Oxidative Stress in Liver Metabolic Dysfunction and Diseases, with a Focus on Hepatogenic Diabetes: Effect of Alcohol...

Metabolic dysfunction-associated fatty liver disease (MASLD) is associated with severe forms of liver injury, including fibrosis and cirrhosis. The main risk factors for MASLD-obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and insulin resistance (IR)-contribute to metabolic disturbances that initiate hepatic steatosis. Metabolic and alcohol-related liver disease (MetALD) describes patients with MASLD who also present alcohol-associated hepatic injury. Chronic oxidative and inflammatory stress promotes the progression of steatosis in both conditions. T2DM and chronic alcohol consumption are independent lifestyle-related risk factors for cirrhosis within the spectrum of metabolic dysfunction-related liver disease (MASLD and MetALD). The coexistence of both conditions may exacerbate hepatic pathological alterations. IR, which is frequently observed in patients with cirrhosis, can lead to the development of a condition known as hepatogenic diabetes (HD). HD is characterized by hyperinsulinemia, IR, and β-cell dysfunction occurring during the onset of cirrhosis and is associated with hepatic inflammation even in the absence of traditional metabolic risk factors such as obesity or a prior history of T2DM. In this context, alcohol intake enhances lipolysis in peripheral tissues, promotes hepatic steatosis, and aggravates metabolic dysfunction, ultimately contributing to excessive mitochondrial production of reactive oxygen species (ROS). Therefore, the present review examines the role of oxidative stress-both alcohol-related and non-alcohol-related-in the pathogenesis of HD, with particular emphasis on ethanol metabolism, oxidative stress, and their interactions in conditions such as T2DM and MetALD.