GSTP1 Attenuates DOX-Induced Cardiomyopathy by Inhibiting Iron Deposition via JNK

GSTP1 inhibits iron deposition through JNK to alleviate DOX-induced myocardial disease.

Doxorubicin (DOX) is a widely used chemotherapy drug, but its clinical application is often limited by cardiotoxicity. Iron deposition is a critical factor contributing to DOX-induced cardiomyopathy. Our previous study showed that GSTP1, a glutathione S-transferase enzyme, protects against DOX-induced cardiotoxicity. However, the underlying mechanism remains unclear. In this study, we investigated the role of GSTP1 in regulating iron deposition in the heart and its impact on DOX-induced cardiomyopathy.

We found that GSTP1 expression was significantly reduced in the hearts of DOX-treated mice, accompanied by increased iron accumulation. Overexpression of GSTP1 in cardiomyocytes attenuated iron deposition and ameliorated DOX-induced cardiac dysfunction. Conversely, knockdown of GSTP1 exacerbated iron deposition and cardiac damage. Further investigation revealed that GSTP1 inhibited iron deposition by suppressing the JNK signaling pathway. Activation of JNK promoted iron accumulation in cardiomyocytes, whereas inhibition of JNK reduced iron deposition. GSTP1 directly interacted with JNK and blocked its phosphorylation, thereby inhibiting its activation.

These findings suggest that GSTP1 plays a protective role against DOX-induced cardiomyopathy by suppressing iron deposition through the inhibition of JNK signaling. Our study provides novel insights into the mechanism underlying GSTP1-mediated cardioprotection and highlights its potential as a therapeutic target for the treatment of DOX-induced heart disease.