{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:56:08Z","timestamp":1790258168565,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"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-2025-00516653"],"award-info":[{"award-number":["RS-2025-00516653"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Resistance to 5-fluorouracil (5-FU), a cornerstone chemotherapy for gastric cancer (GC), is a major clinical obstacle, often driven by the upregulation of its target enzyme, thymidylate synthase (TS). In this study, we investigated the potential of the pan-histone deacetylase inhibitor (HDACi) panobinostat to synergize with 5-FU. In GC cell lines, panobinostat treatment alone suppressed cell viability, clonogenicity, and migration, and this was associated with the induction of G1-phase cell cycle arrest and mitochondria-mediated apoptosis. Crucially, Panobinostat acted synergistically with 5-FU, leading to enhanced cytotoxicity. Mechanistically, 5-FU treatment alone induced a compensatory upregulation of TS protein, a known resistance mechanism. Panobinostat not only suppressed basal TS expression but, more importantly, abrogated this 5-FU-induced upregulation. Furthermore, panobinostat downregulated a network of oncogenes and cell cycle regulators, including c-Myc and key cyclins. These findings indicate that panobinostat can enhance 5-FU cytotoxicity by targeting TS expression and reprogramming oncogenic transcriptional networks, supporting its potential as a complementary strategy for overcoming fluoropyrimidine resistance in GC therapy.<\/jats:p>","DOI":"10.3390\/ijms27031516","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T16:46:28Z","timestamp":1770137188000},"page":"1516","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Panobinostat Potentiates the Antitumor Efficacy of 5-Fluorouracil in Gastric Cancer by Suppressing Thymidylate Synthase Expression"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3022-8735","authenticated-orcid":false,"given":"Sooyeon","family":"Park","sequence":"first","affiliation":[{"name":"Department of Science Education, Ewha Womans University, Seoul 03760, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Science Education, Ewha Womans University, Seoul 03760, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5326-9124","authenticated-orcid":false,"given":"Changwon","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Science Education, Ewha Womans University, Seoul 03760, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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