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

## TL;DR

Shen-yuan-dan capsule improves heart function after heart attacks by inhibiting METTL3 and restoring autophagy.

## Contribution

This study reveals a novel mechanism by which SYD alleviates post-MI heart failure through METTL3-mediated m6A methylation and autophagy regulation.

## Key findings

- SYD treatment improved cardiac function and reduced hypertrophy in post-MI mice.
- SYD inhibited m6A methylation and METTL3 expression in both in vivo and in vitro models.
- SYD restored autophagy by modulating the mTOR/TFEB pathway.

## Abstract

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.

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.

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.

SYD alleviates post-MI HF by regulating the mTOR/TFEB autophagy pathway through inhibition of METTL3-mediated m6A modification.

Diagram illustrating the pathway by which SYDC inhibits METTL3, reducing m6A RNA methylation and mTOR phosphorylation, leading to TFEB activation and promoting autophagy progression from phagophore to degradation via autolysosome.