Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy. Doxorubicin (DOX) is a chemotherapy drug used for various cancers but causes cardiotoxicity, limiting its clinical use. Lipid peroxidation, driven by excessive iron, is a key mechanism of DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ) is the only FDA-approved drug for reducing DIC but has significant side effects. This study shows that selenomethione (SeMet), a GPX4 activator, significantly reduces lipid peroxidation and protects against DIC. SeMet improved survival and reduced cardiac injury markers in mice and breast cancer patients. GPX4 depletion reversed SeMet's protective effects, indicating GPX4's role in preventing DIC. SeMet also enhanced DOX's antitumor effects without compromising its efficacy. Clinical trials showed SeMet reduced cardiac enzymes in breast cancer patients without adverse effects. SeMet, a selenium compound, activates GPX4, reducing lipid peroxidation and ferroptosis. It does not interfere with DOX's antitumor activity, making it a promising strategy for preventing DOX-induced cardiotoxicity. The study highlights the potential of GPX4 activation via selenium compounds as a novel therapeutic approach for DIC.Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy. Doxorubicin (DOX) is a chemotherapy drug used for various cancers but causes cardiotoxicity, limiting its clinical use. Lipid peroxidation, driven by excessive iron, is a key mechanism of DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ) is the only FDA-approved drug for reducing DIC but has significant side effects. This study shows that selenomethione (SeMet), a GPX4 activator, significantly reduces lipid peroxidation and protects against DIC. SeMet improved survival and reduced cardiac injury markers in mice and breast cancer patients. GPX4 depletion reversed SeMet's protective effects, indicating GPX4's role in preventing DIC. SeMet also enhanced DOX's antitumor effects without compromising its efficacy. Clinical trials showed SeMet reduced cardiac enzymes in breast cancer patients without adverse effects. SeMet, a selenium compound, activates GPX4, reducing lipid peroxidation and ferroptosis. It does not interfere with DOX's antitumor activity, making it a promising strategy for preventing DOX-induced cardiotoxicity. The study highlights the potential of GPX4 activation via selenium compounds as a novel therapeutic approach for DIC.