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Inhibition of salt-inducible kinases 2 and 3 reduces inflammatory signature in psoriasis.
J. Invest. Dermatol., DOI: 10.1016/j.jid.2026.07.033 (2026)
Psoriasis is a highly prevalent inflammatory skin disease for which good systemic therapeutic agents are available. However, there is still a great need for new treatment options, especially oral ones. Salt-inducible kinases (SIKs) are emerging as new druggable targets in immune diseases, and the SIK2/SIK3 inhibitor GLPG3970 recently proved to efficiently reduce psoriasis lesions in a phase Ib trial. This study assesses the molecular events underlying the beneficial effects of SIK2/SIK3 inhibition through GLPG3970 in psoriasis. Using spatial transcriptomics and single-cell sequencing, abundant expression of SIK2 and SIK3 but not of SIK1 was observed in psoriatic skin. In vitro, GLPG3970 reduced psoriasis marker cytokines and chemokines (TNF, IFNγ, IL-1β, IL-6, CXCL8, CXCL10) in peripheral mononuclear cells, T cells, and fibroblasts but not in keratinocytes. Bulk RNA sequencing of lesional psoriasis biopsies treated ex vivo with GLPG3970 and of biopsies received from responders versus placebo-treated patients from the clinical trial showed downregulation of inflammatory pathways with suppression of IL1B , CXCL1 , CXCL8 , CEBPB , CD177 , and CLEC5A in both settings. In summary, this study suggests that specific inhibition of SIK2/SIK3 reduces acute-phase immunity and neutrophil recruitment in psoriasis.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Acute Inflammation ; Dendritic Cells ; Macrophages ; Monocytes ; Neutrophils
ISSN (print) / ISBN
0022-202X
e-ISSN
1523-1747
Publisher
Elsevier
Publishing Place
New York, NY
Reviewing status
Peer reviewed