Zhong Mengjun, Zhong Shuxin, Qiu Kangjie, Peng Xueting, Liu Xin, Sui Songnan, Dai Zhangshuai, Wang Xianfeng, Nie Dingrui, Yu Zhi, Yu Quan, Chen Cunte, Li Yangqiu, Zeng Chengwu
Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China; Department of Hematology, Guangzhou First People's Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical University, Guangzhou, 510180, PR China.
Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China.
Eur J Pharmacol. 2025 Jul 5;998:177652. doi: 10.1016/j.ejphar.2025.177652. Epub 2025 Apr 17.
In acute myeloid leukemia (AML), high expression of BRD4 is associated with poor prognosis. BET inhibitors that mainly inhibit BRD4 can induce AML cell death, but some AML cells are insensitive to BET inhibitors. We found that BET inhibitors could promote the up-regulation of the ferroptosis signaling pathway in AML. In this study, we intend to investigate the synergistic effects of BET inhibitors with ferroptosis inducers in AML cells. The combination of BET inhibitors with ferroptosis inducers (RSL3, FIN56, and Erastin) markedly reduced AML cell viability and increased cell death, as demonstrated by CCK-8 assays and flow cytometry analysis across multiple AML cell lines and primary AML patient samples. Moreover, BET inhibitors combined with ferroptosis inducers elevated the lipid reactive oxygen species (ROS) levels, indicating heightened lipid peroxidation, a hallmark of ferroptosis. Mechanistically, BET inhibitor and ferroptosis inducer co-targeted the BRD4/c-Myc/NRF2 axis, leading to downregulation of NRF2, key regulators of AML cell survival and oxidative stress resistance. NRF2 knockdown amplified the anti-AML effect of this combined treatment, whereas NRF2 overexpression negated this synergy, highlighting its critical role in mediating ferroptosis resistance. Finally, survival analyses of AML patients from the TCGA and GSE71014 datasets revealed that elevated expression of BRD4, NRF2, and its downstream target GPX4, an essential ferroptosis regulator, correlated with poor overall survival, highlighting the clinical relevance of our findings. In all, combining BET inhibition with ferroptosis induction could enhance anti-leukemia effect and represent a novel therapeutic strategy for targeting AML cells.
在急性髓系白血病（AML）中，BRD4的高表达与不良预后相关。主要抑制BRD4的BET抑制剂可诱导AML细胞死亡，但一些AML细胞对BET抑制剂不敏感。我们发现BET抑制剂可促进AML中铁死亡信号通路的上调。在本研究中，我们旨在探讨BET抑制剂与铁死亡诱导剂在AML细胞中的协同作用。CCK-8检测和流式细胞术分析表明，BET抑制剂与铁死亡诱导剂（RSL3、FIN56和Erastin）联合使用可显著降低多种AML细胞系和原发性AML患者样本中的AML细胞活力并增加细胞死亡。此外，BET抑制剂与铁死亡诱导剂联合使用可提高脂质活性氧（ROS）水平，表明脂质过氧化增强，这是铁死亡的一个标志。从机制上讲，BET抑制剂和铁死亡诱导剂共同靶向BRD4/c-Myc/NRF2轴，导致AML细胞存活和抗氧化应激关键调节因子NRF2的下调。NRF2敲低增强了这种联合治疗的抗AML作用，而NRF2过表达则消除了这种协同作用，突出了其在介导铁死亡抗性中的关键作用。最后，对来自TCGA和GSE71014数据集的AML患者进行的生存分析表明，BRD4、NRF2及其下游靶点GPX4（一种重要的铁死亡调节因子）的表达升高与总生存期较差相关，突出了我们研究结果的临床相关性。总之，将BET抑制与铁死亡诱导相结合可增强抗白血病作用，并代表一种靶向AML细胞的新型治疗策略。
