Single cell transcriptomics in a treatment-segregated cohort exposes a STAT3-regulated therapeutic gap in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic pulmonary disease with unknown etiology. Since approved idiopathic pulmonary fibrosis (IPF) drugs only slow disease progression, novel therapeutics are required that improve clinical outcomes. Here, we report a single cell RNA-Seq and regulatory network analysis of the largest IPF cohort assembled to date. Segregating this cohort based on status of treatment with approved antifibrotics (untreated, nintedanib- and pirfenidone-treated), we describe for the first time the transcriptional landscape of untreated IPF across 40 lung cell types, and the elements of this program that are impacted by approved antifibrotics. On average, 60% of the untreated IPF-dysregulated transcriptome is refractory to treatment with these drugs, a transcriptional deficit we refer to as the IPF therapeutic gap. Regulatory network analysis indicated a dominant functional footprint for the transcription factor STAT3 in both untreated IPF and in the IPF therapeutic gap. Validating our analysis in a translational precision cut lung slice platform that recapitulates IPF explants, treatment with a STAT3 inhibitor reduced the IPF therapeutic gap in numerous lung cell types. Finally, we implicated STAT3 as a master transcription factor that regulates a network comprising numerous profibrotic transcription factors in IPF alveolar fibroblasts, a critical fibrotic cell lineage. Our study represents a comprehensive resource for translational lung fibrosis research and establishes a novel strategy for drug discovery in human disease more broadly.