DGAT2 reduction and lipid dysregulation drive psoriasis development in keratinocyte-specific SPRY1-deficient mice

Psoriasis is a chronic autoimmune skin disease characterized by abnormal keratinocyte proliferation and immune dysregulation. Altered lipid metabolism has been implicated in its pathogenesis, but the underlying mechanisms remain unclear. In this study, we generated an keratinocyte-specific Sprouty RTK signaling antagonist 1 (SPRY1) knockout (Spry1ΔEpi) mouse model, which exhibits psoriasis-like symptoms. Using both psoriasis patient samples and Spry1ΔEpi mice, we investigated the role of diacylglycerol acyltransferase 2 (DGAT2) in psoriasis. Our results show that DGAT2 expression is reduced, and glycerides metabolism is disrupted in psoriatic lesions in both psoriasis patients and Spry1ΔEpi mice. Lipidomic analysis reveals significant alterations in glycerides, glycerophospholipids, sphingolipids, and fatty acids in Spry1ΔEpi mice. At the cellular level, DGAT2 downregulation and lipid dysregulation enhance Toll-like receptor 3 (TLR3)-mediated inflammatory signaling in keratinocytes. Furthermore, increased DGAT2 secretion from keratinocytes promotes CD8⁺ T cell activation, proliferation and survival, amplifying psoriatic inflammation. These findings highlight the role of DGAT2 and lipid metabolism in the pathogenesis of psoriasis and reveal their interaction with immune responses in psoriasis.