Exploring the Mechanisms of Total Saponins of Black Ginseng and Ginsenoside Rg3 Against Doxorubicin‐Induced Cardiotoxicity

Doxorubicin (DOX), a widely utilized chemotherapeutic agent, is constrained by its intricate cardiotoxicity, which involves oxidative stress, mitochondrial dysfunction, and cell death. Black ginseng (BG), processed to enhance rare saponins such as ginsenoside Rg3, demonstrates augmented anticancer and cardioprotective properties. The combination of DOX with total saponins of BG (TSF) or the active component Rg3 may provide synergistic antitumor effects while mitigating cardiotoxicity, although the underlying mechanisms necessitate further investigation. This study aimed to evaluate the protective effects of TSF and Rg3 against DOX-induced cardiotoxicity (DIC) and to explore their potential to enhance mitochondrial function by modulating the HDAC8/BRCA2/DRP1 pathway. The research involved in vitro studies using H9c2 cells and in vivo experiments with mouse models to assess the pharmacological actions of TSF and Rg3. Network pharmacology was employed to predict the potential mechanisms by which TSF regulates the HDAC8/BRCA2/DRP1 pathway. Verification was conducted through Western blot analysis and immunofluorescence colocalization techniques. In vitro experiments demonstrated that TSF and Rg3 enhanced the viability of H9C2 cells subjected to DOX induction. In vivo studies revealed that TSF and Rg3 significantly improved cardiac function and mitigated myocardial structural damage in mice. Notably, the effects of Rg3 were particularly pronounced. TSF and Rg3 also effectively reduced oxidative stress markers, such as SOD and MDA, and decreased inflammation. Furthermore, they inhibited apoptosis, restored cardiomyocyte morphology, and enhanced mitochondrial function by increasing ATP activity. Cyberpharmacological analysis suggested that the HDAC8/BRCA2/DRP1 signaling pathway may be a target for regulation by TSF and Rg3 during DOX-induced progression. Our findings demonstrated that TSF and Rg3 reverse DOX-induced upregulation of HDAC8 and DRP1 protein expression while downregulating BRCA2 protein expression in cardiac tissues. Additionally, immunofluorescence colocalization confirmed direct interactions among HDAC8, BRCA2, and DRP1. TSF and Rg3 demonstrate significant cardioprotective effects against DIC by mitigating oxidative stress, inflammation, and apoptosis, while preserving mitochondrial function. These findings provide novel insights into the clinical relevance of TSF and Rg3 in the management of DIC. The regulation of the HDAC8/BRCA2/DRP1 pathway underscores the potential of TSF and Rg3 as a promising therapeutic strategy for the prevention and treatment of DIC.