Activation of Intestinal HIF2α Ameliorates Iron‐Refractory Anemia
Abstract: In clinics, hepcidin levels are elevated in various anemia‐related conditions, particularly in iron‐refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron‐refractory anemia, the potential effect of hypoxia and pharmacologically‐mimetic drug FG‐4592 (Roxadustat) are evaluated, a hypoxia‐inducible factor (HIF)‐prolyl hydroxylase (PHD) inhibitor, on mouse models of iron‐refractory iron‐deficiency anemia (IRIDA), anemia of inflammation and 5‐fluorouracil‐induced chemotherapy‐related anemia. The potent protective effects of both hypoxia and FG‐4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG‐4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin‐activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5‐fluorouracil‐induced anemia, which can not be rescued by FG‐4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia‐related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Activation of Intestinal HIF2α Ameliorates Iron‐Refractory Anemia ; day:20 ; month:01 ; year:2024 ; extent:15
Advanced science ; (20.01.2024) (gesamt 15)
- Creator
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Yu, Yingying
Su, Yunxing
Yang, Sisi
Liu, Yutong
Lin, Zhiting
Das, Nupur K.
Wu, Qian
Zhou, Jiahui
Sun, Shumin
Li, Xiaopeng
Yue, Wuyang
Shah, Yatrik M.
Min, Junxia
Wang, Fudi
- DOI
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10.1002/advs.202307022
- URN
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urn:nbn:de:101:1-2024012014153984359950
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:26 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Yu, Yingying
- Su, Yunxing
- Yang, Sisi
- Liu, Yutong
- Lin, Zhiting
- Das, Nupur K.
- Wu, Qian
- Zhou, Jiahui
- Sun, Shumin
- Li, Xiaopeng
- Yue, Wuyang
- Shah, Yatrik M.
- Min, Junxia
- Wang, Fudi
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