One-Carbon Metabolic Reprogramming Stratifies Prognosis and Defines Distinct Biological States in IDH1-Mutant Gliomas

Abstract

Background: IDH1 mutations in diffuse gliomas undergo epigenetic transformation and metabolic stress, through accumulation of 2-hydroxyglutarate. While these tumours generally exhibit a less aggressive phenotype, significant prognostic heterogeneity persists. The extent to which the One Carbon Metabolism (OCM) network is rewired in IDH1-MT gliomas and its contribution to this heterogeneity remain poorly understood. Methods: We analysed the expression of 64 OCM genes using TCGA and CGGA transcriptomic datasets (n = 709). Composite OCM score, Cohen's d, PCA and driver gene analysis were used to quantify effect sizes between IDH1-WT and MT cohorts. Prognostic relevance was assessed using Kaplan-Meier and Cox regression analyses. OCM metabolic rewiring and dependency were validated using in vitro U87 IDH1-WT and IDH1-R132H mutant glioblastoma cell line models. Furthermore, immune microenvironment interactions were evaluated using CIBERSORTx to dissect OCM-associated correlations. Results: Using transcriptional profiling and targeted in-vitro validation, we reveal a distinct two-state metabolic phenotype governed by the OCM network. We demonstrate that while IDH1-MT tumors primarily rely on a suppressed metabolic phenotype, they are supported by compensatory mitochondrial pathways and an aggressive subset aberrantly hyperactivates specific proliferative OCM genes. This high aggregate OCM score was significantly associated with poor overall survival in the IDH1-MT cohort (CGGA HR = 1.61, p < 0.001), identifying an aggressive subset that predominates the favourable IDH mutation status. Functional validation showed aggressive IDH1-MT cells lose their baseline metabolic flexibility with changes in critical OCM genes and exhibit a strict auxotrophic dependence. Further, we also define that OCM rewiring was also associated with immune cell abundance, suggesting high OCM activity correlating with monocyte infiltration and low M2 macrophage polarisation. Conclusion: Our findings offer a framework to identify high-risk patients and propose translational strategies for IDH1-MT tumors that may be refractory to standard IDH inhibitors. Therefore, the study presents a conceptual model for metabolic precision therapy defining OCM metabolic subsets that distinguish indolent, mitochondrial-dependent tumours from aggressive, proliferation-dependent phenotypes in IDH1-MT gliomas.