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Updated: Mar 18, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
GPR40 Attenuates Glioma TMZ-Resistance Through Ferroptosis Inhibition
Jieqiong Yang1,2, Yan Zou1,3, Shenqian Xu4
1Department of Neurosurgery, Jiangnan University Medical Center, Wuxi, 214005, Jiangsu, China.
Abstract:
Glioblastoma (GBM), a highly aggressive primary brain tumor, presents substantial treatment challenges due to its resistance to genotoxic therapies and frequent recurrence. Oncogenic alterations significantly impact lipid metabolism in GBM cells. G Protein-Coupled Receptor 40 (GPR40), a receptor for polyunsaturated fatty acids (PUFAs), plays a key role in neural development and neurogenesis. Additionally, ferroptosis induction in GBM relies on PUFA peroxidation within cell membranes. Considering the persistent oxidative stress in the central nervous system, aberrant GPR40 activation in glioma lipid metabolism might suppress ferroptosis, thus contributing to chemotherapy resistance. Transcriptomic analysis of TCGA data revealed upregulated GPR40 expression in malignant gliomas, alongside alterations in ferroptosis-related and drug resistance pathways. To model GBM temozolomide (TMZ) resistance, a TMZ-resistant GL261 cell line was established. Additionally, key ferroptosis markers, including iron metabolism, lipid peroxidation, and glutathione levels, as well as TMZ treatment sensitivity, were assessed. Our findings confirm that GPR40 reduces glioma sensitivity to TMZ chemotherapy by inhibiting ferroptosis. These results highlight the GPR40-ferroptosis regulatory axis as a potential therapeutic target to enhance ferroptosis-induced treatment and overcome TMZ chemotherapy resistance in GBM.
Insights
Glioblastoma (GBM) exhibits resistance to chemotherapy partly due to upregulated G Protein-Coupled Receptor 40 (GPR40). This receptor inhibits ferroptosis, a cell death pathway crucial for overcoming treatment resistance in brain tumors.
Area of Science:
- Oncology
- Neuroscience
- Molecular Biology
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis.
- GBM cells exhibit resistance to genotoxic therapies and frequently recur.
- Altered lipid metabolism and suppressed ferroptosis contribute to GBM's therapeutic resistance.
Purpose of the Study:
- To investigate the role of G Protein-Coupled Receptor 40 (GPR40) in GBM chemoresistance.
- To explore the relationship between GPR40, lipid metabolism, and ferroptosis in GBM.
- To identify GPR40 as a potential therapeutic target for overcoming temozolomide (TMZ) resistance.
Main Methods:
- Transcriptomic analysis of TCGA data to assess GPR40 expression in gliomas.
- Establishment of a temozolomide (TMZ)-resistant GL261 cell line to model GBM.
- Assessment of ferroptosis markers (iron metabolism, lipid peroxidation, glutathione) and TMZ sensitivity.
Main Results:
- GPR40 expression is upregulated in malignant gliomas.
- GPR40 activation was found to inhibit ferroptosis in GBM cells.
- GPR40 was confirmed to reduce glioma sensitivity to TMZ chemotherapy by suppressing ferroptosis.
Conclusions:
- The GPR40-ferroptosis axis plays a significant role in GBM chemoresistance.
- Targeting GPR40 may represent a novel therapeutic strategy to enhance ferroptosis and overcome TMZ resistance in GBM.
- Further research into GPR40 modulation could lead to improved GBM treatment outcomes.
