Esculetin Attenuates Doxorubicin‐Induced Cardiotoxicity via Modulation of Apoptotic and Mitochondrial Gene Expression Networks

ABSTRACT Doxorubicin (DOX), although widely used as a potent chemotherapeutic agent, is limited by its dose‐dependent cardiotoxicity. Esculetin (E), a naturally occurring coumarin derivative, has been reported to exert antioxidant and anti‐apoptotic effects in various tissues. This study aimed to evaluate the cardioprotective effects of esculetin against DOX‐induced cardiac injury in rats by examining changes in the expression of genes related to apoptosis, oxidative stress, and mitochondrial function. Male Wistar rats were randomly assigned into six groups (Control, DOX, E50, E100, DOX + E50, DOX + E100). Cardiotoxicity was induced by administering DOX was administered as six intraperitoneal injections of 5 mg/kg each over 14 days (cumulative dose = 30 mg/kg). Serum cardiac markers (CK‐MB, LDH, and cTn‐I) were measured, and cardiac tissues were subjected to histopathological examination and RT‐qPCR analysis for target gene expression. In addition, hierarchical clustering heatmap was employed to evaluate multidimensional gene expression patterns across groups. DOX treatment significantly elevated serum cardiac injury markers and upregulated pro‐apoptotic genes ( Casp3, Casp9, Anf, Bnp, β‐Mhc ), while downregulating genes associated with mitochondrial biogenesis ( Pgc1α ) and antioxidant response ( Foxo1, Cox2 ). These findings suggest esculetin as a potential adjunctive candidate for cardioprotection during DOX chemotherapy. However, given the absence of protein‐level validation, further studies are warranted to confirm whether the observed gene expression changes translate into corresponding alterations at the protein level.