Apigenin ameliorates methionine-choline deficient diet-induced metabolic-associated fatty liver disease through modulation of gut microbiota-liver axis

Apigenin alleviates methionine-choline deficient (MCD) diet-induced metabolic-associated fatty liver disease (MAFLD), with improved liver function and reduced oxidative stress. • Lipidomic evidence of apigenin-driven hepatic remodeling: decreased SFAs/PUFAs and increased MUFAs. • Lactobacillus and Akkermansia reshaping as mediators of apigenin’s protective effects in MAFLD. • Homocysteine identified as a microbiota-associated metabolite driving oxidative stress and lipid dysregulation. • Translational potential of apigenin as a phytochemical therapy targeting the gut–liver axis in MAFLD. Introduction Apigenin, a naturally occurring flavone widely present in the plant kingdom, possesses antioxidant, anti-inflammatory, and metabolic regulatory activities. Metabolic-associated fatty liver disease (MAFLD), a chronic liver disorder driven by metabolic stress, currently lacks effective pharmacological therapies. Given these pharmacological properties, apigenin may represent a promising candidate for MAFLD intervention. Objective This study aimed to evaluate the therapeutic potential of apigenin in MAFLD and to elucidate the underlying mechanisms linking the gut microbiota and host lipid metabolism. Methods A methionine-choline deficient (MCD) diet-induced mouse model of MAFLD, combined with lipidomic profiling, microbiota analysis, and metabolite assessment, was used to determine the beneficial effects of apigenin. Results Apigenin markedly ameliorated hepatic steatosis in MCD-fed mice, as demonstrated by reduced hepatic triglyceride accumulation, improved liver function markers, and alleviated hepatic inflammation and oxidative stress. Lipidomic profiling showed decreased hepatic saturated and polyunsaturated fatty acids accompanied by an increase in monounsaturated fatty acids and their related lipid species. Apigenin remodeled the gut microbiota, characterized by increased Lactobacillus abundance and decreased Akkermansia abundance. Further analyses identified homocysteine (HCY) as a key microbiota-associated metabolite that induced oxidative stress and reproduced the lipid dysregulation observed in MAFLD, thereby linking microbial alterations to hepatic lipid metabolism. Conclusion These findings demonstrate that apigenin alleviates MAFLD by remodeling the gut microbiota-metabolite network, lowering HCY levels, and subsequently improving hepatic function, lipid metabolism, and oxidative stress, highlighting its potential as a phytochemical-based therapeutic strategy. Download: Download high-res image (198KB) Download: Download full-size image