Immunopathogenic mechanisms and immunoregulatory therapies in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, with an estimated global prevalence of approximately 30%; however, effective pharmacotherapies are still limited due to its complex pathogenesis and etiology. Therefore, a more thorough understanding of disease pathogenesis is urgently needed. An increasing number of studies suggest that MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are driven by chronic overnutrition, multiple genetic susceptibility factors, and pathogenic consequences, including hepatocyte damage and liver inflammation. Hepatic inflammation is the key event fueling the conversion from simple steatosis to steatohepatitis and fibrosis. Current therapies for MASH, including the recently approved thyroid hormone receptor-beta agonist resmetirom or the available incretin mimetics, mainly target metabolic injury to the liver but not inflammation directly. In this review, we provide an in-depth discussion of current data related to the immunological mechanisms of MASLD and summarize the effects of current and experimental therapies on immunoregulation in MASLD.