoxin Tang ,&nbsp;Hui Zhang","doi":"10.1016/j.cellsig.2025.112104","DOIUrl":"10.1016/j.cellsig.2025.112104","url":null,"abstract":"<div><div>Thiram, an environmentally persistent pesticide, poses significant hepatotoxic risks through oral exposure. However, the mechanisms linking gut dysbiosis to hepatic cell death remain unclear. Using a 5-week thiram exposure mouse model, we demonstrate that thiram-induced gut microbiota dysbiosis amplifies hepatotoxicity by disrupting the mitochondrial-autophagy-apoptosis axis via the gut-liver axis. We found that oral thiram exposure severely compromises intestinal barrier integrity, evidenced by colonic muscular layer thinning, goblet cell depletion, and downregulation of tight junction proteins (ZO-1, Occludin). Simultaneously, thiram induces dysbiosis characterized by an elevated <em>Firmicutes</em>/<em>Bacteroidetes</em> (F/B) ratio and altered abundances of <em>Muribaculum intestinale, Bacteroides caecimuris, Lactobacillus johnsonii.</em> These gut-derived perturbations triggered hepatic mitochondrial dynamics imbalance, driving aberrant de novo fatty acid synthesis and β-oxidation. Crucially, thiram disrupted autophagic flux and activated the mitochondrial apoptosis pathway, establishing a self-amplifying cycle of metabolic dysfunction and cellular demise. Our findings reveal that gut-mediated disruption of fatty acid metabolism orchestrates the collapse of crosstalk between mitochondria, autophagy, and apoptosis, ultimately culminating in hepatotoxicity. This work establishes the gut-liver axis as a central regulator of environmentally triggered apoptotic cell death.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112104"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926397","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 regulates accumulation of lipids in the liver via the IP3R on the mitochondria-associated membranes (MAMs)","authors":"Mei-yu Jin ,&nbsp;Hao Yu ,&nbsp;Yun-fei Wei ,&nbsp;Xin Ma ,&nbsp;Xu-ming Deng ,&nbsp;Jian-feng Wang ,&nbsp;Hai-hua Feng","doi":"10.1016/j.cellsig.2025.112109","DOIUrl":"10.1016/j.cellsig.2025.112109","url":null,"abstract":"<div><div>Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disease of the liver that can progress to hepatitis, cirrhosis, and even cancer in extreme cases. In this study, we investigated the effect of Melatonin (Mel) on lipid accumulation and explored the molecular mechanism behind it. Mel treatment reduced lipid accumulation and enhanced autophagy in oleic acid (OA) + palmitic acid (PA)-induced cells. Notably, Mel could regulate the inositol 1,4,5-triphosphate receptor (IP3R) pathway in OA + PA-induced cells and form hydrogen bonds with the IP3R protein. Interestingly, when cells were transfected with siRNA-IP3R, the regulatory effects of Mel on lipid accumulation and autophagy were lost in OA + PA-induced cells. We found that this might be due to Mel-regulated IP3R acting on the AMPK/mTOR pathway rather than on Bcl-2 and Beclin1. More importantly, we found that Mel could reduce the increase in MAMs caused by OA + PA-induced cells. And the integrity of MAMs could influence the role of Mel in regulating IP3R, as well as the regulation of lipid accumulation and autophagy by Mel. In summary, this study revealed that Mel has the function of ameliorating lipid accumulation by regulating the expression of IP3R on MAMs. This is because Mel-regulated IP3R can induce autophagy and alleviate lipid accumulation. This provides a new theoretical basis for Mel to regulate lipid accumulation.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112109"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989285","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":"S100A9 plays a role in neuropathic pain by regulating GPR153/Kcnk16 function in DRG neurons","authors":"Molei Liu ,&nbsp;Dawei Han ,&nbsp;Mingwei Sheng ,&nbsp;Ling Liu ,&nbsp;Lili Jia ,&nbsp;Hongxia Li ,&nbsp;Yiqi Weng ,&nbsp;Yinghui Ren ,&nbsp;Wenli Yu","doi":"10.1016/j.cellsig.2025.112101","DOIUrl":"10.1016/j.cellsig.2025.112101","url":null,"abstract":"<div><div>Neuropathic pain, attributed to its intricate pathogenesis, remains challenging to treat effectively. This study delineates neuroimmune-glial cell interactions within the ganglia as a pivotal mechanism initiating nerve damage, thereby contributing to neuropathic pain. Utilizing a chronic constriction injury (CCI) mouse model, we explored the pro-inflammatory molecule S100A9, secreted by myeloid cells, in the context of neuropathic pain development. Our findings revealed an upregulation of S100A9 in the dorsal root ganglia (DRGs) of CCI mice, predominantly due to neutrophil infiltration. Notably, S100A9 knockout significantly mitigated mechanical pain hypersensitivity and inflammation induced by CCI. We further elucidated the role of S100A9 in mechanical pain hypersensitivity using inhibitors and recombinant S100A9 proteins. Transcriptome sequencing indicated that S100A9 potentially influenced neuropathic pain by modulating the expression of orphan G protein-coupled receptor 153 (GPR153) and potassium channel Kcnk16 on the DRG neuron membrane. Collectively, our research underscores the significant role of S100A9 in neuropathic pain pathogenesis and presents it as a promising therapeutic target.</div></div><div><h3>Key Innovations</h3><div><ul><li><span>•</span><span><div>Identifies <strong>neutrophil-derived S100A9</strong> as a key mediator of peripheral neuropathic pain.</div></span></li><li><span>•</span><span><div>Reveals a <strong>new mechanism: S100A9-GPR153-Kcnk16-CSF1</strong>, linking peripheral inflammation to central microglial activation.</div></span></li><li><span>•</span><span><div>Supports <strong>translational potential</strong> of S100A9-targeted therapies (e.g., PAQ) for pain management.</div></span></li></ul></div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112101"},"PeriodicalIF":3.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944827","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":"VMP1 enhances autophagy to mitigate cardiac fibroblast activation and reduce post-ischemia-reperfusion fibrosis","authors":"Ya Li ,&nbsp;Cuina Feng ,&nbsp;Yugang Zu ,&nbsp;Pan Long ,&nbsp;Aijun Chen","doi":"10.1016/j.cellsig.2025.112105","DOIUrl":"10.1016/j.cellsig.2025.112105","url":null,"abstract":"<div><h3>Background</h3><div>Myocardial ischemia-reperfusion (I/R) injury contributes significantly to cardiac fibrosis, yet the regulatory mechanisms linking autophagy to fibroblast activation remain unclear. Vacuole membrane protein 1 (VMP1), an endoplasmic reticulum protein critical for autophagy initiation, has not been explored in this context.</div></div><div><h3>Methods</h3><div>We established a mouse model of I/R injury through left anterior descending (LAD) artery ligation, followed by reperfusion. Cardiac function was evaluated using echocardiography, while fibrosis and infarct size were assessed via Masson's trichrome and TTC staining. In vitro, primary cardiac fibroblasts were isolated and treated with TGF-β1 and PDGF-BB to simulate fibroblast activation. VMP1 was overexpressed using adenoviral vectors to investigate its effect on fibroblast activation, autophagic flux, and extracellular matrix (ECM) deposition.</div></div><div><h3>Results</h3><div>VMP1 expression was markedly downregulated in I/R-injured hearts and TGF-β1-stimulated fibroblasts. Overexpression of VMP1 enhanced autophagic flux (increased LC3-II/LC3-I, decreased p62) and suppressed fibroblast activation, reducing α-SMA and collagen I levels. Mechanistically, VMP1 inhibited mTOR phosphorylation, and alleviated endoplasmic reticulum stress.</div></div><div><h3>Conclusions</h3><div>VMP1 mitigates cardiac fibrosis by enhancing autophagy and restraining fibroblast-to-myofibroblast transition, highlighting its therapeutic potential for post-I/R injury. Further studies should explore clinical translation of VMP1-targeted strategies.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112105"},"PeriodicalIF":3.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144933376","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":"The RNA-binding protein Quaking modulates cell proliferation through the SFRP1 mediated Wnt signaling pathway in NIH3T3 fibroblasts","authors":"Bairong Ma ,&nbsp;Dengke Gao ,&nbsp;Guohao Han ,&nbsp;Haisen Zhang ,&nbsp;Wanghao Yang ,&nbsp;Yang Tao ,&nbsp;Wei Liu ,&nbsp;Keqiong Tang ,&nbsp;Aihua Wang ,&nbsp;Yaping Jin ,&nbsp;Huatao Chen","doi":"10.1016/j.cellsig.2025.112102","DOIUrl":"10.1016/j.cellsig.2025.112102","url":null,"abstract":"<div><div>As an RNA-binding protein, Quaking (QKI) plays a pivotal role in regulating RNA metabolism, including mRNA transcription, pre-mRNA splicing, RNA localization, and RNA stability. To further investigate its specific role in mammalian cells, a QKI-knockout NIH3T3 cell line was generated using CRISPR/Cas9 technology in this study. RNA sequencing analysis showed that QKI deficiency alters several biological processes in NIH3T3 cells, including the Wnt signaling pathway, regulation of epithelial cell proliferation, epithelial cell and tissue migration. Functional analyses revealed that QKI deficiency potently suppressed cell proliferation and migration in NIH3T3 cells. In addition, SFRP1, a negative regulator of the Wnt signaling pathway, was significantly upregulated in QKI knockout NIH3T3 cells. Notably, the expression of several Wnt signaling pathway-related factors (WNT5A, FZD8, β-catenin, CCND1 and CCN4) was significantly downregulated in QKI knockout NIH3T3 cells. CLIP-seq analysis further identified a fragment with the 3’UTR of <em>Sfrp1</em> mRNA that interacts with QKI and contains two canonical QKI response elements (QKI-REs). Dual-luciferase reporter assays verified that QKI exerts its inhibitory effect by binding to QKI-RE1 within the 3’UTR of <em>Sfrp1</em> mRNA. Additionally, the actinomycin D assay demonstrated that QKI regulates <em>Sfrp1</em> expression by suppressing <em>Sfrp1</em> mRNA stability. Moreover, SFRP1 overexpression inhibited the cell proliferation and migration of NIH3T3 cells, mirroring the effects of QKI knockout. In summary, these findings demonstrate that QKI inhibits <em>Sfrp1</em> expression by binding to QKI-RE1 within its 3’UTR, leading to activation of the Wnt signaling pathway and subsequent promotion of cell proliferation and cell migration. This study identifies a QKI-SFRP1-Wnt regulatory axis that expands the functional repertoire of QKI in post-transcriptional control of cell dynamics.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112102"},"PeriodicalIF":3.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144921609","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":"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}