Exercise as a Molecular Therapeutic Tool in MASLD: From Signaling Pathways to Clinical Translation—A Narrative Review

Physical exercise is a potent non-pharmacological strategy for the prevention and management of Metabolic dysfunction-associated steatotic liver disease (MASLD), a multifactorial disorder characterized by hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammation. Emerging evidence demonstrates that the benefits of exercise extend beyond caloric expenditure and are largely mediated by coordinated molecular and cellular adaptations within the liver and peripheral tissues. This review synthesizes current knowledge on the mechanisms through which exercise modulates MASLD pathophysiology, emphasizing intracellular signaling pathways, mitochondrial remodeling, antioxidant defenses, and myokine-driven muscle-liver crosstalk. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, Nrf2, and Akt, resulting in enhanced mitochondrial biogenesis, improved fatty acid oxidation, restored insulin signaling, and reduced inflammatory and oxidative stress. Repeated skeletal muscle contraction stimulates the release of myokines-including irisin, IL-6, and FGF21-that act through endocrine and paracrine routes to regulate hepatic lipid metabolism, promote systemic metabolic flexibility, and attenuate disease progression. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term hepatic metabolic reprogramming. Collectively, these molecular adaptations position exercise as a systemic, disease-modifying stimulus capable of restoring hepatic homeostasis, slowing the transition from steatosis to NASH and fibrosis, and improving long-term metabolic health. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in the clinical management of MASLD.