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Our group identified ATPase copper transporting beta (ATP7B) as a mediator of CDDP resistance through its role in drug efflux and small extracellular vesicle (sEV) secretion. Herein, we uncovered a novel mechanism by which ATP7B regulates sEV dynamics and the intercellular transmission of CDDP resistance. Using transcriptomic analyses of HNSC datasets, we demonstrate that ATP7B expression correlates with endocytosis- and epithelial-mesenchymal transition (EMT)-related gene sets and with elevated levels of EV-associated proteins. CDDP-resistant HNSC cells exhibited upregulated ATP7B, Rab5\/Rab7, and preferentially secreted HSP90- and EpCAM-rich sEVs. These sEVs were leading to increased ATP7B expression and reduced CDDP sensitivity in recipient cells. A pharmacological inhibition of sEV biogenesis with GW4869 suppressed ATP7B and Atox1 expressions, inhibited late endosome maturation, and significantly enhanced CDDP-induced apoptosis in HNSC cells. In vivo, GW4869 reduced the sEV protein content and ATP7B expression in xenograft tumors. These findings establish that ATP7B is a critical modulator of sEV cargo and resistance propagation. Our results highlight a previously unrecognized ATP7B\u2013sEV axis driving chemoresistance and identify sEV inhibition as a promising strategy to overcome therapeutic failure in HNSC.<\/jats:p>","DOI":"10.1038\/s41417-025-00975-9","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T11:45:04Z","timestamp":1760701504000},"page":"39-54","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["ATPase copper transporting beta contributes to cisplatin resistance as a regulatory factor of extracellular vesicles in head and neck squamous cell carcinoma"],"prefix":"10.1038","volume":"33","author":[{"given":"Tatsuo","family":"Ogawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0199-9907","authenticated-orcid":false,"given":"Kisho","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Ryumon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hotaka","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koki","family":"Umemori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunihiro","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoichi","family":"Obata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6356-0740","authenticated-orcid":false,"given":"Yuki","family":"Kunisada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuo","family":"Okui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuniaki","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Nagatsuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Momen-Heravi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichiro","family":"Ibaragi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"975_CR1","volume":"163","author":"H Hu","year":"2023","unstructured":"Hu H, Li B, Wang J, Tan Y, Xu M, Xu W, et al. 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