Unlocking the benefits of aerobic exercise for MAFLD: a comprehensive mechanistic analysis

Metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by abnormal accumulation of triglycerides (TG) and cholesterol in hepatocytes, is a globally prevalent chronic liver disease with a rising incidence that poses a severe threat to human health. In the absence of effective targeted drugs and long-term prognostic interventions for MAFLD, aerobic exercise, as a safe and accessible non-pharmacological strategy, is widely recognized to slow MAFLD progression. However, a systematic summary of its mechanisms in ameliorating MAFLD remains insufficient.

This review integrates recent high-quality PubMed studies and classic models (e.g., high-fat diet-induced C57BL/6J mice, HepG2 cells) to analyze aerobic exercise's therapeutic effects on MAFLD and underlying molecular mechanisms. Aerobic exercise regulates MAFLD via a multi-dimensional network. SESN family signaling regulates hepatic lipid metabolism, improves insulin resistance, enhances antioxidant capacity, and promotes lipophagy. miRNA-mediated regulation modulates lipogenic gene expression, insulin signaling, and fatty acid oxidation via exercise-induced changes in key miRNAs and their upstream regulators or downstream targets. AMPK-centered energy metabolism orchestrates fatty acid β-oxidation promotion and de-novo lipogenesis suppression through its related pathways. Other key pathways include inhibiting lipogenesis via exercise-induced IL-6, blocking hepatic inflammation through brown adipose-derived Nrg4, optimizing lipid droplet-mitochondria interaction by regulating PLIN5 and Mfn-2, and suppressing ferroptosis via activating antioxidant pathways. Notably, mechanisms initially validated in non-alcoholic fatty liver disease (NAFLD) are equally applicable to MAFLD, as both are characterized by core metabolic dysfunction.

Aerobic exercise alleviates MAFLD progression by orchestrating a complex regulatory network involving energy metabolism, stress response, post-transcriptional modification, and inter-organ crosstalk. This review clarifies the key molecular targets and signaling pathways underlying aerobic exercise's therapeutic effects, providing a theoretical basis for exploring potential targeted interventions and guiding future drug development for MAFLD.