A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis

Hemeng Zhang, Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Jialin Ma, Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.
Chunyan Hou, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Xuehui Luo, Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Shiya Zhu, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Yihan Peng, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Changmin Peng, GW Cancer Center, Department of Biochemistry & Molecular Medicine, George Washington University, Washington DC, USA.
Ping Li, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Heng Meng, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Yuqi Xia, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Zhinuo Jiang, Flow Cytometry and Cell Sorting Center, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Susree Modepalli, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Anju Duttargi, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Gary M. Kupfer, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
Mengjiao Cai, Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Heng Zhang, Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China. tracyheng0719@163.com.
Junfeng Ma, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA. junfeng.ma@georgetown.edu.
Juanjuan Li, Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China. juanjuan.li@whu.edu.cn.
Suxia Han, Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. shan87@xjtu.edu.cn.
Huadong Pei, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA. huadong.pei@georgetown.edu.

Document Type

Journal Article

Publication Date

7-18-2025

Journal

Nature cell biology

DOI

10.1038/s41556-025-01722-w

Abstract

Reactive oxygen species (ROS) play a crucial role in lipid peroxidation and the initiation of ferroptosis, markedly affecting chemotherapeutic drug resistance. However, the mechanisms by which ROS function and are sensed remain poorly understood. In this study, we identified O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, as a sensor for ROS during ferroptosis. The ROS-induced oxidation of OGT at C845 in its catalytic domain activates the enzyme. Once activated, OGT O-GlcNAcylates FOXK2, enhancing its interaction with importin α, which facilitates FOXK2's nuclear translocation and binding to the SLC7A11 promoter region. This, in turn, boosts SLC7A11 transcription, thereby inhibiting ferroptosis. The elevated OGT-FOXK2-SLC7A11 axis contributes to tumorigenesis and resistance to chemoradiotherapy in hepatocellular carcinoma (HCC). Our findings elucidate a ROS-induced oxidation-O-GlcNAcylation cascade that integrates ROS signalling, O-GlcNAcylation, FOXK2-mediated SLC7A11 transcription and resistance to both ferroptosis and chemoradiotherapy.

Department

Biochemistry and Molecular Medicine

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