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Recent evidence has implicated dysregulated polyunsaturated fatty acid (PUFA) metabolism in its pathogenesis. In this study, fatty acid desaturase 2 (FADS2), the rate\u2010limiting \u03946\u2010desaturase 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\u2010intrinsic\n                    <jats:italic>Fads2<\/jats:italic>\n                    knockdown exacerbates imiquimod\u2010induced psoriasis\u2010like dermatitis, which is marked by enhanced neutrophil recruitment and NF\u2010\u03baB activation, whereas\n                    <jats:italic>Fads2<\/jats:italic>\n                    overexpression exerts protective effects and alleviates skin inflammation. In vitro,\n                    <jats:italic>FADS2<\/jats:italic>\n                    knockdown in keratinocytes enhances M5\u2010induced pro\u2010inflammatory cytokine production, whereas\n                    <jats:italic>FADS2<\/jats:italic>\n                    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\u2010\u03baB phosphorylation in keratinocytes to attract neutrophils. Furthermore, PPAR\u03b1 is identified as an upstream transcriptional activator of FADS2, and pharmacological activation of PPAR\u03b1 alleviates psoriatic inflammation in a FADS2\u2010dependent manner. Together, these findings uncover a PPAR\u03b1\u2010FADS2\u2010DHA\u2010NF\u2010\u03baB axis that links lipid metabolism to immune regulation in psoriasis, highlighting a potential therapeutic strategy for restoring cutaneous immune homeostasis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202417049","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T07:00:56Z","timestamp":1756450856000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Reprogramming of Fatty Acid Metabolism via PPAR\u03b1\u2010Orchestrated FADS2 in Keratinocytes Modulates Skin Inflammation in Psoriasis"],"prefix":"10.1002","volume":"12","author":[{"given":"Jiangluyi","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Dermatology, Shanghai Skin Disease Hospital, Institute of Psoriasis Tongji University School of Medicine  Shanghai 200443 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Shanghai Skin Disease Hospital, Institute of Psoriasis Tongji University School of Medicine  Shanghai 200443 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youdong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Shanghai Skin Disease Hospital, Institute of Psoriasis Tongji University School of Medicine  Shanghai 200443 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Shanghai Skin Disease Hospital, Institute of Psoriasis Tongji University School of Medicine  Shanghai 200443 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Shanghai Skin Disease Hospital, Institute of Psoriasis Tongji University School of Medicine  Shanghai 200443 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