A prognostic neural epigenetic signature in high-grade glioma identifies a distinct molecular profile associated with poor patient outcomes. The study reveals that high-neural glioblastomas, characterized by hypomethylated CpG sites and upregulated genes related to synaptic integration, exhibit increased malignant stem-cell-like cells and synapse formation with neurons. These tumors show worse survival rates and are linked to increased functional connectivity in brain imaging. The neural signature is detectable in patient plasma and is associated with reduced overall and progression-free survival. The signature is also validated in diffuse midline glioma, highlighting its prognostic importance. The neural signature is stable across different tumor subtypes and is linked to increased proliferation and synapse formation when exposed to neuronal input. Serum biomarkers like BDNF correlate with the neural signature and are elevated in high-neural glioblastomas. The study also shows that high-neural glioblastomas require more extensive surgical resection for improved outcomes. The epigenetic neural signature provides a reliable marker for prognosis and may guide targeted therapies in glioma treatment. The findings underscore the importance of neural interactions in glioma progression and suggest that targeting these networks could be a promising therapeutic approach.A prognostic neural epigenetic signature in high-grade glioma identifies a distinct molecular profile associated with poor patient outcomes. The study reveals that high-neural glioblastomas, characterized by hypomethylated CpG sites and upregulated genes related to synaptic integration, exhibit increased malignant stem-cell-like cells and synapse formation with neurons. These tumors show worse survival rates and are linked to increased functional connectivity in brain imaging. The neural signature is detectable in patient plasma and is associated with reduced overall and progression-free survival. The signature is also validated in diffuse midline glioma, highlighting its prognostic importance. The neural signature is stable across different tumor subtypes and is linked to increased proliferation and synapse formation when exposed to neuronal input. Serum biomarkers like BDNF correlate with the neural signature and are elevated in high-neural glioblastomas. The study also shows that high-neural glioblastomas require more extensive surgical resection for improved outcomes. The epigenetic neural signature provides a reliable marker for prognosis and may guide targeted therapies in glioma treatment. The findings underscore the importance of neural interactions in glioma progression and suggest that targeting these networks could be a promising therapeutic approach.