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ResearchIn-Press PreviewCell biologyMetabolism Open Access | 10.1172/JCI178550

TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism

Yu Zeng,1 Liqian Zhao,2 Kunlin Zeng,1 Ziling Zhan,1 Zhengming Zhan,2 Shangbiao Li,1 Hongchao Zhan,1 Peng Chai,2 Cheng Xie,2 Shengfeng Ding,2 Yuxin Xie,1 Li Wang,1 Cuiying Li,1 Xiaoxia Chen,1 Daogang Guan,3 Enguang Bi,3 Jian-you Liao,4 Fan Deng,1 Xiaochun Bai,1 Ye Song,2 and Aidong Zhou1

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Zeng, Y. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Zhao, L. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Zeng, K. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Zhan, Z. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Zhan, Z. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Li, S. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Zhan, H. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Chai, P. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Xie, C. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Ding, S. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Xie, Y. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Wang, L. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Li, C. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Chen, X. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Guan, D. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Bi, E. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Liao, J. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Deng, F. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Bai, X. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Song, Y. in: JCI | PubMed | Google Scholar

1Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

2Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

3Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Find articles by Zhou, A. in: JCI | PubMed | Google Scholar

Published February 11, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI178550.
Copyright © 2025, Zeng et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 11, 2025 - Version history
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Abstract

Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation-induced cell death, although the precise mechanisms involved remain unclear. Herein, we report that loss of tumor necrosis factor receptor-associated factor 3 (TRAF3) in GBM critically regulates lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 is frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacts with enoyl-CoA hydratase 1 (ECH1), an enzyme catalyzing the isomerization of unsaturated fatty acids (UFAs), and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impedes TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promotes the oxidation of UFAs, preferentially the PUFAs, and limits lipid peroxidation. Overexpression of TRAF3 enhances the sensitivity of GBM to ferroptosis and anti-PD-L1 immunotherapy in mice. Thus, the TRAF3-ECH1 axis plays a key role in the metabolism of PUFAs, and is crucial for lipid peroxidation damage and immune elimination in GBM.

Graphical Abstract
graphical abstract
Supplemental material

View Supplemental Table 1 RNA-seq analysis of GBM cells following TRAF3 overexpression

View Supplemental Table 2 GSEA analysis shows the enriched pathways following the overexpression of TRAF3

View Supplemental Table 3 Identification of TRAF3 interacting proteins by IP-MS/MS

View Supplemental Table 4 Lipidomic analysis of GBM cells following ECH1 depletion

View Supplemental Table 5 Lipidomic analysis of GBM cells with reconstituted expression of wild-type or K214R mutant ECH1 following TRAF3 overexpression

View Supplemental Table 6 Patient information of the NFYY glioma cohort

View Unedited blot and gel images

View Checklist

View Publication license for graphic abstract from Biorender.

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Version history
  • Version 1 (February 11, 2025): In-Press Preview
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