5-Methoxypsoralen

Doxorubicin (DOX) is a frequently recommended chemotherapeutic agent. The dose-dependent and cumulative cardiotoxicity of DOX prevents its therapeutic use despite its clinical efficacy. Bergapten (BeG) is a naturally occurring furanocoumarin found in citrus fruits. We investigated the cardioprotective potential of BeG against DOX-induced cardiotoxicity. In both in vitro and in vivo models, BeG intervention lessens DOX-induced reactive oxygen species (ROS) generation, maintains mitochondrial membrane potential, lowers cardiomyocyte apoptosis, and restores the antioxidant defence system. Mechanistically, BeG mitigates oxidative damage by downregulating NADPH oxidase 4 (NOX4) expression, a key mediator of ROS production in cardiomyocytes. BeG intervention markedly impeded the DOX-induced downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant protein, heme oxygenase-1 (HO-1). In contrast, Nrf2 silencing abrogated the beneficial effects of BeG on DOX-treated H9c2 cells. These molecular events, through modulation of the NOX4/Nrf2/HO-1 signaling axis, collectively restore redox balance, reduce lipid peroxidation, and inhibit pro-apoptotic signaling by inhibiting the caspase-3 protein, while upregulating the anti-apoptotic Bcl-2 protein. Furthermore, BeG intervention improved echocardiography parameters, maintained cardiac histology, and reduced TUNEL-positive cells in DOX-treated animals. These findings suggest that BeG is a promising cardioprotective agent that targets key oxidative and apoptotic pathways and may be considered as an adjunctive therapy in DOX-induced toxicities.