Publication:

Integrative hypoxia preconditioning: linking iron– hypoxia-inducible factor pathways and oxygen-based therapies from high-altitude physiology to clinical application: a comprehensive review

Hypoxia, once seen solely as a threat, is now recognized as a potent driver of human adaptation. From Himalayan sojourners to critically ill patients, survival under low oxygen relies on a shared molecular axis the hypoxia-inducible factor (HIF)-iron-erythropoietin (EPO) network. Iron acts as the pivotal regulator, as prolyl hydroxylase enzymes that degrade HIF require ferrous iron, directly linking oxygen sensing to erythropoiesis. At high altitude, hepcidin suppression and erythroferrone induction mobilize iron stores for hemoglobin synthesis, while genetic variants such as EPAS1 and EGLN1 fine-tune erythropoietic response to prevent excessive polycythemia. Controlled hypoxia or hyperbaric oxygen preconditioning at sea level similarly activates HIF and Nrf2-mediated antioxidant defences, improving mitochondrial efficiency and tissue resilience. Clinically, HIF-prolyl hydroxylase inhibitors like roxadustat exploit this pathway to manage renal anemia. Emerging concepts in adaptive oxygen medicine including portable hyperbaric therapy and intermittent hypoxia training translate altitude physiology into therapeutic strategy. Thus, oxygen is redefined not only as a vital substrate but as a modifiable signal coordinating iron metabolism, redox balance, and cellular adaptation, a continuum linking acclimatization, preconditioning, and healing.