Hemerocallis lilioasphodelus root water extract ameliorates non-alcoholic fatty liver disease by regulating the gut-liver axis and activating AMPK-mediated lipid metabolism: an integrated study based on metabolomics and 16S rRNA sequencing.

ETHNOPHARMACOLOGICAL RELEVANCE: Hemerocallis lilioasphodelus L. is a traditional medicinal herb used for liver and spleen disorders. However, its pharmacological effects and underlying mechanisms against nonalcoholic fatty liver disease (NAFLD) remain unclear. AIM OF THE STUDY: This study aimed to investigate the protective effects of Hemerocallis lilioasphodelus root water extract (HL) against high-fat diet (HFD) induced NAFLD in mice and to elucidate the underlying molecular mechanisms. MATERIALS AND METHODS: The chemical constituents of HL were analyzed using UHPLC-QE-MS technology, and a NAFLD mouse model was established through HFD induction, followed by HL intervention. By integrating serum pharmacochemistry, network pharmacology, and multi-omics techniques, combined with in vivo and in vitro experimental validation, this study systematically elucidates the mechanism by which HL ameliorates NAFLD. RESULTS: A total of 143 active components were identified in HL, 15 of which were absorbed into the bloodstream. Network pharmacology analysis suggested that the AMPK signaling pathway may be associated with the therapeutic effects of HL against NAFLD. In vivo experiments confirmed that HL significantly ameliorated HFD-induced dyslipidemia, hepatic lipid accumulation, and histopathological injury in mice. Mechanistically, HL suppressed de novo lipogenesis by activating the hepatic AMPK/SREBP1c axis. Furthermore, HL treatment remodeled the gut microbiota specifically enriching Akkermansia and strengthened the intestinal barrier, thereby reducing the translocation of gut-derived harmful signals to the liver. CONCLUSION: HL presumably ameliorates NAFLD by regulating the AMPK signaling pathway and intestinal microbiota homeostasis, providing an important basis for further research on the treatment of NAFLD with HL.