The Warburg Effect Beyond Cancer: Melatonin as a Metabolic Modulator in Non-Neoplastic Disorders

Aerobic glycolysis, also known as the Warburg effect, and the accumulation of lactate that it causes, are increasingly recognized outside the field of oncology as triggers of chronic non-neoplastic disorders. This review integrates preclinical and clinical evidence to evaluate the ability of melatonin to reverse Warburg-effect-like metabolic reprogramming. Literature on neurodegeneration, age-related sarcopenia, type 2 diabetes, chronic kidney disease, heart failure and pulmonary arterial hypertension (PAH) has been reviewed and synthesised. In all of these conditions, hypoxia-inducible factor 1α (HIF-1α) and pyruvate dehydrogenase kinase 4 (PDK4) inhibit the pyruvate dehydrogenase complex. This diverts pyruvate away from the tricarboxylic acid (TCA) cycle and promotes glycolysis. In cell and animal models, melatonin consistently inhibits PDK4, destabilizes HIF-1α under normoxic conditions, activates SIRT1/3-dependent mitochondrial biogenesis and mitophagy, and eliminates reactive oxygen and nitrogen species. These actions reduce lactate production, restore oxidative phosphorylation and attenuate tissue damage. This appears to induce cognitive and synaptic improvements in Alzheimer’s and Parkinson’s disease models, increased muscle mass and function in ageing rodents, improved insulin sensitivity alongside suppression of hepatic gluconeogenesis in diabetic models, reduced fibrosis in nephropathy,and normalization of vascular remodeling in hypoxia-induced pulmonary arterial hypertension (PAH). Early-stage clinical trials corroborate a decrease in oxidative and inflammatory markers, improved sleep quality and modest cognitive benefits. However, they report conflicting effects on insulin sensitivity, which are largely related to the dose and timing of administration in relation to food intake. Overall, the current data suggest that melatonin is a pleiotropic metabolic modulator capable of counteracting the Warburg phenotype in multiple organs. However, human studies remain scarce, and well-designed randomised trials incorporating chronotherapy are needed before clinical adoption.