EPAS1 (endothelial PAS domain protein 1) is a hypoxia-inducible transcription factor that heterodimerizes with ARNT to bind hypoxia response elements (HREs) and regulate oxygen-dependent gene expression. Primary functions include regulating vascular endothelial growth factor (VEGF) expression and controlling genes essential for blood vessel development, lung tubular system formation, and blood-brain barrier endothelium development 1. EPAS1 acts as a potent activator of Tie-2 tyrosine kinase and requires transcriptional coactivators including CREBBP and EP300 for activation 2. EPAS1 demonstrates critical roles in systemic physiology: it regulates intestinal iron absorption as a master transcription factor of iron homeostasis 2, and hepatic EPAS1 stabilization promotes liver fibrosis 3. Genetically, EPAS1 shows remarkable evolutionary significance, with Tibetan populations carrying Denisovan-introgressed EPAS1 variants that enable high-altitude adaptation through altered hemoglobin regulation 41. Clinically, EPAS1 mutations cause familial erythrocytosis and are associated with pheochromocytoma/paraganglioma (PPGL). EPAS1-related PPGLs represent a distinct molecular cluster characterized by noradrenergic biochemistry with increased metastatic risk 5, though distant metastases are typically indolent 6. The HIF2α inhibitor belzutifan shows promise for EPAS1-driven tumors 7. Endothelial EPAS1 dysfunction contributes to pulmonary hypertension pathogenesis through mitochondrial dysfunction and pseudohypoxia 8.