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.