Ma Qiang, Zhou Longnian, Li Zhongde
Department of Neurosurgery II, Hexi University Affiliated Zhangye People's Hospital, No. 67 Xihuan Road, Ganzhou District, Zhangye, Gansu Province, 734000, China.
BMC Pharmacol Toxicol. 2025 Apr 17;26(1):86. doi: 10.1186/s40360-025-00921-3.
Intracranial aneurysm (IA) is a critical cerebrovascular condition, and nicotine exposure is a known risk factor. This study delves into the toxicological mechanisms of nicotine in IA, aiming to identify key biomarkers and therapeutic targets.
Gene Set Variation Analysis (GSVA), Weighted Gene Co-Expression Network Analysis (WGCNA), and enrichment analyses were conducted on differentially expressed genes (DEGs) from the GSE122897 dataset. Additionally, nicotine-related targets were identified using CTD, SwissTargetPrediction, and Super-PRED databases. Integrative machine learning approaches, such as Random Forest (RF) and Support Vector Machine (SVM), were employed to pinpoint key toxicity targets. Molecular docking and immune cell infiltration analyses were also performed.
DEGs in IA showed significant alterations in metabolic, secretory, signaling, and homeostatic pathways. Several immune and metabolic response pathways were notably disrupted. WGCNA identified 1127 DEGs with 37 overlapping toxic targets between IA and nicotine. ssGSEA revealed substantial upregulation in immune response and inflammation-related processes. Integrative analyses highlighted TGFB1, MCL1, and CDKN1A as core toxicity targets, confirmed via molecular docking studies. Immune cell infiltration analysis indicated significant correlations between these core targets and various immune cell populations.
This study uncovers significant disruptions in metabolic and immune pathways in IA under nicotine influence, identifying TGFB1, MCL1, and CDKN1A as critical biomarkers. These findings offer a deeper understanding of IA's molecular mechanisms and potential therapeutic targets for nicotine-related toxicity.
颅内动脉瘤（IA）是一种严重的脑血管疾病，而尼古丁暴露是已知的危险因素。本研究深入探讨尼古丁在IA中的毒理学机制，旨在确定关键生物标志物和治疗靶点。
对来自GSE122897数据集的差异表达基因（DEG）进行基因集变异分析（GSVA）、加权基因共表达网络分析（WGCNA）和富集分析。此外，使用CTD、SwissTargetPrediction和Super-PRED数据库鉴定尼古丁相关靶点。采用随机森林（RF）和支持向量机（SVM）等综合机器学习方法来确定关键毒性靶点。还进行了分子对接和免疫细胞浸润分析。
IA中的DEG在代谢、分泌、信号传导和稳态途径中显示出显著变化。几个免疫和代谢反应途径明显受到干扰。WGCNA鉴定出1127个DEG，IA和尼古丁之间有37个重叠的毒性靶点。单样本基因集富集分析（ssGSEA）显示免疫反应和炎症相关过程显著上调。综合分析突出了转化生长因子β1（TGFB1）、髓细胞白血病-1（MCL1）和细胞周期蛋白依赖性激酶抑制剂1A（CDKN1A）作为核心毒性靶点，分子对接研究证实了这一点。免疫细胞浸润分析表明这些核心靶点与各种免疫细胞群体之间存在显著相关性。
本研究揭示了在尼古丁影响下IA中代谢和免疫途径的显著破坏，确定TGFB1、MCL1和CDKN1A为关键生物标志物。这些发现为IA的分子机制以及尼古丁相关毒性的潜在治疗靶点提供了更深入的理解。
