This study investigates the role of N6-methyladenosine (m6A) RNA modification and its methyltransferase METTL3 in doxorubicin (DOX)-induced cardiotoxicity (DIC). The authors found that DOX treatment increased m6A modification and METTL3 expression in cardiomyocytes, which was dependent on c-Jun. Cardiomyocyte-specific conditional knockout of METTL3 improved cardiac function and reduced injury following DOX exposure. Inhibition of METTL3 alleviated DOX-induced iron accumulation and ferroptosis in cardiomyocytes, while METTL3 overexpression had the opposite effect. Mechanistically, METTL3 promoted m6A modification of TFRC mRNA, a gene regulating iron uptake, and enhanced its stability through the recognition of the m6A reader protein IGF2BP2. Pharmacological inhibition of METTL3 with a selective inhibitor, STM2457, effectively ameliorated DIC in mice. These findings suggest that METTL3 plays a crucial role in DIC by regulating cardiac iron metabolism and ferroptosis through TFRC m6A modification, and targeting METTL3 may be a potential therapeutic approach for DIC.This study investigates the role of N6-methyladenosine (m6A) RNA modification and its methyltransferase METTL3 in doxorubicin (DOX)-induced cardiotoxicity (DIC). The authors found that DOX treatment increased m6A modification and METTL3 expression in cardiomyocytes, which was dependent on c-Jun. Cardiomyocyte-specific conditional knockout of METTL3 improved cardiac function and reduced injury following DOX exposure. Inhibition of METTL3 alleviated DOX-induced iron accumulation and ferroptosis in cardiomyocytes, while METTL3 overexpression had the opposite effect. Mechanistically, METTL3 promoted m6A modification of TFRC mRNA, a gene regulating iron uptake, and enhanced its stability through the recognition of the m6A reader protein IGF2BP2. Pharmacological inhibition of METTL3 with a selective inhibitor, STM2457, effectively ameliorated DIC in mice. These findings suggest that METTL3 plays a crucial role in DIC by regulating cardiac iron metabolism and ferroptosis through TFRC m6A modification, and targeting METTL3 may be a potential therapeutic approach for DIC.