Novel metabolic subtypes in IDH-mutant gliomas: implications for prognosis and therapy

TL;DR

This study identifies three metabolic subtypes in IDH-mutant gliomas, each with different prognoses and immune features, offering new insights for personalized treatment.

Contribution

The study introduces novel metabolic subtypes in IDH-mutant gliomas and links them to prognosis and drug sensitivity.

Findings

Three metabolic subtypes (C1–C3) with distinct prognostic outcomes were identified.

Each subtype shows unique metabolic profiles and immune infiltration patterns.

A 13-gene metabolic signature was developed to predict risk and drug responses.

Abstract

Although IDH-mutant glioma generally has a better prognosis than their IDH-wildtype counterparts, considerable prognostic heterogeneity persists among patients with the same IDH mutation. Current study has primarily focused on the different IDH statuses or grades, while the metabolic heterogeneity within IDH-mutant gliomas remains insufficiently characterized. This study aims to identify transcriptomic metabolic subtypes and associated immune microenvironment differences to better understand survival variability and potential therapeutic targets in IDH-mutant glioma.

Patients with IDH-mutant gliomas were included from four public datasets (TCGA, n = 373; CGGA325, n = 167; CGGA693, n = 333; GLASS, n = 100), supplemented by 22 cases from Beijing Tiantan Hospital as an independent cohort. Consensus clustering was used to define novel metabolic subtypes. Clinical features were assessed using chi-square tests and Kaplan–Meier analysis. Metabolic profiles were characterized through enrichment analysis and GSVA; immune infiltration was analyzed using CIBERSORTx and ESTIMATE. Tumor samples from the independent cohort underwent untargeted metabolomics for validation. LASSO regression was applied to select metabolic signatures, and the CGP2014 drug library was used for drug screening.

Three metabolic subtypes (C1–C3) with distinct prognoses (p < 0.05) were identified. C1 exhibited enhanced carbohydrate and nucleotide metabolism; C2 displayed upregulated amino acid and lipid metabolism; and C3 demonstrated elevated lipid, nucleotide, and vitamin metabolism. These patterns were validated in the independent cohort. Subtypes were also correlated with immune infiltration. A 13-gene metabolic signature was established to stratify prognostic risk and suggest subtype-specific drug sensitivities.

Our study provided a novel metabolic subtype for IDH-mutant glioma and highlighted these patients' metabolic heterogeneity and potential therapeutic strategies.

The online version contains supplementary material available at 10.1186/s12885-025-14176-y.

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