Single-Cell Transcriptomic Analysis Identifies a Translation/RBP-Related Fibroblast Signature for Drug Repurposing in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by persistent fibroblast activation and excessive extracellular matrix deposition. However, transcriptional heterogeneity associated with translation- and RNA-binding protein (RBP)-related processes within IPF fibroblasts remains incompletely characterized. Here, we analyzed two independent human IPF single-cell RNA-sequencing cohorts to identify fibroblast states that differed in Translation/RBP-related transcriptional programs while sharing high fibrotic output. Donor-paired pseudobulk analysis in GSE136831 identified a transcriptional signature distinguishing these states, and genes showing consistent directional changes in the independent GSE135893 cohort were retained to derive a cross-cohort signature. Reverse-connectivity analysis across CLUE, L1000CDS2, and iLINCS was then used to prioritize compounds predicted to transcriptionally oppose this signature. Candidate compounds were subsequently evaluated in transforming growth factor-β1 (TGF-β1)-stimulated human fetal lung fibroblasts (HFL-1), with cell viability, α-smooth muscle actin (α-SMA), and collagen I used for initial phenotypic assessment. PP-1, PK-11195, dabrafenib, GSK-1059615, and dasatinib reduced both profibrotic markers within the tested concentration ranges, identifying them as candidates for further investigation. Together, these findings define a cross-cohort Translation/RBP-related fibroblast signature in IPF and support its use as a transcriptome-guided strategy for prioritizing compounds with antifibrotic phenotypic activity.