Finerenone improves doxorubicin-induced cardiotoxicity by inhibiting cardiomyocyte apoptosis through the TAK1-p38 axis.

Although doxorubicin (DOX) is a potent chemotherapeutic agent, its clinical use is limited by dose-dependent cardiotoxicity. Doxorubicin-induced cardiotoxicity (DIC) promotes cardiomyocyte apoptosis, which leads to cardiac dysfunction, remodeling, and even heart failure. Although Finerenone (Fin), a selective mineralocorticoid receptor antagonist, has demonstrated benefit in the treatment of heart failure, its role in DIC remains unclear. Our study found that Finerenone mitigated myocardial injury, cardiac dysfunction, fibrosis, and remodeling by attenuating DOX-induced cardiomyocyte apoptosis, and it improved survival in a DIC mouse model. Similarly, Finerenone reduced injury and apoptosis in DOX-treated H9c2 cells. We identified key targets of Finerenone in DIC using proteomics and network pharmacology and demonstrated that it prevented the upregulation of p38 phosphorylation induced by DOX. Through in vitro experiments, we confirmed that TAK1-p38 played a critical role in mediating the protective effects of Finerenone against DIC. Furthermore, we found that Finerenone inhibits TAK1-p38 phosphorylation and cardiomyocyte apoptosis by antagonizing MR to suppress ROS. Overall, these results suggested that Finerenone ameliorated DIC primarily by inhibiting cardiomyocyte apoptosis via the TAK1-p38 pathway. Our findings elucidate a key mechanism underlying the cardioprotective effect of Finerenone in DIC and provide a theoretical basis for expanding its clinical applications.