Fisetin as a Promising Agent in Non-Alcoholic Fatty Liver Disease: Insights into Pathogenic Mechanisms and Therapeutic Potential

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a prevalent 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 also explores the mechanisms by which fisetin intervention influences NAFLD management, highlighting its role in glycemic control through postprandial 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 by enhancing hepatic β-oxidation and reducing lipogenesis. Its anti-inflammatory effects are observed both systemically and locally within the liver. Fisetin also strengthens 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