Cellular signalling最新文献

{"title":"TFAP2A-mediated downregulation of UBE2C is crucial for endometrial decidualization and embryo implantation","authors":"Li Yu ,&nbsp;Yifan Luo ,&nbsp;Yixia Yang ,&nbsp;Liqun Lou ,&nbsp;Xinbao Zhang ,&nbsp;Jiamin Zhu ,&nbsp;Yan Zhang ,&nbsp;Hong Liao ,&nbsp;Mingzhu Bai ,&nbsp;Zuoshu Qin ,&nbsp;Zhenbo Zhang","doi":"10.1016/j.cellsig.2025.112016","DOIUrl":"10.1016/j.cellsig.2025.112016","url":null,"abstract":"<div><div>Decidualization triggered by human endometrial stromal cells (HESCs) is a critical step in the establishment of endometrial receptivity, which provides an ideal environment for embryo implantation. However, the specific regulatory networks and core genes involved in the decidualization process remain incompletely characterized. Here, we identified ubiquitin-conjugating enzyme 2C (UBE2C), a key cell cycle regulator, as a pivotal factor in decidualization through comprehensive <em>in vitro</em> and <em>in vivo</em> investigations. RNA sequencing revealed UBE2C as a potential hub gene in the human endometrium. We found UBE2C expression was significantly downregulated in secretory-phase endometrium and <em>in vitro</em> decidual HESCs. Functional studies demonstrated that UBE2C overexpression attenuated decidual marker expression and disrupted normal proliferation in HESCs, mechanistically linked to NF-κB signaling pathway. Consistent with <em>in vitro</em> findings, mice studies showed UBE2C downregulation in peri-implantation uterine tissue, with uterine-specific UBE2C overexpression impairing both embryo implantation and decidualization. Further mechanistic exploration identified transcription factor AP-2 alpha (TFAP2A) as a novel mediator of UBE2C. Decidual stimulation promoted TFAP2A degradation <em>via</em> the ubiquitination pathway. Clinical relevance was established through the observation of elevated UBE2C and TFAP2A expression in secretory endometrium from recurrent implantation failure (RIF) patients. In conclusion, for endometrial decidualization and embryo implantation, TFAP2A-mediated downregulation of UBE2C is required. Dysregulation of this axis may compromise endometrial receptivity, suggesting UBE2C and TFAP2A as promising therapeutic targets for decidualization-related disorders such as RIF.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112016"},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695111","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":"N-glycosylation stabilized TNFAIP6 promotes ovarian cancer metastasis by activating the PI3K-AKT signaling pathway","authors":"Xiangxiang Liu ,&nbsp;Dongze Ji ,&nbsp;Zhifa Wen ,&nbsp;Qi Tang ,&nbsp;Yajun Chen","doi":"10.1016/j.cellsig.2025.112013","DOIUrl":"10.1016/j.cellsig.2025.112013","url":null,"abstract":"<div><h3>Background</h3><div>Ovarian cancer (OC) represents the most lethal gynecological malignancy, with a dismal 5-year survival rate of ∼30 % in advanced-stage patients, largely due to metastatic dissemination and limited therapeutic options. Elucidating the molecular drivers of OC metastasis remains imperative for developing targeted interventions.</div></div><div><h3>Methods</h3><div>Integrative multi-omics analyses were performed using bulk RNA-seq and scRNA-seq data from TCGA and GEO repositories. Protein dynamics were validated via Western blot and immunofluorescence. Prognostic significance was assessed through Kaplan-Meier survival analysis with log-rank tests. Functional characterization of TNFAIP6 was achieved through lentivirus-mediated shRNA knockdown/overexpression, complemented by in vitro assays and in vivo metastasis models. The ubiquitination levels of TNFAIP6 were detected through Co-IP experiments. Immune cell infiltration was quantified via computational deconvolution algorithms.</div></div><div><h3>Results</h3><div>TNFAIP6 emerged as a metastasis-associated oncogene, with elevated expression correlating significantly with poor prognoses. Mechanistically, N-glycosylation stabilized TNFAIP6 by impeding ubiquitin-proteasomal degradation. TNFAIP6 knockdown genetically attenuated OC cell invasion, migration, and peritoneal dissemination. Pathway analyses revealed TNFAIP6-driven activation of the PI3K/AKT signaling pathway, which orchestrated epithelial-mesenchymal transition. Notably, TNFAIP6 upregulation was significantly correlated with tumor immune-suppressing microenvironment and predicted resistance to immune checkpoint inhibitors and chemotherapy.</div></div><div><h3>Conclusions</h3><div>Our study establishes TNFAIP6 as a critical regulator of OC metastasis via PI3K/AKT pathway activation and a biomarker of therapeutic resistance. Targeting TNFAIP6 may offer dual strategies to counteract metastatic progression and therapeutic resistance in OC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112013"},"PeriodicalIF":4.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697747","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":"Ferroptosis promotes sepsis-related lung injury via endothelial cell senescence","authors":"Yingying Yao ,&nbsp;Shuang Wang ,&nbsp;Wenya Shi ,&nbsp;Li Yang ,&nbsp;Yunping Tian ,&nbsp;Deling Wang ,&nbsp;Daolin Xia","doi":"10.1016/j.cellsig.2025.112018","DOIUrl":"10.1016/j.cellsig.2025.112018","url":null,"abstract":"<div><div>This study investigated the role of ferroptosis in vascular cell senescence induced by sepsis and elucidated the regulatory mechanism of the SIRT4-STAT3-ACSL4 signaling axis. The results showed that ferroptosis was significantly activated in pulmonary vascular endothelial cells under septic conditions, leading to the promotion of cellular senescence and exacerbation of lung injury. Inhibition of ferroptosis effectively attenuated cellular senescence and alleviated sepsis-associated lung damage. This study identified ACSL4 as a key regulator of ferroptosis, with its expression markedly elevated in senescent cells and in the lung tissues of septic mice. Further mechanistic studies revealed that SIRT4 suppresses ACSL4 transcription by modulating STAT3 acetylation, while SIRT4 deficiency enhances both ferroptosis and the senescence phenotype. Functional experiments confirmed that SIRT4 overexpression reversed LPS-induced cellular senescence and ferroptosis. This study highlights the critical role of ferroptosis in sepsis-related senescence and proposes that the SIRT4-STAT3-ACSL4 axis serves as a central regulatory mechanism in lung injury. These findings provide new insights into the interplay between ferroptosis and cellular senescence.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112018"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697719","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":"Paederia scandens-derived exosome-like nanoparticles as a delivery system for andrographolide to treat ulcerative colitis","authors":"Yuxuan Peng ,&nbsp;Vadim Demidchik ,&nbsp;Yan Li ,&nbsp;Xianglan Lei ,&nbsp;Yaqin Lin ,&nbsp;Yixin Zhang ,&nbsp;Donghai Zhou","doi":"10.1016/j.cellsig.2025.112014","DOIUrl":"10.1016/j.cellsig.2025.112014","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing colon inflammation. Side effects and drug resistance limit current therapies. Andrographolide (AG), an <em>NF-κB</em> pathway inhibitor, shows promise in UC treatment but suffers from poor oral bioavailability. In this study, <em>Paederia scandens</em>-derived exosome-like nanoparticles (P-ELNs) were used as a delivery system to enhance the therapeutic efficacy of AG in UC. P-ELNs were extracted from <em>Paederia scandens</em> leaves and characterized for size, zeta potential, and morphology using transmission electron microscopy (TEM) and nanoparticle tracking analysis. AG was loaded into P-ELNs (AG-P-ELNs), and the complex was characterized for encapsulation efficiency using high-performance liquid chromatography (HPLC). The anti-inflammatory effects of AG, P-ELN, and the AG-P-ELNs complex were assessed in LPS-stimulated RAW264.7 macrophages (<em>in vitro</em>) and in a dextran sulphate sodium (DSS)-induced colitis mouse model (<em>in vivo</em>). According to the results, AG-P-ELNs demonstrated a high encapsulation efficiency of 38.64 % and a stable dispersion system with a zeta potential of −38.55 mV, indicating good colloidal stability. <em>In vitro</em>, AG-P-ELNs significantly reduced the production of pro-inflammatory cytokines IL-1β, IL-6, IL-18 and TNF-α, promoting M1 macrophage polarized to M2. <em>In vivo</em>, AG-P-ELN treatment ameliorated DSS-induced colitis, normalized colon length, and mitigated inflammatory cell infiltration. The AG-P-ELN group showed the lowest <em>NF-κB</em>, <em>NLRP3</em>, and <em>iNOS</em> expression, suggesting a synergistic therapeutic effect in modulating macrophage polarization and inflammation. P-ELNs effectively enhance the bioavailability and therapeutic efficacy of AG in treating UC by improving its solubility, stability, and cellular uptake while modulating macrophage polarization and inflammation. This study provides a novel approach for the delivery of AG and highlights the potential of plant-derived nanoparticles in inflammatory bowel disease management<strong>.</strong></div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112014"},"PeriodicalIF":4.4,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685506","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":"Adaptor protein complex 1 facilitates ciliary localization of serotonin receptor type 6","authors":"Yuanyuan Qin ,&nbsp;Ko Miyoshi ,&nbsp;Zhuoma Yinsheng ,&nbsp;Yuuki Fujiwara ,&nbsp;Takeshi Yoshimura ,&nbsp;Taiichi Katayama","doi":"10.1016/j.cellsig.2025.112008","DOIUrl":"10.1016/j.cellsig.2025.112008","url":null,"abstract":"<div><div>The primary cilium, an immotile protrusion of vertebrate cells, detects chemical and mechanical stimuli in the extracellular milieu and transduces them into the cell body, thereby contributing to cellular development and homeostasis. In the mammalian brain, serotonin receptor type 6 (Htr6) and other specific G protein-coupled receptors (GPCRs) localize preferentially to primary cilia and function in ciliary chemical detection; however, the molecular mechanism by which a subset of GPCRs is transported to primary cilia has not been fully elucidated. In the present study, we demonstrate that a region in the fourth intracellular domain of Htr6 (Htr6 i4) is sufficient for ciliary localization. In yeast, the interaction of this region with the C-terminal region of γ1-Adaptin, a subunit of adaptor protein complex 1 (AP-1), was identified. The interaction between Htr6 and γ1-Adaptin was confirmed by immunoprecipitation analysis using HEK293T cells. The preference for ciliary localization of Htr6 and Htr6 i4 was significantly decreased by ablation of <em>γ1-Adaptin</em> in hTERT RPE-1 cells, which was rescued by exogenous expression of γ1-Adaptin. Furthermore, Htr6 and Htr6 i4 showed reduced localization to primary cilia in <em>γ1-Adaptin</em>-depleted cultured hippocampal neurons compared with control neurons. These results indicate that the ciliary localization of Htr6 is facilitated by AP-1-mediated membrane trafficking.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112008"},"PeriodicalIF":4.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673973","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":"Cardiomyocyte-specific knockout of Oip5-as1 exacerbates MI/R-induced ferroptosis via p62/KEAP1/NRF2 inhibition","authors":"Shuwen Hu ,&nbsp;Cheng Chen ,&nbsp;Shihan Wei ,&nbsp;Ming Bai ,&nbsp;Xiaowei Niu","doi":"10.1016/j.cellsig.2025.112007","DOIUrl":"10.1016/j.cellsig.2025.112007","url":null,"abstract":"<div><div>Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes after acute myocardial infarction. Ferroptosis is an iron-dependent and lipid-peroxidation-driven form of cell death implicated in this injury. However, the regulatory role of long non-coding RNAs (lncRNAs) in this process remains unclear. Here, we investigated whether the lncRNA OIP5 antisense RNA 1 (Oip5-as1) modulates ferroptosis during MI/R. A cardiomyocyte-specific Oip5-as1 knockout mouse was generated using CRISPR/Cas9 technology combined with the Cre-LoxP system. Isolated hearts were then exposed to MI/R in a Langendorff perfusion apparatus. Compared with floxed controls, Oip5-as1-deficient hearts exhibited impaired hemodynamic parameters, larger infarcts, more severe histopathological damage, and marked mitochondrial disruption, as determined by Langendorff system analysis, triphenyltetrazolium chloride staining, hematoxylin-eosin staining, and transmission electron microscopy, respectively. These structural and functional deficits were accompanied by elevated ferrous iron levels, increased lipid peroxidation, reduced antioxidant capacity, upregulation of the ferroptosis driver ACSL4, and downregulation of the ferroptosis suppressors FTH1, SLC7A11, and GPX4. Administration of the selective ferroptosis inhibitor Ferrostatin-1 restored antioxidant capacity, normalized the expression of ferroptosis-related proteins, and significantly reduced infarct size and cardiac functional impairment in Oip5-as1-deficient hearts. Mechanistic analyses revealed that Oip5-as1 deletion suppressed the p62/KEAP1/NRF2 signaling pathway, whereas disruption of KEAP1-NRF2 binding with KI696 reactivated NRF2 signaling and reinstated resistance to ferroptosis. Collectively, these findings demonstrate that Oip5-as1 limits MI/R injury by sustaining p62/KEAP1/NRF2-mediated suppression of ferroptosis. Furthermore, Oip5-as1 is identified as a promising therapeutic target for cardioprotection.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112007"},"PeriodicalIF":4.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673974","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 \"circPHF16 suppresses prostate cancer metastasis via modulating miR-581/RNF128/Wnt/β-catenin pathway\" [Cell Signal. 2023 Feb;102n110557].","authors":"Lifeng Ding, Yudong Lin, Xianjiong Chen, Ruyue Wang, Haohua Lu, Huan Wang, Wenqin Luo, Zeyi Lu, Liqun Xia, Xiaobo Zhou, Gonghui Li, Sheng Cheng","doi":"10.1016/j.cellsig.2025.111995","DOIUrl":"https://doi.org/10.1016/j.cellsig.2025.111995","url":null,"abstract":"","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"111995"},"PeriodicalIF":4.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667296","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":"Transcription factor ZNF207 drives aerobic glycolysis and facilitates malignancy progression in hepatocellular carcinoma","authors":"Chen Chen ,&nbsp;Jian-Fei Hu ,&nbsp;Bing-Yan Liu ,&nbsp;Yi-Min Sun ,&nbsp;Bao-Lai Xiao","doi":"10.1016/j.cellsig.2025.112009","DOIUrl":"10.1016/j.cellsig.2025.112009","url":null,"abstract":"<div><div>Zinc-finger protein 207 (ZNF207), a prominent member of the zinc finger protein family, exhibits consistent upregulation in various cancer types, including hepatocellular carcinoma (HCC). Unfortunately, the specific oncogenic mechanism of ZNF207 in HCC remains unknown. Our research involved a comprehensive approach, utilizing bioinformatics analysis alongside cell functional experiments, dual-luciferase reporter gene assays, ChIP and qPCR investigations, as well as <em>in vivo</em> studies involving nude mice models for subcutaneous tumor transplantation and tail vein lung metastasis, to delve into the molecular mechanisms underlying its oncogenic properties. The study revealed ZNF207's overexpression in HCC tissues, its correlation with diminished overall survival, and the independent prognostic significance of its expression level in HCC. Furthermore, overexpression of ZNF207 was shown to enhance cell viability, proliferation, and invasive capabilities in HCC cells. Mechanistic analyses pointed towards the modulation of ENO1 and GAPDH transcription by ZNF207, fostering aerobic glycolysis and malignant progression. Subsequent <em>in vivo</em> experiments validated that ZNF207 silencing could impede the growth of subcutaneous tumors and lung metastatic nodules in nude mice, consequently extending their survival. More importantly, Pinosylvin exerts its anti-tumor effects by specifically targeting ZNF207, leading to downregulation of GAPDH and ENO1 expression, inhibition of aerobic glycolysis, and suppression of HCC progression <em>in vitro</em>. In conclusion, these observations highlight ZNF207 as a pivotal oncogene in HCC, with potential for therapeutic targeting in patients with this malignancy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112009"},"PeriodicalIF":4.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674002","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":"Epigenetic upregulation of FGF2 promotes glioblastoma progression by enhancing the Warburg effect","authors":"Yefeng Shi ,&nbsp;Yang Zhang ,&nbsp;Le Xu ,&nbsp;Changwei Luo ,&nbsp;Shun Xi ,&nbsp;Xinyu Xu ,&nbsp;Jianquan Liu ,&nbsp;Haoyue Xu ,&nbsp;Baole Zhang","doi":"10.1016/j.cellsig.2025.112011","DOIUrl":"10.1016/j.cellsig.2025.112011","url":null,"abstract":"<div><div>Glioblastoma (GBM), the most common primary intracranial malignancy, remains poorly understood in terms of its underlying etiology. Although fibroblast growth factor 2 (FGF2) is highly expressed in GBM, its epigenetic regulation and functional contributions to disease progression are incompletely defined. Here, through integrated bioinformatics analysis, real-time PCR, and western blot, we demonstrate that FGF2 expression is significantly upregulated in GBM patient-derived tissues and cells. Functional assays revealed that silencing FGF2 markedly suppressed GBM cell proliferation and migration in vitro. Mechanistically, we identified cyclic AMP response element-binding protein 1 (CREB1) as a critical transcription factor regulating <em>FGF2</em> transcription through binding to cAMP response elements (CREs) within the <em>FGF2</em> gene's silencer I and core promoter regions. Intriguingly, these CREs exerted opposing regulatory effects: hypermethylation of the silencer I and hypomethylation of the core promoter favored preferential CREB1 binding to the core promoter in GBM cells. CREB1 recruitment of histone acetyltransferase CBP further promoted histone H3K27 acetylation and enhanced chromatin accessibility at the <em>FGF2</em> core promoter, thereby driving transcriptional activation. Additionally, FGF2 has been shown to significantly enhance glycolysis and lactate production in GBM cells, fueling malignant growth. Collectively, our findings highlight the CREB1/FGF2/lactate axis as a promising therapeutic target for GBM treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112011"},"PeriodicalIF":4.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673975","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":"Histone methyltransferase G9a drives ferroptosis to aggravate vascular calcification by inhibiting SLC7A11 transcription","authors":"Qi An ,&nbsp;Haoqi Sun ,&nbsp;Binhong Yang ,&nbsp;Meijuan Cheng ,&nbsp;Jingjing Jin ,&nbsp;Dongxue Zhang ,&nbsp;Lixin Chang ,&nbsp;Shenglei Zhang ,&nbsp;Yaling Bai ,&nbsp;Jinsheng Xu","doi":"10.1016/j.cellsig.2025.112010","DOIUrl":"10.1016/j.cellsig.2025.112010","url":null,"abstract":"<div><div>Vascular calcification (VC) exacerbates the risk of cardiovascular morbidity and mortality in individuals with chronic kidney disease (CKD), and recent advances in pathogenesis have highlighted the significance of ferroptosis. The histone methyltransferase G9a participates in the regulation of different types of cell death including ferroptosis, but its role in VC needs to be further explored. Here, we found that G9a expression was elevated in microarray data obtained from CKD mouse VSMC specimens, and further experiments demonstrated similar results in CKD patients, mouse calcified arteries and rat calcified VSMCs. Functionally, G9a overexpression promoted high calcium and phosphate-induced VSMCs calcification, whereas G9a deficiency had a protective effect. Moreover, our results confirmed that G9a promoted VSMCs calcification through cystine pathway-mediated ferroptosis. Mechanistically, histone H3 lysine 9 dimethylation (H3K9me2) which was catalyzed by G9a, interacted with the promoter of solute carrier family 7 member 11 (SLC7A11) to inhibit its transcription and ferroptosis-related signaling pathways. SLC7A11, a cysteine transporter and ferroptosis suppressor, eliminated the adverse effects of G9a overexpression on ferroptosis and VC in VSMCs. Finally, in vivo overexpression of G9a aggravated VC and ferroptosis in the aorta of CKD mice, accompanied by down-regulation of SLC7A11 expression. In summary, our study reveals that the G9a/H3K9me2/SLC7A11 pathway is a new molecular mechanism for ferroptosis in VC, offering potential guidance for the development of new strategies in the treatment of VC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112010"},"PeriodicalIF":4.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673976","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}