Tan Cunxin, Wang Jing, Wang Yanru, Xu Shaoqi, Zhou Zhenyu, Zhang Junze, He Shihao, Duan Ran
Department of Neurosurgery, Peking University International Hospital, Beijing, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Bioinform Biol Insights. 2025 May 24;19:11779322251342412. doi: 10.1177/11779322251342412. eCollection 2025.
Moyamoya disease (MMD) is a rare, chronic cerebrovascular disorder of uncertain etiology. Although abnormal glucose metabolism has been implicated, the contribution of glycosylation-related genes in MMD remains elusive. In this study, we analyzed 2 transcriptome data sets (GSE189993 and GSE131293) from the Gene Expression Omnibus (GEO) database to identify 723 differentially expressed genes (DEGs) between MMD patients and controls. Intersection genes with known glycosylation-related genes underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We utilized machine learning to select key hub genes, followed by immune cell infiltration and correlation analyses. In-depth immune cell analysis indicated that both CFP and MGAT5B were closely tied to various immune components, suggesting potential crosstalk between glycosylation pathways and immune regulation. Notably, CFP was positively associated with pDCs, HLA, and CCR, whereas MGAT5B correlated with B-cells, check-points, and T helper cells but showed a negative relationship with Tregs, hinting at an immunoregulatory mechanism influencing MMD progression. Motif-TF annotation highlighted csibp_M2095 as the motif with the highest normalized enrichment score (NES: 6.57). Reverse microRNA (miRNA)-gene prediction identified 75 miRNAs regulating these focus genes, along with 126 miRNA-miRNA interconnections. Connectivity Map (Cmap) analysis revealed that Chenodeoxycholic acid, MRS-1220, Phenytoin, and Piceid were strongly negatively correlated with MMD expression profiles, suggesting potential therapeutic candidates. Enzyme-linked immunosorbent assays confirmed elevated CFP and MGAT5B and reduced PTPN11 in MMD, aligning with our bioinformatic findings. Moreover, PTPN11 knockdown in human brain microvascular endothelial cells (HBMECs) significantly enhanced tube formation, indicating a role in vascular remodeling. Collectively, these results emphasize the importance of glycosylation-related genes and immune dysregulation in MMD pathogenesis. These findings broaden our understanding of MMD's underlying mechanisms and underscore the necessity of continued research into glycosylation-driven pathways for improved disease management.
烟雾病（MMD）是一种病因不明的罕见慢性脑血管疾病。尽管异常糖代谢与之有关，但糖基化相关基因在烟雾病中的作用仍不清楚。在本研究中，我们分析了来自基因表达综合数据库（GEO）的2个转录组数据集（GSE189993和GSE131293），以鉴定烟雾病患者与对照组之间的723个差异表达基因（DEG）。将与已知糖基化相关基因的交集基因进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析。我们利用机器学习选择关键的枢纽基因，随后进行免疫细胞浸润和相关性分析。深入的免疫细胞分析表明，CFP和MGAT5B均与各种免疫成分密切相关，提示糖基化途径与免疫调节之间可能存在相互作用。值得注意的是，CFP与浆细胞样树突状细胞（pDC）、人类白细胞抗原（HLA）和趋化因子受体（CCR）呈正相关，而MGAT5B与B细胞、检查点和辅助性T细胞相关，但与调节性T细胞（Treg）呈负相关，提示存在影响烟雾病进展的免疫调节机制。基序-转录因子注释突出显示csibp_M2095是标准化富集分数最高的基序（NES：6.57）。反向微小RNA（miRNA）-基因预测确定了75个调节这些重点基因的miRNA，以及126个miRNA-miRNA相互连接。连通图（Cmap）分析显示，鹅去氧胆酸、MRS-1220、苯妥英和白藜芦醇苷与烟雾病表达谱呈强烈负相关，提示可能的治疗候选物。酶联免疫吸附测定证实烟雾病中CFP和MGAT5B升高，蛋白酪氨酸磷酸酶非受体型11（PTPN11）降低，与我们的生物信息学结果一致。此外，在人脑微血管内皮细胞（HBMEC）中敲低PTPN11可显著增强管形成，表明其在血管重塑中的作用。总体而言，这些结果强调了糖基化相关基因和免疫失调在烟雾病发病机制中的重要性。这些发现拓宽了我们对烟雾病潜在机制的理解，并强调了继续研究糖基化驱动途径以改善疾病管理的必要性。
