铜死亡相关分子特征在肺结核中的实验验证及其免疫学意义

Experimental validation of cuproptosis-associated molecular signatures and their immunological implications in pulmonary tuberculosis.

作者信息

Liu Xiaofang, Ma Qianqian, Li Zhiming, Xue Yong, Mi Jie, Li Yuxi, Bai Chunfeng, Guo Donglin, Liu Yinping, Liang Yan, Liang Jianqin, Wu Xueqiong

机构信息

Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, Senior Department of Tuberculosis, the Eighth Medical Center of People's Liberation Army (PLA) General Hospital, Beijing, China.

People's Liberation Army (PLA) General Hospital, Beijing, China.

出版信息

Front Immunol. 2025 Jul 30;16:1570992. doi: 10.3389/fimmu.2025.1570992. eCollection 2025.

DOI:10.3389/fimmu.2025.1570992

PMID:40808944

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12343668/

Abstract

BACKGROUND

The pathogenic mechanism underlying (MTB) remains elusive, posing challenges to its diagnosis and treatment. Cuproptosis is a newly identified mechanism of cell death. This study explores the role of cuproptosis-related genes (CRGs) in pulmonary tuberculosis (PTB) to uncover potential diagnostic biomarkers and therapeutic targets.

METHODS

Differentially expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) were carried out using the GSE83456 dataset. PTB-associated DEGs were intersected with CRGs to identify PTB-related CRGs. Subsequent analyses included functional enrichment, gene interaction, and protein-protein interaction (PPI) network construction. Hub CRGs were screened out via least absolute shrinkage and selection operator (LASSO) regression and random forest (RF) algorithms. Diagnostic models were subsequently constructed and validated. The associations of immune cell infiltration and pathway with the identified hub genes were evaluated through single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. Hub gene expressions were validated in the GSE42834 and GSE89403 datasets, as well as by RT-qPCR and Western blot (WB) in PTB and extrapulmonary tuberculosis (EPTB) patients. The GSE89403 dataset and gene expression profiling were leveraged to analyze the differential expression of hub genes and their dynamic changes during treatment.

RESULTS

Seven PTB-related CRGs were significantly upregulated, were significantly upregulated, among which ASPHD2, GK, and GCH1 were identified as hub genes. These genes exhibited high expression levels in patients with PTB and EPTB, with marked reductions observed following treatment. Notable alterations in immune cell infiltration and immune function in PTB patients were closely related to these hub genes, suggesting activation of innate immune responses and suppression of adaptive immune function.

CONCLUSION

The cuproptosis hub genes ASPHD2, GK, and GCH1 influence the pathogenesis of PTB, and possibly serve as novel diagnostic biomarkers and therapeutic targets.

摘要

背景

结核分枝杆菌（MTB）的致病机制仍不清楚，对其诊断和治疗构成挑战。铜死亡是一种新发现的细胞死亡机制。本研究探讨铜死亡相关基因（CRGs）在肺结核（PTB）中的作用，以发现潜在的诊断生物标志物和治疗靶点。

方法

使用GSE83456数据集进行差异表达基因（DEG）分析和加权基因共表达网络分析（WGCNA）。将PTB相关的DEG与CRG进行交叉分析，以鉴定PTB相关的CRG。随后的分析包括功能富集、基因相互作用和蛋白质-蛋白质相互作用（PPI）网络构建。通过最小绝对收缩和选择算子（LASSO）回归和随机森林（RF）算法筛选出核心CRG。随后构建并验证诊断模型。通过单样本基因集富集分析（ssGSEA）和CIBERSORT评估免疫细胞浸润和通路与鉴定出的核心基因的关联。在GSE42834和GSE89403数据集中验证核心基因表达，并通过RT-qPCR和蛋白质免疫印迹（WB）在PTB和肺外结核（EPTB）患者中进行验证。利用GSE89403数据集和基因表达谱分析核心基因的差异表达及其在治疗过程中的动态变化。