Exercise-Induced Hepatic Mitochondrial Reprogramming Across Muscle-Gut-Thyroid Axes in MASLD/MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health burden driven by complex interactions among hepatic lipid accumulation, insulin resistance, chronic inflammation, and mitochondrial dysfunction. Exercise remains the cornerstone of lifestyle therapy for MASLD/MASH; however, its therapeutic benefits extend well beyond weight reduction and involve coordinated molecular adaptations across multiple organ systems. In this review, we introduce hepatic mitochondrial reprogramming as a conceptual framework describing the coordinated remodeling of mitochondrial energetics, quality-control pathways, and redox homeostasis that collectively restore metabolic flexibility and hepatocellular resilience. Exercise activates key metabolic regulators, including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuin signaling, promoting mitochondrial biogenesis, fatty acid oxidation, oxidative phosphorylation, and mitophagy while suppressing hepatic lipogenesis and oxidative injury. Skeletal muscle-derived myokines, alterations in gut microbial metabolism, and thyroid hormone signaling converge upon hepatic mitochondrial function through complementary endocrine and metabolic pathways. Together, these adaptations reduce hepatic steatosis, lipotoxicity, inflammation, and fibrogenesis while improving insulin sensitivity and metabolic flexibility. Emerging evidence further suggests that exercise-induced mitochondrial remodeling may complement pharmacologic therapies targeting hepatic metabolism, including thyroid hormone receptor-β agonists. Although multi-omics technologies continue to expand our understanding of these adaptive responses, the present review emphasizes the underlying molecular and physiological mechanisms through which exercise remodels hepatic mitochondrial function. We propose that exercise acts as a systems-level mitochondrial remodeling stimulus integrating skeletal muscle-, gut-, and thyroid-derived signals to improve hepatic metabolism and attenuate MASLD/MASH progression. This conceptual framework provides a mechanistic basis for precision exercise prescriptions and future combination therapeutic strategies targeting mitochondrial health.