Hesperetin alleviates liver fibrosis by improving intestinal microbiota composition and regulating hepatic stellate...

Liver fibrosis can be commonly observed in numerous chronic liver diseases. Disruptions in the gut microbiota aggravate liver injury and fibrosis. Autophagy is an intracellular catabolic and recycling process regulated by lysosome, which has a vital impact on maintaining normal liver function. Hesperetin (HES), a flavonoid compound with numerous activities including anti-inflammation, antioxidation, and antitumor, has shown promise in various studies. However, its potential antifibrotic effects are largely unclear. Since both the gut microbiota and autophagy are crucial for the onset and development of liver fibrosis, this study aimed to investigate how HES influenced autophagy and gut microbiota using the carbon tetrachloride (CCl₄)-induced liver fibrosis mouse model and explore the underlying mechanisms. These findings demonstrated that HES remarkably relieved the CCl₄-induced mouse liver injury and fibrosis. In addition, it also ameliorated liver histology and inhibited the expression of autophagy-related markers. Meanwhile, HES inhibited hepatic stellate cell (HSC) activation and decreased intrahepatic inflammatory cell infiltration. In addition, 16S rDNA sequencing further demonstrated that HES altered the gut microbial composition of mice with liver fibrosis. It increased the Firmicutes proportion and elevated relative abundances of lactic acid bacteria, both of which contributed to alleviating liver inflammation and fibrosis. Overall, HES reduced liver fibrosis by modulating inflammation, regulating gut microbiota, while inhibiting autophagy in HSCs upon CCl₄-induced damage.