Limitations of Ferroptosis Inhibitors on the Doxorubicin-Induced Cardiotoxicity

Abstract

Doxorubicin is an anthracycline anticancer drug commonly used to treat lymphoma and breast cancer. Its major side effect is cardiotoxicity, which occurs by damaging cardiomyocytes. The mechanisms of doxorubicin-induced cardiotoxicity remain unclear; however, recent studies suggest that ferroptosis, an iron-dependent form of lipid peroxidation-mediated cell death, may play a key role. In this study, we investigated the role of ferroptosis in doxorubicin-induced cardiotoxicity using ferroptosis-specific inhibitors (ferrostatin-1 and liproxstatin-1). In both H9c2 cardiomyocyte cell lines and human induced pluripotent stem cell-derived cardiomyocytes, ferrostatin-1 and liproxstatin-1 rescued cell death induced by RSL3, a ferroptosis inducer, but failed to prevent doxorubicin-induced cell death. Additionally, the ferroptosis inhibitors did not restore the electrophysiological function of cardiomyocytes, measured using a multi-electrode array system, and instead slightly accelerated cardiomyocyte beating. Finally, doxorubicin-injected mice treated with ferroptosis inhibitors exhibited significantly reduced survival and increased levels of N-terminal pro B-type natriuretic peptide, a biomarker of heart failure. These findings suggest that inhibiting ferroptosis alone is insufficient to mitigate doxorubicin-induced cardiotoxicity.