In vivo characterization of the redox balance in IDH-wildtype glioblastomas: a J-difference edited MEGA-sLASER MRS study at 3T.

Overview

1. Goethe University Frankfurt, University Hospital, Institute of Neuroradiology and Cooperative Brain Imaging Center - CoBIC, Frankfurt am Main, Germany
2. University Cancer Center Frankfurt (UCT), Frankfurt am Main, Germany
3. Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
4. German Cancer Research Center (DKFZ) Heidelberg, Germany and German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Germany
5. Goethe University Frankfurt, University Hospital, Dr. Senckenberg Institute of Neurooncology, Frankfurt am Main, Germany
6. Goethe University Frankfurt, University Hospital, Institute of Neurology (Edinger-Institute), Frankfurt am Main, Germany
7. Goethe University Frankfurt, University Hospital, Department of Neurosurgery, Frankfurt am Main, Germany
8. Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, USA
9. Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD USA

Abstract

Background: Isocitrate dehydrogenase-wildtype glioblastoma (IDHwtGB) is the most common primary malignant brain tumor in adults, with a universally poor prognosis. For survival and growth under conditions of the tumor microenvironment, glioblastoma cells require antioxidant glutathione (GSH) and its metabolic precursor cystathionine (Cth) to maintain redox balance. We aimed to characterize GSH and Cth in vivo, in IDHwtGB patients, using edited MR spectroscopy (MRS). Our goal was to evaluate their tumor-molecular-status-dependent alterations and assess their potential as biomarkers for therapies targeting redox imbalance, following a reproducibility assessment of the measurement protocol in healthy subjects.

Methods: In this prospective study (January 2023 - July 2025), 5 healthy subjects and 27 patients with MRI-suspected glioma were scanned on a 3T MR scanner using single-voxel MEGA-sLASER MRS. Tumoral and contralateral metabolite concentrations were compared using linear mixed models. Associations between tumoral GSH and other metabolite concentrations, as well as tumor subregion fractions, were assessed via multiple linear regression. Spearman correlation was used to evaluate the association between GSH and p53 immunoreactivity. The GSH concentration was compared across MGMT status and molecular subtypes with the Wilcoxon rank-sum test.

Results: A good scan-rescan reproducibility was observed in metabolite quantification in healthy subjects. Fifteen patients with IDHwtGB and high-quality spectra (mean age 59 ± 11 years; 9 men) were included in the final analysis. Tumor tissue exhibited significantly elevated Cth (1.17 ± 1.30 mM vs. 0.63 ± 0.59 mM, p = 0.03) and lower gamma-aminobutyric acid levels (2.36 ± 0.70 mM vs. 3.04 ± 0.89 mM, p = 0.006) compared to contralateral. Tumoral GSH concentrations correlated positively with Cth (p < 0.001) and enhancing-tumor fraction (p < 0.001), and negatively with p53 accumulation (p = 0.008). No difference in GSH levels was observed with respect to MGMT status (p = 0.66), whereas lower GSH concentrations were found in the mesenchymal subtype (p = 0.04).

Conclusions: GSH and Cth show promise as in vivo MRS biomarkers for therapies aimed at modulating redox balance.

Trial registration: German Clinical Trials Register (DRKS00032097), retrospectively registered on 25 November 2024.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40170-026-00432-7.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data availability

MRS result tables and statistical analysis code that support the findings of this study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 1 funder, 34 references.

Cite

This paper

Alcicek, S., Manzhurtsev, A., Thomas, D. C., Divé, I., Weber, K. J., Prinz, V., Jussen, D., Deelchand, D. K., Oeltzschner, G., Ronellenfitsch, M. W., Steinbach, J. P., Hattingen, E., Pilatus, U., & Wenger, K. J. (2026). In vivo characterization of the redox balance in IDH-wildtype glioblastomas: a J-difference edited MEGA-sLASER MRS study at 3T. Cancer & metabolism, 14(1), 10. https://doi.org/10.1186/s40170-026-00432-7

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