Journal Article

Topical MTH1 Inhibition Suppresses SKP2-WNT5a-Driven Psoriatic Hyperproliferation

Bivik Eding, Cecilia, Verma, Deepti, Andersson, Blanka, Das, Debojyoti, Enerbäck, Charlotta, Warpman Berglund, Ulrika, Sjögren, Florence, Scobie, Martin, Köhler, Ines, Moparthi, Lavanya

2025

Overview

Topically applied TH1579 alleviated the psoriatic phenotype in the imiquimod-induced psoriasis mouse model by decreasing CD45+, Ly6b+, and CD3+ cell infiltration and downregulating the expression of the proliferation marker PCNA. Moreover, TH1579 strongly suppressed IL-17 expression in mouse skin, accompanied by reduced infiltration of IL-17-producing γδ-T cells. Furthermore, TH1579 decreased keratinocyte viability and proliferation. Mass spectrometry data analysis revealed the enrichment of proteins associated with nucleotide excision repair and cell cycle regulation. The key cell cycle regulatory protein F-box protein S-phase kinase-associated protein 2 (SKP2) was significantly downregulated, along with the psoriasis-associated proliferation marker WNT5a, identified as a SKP2 downstream target. The downregulation of SKP2 and WNT5a was confirmed in MTH1i-treated mouse skin. Our findings support the topical administration of MTH1i TH1579 as a psoriasis treatment. The therapeutic effects depended on the SKP2/WNT5a pathway, which mediates psoriatic hyperproliferation. This study introduces a conceptually innovative topical treatment for psoriasis patients with mild-to-moderate disease who have limited therapeutic options.

• Publisher: MDPI AG,MDPI
• Subject: Administration, Topical / Animals / Antioxidants / Cancer therapies / Cell cycle / Cell Proliferation - drug effects / Cyclin-dependent kinases / Disease Models, Animal / DNA repair / DNA Repair Enzymes - antagonists & inhibitors / DNA Repair Enzymes - metabolism / Gene expression / Humans / Imiquimod / Inflammation / Keratinocytes - drug effects / Keratinocytes - metabolism / Kinases / Lymphocytes / Mass spectrometry / Metabolism / Mice / Phosphoric Monoester Hydrolases - antagonists & inhibitors / Phosphoric Monoester Hydrolases - metabolism / Proteins / Psoriasis / Psoriasis - chemically induced / Psoriasis - drug therapy / Psoriasis - metabolism / Psoriasis - pathology / S-Phase Kinase-Associated Proteins - genetics / S-Phase Kinase-Associated Proteins - metabolism / Scientific imaging / Skin - drug effects / Skin - metabolism / Skin - pathology / Topical medication / Wnt-5a Protein - genetics / Wnt-5a Protein - metabolism