G Protein-Coupled Receptor in High-Altitude Diseases: Mechanistic Insights and Therapeutic Opportunities.

High-altitude diseases (HADs) encompass a spectrum of acute and chronic disorders-including acute mountain sickness, high-altitude cerebral edema, high-altitude pulmonary edema, high-altitude polycythemia, high-altitude pulmonary hypertension, and high-altitude heart disease-that arise from insufficient adaptation to hypobaric hypoxia. Despite their heterogeneous clinical manifestations, these conditions represent a continuum from acute adaptive stress to chronic maladaptive compensation, unified by persistent oxygen deprivation and dysregulated systemic homeostasis. G protein-coupled receptors (GPCRs), the largest superfamily of membrane receptors, have emerged as central regulators of hypoxia sensing, ventilatory control, vascular tone, barrier integrity, erythropoiesis, immune activation, and metabolic reprogramming. However, how specific GPCR subtypes and their downstream signaling networks coordinate adaptation versus maladaptation across distinct organ systems and disease stages remains incompletely defined. This review synthesizes recent mechanistic insights into GPCR-mediated pathways that govern neural, pulmonary, vascular, and hematologic responses to hypoxia. We examine the transition from protective to pathological signaling, highlight receptor-level divergence that enables therapeutic selectivity, and evaluate translational prospects for GPCR-targeted strategies, including biased agonism, receptor-specific modulation, and sex-based interventions. These advances establish a framework for precision therapies tailored to high-altitude populations.