Related Experiment Video

Updated: Sep 14, 2025

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis

Hemeng Zhang1,2, Jialin Ma3, Chunyan Hou2

  • 1Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Nature Cell Biology
|July 18, 2025
PubMed

Insights

Reactive oxygen species (ROS) activate O-GlcNAc transferase (OGT) to prevent ferroptosis. This OGT-FOXK2-SLC7A11 pathway enhances cancer cell survival and drug resistance.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • Reactive oxygen species (ROS) are implicated in lipid peroxidation and ferroptosis initiation, influencing chemotherapeutic drug resistance.
  • The precise mechanisms of ROS function and sensing in ferroptosis remain incompletely understood.

Purpose of the Study:

  • To identify novel sensors of reactive oxygen species (ROS) involved in ferroptosis.
  • To elucidate the molecular mechanisms linking ROS, O-GlcNAcylation, and ferroptosis regulation.

Main Methods:

  • Enzyme activity assays to assess O-GlcNAc transferase (OGT) activation.
  • Western blotting and co-immunoprecipitation to study protein interactions and modifications.
  • Quantitative PCR and reporter assays to analyze gene transcription.

Main Results:

  • O-GlcNAc transferase (OGT) was identified as a sensor for ROS during ferroptosis, activated by oxidation at C845.
  • Activated OGT O-GlcNAcylates FOXK2, promoting its nuclear translocation and binding to the SLC7A11 promoter.
  • This cascade elevates SLC7A11 transcription, inhibiting ferroptosis and contributing to hepatocellular carcinoma (HCC) tumorigenesis and chemoradiotherapy resistance.

Conclusions:

  • A novel ROS-induced oxidation-O-GlcNAcylation cascade integrating ROS signaling, O-GlcNAcylation, and FOXK2-mediated SLC7A11 transcription was discovered.
  • This pathway confers resistance to ferroptosis and chemoradiotherapy, highlighting the OGT-FOXK2-SLC7A11 axis as a potential therapeutic target in HCC.

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