目的 系统评估胶质瘤中嘌呤代谢相关基因的临床意义,鉴定关键治疗靶点,并验证天然小分子抑制剂联合替莫唑胺的抗肿瘤潜力。方法 基于公共数据库,筛选胶质瘤中嘌呤代谢差异表达基因,通过机器学习算法构建并验证预后预测模型,识别核心候选基因。结合分子对接技术,筛选并鉴定靶向PAICS（phosphoribosylaminoimidazole carboxylase and phosphoribosyla- minoimidazolesuccinocarboxamide synthase,磷酸核糖氨基咪唑羧化酶和磷酸核糖氨基咪唑琥珀酰羧酰胺合酶）的天然抑制剂,通过体外实验评估其对PAICS表达及细胞增殖的抑制作用,并进一步检测其与替莫唑胺的联合效应。结果 成功筛选出嘌呤代谢核心基因,建立的预后模型在独立队列中表现出良好区分度。PAICS被确认为关键基因,分子对接筛选出长春花碱和雷公藤内酯甲作为潜在PAICS抑制剂。细胞实验显示,两种天然化合物可降低PAICS表达并显著抑制胶质瘤细胞增殖,与替莫唑胺联用可进一步增强抗增殖效果。结论 PAICS是胶质瘤潜在的预后标志物和治疗靶点,长春花碱与雷公藤内酯甲通过靶向PAICS增强替莫唑胺增殖抑制作用,为胶质瘤联合治疗提供新的策略依据。
Abstract
Objective A systematic evaluation of the clinical significance of purine metabolism-related genes in glioma, identification of key therapeutic targets, and validation of the antitumor potential of natural small-molecule inhibitors in combination with temozolomide. Methods Based on public databases, differentially expressed purine metabolism-related genes in glioma were identified. A prognostic prediction model was constructed and validated using machine learning algorithms, leading to the identification of key candidate genes. Molecular docking was employed to screen and identify natural inhibitors targeting PAICS. The inhibitory effects of these compounds on PAICS expression and cell proliferation were evaluated through in vitro experiments, and their synergistic efficacy with temozolomide was further assessed. Results Core purine metabolism-related genes were successfully identified, and the constructed prognostic model demonstrated robust discriminative performance in an independent cohort. PAICS was identified as a key gene, with vindoline and triptolide recognized through molecular docking as potential PAICS inhibitors. Cellular experiments revealed that both natural compounds downregulated PAICS expression and significantly suppressed glioma cell proliferation, with enhanced antiproliferative effects observed when combined with temozolomide. Conclusion PAICS serves as a potential prognostic biomarker and therapeutic target in glioma. Vindoline and triptolide enhance the antiproliferative effect of temozolomide by targeting PAICS, providing a novel strategic basis for combination therapy in glioma.
关键词
胶质瘤 /
PAICS /
抑制剂 /
联合用药
Key words
glioma /
PAICS /
inhibitors /
combination therapy
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基金
湖南省自然科学基金面上项目“BDH1通过p300介导的LRRC31转录活化促进肺癌进展的功能和机制研究”（2023JJ30427）; 湖南省自然科学基金面上项目“DFMG通过DNA甲基化抑制动脉粥样硬化巨噬细胞炎症反应的机制研究”（2023JJ30425）
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