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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.
Neurochemical Research
|March 16, 2026
Summary
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.
