Abstract Psoriasis (Ps) is a chronic inflammatory skin disease with systemic manifestations, such as psoriatic arthritis (PsA), cardiovascular and psychiatric complications, and subsequent negative effects on patients’ quality of life. Although biologics targeting specific disease mediators have become a mainstay in Ps treatment, exploration of new disease targets to improve treatment is still needed. Here we show that fatty-acid binding protein 5 (Fabp5) promotes skin inflammation through a therapeutically relevant modulation of the ferroptotic response. In epidermal-specific inducible c-Jun and JunB knockout (DKO*) mice, a preclinical model for Ps with PsA-like manifestations, dermal fat is reduced, serum free fatty acids (FFA) decreased, and β-hydroxybutyric acids (β-OHB) altered. Comparing RNA-seq and proteomic datasets from DKO* mice and Ps patients revealed shared alterations in fatty acid metabolism and ferroptosis signatures. Specifically, increased expression of Fabp5 and decreased expression of glutathione peroxidase 4 (Gpx4), a lipid-modifying enzyme and ferroptosis suppressor, are observed in the epidermis of DKO* mice and Ps patients. Treatment of DKO* mice with the Fabp inhibitor BMS increased Gpx4 expression, reduced lipid peroxidation products and neutrophil infiltration, ameliorated the skin phenotype, and alleviated keratinocyte hyperproliferation without affecting systemic IL-17a signaling and PsA-like manifestations. Importantly, dysregulated epidermal Fabp5 and Gpx4 expression was normalized after anti-IL17a or anti-TNFα antibody administration in DKO* mice, as well as in Ps patients treated with the corresponding Ps biologics. Furthermore, treatment with the ferroptosis inhibitor, liproxstatin-1, suppressed Ps-like skin thickening in DKO* mice, but did not affect the joint phenotype. These results support a functional and disease-relevant link between Fabp5, Gpx4 and ferroptosis in the skin that should be therapeutically exploited.
Mieczkowski et al. (Sat,) studied this question.