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As OV progresses, tumor cells spread outside the ovaries to the peritoneal and abdominal cavities, forming cell clusters that float in the ascitic fluid caused by peritonitis carcinomatosa, leading to further dissemination and metastasis. These cell clusters are enriched with cancer stem cells (CSCs) which are responsible for treatment resistance, recurrence, and metastasis. Therefore, targeting CSCs is a potentially effective approach for treating OV. However, understanding how CSCs acquire treatment resistance and identifying targets against CSCs remains challenging. In this study, we demonstrate that 3D-spheroids of OV cell lines exhibit higher stemness than conventional adherent cells. Metabolomics profiling studies have revealed that 3D-spheroids maintain a high-energy state through increased glucose utilization in the citric acid cycle (TCA), efficient nucleotide phosphorylation, and elevated phosphocreatine as an energy buffer. We also found that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD\n                    <jats:sup>+<\/jats:sup>\n                    production, is highly expressed in OV. Furthermore, the approach based on NAMPT dependence rather than histology found NAMPT to be a potential therapeutic target against CSCs, while also serving as a prognostic indicator in OV. Moreover, we identified a previously unrecognized anti-tumor mechanism whereby disulfiram, an aldehyde dehydrogenase (ALDH) inhibitor, synergistically inhibited mitochondrial function when combined with NAMPT inhibitors - leading to cell cycle arrest in G2\/M. Finally, the combination of a NAMPT inhibitor and disulfiram showed significant anti-tumor effects and extended survival in an animal model. Our findings demonstrate the potential of spheroids as a preclinical model for targeting OV CSCs and also indicate that the combination of NAMPT inhibitors and disulfiram is a promising therapeutic strategy to overcome recurrent OV.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-07672-3","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T13:22:35Z","timestamp":1745587355000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting metabolic vulnerability by combining NAMPT inhibitors and disulfiram for treatment of recurrent ovarian cancer"],"prefix":"10.1038","volume":"16","author":[{"given":"Kei","family":"Kudo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimi Endo","family":"Greer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Crooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Brender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruhiko","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittney S.","family":"Harrington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Kamdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya","family":"Korrapati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Shibuya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Henegar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Kopp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3747-2688","authenticated-orcid":false,"given":"Takeo","family":"Fujii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6103-2255","authenticated-orcid":false,"given":"Stanley","family":"Lipkowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Annunziata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"7672_CR1","doi-asserted-by":"publisher","first-page":"284","DOI":"10.3322\/caac.21456","volume":"68","author":"LA Torre","year":"2018","unstructured":"Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. 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Trends Analyt Chem. 2020;123:115676.","DOI":"10.1016\/j.trac.2019.115676"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07672-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07672-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07672-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T15:03:11Z","timestamp":1745593391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07672-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,25]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7672"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-07672-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-4150814\/v1","asserted-by":"object"}]},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,25]]},"assertion":[{"value":"22 March 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"LH is an employee of Karyopharm Therapeutics. The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All aspects of this study were approved by the NCI Animal Care and Use Committee (IACUC number MOB-025). All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"342"}}