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Mettl1\u2010catalyzed RNA N7\u2010methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 and the mechanism underlying non\u2010ischemic cardiac hypertrophy and HF. It is found that Mettl1 is upregulated in human failing hearts and hypertrophic murine hearts following transverse aortic constriction (TAC) and Angiotensin II (Ang II) infusion. YY1 acts as a transcriptional factor for Mettl1 during cardiac hypertrophy. Mettl1 knockout alleviates cardiac hypertrophy and dysfunction upon pressure overload from TAC or Ang II stimulation. Conversely, cardiac\u2010specific overexpression of Mettl1 results in cardiac remodeling. Mechanically, Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA, facilitating alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy. Moreover, the knockdown of SRSF9 protects against TAC\u2010 or Mettl1\u2010induced cardiac hypertrophic phenotypes in vivo and in vitro. The study identifies Mettl1 as a crucial regulator of cardiac hypertrophy, providing a novel therapeutic target for HF.<\/jats:p>","DOI":"10.1002\/advs.202308769","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T14:54:41Z","timestamp":1716994481000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9\u2010Mediated Splicing of NFATc4"],"prefix":"10.1002","volume":"11","author":[{"given":"Shuting","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD) Department of Pharmacology (The State\u2010Province Key Laboratories of Biomedicine\u2010Pharmaceutics of China Key Laboratory of Cardiovascular Research Ministry of Education) College of Pharmacy Harbin Medical University Harbin 150081 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