4.7 Article

Stimulation of Hepatic Ferritinophagy Mitigates Irp2 Depletion-Induced Anemia

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ANTIOXIDANTS
卷 12, 期 3, 页码 -

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MDPI
DOI: 10.3390/antiox12030566

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IRP2; Hif2 inhibition; Fe-S clusters; ferritinophagy; microcytic anemia

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This study found that inhibiting Hif2 can improve anemia caused by Irp2 deficiency. The improvement is mainly achieved by releasing iron ions from the liver and enhancing intestinal absorption. The upregulation of nuclear receptor coactivator 4 (Ncoa4) facilitates iron release through ferritinophagy. The released iron is used for intracellular Fe-S biogenesis and erythropoiesis after being exported from the liver to circulation. Hepatic iron export reduces hepcidin expression and alleviates intestinal iron overload through the hepcidin-ferroportin axis.
Background: Iron regulatory proteins (IRPs) maintain cellular iron homeostasis. Due to aberrant tissue-iron distribution, Irp2-deficient mice suffer microcytic anemia and neurodegeneration, while iron overload occurs in the liver and intestine. We previously found that Irp2 deficiency-induced Hif2 plays an important role in neurodegeneration. Methods: To test the role of Hif2 in Irp2 deficiency-induced anemia, we used Irp2 global knockout mice. Following Hif2 inhibition, routine blood tests, iron availability in bone marrow, histological assays, and biochemical analysis were performed to assess anemia improvement and tissue iron distribution. Results: We found that Hif2 inhibition improved anemia. The increased iron bioavailability for erythropoiesis was mainly derived from hepatic iron release, and secondly from enhanced intestinal absorption. We further demonstrate that nuclear receptor coactivator 4 (Ncoa4) was upregulated for iron release via the process of ferritinophagy. The released iron was utilized not only for intracellular Fe-S biogenesis but also for erythropoiesis after being exported from the liver to circulation. The hepatic iron export reduced hepcidin expression to further support iron absorption through the hepcidin-ferroportin axis to alleviate intestinal iron overload. Conclusion: Irp2 not only regulates cellular iron homeostasis but also tissue iron distribution by managing the involvement of Hif2-Ncoa4.

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