目的 探讨苦鬼臼毒素在动脉粥样硬化中的潜在作用靶点及分子机制。方法 采用ADMETlab 3.0对苦鬼臼毒素的吸收、分布、代谢、排泄及毒性特征进行评估。以苦鬼臼毒素与动脉粥样硬化交集靶点构建蛋白相互作用（PPI）网络，并利用CytoNCA筛选Hub靶点。采用基因本体（GO）、京都基因与基因组百科全书（KEGG）及疾病本体（DO）富集分析解析功能特征。基于GSE40231数据进行差异分析，并通过ROC曲线评估核心基因的诊断效能；采用分子对接与分子动力学模拟验证靶点蛋白的结合稳定性。结果 苦鬼臼毒素在体内具备成药潜力。共获得196个与苦鬼臼毒素抗动脉粥样硬化相关的候选靶点，最终确定CDC42为核心靶点。CDC42在动脉粥样硬化病变组织中高表达，其AUC为0.893，具有良好的诊断潜力。相关靶点主要参与血管内皮功能维持、炎症信号调控及细胞迁移过程，重点涉及磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）、c-Jun氨基末端激酶（JNK）及血管内皮生长因子（VEGF）等关键信号通路。分子对接与分子动力学模拟支持苦鬼臼毒素与CDC42之间存在稳定的相互作用。结论 苦鬼臼毒素可能是具有抗动脉粥样硬化潜力的木脂素类化合物，其作用及安全性尚需进一步实验验证。

Objective To investigate the potential target sites and molecular mechanisms of (+)-picropodophyllotoxin in atherosclerosis. Methods The absorption, distribution, metabolism, excretion and toxicity profiles of (+)-picropodophyllotoxin were evaluated using ADMETlab 3.0. PPIs were constructed with (+)-picropodophyllotoxin and atherosclerosis intersection targets, and Hub genes were screened using CytoNCA. GO, KEGG and DO enrichment analyses were used to resolve functional features. Differential analysis was performed based on GSE40231 data, and the diagnostic efficacy of the core genes was evaluated by ROC curves; molecular docking and molecular dynamics simulations were used to verify the binding stability of the target proteins. Results (+)-Picropodophyllotoxin have the potential to become drugs in vivo. A total of 196 (+)-picropodophyllotoxin were identified as anti-atherosclerosis targets, and CDC42 was identified as the core target, which was highly expressed in atherosclerosis lesions with an AUC of 0.893, and has good diagnostic potential. The target is mainly involved in the maintenance of vascular endothelial function, inflammatory signalling and cell migration, with a focus on key signalling pathways such as PI3K/Akt, JNK, and VEGF. Molecular docking and molecular dynamics simulations confirm the stable interaction between (+)-picropodophyllotoxin and CDC42. Conclusion (+)-Picropodophyllotoxin may be a lignan compound with potential anti-atherosclerotic activity, and its effects and safety require further experimental validation.

R285.5;R286.2

国家自然科学基金地区项目（82360063）；海南省普通高等学校研究生创新科研课题（HYYB2024-S002）