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Open Access 01-12-2023 | Acute Myeloid Leukemia | Research

Targeting NRF2 uncovered an intrinsic susceptibility of acute myeloid leukemia cells to ferroptosis

Authors: Xin Liu, Shuxin Zhong, Kangjie Qiu, Xi Chen, Weiyue Wu, Jiamian Zheng, Yanwen Liu, Haolong Wu, Shiyun Fan, Dingrui Nie, Xianfeng Wang, Zhi Yu, Ziwei Liao, Mengjun Zhong, Yangqiu Li, Chengwu Zeng

Published in: Experimental Hematology & Oncology | Issue 1/2023

Abstract

Drug resistance and poor treatment response are major obstacles to the effective treatment of acute myeloid leukemia (AML). A deeper understanding of the mechanisms regulating drug resistance and response genes in AML is therefore urgently needed. Our previous research has highlighted the important role of nuclear factor E2-related factor 2 (NRF2) in AML, where it plays a critical role in detoxifying reactive oxygen species and influencing sensitivity to chemotherapy. In this study, we identify a core set of direct NRF2 targets that are involved in ferroptosis, a novel form of cell death. Of particular interest, we find that glutathione peroxidase 4 (GPX4) is a key ferroptosis gene that is consistently upregulated in AML, and high expression of GPX4 is associated with poor prognosis for AML patients. Importantly, simultaneous inhibition of NRF2 with ML385 and GPX4 with FIN56 or RSL3 synergistically targets AML cells, triggering ferroptosis. Treatment with ML385 + FIN56/RSL3 resulted in a marked reduction in NRF2 and GPX4 expression. Furthermore, NRF2 knockdown enhanced the sensitivity of AML cells to the ferroptosis inducers. Taken together, our results suggest that combination therapy targeting both NRF2 and GPX4 may represent a promising approach for the treatment of AML.

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Title: Targeting NRF2 uncovered an intrinsic susceptibility of acute myeloid leukemia cells to ferroptosis
Authors: Xin Liu
Shuxin Zhong
Kangjie Qiu
Xi Chen
Weiyue Wu
Jiamian Zheng
Yanwen Liu
Haolong Wu
Shiyun Fan
Dingrui Nie
Xianfeng Wang
Zhi Yu
Ziwei Liao
Mengjun Zhong
Yangqiu Li
Chengwu Zeng
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Acute Myeloid Leukemia
Published in: Experimental Hematology & Oncology / Issue 1/2023
Electronic ISSN: 2162-3619
DOI: https://doi.org/10.1186/s40164-023-00411-4

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