Dermal hypoxia adaptation promotes psoriasis progression by activating HIF2α-NAMPT pathway

Oxygen availability is a fundamental regulator of tissue homeostasis, yet how tissues adapt to hypoxia during disease progression remains poorly understood. Although psoriasis is mostly characterized as an immune-mediated skin disease, the hallmark hypoxia-related features such as epidermal hyperproliferation and pronounced dermal perivascular recruitment indicate hypoxia importance in psoriasis progression. Here, using spatially resolved hypoxia mapping, multi-omics profiling, transgenic mouse models, psoriatic skin organoids, and functional assays, we identify a dermal hypoxic environment in which perivascular fibroblasts robustly upregulate EPAS1 (encoding HIF2α). These EPAS1 ⁺ fibroblasts secrete NAMPT, which activates INSR in vascular endothelial cells that subsequently stimulate epidermal hyperproliferation to drive pathological angiogenesis. Notably, dysregulated blood vessels exhibit impaired retinol transport capacity, compromising keratinocyte differentiation while promoting hypoxic survival. Our findings define an HIF2α–NAMPT signaling axis that spatially segregates hypoxic and metabolic adaptations between dermal and epidermal compartments. This work reframes hypoxia-driven dermal-epidermal crosstalk in psoriasis and provides a conceptual framework for targeting metabolic dysregulation in hypoxia-associated inflammatory diseases.