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This study aimed to elucidate the role of RNA-binding motif single-stranded interacting protein 1 (RBMS1), an RNA-binding protein, in the development of HF by regulating AS and its effect on cardiac fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The level of RBMS1 was investigated in the hearts of both HF patients and mice. Fibroblast-specific knockout RBMS1 mice were generated to investigate the role of RBMS1 in cardiac fibrosis and HF. Unbiased RNA sequencing and RNA immunoprecipitation combined with RNA pull-down were conducted to identify the downstream effector of RBMS1 in fibroblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>RBMS1 expression was increased in murine hearts following myocardial infarction, as well as in the hearts of patients with ischaemic cardiomyopathy and hypertrophic cardiomyopathy. Moreover, RBMS1 levels in the hearts of HF patients were positively associated with cardiac fibrosis. Furthermore, fibroblast-specific ablation of RBMS1 improved cardiac dysfunction by mitigating myocardial fibrosis. Mechanistically, RBMS1 regulated the alternative splicing of LIM domain 7 (LMO7) by binding to intron 19 and splicing out exon 20, resulting in the formation of the LMO7-\u0394e20 isoform, which thus activated the transforming growth factor (TGF)-\u03b21 pathway by upregulating activator protein 1. More importantly, overexpression of LMO7-\u0394e20 in mice resulted in cardiac fibrosis and cardiac dysfunction, which was ablated after treatment with TGF-\u03b21 pathway inhibitor SB431542. In addition, SB431542 attenuated the RBMS1-driven fibrogenesis in human cardiac fibroblasts. Strikingly, pharmacologically inhibiting RBMS1 by low-dose nortriptyline or antisense oligonucleotide-mediated RBMS1 deficiency alleviated myocardial fibrosis and improved cardiac function in HF mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings unveil a critical role of RBMS1 in regulating cardiac fibrosis through controlling the splicing of LMO7 to activate the TGF-\u03b21 pathway. Genetic ablation or pharmacological inhibition of RBMS1 improves cardiac function in mice, suggesting its potential as a therapeutic target for HF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf370","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T08:20:46Z","timestamp":1747383646000},"page":"110-127","source":"Crossref","is-referenced-by-count":17,"title":["Deficiency of the RNA-binding protein RBMS1 improves myocardial fibrosis and heart failure"],"prefix":"10.1093","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5493-4809","authenticated-orcid":false,"given":"Liangliang","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University , 157 Baojian Road, Harbin 150081 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4051-7904","authenticated-orcid":false,"given":"Jiayu","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University , 157 Baojian Road, Harbin 150081 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayue","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of 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