Fisetin against the development of MAFLD

Fisetin, a natural flavonoid found in fruits and vegetables like strawberries and apples, has shown significant potential in combating metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD, a chronic liver condition linked to obesity, insulin resistance, and type 2 diabetes, affects nearly 30% of the global population. In a study using a high-fat diet (HFD)-induced mouse model and sodium oleate (OA)-treated HepG2 cells, fisetin demonstrated remarkable therapeutic effects against MAFLD progression.

Fisetin significantly reduced body weight gain, liver mass, and fat accumulation in HFD-fed mice without altering food intake, indicating metabolic improvement. It improved blood glucose levels, glucose tolerance, and lipid profiles, including lowering triglycerides, total cholesterol, and LDL-C while increasing protective HDL-C levels. Fisetin also enhanced liver function by reducing serum AST and ALT levels, markers of hepatic injury.

Histological analyses confirmed reduced hepatic lipid accumulation and increased glycogen storage, reflecting improved glucose utilization and suppressed gluconeogenesis. Fisetin restored antioxidant balance by enhancing superoxide dismutase (SOD) activity and reducing reactive oxygen species (ROS) and nitric oxide (NO) levels. Mechanistically, fisetin activated the GSK-3β/Nrf2/HO-1 pathway, upregulated antioxidant enzymes, and downregulated gluconeogenic enzymes (PEPCK, G6PC), promoting glucose and lipid homeostasis. These findings suggest fisetin as a promising natural therapeutic for MAFLD.