目的 基于網(wǎng)絡(luò)藥理學(xué)、分子對(duì)接技術(shù)和實(shí)驗(yàn)驗(yàn)證探究狼毒大戟治療甲狀腺癌的作用機(jī)制。方法 通過(guò)SwissADME、Swiss Target Prediction數(shù)據(jù)庫(kù)篩選狼毒大戟活性成分和相關(guān)作用靶點(diǎn)；利用GeneCards、OMIM、DisGeNET數(shù)據(jù)庫(kù)篩選甲狀腺癌靶點(diǎn)基因；基于STRING平臺(tái)和Cytoscape軟件構(gòu)建蛋白互作網(wǎng)絡(luò)（PPI）、狼毒大戟-有效活性成分-交集靶點(diǎn)網(wǎng)絡(luò)以及篩選核心靶點(diǎn)；使用DAVID數(shù)據(jù)庫(kù)進(jìn)行基因本體（GO）功能注釋分析與京都基因與基因組百科全書（KEGG）通路富集分析；利用AutoDockTools軟件對(duì)狼毒大戟核心成分和關(guān)鍵靶點(diǎn)進(jìn)行分子對(duì)接驗(yàn)證；Western blotting分析狼毒大戟對(duì)表皮生長(zhǎng)因子受體（EGFR）/Janus激酶（JAK2）/信號(hào)轉(zhuǎn)導(dǎo)因子和轉(zhuǎn)錄激活因子3（STAT3）信號(hào)通路的作用。結(jié)果 共獲得狼毒大戟潛在活性成分38種、成分靶點(diǎn)488個(gè)，甲狀腺癌靶點(diǎn)3 050個(gè)，交集靶點(diǎn)175個(gè)；狼毒大戟治療甲狀腺癌的生物過(guò)程包括磷酸化、蛋白磷酸化、細(xì)胞群增殖正調(diào)控等，相關(guān)信號(hào)通路涉EGFR/JAK2/STAT3、磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）、絲裂原活化蛋白激酶（MAPK）、EGFR、腫瘤壞死因子（TNF）、高級(jí)糖基化終末產(chǎn)物-受體（AGE-RAGE）、凋亡、Th17細(xì)胞分化等信號(hào)通路；分子對(duì)接結(jié)果表明狼毒大戟治療甲狀腺癌的核心成分與JAK2、EGFR、STAT3具有顯著的親和力，結(jié)合性能穩(wěn)定；Western blotting實(shí)驗(yàn)提示巖大戟內(nèi)酯A呈濃度相關(guān)性抑制EGFR/JAK2/STAT3信號(hào)通路。結(jié)論 狼毒大戟可能通過(guò)調(diào)控多個(gè)關(guān)鍵靶點(diǎn)、多種生物學(xué)過(guò)程和多條信號(hào)通路，尤其是EGFR/JAK2/STAT3信號(hào)通路發(fā)揮抗甲狀腺癌效應(yīng)，為今后深入研究狼毒大戟對(duì)甲狀腺癌的調(diào)控機(jī)制提供理論依據(jù)。

Objective To investigate the action mechanism of Euphorbia fischeriana in treatment of thyroid cancer based on network pharmacology, molecular docking technology, and experimental validation. Methods Screening the main active ingredient and corresponding targets of E. fischeriana through databases such as SwissADME and Swiss Target Prediction. GeneCards, OMIM and DisGeNET databases were used to collect the target genes of thyroid cancer. PPI network and “E. fischeriana–active ingredient–intersection targets” network diagrams were constructed using the STRING platform and Cytoscape software, from which core targets were screened. DAVID database was applied for GO functional annotation analysis and KEGG pathway enrichment analysis, and molecular docking analysis validated binding affinity values for the core components and key targets via AutoDockTools software. Western blotting was assessed for its effects of E. fischeriana on EGFR/JAK2/STAT3 signaling pathway. Results A total of 38 potential effective constituents, 488 drug related targets, 3 050 thyroid cancer targets, and 175 overlapping targets were obtained. Biological processes mainly included phosphorylation, protein phosphorylation, and positive regulation of cell population proliferation, etc. Relevant signaling pathways involved EGFR/JAK2/STAT3, PI3K/Akt, MAPK, EGFR, TNF, AGE-RAGE, apoptosis, and Th17 cell differentiation signaling pathways. Molecular docking revealed that the core active component jolkinolide A was stable in docking with JAK2, EGFR, and STAT3, implied with significant affinity. Western blotting assay showed that E. fischeriana inhibited EGFR/JAK2/STAT3 signaling pathway in a concentration-dependent manner. Conclusion E. fischeriana can exert an antithyroid cancer effect by regulating multiple key targets, multiple biological processes and multiple pathways, especially EGFR/JAK2/STAT3 signaling pathway, which will provide theoretical reference for further in-depth investigating the regulatory mechanism of E. fischeriana on thyroid cancer.

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國(guó)家自然科學(xué)基金資助項(xiàng)目（82473266；82160129）；甘肅省科技重大專項(xiàng)（22ZD6FA054）；甘肅省創(chuàng)新驅(qū)動(dòng)助力工程項(xiàng)目（GXH20230817-14）