Wu Chengsong, Ren Yuanyuan, Li Yang, Cui Yue, Zhang Liyao, Zhang Pan, Zhang Xuejiao, Kan Shangguang, Zhang Chan, Xiong Yuyan
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, 710069 Xi'an, Shaanxi, P. R. China.
Department of Blood Transfusion, the First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, 650032 Kunming, Yunnan, China.
J Chem Inf Model. 2025 Apr 14;65(7):3771-3788. doi: 10.1021/acs.jcim.4c02318. Epub 2025 Mar 19.
Abdominal aortic aneurysm (AAA) is a life-threatening disorder with limited therapeutic options. Neutrophil extracellular traps (NETs) are formed by a process known as "NETosis" that has been implicated in AAA pathogenesis, yet the roles and prognostic significance of NET-related genes in AAA remain poorly understood. This study aimed to identify key AAA- and NET-related genes (AAA-NETs-RGs), elucidate their potential mechanisms in contributing to AAA, and explore potential therapeutic compounds for AAA therapy. Through bioinformatics analysis of multiomics and machine learning, we identified six AAA-NETs-RGs: DUSP26, FCN1, MTHFD2, GPRC5C, SEMA4A, and CCR7, which exhibited strong diagnostic potential for predicting AAA progression, were significantly enriched in pathways related to cytokine-cytokine receptor interaction and chemokine signaling. Immune infiltration analysis revealed a causal association between AAA-NETs-RGs and immune cell infiltration. Cell-cell communication analysis indicated that AAA-NETs-RGs predominantly function in smooth muscle cells, B cells, T cells, and NK cells, primarily through cytokine and chemokine signaling. Gene profiling revealed that CCR7 and MTHFD2 exhibited the most significant upregulation in AAA patients compared to non-AAA controls, as well as in AAA models. Notably, genetic depletion of CCR7 and MTHFD2 strongly inhibited Ang II-induced phenotypic switching, functional impairment, and senescence in vascular smooth muscle cells (VSMCs). Based on AAA-NETs-RGs, molecular docking analysis combined with the Connectivity Map (CMap) database identified mirdametinib as a potential therapeutic agent for AAA. Mirdametinib effectively alleviated Ang II-induced phenotypic switching, biological dysfunction, and senescence. These findings provide valuable insights into understanding the pathophysiology of AAA and highlight promising therapeutic strategies targeting AAA-NETs-RGs.
腹主动脉瘤（AAA）是一种威胁生命的疾病，治疗选择有限。中性粒细胞胞外陷阱（NETs）由一种称为“NETosis”的过程形成，该过程与AAA的发病机制有关，但NET相关基因在AAA中的作用和预后意义仍知之甚少。本研究旨在鉴定关键的AAA和NET相关基因（AAA-NETs-RGs），阐明它们在导致AAA中的潜在机制，并探索用于AAA治疗的潜在治疗化合物。通过多组学的生物信息学分析和机器学习，我们鉴定出六个AAA-NETs-RGs：DUSP26、FCN1、MTHFD2、GPRC5C、SEMA4A和CCR7，它们在预测AAA进展方面具有很强的诊断潜力，在与细胞因子-细胞因子受体相互作用和趋化因子信号传导相关的途径中显著富集。免疫浸润分析揭示了AAA-NETs-RGs与免疫细胞浸润之间的因果关系。细胞间通讯分析表明，AAA-NETs-RGs主要在平滑肌细胞、B细胞、T细胞和NK细胞中发挥作用，主要通过细胞因子和趋化因子信号传导。基因谱分析显示，与非AAA对照组相比，CCR7和MTHFD2在AAA患者以及AAA模型中表现出最显著的上调。值得注意的是，CCR7和MTHFD2的基因缺失强烈抑制血管紧张素II诱导的血管平滑肌细胞（VSMCs）表型转换、功能障碍和衰老。基于AAA-NETs-RGs，分子对接分析结合连接图谱（CMap）数据库确定米哚妥林为AAA的潜在治疗药物。米哚妥林有效减轻了血管紧张素II诱导的表型转换、生物功能障碍和衰老。这些发现为理解AAA的病理生理学提供了有价值的见解，并突出了针对AAA-NETs-RGs的有前景的治疗策略。
