系统药理学探讨山柰酚治疗特发性肺纤维化的分子机制  

Molecular Mechanisms of Kaempferol in the Treatment of Idiopathic Pulmonary Fibrosis Based on Systems Pharmacology

作　　者：张欣欣 谢铱子 谢依 詹少锋[1,4] 江勇 吴鹏 温武金 彭晓芸 李航 黄秀芳 ZHANG Xinxin;XIE Yizi;XIE Yi;ZHAN Shaofeng;JIANG Yong;WU Peng;WEN Wujin;PENG Xiaoyun;LI Hang;HUANG Xiufang(The First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510001,China;The First Clinical Medical College of Guangzhou University of Chinese medicine,Guangzhou 510000,China;Lingnan Medical Research Center of Guangzhou University of Chinese Medicine,Guangzhou 510000,China;Guangdong Clinical Research Academy of Chinese Medicine,Guangzhou 510000,China;Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine,Shenzhen 518072,China;Shenzhen Bao′an Hospital of Traditional Chinese Medicine,Shenzhen 518133,China)

机构地区：[1]广州中医药大学第一附属医院,广州5100001 [2]广州中医药大学第一临床医学院,广州510000 [3]广州中医药大学岭南医学研究中心,广州510000 [4]广东省中医临床研究院,广州510000 [5]深圳市中西医结合医院,深圳518072 [6]深圳市宝安中医院,深圳518133

出　　处：《世界中医药》2025年第4期538-546,共9页World Chinese Medicine

基　　金：国家自然科学基金项目(82004141);深圳市科创委项目(JCYJ20190808160407500);深圳市宝安区中医药临床研究专项(2023ZYYLCZX-9,2023ZYYLCZX-11);深圳市宝安区医疗卫生科研项目(2023JD124,2023JD105);深圳市中西医结合医院院内课题(Y-2023-106,Y-2023-115);深圳市“医疗卫生三名工程”建设项目(SZZYSM202206013);国家中医优势专科建设项目(广州中医药大学第一附属医院肺病科);广东省重点科室(中西医协同科室)建设项目;广州中医药大学青年拔尖人才(团队)培育“揭榜挂帅”项目。

摘　　要：目的:基于生物信息学与网络药理学方法预测山柰酚治疗特发性肺纤维化(IPF)的潜在靶点及机制,动物实验验证所预测的分子机制。方法:通过基因综合表达(GEO)数据库挖掘IPF差异表达基因;TCMSP、SITITCH、Pubchem和Swiss Target Prediction数据库获取山柰酚潜在靶点,富集分析关键靶基因,预测山柰酚治疗IPF的关键机制。博来霉素气管内滴注构建IPF小鼠模型并验证关键信号通路。HE、Masson、Sirus Red染色观察小鼠肺组织炎症及胶原沉积情况;免疫荧光和蛋白质印迹法检测相关蛋白水平。结果:山柰酚中治疗IPF的潜在靶点有53个,涉及AKT丝氨酸/苏氨酸激酶1(AKT1)、前列腺素内过氧化物合酶2(PTGS2)、缺氧诱导因子1A(HIF1A)、胱天蛋白酶3(CASP3)及血红素氧化酶1(HMOX1)等关键靶点。山柰酚可能通过调控氧化应激、细胞外基质分解等生物过程,作用于肿瘤坏死因子(TNF)信号通路、核因子κB(NF-κB)信号通路和白细胞素-17(IL-17)信号通路治疗IPF;动物实验表明,山柰酚治疗减轻IPF小鼠肺部炎症浸润和胶原沉积,并降低α-平滑肌肌动蛋白(α-SMA)和纤连蛋白(Fibronectin)表达,下调肺组织中p-NF-κB、TNF-α、p-IκB-α和IL-6蛋白表达,发挥缓解小鼠肺纤维化进展的作用。结论:山柰酚治疗IPF具有多靶点和多通路的特性,减轻IPF肺纤维化进展与抑制TNF/NF-κB信号通路相关。Objective:To predict the potential targets and mechanisms of kaempferol in the treatment of idiopathic pulmonary fibrosis(IPF)based on bioinformatics and network pharmacology methods,and to validate the predicted molecular mechanisms through animal experiments.Methods:Differentially expressed genes(DEGs)in IPF were mined from the Gene Expression Omnibus(GEO)database.Potential targets of kaempferol were obtained from the TCMSP,STITCH,PubChem,and Swiss Target Prediction databases.Enrichment analysis of key target genes was performed to predict the key mechanisms of kaempferol in treating IPF.An IPF mouse model was constructed by intratracheal instillation of bleomycin,and key signaling pathways were validated.HE,Masson,and Sirius Red staining were used to observe inflammation and collagen deposition in lung tissues.Immunofluorescence and Western blot were employed to detect the expression levels of relevant proteins.Results:A total of 53 potential targets of kaempferol in treating IPF were identified,including key targets such as AKT serine/threonine kinase 1(AKT1),prostaglandin-endoperoxide synthase 2(PTGS2),hypoxia-inducible factor 1A(HIF1A),caspase 3(CASP3),and heme oxygenase 1(HMOX1).Kaempferol may exert its therapeutic effects on IPF through the regulation of biological processes(e.g.,oxidative stress,extracellular matrix degradation)to act on the tumor necrosis factor(TNF)signaling pathway,nuclear factor kappa B(NF-κB)signaling pathway,and interleukin-17(IL-17)signaling pathway.Animal experiments showed that kaempferol treatment reduced pulmonary inflammatory infiltration and collagen deposition in IPF mice,as well as decreased the expression ofα-smooth muscle actin(α-SMA)and fibronectin.It also downregulated the protein expression of p-NF-κB,TNF-α,p-IκB-α,and IL-6 in lung tissue,alleviating the progression of lung fibrosis in mice.Conclusion:Kaempferol demonstrates multi-target and multi-pathway characteristics in treating IPF.The alleviation of IPF progression is associated with the inhibition of the

关 键 词：山柰酚 特发性肺纤维化 生物信息学 网络药理学 实验验证 作用机制 

分 类 号：R285[医药卫生—中药学]