目的 采用网络药理学、动物实验与转录组学相结合的方法，探讨连翘叶改善糖尿病小鼠肾损伤的作用机制。方法 通过网络药理学筛选连翘叶有效成分，确认作用靶基因，进行基因本体（GO）功能富集分析及京都基因与基因组百科全书（KEGG）通路富集分析预测连翘叶潜在作用通路及机制。动物实验以db/db小鼠建立糖尿病小鼠模型，分为模型组、连翘叶组，另设对照组，灌胃干预10周后，观察肾组织病理形态，检测肾功能及炎症指标。转录组学则对肾组织RNA测序，分析差异基因及富集通路及分子对接验证。结果 网络药理学筛选出白蛋白（ALB）、RAC-α丝氨酸/苏氨酸蛋白激酶（Akt1）等核心靶点，富集到磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（Akt）通路、晚期糖基化终末产物（AGEs）-糖基化终末产物受体（RAGE）信号通路等。动物实验中，连翘叶组肾组织病理损伤较模型组减轻，血清尿素氮（BUN）、肌酐（SCr）等肾功能指标明显改善，及AGEs、肿瘤坏死因子-α（TNF-α）等炎症因子水平降低。转录组学发现连翘叶逆转209个差异基因，雌激素受体1（ESR1）和纤溶酶原（PLG）为网络药理学与转录组学交集关键基因，分子对接表明连翘叶有效成分与关键基因结合稳定，且肿瘤坏死因子（TNF）通路、白细胞介素-17（IL-17）通路等在两者中均富集，这可能是连翘叶治疗糖尿病肾损伤的关键通路。结论 连翘叶可能通过作用于ESR1、PLG等关键靶点，调控AGEs-RAGE、PI3K-Akt、TNF、IL-17等通路，减少促炎因子和AGEs生成，抑制肾脏炎症反应，从而改善糖尿病小鼠肾损伤。

Objective To explore the mechanism of Forsythia suspensa leaves in improving renal injury in diabetic mice by combining network pharmacology, animal experiments and transcriptomics. Methods Network pharmacology was used to screen the effective components of F. suspensa leaves, identify the target genes, and conduct GO and KEGG enrichment analysis to predict the potential action pathways and mechanisms of F. suspensa leaves. A diabetic mouse model was established using db/db mice and divided into a model group, a F. suspensa leaves group, and a normal group. After 10 weeks of intragastric administration, the pathological morphology of the kidney tissue was observed, and the renal function and inflammatory indicators were detected. Transcriptomics was used to sequence the RNA of the kidney tissue, analyze the differentially expressed genes and enriched pathways, and verify through molecular docking. Results Network pharmacology identified core targets such as ALB and Akt1, and enriched pathways such as PI3K-Akt and AGE-RAGE. In the animal experiments, the pathological damage of the kidney tissue in the F. suspensa leaves group was less than that in the model group, and the renal function indicators such as serum BUN and Cr were significantly improved, as well as the levels of inflammatory factors such as AGEs and TNF-α were decreased. Transcriptomics revealed that F. suspensa leaves reversed 209 differentially expressed genes, with ESR1 and PLG being the key genes at the intersection of network pharmacology and transcriptomics. Molecular docking indicated that the effective components of F. suspensa leaves had stable binding with the key genes, and the TNF and IL-17 pathways were enriched in both, which might be the key pathways for F. suspensa leaves in treating diabetic kidney injury. Conclusion F. suspensa leaves may improve renal injury in diabetic mice by acting on key targets such as ESR1 and PLG, regulating pathways such as AGE-RAGE, PI3K-Akt, TNF, and IL-17, reducing the production of pro-inflammatory factors and AGEs, and inhibiting renal inflammatory responses.

R285.5;R286.7

山西省卫生健康委科研课题[晋卫办科教函(2022)4号2022084]