{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:29:58Z","timestamp":1787509798624,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008308","name":"Integrated Drug Development Venture of City of Hope","doi-asserted-by":"publisher","award":["IDDV-COH33"],"award-info":[{"award-number":["IDDV-COH33"]}],"id":[{"id":"10.13039\/100008308","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense Lung Cancer Research Program","doi-asserted-by":"publisher","award":["W81XWH-22-1-0306"],"award-info":[{"award-number":["W81XWH-22-1-0306"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Cancer Institute of the National Institutes of Health","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ubiquitin-specific protease 22 (USP22) regulates epigenetic gene expression by deubiquitinating histone H2B (H2Bub1) and upregulating oncogenic proteins and pathways, while antagonizing p53-mediated tumor suppression. USP22 is frequently overexpressed in cancers and associated with therapy resistance and poor prognosis yet remains largely untargeted pharmacologically. Here, using a fluorescence-based USP22 deubiquitinase assay to screen the LOPAC\u00ae1280 library, we identified \u03b2-Lapachone, a natural ortho-naphthoquinone with strong anticancer activities, as a potent USP22 inhibitor. \u03b2-Lapachone potently inhibited USP22 enzymatic activity, with a half-maximal inhibitory concentration (IC50) of ~0.75 \u03bcM, and molecular docking revealed its occupation of the catalytic pocket adjacent to the USP22 active-site triad, supporting a potential binding mode. Functionally, \u03b2-Lapachone suppressed proliferation and induced apoptosis in A549 and H1299 RAS-mutant lung adenocarcinoma (LUAD) cells, while USP22 knockout conferred marked resistance, indicating partial USP22 dependence. In patient-derived LUAD models, \u03b2-Lapachone inhibited sphere formation and reduced CD133+ cancer stem cell populations. Notably, it synergized with cisplatin to enhance DNA damage and apoptosis. In vivo, \u03b2-Lapachone significantly suppressed tumor growth in a syngeneic KRAS-mutant\/p53-Null mouse lung cancer model and further potentiated cisplatin-induced antitumor effects. Collectively, these findings identify \u03b2-Lapachone as a potent inhibitor of USP22 and validate USP22 inhibition as a key mechanism underlying its anticancer activity in LUAD cells, both in vitro and in vivo.<\/jats:p>","DOI":"10.3390\/ijms27125561","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:37:42Z","timestamp":1781879862000},"page":"5561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of \u03b2-Lapachone as a Potent USP22 Inhibitor That Suppresses Cancer Stemness and Enhances Chemosensitivity in Lung Adenocarcinoma"],"prefix":"10.3390","volume":"27","author":[{"given":"Yuanyuan","family":"Gao","sequence":"first","affiliation":[{"name":"Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA"},{"name":"School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendong","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kwon","sequence":"additional","affiliation":[{"name":"Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian","family":"Gu","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimin","family":"Li","sequence":"additional","affiliation":[{"name":"Pathology Core of Shared Resources, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-663X","authenticated-orcid":false,"given":"Hongwei Holly","family":"Yin","sequence":"additional","affiliation":[{"name":"Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Kowolik","sequence":"additional","affiliation":[{"name":"Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahima","family":"Raul","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Horne","sequence":"additional","affiliation":[{"name":"Cancer Biology and Molecular Medicine, City of Hope Beckman Research Institute, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan J.","family":"Raz","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/S0092-8674(94)90462-6","article-title":"Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules","volume":"78","author":"Rock","year":"1994","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/(SICI)1097-4644(2000)77:34+<40::AID-JCB9>3.0.CO;2-6","article-title":"The ubiquitin-mediated proteolytic pathway: Mode of action and clinical implications","volume":"34","author":"Ciechanover","year":"2000","journal-title":"J. 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