Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation

Abstract Psoriasis is a common, chronic, and recurrent inflammatory disease. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes. Keratinocyte death is also involved in many pathophysiological conditions and amplifies the inflammatory cascade. As a newly recognized form of cell death, ferroptosis is involved in several inflammatory diseases. In this study, we aimed to investigate a previously unrecognized role for ferroptosis in psoriasis. Ferroptosis is mediated by lipid peroxidation and iron overload. Compared with normal lesions, the mRNA expression of acyl-CoA synthetase long-chain family member 4 ( ACSL4 ), prostaglandin-endoperoxide synthase 2 ( PTGS2 ), and transferrin receptor ( TFRC ) were highly expressed in psoriatic lesions, with decreased levels of glutathione peroxidase 4 ( GPX4 ), ferritin light chain ( FTL ), and ferritin heavy chain 1 ( FTH1 ). The protein levels of ACSL4 and GPX4 were consistent with their mRNA levels. A similar tendency of ferroptosis was also observed in erastin-treated human primary keratinocytes and the Imiquimod (IMQ)-induced model of psoriasis. To investigate the correlation between inflammation and peroxidation, we analyzed single-cell RNA-sequencing data and identified 15 cell types. There was a high correlation between the activity of the lipid oxidation and the Th22/Th17 response in keratinocytes at a single-cell level. Moreover, ferrostatin-1 (Fer-1), a potent inhibitor of lipid peroxidation, suppressed ferroptosis-related changes in erastin-treated keratinocytes and alleviated psoriasiform dermatitis of IMQ-induced models. Additionally, Fer-1 blocked inflammatory responses in vitro and in vivo, reducing the production of cytokines including TNF-α , IL-6 , IL-1α , IL-1β , IL-17 , IL-22 , and IL-23 . This study revealed an expression pattern of ferroptosis in which specific molecules enhance inflammatory reactions in psoriasis.