Ginsenoside Rg2 Ameliorates Metabolic Dysfunction-related Steatohepatitis via the Nrf2 Pathway by Suppressing Inflammation, Apoptosis, Oxidative Stress and Fibrosis

Background : Ginsenoside Rg2 (G-Rg2) is a bioactive saponin derived from Panax ginseng, recognized for its diverse pharmacological activities, which include anti-inflammatory, antioxidant, and hepatoprotective effects. Nevertheless, the therapeutic mechanisms underlying its effects in metabolic dysfunction-associated steatohepatitis (MASH) are still not well understood. Purpose : The current work examined the protective role of G-Rg2 on MASH and elucidate the molecular mechanisms. Methods : Eight-week-old male C57BL/6J mice received a standard diet containing Methionine- and choline-deficient diet (MCD), while LX2 cells were induced by TGFβ, serving as in vivo and in vitro models, respectively. To assess the protective effect of G-Rg2 in alleviating MASH, we conducted histopathological staining, utilized commercial kits, performed qPCR, immunoblotting, and immunofluorescence, as well as executed a cellular thermal shift assay. Additionally, network pharmacology prediction, molecular docking, and molecular dynamics simulation analyses were employed. Results : G-Rg2 reduced body weight loss (p<0.001), AST/ALT (p<0.001), hepatic inflammation (CD68, NFκB, IL1β downregulated, CD206 upregulated; p<0.05), apoptosis (Bcl-2 up, Bax down), oxidative stress (SOD, GSH increased, MDA reduced; p<0.05), and fibrosis (α-SMA decreased). In TGFβ-induced LX2 cells, it suppressed inflammation (IL6, TNFα down; p<0.05), ROS, and fibrosis (COL1A1, α-SMA down; p<0.001) via stabilizing NRF2 binding. In NRF2⁻/⁻ mice or with ML385 (Nrf2 inhibitor), G-Rg2’s effects were abrogated (p>0.05), confirming NRF2 dependency. Conclusion : This study is the first to confirm that G-Rg2 binds to and regulates Nrf2, and further illustrates that it alleviates MASH by activating the NRF2 signaling pathway to inhibit inflammation, cell apoptosis, oxidative stress, and fibrosis. This establishes a conceptual foundation for the future use of G-Rg2 in MASH treatment and supports the development of natural product–based therapeutic strategies derived from dietary sources.