目的 基于异病同治理论通过生物信息学的方法从卵巢早衰（premature ovarian failure，POF）角度探究干眼症（dry eye disease，DED）的关键基因及作用机制，并进一步寻找治疗干眼症的天然活性成分，以期拓展干眼症的治疗策略及药物开发途径。方法 通过基因表达综合数据库（gene expression omnibus，GEO）对卵巢早衰与干眼症相关基因和数据集进行鉴定，对获得的数据集分别进行加权基因共表达网络分析（weighted gene co-expression network analysis，WGCNA）。随后，通过构建蛋白相互作用（protein-protein interaction，PPI）网络，筛选出该网络中的关键基因。对关键基因进行基因本体论（gene ontology，GO）及京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）富集分析。同时，利用机器学习方法及受试者工作特征（receiver operating characteristic，ROC）分析获得具有更有诊断价值的特征基因。将关键基因用于天然活性成分预测，构建天然活性成分-靶标网络。利用分子对接技术验证具有潜在治疗效果的天然活性成分，并对预测的天然活性成分进行体外实验验证。结果 通过筛选确定GSE44101及GSE39501作为基础数据集，获得151个卵巢早衰与干眼症共表达基因靶点，获得37个关键靶基因，主要富集于细胞循环、DNA修复、卵细胞减数分裂等过程。通过机器学习及ROC分析进行筛选后获得7个特征基因。预测发现染料木素为关键的天然活性成分。细胞实验验证结果表明，角膜上皮细胞干眼症模型在12.5 μmol/L染料木素干预24 h后细胞生存率最高，其发挥作用的机制与抑制Polo样激酶1（Polo-like kinase 1，PLK1）、DNA甲基转移酶1（DNA methyltransferase 1，DNMT1）、丝裂原活化蛋白激酶激酶4（mitogen-activated protein kinase kinase 4，MAP2K4）的表达及促进细胞分裂周期蛋白20（cell division cycle 20，CDC20）的表达相关。结论 卵巢早衰可与干眼症共病发生，其机制与炎症及细胞凋亡相关，染料木素可减少炎症损害与异常细胞凋亡的发生，从而达到治疗卵巢早衰并发干眼症的作用。

Objective Based on the theory of “the same treatment for different diseases” (异病同治), this study aims to explore the key genes and mechanisms of dry eye disease (DED) from the perspective of premature ovarian failure (POF) using bioinformatics methods, and to search for natural active ingredients for treating DED, with the goal of expanding targeted treatment strategies and drug development avenues for DED. Methods POF- and DED-related genes and datasets were identified from the gene expression omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed on the obtained datasets. A protein-protein interaction (PPI) network was constructed to screen key genes, followed by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses. Machine learning methods and receiver operating characteristic (ROC) analysis were used to identify diagnostically significan characteristic genes. These genes were applied to predict natural active ingredients, and a natural active ingredient-target network was constructed. Molecular docking was employed to observe natural active ingredients with potential therapeutic effects.In vitro experiments were conducted to validate the predicted natural active ingredients. Results The GSE44101 and GSE39501 datasets were selected as the basis for analysis. A total of 151 shared genes between POF and DED were identified, and 37 key target genes were obtained. These genes were primarily enriched in biological processes such as cell cycle, DNA repair, and oocyte meiosis. Machine learning and ROC analysis revealed seven characteristics genes. Genistein was predicted as a key natural active ingredient. The verification results of cell experiments showed that 12.5 μmol/L genistein significantly enhanced the viability of corneal epithelial cells in a DED model at 24 h, mechanistically linked to downregulation of Polo-like kinase 1 (PLK1), DNA methyltransferase 1 (DNMT1), and mitogen-activated protein kinase kinase 4 (MAP2K4) and upregulation of cell division cycle 20 (CDC20). Conclusion POF may comorbidly occur with DED, where shared mechanisms involve inflammatory dysregulation and aberrant apoptosis. Genistein can reduce the occurrence of inflammatory damage and aberrant apoptosis, thereby achieving the therapeutic effect of treating POF complicated with DED.

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国家自然科学基金面上项目（81574031）；2021年度“刘良院士工作站”指导项目（21YS002）；中医药防治五官科疾病湖南省重点实验室建设项目（2017TP1018）；国家中医药管理局中医眼科学重点学科建设项目（ZK1801YK015）；湖南省教育厅科研基金重点项目（23A0300）；湖南中医药大学中医学国内一流建设学科建设项目；湖南中医药大学研究生创新课题项目（2024CX041）