HIF-2α in Lung Biology and Disease: From Adaptation and Repair to Therapeutic Modulation

Hypoxia-inducible factor 2α (HIF-2α), encoded by EPAS1, has long been studied in erythropoiesis, high-altitude adaptation, and cancer. Recent studies also implicate HIF-2α within non-malignant lung development and disease. This review examines HIF-2α as a dosage-sensitive, context-dependent regulator of lung cell state rather than a uniformly protective or pathogenic transcription factor. HIF-2α inhibitors have been approved in oncology, while pulmonary studies demonstrate roles for HIF-2α in fetal lung maturation, endothelial barrier integrity, alveolar–capillary maintenance, pulmonary vascular remodeling, aberrant epithelial repair, fibroblast persistence, airway differentiation, and alveolar macrophage metabolic and surfactant homeostasis. We summarize the canonical EGLN/PHD–VHL–HIF pathway, the HIF-1α/HIF-2α isoform bias, human genetic evidence from chronic hypoxia adaptation, and emerging disease-specific data in pulmonary arterial hypertension, pulmonary fibrosis, COPD/emphysema, acute lung injury/ARDS, and muco-obstructive disease. We also highlight chromatin, long noncoding RNA, and post-transcriptional mechanisms that tune HIF-2α activity. Together, these findings support the need to precisely tailor HIF-2α modulation in lung disease, guided by cell type, disease phase, spatial context, and biological objective.