Seralutinib targets fibrotic pathways in IPF: Evidence from single-cell transcriptomics

<bold>Introduction.</bold> Seralutinib, an inhaled receptor tyrosine kinase inhibitor under development for pulmonary hypertension, including pulmonary arterial hypertension and interstitial lung disease, reduced circulating proteins associated with extracellular matrix (ECM) remodeling in the phase 2 TORREY trial (<ext-link>NCT04456998</ext-link>). To further investigate its antifibrotic potential, we identified seralutinib-associated signatures in a human precision-cut lung slice (PCLS) fibrosis model and mapped them to scRNAseq profiles from idiopathic pulmonary fibrosis (IPF) patient lungs. <bold>Methods.</bold> Seralutinib-associated signatures were identified from circulating proteins in TORREY and RNA-seq analysis of PCLS cultures stimulated with pro-fibrotic cocktail and treated with 10 μM seralutinib. Signatures were mapped to seven public scRNAseq datasets (80 IPF; 58 controls; 486,114 cells). <bold>Results.</bold> ECM-related proteins decreased by seralutinib in TORREY, including COL1A1, COL6A3, COL24A1 and ITGB1, were upregulated in IPF myofibroblasts, fibroblasts, AT2 and endothelial cells. Top enriched pathways included ECM organization, epithelial-mesenchymal transition (EMT), and collagen turnover. In the PCLS model, seralutinib significantly reversed fibrotic patterns, downregulating 262 genes associated with ECM, EMT and epithelial repair pathways. This gene signature is significantly elevated across many IPF cell populations including fibroblasts, AT2, secretory cells and macrophages. <bold>Conclusions.</bold> Seralutinib downregulated pathways elevated in IPF disease-relevant cell populations, suggesting a broad, multi-cellular impact on fibrosis, thus supporting the development of seralutinib as a novel inhaled therapy for fibrotic lung diseases.