Topical febuxostat attenuates imiquimod-induced psoriasiform dermatitis and modulates NFE2L2 (NRF2)/NLRP3 mRNA expression

Abstract

Background : Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by excessive keratinocyte proliferation, persistent oxidative stress, and dysregulated inflammatory responses. Increasing evidence suggests that impaired antioxidant defenses and altered NLRP3-associated inflammatory signaling may contribute to psoriasis pathogenesis. Febuxostat, a selective xanthine oxidase inhibitor, has demonstrated antioxidant and anti-inflammatory effects in experimental models of various diseases; however, its potential as a topical treatment for psoriasis has not been investigated. Objective : The present study evaluated the therapeutic effects of topical febuxostat ointment in an imiquimod-induced mouse model of psoriasiform dermatitis and investigated its effects on oxidative stress biomarkers, inflammatory cytokines, and NFE2L2 (NRF2) and NLRP3 mRNA expression. Methods : Psoriasiform dermatitis was induced in BALB/c mice by daily topical application of 5% imiquimod cream. Animals were randomly assigned to the normal control, imiquimod control, clobetasol, and topical febuxostat treatment groups. Disease severity was evaluated using a modified PASI-like scoring system, clinical skin thickness assessment, and histopathological examination. Oxidative stress biomarkers, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and nitric oxide (NO), were determined. Tissue concentrations of TNF-α, IL-17A, and IL-23 were quantified by ELISA, while NFE2L2 (NRF2) and NLRP3 mRNA expression levels were assessed using quantitative real-time PCR. Results : Topical febuxostat markedly attenuated imiquimod-induced psoriasiform dermatitis, as evidenced by reduced clinical severity and improvement in histopathological abnormalities, including epidermal hyperplasia and inflammatory cell infiltration. Febuxostat treatment significantly reduced MDA, NO, TNF-α, IL-17A, and IL-23 levels, while increasing SOD activity and GSH levels. Furthermore, febuxostat increased NFE2L2 mRNA expression and reduced NLRP3 mRNA expression, particularly at the 2% concentration. These molecular changes were associated with improved oxidative and inflammatory profiles but did not by themselves establish direct activation of the NRF2 pathway or inhibition of the NLRP3 inflammasome. Conclusion : Topical febuxostat demonstrated significant antipsoriatic effects in the imiquimod-induced mouse model, accompanied by improvements in oxidative stress, inflammatory cytokines, and histopathological abnormalities. The associated changes in NFE2L2 and NLRP3 mRNA expression suggest a potential contribution of altered redox- and inflammation-related gene expression to the observed therapeutic effects. However, protein-level and functional studies are required to determine whether these transcriptional changes translate into direct modulation of the NRF2/NLRP3 signaling pathways. These findings support further investigation of topical febuxostat as a potential nonsteroidal candidate for psoriasis.