Oxidative stress in metabolic dysfunction-associated steatohepatitis: Mechanisms and emerging therapeutic strategies

Metabolic dysfunction-associated steatotic liver disease and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), affect a substantial proportion of the global population and have emerged as a major disease burden. If left untreated, MASH can progress to cirrhosis and hepatocellular carcinoma. However, effective pharmacological therapies for MASH remain limited. Accumulating evidence indicates that oxidative stress plays an important role in MASH pathogenesis by coordinating inflammatory responses and contributing to hepatocyte injury. Although previous studies have emphasized the importance of oxidative stress, a panoramic view of how oxidative stress emerges during the onset of MASH and sustains a vicious cycle of progression is still lacking. This review systematically discusses the mechanisms underlying oxidative stress-driven MASH progression, highlighting its interactions with inflammation, hepatocyte apoptosis, necroptosis, emerging ferroptosis, and mitochondria-associated membranes. Furthermore, we summarize the recent advances in investigational drugs targeting oxidative stress, encompassing key druggable targets as well as representative synthetic compounds, natural products, and biotechnology drugs. Collectively, this review aims to deepen the mechanistic understanding of oxidative stress in MASH and to provide insights into potential therapeutic strategies.