Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis. Doxorubicin (DOX) is a chemotherapeutic drug with significant cardiotoxicity, limiting its clinical use. This study demonstrates that METTL3, a methyltransferase involved in m⁶A RNA modification, plays a critical role in DOX-induced cardiotoxicity (DIC) by regulating iron metabolism and ferroptosis in cardiomyocytes. DOX increases METTL3 expression and m⁶A modification in cardiomyocytes, which promotes TFRC mRNA stability through the m⁶A reader protein IGF2BP2. This enhances iron uptake and ferroptosis, leading to cardiac injury. Inhibition of METTL3, either through genetic knockout or pharmacological agents like STM2457, reduces iron accumulation, ferroptosis, and cardiac dysfunction. METTL3 deficiency prevents DOX-induced cardiac injury by suppressing TFRC-mediated iron uptake and ferroptosis. These findings suggest that targeting METTL3 could be a potential therapeutic strategy for DIC. The study highlights the role of m⁶A modification in regulating iron homeostasis and ferroptosis in cardiomyocytes, providing new insights into the mechanisms underlying DOX-induced cardiotoxicity.Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis. Doxorubicin (DOX) is a chemotherapeutic drug with significant cardiotoxicity, limiting its clinical use. This study demonstrates that METTL3, a methyltransferase involved in m⁶A RNA modification, plays a critical role in DOX-induced cardiotoxicity (DIC) by regulating iron metabolism and ferroptosis in cardiomyocytes. DOX increases METTL3 expression and m⁶A modification in cardiomyocytes, which promotes TFRC mRNA stability through the m⁶A reader protein IGF2BP2. This enhances iron uptake and ferroptosis, leading to cardiac injury. Inhibition of METTL3, either through genetic knockout or pharmacological agents like STM2457, reduces iron accumulation, ferroptosis, and cardiac dysfunction. METTL3 deficiency prevents DOX-induced cardiac injury by suppressing TFRC-mediated iron uptake and ferroptosis. These findings suggest that targeting METTL3 could be a potential therapeutic strategy for DIC. The study highlights the role of m⁶A modification in regulating iron homeostasis and ferroptosis in cardiomyocytes, providing new insights into the mechanisms underlying DOX-induced cardiotoxicity.