Ergothioneine Ameliorates Alcoholic Fatty Liver Disease: A Dual Strategy of Accelerated Ethanol Elimination and Reducing Oxidative Stress.

Abstract

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 Food and Drug Administration (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 Ergothioneine (EGT) in a clinically relevant preclinical model. 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 National Institute on Alcohol Abuse and Alcoholism (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. EGT treatment significantly ameliorated hepatic steatosis and necrosis, as confirmed by Hematoxylin and Eosin (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, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), and corrected dyslipidemia by lowering triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) while elevating high-density lipoprotein cholesterol (HDL-C). Mechanistically, EGT suppressed pro-inflammatory cytokines (Interleukin-6 [IL-6], Interleukin-1 beta [IL-1β]) and mitigated oxidative stress by reducing malondialdehyde (MDA) accumulation and restoring superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. 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.