{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:01:57Z","timestamp":1789635717521,"version":"4.0.0"},"reference-count":32,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2022-NR067525"],"award-info":[{"award-number":["RS-2022-NR067525"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2026-25487615"],"award-info":[{"award-number":["RS-2026-25487615"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2022-NR067525"],"award-info":[{"award-number":["RS-2022-NR067525"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2026-25487615"],"award-info":[{"award-number":["RS-2026-25487615"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2120240615414"],"award-info":[{"award-number":["2120240615414"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Daegu ANCHOR Center","award":["2026-ANCHOR-03-001"],"award-info":[{"award-number":["2026-ANCHOR-03-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Lung cancer recurrence and therapeutic resistance are driven by cancer stem cells (CSCs), yet clinically available CSC-targeted therapies remain lacking. To identify actionable anti-CSC agents, we screened 1018 FDA-approved drugs using a 3D sphere culture system enriching lung CSC-like cells. Trimebutine, a gastrointestinal motility regulator targeting G-protein-coupled receptors (GPCRs), was identified as a potent agent with over 49.5-fold higher selectivity toward lung CSC-like cells (SI &gt; 49.55) compared with standard therapies such as cisplatin (SI = 1.39) and gefitinib (SI = 1.00). In H460-SP spheres, trimebutine markedly impaired sphere-forming capacity, reduced cell viability, and downregulated key CSC surface markers (CD133, CD44) alongside stemness regulators (c-MYC, EpCAM, BMI1, OCT3\/4, NANOG, SOX2, SMAD3). Mechanistically, trimebutine suppressed overexpressed calcium and potassium channels (CACNA1F, CACNA1B, CACNA1E, CACNA1H, KCNH2), attenuating downstream YAP\/TAZ\u2013TEAD signaling within the Hippo pathway to trigger apoptosis. In combination with cisplatin, trimebutine exhibited strong synergistic efficacy (Chou\u2013Talalay combination index, CI = 0.015\u20130.228) in H460-SP spheres and patient-derived lung tumor organoids, suppressing cell viability, stemness marker suppression, and apoptotic cleavage of caspase-3 and PARP compared to monotherapies. Overall, trimebutine targets lung CSC populations by disrupting GPCR\u2013ion channel\u2013Hippo signaling crosstalk, providing a strong preclinical rationale for trimebutine\u2013cisplatin combination strategies to overcome drug resistance and recurrence in lung cancer.<\/jats:p>","DOI":"10.3390\/ijms27188211","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:33:42Z","timestamp":1789479222000},"page":"8211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Lung Cancer Stem Cells with Trimebutine: Synergistic Antitumor Activity in Combination with Cisplatin"],"prefix":"10.3390","volume":"27","author":[{"given":"JiHye","family":"Seo","sequence":"first","affiliation":[{"name":"School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"Daegu ANCHOR Center, Kyungpook National 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Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Young-Kyu","family":"Kim","sequence":"additional","affiliation":[{"name":"New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Somin","family":"Woo","sequence":"additional","affiliation":[{"name":"Daegu ANCHOR Center, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"Graduate School of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"BK21 Infectious Disease Healthcare Program, Kyungpook National University, Daegu 41566, Republic of 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