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Ac4C acetylation is an important epigenetic regulation of RNAs that has been recently discovered, and it is solely carried out by NAT10, the exclusive enzyme used for the modification. However, the potential regulatory mechanisms of ac4C acetylation in myocardial fibrosis following myocardial infarction remain poorly understood. In our study, we activated fibroblasts in\u00a0vitro using TGF\u2010\u03b21 (20\u2009ng\/mL), followed by establishing a myocardial infarction mouse model to evaluate the impact of NAT10 on collagen synthesis and cardiac fibroblast proliferation. We utilized a NAT10 inhibitor, Remodelin, to attenuate the acetylation capacity of NAT10. In the cardiac fibrosis tissues of chronic myocardial infarction mice and cultured cardiac fibroblasts (CFs) in response to TGF\u2010\u03b21 treatment, there was an elevation in the levels of NAT10 expression. This increase facilitated proliferation, the accumulation of collagens, as well as fibroblast\u2010to\u2010myofibroblast transition. Through the administration of Remodelin, we effectively reduced cardiac fibrosis in myocardial infarction mice by inhibiting NAT10's ability to acetylate mRNA. Inhibition of NAT10 resulted in changes in collagen\u2010related gene expression and ac4C acetylation levels. Mechanistically, we found that NAT10 upregulates the acetylation modification of BCL\u2010XL mRNA and enhances the stability of BCL\u2010XL mRNA, thereby upregulating its protein expression, inhibiting the activation of Caspase3 and blocking the apoptosis of CFs. Therefore, the crucial involvement of NAT10\u2010mediated ac4C acetylation is significant in the cardiac fibrosis progression, affording promising molecular targets for the treatment of fibrosis and relevant cardiac diseases.<\/jats:p>","DOI":"10.1111\/jcmm.70141","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T07:39:33Z","timestamp":1730446773000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["NAT10\u2010mediated RNA ac4C acetylation contributes to the myocardial infarction\u2010induced cardiac fibrosis"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5263-0918","authenticated-orcid":false,"given":"Jun","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan Hubei China"},{"name":"Cardiovascular Research Institute Wuhan University  Wuhan Hubei China"},{"name":"Hubei Key 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Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 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