基于数据挖掘、网络药理学探索名老中医治疗系统性红斑狼疮治疗靶点

Exploration of Therapeutic Targets of Renowned Senior Traditional Chinese Medicine Practitioners in the Treatment of Systemic Lupus Erythematosus Based on Data Mining and Network Pharmacology

摘要: 背景：系统性红斑狼疮(Systemic Lupus Erythematosus, SLE)是一种多器官、多系统受累的自身免疫性炎症疾病，临床症状多样。本次研究旨在通过总结名老中医张鸣鹤教授治疗SLE的处方用药规律，探索相关药对治疗SLE的潜在靶点。方法：从公共数据库中获取GSE20864数据集，从FangNet网站收集116例张鸣鹤治疗SLE相关病例及处方，构建中药–中药联系网络，使用PageRank算法识别重要节点，通过Fisher检验分析得到中药共现水平和互斥水平，预测潜在药对。并与GSE20864中差异表达基因(SLE与正常)重叠以获得候选靶点。然后，利用孟德尔随机化分析，验证候选靶点与SLE的因果关系得到关键靶点。在GSE20864中构建并评估诊断列线图，并进行GSEA富集分析。结果：共预测6个候选靶点，其中HLA-A、IFIT3和ISG15被筛选为关键靶点，并与SLE存在因果关系作为疾病的保护因素(P < 0.05, OR < 1)。此外，列线图表现出相当高的预测精度和效率，提示半枝莲–白花蛇舌草药对可能通过影响针对HLA-A的“Human papillomavirus infection”等途径在治疗SLE中发挥作用。对于其他潜在通路和药物作用，IFIT3和ISG15可能参与“Epstein-Barr virus infection”和“Hepatitis C”等通路。GSEA富集分析显示，HLA-A与SLE相关的显著上调的基因通路21个，显著下调的基因通路19个；IFIT3与SLE相关的显著上调的基因通路16个，显著下调的基因通路24个；ISG15与SLE相关的显著上调的基因通路22个，显著下调的基因通路18个。这些上调基因通路可作为SLE相关的候选通路。结论：半枝莲–白花蛇舌草药对被确定为治疗系统性红斑狼疮的潜在药对，具有显著的临床意义。其潜在作用机制涉及多个生物学过程和信号通路，包括病毒免疫应答、细胞质和蛋白质结合等功能。此外，HLA-A、IFIT3和ISG15被预测为与SLE具有因果关系的保护靶点，在SLE的诊断和治疗中可能发挥重要作用，值得临床进一步研究。

Abstract: Background: Systemic lupus erythematosus (SLE) is a multi-organ, multi-system autoimmune inflammatory disease characterized by diverse clinical manifestations. This study aimed to summarize the prescription patterns of Professor Zhang Minghe, a renowned senior traditional Chinese medicine practitioner, in the treatment of SLE, and to explore the potential therapeutic targets of the related herb pair for SLE. Methods: The Gene Expression Omnibus (GEO) dataset GSE20864 was retrieved from a public database. A total of 116 SLE-related cases and corresponding prescriptions treated by Zhang Minghe were collected from the FangNet website. A traditional Chinese medicine (TCM)-TCM association network was constructed, and the PageRank algorithm was applied to identify key nodes. Fisher’s exact test was used to analyze the co-occurrence and mutual exclusivity levels of herbs to predict potential herb pairs. These were overlapped with differentially expressed genes (SLE vs. normal) in GSE20864 to obtain candidate targets. Subsequently, Mendelian randomization analysis was performed to validate the causal relationship between candidate targets and SLE, thereby identifying key targets. A diagnostic nomogram was constructed and evaluated based on GSE20864, followed by gene set enrichment analysis (GSEA). Results: A total of six candidate targets were predicted, among which HLA-A, IFIT3, and ISG15 were screened as key targets and demonstrated a causal relationship with SLE, serving as protective factors for the disease (P < 0.05, OR < 1). In addition, the nomogram exhibited relatively high predictive accuracy and efficiency. The herb pair Scutellaria barbata-Hedyotis diffusa (Ban Zhi Lian-Bai Hua She She Cao) may exert therapeutic effects on SLE by influencing pathways such as “Human papillomavirus infection” associated with HLA-A. Furthermore, regarding other potential pathways and mechanisms, IFIT3 and ISG15 may participate in pathways including “Epstein-Barr virus infection” and “Hepatitis C”. GSEA results showed that HLA-A was associated with 21 significantly upregulated and 19 significantly downregulated gene pathways in SLE; IFIT3 was associated with 16 significantly upregulated and 24 significantly downregulated pathways; and ISG15 was associated with 22 significantly upregulated and 18 significantly downregulated pathways. These upregulated pathways may serve as candidate pathways related to SLE. Conclusion: The herb pair Scutellaria barbata-Hedyotis diffusa was identified as a potential therapeutic combination for systemic lupus erythematosus (SLE), with significant clinical implications. Its potential mechanisms involve multiple biological processes and signaling pathways, including antiviral immune responses, cytoplasmic activity, and protein-binding functions. Moreover, HLA-A, IFIT3, and ISG15 were predicted as protective targets with causal associations with SLE, and they may play important roles in the diagnosis and treatment of SLE and warrant further clinical investigation.