Downregulation of RSAD2 ameliorates keratinocyte hyperproliferation and skin inflammation in psoriasis via the TAK1/NF-κB axis

Immune cell infiltration and keratinocyte (KC) hyperproliferation are characteristics of psoriasis. Radical S-adenosyl methionine domain-containing 2 (RSAD2) plays an integral role in the innate immune response and is associated with various immune-related diseases. However, RSAD2's expression and role in modulating immune responses in psoriasis remain unexplored. In this study, we demonstrated a significant upregulation of RSAD2 expression in both psoriatic lesions and psoriasis-like mouse epidermis, with its expression positively correlated with psoriasis severity. In psoriatic cell models, RSAD2 was shown to promote the proliferation and secretion of pro-inflammatory cytokines by activating the transforming growth factor-β-activated kinase 1 (TAK1)-mediated nuclear factor kappa-B (NF-κB) signaling pathway. Additionally, it was found that the expression of RSAD2 is increased by the action of interferon regulatory factor-1 (IRF1), which binds to the promoter region of RSAD2. Therefore, the function of RSAD2 in psoriasis is regulated by IRF1. Notably, RSAD2 inhibition decreased epidermal hyperplasia and alleviated imiquimod (IMQ)-induced psoriatic dermatitis. In summary, our study highlights the modulation of the IRF1-RSAD2-TAK1 axis as a potential innovative therapeutic approach for psoriasis, offering new insights into the molecular mechanisms by which KCs drive inflammation in psoriasis.