METTL5 triggers the ferroptosis of cardiomyocytes in sepsis-induced myocardial injury.

Sepsis frequently precipitates a spectrum of serious organ dysfunction syndromes, notably inducing severe cardiac insufficiency. Emerging evidence have linked the roles of N6-methyladenosine (m6A) modification and ferroptosis to sepsis-induced myocardial injury. However, the potential mechanism of m6A regulator methyltransferase-like 5 (METTL5) in sepsis-induced myocardial injury is still unclear. In vivo rats' sepsis model, lipopolysaccharide (LPS) administration increased the level of METTL5 and m6A modification enrichment. In LPS-induced cardiomyocytes, METTL5 silencing (shRNA-METTL5) alleviated the lipid ROS accumulation, MDA, or iron overload, which also promoted cardiomyocytes' proliferation. The data indicated that METTL5 acted as a driver of ferroptosis in sepsis-induced myocardial injury. Mechanistically, METTL5 installed the m6A modification of NRF2 mRNA, and YTHDF2 targeted NRF2 mRNA to trigger its degradation. NRF2 could repress the ferroptosis in LPS-induced cardiomyocytes. Thus, METTL5 consequently accelerated the ferroptosis in sepsis-induced myocardial injury via YTHDF2/NRF2 axis and m6A-dependent manner. In summary, the findings revealed the function of METTL5 on LPS-induced cardiomyocytes' ferroptosis, providing a potential therapeutic target for sepsis-induced myocardial injury.