中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (33): 8676-8686.doi: 10.12307/2026.482

• 口腔组织构建 oral tissue construction • 上一篇    下一篇

铜死亡在牙周炎中作用的生物信息学分析及牙周炎模型大鼠验证

秦玉凤1，2，冯小云3，高红丽2，熊  林2，张玥晗1，陈河林1，2   

  1. 1贵州医科大学口腔医学院，贵州省贵阳市   550004；2贵州医科大学附属口腔医院，贵州省贵阳市   550004；3贵州中医药大学时珍学院，贵州省贵阳市   550000
  • 收稿日期:2025-10-29 修回日期:2026-03-12 出版日期:2026-11-28 发布日期:2026-06-13
  • 通讯作者: 陈河林，博士，副主任医师，硕士研究生导师，贵州医科大学口腔医学院/贵州医科大学附属口腔医院口腔修复种植科，贵州省贵阳市 550004
  • 作者简介:秦玉凤，女，1999年生，贵州省遵义市人，汉族，贵州医科大学口腔修复种植科在读硕士，主要从事口腔种植骨组织工程研究。
  • 基金资助:
    国家自然科学基金地区项目(82160186)，项目负责人：陈河林；贵州省科技厅计划项目(黔科合基础-ZK[2021]一般433)，项目负责人：陈河林

Bioinformatics analysis of cuproptosis in periodontitis and verification in a periodontitis rat model 

Qin Yufeng1, 2, Feng Xiaoyun3, Gao Hongli2, Xiong Lin2, Zhang Yuehan1, Chen Helin1, 2   

  1. 1College of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China; 2Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China; 3Shizhen College, Guizhou University of Traditional Chinese Medicine, Guiyang 550000, Guizhou Province, China
  • Received:2025-10-29 Revised:2026-03-12 Online:2026-11-28 Published:2026-06-13
  • Contact: Chen Helin, PhD, Associate chief physician, Master’s supervisor, College of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China; Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
  • About author:Qin Yufeng, MS candidate, College of Stomatology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China; Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
  • Supported by:
    the National Natural Science Foundation of China (Regional Program), No. 82160186 (to CHL); Plan Project of Guizhou Provincial Science and Technology Department, No. Qiankehejichu-ZK[2021]General 433 (to CHL)

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摘要：


文题释义：
牙周炎：是一种慢性炎症性破坏性疾病，不仅对患者的身心健康产生不良影响，还参与多种全身性疾病进展，因此探索牙周炎的潜在致病机制至关重要。
铜死亡：铜死亡主要依赖于线粒体呼吸，由铜离子过量积累所导致，研究表明铜死亡参与了牙周炎的进展。

背景：通过分析铜死亡相关基因在牙周炎组织中的表达，探索牙周炎发展过程中铜死亡相关生物标志物对于牙周炎的诊断与治疗具有重要意义。
目的：通过生物信息学分析及动物实验验证探索牙周炎中铜死亡相关基因的表达及潜在的作用机制。
方法：基于基因表达综合数据库获取牙周炎转录组数据集GSE10334和GSE156993，经消除批次效应后整合为元队列。利用最小绝对收缩和选择算子、支持向量机-递归特征消除和韦恩分析筛选鉴定出关键基因，随后基于受试者工作特征曲线、功能富集分析、免疫细胞浸润、单细胞分析(数据集GSE171213)、基因-药物网络分析、列线模型构建和共识聚类等综合分析关键特征基因在牙周炎中的分布与作用，并进一步在SD大鼠牙周炎模型中进行验证。
结果与结论：①使用机器学习算法筛选出NOD样受体热蛋白结构域相关蛋白3、二氢硫辛酰琥珀酰转移酶和谷氨酰胺合成酶为牙周炎中3个铜死亡关键特征基因，在牙周炎组织中这3个铜死亡关键特征基因表达显著上调，且 NOD样受体热蛋白结构域相关蛋白3(曲线下面积= 0.828)、谷氨酰胺合成酶(曲线下面积=0.830)具有良好的诊断价值，可作为牙周炎的潜在诊断标志物；②二氢硫辛酰琥珀酰转移酶通过调控三羧酸循环与硫辛酸代谢诱导线粒体功能紊乱，NOD样受体热蛋白结构域相关蛋白3通过激活炎症小体放大炎症反应，谷氨酰胺合成酶通过增强谷氨酰胺代谢支持免疫细胞功能，三者协同调控铜死亡推动牙周炎进展；③在SD大鼠牙周炎模型中NOD样受体热蛋白结构域相关蛋白3、二氢硫辛酰琥珀酰转移酶和谷氨酰胺合成酶表达上调，且与牙槽骨吸收量呈正相关，为机制假说提供体内证据。结果表明，NOD样受体热蛋白结构域相关蛋白3、二氢硫辛酰琥珀酰转移酶和谷氨酰胺合成酶作为铜死亡关键特征基因，在牙周炎的发生发展中起重要作用，具有潜在的诊断价值。

https://orcid.org/0009-0004-1200-4479 (秦玉凤) 


中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: 铜死亡, 牙周炎, 生物信息学, NOD样受体热蛋白结构域相关蛋白3(NLRP3), 谷氨酰胺合成酶(GLS), 二氢硫辛酰琥珀酰转移酶(DLST)

Abstract: BACKGROUND: Through analyzing the expression of cuproptosis-related genes in periodontitis tissues, this study attempted to explore the significance of cuproptosis-related biomarkers in the diagnosis and treatment of periodontitis during the development of periodontitis. 
OBJECTIVE: To explore the expression of cuproptosis-related genes in periodontitis and their potential mechanisms through bioinformatics analysis. 
METHODS: Periodontitis transcriptome datasets GSE10334 and GSE156993 were obtained from the Gene Expression Omnibus (GEO) database. After eliminating batch effects, they were integrated into a meta-cohort. Hub genes were screened and identified using the Least Absolute Shrinkage and Selection Operator, Support Vector Machine-Recursive Feature Elimination, and Venn analysis. Subsequently, a comprehensive analysis of the distribution and role of these hub genes in periodontitis was performed using receiver operating characteristic curves, functional enrichment analysis, immune cell infiltration analysis, single-cell analysis (dataset GSE171213), gene-drug network analysis, nomogram model construction, and consensus clustering. Further validation was conducted in a Sprague-Dawley rat periodontitis model.

RESULTS AND CONCLUSION: (1) Three hub cuproptosis signature genes (NOD-like receptor pyrin domain-containing protein 3, dihydrolipoamide succinyltransferase and glutamine synthetase) in periodontitis were identified using machine learning algorithms. These genes were significantly upregulated in periodontal tissues, with NOD-like receptor pyrin domain-containing protein 3 (the area under the curve=0.828) and glutamine synthetase (the area under the curve=0.830) showing good diagnostic value, suggesting their potential as diagnostic biomarkers for periodontitis. (2) Dihydrolipoamide succinyltransferase induced mitochondrial dysfunction by regulating the tricarboxylic acid cycle and lipoic acid metabolism; NOD-like receptor pyrin domain-containing protein 3 amplified inflammatory responses through inflammasome activation; and glutamine synthetase supported immune cell function by enhancing glutamine metabolism. These three genes synergistically regulated cuproptosis to drive the progression of periodontitis. (3) The expression levels of NOD-like receptor pyrin domain-containing protein 3, dihydrolipoamide succinyltransferase and glutamine synthetase were upregulated in the Sprague-Dawley rat model of periodontitis and positively correlated with the amount of alveolar bone resorption, providing in vivo evidence for the proposed mechanistic hypothesis. These findings indicate that NOD-like receptor pyrin domain-containing protein 3, dihydrolipoamide succinyltransferase and glutamine synthetase, as hub genes of cuproptosis, play important roles in the occurrence and development of periodontitis and possess potential diagnostic value.

Key words: cuproptosis, periodontitis, bioinformatics, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), glutamine synthetase (GLS), dihydrolipoamide succinyltransferase (DLST)

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