Inflammatory stress disrupts retinal lactate homeostasis under high-altitude hypoxia

The retina is a highly metabolically active tissue that is particularly sensitive to hypoxic stress, yet how its metabolic homeostasis is maintained under hypobaric hypoxia and modified by inflammation remains unclear. Here, we investigated retinal lactate dynamics and their functional role under hypoxia alone and combined hypoxic-inflammatory stress using a murine model of simulated high-altitude hypobaric hypoxia (7 km). Retinal lactate levels remained stable during acute hypoxic exposure (3-24 h), in contrast to transient brain lactate elevation and a gradual decline in blood lactate. However, when inflammation was induced by lipopolysaccharide (LPS), hypoxia combined with inflammation led to a marked reduction in retinal lactate, accompanied by microglial activation, oxidative stress, and blood-retinal barrier disruption. Neither hypoxia nor inflammation alone caused significant retinal injury or altered lactate homeostasis. Mechanistically, hypoxia with or without LPS increased hypoxia-inducible factor-1α (HIF-1α) expression, whereas key glycolytic enzymes and adenosine triphosphate (ATP) levels remained unchanged, indicating dissociation between hypoxic signaling and downstream glycolytic output. Although systemic glucose and lactate were reduced under inflammatory conditions, retinal lactate dynamics were only partially dependent on systemic metabolism, suggesting tissue-specific regulation. Importantly, exogenous lactate supplementation restored retinal lactate levels and attenuated oxidative stress and barrier leakage without affecting systemic lactate. In conclusion, lactate depletion-not energy failure-is a key determinant of retinal injury under inflammatory hypoxia. Lactate homeostasis thus represents a central mechanism of retinal resilience and a potential therapeutic target in hypoxia-related retinal disorders.