Multiomic profiling reveals early disease mechanisms of lung fibrosis progression

Fibrotic interstitial lung diseases (fILDs) exhibit heterogeneous trajectories, ranging from stable fibrosis to rapidly progressive scarring. The molecular mechanisms underlying these divergent outcomes remain poorly defined, as most mechanistic insights derive from end-stage tissue. We performed integrated single-cell multiomic profiling of early-stage diagnostic lung biopsies from patients with fILD (n=43) and controls (n=12), combining single-cell RNA sequencing (scRNA-seq) and spatial proteomic imaging (4i; 36 markers) to elucidate the cellular programs and spatial niches underlying stable vs progressive disease. scRNA-seq of over 152,000 cells identified 45 distinct cell populations exhibiting marked differences in transcriptional, compositional, and intercellular communication between stable and progressive courses. Stable trajectories were enriched in multicellular immune-regulatory programs, whereas progressive disease was characterized by enrichment of fibrogenic circuits involving CTHRC1⁺ myofibroblasts, KRT17⁺/KRT5⁻ basaloid epithelial cells, SPP1⁺ macrophages, and PLVAP⁺/VWA1⁺ systemic venous endothelial cells (ECs). Spatial 4i analysis revealed that these fibrogenic cell types co-localize within an expanded perivascular niche enriched for PLVAP⁺/VWA1⁺ ECs in regions of active fibrosis, implicating endothelial-driven remodelling as a central amplifier of fibrotic progression. In conclusion, integrated single-cell and spatial multiomics identify a coordinated fibro–vascular niche emerging early in progressive fILD and highlight PLVAP⁺/VWA1⁺ ECs as potential mediators and therapeutic targets of fibrosis progression.