GSTP1 Protects Against Doxorubicin-Induced Cardiotoxicity by Inhibiting Ferroptosis via JNK Suppression

GSTP1 reduces doxorubicin-induced myocardial damage through JNK inhibition. Doxorubicin (DOX) is a widely used chemotherapy drug, but its clinical application is limited by its cardiotoxicity. Ferroptosis, a newly recognized form of regulated cell death characterized by iron accumulation and lipid peroxidation, has been implicated in DOX-induced cardiotoxicity. Glutathione S-transferase P1 (GSTP1) is an antioxidant enzyme that plays a protective role in various diseases. In this study, we investigated the role of GSTP1 in DOX-induced cardiotoxicity and its underlying mechanisms. We found that DOX treatment significantly increased the levels of lipid peroxidation and iron accumulation in cardiomyocytes, leading to ferroptosis. Interestingly, overexpression of GSTP1 significantly attenuated DOX-induced ferroptosis and myocardial damage. Further investigation revealed that GSTP1 inhibited the activation of c-Jun N-terminal kinase (JNK), a key signaling pathway involved in ferroptosis. Inhibition of JNK by a specific inhibitor effectively reduced DOX-induced ferroptosis, suggesting that JNK is a downstream target of GSTP1 in protecting against DOX-induced cardiotoxicity. Our findings demonstrate that GSTP1 protects against DOX-induced cardiotoxicity by inhibiting ferroptosis through JNK suppression. These results highlight the potential therapeutic value of targeting GSTP1 and JNK signaling pathway for mitigating DOX-induced cardiotoxicity.