Hematopoietic stem cells (HSCs) have a number of unique physiologic adaptations that enable lifelong maintenance of blood cell production, including a highly regulated rate of protein synthesis. Yet, the precise vulnerabilities that arise from such adaptations have not been fully characterized. Here, inspired by a bone marrow failure disorder due to the loss of the histone deubiquitinase MYSM1, characterized by selectively disadvantaged HSCs, we show how reduced protein synthesis in HSCs results in increased ferroptosis. HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates. Importantly, this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency but also characterizes a broader liability of human HSCs. Increasing protein synthesis rates via MYSM1 overexpression makes HSCs less susceptible to ferroptosis, more broadly illustrating the selective vulnerabilities that arise in somatic stem cell populations as a result of physiologic adaptations.

造血干细胞 (HSC) 具有许多独特的生理适应性，可以终生维持血细胞生成，包括高度调节的蛋白质合成速率。然而，这种适应所产生的确切脆弱性尚未得到充分表征。在这里，受组蛋白去泛素化酶 MYSM1 缺失导致的骨髓衰竭障碍的启发，以选择性处于不利地位的 HSC 为特征，我们展示了 HSC 中蛋白质合成减少如何导致铁死亡增加。尽管蛋白质合成率没有改变，但通过阻断铁死亡可以完全挽救 HSC 的维持。重要的是，这种对铁死亡的选择性脆弱性不仅是 MYSM1 缺陷导致 HSC 丢失的基础，而且还表征了人类 HSC 更广泛的责任。