Cantharidin (CTD) has been traditionally used in Traditional Chinese Medicine (TCM) and exhibits pronounced antitumor activity, particularly in hepatocellular carcinoma (HCC). However, its preclinical translation has been substantially constrained by dose-limiting toxicity. Inspired by traditional Mylabris and Ginseng combinations, we conducted an investigation into the synergistic efficacy of CTD and Ginsenoside-Rg3 (Rg3), one of the most prevalent and bioactive ginsenosides, in combating HCC. We find that CTD/Rg3 co-treatment synergistically suppressed HCC cell proliferation, migration, and invasion. Mechanistically, an integrated multi-omics approach analyses illuminated the involvement of multi-target and multi-pathway mechanisms in CTD/Rg3 combination therapy for HCC. Function enrichment analyses reveal that targets of CTD/Rg3 were significantly associated with metabolic pathways and immune responses. Further screening identified AKR1D1, SLC16A4, and ALDH3B1 as potential drug targets. Subsequent correlation analysis with clinical data from liver cancer patients indicated that AKR1D1 and SLC16A4 were activated, whereas ALDH3B1 was inhibited, during CTD/Rg3 intervention in HCC progression. Molecular docking studies further demonstrated that both CTD and Rg3 bind with high affinity and stability to the active site of ALDH3B1, a molecule associated with immune microenvironment remodeling in HCC. Collectively, our findings demonstrate that CTD/Rg3 combination therapy exerts potent anti-HCC effects through multi-targeted mechanisms. By simultaneously modulating metabolic pathways and immune responses, this strategy represents a novel integrative approach for HCC treatment. These results not only elucidate the molecular basis of CTD/Rg3 efficacy but also provide robust preclinical support for its clinical translation in HCC management.
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