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To identify effective treatment options for various types of iron\u2010refractory anemia, the potential effect of hypoxia and pharmacologically\u2010mimetic drug FG\u20104592 (Roxadustat) are evaluated, a hypoxia\u2010inducible factor (HIF)\u2010prolyl hydroxylase (PHD) inhibitor, on mouse models of iron\u2010refractory iron\u2010deficiency anemia (IRIDA), anemia of inflammation and 5\u2010fluorouracil\u2010induced chemotherapy\u2010related anemia. The potent protective effects of both hypoxia and FG\u20104592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG\u20104592 could stabilize duodenal Hif2\u03b1, leading to the activation of\n                    <jats:italic>Fpn<\/jats:italic>\n                    transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin\u2010activated anemias. Moreover, duodenal\n                    <jats:italic>Hif2\u03b1<\/jats:italic>\n                    overexpression fully rescues phenotypes of\n                    <jats:italic>Tmprss6<\/jats:italic>\n                    knockout mice, and\n                    <jats:italic>Hif2\u03b1<\/jats:italic>\n                    knockout in the gut significantly delays the recovery from 5\u2010fluorouracil\u2010induced anemia, which can not be rescued by FG\u20104592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia\u2010related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.\n                  <\/jats:p>","DOI":"10.1002\/advs.202307022","type":"journal-article","created":{"date-parts":[[2024,1,20]],"date-time":"2024-01-20T07:19:31Z","timestamp":1705735171000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Activation of Intestinal HIF2\u03b1 Ameliorates Iron\u2010Refractory Anemia"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9857-2407","authenticated-orcid":false,"given":"Yingying","family":"Yu","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital The Second Affiliated Hospital Institute of Translational Medicine School of Public Health State Key Laboratory of Experimental 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