Metabolic Reprogramming in IDH1/2‑Mutant Gliomas: Redox, Anaplerosis, and Therapeutic Vulnerabilities

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are defining oncogenic events in lower-grade gliomas and secondary glioblastomas. These mutations confer a neomorphic activity that produces the oncometabolite D-2-hydroxyglutarate (D-2HG), initiating profound metabolic reprogramming with cascading epigenetic and cellular consequences. This review synthesizes current understanding of how IDH1/2 mutations rewire central carbon metabolism, redox balance, lipid homeostasis, and DNA damage response (DDR) pathways. We detail the resulting dependencies on compensatory systems such as glu-tamine anaplerosis, NRF2-driven glutathione synthesis, NAD⁺ salvage, and altered DDR signaling, which collectively establish a network of targetable vulnerabilities. Furthermore, we explore how this metabolic rewiring influences the tumor microenvironment and anti-tumor immunity. We then evaluate emerging therapeutic strategies—including direct mutant IDH inhibition, redox modulation, DDR targeting, and epi-genetic therapy—highlighting the importance of rational combinations and biomarker-driven approaches. Finally, we discuss metabolic heterogeneity among IDH-mutant gliomas and the critical role of physiologically relevant model systems for translating these insights into effective clinical interventions.