Bian Ruipeng, Shang Yingying, Xu Nahua, Liu Baiping, Ma Yanni, Li Hui, Chen Jieping, Yao Qi
Guizhou University Medical College, Guiyang 550025, Guizhou Province, China.
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Cell Signal. 2025 Mar;127:111583. doi: 10.1016/j.cellsig.2024.111583. Epub 2025 Jan 3.
Acute Myeloid Leukemia (AML) are challenging blood cancers with limited long-term survival rates, necessitating novel therapeutic strategies. This study explored the role of Histone deacetylase (HDAC) inhibitors in enhancing ferroptosis in AML cells by modulating iron metabolism. We demonstrated that HDAC inhibitors (Entinostat and Vorinostat) sensitize AML cells to ferroptosis both in vitro and in vivo. Mechanistically, we show that HDAC inhibitor treatment upregulated the expression of iron metabolism genes that lead to increased labile iron pool. Notably, NCOA4, a ferritin degradation mediator, and HMOX1/2 proteins, involved in heme breakdown, were identified as critical contributors to this process. The functional role of these genes was confirmed through CRISPR-Cas9 mediated knockouts, which significantly rescued cells from HDAC-induced ferroptosis sensitivity. Our results suggest a novel therapeutic approach for AML, where combining HDAC inhibitors with ferroptosis inducers could exploit the disrupted iron metabolism in AML cells. This study highlights the potential of HDAC inhibitors to modulate iron metabolism pathways, offering new insights into the treatment of these malignancies.
急性髓系白血病（AML）是具有挑战性的血癌，长期生存率有限，因此需要新的治疗策略。本研究探讨了组蛋白去乙酰化酶（HDAC）抑制剂通过调节铁代谢增强AML细胞铁死亡的作用。我们证明HDAC抑制剂（恩替诺特和伏立诺他）在体外和体内均使AML细胞对铁死亡敏感。从机制上讲，我们表明HDAC抑制剂处理上调了导致不稳定铁池增加的铁代谢基因的表达。值得注意的是，铁蛋白降解介质NCOA4以及参与血红素分解的HMOX1/2蛋白被确定为这一过程的关键因素。这些基因的功能作用通过CRISPR-Cas9介导的敲除得到证实，该敲除显著挽救了细胞对HDAC诱导的铁死亡敏感性。我们的结果提示了一种针对AML的新治疗方法，即联合使用HDAC抑制剂和铁死亡诱导剂可以利用AML细胞中紊乱的铁代谢。本研究突出了HDAC抑制剂调节铁代谢途径的潜力，为这些恶性肿瘤的治疗提供了新的见解。
