Current research on the HIF-2α-EPO–Hb axis in hypoxic environments: from molecular mechanisms to clinical

Hypoxic environments modulate downstream gene expression via activation of the hypoxia-inducible factor (HIF) signaling pathway, which facilitates adaptive responses to low oxygen. Under hypoxic conditions, HIF-2α is stabilized and translocated to the nucleus, where it binds to hypoxia-response elements and upregulates transcription of the erythropoietin (EPO) gene. Increased EPO stimulates red blood cell production in the bone marrow, raising hemoglobin (Hb) levels to improve oxygen transport. This review examines the principal regulatory pathway, the Hypoxia-Inducible Factor-2α-Erythropoietin-Hemoglobin axis (HIF-2α-EPO-Hb), which governs physiological and pathological responses to hypoxia. The HIF-2α-EPO-Hb axis dynamically regulates erythropoietin and hemoglobin production in response to fluctuations in oxygen levels, maintaining systemic oxygen homeostasis. This pathway is involved in both physiological processes, such as high-altitude adaptation, and pathological conditions. Disruption of this axis leads to anemia associated with chronic kidney disease, while excessive activation contributes to high-altitude polycythemia and tumor progression, including renal cell carcinoma. The complex regulatory networks of this axis across diverse tissue microenvironments and disease states remain incompletely characterized. Targeted interventions, such as hypoxia-inducible factor-prolyl hydroxylase inhibitors and hypoxia-inducible factor-2α inhibitors, face significant challenges in tissue selectivity, long-term safety, and efficacy prediction. This review elucidates the molecular regulatory mechanisms of the HIF-2α-EPO-Hb axis, delineates its dysregulation in chronic hypoxic diseases and tumorigenesis, and evaluates current research progress and clinical limitations of related therapies. The discussion provides theoretical foundations and future perspectives for mechanistic research and clinical intervention in relevant diseases.