High-altitude hypoxia and blood-brain barrier injury: cellular mechanisms and clinical targets.

High-altitude regions, characterized by unique geographical and environmental conditions, are endowed with striking natural landscapes and abundant resources, attracting large numbers of people for exploration, habitation, and work. However, high-altitude hypoxia remains a persistent environmental challenge that threatens human health. Hypoxia is a principal environmental stressor that induces structural and functional injury to the blood-brain barrier (BBB). Its mechanisms involve disruption of tight junctions in the paracellular pathway, enhanced transcellular permeability, dysregulation of key signaling cascades, aberrant inflammatory responses and emerging processes such as autophagy and ferroptosis. Previous studies have shown that hypoxic exposure alters neuronal structure and function, promotes apoptosis and functional impairment, and affects neurotransmitters and their receptors, thereby compromising cognitive performance. High-altitude hypoxia is also associated with a spectrum of neurological disorders, including headache, cognitive dysfunction, sleep disturbances, epilepsy, and high-altitude cerebral edema (HACE). Beyond summarizing recent advances, this review provides an integrated mechanistic and translational perspective on high-altitude hypoxia-induced BBB injury by linking molecular pathways with population-specific adaptation, neurological disorders, and emerging therapeutic strategies. In particular, BBB-targeted interventions aimed at preserving barrier integrity, limiting neuroinflammation, and restoring transporter and junctional function may offer translational opportunities for preventing or mitigating high-altitude neurological injury. We further propose future directions integrating multi-omics, advanced BBB models, and precision interventions.