NGR1 Ameliorates Hepatocyte Steatosis and Mitochondrial Dysfunction Associated with the Restoration of NDUFS2

Background: Metabolic disorder-associated fatty liver disease (MASLD) is closely related to obesity and type 2 diabetes. Its pathogenesis involves many factors, including mitochondrial dysfunction, endoplasmic reticulum stress and intestinal flora disorders. Notoginsenoside R1 (NGR1) is a key bioactive component of Panax notoginseng. The purpose of this study was to investigate the therapeutic effect of notoginsenoside R1 (NGR1) on metabolic disorder-associated steatohepatitis (MASH) and its potential mechanism. Methods: Mice were fed a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) for 6 weeks and received NGR1 (50/100 mg/kg/day) in the last 3 weeks. The role of NGR1 was evaluated by developing metabolomics, proteomics and functional analysis. In addition, the effects of NGR1 on lipid droplet content, mitochondrial function and fatty acid oxidation in hepatocytes were also verified. Results: NGR1 improved MASH progression in CDAHFD-fed mice, significantly reduced liver triglyceride content from 31.2 ± 5.1 mmol/g to 20.5 ± 4.8 mg/g (p < 0.001), free fatty acid from 0.12 ± 0.03 mmol/g prot to 0.06 ± 0.028 mg/g (p < 0.001), TNF-α (p < 0.01), IL-1β (p < 0.001), α-SMA (p < 0.05) and Collagen1A1 levels (p < 0.01), as well as serum ALT and AST concentrations (p < 0.001), and alleviated hepatomegaly and lipid droplet accumulation. Metabolomics and proteomics analysis showed that NGR1 normalized liver metabolism in MASH mice and upregulated mitochondrial OXPHOS components, including NADH: ubiquinone oxidoreductase core subunit S2 (NDUFS2), and effectively reversed CDAHFD-induced mitochondrial dysfunction. Mitochondrial membrane potential and ATP production were restored. Conclusions: This study confirmed that NGR1 has significant therapeutic potential for MASH and improves mitochondrial function by upregulating NDUFS2. This study provides new insights for the future clinical treatment of MASH.