HIF-1α in Gout: A central regulator of metabolism, inflammation, and environmental stress

Gout is a chronic inflammatory disease characterized by the deposition of monosodium urate crystals in the joints. However, growing research suggests a more complex pathophysiology involving genetic susceptibility, metabolic stress, and environmental factors. Among emerging contributors, hypoxia-inducible factor 1 alpha (HIF-1α) has been proposed as a potential regulator that links these processes, though its role in gout remains underexplored. This review examines the emerging evidence supporting HIF-1α's role in both urate production and inflammation, to offer a unifying framework connecting these contributors to gout pathogenesis. Systemically, HIF-1α has been shown to promote a metabolic shift towards glycolysis and purine metabolism, providing a plausible mechanism for hyperuricemia. Locally, metabolic priming helps sustain immune responses, particularly through the release of interleukin-1 beta. Environmental stressors, including hypoxia and pseudohypoxia (e.g., obstructive sleep apnea), can further stabilize HIF-1α and amplify inflammatory signaling. This framework supports a model in which HIF-1α links metabolic stress, immune activation, and environmental exposures, reframing gout as a disorder of metabolic maladaptation and suggesting HIF-1α as a potential therapeutic target.