New perspectives in alleviating MASLD: synergism and prospects of exercise and natural products

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease globally with rapidly increasing incidence. This narrative review summarizes MASLD pathogenesis from hepatic lipid accumulation and insulin resistance through endoplasmic reticulum stress-induced inflammation to irreversible fibrosis and hepatocellular carcinoma. We evaluate therapeutic potential of natural products-including polyphenols, omega-3 fatty acids, taurine, probiotics, and bioactive peptides-that target activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and peroxisome proliferator-activated receptor-alpha (PPARα) signal pathways. Exercise modulates lipid metabolism, enhances mitochondrial quality control, and restores gut-liver axis homeostasis. The core emphasis lies in synergistic mechanisms whereby exercise combined with natural product supplementation produces superior therapeutic efficacy through multi-pathway crosstalk, coordinating lipid metabolism regulation via AMPK/SIRT1/PPARα networks, attenuating oxidative stress and inflammation through PI3K/AKT and toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells modulation, enhancing mitochondrial function and biogenesis, and restoring intestinal barrier integrity and microbiota composition. Finally, we identify critical methodological limitations including heterogeneity of exercise protocols, poor bioavailability of natural compounds, species-specific differences in preclinical models, and scarcity of robust human trials. This review provides a mechanistic framework for developing evidence-based, integrated interventions for MASLD management.