NGR1 Restores Mitochondrial Oxphos and Reduces Steatosis in a CDAFHD Mash Model

Using a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) mouse model of metabolic dysfunction–associated steatohepatitis (MASH), a recent study reports that notoginsenoside R1 (NGR1) lessened MASH-like liver changes. They present multi-omics and functional assays as consistent with upregulation of mitochondrial oxidative phosphorylation (OXPHOS) components and improved mitochondrial function. Evidence in the report spans liver biochemistry, gross and histologic readouts, metabolomics/proteomics profiling, and mitochondrial functional measurements.

Male C57BL/6J mice underwent a 6-week CDAHFD protocol, with NGR1 administered by gavage during the final 3 weeks at two dose levels. In Methods, NGR1 was delivered as a suspension in 0.5% carboxymethylcellulose sodium (CMC-Na) at 0.1 mL per 10 g body weight, with concentrations described as 5 or 10 mg/mL to yield intragastric NGR1 at 50 or 100 mg/kg/day; control and model groups received the same vehicle schedule. The investigators report fasting before sacrifice, with serum and liver collected for biochemical testing, tissue staining, and multi-omics workflows.

At the phenotype level, the authors describe NGR1 as being associated with lower hepatic triglycerides and non-esterified fatty acids, and with reduced serum aminotransferases (ALT and AST) relative to CDAHFD model mice. They also report macroscopic improvement in liver appearance alongside a lower liver index, presented as consistent with less hepatomegaly in treated groups. On histology, the report describes improvements on H&E and Oil Red O assessments of steatosis and inflammatory cell infiltration, along with reduced collagen deposition by Masson staining.

Proteomics and metabolomics analyses are reported to shift the CDAHFD-associated molecular profile toward control, with pathway/enrichment results highlighting oxidative phosphorylation after NGR1 exposure. In proteomic comparisons, the authors describe reversal of CDAHFD-linked suppression of respiratory chain proteins, including complex I components such as NDUFS2 and NDUFA13, alongside additional electron transport chain proteins including COX5A and ATP5PD. On the metabolite side, they report changes discussed as consistent with riboflavin-related cofactor recovery (including FAD and FMN) and increases in ATP and ADP alongside an improved ATP/ADP ratio, considered together with functional assays of mitochondrial membrane potential (JC-1) and ATP production.

Additional experiments are reported to connect NGR1 exposure with NDUFS2-centered mitochondrial effects across multiple analysis layers. In palmitate-treated HepG2 cells, the authors describe reduced neutral lipid droplet staining (BODIPY) alongside recovery of mitochondrial membrane potential and intracellular ATP compared with palmitate alone. They further report molecular docking results predicting a stable interaction between NGR1 and NDUFS2, including hydrogen-bond contacts identified in the model, and they present public-dataset (GEO) observations in which NDUFS2 expression is described as reduced with progression from steatosis to MASH. Finally, correlation/network analyses integrating proteomic and metabolomic features are reported to map coordinated relationships around the treatment-associated shifts, which the authors discuss as supportive of an NGR1–NDUFS2/OXPHOS theme across in vivo, cellular, and in silico analyses.

Key Takeaways:

• In mice, the authors report that a 6-week CDAHFD model with NGR1 gavage during the final 3 weeks was associated with lower ALT/AST and hepatic lipid measures, improved gross morphology, and staining-based steatosis/inflammation/fibrosis readouts.
• Multi-omics analyses are described as highlighting OXPHOS pathway recovery after NGR1, including reported restoration of NDUFS2 and other electron transport chain components alongside mitochondrial membrane potential and ATP-related measures.
• Supportive layers in the report include palmitate-treated HepG2 assays, molecular docking predicting NGR1–NDUFS2 interaction, and GEO/correlation-network analyses relating NDUFS2 expression patterns to MASH-associated features.