目的 通过网络毒理学及分子对接的研究方法，探究鬼臼毒素导致肺损伤的致毒机制。方法 通过SwissTargetPrediction、GeneCards、ChEMBL、STITCH数据库收集鬼臼毒素潜在作用靶点；在OMIM、PharmGKB、GeneCards等数据库收集肺毒性相关靶点，取得鬼臼毒素与肺毒性交集靶点。通过STRING平台对得到的候选靶点构建蛋白质相互作用（PPI）网络，通过Cytoscape 3.10.3构建网络图并进行网络拓扑分析，筛选核心成分与靶点；利用STRING数据库对交集靶点进行基因本体论（GO）功能和京都基因和基因组百科全书（KEGG）通路富集分析；使用Autodock 4.2.6软件对鬼臼毒素与关键作用靶点进行分子对接，使用PyMOL软件将分子对接结果进行可视化。结果 得到鬼臼毒素与肺毒性二者交集靶点133个。通路富集结果显示鬼臼毒素产生肺毒性可能与炎症反应、细胞凋亡等通路密切相关；鬼臼毒素产生肺毒性的核心靶点有细胞肿瘤抗原p53（TP53）、白细胞介素（IL）-1β、蛋白激酶B1（Akt1）等。结论 鬼臼毒素可能通过与核心靶点TP53、IL-1β、Akt1等靶点的结合，诱导炎症反应、调控细胞周期促使细胞凋亡，进而引起肺损伤。

Objective To explore the toxic mechanism of podophyllotoxin induced pulmonary toxicity through the research methods of network toxicology and molecular docking. Methods Potential targets of podophyllotoxin were collected from databases including SwissTargetPrediction, GeneCards, ChEMBL, and STITCH. Lung toxicity-related targets were retrieved from OMIM, PharmGKB, and GeneCards. Intersection targets between podophyllotoxin and lung toxicity were identified. PPI network was constructed using the STRING platform, and network topology analysis was performed with Cytoscape 3.10.3 to screen core components and targets. GO functional annotation and KEGG pathway enrichment analysis of the intersection targets were conducted via the STRING database. Molecular docking between podophyllotoxin and key targets was performed using AutoDock 4.2.6, and visualization of docking results was achieved with PyMOL. Results A total of 133 intersection targets between podophyllotoxin and lung toxicity were identified. Pathway enrichment analysis revealed that podophyllotoxin-induced pulmonary toxicity may be closely associated with inflammatory response, apoptosis, and related signaling pathways. Core targets including TP53, IL-1β, and Akt1 were identified as pivotal mediators. Conclusion Podophyllotoxin likely induces lung injury by binding to core targets such as TP53, IL-1β, and Akt1, triggering inflammatory responses, dysregulating cell cycle progression, and promoting apoptosis.

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国家自然科学基金资助项目（82400015，82404774）；河南省医学科技攻关计划项目（LHGJ20240427）