WS09.04Beyond chloride: a multi-omic integration analysis to identify the effects of elexacaftor/tezacaftor/ivacaftor in F508del primary airway epithelial cultures

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.543

M. Kelly-Aubert , V. Laigle , E. Bardin , A. Hatton , C. Guerrera , C. Bole , S. Grassin Delyle , V. Stoven , I. Sermet-Gaudelus

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引用次数: 0

Abstract

Elexacaftor/Tezacaftor/Ivacaftor (ETI) has changed the prognosis and quality of life of CF patients, and functional studies have ascertained their role in restoring CFTR-dependent chloride secretion; however, other pathways could be improved by ETI. We undertook a multi-omic approach to decipher which pathways, other than chloride secretion, could be involved in ETI's mechanisms of action.

Methods: We generated air-liquid differentiated primary epithelial cultures from nasal brushings from eight F508del homozygous patients and seven healthy age- and sex-paired controls. After a 48-hour treatment with ETI or DMSO, samples were collected for transcriptomic, proteomic and untargeted metabolomic analysis.

Results: In F508del cultures, ETI induced a significant differential expression of 208 genes, 37 proteins, 16 polar and 168 apolar metabolites. Gene set enrichment analysis on the transcriptomic and proteomic data and a similar metabolite-based pathway enrichment analysis on the untargeted metabolomic data revealed that several pathways were significantly up- or down-regulated by ETI in F508del cultures whereas none were significantly modified in WT cultures. This included TNFa/NFKB signaling and the epithelial mesenchymal transition pathway, both down regulated by ETI; and the interferon-dependent immune response pathways, upregulated by ETI. The pathway most affected by ETI, both at a transcriptomic and proteomic level was oxidative phosphorylation. Multi-omics integration and network analysis allowed to build a network comprising the differentially expressed genes, proteins, and metabolites and highlighted key mitochondria-related pathways: oxidative phosphorylation, Krebs cycle and fatty acid metabolism.

Conclusion: The convergence of our transcriptomic, proteomic and metabolomic data and integrated network underlines the robustness of multi-omic approaches and pinpoints an unexpected effect of ETI on mitochondrial metabolism in F508del cells.

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[03:09 .04]超越氯：多基因组整合分析鉴定elexaftor /tezacaftor/ivacaftor对F508del原代气道上皮细胞培养的影响

elexaftor /Tezacaftor/Ivacaftor （ETI）改变了CF患者的预后和生活质量，功能研究已经确定了它们在恢复cftr依赖的氯化物分泌中的作用；然而，ETI可以改善其他途径。我们采用多组学方法来破译除氯化物分泌外，哪些途径可能参与ETI的作用机制。方法：从8例F508del纯合子患者和7例年龄和性别配对的健康对照组的鼻刷液中培养气液分化的原代上皮细胞。用ETI或DMSO治疗48小时后，收集样本进行转录组学、蛋白质组学和非靶向代谢组学分析。结果：在F508del培养中，ETI诱导了208个基因、37个蛋白、16个极性代谢物和168个极性代谢物的显著差异表达。转录组学和蛋白质组学数据的基因集富集分析，以及类似的基于代谢物的非靶向代谢组学数据的途径富集分析显示，F508del培养中ETI显著上调或下调了一些途径，而WT培养中没有显著改变。这包括TNFa/NFKB信号和上皮间充质转化途径，两者都被ETI下调；干扰素依赖的免疫反应途径，被ETI上调。在转录组学和蛋白质组学水平上，受ETI影响最大的途径是氧化磷酸化。多组学整合和网络分析允许构建一个包含差异表达基因、蛋白质和代谢物的网络，并突出了线粒体相关的关键途径：氧化磷酸化、克雷布斯循环和脂肪酸代谢。结论：我们的转录组学、蛋白质组学和代谢组学数据的融合和集成网络强调了多组学方法的稳健性，并指出了ETI对F508del细胞线粒体代谢的意想不到的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.