Abstract
Prurigo nodularis (PN) is a chronic, neuroimmune-driven skin disease characterized by intensely pruritic nodules and marked impairment in QOL. Although PN shares inflammatory features with atopic dermatitis and psoriasis, its underlying pathogenesis remains poorly defined. In this study, we performed NanoString-based transcriptomic profiling on lesional skin biopsies from patients with PN (n = 26), those with atopic dermatitis (n = 25), those with psoriasis (n = 15), and healthy controls (n = 12) using a custom neuroinflammation-focused panel. PN demonstrated a unique molecular signature involving neuroimmune activation (TMEM119, S100A10), extracellular matrix remodeling (matrix metalloproteinase 14 gene MMP14, COL6A3), and fibrotic signaling (TGFBR1, ITGB5), with IL-6 and MAPK12 as key inflammatory mediators. Compared with atopic dermatitis, PN displayed reduced T helper 2 signaling but greater neuroinflammatory and fibrotic activity. Relative to psoriasis, PN lacked T helper 17-driven hyperproliferation but showed macrophage and extracellular matrix activation. STRING network analysis also revealed IL-6 and TGF-β signaling as central hubs linking neuroinflammation and fibrosis. These findings establish PN as a distinct inflammatory skin disease at the intersection of neuroimmune dysregulation and tissue remodeling. Our results highlight key pathways that may guide precision therapies beyond current T helper 2-targeted treatments, supporting the development of IL-6, TGF-β, and Jak/signal transducer and activator of transcription-directed strategies in PN. This transcriptomic analysis establishes a framework to guide mechanistic and therapeutic investigations in PN.