Lipid peroxidation and immune activation: TRAF3’s double-edged strategy against glioblastoma
Tzu-Yi Chia, … , Nishanth S. Sadagopan, Jason Miska
Tzu-Yi Chia, … , Nishanth S. Sadagopan, Jason Miska
Published April 1, 2025
Citation Information: J Clin Invest. 2025;135(7):e190471. https://doi.org/10.1172/JCI190471.
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Commentary

Lipid peroxidation and immune activation: TRAF3’s double-edged strategy against glioblastoma

Abstract

Glioblastoma (GBM), the most aggressive type of primary brain tumor, continues to defy therapeutic advances with its metabolic adaptability and resistance to treatment. In this issue of the JCI, Zeng et al. delve into a pivotal mechanism underpinning this adaptability. They identified an important role for TNF receptor–associated factor 3 (TRAF3) in regulating lipid metabolism through its interaction with enoyl-CoA hydratase 1 (ECH1). These findings elucidate a unique signaling axis that shields GBM cells from lipid peroxidation and antitumor immunity, advancing therapeutic strategies for GBM that may also carry over to other cancers with similar metabolic vulnerabilities.

Authors

Tzu-Yi Chia, Nishanth S. Sadagopan, Jason Miska

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Figure 1

TRAF3 has a regulatory role in GBM via PUFA metabolism and its hypermethylation.

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TRAF3 has a regulatory role in GBM via PUFA metabolism and its hypermeth...
(A) In the context of GBM, promoter hypermethylation suppresses TRAF3 expression. The absence of TRAF3 permits ECH1-mediated metabolism of PUFAs and efficient FAO. (B) Zeng et al. showed that TRAF3 overexpression resulted in the ubiquitination (Ub) of ECH1, which impeded FAO, promoted lipid peroxidation, and induced ferroptosis. Furthermore, ECH1 depletion via shRNA induced mitochondrial damage and inhibited tumorigenesis. These findings underscore the therapeutic potential of targeting hypermethylation and the TRAF3/ECH1 axis to suppress tumor growth and enhance sensitivity to immunotherapy.