Tehran University of Medical Sciences Acta Biochimica Iranica 0001-5261 2 4 2024 12 11 186 195 Mahboobe Sattari esearch Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran. Kosar Ostadmohammadi Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran. Hajar Hajian Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran. Amin Karimpour Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Fahime Sedghgou Shahid Beheshti Hospital, Kashan University of Medical Sciences, Kashan, Iran. Mohadese Sattari Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran. Ghodratollah Panahi Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 2025 06 29 Non-alcoholic fatty liver disease (NAFLD) is a widespread liver condition characterized by fat accumulation in the liver, with its development involving intricate processes such as inflammation, oxidative damage, and lipid metabolism disturbances. Current treatment options are limited, emphasizing the need for multi-targeted approaches that can simultaneously address these pathogenic pathways to improve liver health. This review synthesizes current evidence on how fisetin impacts molecular pathways relevant to NAFLD. It focuses on its effects in reducing inflammation, oxidative stress, and lipid accumulation, based on experimental and clinical studies examining gene expression, enzyme activity, and signaling pathways involved in hepatic steatosis and injury. This review examines the mechanisms by which fisetin intervention influences NAFLD management. It emphasizes glycemic control through post-prandial glucose reduction, mitigation of insulin resistance, improvements in pancreatic insulin secretion, and suppression of hepatic gluconeogenesis and glycogenolysis. Additionally, fisetin exerts plasma lipid-lowering effects via enhancement of hepatic β-oxidation and reduction of lipogenesis. The anti-inflammatory effects are observed both systemically and locally within the liver. Fisetin also enhances antioxidant defenses by activating antioxidant enzymes, reducing superoxide levels, chelating metal ions, and scavenging free radicals. Furthermore, fisetin modulates endoplasmic reticulum (ER) stress and promotes autophagy, contributing to the amelioration of NAFLD pathology. Taken together, Fisetin exhibits a promising hepatoprotective profile and may serve as a beneficial natural supplement for liver health. Its potential benefits in reducing liver steatosis and supporting NAFLD management, combined with its minimal side effects, make it an attractive candidate for further exploration as a complementary therapy.   https://abi.tums.ac.ir/index.php/abi/article/view/129 https://abi.tums.ac.ir/index.php/abi/article/download/129/72