Ferroptosis is an iron-dependent and phospholipid peroxidation-mediated cell death, which has been identified to be involved in sepsis-induced injury. However, the in-depth molecular mechanisms of N 6 -methyladenosine (m 6 A) and ferroptosis on sepsis-induced myocardial injury are still unclear. Here, in the septic myocardial injury, m 6 A methyltransferase METTL3 level and methylation level high-expressed in lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2). Functionally, METTL3 silencing repressed the ferroptosis phenotype induced by LPS. Mechanistically, METTL3-mediated m 6 A methylation on solute carrier family 7 member 11 (SLC7A11) empowered its mRNA with high methylation level. Moreover, YTHDF2 directly bound to the m 6 A modification sites of SLC7A11 to mediate the mRNA degradation. The m 6 A modified SLC7A11 mRNA was recognized by YTHDF2, which promoted the decay of SLC7A11 mRNA, consequently up-regulating ferroptosis in sepsis-induced myocardial injury. Together, these findings establish a role of METTL3 in the ferroptosis of LPS-induced cardiomyocytes, and provide potential therapeutic target to treat the sepsis-induced myocardial injury.
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