目的 通過網(wǎng)絡(luò)毒理學(xué)及分子對接的研究方法，探究鬼臼毒素導(dǎo)致肺損傷的致毒機制。方法 通過SwissTargetPrediction、GeneCards、ChEMBL、STITCH數(shù)據(jù)庫收集鬼臼毒素潛在作用靶點；在OMIM、PharmGKB、GeneCards等數(shù)據(jù)庫收集肺毒性相關(guān)靶點，取得鬼臼毒素與肺毒性交集靶點。通過STRING平臺對得到的候選靶點構(gòu)建蛋白質(zhì)相互作用（PPI）網(wǎng)絡(luò)，通過Cytoscape 3.10.3構(gòu)建網(wǎng)絡(luò)圖并進行網(wǎng)絡(luò)拓撲分析，篩選核心成分與靶點；利用STRING數(shù)據(jù)庫對交集靶點進行基因本體論（GO）功能和京都基因和基因組百科全書（KEGG）通路富集分析；使用Autodock 4.2.6軟件對鬼臼毒素與關(guān)鍵作用靶點進行分子對接，使用PyMOL軟件將分子對接結(jié)果進行可視化。結(jié)果 得到鬼臼毒素與肺毒性二者交集靶點133個。通路富集結(jié)果顯示鬼臼毒素產(chǎn)生肺毒性可能與炎癥反應(yīng)、細胞凋亡等通路密切相關(guān)；鬼臼毒素產(chǎn)生肺毒性的核心靶點有細胞腫瘤抗原p53（TP53）、白細胞介素（IL）-1β、蛋白激酶B1（Akt1）等。結(jié)論 鬼臼毒素可能通過與核心靶點TP53、IL-1β、Akt1等靶點的結(jié)合，誘導(dǎo)炎癥反應(yīng)、調(diào)控細胞周期促使細胞凋亡，進而引起肺損傷。

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.

R285

國家自然科學(xué)基金資助項目（82400015，82404774）；河南省醫(yī)學(xué)科技攻關(guān)計劃項目（LHGJ20240427）