The FAK-NRF2 Axis Alleviates DOX-Induced Cardiotoxicity by Inhibiting Ferroptosis

Doxorubicin (DOX), a prevalent anthracycline chemotherapeutic agent, is associated with considerable cardiotoxicity, the molecular mechanisms of which remain incompletely understood. Focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase, plays a crucial role in cardiac survival signaling during both developmental and pathological stress conditions. In this study, we demonstrate that FAK overexpression in SKOV3 mice and AC16 cardiomyocytes ameliorates DOX-induced cardiomyopathy by inhibiting Ferroptosis. Mechanistically, DOX treatment induces Ferroptosis in cardiomyocytes by suppressing FAK activity. Furthermore, we reveal that FAK overexpression reduces DOX cardiotoxicity, at least in part, through the upregulation of the transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2). The protective effects of FAK against myocardial injury are nullified by NRF2 knockdown. Additionally, histone deacetylase 5 (HDAC5) may be involved in this protective pathway. These findings identify FAK as a critical regulator of DOX-induced cardiotoxicity and suggest that enhancing the FAK/NRF2/HDAC5 signaling axis in cardiac tissue could represent a promising strategy for preserving myocardial function in patients.

DOX; FAK; HDAC5; NRF2; cardiotoxicity.