The impact of YTHDF2-mediated NCOA4 methylation on myocardial ferroptosis.

The N6-Methyladenosine (m6A) modification is prevalent across various RNA species, including messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs), and has garnered significant interest due to its potential implications in cardiovascular disease. Despite extensive research, the precise relationship between m6A and myocardial infarction (MI) remains inadequately understood. The human YTH domain family 2 (YTHDF2) protein has emerged as a critical factor in this context, selectively recognizing m6A-modified RNAs and modulating their degradation. Our investigation revealed that the knockdown of YTHDF2 markedly enhanced ferroptosis in vitro, whereas the overexpression of YTHDF2 exhibited a significant protective effect. Mechanistically, it was elucidated that YTHDF2 suppresses the expression of nuclear receptor coactivator 4 (NCOA4) via m6A methylation. Furthermore, the inhibition of cardiomyocyte ferroptosis by YTHDF2 is contingent upon its regulation of NCOA4. Additionally, the enzyme methyltransferase-like 3 (METTL3) was identified as a pivotal factor in the m6A-mediated degradation of NCOA4 mRNA. Taken together, our results highlight the significant role of YTHDF2-mediated NCOA4 m6A methylation in the regulation of myocardial infarction and myocardial ferroptosis, suggesting that YTHDF2 may be a promising target for therapeutic interventions in myocardial infarction.