Unrevealing the Role of Flavonoids in Mitigation of Non-Alcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disorder and an important contributor to hepatocellular carcinoma. It is characterized by excessive hepatic lipid accumulation, which can progress to a more severe inflammatory condition known as non-alcoholic steatohepatitis (NASH). Recently, NAFLD has been globally redefined as metabolic dysfunction-associated steatotic liver disease (MASLD). It is closely associated with metabolic disorders such as type 2 diabetes mellitus, obesity, insulin resistance and dyslipidaemia. NAFLD is now a major cause of liver-related morbidity and mortality because proper pharmacological treatments are limited. Naturally occurring polyphenolic compounds such as flavonoids exert a potential role on NAFLD due to their antioxidant, anti-inflammatory, and lipid-regulating properties. The pathogenesis of NAFLD is complex and involves multiple interrelated mechanisms, including hepatic lipid accumulation, insulin resistance, oxidative stress, mitochondrial dysfunction, and chronic inflammation, which collectively contribute to disease progression toward NASH, fibrosis, and cirrhosis. Several flavonoids, including quercetin, naringenin, kaempferol, luteolin, dihydromyricetin, and tetrahydrocurcumin, have demonstrated beneficial effects in experimental and clinical studies by reducing hepatic lipid accumulation, oxidative stress, and inflammation. These compounds exert their effects by modulating key molecular pathways, including nuclear factor erythroid 2–related factor 2 (Nrf2), AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptors (PPARs). Activation of these pathways enhances mitochondrial function, promotes fatty acid oxidation, and improves insulin sensitivity. However, poor bioavailability and limited clinical evidence remain major challenges. Future studies should focus on optimized formulations, standardized dosing, and well-designed clinical trials.