Keratinocyte TMEM79 protects early life epidermal homeostasis and restrains STING-dependent skin inflammation

Abstract Chronic inflammatory skin diseases are characterized by epithelial barrier dysfunction and immune dysregulation, yet the epithelial-intrinsic mechanisms that initiate inflammation remain poorly understood. TMEM79 is a dermatitis-associated transmembrane protein expressed in keratinocytes, but how its loss promotes skin disease remains unclear. Here, using keratinocyte-specific Tmem79 conditional knockout (cKO) mice and TMEM79-deficient human keratinocytes, we find that TMEM79 is required for proper epithelial differentiation and barrier formation, and that its loss induces keratinocyte stress and ferroptosis-associated lipid peroxidation. Longitudinal analysis of neonatal and early postnatal Tmem79-deficient skin revealed disrupted epidermal homeostasis and early type I IFN signaling preceding the later emergence of type 17 inflammation. Mechanistically, genetic ablation of Sting1, but not Mavs, ameliorated dermatitis and downstream type 17 inflammation, while IL-17A was required for subsequent epidermal hyperplasia. These findings establish STING-dependent signaling as an upstream driver of skin immune activation and pathology. Together, our findings link early-life epithelial stress to innate immune activation and suggest that targeting lipid peroxidation or STING signaling may help prevent inflammatory skin disease progression.