Integrated RNA-Seq Profiling Identifies NRXN1+ Cell-Fibroblast Associated MAPK Signaling in Prurigo Nodularis

Abstract

Purpose Prurigo nodularis (PN) is chronic pruritic dermatosis with hyperkeratotic nodules and persistent itch, occurring alone or with atopic dermatitis (AD). The molecular basis of nodular architecture and sustained pruritus remain poorly defined, particularly the role of fibroblasts and their interactions with neuronal components. This study aimed to identify PN-specific pathogenic profiles by comparing lesional transcriptomes from AD, atopic prurigo (AP), and PN. Methods Bulk RNA sequencing was performed on lesional skin from AD (n = 6), AP (n = 7), PN (n = 7), and healthy controls (HC; n = 4). Publicly available single-cell RNA-sequencing datasets were reanalyzed for cell-type signatures. Integrated analyses included differentially expressed genes, pathway enrichment, cell-type deconvolution, ligand–receptor inference, and immune cell profiling. Results PN lesions showed MAPK/ERK pathway enrichment in fibroblasts compared with AD and AP. NRXN1+ cells were inferred as major interacting partners of fibroblasts, with ligand–receptor interactions consistent with enhanced fibroblast MAPK/ERK activity. Immune pathway analyses showed weaker Th2 pathway activity in PN compared with AD/AP, providing context for neuronal-stromal interactions as a putative distinguishing feature. Conclusions PN shows enhanced MAPK/ERK pathway enrichment in fibroblasts and inferred NRXN1+ cell-fibroblast interactions. This candidate axis may contribute to nodular lesion architecture and persistent pruritus, suggesting potential therapeutic strategies.