Inflammatory diseases, including psoriasis, are characterized by changes in redox regulation. The MutT homolog 1 (MTH1) prevents the incorporation of oxidized nucleotides during DNA replication. Using MTH1 small-molecule inhibitors, we found induced apoptosis through 8-oxo-dGTP accumulation and DNA double-strand breaks following oxidative stress in normal and malignant keratinocytes. In psoriasis, we detected increased MTH1 expression in lesional skin and PBMCs compared with controls. Using the Imiquimod (IMQ) psoriasis mouse model, we found that MTH1 inhibition diminished psoriatic histological characteristics and normalized the levels of neutrophils and T cells in skin and skin-draining lymph nodes. The inhibition abolished the expression of Th17-associated cytokines in the skin, which was in line with decreased levels of IL-17-producing γδ T cells in lymph nodes. In human keratinocytes, MTH1 inhibition prevented the upregulation of IL-17 downstream genes, which was independent of ROS-induced apoptosis. In conclusion, our data support MTH1 inhibition using small molecules suitable for topical application, as a promising therapeutic approach to psoriasis.

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.

Psoriasis is an immune-mediated systemic skin disorder with a strong genetic predisposition. The gene expression of the psoriasis susceptibility | POSTER