Shen-yuan-dan capsule inhibits METTL3-mediated m6A methylation to restore autophagy homeostasis and attenuate post-myocardial infarction heart failure

Background Heart failure (HF) after myocardial infarction (MI) is a serious health issue. This study investigates the therapeutic effects of Shen-Yuan-Dan Capsule (SYD) on post-MI HF and explores its mechanisms, particularly involving m6A modification and autophagy. Methods Network pharmacology and MeRIP-seq were used to predict potential targets. A murine model of post-MI HF was established by ligating the left anterior descending artery in C57BL/6J mice, which were treated with SYD for 6 weeks. Cardiac function, autophagy-related proteins, m6A methylation, and METTL3 levels were assessed. In vitro , H9c2 cardiomyocytes were treated with Phenylephrine (PE) and SYD for 24 h, and hypertrophic biomarkers, autophagy proteins, and m6A methylation were measured. METTL3-overexpressing H9c2 cells were also used to investigate SYD’s effects on gene expression. Results In vivo , SYD treatment significantly improved cardiac function in MI mice, including reduced cardiac hypertrophy, enhanced ejection fraction and fractional shortening, and alleviated myocardial damage, fibrosis, and HF biomarkers. In vitro , SYD inhibited PE-induced hypertrophy in H9c2 cells, including a reduction in cell surface area and a decrease in hypertrophic biomarker levels. SYD also inhibited m6A methylation and METTL3 expression. In both MI mice and PE-treated H9c2 cells, SYD lowered m6A levels and METTL3 expression. Bioinformatics analysis identified autophagy-related signaling pathways. Electron microscopy and autophagy marker detection in myocardial tissue and H9c2 cells showed that SYD restored autophagy levels by regulating the mTOR/TFEB autophagy pathway. In METTL3-overexpressing H9c2 cells, SYD treatment reversed the hypertrophy induced by METTL3 overexpression. Conclusion SYD alleviates post-MI HF by regulating the mTOR/TFEB autophagy pathway through inhibition of METTL3-mediated m6A modification.