{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T14:25:13Z","timestamp":1766067913279,"version":"3.40.5"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K07175"],"award-info":[{"award-number":["17K07175"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We aimed to determine the role of dihydroorotate dehydrogenase (DHODH) in pathogenesis of adult T\u2010cell leukemia (ATL) caused by human T\u2010cell leukemia virus type 1 (HTLV\u20101) and the effects of its inhibition on the de novo pyrimidine biosynthesis pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cell proliferation, viability, cycle, and apoptosis were analyzed using WST\u20108 assays, flow cytometry, and Hoechst 33342 staining. To elucidate the molecular mechanisms involved in the anti\u2010ATL effects of DHODH knockdown and inhibition, RT\u2010PCR and immunoblotting were conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HTLV\u20101\u2010infected T\u2010cell lines aberrantly expressed DHODH. Viral infection and the oncoprotein, Tax, enhanced DHODH expression, while knockdown of DHODH decreased HTLV\u20101\u2010infected T\u2010cell growth. In addition, BAY2402234, a DHODH inhibitor, exerted an anti\u2010proliferative effect, which was reversed by uridine supplementation. BAY2402234 induced DNA damage and S phase arrest by downregulating c\u2010Myc, CDK2, and cyclin A and upregulating p53 and cyclin E. It also induced caspase\u2010mediated apoptosis by the upregulation of pro\u2010apoptotic and downregulation of anti\u2010apoptotic proteins. Furthermore, BAY2402234 induced caspase\u2010independent ferroptosis and necroptosis. It decreased phosphorylation of IKK, I\u03baB\u03b1, PTEN, Akt, and its downstream targets, suggesting that inhibition of NF\u2010\u03baB and Akt signaling is involved in its anti\u2010ATL action.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings highlight DHODH as a potential therapeutic target for treating ATL.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ejh.14209","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T09:49:25Z","timestamp":1711964965000},"page":"99-109","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pivotal role of dihydroorotate dehydrogenase as a therapeutic target in adult T\u2010cell leukemia"],"prefix":"10.1111","volume":"113","author":[{"given":"Chie","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Department of Microbiology and Oncology Graduate School of Medicine, University of the Ryukyus  Nishihara Japan"},{"name":"Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies University of the Ryukyus  Nishihara Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3998-6711","authenticated-orcid":false,"given":"Naoki","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Oncology Graduate School of Medicine, University of the Ryukyus  Nishihara 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