Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia
© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Advanced science (Weinheim, Baden-Wurttemberg, Germany) - 11(2024), 12 vom: 27. März, Seite e2307022 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yu, Yingying [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.03.2024 Date Revised 30.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/advs.202307022 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Liu, Yutong |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Zhiting |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Nupur K |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Jiahui |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Shumin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiaopeng |e verfasserin |4 aut | |
| 700 | 1 | |a Yue, Wuyang |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Yatrik M |e verfasserin |4 aut | |
| 700 | 1 | |a Min, Junxia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Fudi |e verfasserin |4 aut | |
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