Subtype-Resolved Secretome and Surface-Marker Remapping of Lung Fibroblasts in Idiopathic Pulmonary Fibrosis

Single-cell atlases have resolved the fibroblast compartment of idiopathic pulmonary fibrosis (IPF) into discrete subtypes [1], but subtype-resolved secretory output and surface-marker logic for prospective isolation remain incompletely defined. We re-analyzed the Habermann et al. single-cell atlas of fibrotic lung (GSE135893; 114,396 cells, including 3,605 fibroblast-lineage cells, of which 2,653 IPF/control cells entered the main contrasts) [1], quantifying detection rates and mean expression of 72 secreted genes and 16 candidate surface markers across four curated subtypes, validated by full-transcriptome re-clustering. Inflammatory chemokine production was concentrated in HAS1-high fibroblasts (CXCL2 in 70.4% of cells, CXCL8 in 46.9%), whereas PLIN2+ fibroblasts carried an angiogenic bias (VEGFA 65.6%). CSF1 was silenced upon myofibroblast differentiation irrespective of diagnosis (fibroblasts 34.2–48.6% versus myofibroblasts 8.7–14.8%), a differentiation-linked rather than disease-specific switch, and the interferon-γ–inducible chemokines CXCL9, CXCL10 and CXCL11 were detected in only 0.0–2.6% of cells across subtypes (maximum 2.6% = CXCL9, 5/196 control myofibroblasts). A CD34-low/PDPN-high/CD73-high/FAP+ panel resolved all four subtypes at the marginal transcript level (pending joint, antibody-level validation), whereas CD90 lost discriminatory value in disease. CD10 (MME) marked a control-enriched, putatively resolving myofibroblast state that contracted from 23.0% to 5.4% in IPF; its interleukin-4 induction was tested across cohorts and remains unresolved. Key findings replicated in two independent cohorts (GSE136831; GSE122960) and were spatially corroborated by GeoMx profiling (GSE255174), while CSF1 and compartment-level chemokine effects varied across cohorts. Fibroblast subsets thus carry distinct, isolable secretory identities in IPF, providing a transcriptome-resolved resource for protein-level and spatial validation of fibroblast functions in fibrotic lung.