Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating disease with a high clinical burden. The molecular signatures of IPF were analyzed to distinguish molecular subgroups and identify key driver genes and therapeutic targets.MethodsThirteen datasets of lung tissue transcriptomics including 585 IPF patients and 362 normal controls were obtained from the databases and subjected to filtration of differentially expressed genes (DEGs). A functional enrichment analysis, agglomerative hierarchical clustering, network-based key driver analysis, and diffusion scoring were performed, and the association of enriched pathways and clinical parameters was evaluated.ResultsA total of 2,967 upregulated DEGs was filtered during the comparison of gene expression profiles of lung tissues between IPF patients and healthy controls. The core molecular network of IPF featured p53 signaling pathway and cellular senescence. IPF patients were classified into two molecular subgroups (C1, C2) via unsupervised clustering. C1 was more enriched in the p53 signaling pathway and ciliated cells and presented a worse prognostic score, while C2 was more enriched for cellular senescence, profibrosing pathways, and alveolar epithelial cells. The p53 signaling pathway was closely correlated with a decline in forced vital capacity and carbon monoxide diffusion capacity and with the activation of cellular senescence. CDK1/2, CKDNA1A, CSNK1A1, HDAC1/2, FN1, VCAM1, and ITGA4 were the key regulators as evidence by high diffusion scores in the disease module. Currently available and investigational drugs showed differential diffusion scores in terms of their target molecules.ConclusionsAn integrative molecular analysis of IPF lungs identified two molecular subgroups with distinct pathobiological characteristics and clinical prognostic scores. Inhibition against CDKs or HDACs showed great promise for controlling lung fibrosis. This approach provided molecular insights to support the prediction of clinical outcomes and the selection of therapeutic targets in IPF patients.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by progressive scarring of the lung parenchyma associated with a steady worsening of respiratory symptoms and a decline in pulmonary function, leading to death [1]
Expressed genes and their network and enriched pathways A total of 2,967 upregulated Differentially expressed gene (DEG) was filtered during the comparison of gene expression profiles of lung tissues between IPF patients and healthy controls (Additional file 2: Figure S2)
The network included DSP gene, a variant of which are known to confer the risk of developing IPF [42, 43], and 14 biomarkers (CCL18, CD28, CHI3L1, CLU, CXCL13, HSPA4, KRT19, MMP1, MMP7, MUC16, POSTN, SPP1, TNFSF13B, and VCAM1) [2, 44, 45]
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by progressive scarring of the lung parenchyma associated with a steady worsening of respiratory symptoms and a decline in pulmonary function, leading to death [1]. Therapeutic interventions targeting the immune response, inflammation, or oxidative stress have been attempted, none have been proven to be successful, and no effective pharmacotherapy for IPF exists yet [3,4,5]. These unsatisfactory results in drug development might be partially ascribed to the complexity and heterogeneity of IPF. IPF is associated with diverse clinical progressions, from an asymptomatic stable state to gradual progressive respiratory failure or rapid deterioration of respiratory function through acute exacerbation [8]
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