Esculetin attenuates doxorubicin-induced cardiac toxicity: Evidence from gene expression, enzyme activity, and molecular docking analyses

Abstract

Doxorubicin (DOX) is a potent chemotherapeutic agent whose dose-dependent cardiotoxicity is associated with oxidative stress, inflammation, and enzymatic dysfunction. This study evaluates the cardioprotective potential of esculetin, a natural coumarin derivative, against DOX-induced cardiac injury in rats. Forty-eight male Sprague-Dawley rats were divided into six groups, including control, DOX, esculetin (50 and 100 mg/kg), and combination treatments. DOX markedly altered the expression of oxidative stress-related genes (Ache, Ar, Sord upregulated; Pon1, Gst downregulated) and impaired enzyme activities, accompanied by increased malondialdehyde and depleted glutathione levels. Esculetin administration, particularly at 100 mg/kg, reversed these molecular and biochemical disturbances, restoring antioxidant defense and normalizing gene expression. Molecular docking revealed strong binding interactions of esculetin with the active sites of key enzymes including AR, SORD, AChE, GST, and PON1, supporting its regulatory role. These findings suggest that esculetin exerts multi-targeted protective effects and may serve as a promising candidate for mitigating chemotherapy-induced cardiotoxicity. Further research is warranted to explore its integration into clinical cardioprotective strategies.