The Vitamin D Receptor– AADAC Signaling Axis Mediates Epidermal Inflammation and Dermal Fibrosis in Prurigo Nodularis via Regulation of Endoplasmic Reticulum Stress

ABSTRACT Prurigo nodularis (PN) is a chronic inflammatory skin disease, but the role of vitamin D receptor (VDR) in its pathogenesis remains unclear. VDR expression in clinical PN skin samples was assessed by qRT‐PCR, Western blot, IHC, and IF staining. RNA sequencing combined with GO, KEGG, and PPI analyses was used to identify arylacetamide deacetylase (AADAC) as a VDR‐associated candidate molecule. The mechanistic role of VDR‐associated AADAC regulation was then investigated using an H 2 O 2 ‐induced oxidative stress model in HaCaT cells, vitamin D (VD) intervention, VDR knockdown, and a Transwell‐based indirect HaCaT–fibroblast co‐culture system. VDR and AADAC were significantly downregulated in PN lesions, accompanied by increased fibrosis‐related proteins. Transcriptomic analysis identified AADAC as a VDR‐associated candidate. In vitro, H 2 O 2 activated the endoplasmic reticulum stress (ERS) pathway, increased inflammatory cytokines, and suppressed VDR/AADAC expression. VD restored AADAC expression, attenuated ERS and inflammation, and inhibited the profibrotic paracrine effect of stressed HaCaT cells on fibroblasts. These protective effects were abolished after VDR knockdown, and VD intervention failed to restore AADAC expression. VDR‐AADAC signaling deficiency promotes PN‐related inflammation and fibrosis through ERS activation and paracrine fibroblast activation, suggesting this axis as a potential therapeutic target.