Protective Effects of Ziziphus jujuba Mill. Leaves Against Metabolic Dysfunction-Associated Steatotic Liver Disease Are Associated with Gut Microbiota and Hepatic Metabolic Remodeling

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder with limited effective pharmacological treatments. Ziziphus jujuba Mill. leaves (ZJL) contain multiple bioactive compounds, but their effects on MASLD and underlying mechanisms remain unclear. Methods: The chemical constituents of ethanolic ZJL extract were characterized using UHPLC-Q-Orbitrap MS. A high-fat diet (HFD)-induced MASLD mouse model was used to evaluate its protective effects. Serum biochemical parameters, liver histopathology, and inflammatory indicators were assessed. Gut microbiota and hepatic metabolic alterations were investigated using 16S rDNA sequencing and untargeted metabolomics, respectively. Potential microbiota–metabolite associations and key regulatory targets were further explored by correlation analysis, molecular docking, and qRT-PCR. Results: Fifty-five compounds were identified in ZJL, mainly flavonoids, organic acids, and triterpenoids. ZJL treatment significantly reduced HFD-induced body weight gain, dyslipidemia, hyperglycemia, hepatic injury, inflammation, and lipid accumulation. ZJL also partially restored gut microbial homeostasis, particularly by decreasing the abundances of Blautia and Dorea. Metabolomic analysis indicated that glycerophospholipid metabolism was the major affected pathway, together with fatty acid biosynthesis and cytochrome P450-related metabolism. Microbial alterations were closely associated with lipid-related metabolites. Moreover, ZJL downregulated key genes, including Pla2g2a, Fasn, and Cyp2e1. Conclusions: ZJL alleviated HFD-induced MASLD, accompanied by coordinated alterations in gut microbiota composition, hepatic metabolism, and lipid-related gene expression, suggesting that these changes may contribute to its protective effects.