Metabolic dysfunction-associated steatotic liver disease: pathogenic mechanisms and exercise-induced molecular adaptations

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic metabolic disorder that spans steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Although hepatic lipid overload is a central pathological feature, MASLD progression is driven by interconnected disturbances in lipid handling, mitochondrial function, oxidative stress, immune-inflammatory activation, programmed cell death, autophagy–lysosomal homeostasis, and gut–liver communication. This review critically synthesizes current evidence on the pathogenic mechanisms of MASLD and the molecular adaptations induced by exercise. We discuss how impaired lipid storage, oxidation, export, and detoxification interact with organelle stress, macrophage activation, inflammasome and cell-death signaling, defective autophagic clearance, and bidirectional gut–liver inputs to promote hepatocellular injury and fibrogenesis. We further examine how exercise modality, intensity, dose, and timing influence MASLD, and summarize evidence suggesting that exercise may enhance lipid mobilization and fatty acid oxidation, improve mitochondrial and autophagic quality control, restrain inflammatory and programmed cell-death pathways, and reshape gut–liver axis function. Defining disease-stage- and phenotype-specific responses, together with reliable metabolic and molecular biomarkers, will be essential for translating exercise-induced adaptations into individualized MASLD management.