Abnormal lipid metabolism in metabolic dysfunction-associated steatohepatitis (MASH)

Abstract

Metabolic dysfunction-associated steatotic liver disease encompasses a spectrum of liver disorders driven by systemic metabolic imbalance, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), a progressive condition characterized by hepatocellular injury, inflammation, and fibrosis. Growing evidence indicates that dysregulated hepatic lipid metabolism is a central determinant of disease initiation and progression, extending beyond quantitative lipid accumulation to qualitative changes in lipid composition that induce lipotoxic stress. In MASH, excessive activation of de novo lipogenesis, impaired mitochondrial fatty acid oxidation, increased hepatic free fatty acid uptake, and defective very low-density lipoprotein secretion collectively promote lipid overload and cellular stress responses. These alterations trigger endoplasmic reticulum stress, oxidative stress, and inflammatory signaling, leading to hepatocyte death and activation of hepatic macrophages and stellate cells, thereby driving fibrogenesis. In parallel, disruption of intracellular lipid clearance mechanisms, particularly autophagy and chaperone-mediated autophagy, exacerbates lipid accumulation, inflammation, and fibrosis. Importantly, hepatic lipid metabolism is further modulated by environmental and metabolic factors, including dietary composition, gut microbiota, metabolic comorbidities, aging, and exposure to endogenous and exogenous chemicals, which can reprogram lipid handling and accelerate disease progression. This review provides an integrated perspective on the molecular mechanisms governing hepatic lipid metabolism in MASH, emphasizing the interplay between lipid dysregulation, cellular stress responses, and fibrogenesis. We further highlight emerging evidence linking impaired autophagic pathways and chemically induced metabolic stress to disrupted lipid homeostasis, underscoring their relevance from a toxicological perspective. A deeper understanding of these interconnected pathways will be essential for identifying therapeutic targets and improving risk assessment strategies for metabolic and drug-induced liver injury.