Cellular signalling最新文献

{"title":"TYROBP facilitates metastatic progression in pancreatic cancer through CTSZ-driven glycolytic rewiring and macrophage recruitment","authors":"Dingwen Zhong ,&nbsp;Yonghui Liao ,&nbsp;Xianyu Huang ,&nbsp;Wenhui Chen ,&nbsp;Jiaxin Liu ,&nbsp;Xinsong Fu","doi":"10.1016/j.cellsig.2025.112142","DOIUrl":"10.1016/j.cellsig.2025.112142","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains intractable because metastasis outruns intervention. Here we define TYROBP—a microglial adaptor previously unlinked to PDAC—as a pivotal metastatic driver. Transcriptomic mining and validation across paired human specimens revealed pronounced TYROBP up-regulation that trended with poorer survival. Gain- and loss-of-function studies showed that TYROBP potentiates PDAC cell migration and invasion without influencing proliferative indices in vitro or subcutaneous tumor growth in vivo. Mechanistically, transcription factor SP1 occupies a promoter motif (P1) to enforce TYROBP expression; TYROBP then complexes with cathepsin Z (CTSZ), enhancing CXCL8-mediated tumor-associated macrophage recruitment and activating a pAKT–CD44 axis independent of epithelial-to-mesenchymal transition while simultaneously accelerating glycolysis. The flavonoid baicalein engages TYROBP directly, abrogates CTSZ/pAKT/CD44 signaling, and curtails hepatic metastasis in mice without systemic toxicity. TYROBP knock-down blunts dissemination, whereas enforced TYROBP expression exacerbates metastasis—effects reversed by baicalein. Thus, the SP1-TYROBP-CTSZ axis licenses PDAC metastasis, and baicalein-mediated TYROBP inhibition offers a tractable therapeutic strategy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112142"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112161","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 of RNA binding proteins in regulating oocyte maturation","authors":"Lin Chen ,&nbsp;Jing Chen","doi":"10.1016/j.cellsig.2025.112150","DOIUrl":"10.1016/j.cellsig.2025.112150","url":null,"abstract":"<div><div>Oocyte maturation is a complex and delicate process involving multiple gene expression levels. RNA-binding proteins (RBPs) are pivotal regulators in oocyte maturation and mRNA metabolism through spatiotemporal control of processing, stability, localization, and translational activation. This review synthesizes current knowledge on RBPs-mediated regulatory networks on oocyte maturation and their impacts on oocyte quality and reproductive health. The characteristics of RBPs across species are also discussed, establishing a conceptual framework for developing novel therapeutic strategies to improve female fertility.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112150"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112219","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":"Intrabody targeting of insulin receptor pY1150: A novel approach to modulate signaling pathways in colorectal cancer cells","authors":"Ha Gyeong Shin ,&nbsp;Na-Oh Yunn ,&nbsp;Ji Woong Kim ,&nbsp;Yea Bin Cho ,&nbsp;Sung Ho Ryu ,&nbsp;Hyunbo Shim ,&nbsp;Sukmook Lee","doi":"10.1016/j.cellsig.2025.112143","DOIUrl":"10.1016/j.cellsig.2025.112143","url":null,"abstract":"<div><div>The activation of the insulin receptor (IR) is central to the regulation of physiological metabolism, growth, and proliferation, and is associated with various cancers, including colorectal cancer (CRC). Among the tyrosine residues in the intracellular kinase domain of IR, Tyr1150 plays a pivotal role in receptor activation by regulating substrate binding to the kinase active site. In this study, we introduce a novel approach for selectively modulating insulin signaling in CRC through the development of an intrabody targeting phosphorylated Tyr1150 (IR pY1150). Using phage display technology, we isolated a phosphorylation site-specific single-chain variable fragment (scFv), K109.1, from a human scFv antibody library, which specifically binds to IR pY1150. K109.1 was subsequently engineered as an intrabody designed to function within cells. Ectopic expression of K109.1 in CRC cells selectively inhibited insulin-mediated phosphorylation of key downstream effectors, including insulin receptor substrates and Akt, thereby leading to a significant reduction in insulin-dependent glucose uptake. Notably, K109.1 did not affect extracellular signal-regulated kinase phosphorylation or alter cell proliferation, migration, or invasion. We further evaluated K109.1 in BT-474 and HEK293 cells to assess its effects in additional cellular models. In BT-474 breast cancer cells, K109.1 selectively inhibited Akt phosphorylation, while in HEK293 cells it suppressed both Akt and ERK phosphorylation, indicating context-specific signaling responses. Taken together, these findings indicate that intrabody-mediated targeting of IR pY1150 is crucial for regulating glucose metabolism, suggesting that the developed antibody, K109.1, could serve as a tool for modulating insulin-mediated signaling pathways.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112143"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112186","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":"Exosomal non-coding RNA as a key mediator of ferroptosis in lung cancer","authors":"Chou-Yi Hsu ,&nbsp;Shaker Al-Hasnaawei ,&nbsp;Ashok Kumar ,&nbsp;Suhas Ballal ,&nbsp;Abdulrahman Abdulkaliq Mahmood ,&nbsp;Rishiv Kalia ,&nbsp;Kamal Kant Joshi ,&nbsp;Subhashree Ray ,&nbsp;Atreyi Pramanik","doi":"10.1016/j.cellsig.2025.112135","DOIUrl":"10.1016/j.cellsig.2025.112135","url":null,"abstract":"<div><div>Non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play essential roles in the pathogenesis of lung cancer by modulating ferroptosis, an iron-dependent form of regulated cell death. Given that lung cancer remains one of the leading causes of cancer-related mortality, elucidating its molecular mechanisms is of paramount importance. Exosomes, which act as carriers of bioactive molecules, facilitate intercellular communication through the transport of ncRNAs. Ferroptosis-associated exosomal ncRNAs influence critical biological processes such as lipid peroxidation, iron homeostasis, and antioxidant defense, thereby modulating tumor progression and therapeutic outcomes. Importantly, these ncRNAs exhibit context-dependent functions, acting as either tumor suppressors or oncogenic drivers. Their dual regulatory capacity underscores their promise as diagnostic biomarkers and potential therapeutic targets. This review highlights the emerging significance of exosomal ncRNAs in ferroptosis regulation within lung cancer and discusses their translational relevance in clinical settings.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112135"},"PeriodicalIF":3.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102765","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":"Primary cilia integrity governs TRPV4-mediated NF-κB/COL2 signaling in osteoarthritis pathogenesis","authors":"Yuyan Sun ,&nbsp;Ziyu Luo ,&nbsp;Haiqi Zhou ,&nbsp;Sha Wu ,&nbsp;Hongwei Shen ,&nbsp;Yuanyuan Fu ,&nbsp;ThaiNamanh Ngo ,&nbsp;Wen Wang ,&nbsp;Yuanrong Wang ,&nbsp;Ying Kong","doi":"10.1016/j.cellsig.2025.112141","DOIUrl":"10.1016/j.cellsig.2025.112141","url":null,"abstract":"<div><div>Chondrocyte mechanotransduction dysfunction is a key feature of osteoarthritis (OA). Previous studies have demonstrated that primary cilia play a crucial role in chondrocyte mechanosensation and signal transduction. Transient Receptor Potential Vanilloid 4 (TRPV4), which is highly expressed on primary cilia, is a critical mechanotransduction protein and one of the most important Ca²⁺ channels. However, the interplay between the mechanism of primary cilia-mediated signaling and that of TRPV4 channel regulation remains poorly understood. Here, we demonstrate that OA chondrocytes and Intraflagellar Transport Protein 88 (Ift88) conditional knockout (cKO) mice exhibit reduced ciliary incidence resulting in cartilage degeneration. TRPV4 expression inversely correlated with ciliary integrity, increasing as cilia were lost. In cilia-intact healthy chondrocytes, TRPV4 antagonism inhibited Ca²⁺-dependent NF-κB activation while promoting type II collagen (COL2) synthesis. These effects were abolished by Interleukin-1 beta (IL-1β)-induced ciliary defect or IFT88 deficiency. Chromatin immunoprecipitation (ChIP) analysis revealed disrupted p65 binding to the COL2 promoter upon the loss of ciliary integrity. Crucially, Ift88 cKO chondrocytes showed unresponsiveness of the TRPV4 channel, as confirmed by Ca²⁺ flux and changes in the expression levels of NF-κB and COL2. Our findings position primary cilia as indispensable regulators of TRPV4-mediated NF-κB - COL2 signaling, offering mechanistic insights into OA pathogenesis and identifying IFT88 as a therapeutic checkpoint.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112141"},"PeriodicalIF":3.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102805","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":"YTHDF2 drives oral squamous cell carcinoma progression via m6A-dependent degradation of MTUS1/ATIP1 mRNA and mitochondrial dysregulation","authors":"Dongxiao Tang ,&nbsp;Congyuan Cao ,&nbsp;Shuojin Huang ,&nbsp;Qianting He ,&nbsp;Anxun Wang","doi":"10.1016/j.cellsig.2025.112145","DOIUrl":"10.1016/j.cellsig.2025.112145","url":null,"abstract":"<div><div>N6-methyladenosine (m⁶A), the most abundant RNA modification, regulates mRNA stability through reader proteins such as YTHDF2. Here, we investigate YTHDF2's role in oral squamous cell carcinoma (OSCC) progression. Clinical analyses revealed elevated YTHDF2 expression in OSCC tumors compared to normal tissues, correlating with advanced disease stage, metastasis, and reduced patient survival. Mechanistically, OSCC exhibits global m⁶A hypomethylation, while YTHDF2 selectively destabilizes tumor-suppressive MTUS1/ATIP1 mRNA by recognizing m⁶A motifs in its 3′ untranslated region. Functional studies using lentiviral overexpression and knockdown models demonstrated that YTHDF2 promotes tumor growth and mitochondrial dysfunction, whereas its suppression inhibits malignant behaviors and stabilizes MTUS1/ATIP1. Co-silencing MTUS1/ATIP1 reversed the anti-tumor effects of YTHDF2 depletion in vitro and in subcutaneous xenograft models. These findings establish YTHDF2 as a driver of OSCC progression through m⁶A-dependent suppression of MTUS1/ATIP1, linking mitochondrial dysregulation to tumorigenesis. Our study proposes therapeutic targeting of the YTHDF2-MTUS1/ATIP1 axis to improve OSCC management.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112145"},"PeriodicalIF":3.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102764","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":"SIRT5 regulates fatty acid oxidation and mitochondrial oxidative stress to exacerbate airway inflammation in experimental asthma","authors":"Jie Wu ,&nbsp;Yanhong Wang ,&nbsp;Qian Zhang ,&nbsp;Yisheng Lan ,&nbsp;Meijia Chen ,&nbsp;Junrao Wang ,&nbsp;Xueying Zhao ,&nbsp;Yaoxin Chen ,&nbsp;Xianru Peng ,&nbsp;Wenqu Zhao ,&nbsp;Haijin Zhao","doi":"10.1016/j.cellsig.2025.112149","DOIUrl":"10.1016/j.cellsig.2025.112149","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial dysfunction is a critical factor in the pathogenesis of asthma. SIRT5(sirtuin 5), a key regulator of metabolic homeostasis, modulates various pathways, including fatty acid oxidation (FAO), through the desuccinylation of essential enzymes. However, the precise role of SIRT5 and FAO in mitochondrial dysfunction and their contribution to asthma progression remain unclear.</div></div><div><h3>Methods</h3><div>Male C57BL/6J mice were sensitized and challenged with toluene-2, 4-diisocyanate (TDI) to generate a steroid-insensitive asthma model, and mice were treated by SIRT5 inhibitor MC3482. In vitro, human bronchial epithelial cells (16HBE) were pretreated by MC3482 before TDI-human serum albumin (HSA) stimulation.</div></div><div><h3>Results</h3><div>We observed an upregulation of SIRT5 in TDI-exposed mice and 16HBE cells. Inhibiting SIRT5 with MC3482 dramatically attenuated airway hyperresponsiveness (AHR), airway inflammation, airway goblet cell metaplasia and collagen deposition in TDI-induced asthmatic mice. In addition, MC3482 effectively decreased mitochondrial ROS production, alleviated mitochondrial morphology disruption, mitochondrial membrane potential deficiency and superoxide dismutase(<em>SOD</em>)activity, as well as reduced the expression of IL-6 and IL-1β in 16HBE cells treated by TDI-HSA. Mechanistically, succinylation of CPT2, VLCAD and HADHA was significantly increased by SIRT5 inhibition, leading to the inactivation of its enzymatic activity and the subsequent decrease of FAO in asthma.</div></div><div><h3>Conclusions</h3><div>We identify SIRT5 as a novel regulator of FAO and mitochondrial oxidative stress in TDI-induced asthma. Targeting SIRT5 by MC3482 may provide promising therapeutic approach for asthma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112149"},"PeriodicalIF":3.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102807","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":"LRRc17-RANKL pathway regulates mitophagy and contributes to atrial remodeling in diabetes","authors":"Lu Zhou ,&nbsp;Daiqi Liu ,&nbsp;Qiankun Bao ,&nbsp;Zandong Zhou ,&nbsp;Ziheng Jia ,&nbsp;Xinyi Gao ,&nbsp;Wenhua Song ,&nbsp;Gary Tse ,&nbsp;Gregory Y.H. Lip ,&nbsp;Tong Liu ,&nbsp;Qingmiao Shao","doi":"10.1016/j.cellsig.2025.112148","DOIUrl":"10.1016/j.cellsig.2025.112148","url":null,"abstract":"<div><h3>Background</h3><div>Impaired autophagy and mitochondrial dysfunction are significant causes of atrial remodeling, increasing the risk of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). Both LRRc17 and RANKL proteins are involved in the autophagic mechanism. Nevertheless, there is limited understanding of the mechanisms how LRRc17 and RANKL regulate mitophagy to facilitate atrial remodeling under diabetic conditions.</div></div><div><h3>Methods</h3><div>Echocardiography, intracardiac programmed electrical stimulation, and epicardial electrical activation mapping were used to identify atrial remodeling. Mitophagy was identified by western blot analysis and immunofluorescence techniques. The regulatory relationship between LRRc17 and RANKL was validated using lentiviral transfection and siRNA knockdown. This work employed AAV9-cTNT-RANKL vectors to overexpress RANKL in the myocardium of diabetic mice for determining its specific involvement.</div></div><div><h3>Results</h3><div>Significant atrial remodeling caused by diabetes was characterized by enlarged atrium, increased fibrotic interstitial deposits, and abnormal electrical conduction. In diabetic atrial tissue, the level of LRRc17 protein was downregulated and RANKL protein expression was elevated. The negative regulatory function of LRRc17 on RANKL in atrial myocytes was elucidated using HL-1 cells. Overexpression of RANKL highlighted its critical role in causing mitochondrial malfunction. And the administration of the RANKL antagonist, denosumab, markedly improved the compromised mitophagy.</div></div><div><h3>Conclusion</h3><div>In atrial myocytes, mitophagy is mediated by the LRRc17-RANKL pathway. Diabetes induced atrial remodeling may worsen due to the overexpression of RANKL brought on by the decrease in LRRc17. The LRRc17-RANKL pathway may be a therapy option for diabetic atrial remodeling by improving mitochondrial function.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112148"},"PeriodicalIF":3.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102749","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":"PIGK regulates lipophagy in colorectal cancer through ABHD5","authors":"Di Lu ,&nbsp;Xiaofang Li ,&nbsp;Yuan Yuan ,&nbsp;Yuanzeng Zhu ,&nbsp;Zhiyu Yang ,&nbsp;Haifeng Guo ,&nbsp;Jiannan Wang ,&nbsp;XiuLei Zhang ,&nbsp;Qian Zhang ,&nbsp;Bingxi Zhou","doi":"10.1016/j.cellsig.2025.112147","DOIUrl":"10.1016/j.cellsig.2025.112147","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal Cancer (CRC) is a prevalent malignant tumor with a high incidence and mortality rate worldwide. Despite the availability of various treatment options, CRC remains a significant health challenge due to its complexity and heterogeneity. The objective of this study is to investigate the role of PIGK in CRC and to elucidate the underlying mechanisms that contribute to its impact on the disease.</div></div><div><h3>Results</h3><div>Our analysis of the TCGA database revealed that PIGK expression is significantly elevated in CRC tissues compared to normal tissues, with higher expression levels correlating with improved patient prognosis. In vitro experiments demonstrated that PIGK can suppress the proliferation of CRC cells by promoting autophagy. Further mechanistic exploration showed that PIGK upregulates the expression of ABHD5, influencing lipophagy. We also identified the pivotal role of the PIGK-ABHD5-PPARα signaling pathway in the regulation of lipophagy. Tumorigenesis experiments in nude mice confirmed PIGK's inhibitory effect on tumor growth and its role in modulating lipophagy through ABHD5.</div></div><div><h3>Conclusions</h3><div>In summary, our findings not only highlight PIGK as a novel molecular target in CRC but also suggest that targeting the PIGK-ABHD5-PPARα signaling axis could offer a promising therapeutic strategy. By influencing lipophagy, PIGK presents a potential avenue for improving CRC treatment outcomes, which could have significant implications for patient management and the development of new treatment protocols.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112147"},"PeriodicalIF":3.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102745","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":"Fibroblast-secreted ADAMTSL2 promotes cardiac repair after myocardial infarction by activating LRP6/β-catenin signaling","authors":"Wenjing Wang ,&nbsp;Ye He ,&nbsp;Daheng Liang,&nbsp;Liuhua Zhou,&nbsp;Tongtong Yang,&nbsp;Lingfeng Gu,&nbsp;Chong Du,&nbsp;Sibo Wang,&nbsp;Hao Wang,&nbsp;Liansheng Wang,&nbsp;Qiming Wang","doi":"10.1016/j.cellsig.2025.112144","DOIUrl":"10.1016/j.cellsig.2025.112144","url":null,"abstract":"<div><div>When coronary reperfusion is delayed in myocardial infarction (MI), persistent ischemic injury induces progressive loss of cardiomyocytes, ultimately resulting in pathological ventricular remodeling and heart failure. Secreted proteins may play a critical role in modulating cardiomyocyte death following MI, offering potential therapeutic targets. This study elucidated the biological function of fibroblast-secreted ADAMTSL2 in cardiomyocyte apoptosis post-MI. Elevated ADAMTSL2 levels were detected by ELISA in the serum of acute myocardial infarction patients and by immunoblotting in the infarcted myocardium of mice. Hypoxia treatment significantly upregulated ADAMTSL2 expression in neonatal rat cardiac fibroblasts (NRCFs), whereas no such hypoxic response was observed in neonatal rat cardiomyocytes (NRCMs). In vitro, overexpression of ADAMTSL2 in NRCFs attenuated oxygen-glucose deprivation (OGD)-induced apoptosis in NRCMs, whereas knockdown of ADAMTSL2 in NRCFs exacerbated cardiomyocyte apoptosis. In vivo, fibroblast-targeted overexpression of ADAMTSL2 by adenovirus 5 significantly reduced cardiomyocyte apoptosis and ameliorated adverse left ventricular remodeling post-MI. Conversely, ADAMTSL2 knockdown exacerbated infarct size and accelerated pathological remodeling. Mechanistically, ADAMTSL2 overexpression increased the expression of β-catenin in cardiomyocytes. Co-immunoprecipitation (Co-IP) assay showed that ADAMTSL2 could directly bind to LRP6 and promote its phosphorylation, leading to β-catenin stabilization and subsequent nuclear translocation. In summary, our study indicates that ADAMTSL2 protects against cardiomyocyte apoptosis and promotes cardiac repair by activating LRP6/β-catenin signaling.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112144"},"PeriodicalIF":3.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102782","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}