Wu-Mei-Wan retards NAFLD progression by ameliorating obesity and regulating serum metabolites in high-fat diet-fed mice

Background: Non-alcoholic fatty liver disease (NAFLD), closely associated with obesity and metabolic syndrome, lacks universally effective therapies. Wu-Mei-Wan (WMW), a traditional Chinese medicine formula, has been used to treat metabolic disorders, but its efficacy and mechanism against NAFLD remain unclear. Objectives: This study investigated the therapeutic potential of WMW in a high-fat diet (HFD)-induced NAFLD mouse model. Methods: After 24 weeks of HFD feeding, mice were allocated to control, model, low/middle/high-dose WMW (L-/M-/H-WMW), or metformin groups. Physiological parameters and liver pathology were assessed. Untargeted serum metabolomics was employed to identify altered metabolic pathways. Results: H-WMW treatment significantly alleviated NAFLD phenotypes, reducing body weight, hepatic steatosis, dyslipidemia, and insulin resistance. Metabolomic analysis identified vitamin B6 metabolism as a key target, with H-WMW restoring levels of pyridoxal 5'-phosphate and 4-pyridoxic acid to near-normal. Mechanistically, WMW coordinately modulated interconnected purine and vitamin B6 metabolic networks. Conclusion: WMW demonstrates significant efficacy against NAFLD, likely through multi-target reprogramming of hepatic metabolism. These findings position WMW as a promising phytopharmaceutical candidate worthy of further clinical investigation.