Author(s) :

Wenhan Zhang.

Volume/Issue :

Abstract :

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Its poor prognosis largely arises from its tendency to recur despite standard treatment with surgery, radiotherapy, and temozolomide. Glioblastoma stem cells (GSCs) are a major driver of recurrence because they possess stem-like properties and can regenerate the tumor after resisting treatment. Increasing evidence indicates that metabolic reprogramming within GSCs supports their survival following therapy. GSCs can switch between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) in response to therapyinduced stress. Unlike bulk GBM cells, which predominantly rely on aerobic glycolysis known as the Warburg effect, GSCs can be glycolytic, OXPHOS-dependent, or hybrid, and can transition between these states under stress. Furthermore, the ability of GSCs to survive and recur also depends on antioxidant pathways that counteract therapy-induced oxidative stress. Key mechanisms include activation of the NRF2 pathway and upregulation of the glutathione and thioredoxin systems. This review synthesizes current literature to highlight how alterations in glucose metabolism and antioxidant reprogramming in GSCs contribute to GBM recurrence. It also discusses key therapeutic challenges, including intratumoral heterogeneity, metabolic state switching, limited drug delivery across the blood-brain barrier, and the risk of toxicity when disrupting metabolic pathways required by normal neural cells.