Eczema-like Granular Parakeratosis Exhibits Inflammatory Keratinocyte Remodeling and Aberrant Epidermal Differentiation.

Granular parakeratosis (GP) is an uncommon keratinization disorder that predominantly affects intertriginous areas and may clinically mimic atopic dermatitis or psoriasis. Histologically, GP is characterized by compact hyperkeratosis, parakeratosis, and retention of keratohyalin granules within the stratum corneum, although its histopathological spectrum is heterogeneous. Previous studies have consisted mainly of case reports, while mechanistic investigations remain limited, and whether GP represents a purely cornification-related abnormality is unclear. During and after the coronavirus disease 2019 (COVID-19) pandemic, increased use of benzalkonium chloride (BAC)-containing laundry disinfectants coincided with more patients presenting with recurrent erythema and scaling that responded poorly to conventional treatment, prompting renewed attention to this disease. We performed single-cell RNA sequencing of lesional skin from three patients with GP and matched skin samples from three healthy controls, followed by keratinocyte subclustering, pseudotime analysis, and cell-cell communication analysis. Key findings were further validated by immunofluorescence in an independent cohort of four patients with GP and three healthy controls. HaCaT cells were exposed to BAC and analyzed by the Cell Counting Kit-8 (CCK-8) assay and bulk RNA sequencing. Single-cell analysis revealed the expansion of inflammatory keratinocytes in GP lesions. Pathway enrichment showed the activation of innate immune and antimicrobial responses and dysregulation of keratinocyte differentiation. S100A8/S100A9 were increased in GP keratinocytes and validated at the protein level. BAC induced interleukin-1 (IL-1)-related inflammatory activation and cellular stress responses, suggesting that GP is an exposure-associated inflammatory epidermal differentiation disorder.