Comparison of different ginsenosides with C-3 or C-6 sugar moieties on activities in alcohol-induced liver injury mice

Background Alcohol-induced liver injury contributes to various liver diseases, with dietary interventions of ginsenosides being a promising solution. Ginsenosides, the major active compounds of Panax ginseng Meyer , are divided into protopanaxadiol (PPD) and protopanaxatriol (PPT) based on C-3 or C-6 glycosylation, which have anti-inflammatory and antioxidant effects, but structure-activity relationships remain unclear. Methods Using C57BL/C mice with alcohol-induced liver injury, we evaluated Rg5 and F4 effects on liver function, inflammation, lipid deposition, apoptosis, alcohol metabolism, and lipid synthesis. Results Rg5 (60 mg/kg) demonstrated significantly superior efficacy to F4 in alleviating alcohol-induced liver injury, reducing lipid deposition through 33.9% and 25.8% decreases in serum triglyceride (TG) and total cholesterol (TC) levels versus the F4 group. Additionally, Rg5 attenuated hepatic apoptosis by reducing BAX and cleaved-CASPASE-3 protein expression by 26.3% and 28.4% compared to F4. Rg5 enhanced alcohol metabolism through activation of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), thereby restoring AMP-activated protein kinase (AMPK) phosphorylation by 26.1% while reducing sterol regulatory element-binding protein 1 (SREBP-1) expression by 27.8% (compared to F4), with efficacy approaching that of positive control silymarin. Molecular docking revealed that the C-6 sugar moiety of F4 induced hydrogen bond donor repulsion, increasing hydrogen bond length and weakening binding stability with ADH, ALDH and AMPK, providing a structural basis for Rg5's superior hepatoprotective activity. Conclusion These findings highlight the critical influence of glycosylation position on hepatoprotective activity of ginsenosides, and provide insights into the structural modification of ginsenosides, which could contribute to the treatment of alcohol-related liver disease.