线粒体自噬在特发性肺纤维化中的生物学机制  

Biological mechanism of mitophagy in idiopathic pulmonary fibrosis

作　　者：谢铱子 林雪莹 张欣欣 黄秀芳 詹少锋[2,4] 江勇 蔡彦 Xie Yizi;Lin Xueying;Zhang Xinxin;Huang Xiufang;Zhan Shaofeng;Jiang Yong;Cai Yan(The First Clinical Medical College of Guangzhou University of Chinese Medicine,Guangzhou 510000,Guangdong Province,China;The First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510000,Guangdong Province,China;Lingnan Medical Research Center of Guangzhou University of Chinese Medicine,Guangzhou 510000,Guangdong Province,China;Guangdong Clinical Research Academy of Chinese Medicine,Guangzhou 510000,Guangdong Province,China;Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine,Shenzhen 518104,Guangdong Province,China;Guangdong Provincial Hospital of Chinese Medicine,Zhuhai,Zhuhai 519015,Guangdong Province,China)

机构地区：[1]广州中医药大学第一临床医学院,广东省广州市510000 [2]广州中医药大学第一附属医院,广东省广州市510000 [3]广州中医药大学岭南医学研究中心,广东省广州市510000 [4]广东省中医临床研究院,广东省广州市510000 [5]深圳市中西医结合医院,广东省深圳市518104 [6]广东省中医院珠海医院,广东省珠海市519015

出　　处：《中国组织工程研究》2025年第31期6708-6716,共9页Chinese Journal of Tissue Engineering Research

基　　金：广东省中医院珠海医院呼吸疾病区域诊疗中心培育建设项目,项目负责人:蔡彦;广东省中医院中医药科学技术研究专项(YN2023MS09),项目负责人:蔡彦;第二届广东省中医院优秀中医临床人才研修项目[中医二院(2024)88号],项目负责人:蔡彦;深圳市“医疗卫生三名工程”建设项目(SZZYSM202206013);广东省重点科室(中西医协同科室)建设项目,项目负责人:江勇;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),项目负责人:詹少锋。

摘　　要：背景:线粒体自噬与特发性肺纤维化的发生发展关系密切,但其作用机制尚不清楚。目的:探讨线粒体自噬在特发性肺纤维化中的生物学机制,为临床特发性肺纤维化风险预测及亚型区分提供思路。方法:通过GEO和Reactome Pathway数据库等获取特发性肺纤维化的线粒体自噬相关基因,基于组间差异、随机森林模型筛选特发性肺纤维化的线粒体自噬特征基因。采用g:Profiler数据库进行GO功能富集分析和KEGG、Reactome、WIKI通路富集分析。通过共识聚类法区分特发性肺纤维化线粒体自噬亚型,进行亚型间免疫浸润分析,并筛选出线粒体自噬关键基因。最后,通过列线图模型量化线粒体自噬关键基因对临床特发性肺纤维化发生风险的预测价值,并探索线粒体自噬关键基因与特发性肺纤维化临床特征的相关性。结果与结论:①特发性肺纤维化中与线粒体自噬相关的基因共13个,经组间差异、随机森林模型筛选出线粒体自噬特征基因5个,分别是PINK1、RPS27A、SRC、HIF1A和CDH6;②GO分析主要涉及泛素蛋白连接酶结合、细胞对缺氧的反应;通路富集分析主要涉及PINK1-PRKN介导的线粒体自噬、NOTCH信号通路、EGFR的信号传递和血管生成等;③HIF1A在不同特发性肺纤维化亚型间具有显著的表达差异,可能成为特发性肺纤维化线粒体自噬亚型区分的关键基因;④免疫浸润分析提示骨髓来源抑制性细胞、中性粒细胞与1型辅助性T细胞可能在不同亚型之间存在浸润差异,而HIF1A与多种免疫细胞浸润程度呈正相关;⑤列线图模型提示通过HIF1A的表达水平可能预测临床特发性肺纤维化的发生风险;⑥临床特征分析提示,HIF1A高表达患者可能肺功能更差,纤维化程度更严重。结果表明,PINK1、RPS27A、SRC、HIF1A和CDH6可能通过线粒体自噬影响特发性肺纤维化的发生发展,其中HIF1A可能成为特发性肺纤维化风险预测及临床�BACKGROUND:Mitophagy is closely associated with the development of idiopathic pulmonary fibrosis,but its mechanism remains unclear.OBJECTIVE:To investigate the biological mechanism of mitophagy in idiopathic pulmonary fibrosis and provide ideas for the risk prediction of idiopathic pulmonary fibrosis and subtype differentiation.METHODS:The mitophagy-related genes in idiopathic pulmonary fibrosis were obtained through GEO and Reactome Pathway databases.The mitophagyrelated characteristic genes in idiopathic pulmonary fibrosis were screened based on intergroup differences and random forest model.GO functional enrichment analysis and KEGG,Reactome with WIKI pathway enrichment analyses were performed by g:Profiler database.Mitophagy subtypes in idiopathic pulmonary fibrosis were distinguished by consensus clustering method and immune infiltration analysis was performed.The mitophagy-related key gene was screened.Finally,the predictive value of mitophagy-related key gene for the risk of idiopathic pulmonary fibrosis was quantified by alignment diagram and the correlation between mitophagy-related key gene and clinical characteristics of idiopathic pulmonary fibrosis was explored.RESULTS AND CONCLUSION:(1)A total of 13 genes related to mitophagy in idiopathic pulmonary fibrosis were identified and 5 characteristic genes were screened,containing PINK1,RPS27A,SRC,HIF1A,and CDH6.(2)GO analysis was mainly involved in ubiquitin protein ligase binding,and cellular response to hypoxia.Pathway enrichment analysis was mainly involved in PINK1-PRKN mediated mitophagy,NOTCH signaling pathway,signaling by EGFR and angiogenesis.(3)HIF1A had significant expression differences between subtypes,which might serve as a key gene for the differentiation of mitophagy subtypes of idiopathic pulmonary fibrosis.(4)Immune infiltration analysis suggested that myeloid-derived suppressor cell,neutrophil and type 1 T helper cell might have infiltration differences between subtypes,while HIF1A was positively correlated with multiple immune cells.(5

关 键 词：特发性肺纤维化 线粒体自噬 自噬关键基因 亚型分析 富集分析 免疫浸润分析 肺功能 生物信息学 

分 类 号：R459.9[医药卫生—治疗学] R318[医药卫生—临床医学] R563.9