Exploring the role of xanthine oxidase and aldehyde oxidase in metabolic dysfunction-associated steatotic liver disease (MASLD).

Abstract

Globally, metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed as non-alcoholic fatty liver disease (NAFLD), has been affecting millions of people. It includes a spectrum of liver conditions, ranging from simple fat accumulation (steatosis) to advanced stages such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Oxidative stress has been identified as a major contributing factor in driving disease progression. Enzymes such as xanthine oxidase (XO) and aldehyde oxidase (AO) are significant contributors of reactive oxygen species (ROS), which in turn promote inflammation and cause liver damage. While cytochrome (CYP)-P450 enzymes are well studied in MASLD research, the precise roles of XO and AO remain less understood. This review explores the involvement of XO and AO in MASLD, linking their biochemical pathways to oxidative stress, metabolic dysfunction and inflammation. We have also discussed a few other ROS-generating enzymes like NADPH oxidases, lipoxygenases, myeloperoxidase and monoamine oxidases, which exacerbate liver fibrosis and inflammation. Therapeutic strategies targeting these enzymes, such as XO inhibitors (allopurinol, febuxostat) and AO inhibitors (hydralazine), can potentially mitigate the burden of oxidative stress in MASLD treatment. Future research should focus on elucidating enzyme-specific mechanisms and optimizing targeted therapies. A comprehensive approach integrating enzyme inhibition, antioxidants, lifestyle changes and dietary interventions may form the cornerstone of effective management and prevention of MASLD.