{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T19:24:46Z","timestamp":1793215486983,"version":"4.5.0"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>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-2\u03b1 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-2\u03b1-Erythropoietin\u2013Hemoglobin axis (HIF-2\u03b1-EPO-Hb), which governs physiological and pathological responses to hypoxia. The HIF-2\u03b1-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-2\u03b1 inhibitors, face significant challenges in tissue selectivity, long-term safety, and efficacy prediction. This review elucidates the molecular regulatory mechanisms of the HIF-2\u03b1-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.<\/jats:p>","DOI":"10.3389\/fmed.2026.1780669","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T05:28:20Z","timestamp":1771824500000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Current research on the HIF-2\u03b1-EPO\u2013Hb axis in hypoxic environments: from molecular mechanisms to clinical"],"prefix":"10.3389","volume":"13","author":[{"given":"Qiaochu","family":"Zheng","sequence":"first","affiliation":[{"name":"Qinghai University","place":["Xining, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinglan","family":"Li","sequence":"additional","affiliation":[{"name":"Qinghai University","place":["Xining, China"]},{"name":"Qinghai Provincial People's Hospital","place":["Xining, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimei","family":"Li","sequence":"additional","affiliation":[{"name":"Qinghai University","place":["Xining, China"]},{"name":"Qinghai Provincial People's Hospital","place":["Xining, China"]},{"name":"Qinghai Clinical Research Center for High Altitude Diseases","place":["Xining, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"151386","DOI":"10.1016\/j.ejcb.2024.151386","article-title":"Regulation of the HIF switch in human endothelial and cancer cells","volume":"103","author":"Slawski","year":"2024","journal-title":"Eur J Cell Biol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2686","DOI":"10.3390\/cancers14112686","article-title":"Significance of specific oxidoreductases in the design of hypoxia-activated prodrugs and fluorescent turn off\u2013on probes for hypoxia imaging","volume":"14","author":"Janczy-Cempa","year":"2022","journal-title":"Cancers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1038\/cdd.2008.17","article-title":"Biology of hypoxia-inducible factor-2\u03b1 in development and disease","volume":"15","author":"Patel","year":"2008","journal-title":"Cell Death Differ"},{"key":"B4","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1111\/j.1440-1681.2006.04474.x","article-title":"Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression","volume":"33","author":"Stockmann","year":"2006","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1182\/blood.V118.21.1303.1303","article-title":"Tissue-Specific HIF-1 and HIF-2 regulatory elements and their roles in erythropoietin gene expression","volume":"118","author":"Yoon","year":"2011","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1182\/blood.V112.11.481.481","article-title":"HIF-2alpha associated familial erythrocytosis supports the PHD2-HIF- 2alpha-VHL axis as the major regulator of erythropoietin production","volume":"112","author":"Percy","year":"2008","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1172\/JCI83551","article-title":"Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin","volume":"126","author":"Kobayashi","year":"2016","journal-title":"J Clin Invest"},{"key":"B8","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1038\/ki.2009.460","article-title":"Hypoxia-inducible factor-2\u03b1-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization","volume":"77","author":"Paliege","year":"2010","journal-title":"Kidney Int"},{"key":"B9","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/s41585-024-00876-w","article-title":"Von Hippel\u2013Lindau protein signalling in clear cell renal cell carcinoma","volume":"21","author":"Liao","year":"2024","journal-title":"Nat Rev Urol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V126.23.931.931","article-title":"Activation of HIF-2a-EPO Axis in Kidney or Liver Is Sufficient to Drive Erythrocytosis in a Novel Inducible HIF-2a Transgenic Mouse Model","author":"Wang","year":""},{"key":"B11","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/ki.2008.687","article-title":"Nonrenal regulation of EPO synthesis","volume":"75","author":"Weidemann","year":"2009","journal-title":"Kidney Int"},{"key":"B12","doi-asserted-by":"publisher","first-page":"9467","DOI":"10.3390\/ijms22179467","article-title":"S1P stimulates erythropoietin production in mouse renal interstitial fibroblasts by S1P1 and S1P3 receptor activation and HIF-2\u03b1 stabilization","volume":"22","author":"Hafizi","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2201","DOI":"10.1182\/blood.V126.23.2201.2201","article-title":"Erythropoietin mediated increase in monocyte-derived liver macrophages; a role for kupffer cells?","volume":"126","author":"Gilboa","year":"2015","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1093\/ndt\/gfae225","article-title":"Oxygen sensing in the kidney","volume":"40","author":"Geis","year":"2024","journal-title":"Nephrol Dial Transplant"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00174.2010","article-title":"Hypoxic regulation of erythropoiesis and iron metabolism","author":"Haase","year":"2010","journal-title":"Am J Physiol Renal Physiol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/nrneph.2015.82","article-title":"Anaemia in kidney disease: harnessing hypoxia responses for therapy","volume":"11","author":"Koury M","year":"2015","journal-title":"Nat Rev Nephrol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1172\/JCI122359","article-title":"Hepatic hepcidin\/intestinal HIF-2\u03b1 axis maintains iron absorption during iron deficiency and overload","volume":"129","author":"Schwartz","year":"2018","journal-title":"J Clin Invest"},{"key":"B18","doi-asserted-by":"publisher","first-page":"3039","DOI":"10.1182\/blood-2010-02-270322","article-title":"Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia","volume":"116","author":"Kapitsinou","year":"2010","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/s41419-024-07136-0","article-title":"USP7 depletion potentiates HIF2\u03b1 degradation and inhibits clear cell renal cell carcinoma progression","volume":"15","author":"Tu","year":"2024","journal-title":"Cell Death Dis"},{"key":"B20","doi-asserted-by":"publisher","first-page":"7109","DOI":"10.3390\/ijms22137109","article-title":"STAT5 as a key protein of erythropoietin signalization","volume":"22","author":"T\u00f3thov\u00e1","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B21","doi-asserted-by":"publisher","first-page":"7682","DOI":"10.3390\/ijms22147682","article-title":"The Role of PI3K\/AKT and MAPK signaling pathways in erythropoietin signalization","volume":"22","author":"T\u00f3thov\u00e1","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"4511","DOI":"10.1182\/blood-2007-07-102848","article-title":"Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2","volume":"111","author":"Grebien","year":"2008","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1182\/blood-2018-99-120299","article-title":"Target of erythropoietin, Fam210b, regulates erythroid heme synthesis by control of mitochondrial iron import and regulation of fech activity","volume":"132","author":"Yien","year":"2018","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3330","DOI":"10.1182\/blood.V126.23.3330.3330","article-title":"Identification of Erythroid Specific Enhancers By Analyzing Genome Wide Association of Transcriptional Co-Activators CBP and P300","volume":"126","author":"Mayuranathan","year":"2015","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","first-page":"108636","DOI":"10.1016\/j.pharmthera.2024.108636","article-title":"Characteristics of anticancer activity of CBP\/p300 inhibitors\u2014Features of their classes, intracellular targets and future perspectives of their application in cancer treatment","volume":"257","author":"Strachowska","year":"2024","journal-title":"Pharmacol Ther"},{"key":"B26","doi-asserted-by":"publisher","first-page":"100741","DOI":"10.1016\/j.mtbio.2023.100741","article-title":"Microenvironment-targeted strategy steers advanced bone regeneration","volume":"22","author":"Hao","year":"2023","journal-title":"Materials Today Bio"},{"key":"B27","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1111\/j.1365-2141.2005.05580.x","article-title":"Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor","volume":"130","author":"Arcasoy","year":"2005","journal-title":"Br J Haematol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.cell.2019.12.010","article-title":"Stabilizing HIF to Ameliorate Anemia","volume":"180","author":"Voit R","year":"2020","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1515\/jomb-2017-0014","article-title":"Interpretation of erythropoietin and haemoglobin levels in patients with various stages of chronic kidney disease","volume":"36","author":"Panjeta","year":"2017","journal-title":"J Med Biochem"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3216","DOI":"10.1182\/blood.V116.21.3216.3216","article-title":"Hepcidin levels and erythropoietin alfa resistance in patients with chemotherapy induced anemia (CIA)","volume":"116","author":"Schipperus","year":"2010","journal-title":"Blood"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1182\/blood.V118.21.2092.2092","article-title":"The effectiveness of a fixed low dose of erythropoietin (EPO) in anemic solid tumor patients receiving concomitant chemotherapy: a prospective, randomized, controlled study","volume":"118","author":"Youssef","year":"2011","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s00520-023-08267-4","article-title":"Anemia diagnosis and therapy in malignant diseases: implementation of guidelines\u2014a representative study","volume":"32","author":"Link","year":"2024","journal-title":"Support Care Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1146\/annurev-med-042921-102602","article-title":"Regulation of erythropoiesis by the hypoxia-inducible factor pathway: effects of genetic and pharmacological perturbations","volume":"74","author":"Semenza","year":"2023","journal-title":"Annu Rev Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s11658-022-00408-7","article-title":"The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability","volume":"27","author":"Ja\u015bkiewicz","year":"2022","journal-title":"Cell Mol Biol Lett"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1158\/1538-7445.AM2021-1206","article-title":"Abstract 1206: discovery and characterization Of AB521, a novel, potent, and selective hypoxia-inducible factor (HIF)-2\u03b1 Inhibitor","volume":"81","author":"Lawson","year":"2021","journal-title":"Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/J.Cmet.2014.09.017","article-title":"Hif-2\u03b1 promotes degradation of mammalian peroxisomes by selective autophagy","volume":"20","author":"Walter","year":"2014","journal-title":"Cell Metab"},{"key":"B37","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/J.Cmet.2013.01.007","article-title":"The IRP1-HIF-2\u03b1 axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption","volume":"17","author":"Anderson","year":"2013","journal-title":"Cell Metab"},{"key":"B38","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1152\/Physrev.00030.2011","article-title":"Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 And 2","volume":"92","author":"Prabhakar","year":"2012","journal-title":"Physiol Rev"},{"key":"B39","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/s12276-024-01180-8","article-title":"Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer","volume":"56","author":"Bae","year":"2024","journal-title":"Exp Mol Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1101\/gad.250167.114","article-title":"Human high-altitude adaptation: forward genetics meets the HIF pathway","volume":"28","author":"Bigham A","year":"2014","journal-title":"Genes Dev"},{"key":"B41","doi-asserted-by":"publisher","first-page":"eade1942","DOI":"10.1126\/sciadv.ade1942","article-title":"A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans","volume":"8","author":"Gray","year":"2022","journal-title":"Sci Adv"},{"key":"B42","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1097\/01.ASN.0000059308.82322.4F","article-title":"Podocyte expression of hypoxia-inducible factor (HIF)\u22121 and HIF\u22122 during glomerular development","volume":"14","author":"Freeburg","year":"2003","journal-title":"J Am Soc Nephrol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e6201","DOI":"10.1590\/1414-431x20186201","article-title":"Hypoxia-induced hyperpermeability of rat glomerular endothelial cells involves HIF-2\u03b1 mediated changes in the expression of occludin and ZO-1","volume":"51","author":"Luo","year":"2018","journal-title":"Braz J Med Biol Res"},{"key":"B44","article-title":"Hypoxic methods of renal preconditioning favour VEGF expression through HIF-2\u03b1 activation in Renal cells","author":"Sethi","year":"","journal-title":"J Urol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"207","DOI":"10.3233\/NHA-170022","article-title":"A central role for hypoxia-inducible factor (HIF)-2\u03b1 in hepatic glucose homeostasis","volume":"4","author":"Ramakrishnan","year":"2017","journal-title":"Nutr. Healthy Aging"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00052.2019","article-title":"Hypoxia exacerbates nonalcoholic fatty liver disease via the HIF-2\u03b1\/PPAR\u03b1 pathway","author":"Chen","year":"2019","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1172\/JCI38499","article-title":"HIF-2\u03b1, but not HIF-1\u03b1, promotes iron absorption in mice","volume":"119","author":"Mastrogiannaki","year":"2009","journal-title":"J. Clin. Invest"},{"key":"B48","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1182\/blood-2012-11-427765","article-title":"The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions","volume":"122","author":"Mastrogiannaki","year":"2013","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1182\/blood.2022017811","article-title":"Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in \u03b2-thalassemia","volume":"141","author":"Xiao","year":"2023","journal-title":"Blood"},{"key":"B50","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/s41418-022-00941-0","article-title":"The multifaceted role of ferroptosis in liver disease","volume":"29","author":"Chen","year":"2022","journal-title":"Cell Death Differ"},{"key":"B51","doi-asserted-by":"publisher","first-page":"673","DOI":"10.3390\/cells14090673","article-title":"The Distinct Role of HIF-1\u03b1 and HIF-2\u03b1 in Hypoxia and Angiogenesis","volume":"14","author":"Bakleh M","year":"2025","journal-title":"Cells"},{"key":"B52","doi-asserted-by":"publisher","first-page":"e210","DOI":"10.5489\/cuaj.5658","article-title":"Endogenous H2S production deficiencies lead to impaired renal erythropoietin production","volume":"13","author":"Leigh","year":"2018"},{"key":"B53","doi-asserted-by":"publisher","first-page":"4384","DOI":"10.3390\/jcm13154384","article-title":"Impact of serum indoxyl sulfate on one-year adverse events in chronic kidney disease patients with heart failure","volume":"13","author":"Iwasaki","year":"2024","journal-title":"J Clin Med"},{"key":"B54","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.jacc.2008.10.046","article-title":"Anemia: the point of convergence or divergence for kidney disease and heart failure?","volume":"53","author":"Kazory","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1053\/j.ajkd.2014.12.016","article-title":"Cardiorenal Syndrome and the Role of the Bone-Mineral Axis and Anemia","volume":"66","author":"Charytan","year":"2015","journal-title":"Am J Kidney Dis"},{"key":"B56","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3389\/fcell.2020.00185","article-title":"Mechanisms of Cardiovascular Disorders in Patients With Chronic Kidney Disease: A Process Related to Accelerated Senescence","volume":"8","author":"Carracedo","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s12890-019-0933-4","article-title":"High hemoglobin is associated with increased in-hospital death in patients with chronic obstructive pulmonary disease and chronic kidney disease: a retrospective multicenter population-based study","volume":"19","author":"Xu","year":"2019","journal-title":"BMC Pulm Med"},{"key":"B58","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1186\/s12931-024-03071-y","article-title":"Longitudinal anemia status and risk for adverse outcomes in former smokers with COPD","volume":"25","author":"Kunitomo","year":"2024","journal-title":"Respir Res"},{"key":"B59","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.bpa.2023.10.002","article-title":"ESAs in perioperative anemia management: Who, what, how and why?","volume":"37","author":"Lasocki","year":"2023","journal-title":"Best Pract Res Clin Anaesthesiol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"159","DOI":"10.3390\/cancers13010159","article-title":"Ways into understanding HIF inhibition","volume":"13","author":"Sch\u00f6nberger","year":"2021","journal-title":"Cancers"},{"key":"B61","doi-asserted-by":"publisher","first-page":"100436","DOI":"10.1016\/j.coemr.2023.100436","volume":"29","author":"Lanzolla","year":"2023","journal-title":"Curr Opin Endocr Metab Res"},{"key":"B62","doi-asserted-by":"publisher","first-page":"4213","DOI":"10.1242\/jcs.191395","article-title":"HIF-2\u03b1 phosphorylation by CK1\u03b4 promotes erythropoietin secretion in liver cancer cells under hypoxia","volume":"129","author":"Pangou","year":"2016","journal-title":"J Cell Sci"},{"key":"B63","doi-asserted-by":"publisher","first-page":"3745","DOI":"10.3390\/ijms25073745","article-title":"Iron Metabolism and Inflammatory Mediators in Patients with Renal Dysfunction","volume":"25","author":"Matsuoka","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B64","doi-asserted-by":"publisher","first-page":"300","DOI":"10.3390\/oxygen3030020","article-title":"Hypoxia-driven responses in chronic kidney disease","volume":"3","author":"Miguel","year":"2023","journal-title":"Oxygen"},{"key":"B65","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1089\/ham.2015.0015","article-title":"The Local HIF-2\u03b1\/EPO Pathway in the Bone Marrow is Associated with Excessive Erythrocytosis and the Increase in Bone Marrow Microvessel Density in Chronic Mountain Sickness","volume":"16","author":"Su","year":"2015","journal-title":"High Alt Med Biol"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1152\/japplphysiol.00619.2014","article-title":"Decreased plasma soluble erythropoietin receptor in high-altitude excessive erythrocytosis and Chronic Mountain Sickness","volume":"117","author":"Villafuerte","year":"2014","journal-title":"J Appl Physiol"},{"key":"B67","doi-asserted-by":"publisher","first-page":"189079","DOI":"10.1016\/j.bbcan.2024.189079","article-title":"VEGF signaling: Role in angiogenesis and beyond","volume":"1879","author":"Shaw","year":"2024","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B68","doi-asserted-by":"publisher","first-page":"108186","DOI":"10.1016\/j.pharmthera.2022.108186","article-title":"The role of hypoxia-inducible factors in cardiovascular diseases","volume":"238","author":"Yu","year":"2022","journal-title":"Pharmacol. Ther"},{"key":"B69","doi-asserted-by":"publisher","first-page":"3332","DOI":"10.1182\/blood.V126.23.3332.3332","article-title":"Tibetan Gain-of-Function Variant of Prolyl Hydroxylase 2 (EGLN1) and Selected SNPs of HIF-2-Alpha (EPAS1) Are Associated with Lower Hemoglobin Values in Tibetans","volume":"126","author":"Tashi","year":"2015","journal-title":"Blood"},{"key":"B70","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1089\/ham.2010.1099","article-title":"Hypoxia: adapting to high altitude by mutating EPAS-1, the Gene Encoding HIF-2\u03b1","volume":"12","author":"Tissot Van Patot M","year":"2011","journal-title":"High Alt. Med. Biol"},{"key":"B71","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1265\/ehpm.22-00040","article-title":"Genetic and immune changes in Tibetan high-altitude populations contribute to biological adaptation to hypoxia","volume":"27","author":"Bai","year":"2022","journal-title":"Environ Health Prev Med"},{"key":"B72","doi-asserted-by":"publisher","first-page":"1125723","DOI":"10.3389\/fcell.2023.1125723","article-title":"Updated perspective of EPAS1 and the role in pulmonary hypertension","volume":"11","author":"Wang","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"B73","doi-asserted-by":"publisher","first-page":"e0196684","DOI":"10.1371\/journal.pone.0196684","article-title":"The hypoxia inducible factor\/erythropoietin (EPO)\/EPO receptor pathway is disturbed in a rat model of chronic kidney disease related anemia","volume":"13","author":"Landau","year":"2018","journal-title":"PLoS ONE"},{"key":"B74","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.molcel.2010.09.022","article-title":"Hypoxia-inducible factors and the response to hypoxic stress","volume":"40","author":"Majmundar","year":"2010","journal-title":"Mol Cell"},{"key":"B75","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.bjhh.2015.02.001","article-title":"Resistance of dialyzed patients to erythropoietin","volume":"37","author":"Alves","year":"2015","journal-title":"Rev Bras Hematol Hemoter"},{"key":"B76","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1093\/ndt\/17.suppl_11.39","article-title":"Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines","volume":"17","author":"Macdougall","year":"2002","journal-title":"Nephrol Dial.Transplant"},{"key":"B77","doi-asserted-by":"publisher","first-page":"231","DOI":"10.2147\/IJNRD.S239151","article-title":"erythropoietin resistance in patients with chronic kidney disease: current perspectives","volume":"13","author":"Santos","year":"2020","journal-title":"Int J Nephrol Renovasc Dis"},{"key":"B78","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1002\/dat.20365","article-title":"Hemoglobin variability with extended dosing of epoetin alfa in patients with chronic kidney disease and not on dialysis","volume":"38","author":"Bailey","year":"2009","journal-title":"Dial Transplant"},{"key":"B79","doi-asserted-by":"publisher","first-page":"145","DOI":"10.4009\/jsdt.44.145","article-title":"Improvement of hemoglobin (Hb) variability after changing recombinant human erythropoietin (rHuEPO) regimen","volume":"44","author":"Imada","year":"2011","journal-title":"Nihon Toseki Igakkai Zasshi"},{"key":"B80","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s41100-022-00450-3","article-title":"Cardiovascular events by different target hemoglobin levels in ESA-hyporesponsive hemodialysis patients: a multicenter, open-label, randomized controlled study","volume":"8","author":"Nitta","year":"2022","journal-title":"Ren Replace Ther"},{"key":"B81","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1093\/ndt\/gfx324","article-title":"Mechanisms and mediators of hypertension induced by erythropoietin and related molecules","volume":"33","author":"Agarwal","year":"2017","journal-title":"Nephrology Dialysis Transplantation"},{"key":"B82","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1056\/NEJMoa1203165","article-title":"Peginesatide in patients with anemia undergoing hemodialysis","volume":"368","author":"Fishbane","year":"2013","journal-title":"N Engl.J Med"},{"key":"B83","doi-asserted-by":"publisher","first-page":"102273","DOI":"10.1016\/j.eclinm.2023.102273","article-title":"Pegmolesatide for the treatment of anemia in patients undergoing dialysis: a randomized clinical trial","volume":"65","author":"Zhang","year":"2023","journal-title":"eClinicalMedicine"},{"key":"B84","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1097\/MNH.0000000000000617","article-title":"Hypoxia-inducible factor prolyl hydroxylase inhibitor in the treatment of anemia in chronic kidney disease","volume":"29","author":"Kurata","year":"2020","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"B85","doi-asserted-by":"publisher","first-page":"S334","DOI":"10.21037\/atm.2019.09.118","article-title":"Prolyl hydroxylase domain inhibitors: a new era in the management of renal anemia","volume":"7","author":"Kurata","year":"2019","journal-title":"Ann Transl Med"},{"key":"B86","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1200\/JCO.2024.42.4_suppl.445","article-title":"Hypoxia-inducible factor-2 alpha (HIF-2\u03b1) target activation and clinical outcomes in 942 patients with clear cell renal cell carcinoma","volume":"42","author":"Doshi","year":"2024","journal-title":"J Clin Oncol"},{"key":"B87","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1124\/molpharm.122.000525","article-title":"Structural Basis for the Allosteric Inhibition of Hypoxia-Inducible Factor 2 by Belzutifan","volume":"102","author":"Ren","year":"2022","journal-title":"Mol Pharmacol"},{"key":"B88","doi-asserted-by":"publisher","first-page":"2036","DOI":"10.1056\/NEJMoa2103425","article-title":"Belzutifan for Renal Cell Carcinoma in von Hippel\u2013Lindau Disease","volume":"385","author":"Jonasch","year":"2021","journal-title":"N Engl J Med"},{"key":"B89","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/s41581-022-00544-5","article-title":"Belzutifan: a novel therapy for von Hippel\u2013Lindau disease","volume":"18","author":"Zhou","year":"2022","journal-title":"Nat Rev Nephrol"},{"key":"B90","doi-asserted-by":"publisher","first-page":"5027","DOI":"10.1093\/eurheartj\/ehad235","article-title":"Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium\u2013glucose cotransporter 2 inhibitors","volume":"44","author":"Packer","year":"2023","journal-title":"Eur Heart J"},{"key":"B91","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1053\/j.ajkd.2020.04.016","article-title":"Mechanisms leading to differential hypoxia-inducible factor signaling in the diabetic kidney: modulation by SGLT2 Inhibitors and Hypoxia Mimetics","volume":"77","author":"Packer","year":"2021","journal-title":"Am J Kidney Dis"},{"key":"B92","doi-asserted-by":"publisher","first-page":"3778","DOI":"10.1002\/jcp.30851","article-title":"Sodium-glucose co-transporter 2 inhibitors and hematopoiesis","volume":"237","author":"Yaribeygi","year":"2022","journal-title":"J Cell Physiol"},{"key":"B93","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1038\/s41586-020-2820-9","article-title":"Mechanism of strand exchange from RecA\u2013DNA synaptic and D-loop structures","volume":"586","author":"Yang","year":"2020","journal-title":"Nature"},{"key":"B94","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/sj.leu.2403241","article-title":"JAK\/STAT, Raf\/MEK\/ERK, PI3K\/Akt and BCR-ABL in cell cycle progression and leukemogenesis","volume":"18","author":"Steelman","year":"2004","journal-title":"Leukemia"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: from bench to clinic","author":"Hu","year":""},{"key":"B96","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/s10495-010-0552-2","article-title":"Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK\/STAT5-Bcl-2 pathway","volume":"16","author":"Choi","year":"2010","journal-title":"Apoptosis"},{"key":"B97","doi-asserted-by":"publisher","first-page":"2986","DOI":"10.2741\/1755","article-title":"The RAS\/RAF\/MEK\/ERK and PI3K\/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma","volume":"10","author":"Meier","year":"2005","journal-title":"Front Biosci"},{"key":"B98","doi-asserted-by":"publisher","first-page":"2622","DOI":"10.1158\/0008-5472.CAN-11-3605","article-title":"Therapeutics, targets, and chemical biology activation of Ras\/PI 3 K\/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading toargininedeiminaseresistance inmelanomacells","volume":"72","author":"Tsai","year":"2012","journal-title":"null"},{"key":"B99","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/cr.2013.11","article-title":"Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion","volume":"23","author":"Zhou","year":"2013","journal-title":"Cell Res"},{"key":"B100","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1189\/jlb.1A0414-212R","article-title":"PI3K\/Akt regulates survival during differentiation of human macrophages by maintaining NF-\u03baB-dependent expression of antiapoptotic Bcl-xL","volume":"96","author":"Busca","year":"2014","journal-title":"J Leukoc Biol"},{"key":"B101","doi-asserted-by":"publisher","first-page":"48","DOI":"10.4049\/jimmunol.188.Supp.48.7","article-title":"PI3K\/Akt pathway contributes to development of apoptosis resistance during differentiation of human macrophages by maintaining antiapoptotic Bcl-xL protein expression (48","volume":"188","author":"Kumar","year":"2012","journal-title":"J Immunol"},{"key":"B102","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/B978-0-12-801238-3.65381-3","article-title":"Cell signaling and neurotoxicity","volume":"13","author":"Costa","year":"2018","journal-title":"Compr Toxicol"},{"key":"B103","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1039\/C7IB00099E","article-title":"A microfluidic oxygen gradient demonstrates differential activation of the hypoxia-regulated transcription factors HIF-1\u03b1 and HIF-2\u03b1","volume":"9","author":"Rexius-Hall","year":"2017","journal-title":"Integr Biol"},{"key":"B104","doi-asserted-by":"publisher","first-page":"4015","DOI":"10.1158\/0008-5472.CAN-10-4142","article-title":"The hypoxia-associated factor switches cells from HIF-1\u03b1- to HIF-2\u03b1-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion","volume":"71","author":"Koh","year":"2011","journal-title":"Cancer Res"},{"key":"B105","doi-asserted-by":"publisher","first-page":"112945","DOI":"10.1016\/j.celrep.2023.112945","article-title":"HIF-1\u03b1 drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1","volume":"42","author":"Yang","year":"2023","journal-title":"Cell Rep"},{"key":"B106","doi-asserted-by":"publisher","first-page":"160195","DOI":"10.1098\/Rsob.160195","article-title":"Differential sub-nuclear distribution of hypoxia-inducible factors (HIF)-1 And\u22122 alpha impacts on their stability and mobility","volume":"6","author":"Taylor","year":"2016","journal-title":"Open Biol"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1007\/S13402-021-00625-W","article-title":"Mild chronic hypoxia-induced HIF-2\u03b1 Interacts With C-MYC through competition with HIF-1\u03b1 to induce hepatocellular carcinoma cell proliferation","volume":"44","author":"Mu","year":"2021","journal-title":"Cellular Oncology"},{"key":"B108","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.3390\/Cancers14051259","article-title":"Targeting HIF-2\u03b1 In the tumor microenvironment: redefining the role of HIF-2\u03b1 for solid cancer therapy","volume":"14","author":"Davis","year":"2022","journal-title":"Cancers"},{"key":"B109","doi-asserted-by":"publisher","first-page":"2895","DOI":"10.1182\/Blood.V122.21.2895.2895","article-title":"Hypoxia Inducible Factor (HIF)-2\u03b1 Enhances Proliferation Of Malignant Hematopoietic Cells In The Hypoxic Malignant Bone Marrow","volume":"122","author":"Forristal","year":"2013"},{"key":"B110","doi-asserted-by":"publisher","first-page":"389","DOI":"10.3390\/ijms19020389","article-title":"Hypoxia-inducible factor and its role in the management of anemia in chronic kidney disease","volume":"19","author":"Kaplan","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B111","doi-asserted-by":"publisher","first-page":"100590","DOI":"10.1016\/j.blre.2019.100590","article-title":"Update on mutations in the HIF: EPO pathway and their role in erythrocytosis","volume":"37","author":"Lappin","year":"2019","journal-title":"Blood Rev"},{"key":"B112","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1146\/annurev-pharmtox-010818-021637","article-title":"Pharmacologic Targeting of Hypoxia-Inducible Factors","volume":"59","author":"Semenza","year":"2019","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B113","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.kisu.2017.09.002","article-title":"New options for the anemia of chronic kidney disease","volume":"7","author":"Coyne D","year":"2017","journal-title":"Kidney Int. Suppl"},{"key":"B114","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.yexcr.2017.05.004","article-title":"Therapeutic targeting of the HIF oxygen-sensing pathway: lessons learned from clinical studies","volume":"356","author":"Haase","year":"2017","journal-title":"Exp Cell Res"},{"key":"B115","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1124\/jpet.120.265181","article-title":"Nonclinical Characterization of the Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment of Anemia of Chronic Kidney Disease","volume":"374","author":"Del Balzo","year":"2020","journal-title":"J Pharmacol Exp Ther"},{"key":"B116","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.freeradbiomed.2023.07.020","article-title":"Oxygen-independent stabilization of HIF-2\u03b1 in breast cancer through direct interaction with peptidyl-prolyl cis-trans isomerase NIMA-interacting 1","volume":"207","author":"Guillen-Quispe","year":"2023","journal-title":"Free Radic Biol Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1780669\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T05:28:22Z","timestamp":1771824502000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1780669\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":116,"alternative-id":["10.3389\/fmed.2026.1780669"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1780669","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]},"article-number":"1780669"}}