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Updated: Jan 13, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Targeting TRIM25 as a therapeutic strategy to enhance ferroptosis in glioblastoma cells
Maorong Zhu1, Yuxin Wu1, Huihui Ou1
1State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710000, China.
Background:
Glioblastoma (GBM) is the most common malignant brain tumor with a dismal prognosis (< 7% 5-year survival) under current first-line treatment. While inducing programmed cell death (PCD) is a promising antitumor strategy, its effectiveness in GBM remains controversial. Ferroptosis emerged as the most enriched PCD process and was highly correlated with GBM malignant progression.
Methods:
We performed a CRISPR-Cas9 loss-of-function screen to identify critical ferroptosis contributors. Mechanistic studies involved assessing mitochondrial function and morphology. Protein interaction and degradation pathways were investigated using immunoprecipitation and ubiquitination assays. We developed a blood-brain-barrier-penetrating genome editing delivery system, Angiopep-2-modified nanoparticles with disulfide bonds (ANPSS), loaded with Cas9/sgRNA complexes.
Results:
Voltage-dependent anion channel 2 (VDAC2) was identified as a critical contributor to ferroptosis. VDAC2 overexpression induced mitochondrial dysfunction and characteristic ferroptotic mitochondrial morphology. The E3 ubiquitin ligase TRIM25 was identified as a key suppressor of VDAC2, directly interacting with it and inducing its K48-linked polyubiquitination and subsequent proteasomal degradation. In vivo, the ANPSS(sgTRIM25) system effectively targeted GBM cells, significantly promoted ferroptosis, and inhibited GBM progression.
Conclusions:
Our findings demonstrate that TRIM25 is a critical negative regulator of VDAC2-dependent ferroptosis in GBM. Targeting TRIM25 using the ANPSS(sgTRIM25) genome editing system effectively overcomes ferroptosis resistance and suppresses tumor growth, representing a viable therapeutic approach for GBM.
Insights
Targeting TRIM25 overcomes ferroptosis resistance in glioblastoma (GBM). This study identified TRIM25 as a key regulator of ferroptosis, and developed a novel genome editing system to inhibit GBM progression.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Medicine
Background:
- Glioblastoma (GBM) has a poor prognosis with current treatments.
- Programmed cell death (PCD) is a potential strategy, but its effectiveness in GBM is debated.
- Ferroptosis, a form of PCD, is linked to GBM progression.
Purpose of the Study:
- Identify key regulators of ferroptosis in GBM.
- Investigate the role of VDAC2 and TRIM25 in ferroptosis.
- Develop a novel therapeutic approach for GBM using genome editing.
Main Methods:
- CRISPR-Cas9 loss-of-function screen to identify ferroptosis contributors.
- Assessed mitochondrial function and morphology.
- Investigated protein interactions and degradation pathways.
- Developed Angiopep-2-modified nanoparticles with disulfide bonds (ANPSS) for blood-brain-barrier delivery of Cas9/sgRNA.
Main Results:
- VDAC2 was identified as crucial for ferroptosis induction.
- TRIM25, an E3 ubiquitin ligase, suppresses VDAC2 by promoting its degradation.
- The ANPSS(sgTRIM25) system effectively delivered genome editing components to GBM cells in vivo.
- This system significantly enhanced ferroptosis and inhibited GBM tumor growth.
Conclusions:
- TRIM25 negatively regulates VDAC2-dependent ferroptosis in GBM.
- Targeting TRIM25 with the ANPSS(sgTRIM25) system overcomes ferroptosis resistance.
- This approach shows potential as a therapeutic strategy for GBM treatment.
