Ginkgolide B mitigates doxorubicin-induced cardiotoxicity by regulating AMPK-mediated mitochondrial fission via P-Drp1/OPA1 and apoptosis

BACKGROUND Doxorubicin (DOX) is an effective chemotherapeutic agent but is limited by its severe cardiotoxicity, causing mitochondrial dysfunction and apoptosis in cardiomyocytes. Ginkgolide B, derived from Ginkgo biloba, shows potential cardioprotective effects. OBJECTIVE To investigate the protective effects of Ginkgolide B on DOX-induced cardiotoxicity, focusing on mitochondrial stability and apoptosis. METHODS In vitro, H9C2 cardiomyoblasts were treated with DOX and Ginkgolide B to assess cell viability, apoptosis, ROS production, mitochondrial membrane potential, and related protein expression via CCK-8, flow cytometry, fluorescence staining, and Western blot. In vivo, male SD rats were assigned to five unique treatment groups; dose-response analyses compared control, DOX, DOX + Ginkgolide B 5 mg/kg, and DOX + Ginkgolide B 10 mg/kg groups, whereas AMPK-mechanism analyses additionally included the DOX + Ginkgolide B 10 mg/kg + O304 group. Cardiac function, histopathology, serum biomarkers, and mitochondrial/apoptotic signaling proteins were evaluated. RESULTS Ginkgolide B improved the survival rate and cardiac function of DOX treated rats and reduced myocardial injury. It normalizes apoptosis and mitochondrial protein expression, increases mitochondrial membrane potential, reduces ROS levels and apoptosis in H9C2 cells, and also reduces DOX-associated AMPK phosphorylation. O304, an AMPK activator, partially reversed these protective effects, supporting the involvement of AMPK-associated signaling. The Ginkgolide B-associated changes in p-Drp1/OPA1 expression and cell viability were not observed after AMPK knockdown, further supporting AMPK involvement. CONCLUSIONS Ginkgolide B alleviates DOX-induced cardiotoxicity by modulating AMPK-associated mitochondrial homeostasis and inhibiting apoptosis, supporting its potential as an adjunctive therapy in DOX-based treatments.