Aurantio‐Obtusin Regulates Gut Microbiota and Serum Metabolism to Alleviate High‐Fat Diet‐Induced Obesity‐Associated Non‐Alcoholic Fatty Liver Disease in Mice

ABSTRACT Non‐alcoholic fatty liver disease (NAFLD) is a progressive condition with limited effective treatments. This study investigated the therapeutic effects of Aurantio‐obtusin (AO), a bioactive compound from Cassiae Semen , on obesity‐associated NAFLD. An obesity‐related NAFLD model was established in ApoE −/− mice fed a high‐fat diet (HFD) for 24 weeks, with AO administered during the last 16 weeks. Mouse body weight, adipose tissue weights, liver weights, serum lipid levels, hepatic steatosis, inflammatory damage, and colonic tissue barrier integrity were evaluated. Gut microbial communities and serum metabolic profiles were analyzed using 16S rRNA sequencing and untargeted metabolomics. Hepatic lipid metabolism‐related gene expression was assessed using molecular biology techniques. AO treatment significantly ameliorated HFD‐induced adiposity, hyperlipidemia, and NAFLD symptoms. It preserved intestinal barrier integrity, modulated gut microbial composition by enriching beneficial taxa, and improved serum metabolic profiles. AO favorably adjusted hepatic lipid metabolism by upregulating PPARα and CPT1A while downregulating SREBP1, FASN, and SCD1. Correlation analysis revealed significant associations among gut microbial composition, serum metabolites, and disease indicators. AO's therapeutic benefits in NAFLD might be attributed to its ability to modulate gut microbial community composition and serum metabolic profile, enhance intestinal barrier function, and regulate hepatic lipid metabolism gene expression. AO presents a promising therapeutic agent for obesity‐associated NAFLD, warranting further investigation into its potential clinical applications.