The many pathways driving liver inflammation in MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting one-third of the global population. Most patients exhibit simple steatosis, whereas up to 20% develop metabolic dysfunction-associated steatohepatitis (MASH), potentially culminating in liver cirrhosis and hepatocellular carcinoma. Diverse parallel mechanisms contribute to the development of MASH, which are fueled by hepatic lipotoxicity, intestinal dysbiosis, and pro-inflammatory diets shaping innate and adaptive immune responses. Moreover, adipose tissue is driving systemic inflammation in obesity, contributing to the inflammatory burden in obesity-related MASH. Polygenetic and multiomic risk scores identify distinct types of MASLD with dominant aggressive liver disease or extrahepatic cardiometabolic disease. Here, we review the complexity of multiple parallel inflammatory hits in MASH and delineate that most current MASH drugs exert pleiotropic metabolic and anti-inflammatory properties. These new therapies will change the clinical management of this disease in the near future. Intra- and extrahepatic inflammation in MASH is driven by various hits such as lipotoxicity, the gut microbiome, and proinflammatory diets. Inflammation contributes to hepatic and systemic complications, including cardiovascular diseases. Beneficial drugs in MASH might target metabolic and inflammatory pathways.