Ginsenoside Rg5 Targets PRDX1 to Disrupt Redox Homeostasis and Induce Mitochondria-Dependent Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with limited therapeutic options and poor clinical outcomes. Mounting evidence suggests that targeting cancer-specific metabolic and redox adaptations represents a promising therapeutic strategy. Peroxiredoxin 1 (PRDX1), a key antioxidant enzyme that is frequently overexpressed in HCC, enables tumor cells to neutralize excessive Reactive Oxygen Species (ROS), thereby sustaining survival and conferring therapeutic resistance. In this study, using human hepatocellular carcinoma HepG2 cells as an in vitro model, we identify ginsenoside Rg5 (Rg5) as a previously unrecognized small-molecule inhibitor of PRDX1. Structural and functional analyses demonstrate that Rg5 directly binds to the Asn145 residue of PRDX1, effectively suppressing its peroxidase activity. Mechanistically, this inhibition disrupts ROS detoxification in HepG2 cells, leading to mitochondrial ROS accumulation, activation of the intrinsic apoptotic pathway, and consequent HepG2 cell death. Additionally, Rg5 not only suppresses HepG2 cell survival but also acts synergistically with doxorubicin, a first-line chemotherapeutic agent, to markedly enhance antitumor efficacy and potentially mitigate chemoresistance. Collectively, these findings suggest that PRDX1 inhibition may represent a broadly exploitable vulnerability in liver Cancer and establish Rg5 as a promising candidate for developing targeted and combinatorial therapies against HCC.

DOX; ROS; apoptosis; cancer therapy; ginsenoside Rg5; peroxiredoxin 1; synergistic therapy.