# Topical MTH1 Inhibition Suppresses SKP2-WNT5a-Driven Psoriatic Hyperproliferation

## TL;DR

A new topical treatment for psoriasis was found to reduce skin cell overgrowth by targeting specific proteins linked to the disease.

## Contribution

This study introduces a novel topical MTH1 inhibitor that targets the SKP2/WNT5a pathway to treat psoriasis.

## Key findings

- TH1579 reduced immune cell infiltration and proliferation markers in a psoriasis mouse model.
- TH1579 suppressed IL-17 and γδ-T cell infiltration in mouse skin.
- TH1579 downregulated SKP2 and WNT5a, key proteins involved in psoriatic hyperproliferation.

## Abstract

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.