Reprogramming of Fatty Acid Metabolism via PPARα-Orchestrated FADS2 in Keratinocytes Modulates Skin Inflammation in Psoriasis.

Abstract

Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyper-proliferation and immune dysregulation. Recent evidence has implicated dysregulated polyunsaturated fatty acid (PUFA) metabolism in its pathogenesis. In this study, fatty acid desaturase 2 (FADS2), the rate-limiting Δ6-desaturase in PUFA biosynthesis, is identified as a central regulator of psoriatic inflammation. FADS2 expression is consistently reduced in keratinocytes from patients with psoriasis and in mouse models. Keratinocyte-intrinsic Fads2 knockdown exacerbates imiquimod-induced psoriasis-like dermatitis, which is marked by enhanced neutrophil recruitment and NF-κB activation, whereas Fads2 overexpression exerts protective effects and alleviates skin inflammation. In vitro, FADS2 knockdown in keratinocytes enhances M5-induced pro-inflammatory cytokine production, whereas FADS2 overexpression attenuates these effects. Lipidomic analysis reveals that impaired docosahexaenoic acid (DHA) biosynthesis is a key downstream consequence of FADS2 deficiency. Mechanistically, loss of FADS2 disrupts DHA biosynthesis, thus promoting an inflammatory response accompanied by increased NF-κB phosphorylation in keratinocytes to attract neutrophils. Furthermore, PPARα is identified as an upstream transcriptional activator of FADS2, and pharmacological activation of PPARα alleviates psoriatic inflammation in a FADS2-dependent manner. Together, these findings uncover a PPARα-FADS2-DHA-NF-κB axis that links lipid metabolism to immune regulation in psoriasis, highlighting a potential therapeutic strategy for restoring cutaneous immune homeostasis.