TY - JOUR
T1 - A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis
AU - Zhang, Hemeng
AU - Ma, Jialin
AU - Hou, Chunyan
AU - Luo, Xuehui
AU - Zhu, Shiya
AU - Peng, Yihan
AU - Peng, Changmin
AU - Li, Ping
AU - Meng, Heng
AU - Xia, Yuqi
AU - Jiang, Zhinuo
AU - Modepalli, Susree
AU - Duttargi, Anju
AU - Kupfer, Gary M.
AU - Cai, Mengjiao
AU - Zhang, Heng
AU - Ma, Junfeng
AU - Li, Juanjuan
AU - Han, Suxia
AU - Pei, Huadong
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2025.
PY - 2025/8
Y1 - 2025/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105011069624
U2 - 10.1038/s41556-025-01722-w
DO - 10.1038/s41556-025-01722-w
M3 - 文章
C2 - 40681752
AN - SCOPUS:105011069624
SN - 1465-7392
VL - 27
SP - 1288
EP - 1300
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 8
ER -