Inhibition of SIK1 Alleviates the Pathologies of Psoriasis by Disrupting IL-17 Signaling

Psoriasis is a chronic inflammatory skin disorder involving multiple immune cell types, including T cells, macrophages, and dendritic cells, and is characterized by complex pathology and limited treatment options. In this study, we observed that salt-inducible kinase 1 (SIK1) was significantly upregulated in an imiquimod (IMQ)-induced mouse model of psoriasis. This upregulation appears to be driven by elevated levels of interleukin-17 (IL-17), which enhances SIK1 expression in keratinocytes. Pharmacological inhibition of SIK1 using small-molecule inhibitors (HG-9-91-01 or YKL-06-062) markedly ameliorated IMQ-induced psoriatic symptoms, as evidenced by reduced epidermal thickening, inflammation, and keratinocyte hyperproliferation.
Further analysis revealed that SIK1 inhibition suppressed the IL-17-induced expression of key proinflammatory cytokines and chemokines, including Il6, Kc, and Ccl20. Mechanistically, treatment with SIK1 inhibitors reduced phosphorylation of IκBα and p38 MAPK—key components of the NF-κB and MAPK signaling pathways. Conversely, overexpression of SIK1 in keratinocytes promoted activation of these signaling cascades.
Collectively, these findings indicate that SIK1 amplifies IL-17-driven signaling by enhancing NF-κB and MAPK pathway activation, thereby contributing to psoriasis-like skin inflammation. Targeting SIK1 may therefore represent a promising therapeutic strategy for the treatment of psoriasis.