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In most EBV\u2010associated cancers, the viral genome is maintained as an extrachromosomal episome by the EBV nuclear antigen\u20101 (EBNA1). EBNA1 is considered to be a highly stable protein that interacts with the ubiquitin\u2010specific protease 7 (USP7). Here, we show that pharmacological inhibitors and small interfering RNA (siRNA) targeting USP7 reduce EBNA1 protein levels in a proteosome\u2010dependent manner. Proteomic analysis revealed that USP7 inhibitor GNE6776 altered the EBNA1 protein interactome, including disrupting USP7 association with EBNA1. GNE6776 also inhibited EBNA1 binding to EBV <jats:italic>oriP<\/jats:italic> DNA and reduced viral episome copy number. Transcriptomic studies revealed that USP7 inhibition affected chromosome segregation and mitotic cell division pathways in EBV<jats:sup>+<\/jats:sup> cells. Finally, we show that GNE6776 selectively inhibited EBV<jats:sup>+<\/jats:sup> gastric and lymphoid cell proliferation in cell culture and slowed EBV<jats:sup>+<\/jats:sup> tumor growth in mouse xenograft models. These findings suggest that USP7 inhibitors perturb EBNA1 stability and function and may be exploited to treat EBV latent infection and tumorigenesis.<\/jats:p>","DOI":"10.1002\/jmv.70168","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T11:32:23Z","timestamp":1737113543000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["USP7 Inhibitors Destabilize EBNA1 and Suppress Epstein\u2010Barr Virus Tumorigenesis"],"prefix":"10.1002","volume":"97","author":[{"given":"Christopher","family":"Chen","sequence":"first","affiliation":[{"name":"The Wistar Institute Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kush","family":"Addepalli","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha S.","family":"Soldan","sequence":"additional","affiliation":[{"name":"The Wistar Institute Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo Josue","family":"Castro\u2010 Munoz","sequence":"additional","affiliation":[{"name":"The Wistar Institute Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Preston\u2010Alp","sequence":"additional","affiliation":[{"name":"The Wistar Institute Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rishi J.","family":"Patel","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coltin J.","family":"Albitz","sequence":"additional","affiliation":[{"name":"The Wistar Institute Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin\u2010Yao","family":"Tang","sequence":"additional","affiliation":[{"name":"The Wistar Institute Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7893-2914","authenticated-orcid":false,"given":"Italo","family":"Tempera","sequence":"additional","affiliation":[{"name":"The Wistar Institute Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3935-9921","authenticated-orcid":false,"given":"Paul M.","family":"Lieberman","sequence":"additional","affiliation":[{"name":"The Wistar Institute Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.92"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2022.101260"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-021-03824-y"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00713"},{"issue":"1","key":"e_1_2_8_6_1","first-page":"151","article-title":"EBV Persistence\u2010\u2010Introducing the Virus","volume":"390","author":"Thorley\u2010Lawson D. 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