{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:31:53Z","timestamp":1760059913206,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ingrid Asp Foundation"},{"name":"the Welander Foundation"},{"name":"the Swedish Psoriasis Association"},{"name":"ALF Grants, Region \u00d6sterg\u00f6tland"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u03b3\u03b4-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.<\/jats:p>","DOI":"10.3390\/ijms26157174","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T08:13:31Z","timestamp":1753431211000},"page":"7174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Topical MTH1 Inhibition Suppresses SKP2-WNT5a-Driven Psoriatic Hyperproliferation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2769-0016","authenticated-orcid":false,"given":"Cecilia","family":"Bivik Eding","sequence":"first","affiliation":[{"name":"Ingrid Asp Psoriasis Research Center, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9260-8528","authenticated-orcid":false,"given":"Ines","family":"K\u00f6hler","sequence":"additional","affiliation":[{"name":"Ingrid Asp Psoriasis Research Center, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6030-3084","authenticated-orcid":false,"given":"Lavanya","family":"Moparthi","sequence":"additional","affiliation":[{"name":"Ingrid Asp Psoriasis Research Center, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florence","family":"Sj\u00f6gren","sequence":"additional","affiliation":[{"name":"Ingrid Asp Psoriasis Research Center, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9562-0872","authenticated-orcid":false,"given":"Blanka","family":"Andersson","sequence":"additional","affiliation":[{"name":"Ingrid Asp Psoriasis Research Center, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6811-3333","authenticated-orcid":false,"given":"Debojyoti","family":"Das","sequence":"additional","affiliation":[{"name":"Ingrid Asp Psoriasis Research Center, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"},{"name":"Clinical Genomics Link\u00f6ping, SciLife Laboratory, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepti","family":"Verma","sequence":"additional","affiliation":[{"name":"Ingrid Asp Psoriasis Research Center, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Scobie","sequence":"additional","affiliation":[{"name":"Oxcia AB, 113 34 Stockholm, Sweden"},{"name":"Department of Oncology and Pathology, Karolinska Institute, 171 77 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrika","family":"Warpman Berglund","sequence":"additional","affiliation":[{"name":"Oxcia AB, 113 34 Stockholm, Sweden"},{"name":"Department of Oncology and Pathology, Karolinska Institute, 171 77 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1769-3790","authenticated-orcid":false,"given":"Charlotta","family":"Enerb\u00e4ck","sequence":"additional","affiliation":[{"name":"Ingrid Asp Psoriasis Research Center, Department of Biomedical and Clinical Sciences, Link\u00f6ping University, 581 85 Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1146\/annurev-biochem-061516-045037","article-title":"Oxidative Stress","volume":"86","author":"Sies","year":"2017","journal-title":"Annu. 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