Integrative Transcriptomic and Perturbagen Analyses Reveal Sex-Specific Molecular Signatures Across Glioma Subtypes

<i>Background</i>: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response. <i>Methods</i>: We performed a sex-stratified analysis of CGGA (Chinese Glioma Genome Atlas) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM). Using the 3PodR framework, we integrated differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing. <i>Results</i>: These comparisons provide a proxy for biological processes underlying malignant transformation. In LGG vs. HGG, 973 significantly differentially expressed genes (DEGs) were identified in females and 1236 in males, with 15.5% and 33.5% unique to each sex, respectively. In LGG vs. GBM, 2011 DEGs were identified in females and 2537 in males, with 12.6% and 30.7% being unique. Gene-level contrasts included GLI1 upregulation in males and downregulation in females, GCGR upregulation in males, MYOD1 upregulation in females, and HIST1H2BH downregulation in males. Additional top DEGs included PRLHR, DGKK, DNMBP-AS1, HOXA9, CTB-1I21.1, RP11-47I22.1, HPSE2, SAA1, DLK1, H19, PLA2G2A, and PI3. In both sexes, LGG-HGG and LGG-GBM grade comparisons converged on neuronal and synaptic programs, with enrichment of glutamatergic receptor genes and postsynaptic modules, including GRIN2B, GRIN2A, GRIN2C, GRIN1, and CHRNA7. In contrast, collateral pathways diverged by sex: females showed downregulation of mitotic and chromosome-segregation programs, whereas males showed reduction of extracellular matrix and immune-interaction pathways. Perturbagen analysis nominated signature-reversing compounds across sexes, including histone deacetylase inhibitors, Aurora kinase inhibitors, microtubule-targeting agents such as vindesine, and multi-kinase inhibitors targeting VEGFR, PDGFR, FLT3, PI3K, and MTOR. <i>Conclusions</i>: Glioma grade comparisons reveal a shared neuronal-synaptic program accompanied by sex-specific transcriptional remodeling. These findings support sex-aware therapeutic strategies that pair modulation of neuron-glioma coupling with chromatin- or receptor tyrosine kinase/angiogenic-targeted agents, and they nominate biomarkers such as GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH for near-term validation.