白血病干细胞（LSCs）是急性髓系白血病（AML）中关键且罕见的细胞亚群，对AML的起始、维持和复发起着关键作用。靶向LSCs在预防AML复发和改善长期预后方面具有巨大潜力。然而，LSC自我更新的精确分子机制仍然知之甚少。在本文中，我们提出了有力的证据表明潜在的抑瘤微RNA miR-30e-5p在AML样本中的表达显著低于健康骨髓样本。miR-30e的强制表达有效抑制了白血病发生、损害了LSC的自我更新，并延缓了白血病的进展。从机制上讲，Cyb561在LSCs中作为miR-30e-5p的直接靶点，其缺乏通过激活ROS信号限制了LSCs的自我更新，并显著延长了受体生存期。此外，miR-30e-5p的基因或药物过表达，或者Cyb561的敲除抑制了人AML细胞的生长。总之，我们的发现揭示了miR-30e-5p/Cyb561/ROS轴对LSC自我更新的关键作用，凸显了Cyb561作为LSC定向治疗的潜在治疗靶点。

Leukemia stem cells (LSCs) represent a crucial and rare subset of cells within acute myeloid leukemia (AML) that play a pivotal role in the initiation, maintenance, and relapse of AML. Targeting LSCs holds great promise for preventing AML relapse and improving long-term outcomes. However, the precise molecular mechanisms governing LSC self-renewal are still poorly understood. Here, we present compelling evidence that miR-30e-5p, a potential tumorsuppressive microRNA, exhibits significantly lower expression in AML samples compared to healthy bone marrow samples. Forced expression of miR-30e effectively inhibits leukemogenesis, impairs LSC self-renewal, and delays leukemia progression. Mechanistically, Cyb561 acts as a direct target of miR-30e-5p in LSCs, and its deficiency restricts the selfrenewal of LSCs by activating ROS signaling and markedly prolongs recipient survival. Moreover, genetic or pharmacological overexpression of miR-30e-5p or knockdown of Cyb561 suppresses the growth of human AML cells. In conclusion, our findings establish the crucial role of the miR-30e-5p/Cyb561/ROS axis in finely regulating LSC self-renewal, highlighting Cyb561 as a potential therapeutic target for LSC-directed therapies.