Ellagic Acid Attenuates Doxorubicin-induced Cardiomyocyte Ferroptosis Via Nuclear Factor Erythroid 2-Related Factor 2 Signaling

Doxorubicin, a widely used chemotherapeutic agent, is clinically limited by its dose-dependent cardiotoxicity, in which cardiomyocyte ferroptosis has recently been identified as a critical pathogenic mechanism. Consequently, targeting myocardial ferroptosis has emerged as a promising strategy to reduce doxorubicin-induced cardiac injury. Ellagic acid, a naturally occurring polyphenolic compound, possesses potent antioxidant and anti-inflammatory properties that contribute to its cytoprotective effects. This study aimed to investigate the protective role of ellagic acid against doxorubicin-induced cardiomyocyte ferroptosis and elucidate its underlying mechanisms. Using H9C2 cells and human-induced pluripotent stem cell-derived cardiomyocytes, we established in vitro models of doxorubicin-induced cardiac ferroptosis. Ellagic acid treatment markedly upregulated the expression of anti-ferroptosis proteins, reduced reactive oxygen species accumulation, and alleviated lipid peroxidation, thereby suppressing doxorubicin-triggered ferroptosis. Moreover, the anti-ferroptosis effects of ellagic acid were validated in vivo. Mechanistically, these cardioprotective actions were mediated through the activation of the nuclear factor erythroid 2-related factor 2 signaling pathway. In conclusion, our findings identify ellagic acid as a novel nuclear factor erythroid 2-related factor 2 activator that protects against doxorubicin-induced cardiotoxicity by inhibiting ferroptosis in cardiomyocytes.