Metabolic dysfunction-associated steatotic liver disease: the role of oxidative stress and emerging therapeutic strategies

Metabolic dysfunction-associated steatotic liver disease (MASLD) has attracted considerable global concern. Physical inactivity, excessive caloric intake and unhealthy lifestyle factors, have contributed to its development. Obesity and metabolic disorders are strongly correlated with MASLD. It is a complex condition marked by fat accumulation in the hepatocytes, which progresses to more severe stages such as metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Globally, MASLD affects ~ 32% of adults, with a higher prevalence in men and certain populations owing to genetic and metabolic factors. It is closely linked to metabolic syndromes like obesity, type 2 diabetes mellitus, and insulin resistance. Moreover, it affects nonobese individuals. MASLD progression is driven by oxidative stress (OS) resulting from an imbalance between lipid metabolism and antioxidant-based defense responses. Reactive Oxygen Species (ROS) play a crucial role in disease progression, inducing liver inflammation, lipid peroxidation, and immune cell activation. Key byproducts of OS, such as malondialdehyde and 4-hydroxynonenal, directly contribute to cell damage and inflammation. This study examined the pathophysiology of MASLD, focusing on the impact of OS on liver inflammation, fibrosis, and the progression from steatosis to steatohepatitis. It draws attention to the limits of the existing antioxidant treatments as well as the pathways through which ROS and metabolites linked to OS impact liver health. Additionally, it assesses the potential of modulating apoptosis, a consequence of prolonged OS, as a therapeutic approach to mitigating liver damage and metabolic dysregulation in MASLD.