Background: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response.Methods: 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.Results: 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.Conclusions: 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.
背景：新近证据表明，生物性别影响胶质瘤的生物学特性及治疗反应。方法：我们对CGGA（中国胶质瘤基因组图谱）RNA测序数据进行了性别分层分析，比较低级别胶质瘤（LGG）与高级别胶质瘤（HGG）及胶质母细胞瘤（GBM）。运用3PodR分析框架，整合差异表达分析、基因集富集分析（GSEA）、EnrichR富集分析、核心驱动基因分析及iLINCS药物重定位技术。结果：这些比较为恶性转化的生物学过程提供了间接证据。在LGG与HGG比较中，女性组鉴定出973个显著差异表达基因（DEGs），男性组1236个，其中性别特异性基因分别占15.5%和33.5%。在LGG与GBM比较中，女性组鉴定出2011个DEGs，男性组2537个，性别特异性基因分别占12.6%和30.7%。基因层面差异包括：GLI1在男性中上调而在女性中下调，GCGR在男性中上调，MYOD1在女性中上调，HIST1H2BH在男性中下调。其他重要DEGs包括PRLHR、DGKK、DNMBP-AS1、HOXA9、CTB-1I21.1、RP11-47I22.1、HPSE2、SAA1、DLK1、H19、PLA2G2A和PI3。在两种性别中，LGG–HGG与LGG–GBM分级比较均显示神经元与突触相关通路的富集，包括谷氨酸受体基因（GRIN2B、GRIN2A、GRIN2C、GRIN1）及突触后模块基因（如CHRNA7）。而性别特异性通路呈现分化：女性组显示有丝分裂与染色体分离程序下调，男性组则表现为细胞外基质与免疫互作通路减弱。扰动分析筛选出跨性别的特征逆转化合物，包括组蛋白去乙酰化酶抑制剂、极光激酶抑制剂、微管靶向剂（如长春地辛）以及靶向VEGFR、PDGFR、FLT3、PI3K和MTOR的多激酶抑制剂。结论：胶质瘤分级比较揭示了共有的神经元-突触程序与性别特异性转录重塑并存。这些发现支持发展性别差异化治疗策略，将神经元-胶质瘤耦合调控与染色质靶向剂或受体酪氨酸激酶/血管生成靶向剂联合应用，并提名GLI1、MYOD1、GCGR、PRLHR和HIST1H2BH等生物标志物用于近期验证。
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