目的 运用生物信息学、网络药理学及实验验证的方法探究熟地黄Rehmanniae Radix Praeparata治疗2型糖尿病（type 2 diabetes mellitus，T2DM）的作用机制。方法 熟地黄的水提物ig给予T2DM小鼠，并通过超高效液相色谱-高分辨质谱（UPLC-HRMS）对入血及入胰腺成分进行辨识，在瑞士目标预测数据库（Swiss Target Prediction）预测潜在靶点，并与基因表达综合数据库（Gene Expression Omnibus，GEO）中GSE15932、GSE25724数据集及比较毒物基因组学数据库（Comparative Toxicogenomics Database，CTD）、人类基因数据库（GeneCards）取交集获取共同基因，并在Cytoscape中进行聚类分析，得到熟地黄入血和入胰腺靶点。对熟地黄入血和入胰腺的靶点取交集分析。在ADMETab3.0数据库中进行毒性预测、分子对接及信使核糖核酸（messenger ribonucleic acid，mRNA）-微小核糖核酸（microRNA，miRNA）-长链非编码核糖核酸（long non-coding RNA，lncRNA）互作网络分析，运用基因和蛋白相互作用和功能数据库（GeneMANIA）分析主要生物功能，并结合实时荧光定量PCR实验验证。结果 熟地黄可改善T2DM小鼠异常葡萄糖水平和糖耐受量。熟地黄入血化合物138个，相对应的潜在基因靶点分别为18个和1个聚类；入胰腺化合物为359个，相对应的潜在基因靶点分别为141个和6个聚类。甲状腺素转运蛋白基因（transthyretin，TTR）和ATP结合盒转运蛋白B1（ATP binding cassette subfamily B member 1，ABCB1）为熟地黄入血及胰腺的交集基因靶点；得到包含6个相同miRNA及14个相同lncRNA的mRNA-miRNA-lncRNA互作网络。主要生物功能涉及脂质运输和代谢、药物运输、离子和神经递质运输、血管过程及炎症反应的调节等。熟地黄可影响T2DM小鼠血液和胰腺中TTR、ABCB1的mRNA表达水平。结论 TTR和ABCB1可被视为熟地黄治疗T2DM的潜在作用靶点，为T2DM治疗提供依据的同时为后续深入研究熟地黄作用于T2DM的相关问题提供思路。

Objective To investigate the biological mechanisms of Shudihuang (Rehmanniae Radix Praeparata) in treating type 2 diabetes mellitus (T2DM) through bioinformatics, network pharmacology, and experimental validation. Methods T2DM mice were treated with an aqueous extract of Rehmanniae Radix Praeparata by gavage, and the components that entered the blood and pancreas were identified using ultra-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS). Potential targets were predicted in the Swiss Target Prediction database and compared with genes from the Gene Expression Omnibus (GEO) datasets GSE15932 and GSE25724, the Comparative Toxicogenomics Database (CTD), and the GeneCards database to identify common genes. The complex network analysis and visualization with Cytoscape software were performed intersection analysis of targets in the blood and pancreas. Toxicity prediction, molecular docking, and mRNA-miRNA-lncRNA interaction network analysis were conducted in the ADMETab3.0 database. The main biological functions were analyzed using the GeneMANIA database, supported by validation through real-time fluorescent quantitative PCR experiments.Results Rehmanniae Radix Praeparata significantly improved abnormal glucose levels and enhanced glucose tolerance in mice with T2DM. A total of 138 compounds were identified in the blood, with 18 corresponding potential gene targets and one cluster, while 359 compounds were identified in the pancreas, with 141 potential gene targets and six clusters. Transthyretin (TTR) and ATP binding cassette subfamily B member 1 (ABCB1) were identified as common gene targets in the blood and pancreas. The mRNA-miRNA-lncRNA interaction network containing six identical miRNAs and fourteen identical lncRNAs were constructed. The main biological functions involved lipid transport and metabolism, drug transport, ion and neurotransmitter transport, vascular processes, and inflammation regulation. Rehmanniae Radix Praeparata affected the mRNA expression levels of TTR and ABCB1 in the blood and pancreas of T2DM mice. Conclusion TTR and ABCB1 can be considered as potential therapeutic targets for Rehmanniae Radix Praeparata in the treatment of T2DM, providing a basis for T2DM treatment and offering insights for further research into the role of Rehmanniae Radix Praeparata in T2DM-related issues.

Q811.4;R285

山西省应用基础研究计划项目（20210302124694）;中医药管理局科研课题项目（2023ZYYA2012）;山西省留学人员科技活动择优资助项目（重点项目）（20230034）;山西省筹资金资助归国留学人员科研项目（2023-156）;山西省教育厅项目（2021L364）;山西中医药大学博士科研启动基金项目（2023BK38）;山西中医药大学科技创新能力培育计划（太行本草专项）（2022PY-TH-02）