目的 基于网络药理学筛选出的关键靶点，利用分子对接对活性成分进行配体-受体相互作用模拟，再使用动物实验，探究复方丹参滴丸（CDDP）干预脓毒症心肌损伤（SIMD）的作用机制。方法 通过对C57BL/6小鼠实施标准的盲肠结扎穿刺术（CLP）制备脓毒症模型，以模拟其相关的心肌损伤病理过程。将小鼠分为对照组、模型组、CDDP低剂量组、CDDP高剂量组、地塞米松组，使用超声心动图、苏木精-伊红（HE）染色和Western blotting检测CDDP对脓毒症心肌损伤（SIMD）的干预效果。通过中药系统药理学数据库与分析平台（TCMSP）获得CDDP的活性成分和预测靶点，利用Cytoscape3.9.1软件构建化合物-靶点互作网络。同时，从OMIM和GeneCards数据库中收集了与SIMD相关的疾病靶点，构建蛋白质-蛋白质相互作用（PPI）网络，从化合物与疾病靶点中筛选出交集靶点，并将这些靶点提交至STRING数据库，基于该PPI网络的核心节点，系统性地进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析，旨在从多层次揭示其潜在的药理机制。通过分子对接验证关键靶点与核心成分间的相互作用关系。结果 在体实验发现CDDP可以改善CLP小鼠心脏功能，减少炎症细胞浸润，增加B细胞淋巴瘤/白血病-2（Bcl-2）表达（P＜0.05），减少Bax表达（P＜0.05、0.01）。基于网络药理学的预测结果，从CDDP中共获得80种活性成分，并预测得到其对应的870个作用靶点，经疾病靶点映射后发现共有100个共同靶点。通过GO和KEGG富集分析发现，其主要作用于RNA聚合酶II启动子转录的正向调控、细胞凋亡过程的负向调控、脂多糖诱导的细胞反应等生物过程，涉及肿瘤坏死因子（TNF）、白细胞介素-17（IL-17）、NOD样受体、Toll样受体信号通路等。分子对接验证表明，3种活性成分（槲皮素、木犀草素、丹参酚醛）与5个靶点[TNF、丝氨酸/苏氨酸激酶1（AKT1）、IL-6、IL-1β、丝裂原活化蛋白激酶3（MAPK3）]之间存在较好的潜在结合亲和力，其中，MAPK3[即细胞外信号调节激酶（ERK）]与3种活性成分的对接分数最低，结合最稳定。结论 CDDP可以减轻SIMD，减少细胞凋亡，可能是通过调控MAPK/ERK信号通路发挥作用。

Objective Based on the key targets screened through network pharmacology, this study employed molecular docking to simulate ligand-receptor interactions of potential active ingredients. Animal experiments were further conducted to investigate the mechanism of Compound Danshen Dripping Pills (CDDP) in treating sepsis-induced myocardial injury (SIMD). Method Septic myocardial dysfunction models were established by performing cecal ligation and puncture (CLP) on C57BL/6BL/6 mice. The mice were divided into control, model, CDDP-low, high dose group, and dexamethasone group. while echocardiography, HE staining, and Western blot were employed to evaluate the therapeutic effects of CDDP on septic myocardial dysfunction. Active ingredients of CDDP and their predicted targets were obtained from Traditional Chinese Medicine Systems Pharmacology Platform (TCMSP) online platform. A compound-target interaction network was then built with Cytoscape 3.9.1. Meanwhile, targets associated with sepsisinduced myocardial dysfunction (SIMD) were gathered from the OMIM and GeneCards databases. Computational analysis identified the common targets shared between the compound and the disease. Subsequently, the identified intersecting targets were entered into the STRING database to establish a comprehensive protein-protein interaction (PPI) network, which was then visualized and subjected to in-depth analysis. Further in-depth analysis of core targets was conducted through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking studies were performed to validate the interaction relationships between key targets and core components. Results In vivo experiments demonstmiceed that CDDP improved cardiac function, reduced inflammatory cell infiltmiceion, increased Bcl-2 expression (P < 0.01), and decreased Bax expression (P < 0.05, 0.01). Network pharmacology results identified 80 active ingredients and 870 corresponding targets from CDDP. After mapping with disease targets, 100 common targets were identified. Through 6 475 GO and 221 KEGG enrichment analyses, it was found that CDDP primarily acts on biological processes such as transcriptional regulation and apoptosis inhibition, and cellular response to lipopolysaccharide. It involves signaling pathways including TNF, IL-17, NOD-like receptor, and Toll-like receptor pathways. Molecular docking validation indicated stable binding between three active ingredient (quercetin, luteolin, tanshinaldehyde) and five targets (TNF, AKT1, IL-6, IL-1β, MAPK3). Among these, MAPK3 exhibited the lowest docking scores with the three active ingredients, indicating the most stable binding. Conclusion CDDP can alleviate myocardial damage caused by sepsis and reduce cell apoptosis. This effect may be achieved by regulating the MAPK/ERK signaling pathway.

R285.5

“天山英才”-青年拔尖项目（2024TSYCCX0113）；天山英才科技创新团队（2023TSYCTD0020）