Abstract
IDH mutant gliomas, driven by the oncometabolite 2-hydroxyglutarate (2-HG), are associated with profound neurological morbidity and premature mortality. To address the unmet therapeutic needs, we investigated the mechanistic interplay between MTHFD2-driven one-carbon metabolism and ferroptosis susceptibility in these tumors. Our findings revealed that MTHFD2 upregulation, mediated through loss of m5C modification in chromatin associated RNAs (caRNAs)-establishes a metabolic vulnerability to ferroptosis. Crucially, we identified TAF15 as a pivotal RNA-binding protein that orchestrates the spatial recruitment of TET2 by bridging NSUN5-mediated RNA m5C methylation. Therapeutically, combinatorial targeting of MTHFD2 with its selective inhibitor and the hypomethylating agent decitabine induced ferroptosis in patient-derived IDH-mut glioma organoids, demonstrating potent ferroptosis activation. This work delineates an RNA epitranscriptomic-metabolism axis in glioma pathogenesis and provides a translational roadmap for exploiting metabolic dependencies in IDH-driven malignancies. CLINICAL TRIAL NUMBER: Not applicable.