This study investigates the cardioprotective effects of selenomethionine (SeMet) against doxorubicin (DOX)-induced cardiomyopathy (DIC). Single-nucleus RNA sequencing (snRNA-seq) identified myocardial and epithelial cells susceptible to DOX-induced ferroptosis. SeMet, a glutathione peroxidase 4 (GPX4) activator, significantly reduced lipid peroxidation and polyunsaturated fatty acids (PUFAs) levels in vitro and in vivo, improving survival rates and cardiac function in DOX-treated mice compared to other treatments. Depletion of GPX4 in mice eliminated the protective effect of SeMet. SeMet also reduced serum cardiac injury markers in breast cancer patients and breast cancer models with DOX, without compromising the antitumor efficacy of DOX. These findings suggest that pharmacological activation of GPX4 is a promising strategy to prevent DOX-induced cardiotoxicity.This study investigates the cardioprotective effects of selenomethionine (SeMet) against doxorubicin (DOX)-induced cardiomyopathy (DIC). Single-nucleus RNA sequencing (snRNA-seq) identified myocardial and epithelial cells susceptible to DOX-induced ferroptosis. SeMet, a glutathione peroxidase 4 (GPX4) activator, significantly reduced lipid peroxidation and polyunsaturated fatty acids (PUFAs) levels in vitro and in vivo, improving survival rates and cardiac function in DOX-treated mice compared to other treatments. Depletion of GPX4 in mice eliminated the protective effect of SeMet. SeMet also reduced serum cardiac injury markers in breast cancer patients and breast cancer models with DOX, without compromising the antitumor efficacy of DOX. These findings suggest that pharmacological activation of GPX4 is a promising strategy to prevent DOX-induced cardiotoxicity.