Targeting endoplasmic reticulum–associated glucose-6-phosphate metabolism sensitizes glioblastoma to chemoradiotherapy

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Abstract Background Antioxidant capacity is a major determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) and radiotherapy (RT). Endoplasmic reticulum (ER) glucose-6-phosphate (G6P) metabolism, regulated by hexose-6-phosphate dehydrogenase (H6PD) and glucose-6-phosphatase 3 (G6PC3), sustains ER-linked nicotinamide adenine dinucleotide phosphate (NADPH) production and thereby supports glutathione (GSH)-dependent redox buffering; however, its clinical relevance and therapeutic exploitability in GBM remain poorly defined. Methods Public GBM transcriptomic datasets were analyzed to assess the prognostic relevance of H6PD and G6PC3 expression. U87 GBM cells were treated with TMZ and fractionated RT, with or without transient chlorogenic acid (CGA) exposure administered prior to irradiation. CGA was selected as a modulator of ER G6P metabolism due to its capability to inhibit G6P transport across the reticular membrane. Cell survival, oxidative stress, intracellular redox balance, and metabolic activity were evaluated. Results High expression of H6PD and G6PC3 predicted poorer patient survival, with H6PD retaining independent prognostic significance, identifying ER-associated G6P/NADPH metabolism as an adverse metabolic signature in GBM. Transient CGA exposure significantly potentiated TMZ + RT cytotoxicity, increasing membrane damage and reducing cell survival after irradiation. CGA induced an early increase in oxidative stress followed by delayed depletion of reduced NADPH and GSH, amplifying redox imbalance under combinedchemoradiotherapy. Metabolic analyses indicated enhanced glycolytic engagement without further stimulation of mitochondrial respiration. Conclusions ER-associated NADPH metabolism represents a clinically relevant determinant of redox resilience in GBM, with H6PD emerging as an independent prognostic marker within this metabolic axis. In a U87 proof-of-concept model, transient, timing-based metabolic priming with CGA disrupts antioxidant buffering and amplifies oxidative vulnerability during chemoradiotherapy, thereby enhancing tumor in vitro. These findings provide a strong mechanistic and translational rationale for targeting ER-linked redox metabolism as an adjuvant strategy to improve GBM responsiveness to standard chemoradiotherapy.

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