Integrative hypoxia preconditioning: linking iron– hypoxia-inducible factor pathways and oxygen-based therapies from high-altitude physiology to clinical application: a comprehensive review
DOI:
https://doi.org/10.18203/2319-2003.ijbcp20254173Keywords:
Adaptive oxygen medicine, Hepcidin, High-altitude adaptation, Hyperbaric oxygen, Hypoxia preconditioning, Oxidative stressAbstract
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.
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References
West JB. High-altitude medicine. Am J Respir Crit Care Med. 2012;186(12):1229-37.
Bartsch P SER. Acute high-altitude illnesses. N Engl J Med. 2013;3:69.
Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Investig. 2013;123(9):3664-71. DOI: https://doi.org/10.1172/JCI67230
Ratcliffe PJ. Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J Physiol. 2013;591(8):2027-42. DOI: https://doi.org/10.1113/jphysiol.2013.251470
Hackett PH, Roach RC. High-altitude illness. N Engl J Med. 2001;345(2):107-14. DOI: https://doi.org/10.1056/NEJM200107123450206
Forrer A, Gaisl T, Sevik A, Meyer M, Senteler L, Lichtblau M, et al. Partial Pressure of Arterial Oxygen in Healthy Adults at High Altitudes: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2023;6(6):e2318036 DOI: https://doi.org/10.1001/jamanetworkopen.2023.18036
Gassmann M, Muckenthaler MU. Adaptation of iron requirement to hypoxic conditions at high altitude. J Appl Physiol. 2015;119(12):1432-40. DOI: https://doi.org/10.1152/japplphysiol.00248.2015
Thom SR. Hyperbaric Oxygen: Its Mechanisms and Efficacy. Plast Reconstr Surg. 2011;127:131S-41S. DOI: https://doi.org/10.1097/PRS.0b013e3181fbe2bf
Jensen JD, Vincent AL. High Altitude Cerebral Edema. In: StatPearls. Treasure Island (FL): StatPearls Publishing. 2025. Available at: https://www.ncbi.nlm. nih.gov/books/NBK430916/. Accessed on 10 October 2025.
You J, Chen X, Zhou M, Ma H, Liu Q, Huang C. Hyperbaric oxygen preconditioning for prevention of acute high-altitude diseases: Fact or fiction? Front Physiol. 2023;14. DOI: https://doi.org/10.3389/fphys.2023.1019103
Luna-López A, González-Puertos VY, López-Diazguerrero NE, Königsberg M. New considerations on hormetic response against oxidative stress. J Cell Commun Signal. 2014;8(4):323-31. DOI: https://doi.org/10.1007/s12079-014-0248-4
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510-4. DOI: https://doi.org/10.1073/pnas.92.12.5510
Agrawal A, Rathor R, Suryakumar G. Oxidative protein modification alters proteostasis under acute hypobaric hypoxia in skeletal muscles: a comprehensive in vivo study. Cell Stress and Chaperones. 2017;22(3):429-43. DOI: https://doi.org/10.1007/s12192-017-0795-8
Chen X, Zhang J, Lin Y, Li Y, Wang H, Wang Z, et al. Mechanism, prevention and treatment of cognitive impairment caused by high altitude exposure. Front Physiol. 2023;14:1191058. DOI: https://doi.org/10.3389/fphys.2023.1191058
Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 2013;27(1):41-53.
Haase VH. Pathophysiological Consequences of HIF Activation. Ann N Y Acad Sci. 2009;1177(1):57-65. DOI: https://doi.org/10.1111/j.1749-6632.2009.05030.x
Herman NM, Grill D, Anderson P, Miller A, Johnson J, O’Malley K, et al. Peripheral bloodmononuclear cellgene expre ssion in healthy adults rapidly transported to highaltitude. Adv Genomics Genet. 2014;5:1. DOI: https://doi.org/10.2147/AGG.S66784
Pagani A, Nai A, Silvestri L, Camaschella C. Hepcidin and Anemia: A Tight Relationship. Front Physiol. 2019;10:1294. DOI: https://doi.org/10.3389/fphys.2019.01294
Villafuerte FC, Corante N. Chronic Mountain Sickness: Clinical Aspects, Etiology, Management, and Treatment. High Alt Med Biol. 2016;17(2):61-9. DOI: https://doi.org/10.1089/ham.2016.0031
Villafuerte FC. Occupational prophylaxis against high-altitude illness in Peruvian miners. J Occup Health. 2013;55(6):445-52.
Villafuerte FC, Macarlupú JL, Anza-Ramírez C, Corrales-Melgar D, Vizcardo-Galindo G, Corante N, et al. Decreased plasma soluble erythropoietin receptor in high-altitude excessive erythrocytosis and Chronic Mountain Sickness. J Appl Physiol (1985). 2014;117(11):1356-62. DOI: https://doi.org/10.1152/japplphysiol.00619.2014
Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, Goldstein MC, et al. Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol. 1998;106(3):385-400.
Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, et al. Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A. 2010;107(25):11459-64. DOI: https://doi.org/10.1073/pnas.1002443107
Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 2013;27(1):41-53. DOI: https://doi.org/10.1016/j.blre.2012.12.003
Anderson SA, Nizzi CP, Chang YI, Deck KM, Schmidt PJ, Galyet B, et al. The IRP1-HIF-2α Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption. Cell Metab. 2013;17(2):282-90. DOI: https://doi.org/10.1016/j.cmet.2013.01.007
Swenson ER. High-Altitude Pulmonary Edema. In: Textbook of Pulmonary Vascular Disease. Springer US. 2011;871-88. DOI: https://doi.org/10.1007/978-0-387-87429-6_61
Bärtsch P, Swenson ER. Acute High-Altitude Illnesses. New Eng J Med. 2013;368(24):2294-302. DOI: https://doi.org/10.1056/NEJMcp1214870
Obeagu EI. Iron homeostasis and health: understanding its role beyond blood health - a narrative review. Ann Med Surg (Lond). 2025;87(6):3362-71. DOI: https://doi.org/10.1097/MS9.0000000000003100
Prabhakar NR, Semenza GL. Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2. Physiol Rev. 2012;92(3):967-1003. DOI: https://doi.org/10.1152/physrev.00030.2011
West JB. High-Altitude Medicine. Am J Respir Crit Care Med. 2012;186(12):1229-37. DOI: https://doi.org/10.1164/rccm.201207-1323CI
Hackett P. The Incidence, Importance, and Prophylaxis of Acute Mountain Sickness. The Lancet. 1976;308(7996):1149-55. DOI: https://doi.org/10.1016/S0140-6736(76)91677-9
Luks AM. Physiology in Medicine: A physiologic approach to prevention and treatment of acute high-altitude illnesses. J Appl Physiol (1985). 2015;118(5):509-19. DOI: https://doi.org/10.1152/japplphysiol.00955.2014
Luks AM, Swenson ER, Bärtsch P. Acute high-altitude sickness. Eu Resp Rev. 2017;26(143):160096. DOI: https://doi.org/10.1183/16000617.0096-2016
Flueck M. Plasticity of the Muscle Proteome to Exercise at Altitude. High Alt Med Biol. 2009;10(2):183-93. DOI: https://doi.org/10.1089/ham.2008.1104
Hoppeler H, Vogt M. Muscle tissue adaptations to hypoxia. J Exp Biol. 2001;204(18):3133-9. DOI: https://doi.org/10.1242/jeb.204.18.3133
Smith TG, Balanos GM, Croft QP, Talbot NP, Dorrington KL, Ratcliffe PJ, Robbins PA. The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol. 2008;586(24):5999-6005. DOI: https://doi.org/10.1113/jphysiol.2008.160960
León-Velarde F, Maggiorini M, Reeves JT, Aldashev A, Asmus I, Bernardi L, et al. Consensus statement on chronic and subacute high altitude diseases. High Alt Med Biol. 2005;6(2):147-57. DOI: https://doi.org/10.1089/ham.2005.6.147
Richalet JP, Lhuissier FJ. Aging, Tolerance to High Altitude, and Cardiorespiratory Response to Hypoxia. High Alt Med Biol. 2015;16(2):117-24.
Snehashis Singha. Hypoxic Challenges at Altitude: Mechanistic Insights and Translational Approaches to High-Altitude Illness. Int J Pharm Sci Res. 2026;17(3):1000-11.
Tsai MC, Lin HJ, Lin MT, Niu KC, Chang CP, Tsao TC. High-altitude pulmonary edema can be prevented by heat shock protein 70-mediated hyperbaric oxygen preconditioning. J Trauma Acute Care Surg. 2014;77(4):585-91. DOI: https://doi.org/10.1097/TA.0000000000000408
Cozene B, Sadanandan N, Gonzales-Portillo B, Saft M, Cho J, Park YJ, et al. An extra breath of fresh air: hyperbaric oxygenation as a stroke therapeutic. Biomolecules. 2020;10(9):1279. DOI: https://doi.org/10.3390/biom10091279
Andersen AB, Bonne TC, Bejder J, Jung G, Ganz T, Nemeth E, et al. Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial. Am J Physiol Regul Integr Comp Physiol. 2021;321(2):R152-61.
Andersen AB, Bonne TC, Bejder J, Jung G, Ganz T, Nemeth E, et al. Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial. Am J Physiol Regul Integr Comp Physiol. 2021;321(2):R152-61. DOI: https://doi.org/10.1152/ajpregu.00070.2021
Doerr V, Montalvo RN, Nguyen BL, Boeno FP, Sunshine MD, Bindi VE, et al. Effects of Hyperbaric Oxygen Preconditioning on Doxorubicin Cardiorespiratory Toxicity. Antioxidants. 2022;11:2073. DOI: https://doi.org/10.3390/antiox11102073
Semenza GL. Oxygen Sensing, Homeostasis, and Disease. New Eng J Med. 2011;365(6):537-47. DOI: https://doi.org/10.1056/NEJMra1011165
Semenza GL. Hypoxia-Inducible Factors in Physiology and Medicine. Cell. 2012;148(3):399-408. DOI: https://doi.org/10.1016/j.cell.2012.01.021
Cai J, Ruan J, Shao X, Ding Y, Xie K, Tang C, et al. Oxygen Enrichment Mitigates High-Altitude Hypoxia-Induced Hippocampal Neurodegeneration and Memory Dysfunction Associated with Attenuated Tau Phosphorylation. High Alt Med Biol. 2021;22(3):274-84. DOI: https://doi.org/10.1089/ham.2020.0218
Shah YM, Xie L. Hypoxia-inducible factors link iron homeostasis and erythropoiesis. Gastroenterology. 2014;146(3):630-42. DOI: https://doi.org/10.1053/j.gastro.2013.12.031
Liu F, Panagiotakos D. Real-world data: methods, applications, challenges and opportunities. BMC Med Res Methodol. 2022;22:287. DOI: https://doi.org/10.1186/s12874-022-01768-6
Yan X, Liu J, Zhu M, Liu L, Chen Y, Zhang Y, Xiao H. Salidroside orchestrates metabolic reprogramming by regulating the Hif-1α signalling pathway in acute mountain sickness. Pharm Biol. 2021;59(1):1538-48. DOI: https://doi.org/10.1080/13880209.2021.1992449
Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, Goldstein MC, et al. Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol. 1998;106(3):385-400. DOI: https://doi.org/10.1002/(SICI)1096-8644(199807)106:3<385::AID-AJPA10>3.3.CO;2-6
Maggiorini M. Prevention and Treatment of High-Altitude Pulmonary Edema. Prog Cardiovasc Dis. 2010;52(6):500-6. DOI: https://doi.org/10.1016/j.pcad.2010.03.001
Ferrazzini G, Maggiorini M, Kriemler S, Bartsch P, Oelz O. Successful treatment of acute mountain sickness with dexamethasone. BMJ. 1987;294(6584):1380-2. DOI: https://doi.org/10.1136/bmj.294.6584.1380
Bartsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of High-Altitude Pulmonary Edema by Nifedipine. New Eng J Med. 1991;325(18):1284-9. DOI: https://doi.org/10.1056/NEJM199110313251805
Lehmann T, Mairbäurl H, Pleisch B, Maggiorini M, Bärtsch P, Reinhart WH. Platelet count and function at high altitude and in high-altitude pulmonary edema. J Appl Physiol. 2006;100(2):690-4. DOI: https://doi.org/10.1152/japplphysiol.00991.2005
Moore LG. Human genetic adaptation to high altitudes: Current status and future prospects. Quaternary International. 2017;461:4-13. DOI: https://doi.org/10.1016/j.quaint.2016.09.045
Shen G, Wu X, Tang C, Yan Y, Liu J, Guo W, et al. An oxygen enrichment device for lowlanders ascending to high altitude. Biomed Eng Online. 2013;12(1):100. DOI: https://doi.org/10.1186/1475-925X-12-100
Küpper T, Gieseler U, Milledge J, Morrison A, Schöffl V. Portable hyperbaric chambers for the treatment of altitude disease. Health Promotion Physical Activity. 2022;20(3):36-40. DOI: https://doi.org/10.55225/hppa.429
Richalet JP, Lhuissier FJ. Aging, Tolerance to High Altitude, and Cardiorespiratory Response to Hypoxia. High Alt Med Biol. 2015;16(2):117-24. DOI: https://doi.org/10.1089/ham.2015.0030
Singha S, Majumder R. High-Altitude Illness: A Comprehensive Review of Classification, Pathophysiology, And Clinical Management. J Pharm Sci. 2025;1(10):193-205.
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