Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress. Although iron elicits oxidative stress, the importance of iron homeostasis in HSCs has been unknown. Here we show that iron regulation by the F-box protein FBXL5 is required for HSC self-renewal. Conditional deletion of Fbxl5 in mouse HSCs results in cellular iron overload and a reduced cell number. Bone marrow transplantation reveals that FBXL5-deficient HSCs are unable to reconstitute the hematopoietic system of irradiated recipients as a result of stem cell exhaustion. Transcriptomic analysis shows abnormal activation of oxidative stress responses and the cell cycle in FBXL5-deficient mouse HSCs as well as downregulation of FBXL5 expression in HSCs of patients with myelodysplastic syndrome. Suppression of iron regulatory protein 2 (IRP2) accumulation in FBXL5-deficient mouse HSCs restores stem cell function, implicating IRP2 as a potential therapeutic target for human hematopoietic diseases associated with FBXL5 downregulation.

中文翻译：

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FBXL5介导的细胞铁稳态在维持造血干细胞中的重要作用。

造血干细胞（HSC）保持在低氧环境中，以限制氧化应激。尽管铁引起氧化应激，但铁稳态在HSC中的重要性尚不清楚。在这里，我们显示F框蛋白FBXL5的铁调节是HSC自我更新所必需的。小鼠HSC中Fbx15的条件缺失导致细胞铁超负荷和细胞数量减少。骨髓移植显示，由于干细胞衰竭，缺乏FBXL5的HSC无法重建受辐照者的造血系统。转录组学分析显示，骨髓增生异常综合征患者的FBXL5缺陷型小鼠HSC中氧化应激反应和细胞周期异常激活，以及FBXL5表达下调。