Single-cell RNA-seq object (Seurat) and count matrix of ALI-culture dataset

Idiopathic pulmonary fibrosis is a rare and chronic disease. With its progressive nature, studying IPF at earlier time points may reveal unique cellular phenotypes that could be pharmacologically targeted. Recent studies suggest airway epithelial cells play an important role in disease development. To this end, we analyzed single-cell transcriptomes of the airway mucosa using air-liquid interface cultures from newly diagnosed, treatment-naïve IPF patients. We then evaluated their responses to antifibrotic drugs (nintedanib and pirfenidone) and a Src kinase inhibitor (saracatinib). Profiling 129,986 transcriptomes identified primed fibroblasts (<i>PDGFRA</i>⁺, <i>SPP1</i>⁺), dysregulated basal cells (<i>TP63</i>^<em>+</em>, <i>KRT5</i>^<em>+</em>, <i>FN1</i>^<em>+</em>), and proinflammatory airway epithelial cells (SAA, CXCL, CCL). Integrative analyses with single-cell explant IPF atlases, highlighted different basal and fibroblast phenotypes spanning tissue regions and disease stages. While all three drugs effectively downregulated many IPF signatures, saracatinib outperformed other drugs in fibroblast activation assays – highlighting its therapeutic potential. Our findings provide insights into disease mechanisms and antifibrotic drug responses in IPF at an earlier timepoint of disease. These findings may aid in the development of future treatment strategies.