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

) 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. Mechanistically, SPT6 suppresses NF-κB signaling by binding to an enhancer of the RELA gene and preventing its positive transcriptional feedback loop. These findings support a new paradigm in which the default state of the skin may be primed for inflammation, and active suppression by factors such as SPT6 is required to maintain epidermal homeostasis. Taken together, the results of our study reveal a previously unrecognized role for SPT6 as a key regulator of epidermal immune quiescence and tissue integrity.