1567 Single-cell RNA sequencing reveals unique fibroblast subclusters in prurigo nodularis

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory disease that disproportionately affects black patients. However, the pathogenesis poorly understood. We performed single-cell transcriptomic profiling of 28,695 lesional and non-lesional PN skin cells to uncover cell compositions genetic profiles. defined seven subclusters fibroblasts (FBs) in observed a shift FBs towards cancer-associated fibroblast (CAF) phenotypes. Specifically, we found increased WNT5A+ (colocalization coefficient: 0.18 vs 0.023, p<0.05) myofibroblasts (percent total: 3.7 0.39, p<0.01) patients, similar results squamous carcinoma (SCC). A multi-center cohort study subsequently revealed risk SCC (HR 1.67, CI 1.55-1.79) CAF-associated malignancies including breast colorectal cancers (p<0.0001). Systemic fibroproliferative diseases were also upregulated renal sclerosis 5.0, 3.7-6.88) idiopathic pulmonary fibrosis (p<0.001). Ligand receptor analyses demonstrated FB1-derived WNT5A periostin interactions with neuronal receptors MCAM ITGAV, suggesting fibroblast-neuronal axis. Type I IFN responses immune angiogenesis endothelial (p<0.05). As compared atopic dermatitis psoriasis mesenchymal dysregulation unique PN, intermediate resident memory Th2/Th17 phenotype between psoriasis. These findings identify pathogenic role for cancer-like novel targetable subpopulation