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.
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