Zingibroside R1 Isolated From Achyranthes bidentata Blume Ameliorates LPS/D‐GalN‐Induced Liver Injury by Regulating Succinic Acid Metabolism via the Gut Microbiota

ABSTRACT Achyranthes bidentata Blume is a traditional Chinese medicine used to treat liver and kidney protection and improve liver injury; however, its active components and mechanism of action remain unclear. This study focused on the monomer compound zingibroside R1 (R1) from Achyranthes bidentata Blume, specifically studying its effects on liver injury through the modulation of succinic acid‐mediated immunity and inflammation via the gut microbiota. We isolated R1 and investigated its therapeutic effects in a lipopolysaccharide (LPS)‐ and D‐galactosamine‐induced acute liver injury mouse model. Liver tissue pathology, serum biomarkers, oxidative stress parameters, immune inflammation, and the gut microbiota composition were assessed. Metabolic profiling was performed via UPLC–Q‐TOF–MS, and faecal microbiota transplantation experiments were conducted to validate the role of the gut microbiota in the hepatoprotective effects of R1. R1 treatment significantly alleviated LPS/GalN‐induced liver injury, reducing liver haemorrhaging, hepatocyte necrosis, nuclear shrinkage, and inflammatory infiltration. R1 treatment also decreased the serum ALT and AST levels and mitigated oxidative stress. The levels of inflammation and immunity were markedly reduced following R1 treatment. Gut microbiota analysis revealed that R1 treatment restored Lactobacillus levels. Metabolomic analysis indicated that R1 influenced key metabolic pathways, including purine metabolism and glycerophospholipid metabolism pathways, and succinic acid was identified as a critical metabolite in the gut–liver interaction. Faecal microbiota transplantation (FMT) results confirmed that the therapeutic effect of R1 on liver injury is exerted by the gut microbiota, which affects the inflammation mediated by succinic acid metabolism. R1 from Achyranthes bidentata Blume provides hepatoprotective protection against LPS/GalN‐induced liver injury by modulating the gut microbiota and succinic acid metabolism. These findings underscore the potential of R1 as a therapeutic agent for treating liver diseases, highlighting the importance of the gut microbiota in mediating liver health.