Mast-cell driven dermal white adipose tissue remodeling amplifies inflammation and fibrosis in atopic dermatitis

Atopic dermatitis (AD) is characterized by type-2 inflammation, dermal mast-cell (MC) infiltration and progressive dermal fibrosis, but the stromal drivers remain unclear. Using the MC903-induced AD-like mouse model, we show that dermal white adipose tissue (dWAT) undergoes rapid lipolysis and reactive fibrosis concurrent with MC accumulation and activation within dWAT. Single-cell RNA-seq and adipocyte-lineage tracing revealed that MC903 applications triggered mature adipocytes to lose lipids and acquire a F3 ⁺ C/EBPδ ⁺ inflammatory preadipocyte (inf. pAds) phenotype that secrete MC chemokines, SCF and CXCL12. Neutralization or fibroblast-specific deletion of either chemokine abolished MC recruitment, adipocyte loss and collagen deposition, whereas MC depletion prevented inf. pAd expension, revealing a self-amplifying inflammatory–fibrotic loop between adipocytes and MCs. In vitro, MC-conditioned medium or recombinant IL4/IL13/TGFβ induced adipocyte lipolysis and F3⁺C/EBPδ⁺ pre-adipocyte markers; combined STAT6 and TGFβ inhibition abrogated this reprogramming. scRNAseq and immunostaining analysis of human AD lesional skin identified F3 ⁺ C/EBPδ ⁺ dermal fibroblasts that transcriptionally mirror murine inf. pAds, express SCF/CXCL12, and co-localize with MCs. Human adipocytes respond to IL4/IL13/TG-β by lipolysis and acquisition of fibroblast-like phenotype. This study reveals a previously unrecognized adipocyte-to-fibroblast conversion pathway that fuels mast-cell recruitment and dermal fibrosis in AD, offering a novel mechanistic framework and a therapeutic entry point aimed at blocking adipocyte dedifferentiation or its downstream SCF/CXCL12 signals to simultaneously halt inflammation and fibrotic remodeling.