Hepatic exposome as an emerging contributor to metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease is among the most prevalent chronic liver diseases worldwide. Its increasing incidence is typically linked to over-nutrition and metabolic syndrome. However, this account remains insufficiently detailed, particularly regarding diseases in lean individuals and the generational acceleration of metabolic illnesses. The exposome encompasses the entirety of the environmental exposure throughout an individual’s life and provides a complementary framework. The liver is a pivotal organ given that it is the primary location for the biotransformation of xenobiotics. This study synthesized data suggesting that environmental chemical exposure may be a plausible and controllable factor in steatotic liver disease while distinguishing associations from causation. We reviewed the main exposure classes, including per- and polyfluoroalkyl substances, micro- and nanoplastics, endocrine-disrupting plasticizers, persistent organic pollutants, hazardous metals, and air pollution. We assessed the strength of human evidence and delineated the potential mechanisms shared by these agents, including nuclear receptor disruption, mitochondrial and oxidative injury, inflammasome activation, stellate cell fibrogenesis, gut microbiota-bile acid disruption, and developmental reprogramming, along with their documented associations with steatosis, steatohepatitis, fibrosis, and hepatocellular carcinoma. The recognition of environmental exposure redefines metabolic dysfunction-associated steatotic liver disease as chemical environment-driven. These findings have implications in risk assessment, treatment, and prevention.