biorxiv2026-10-20score 94
GLP-1 receptor agonists plus vorasidenib make peroxynitrite that kills mutant IDH glioma
Taglang, Viswanath and colleagues show that glucagon-like peptide-1 receptor (GLP1R) agonists synergize with the mutant isocitrate dehydrogenase inhibitor vorasidenib in patient-derived and murine mutant IDH glioma. GLP1R agonists raise cyclic AMP and protein kinase A, then nitric oxide synthase 1-dependent nitric oxide. That NO S-nitrosylates aconitase and ribonucleotide reductase, which stalls the tricarboxylic acid cycle and DNA synthesis (cytostatic). Vorasidenib relieves D-2-hydroxyglutarate suppression of pyruvate dehydrogenase, raising mitochondrial superoxide without killing on its own. Together, NO and superoxide form peroxynitrite, which damages lipids and DNA and drives apoptosis. The named redox convergence is nitric oxide plus superoxide to peroxynitrite. Aconitase is the metal-site enzyme they inhibit by S-nitrosylation. They do not report 4Fe to 3Fe cluster conversion.
