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

Abstract 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.