SCD1 regulates monounsaturated fatty acid metabolism and contributes to abnormal epidermal differentiation in psoriasis

A BALB/c mouse model of psoriasis was induced with imiquimod (IMQ). Transcriptomic (RNA-seq) and lipidomic analyses revealed alterations in the key lipid metabolism enzyme SCD1. In HaCaT keratinocytes, gene knockdown, pharmacological inhibition (MF-438), and overexpression, combined with a high-calcium differentiation model, were used to assess SCD1’s role in proliferation and differentiation.

Exogenous fatty acid supplementation and topical application in mice confirmed the effects of MUFAs. Results: RNAseq and pathway analyses revealed significant lipid metabolism abnormalities in IMQ-induced psoriatic-like lesions, notably downregulation of SCD1, a key enzyme in unsaturated fatty acid synthesis. Under high-calcium conditions, SCD1 knockdown or inhibition suppressed HaCaT cell differentiation, indicated by decreased differentiation markers (K10, Filaggrin) and increased dedifferentiation markers (K14, P63); conversely, SCD1 overexpression enhanced differentiation.

Lipidomic analysis showed reduced SCD1-catalyzed MUFAs (16:1, 18:1) in IMQ-treated mouse skin, while saturated fatty acid-related phospholipids PC(16:0/16:1) and PC(18:0/18:1) increased. SCD1 knockdown also reduced plasma membrane fluidity. Exogenous oleic acid restored differentiation marker expression and reversed defects caused by SCD1 deficiency in HaCaT cells, whereas stearic acid had no effect.

In vivo, topical oleic acid alleviated IMQ-induced psoriatic-like symptoms in mice, reducing KI67, IL-17A, and p63 expression, while stearic acid worsened these changes. Conclusions: SCD1 promotes normal epidermal keratinocyte differentiation by catalyzing MUFA synthesis. Its downregulation leads to MUFA deficiency, a critical metabolic factor in psoriasis-related abnormal differentiation.

Oleic acid supplementation can partially reverse this, presenting a potential metabolic intervention for psoriasis.