Effect and mechanism of fisetin against the development of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent liver disease that poses a serious health threat. Fisetin (FIS) is a flavonoid compound with multiple biological activities. The aim of this study was to investigate the potential therapeutic effect of FIS on MAFLD and the underlying mechanisms through in vivo and in vitro experiments. Our results demonstrated that FIS mitigated weight gain and improved blood glucose levels, blood lipid disorder and liver steatosis in mice with high-fat diet (HFD)-induced MAFLD. RNA-seq analysis revealed that FIS affected the expression of many genes in the liver of MAFLD mice, including up-regulating the mRNA expression of Glut4 and GPx3 and down-regulating the mRNA expression of IL-1β and Cxcl10 genes. Moreover, FIS reduced sodium oleate-induced lipid accumulation, activated the GSK-3β/Nrf2/HO-1 signaling pathway, and inhibited the expression of PEPCK and G6PC in HepG2 cells. Overall, these findings demonstrate that FIS can alleviate MAFLD by enhancing the antioxidant capacity and reducing the gluconeogenic capacity in the liver, supporting FIS as a potential therapeutic against MAFLD.