Exercise-induced regulation of hepatic lactate metabolism in MASLD: Molecular mechanisms and therapeutic potential

With the escalating global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), exploring effective preventive and therapeutic strategies has become a matter of paramount urgency, particularly given the current lack of clinically approved targeted pharmacotherapies. Accumulating evidence in recent years has shifted the paradigm of hepatic lactate metabolism from a conventional, passive byproduct of glycolysis to a pivotal nexus for deciphering MASLD pathogenesis and exploring novel therapeutic interventions. During the pathogenesis of MASLD, excessive glycolysis-derived lactate acts as a critical carbon source that directly drives hepatic de novo lipogenesis, leading to severe lipid deposition. Concurrently, aberrantly elevated gluconeogenesis precipitates hyperglycemia, while impaired hepatic lactate clearance further aggravates systemic insulin resistance. While exercise is universally acknowledged as a potent intervention for ameliorating MASLD via canonical pathways, such as modulating lipid metabolism, suppressing oxidative stress, activating autophagy, and remodeling gut microbiota, the targeted regulation of hepatic lactate metabolism is emerging as a novel, core mechanism underlying its hepatoprotective effects. The remodeling efficacy of exercise on hepatic lactate metabolism is synergistically governed by exercise modality, intensity, and duration, with long-term regular training significantly enhancing hepatic gluconeogenic capacity and accelerating lactate clearance. At the molecular level, exercise optimizes hepatic lactate metabolic fluxes through the precise fine-tuning of monocarboxylate transporter expression and lactate dehydrogenase activity; this profound regulatory network is fundamentally sustained by the orchestration of intracellular redox homeostasis mediated by the NAD⁺/NADH ratio, as well as lactate metabolism-associated protein post-translational modifications (PTMs). This review systematically summarizes the multidimensional roles of lactate metabolism in the pathological progression of MASLD and comprehensively elucidates the emerging molecular networks through which exercise ameliorates MASLD by optimizing lactate fluxes, reshaping redox status, and mediating protein PTMs. Looking forward, deeply deciphering the specific molecular mechanisms underlying exercise-regulated lactate metabolism will provide a robust theoretical foundation and experimental basis for precise clinical prevention and treatment of MASLD, as well as the development of personalized exercise prescriptions.