Reprogramming of fatty acid metabolism via PPARα-orchestrated FADS2 in keratinocytes modulates skin inflammation in psoriasis

Summary: Abstract Body: Psoriasis is a chronic inflammatory skin disease characterized by excessive keratinocyte proliferation and disrupted immune homeostasis. The precise relationship between metabolic disturbances and inflammatory responses in psoriasis remains poorly understood. This study investigates the role of FADS2- the first and rate-limiting enzyme in PUFA biosynthesis in psoriasis and explored its underlying mechanisms. Our study revealed a marked decrease in FADS2 expression in the keratinocytes of the skin lesions from psoriasis patients and imiquimod (IMQ)-induced psoriasis mouse model. Silencing FADS2 by topical application of small interfering RNA (siRNA) in mice exacerbated IMQ-induced psoriasis-like dermatitis, accompanied by increasing the expression of neutrophil chemotaxis-related genes and neutrophil infiltration in skin lesions. In cultured human keratinocytes, silencing FADS2 elevated the expression of multiple chemokines and antimicrobial peptides. Mechanically, FADS2 suppression disrupted PUFA metabolism with an inhibition of docosahexaenoic acid (DHA) biosynthesis, thereby amplifying inflammation through the NF-κB pathway. Furthermore, we found that FADS2 expression in keratinocytes was regulated by peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor involved in lipid metabolism. A reduction in the PPARα-FADS2 axis was also observed in the lesional skin of both psoriasis patients and IMQ-induced psoriasis mouse model. Enhancing FADS2 expression through PPARα activation using its agonist, WY14643, significantly alleviated psoriatic inflammation in IMQ-induced psoriasis mouse model, and inhibited pro-inflammatory mediator production in cultured human keratinocytes. These findings identify the PPARα-FADS2 axis as a key regulatory pathway in fatty acid metabolism and inflammatory responses in psoriasis. Therefore, targeting the PPARα-FADS2 axis presents a promising therapeutic approach for psoriasis management by restoring PUFA homeostasis and reducing keratinocyte-driven inflammation. Jiangluyi Cai¹, Chunyuan Guo¹, Yuling Shi¹ 1. Shanghai Skin Diseases Hospital, Shanghai, Shanghai, China. Translational Studies: Cell and Molecular Biology