PubMed23 Mar 2026·Cell metabolism● 3/10i The many pathways driving liver inflammation in MASH.
Tilg H, Adolph TE, Romeo S, Loomba R
Multiple parallel inflammatory pathways drive MASH development, fueled by hepatic lipotoxicity, intestinal dysbiosis, and pro-inflammatory diets affecting immune responses. Cell Metabolism review of mechanistic pathways and therapeutic approaches. This mechanistic framework explains why most MASH drugs require pleiotropic metabolic and anti-inflammatory properties rather than single-target approaches.
Strategic signal
The review reinforces the scientific rationale for multi-target MASH therapies, which could support regulatory discussions for combination products or drugs with multiple mechanisms. Given that most MASH programs target single pathways, this complexity narrative may favor companies with platform approaches over single-mechanism assets. The emphasis on pleiotropic effects aligns with how Madrigal positioned resmetirom's dual metabolic-inflammatory profile during FDA review.
Liver/NASHMechanisms
Original Abstract
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.