Idebenone protects against doxorubicin-induced cardiac injury by inhibiting ferroptosis in cardiomyocytes.

Abstract

Heart failure (HF) remains a global health challenge with limited efficacious therapies, necessitating novel strategies targeting its underlying pathological mechanisms. Emerging evidence implicates dysregulated iron metabolism and ferroptosis-an iron-dependent form of regulated cell death-as critical drivers of cardiomyocyte attrition in heart failure pathogenesis. This study investigates the therapeutic potential of idebenone (IDE), a clinically approved mitochondrial-targeted antioxidant and short-chain analog of coenzyme Q10, in modulating ferroptosis-mediated cardiac dysfunction. We confirmed that idebenone significantly attenuated pathological markers of cardiac stress, reducing expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cardiomyocytes. Furthermore, idebenone treatment suppressed lipid peroxidation and mitochondrial iron overload. In the HF animal model, idebenone administration improved left ventricular ejection fraction, restored redox homeostasis and reduced cardiac iron deposition. These findings establish idebenone as a promising strategy to mitigate ferroptosis-driven myocardial injury, providing a translational framework for developing idebenone-based therapies for heart failure management.