Pathogenic Keratinocyte States and Fibroblast Niches Define the Tissue Microenvironment in Severe Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent painful abscesses and tunnels in flexural sites. The mechanisms driving HS pathogenesis, particularly the interactions between epithelial, stromal and immune cell populations, remain incompletely understood. To characterise the cellular and molecular landscape of HS, we analysed lesional skin from severe HS patients using single-cell RNA-sequencing and spatial transcriptomics, with a focus on fibroblast-keratinocyte interactions. We identified a migratory S100+ pathogenic keratinocyte state enriched within HS lesions and observed spatially distinct fibroblast populations associated with different tissue compartments. COL6A5+ papillary fibroblasts showed spatial association with undifferentiated keratinocyte populations and predicted fibroblast-keratinocyte communication networks, whereas APOD+ fibroblasts were associated with immune-rich regions containing activated B cells and plasma cells, consistent with TLO-like immune aggregates. Ligand-receptor inference and spatial analyses predicted extensive fibroblast-keratinocyte and fibroblast-immune interactions within HS lesions. These findings support a model in which severe HS contains distinct epithelial and inflammatory stromal niches that may contribute to disease persistence. More broadly, they provide a framework for understanding how epithelial, stromal and immune compartments interact within HS lesions and may help explain the limited efficacy of therapies targeting individual inflammatory pathways in the treatment of HS.