Korean red ginseng saponins ameliorate metabolic dysfunction-associated steatohepatitis in mice by inhibiting caspase-11 and NLRP3 inflammasomes.

BACKGROUND: Although Korean red ginseng (KRG) has been investigated in various liver disorders, its role in Metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. This study aimed to evaluate the pharmacological effects of the KRG saponin fraction (KRGSF) in MASH and to elucidate its underlying mechanisms in hepatocytes, macrophages, and an in vivo MASH animal model. METHODS: C57BL/6 mice were fed a methionine/choline-deficient (MCD) diet to induce MASH and were orally administered KRGSF at varying doses for 8 weeks. HepG2 cells were treated with free fatty acids (FFA) to induce steatosis and inflammation. RAW264.7 cells were stimulated with either palmitic acid (PA) or lipopolysaccharide (LPS) to model inflammatory responses. RESULTS: KRGSF ameliorated hepatic steatosis in MASH mice by downregulating lipogenic gene expression. It further attenuated liver injury, macrophage infiltration, and fibrosis, concomitant with reduced pro-inflammatory cytokine production, pyroptosis, and serum ALT and AST levels. Mechanistically, KRGSF suppressed the expression of caspase-11 and NLRP3 and inhibited the proteolytic activation of gasdermin D (GSDMD) in MASH mice. In vitro, KRGSF decreased lipid accumulation and lipogenic gene expression in FFA-treated HepG2 cells, while also reducing pro-inflammatory cytokine production and lowering ALT and AST levels. Additionally, KRGSF inhibited pro-inflammatory cytokine production in PA- or LPS-stimulated RAW264.7 cells. CONCLUSION: These findings demonstrate that KRGSF exerts protective effects against MASH by mitigating hepatic steatosis, inflammation, and injury, highlighting its potential as a therapeutic candidate for the prevention and treatment of MASH.