Beyond Glycolysis: Targeting Non‐Glycolytic Metabolic Pathways in Brain Tumors for Therapeutic Innovation: A Narrative Review

ABSTRACT Background and Aims Metabolic reprogramming is a hallmark of brain tumors, extending beyond the classical Warburg effect. While glycolysis has been extensively studied, gliomas and pediatric high‐grade brain cancers demonstrate remarkable metabolic plasticity. This review aims to highlight non‐glycolytic metabolic pathways that sustain tumor growth, contribute to therapy resistance, and offer translational potential in neuro‐oncology. Methods We conducted a comprehensive synthesis of recent preclinical and translational studies focusing on non‐glycolytic metabolic dependencies in brain tumors. Particular emphasis was placed on fatty acid oxidation (FAO), amino acid metabolism, mitochondrial dynamics, and immune metabolic interfaces. Results Emerging evidence indicates that FAO supports ATP synthesis and redox balance under hypoxic conditions. Glutaminolysis and serine/glycine metabolism maintain nucleotide and antioxidant pools essential for tumor survival. Mitochondrial fusion–fission dynamics and Complex I mutations enhance oxidative phosphorylation (OXPHOS) adaptability. Targeting these metabolic nodes, individually or in combination, reduces tumor growth, reverses drug resistance and sensitizes tumors to radiotherapy and immunotherapy. Additionally, the tryptophan–kynurenine–AHR axis contributes to immune evasion, underscoring the interplay between metabolism and tumor immunology. Discussion Non‐glycolytic metabolism represents an emerging frontier for precision neuro‐oncology. The integration of metabolic inhibitors with conventional or immune‐based therapies shows promise in preclinical models. However, overcoming metabolic plasticity and therapeutic resistance will require patient stratification, blood–brain barrier penetrant inhibitors, and biomarker‐guided clinical trials. These insights underscore the need to translate metabolic vulnerabilities into clinically actionable strategies. Conclusion Non‐glycolytic metabolic pathways, including lipid, nucleotide, and amino acid metabolism, offer promising therapeutic targets to overcome tumor survival and therapy resistance in brain tumors. However, despite encouraging preclinical evidence, the clinical development of such targeted metabolic therapies remains in its early stages.