SPT6 maintains epidermal homeostasis by inhibiting an NF-κB- positive feedback loop to prevent excessive inflammation

However, whether and how epidermal stem and progenitor cells (EPSCs) actively suppress proinflammatory signaling pathways to prevent excessive inflammation and maintain epidermal immune quiescence remains unclear. Here, we generated a conditional knockout mouse model (K14-CreERT; Supt6fl/fl) to investigate the role of SPT6, a transcription elongation factor, in epidermal and immune homeostasis.

Loss of SPT6 in basal keratinocytes led to spontaneous, psoriasis-like skin inflammation, characterized by epidermal hyperplasia, immune cell infiltration, parakeratosis, and hyperkeratosis. SPT6-deficient mice also exhibited significantly delayed wound healing accompanied by impaired Wnt signaling. Moreover, single- cell RNA sequencing revealed distinct keratinocyte subpopulations with inflammatory signatures, elevated NF-κB signaling, and suppressed Wnt signaling.