Ginkgetin Alleviates Doxorubicin-Induced Heart Failure by Regulating Mitochondrial Dysfunction Through the AMPK/Sirt1/NF-κB Signaling Pathway

Background: Heart failure (HF) represents the terminal stage of many cardiovascular diseases. Doxorubicin (DOX) can induce HF through oxidative stress (OS), inflammation, and apoptosis. Ginkgetin (GK) has potential cardioprotective effects, but its underlying mechanisms remain unclear. Aims: To investigate of GK against DOX-induced HF and explored its mechanisms, focusing on mitochondrial function and related signaling pathways. Study Design: experimental models. Methods: HF was induced by DOX in mice and H9c2 cardiomyocytes. Cardiac function, myocardial injury, OS, inflammation, and apoptosis were assessed using echocardiography, biochemical assays, enzyme-linked immunosorbent assay, histopathology, immunofluorescence, and Western blot. Mitochondrial function was evaluated via transmission electron microscopy, RT-qPCR, and Seahorse analysis. Compound C was applied to verify the involvement of the adenosine monophosphate-activated protein kinase (AMPK)/Sirt1/nuclear factor-κB (NF-κB) pathway. Results: GK markedly improved DOX-induced cardiac dysfunction and myocardial injury, reduced cardiac injury markers and inflammatory cytokines, and alleviated fibrosis, hypertrophy, apoptosis, and reactive oxygen species accumulation. GK restored superoxide dismutase activity, decreased malondialdehyde levels, increased glutathione and ATP, and preserved mitochondrial structure and respiratory function. GK upregulated AMPK and Sirt1, inhibited NF-κB activation, and regulated apoptosis-related proteins, whereas Compound C reversed these effects. Conclusion: GK protects against DOX-induced HF by activating AMPK/Sirt1 and inhibiting NF-κB signaling, thereby mitigating OS, inflammation, apoptosis, and mitochondrial dysfunction.