Gene III Ergothioneine ameliorates alcoholic fatty liver disease: A dual strategy of accelerated ethanol elimination and reducing oxidative stress

Background Alcoholic fatty liver disease (AFLD) is a progressive hepatic pathology triggered by chronic ethanol consumption, serving as the initial stage of severe liver injury. Currently, there are no FDA-approved pharmacological interventions that specifically target alcohol-induced hepatic steatosis or prevent disease progression, highlighting an urgent need for effective preventive strategies. This study evaluated the preventive efficacy and underlying mechanisms of Gene III Ergothioneine (EGT) in a clinically relevant preclinical model. Methods C57BL/6 mice were randomized into five groups: a Control group, an alcoholic fatty liver Model group, a Positive control group treated with Silybin (100 mg/kg), and three EGT treatment groups (10, 30, and 50 mg/kg). The NIAAA mouse model was utilized to induce alcoholic fatty liver. Various biochemical, histological, and molecular markers were assessed to evaluate liver damage, alcohol metabolism, lipid profiles, oxidative stress, and inflammation. Results Gene III EGT treatment significantly ameliorated hepatic steatosis and necrosis, as confirmed by H&E and Oil Red O staining. Notably, EGT accelerated alcohol clearance, reducing serum ethanol levels by up to 54.4% in a dose-dependent manner. Furthermore, EGT restored liver function markers (ALT, AST, GGT) and corrected dyslipidemia by lowering TG, TC, and LDL-C while elevating HDL-C. Mechanistically, EGT suppressed pro-inflammatory cytokines (IL-6, IL-1 β) and mitigated oxidative stress by reducing malondialdehyde (MDA) accumulation and restoring superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Conclusion Gene III Ergothioneine prevents alcoholic liver injury through a dual mechanism: accelerating ethanol metabolism and enhancing hepatocyte antioxidative and anti-inflammatory defenses. These findings position EGT as a promising therapeutic candidate for AFLD management.