Diosgenin ameliorating non‐alcoholic fatty liver disease via Nrf2 ‐mediated regulation of oxidative stress and ferroptosis

AIM: This study aimed to investigate the mechanisms through which diosgenin inhibits the pathogenesis of non-alcoholic fatty liver disease, focusing particularly on ferroptosis-related pathways and its reliance on nuclear factor erythroid 2-related factor 2. MATERIALS AND METHODS: Using a rat model, we showed diosgenin's efficacy in reducing lipid deposition throughout the body and examined its impact on ferroptosis-related gene expression in vivo. Moreover, in vitro experiments using human hepatocellular liver carcinoma cell line cells were conducted to assess oxidative stress and ferroptosis levels. RESULTS: Diosgenin decreased lipid accumulation and steatosis; lowered serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, glutamic pyruvic transaminase and glutamic oxaloacetic transaminase; reduced interleukin-1β and tumour necrosis factor-α; diosgenin decreased malondialdehyde levels; and increased serum superoxide dismutase levels in a rat model of high-fat diet-induced non-alcoholic fatty liver disease. Diosgenin upregulated the expression of nuclear factor erythroid 2-related factor 2 and its downstream ferroptosis-related genes to inhibit ferroptosis in the livers of rats with non-alcoholic fatty liver disease. Diosgenin decreased reactive oxygen species levels and enhanced the expression of ferroptosis-related genes in human hepatocellular liver carcinoma cells induced by free fatty acids, with its effects being dependent on nuclear factor erythroid 2-related factor 2. CONCLUSIONS: This study highlights the potential of diosgenin from Dioscoreaceae plants in mitigating oxidative stress and ferroptosis levels through nuclear factor erythroid 2-related factor 2 regulation, offering novel insights into the treatment of non-alcoholic fatty liver disease and other metabolic disorders through traditional Chinese medicine.