Explore of potential targets and mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments

Abstract Metabolic dysfunction-associated steatosic liver disease (MASLD) is a serious public health issue globally; however, there is no specific drug treatment. Hesperetin, a flavonoid extracted from citrus, possesses multiple pharmacological properties. However, limited reports have elucidated the pharmacological targets of and molecular mechanisms underlying hesperetin on lipid metabolism disorders in MASLD. First,in vitroexperiments confirmed the ameliorative effect of hesperetin on lipid accumulations. Second, putative target genes of the compounds were screened using public databases. MASLD-related targets were obtained through data mining of the GEO database. Third, a PPI network was constructed to screen for the core targets through the STRING database. Additionally, GO and KEGG enrichment analyses were performed on the key targets to identify the enriched genes with specific biological themes. We analyzed the binding mode of hesperetin to the key targets using molecular docking. Finally, the potential mechanism by which hesperetin affects MASLD was validated experimentally on an invitromodel. The current evidence suggested that hesperetin ameliorated lipid accumulation by inhibiting the IL-6-mediated STAT3-SOCS3 signaling pathway. Our findings provided novel insights into the underlying mechanisms and the clinical potential of hesperetin in MASLD management or prevention.