Metabolic dysfunction–associated steatotic liver disease

Metabolic dysfunction–associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), is a chronic liver disease defined by hepatic fat accumulation (steatosis) arising in the setting of metabolic dysfunction—such as obesity, insulin resistance, type 2 diabetes, hypertension, and dyslipidemia—and may coexist with other causes of liver injury; moderate alcohol intake is classified separately as MetALD. It is among the most common chronic liver diseases worldwide and spans a histological continuum from simple steatosis to metabolic dysfunction–associated steatohepatitis (MASH), the inflammatory subtype that can progress to hepatic fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related death. As the hepatic expression of systemic metabolic derangement, MASLD is closely tied to cardiovascular disease and type 2 diabetes, and MASH has become a leading indication for liver transplantation.

Its pathogenesis is multifactorial, driven by dysregulated lipid metabolism, insulin resistance, oxidative stress, chronic low-grade inflammation, and perturbation of the gut microbiota–bile acid (gut–liver) axis. Excess hepatic lipid, together with impaired fatty acid oxidation, promotes lipotoxic hepatocellular injury, activation of inflammatory signaling, and fibrogenesis in which hepatic stellate cells and mediators such as fibroblast activation protein (FAP) participate; FAP additionally modulates circulating substrates including fibroblast growth factor 21 (FGF21). Peroxisome proliferator-activated receptor alpha (PPARα) and related regulators of lipid handling are central to disease biology and are targets of therapeutic interest. Clinically, MASLD shows marked heterogeneity across age, sex, and racial and ethnic groups, and non-invasive tests are increasingly used to identify MASH and stratify the risk of progression, while metabolic risk factors and MASLD have also been linked to extrahepatic outcomes such as cognitive decline.