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The history of EPO stretches from early observations of hypoxia in the mid\u201019th century to its gene cloning and the clinical use of recombinant forms. Structurally, EPO's extensive glycosylation shapes stability, receptor binding, and therapeutic potential, inspiring engineered analogs with distinct pharmacokinetics. Developmentally, EPO expression shifts from embryonic neural crest and fetal hepatocytes to renal interstitial fibroblasts after birth.\n                    <jats:italic>EPO<\/jats:italic>\n                    gene regulation integrates hypoxia\u2010inducible factors, transcriptional repressors, enhancers, with HIF\u20102\u03b1 as the principal activator, and post\u2010translational mechanisms. Recent findings reveal genetic variants within the\n                    <jats:italic>EPO<\/jats:italic>\n                    gene in patients with erythrocytosis. Isoelectric focusing profiles of EPO in these patients was similar to the hepatic\u2010derived EPO profiles in premature newborns, highlighting a dynamic and context\u2010dependent regulation. These findings suggest that reactivation of\n                    <jats:italic>EPO<\/jats:italic>\n                    expression in the liver could be therapeutically valuable, given that hepatic\u2010derived EPO exhibits enhanced activity. Clinically, erythropoiesis\u2010stimulating agents transformed anemia management but raised safety concerns, leading to refined guidelines. The recent introduction of hypoxia\u2010inducible factor prolyl hydroxylase inhibitors represents a new strategy that restores endogenous EPO production and coordinates iron metabolism through transient HIF stabilization. Outstanding challenges include the absence of faithful human EPO\u2010producing cell models and incomplete understanding of the full molecular mechanisms controlling\n                    <jats:italic>EPO<\/jats:italic>\n                    expression and production. Combining insights from developmental biology, genetics, and epigenomics may open new avenues for therapies targeting disorders of erythropoiesis and oxygen homeostasis.\n                  <\/jats:p>","DOI":"10.1002\/ajh.70173","type":"journal-article","created":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T07:29:26Z","timestamp":1767511766000},"page":"537-549","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Erythropoietin Expression and Regulation:\n                    <scp>\n                      <i>Piecing Together Known Mechanisms and Emerging Insights<\/i>\n                    <\/scp>"],"prefix":"10.1002","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5439-8726","authenticated-orcid":false,"given":"Salam","family":"Idriss","sequence":"first","affiliation":[{"name":"Nantes Universit\u00e9 CNRS, INSERM, l\u2019institut du thorax  Nantes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5547-6004","authenticated-orcid":false,"given":"David","family":"Hoogewijs","sequence":"additional","affiliation":[{"name":"Section of Medicine, Department of Endocrinology, Metabolism and Cardiovascular System University of Fribourg  Fribourg Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Girodon","sequence":"additional","affiliation":[{"name":"Service d'H\u00e9matologie Biologique, p\u00f4le Biologie, CHU de Dijon  Dijon France"},{"name":"Inserm U1231 Universit\u00e9 de Bourgogne  Dijon France"},{"name":"Intergroupe Des Syndromes My\u00e9loprolif\u00e9ratifs Fran\u00e7ais (FIM)  Paris France"},{"name":"Laboratoire d'Excellence GR\u2010Ex  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8206-8329","authenticated-orcid":false,"given":"Betty","family":"Gardie","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9 CNRS, INSERM, l\u2019institut du thorax  Nantes France"},{"name":"Laboratoire d'Excellence GR\u2010Ex  Paris France"},{"name":"EPHE PSL Universit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,3]]},"reference":[{"key":"e_1_2_18_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01534"},{"key":"e_1_2_18_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00128.2013"},{"key":"e_1_2_18_4_1","first-page":"384","article-title":"Sur l'activit\u00e9 H\u00e9mopoi\u00e9tique du S\u00e9rum au Cours de la R\u00e9g\u00e9n\u00e9ration du Sang","volume":"143","author":"Carnot P.","year":"1906","journal-title":"Comptes rendus de l'Acad\u00e9mie des Sciences"},{"key":"e_1_2_18_5_1","first-page":"432","article-title":"Sur I'activite Hematopoietique des Differents Organes au Cours de la Regeneration du Sang","volume":"143","author":"Carnot P.","year":"1906","journal-title":"Comptes Rendus. 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