目的 通過生物信息學方法篩選與鐵死亡相關的特發(fā)性肺纖維化基因，分析其作用機制，并預測潛在具有治療作用的中藥及活性成分。方法 在GEO數(shù)據(jù)庫搜集符合條件的特發(fā)性肺纖維化患者數(shù)據(jù)集，利用R軟件對數(shù)據(jù)集進行差異分析獲得差異表達基因（DEGs）。同時在FerrDb平臺收集鐵死亡相關基因（FRGs）。對DEGs和FRGs取交集得到鐵死亡相關DEGs，進一步對鐵死亡相關DEGs進行蛋白質(zhì)相互作用（PPI）網(wǎng)絡分析，篩選核心基因，并對其進行GESA通路富集分析。將核心基因提交至Coremine數(shù)據(jù)庫查找對應中藥，并通過TCMSP數(shù)據(jù)庫找到對應中藥活性成分，得到藥物-活性成分網(wǎng)絡，進一步篩選得到核心中藥和核心活性成分。對核心基因與核心活性成分進行分子對接分析。結(jié)果 篩選得到723個DEGs，共收集到鐵死亡相關基因487個，兩者取交集得到18個鐵死亡相關DEGs，通過PPI進一步篩選得到5個核心基因：環(huán)加氧酶2（PTGS2）、血紅素加氧酶1（HOMX1）、白細胞介素6（IL6）、轉(zhuǎn)錄因子AP-1（JUN）和轉(zhuǎn)錄激活因子3（ATF3）。GSEA分析顯示核心基因可能通過結(jié)節(jié)樣受體、絲裂原活化蛋白激酶（MAPK）、信號轉(zhuǎn)導子和轉(zhuǎn)錄激活子（JAK/STAT）、T細胞受體等信號通路發(fā)揮干預特發(fā)性肺纖維化的作用。通過預測得到丹參、干姜、人參、桑葉、桑枝等12種中藥，以及4種關鍵活性成分槲皮素、山柰酚、谷甾醇和β-谷甾醇。分子對接顯示核心基因與核心活性成分結(jié)合良好。結(jié)論 以鐵死亡作為切入點，通過生物信息學分析得到特發(fā)性肺纖維化的潛在靶點，并得到潛在具有特發(fā)性肺纖維化治療作用的中藥及其活性成分。

Objective To screen the idiopathic pulmonary fibrosis (IPF) genes associated with ferroptosis by bioinformatics methods, analyze their mechanisms of action, and predict potential therapeutic traditional Chinese medicine. Methods Eligible IPF patient datasets were collected in the GEO database, and differential analysis of the datasets was performed using R software to obtain differentially expressed genes (DEGs). Ferroptosis-associated genes (FRGs) were also collected in the FerrDb platform. The DEGs and FRGs were intersected to obtain ferroptosis -related DEGs, and further protein-protein interaction (PPI) network analysis was performed to screen the core genes for ferroptosis-related DEGs and enrichment analysis of the GESA pathway was performed. The core genes were submitted to the Coremine database to find the corresponding traditional Chinese medicine, and the traditional Chinese medicine-active ingredient network map was produced after finding the corresponding traditional Chinese medicine active ingredients by TCMSP to obtain the core traditional Chinese medicine and core active ingredients. Finally, molecular docking analysis was performed between the core genes and the core active ingredients. Results 723 DEGs were screened, and 487 ferroptosis-related genes were collected. 18 ferroptosis-related DEGs were obtained by taking the intersection of the two, and five core genes were further screened by PPI: PTGS2, HOMX1, IL6, JUN, and ATF3. GSEA analysis showed that the core genes may play a role in interfering with IPF through nodule-like receptors, MAPK, JAK/STAT, T-cell receptors and other signaling pathways to intervene in IPF. Twelve Chinese herbs, including Salviae Miltiorrhizae Radix et Rhizoma, Zingiberis Rhizoma, Ginseng Radix et Rhizoma, Mori Folium and Mori Ramulus, etc. and four key active ingredients, quercetin, kaempferol, glutathione and β-sitosterol were obtained by prediction. Molecular docking showed good binding of the core genes to the core active ingredients. Conclusion Ferroptosis was used as an entry point to obtain potential biomarkers and therapeutic targets of IPF through bioinformatics analysis, and potential therapeutic herbal medicines for IPF and their active ingredients were obtained, providing new ideas for new targets and new drug development for IPF treatment.

R974;R285

國家自然科學基金資助項目（82004141）；深圳市科創(chuàng)委項目（JCYJ20210324131204012）；寶安區(qū)中醫(yī)藥發(fā)展基金會項目（2020KJCX-KTYJ-5）