METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7.

N-methyladenosine (mA) mRNA modification is the most common mRNA internal modification in eukaryotes, which participates in a variety of biological processes. However, the role of mA methylation in regulating autophagy induced by ischemia and hypoxia remains to be widely investigated. Here, we investigated the impact of METTL3, a key mA methyltransferase, on the autophagy regulation in ischemic and hypoxic cardiomyocytes, as well as in mice following acute myocardial infarction (AMI). METTL3 negatively regulated autophagy in cardiomyocytes under ischemia and hypoxia conditions. Silencing METTL3 enhanced autophagy and mitigated cardiomyocyte injury, whereas overexpression of METTL3 exerted the opposite effect. Mechanistically, METTL3 methylated ATG7 mRNA, a crucial autophagy-related gene, leads to the recruitment of the mA-binding protein YTHDF2. Subsequently, YTHDF2 facilitated the degradation of ATG7 mRNA, consequently inhibiting autophagy and exacerbating cellular damage. Our study shed light on the pivotal role of METTL3-mediated mA modification in the regulation of autophagy during AMI, providing novel insights into the functional significance of mA methylation and its regulatory mechanisms.