单细胞测序指导发现水仙环素作为双重VCAM-1/ICAM-1抑制剂用于动脉粥样硬化管理
Single-cell sequencing-guided discovery of narciclasine as a dual VCAM-1/ICAM-1 inhibitor for atherosclerosis management.
摘要(中文译文)
动脉粥样硬化（AS）仍然是全球心血管疾病发病和死亡的主要原因，目前的治疗主要集中于降低低密度脂蛋白水平，但未能修复受损的内皮细胞，因此迫切需要新型治疗药物。为应对这一挑战，我们分析了人类AS患者的单细胞RNA测序数据集以识别疾病驱动基因，随后采用连接图谱分析筛选潜在治疗化合物。研究利用网络药理学和机器学习预测核心药物靶点，并通过分子对接、分子动力学模拟和表面等离子体共振分析验证药物-靶点相互作用，同时利用内皮细胞损伤模型和动脉粥样硬化小鼠进行实验验证。该整合方法成功鉴定出水仙环素（narciclasine）作为一种有前景的治疗化合物，其靶向血管细胞黏附分子-1和细胞间黏附分子-1（VCAM-1/ICAM-1）用于AS治疗，分子研究证实了强结合亲和力，实验验证表明其通过下调VCAM-1/ICAM-1表达显著缓解内皮功能障碍，并减少小鼠模型中的主动脉斑块负荷。这种结合单细胞测序、网络药理学、机器学习、计算模拟和实验验证的多平台方法为药物发现提供了稳健的框架，同时将水仙环素定位为一种有前景的治疗候选物，值得开展临床研究用于AS治疗。
Abstract
Atherosclerosis (AS) remains a leading cause of cardiovascular morbidity and mortality worldwide, with current treatments focused primarily on reducing low-density lipoprotein levels while failing to repair damaged endothelial cells, thus highlighting the urgent need for novel therapeutic drugs. To address this challenge, we analyzed human AS patient single-cell RNA sequencing datasets to identify disease-driving genes and then employed connectivity map analysis to screen for potential therapeutic compounds. Using network pharmacology and machine learning to predict core drug targets, the study validated drug-target interactions through molecular docking, molecular dynamics simulations, and surface plasmon resonance analysis, with experimental validation conducted using endothelial cell damage models and atherosclerotic mice. The integrative approach successfully identified narciclasine as a promising therapeutic compound that targets vascular cell adhesion molecule 1 and intercellular adhesion molecule-1 (VCAM-1/ICAM-1) for AS treatment, with molecular studies confirming strong binding affinity and experimental validation demonstrating significant alleviation of endothelial dysfunction through downregulation of VCAM-1/ICAM-1 expression and reduction of aortic plaque burden in mouse models. This multiplatform methodology combining single-cell sequencing, network pharmacology, machine learning, computational simulation, and experimental validation provides a robust framework for drug discovery while positioning narciclasine as a promising therapeutic candidate warranting clinical investigation for AS treatment.
如何引用
AMA
Yang Wang, Zhen Cao, Huai Lan, Bo Li, Guixue Wang, Qingmei Chen. Single-cell sequencing-guided discovery of narciclasine as a dual VCAM-1/ICAM-1 inhibitor for atherosclerosis management.. Genes & diseases. 2027; doi:10.1016/j.gendis.2026.102167.
APA
Yang Wang, Zhen Cao, Huai Lan, Bo Li, Guixue Wang, Qingmei Chen (2027). Single-cell sequencing-guided discovery of narciclasine as a dual VCAM-1/ICAM-1 inhibitor for atherosclerosis management.. Genes & diseases. https://doi.org/10.1016/j.gendis.2026.102167
GB/T 7714
Yang Wang, Zhen Cao, Huai Lan, Bo Li, Guixue Wang, Qingmei Chen. Single-cell sequencing-guided discovery of narciclasine as a dual VCAM-1/ICAM-1 inhibitor for atherosclerosis management.[J]. Genes & diseases, 2027 doi:10.1016/j.gendis.2026.102167.
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