Protective Effect of Epigallocatechin-3-Gallate Against Fructose-Induced Metabolic Associated Fatty Liver Disease in Mice by Regulating Ferroptosis and Autophagy via SIRT5.

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) lacks effective pharmacological therapies and is strongly associated with excessive fructose consumption. Ferroptosis and autophagy dysregulation are increasingly recognized as key drivers of MAFLD progression. Epigallocatechin-3-gallate (EGCG) exerts hepatoprotective effects. However, whether it regulates SIRT5-mediated ferroptosis and autophagy remains unclear. This study was aimed at investigating whether EGCG ameliorates fructose-induced MAFLD by regulating ferroptosis and autophagy via SIRT5. A fructose-induced MAFLD mouse model and fructose-treated HepG2 cells were established, and EGCG intervention was performed with or without SIRT5 knockdown. Hepatic steatosis, inflammation, ferroptosis- and autophagy-related markers were evaluated by biochemical assays, histological analysis, RT-qPCR, and western blotting analysis. Molecular docking was used to assess the interaction between EGCG and SIRT5. EGCG significantly mitigated hepatic lipid accumulation and inflammation in fructose-induced MAFLD models. It restored SIRT5 expression, alleviated iron overload and oxidative stress, rescued GPX4 and FTH1 expression, and downregulated FTL and COX2 levels. EGCG also improved autophagy, as reflected by an elevated LC3-II/LC3-I ratio and LAMP2 expression, together with reduced SQSTM1/p62 accumulation. Importantly, SIRT5 knockdown abolished these protective effects, suggesting a SIRT5-dependent mechanism. Molecular docking analysis further verified a robust binding affinity between EGCG and SIRT5. Collectively, our results demonstrate that EGCG ameliorates fructose-induced MAFLD by modulating ferroptosis and autophagy through SIRT5 upregulation, highlighting SIRT5 as a potential therapeutic target and supporting EGCG as a promising intervention for MAFLD.