{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T10:04:21Z","timestamp":1784801061253,"version":"3.55.0"},"reference-count":66,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Foundation for Science and Technology","award":["UID\/06304\/2025"],"award-info":[{"award-number":["UID\/06304\/2025"]}]},{"name":"Foundation for Science and Technology","award":["LA\/P\/0050\/2020"],"award-info":[{"award-number":["LA\/P\/0050\/2020"]}]},{"name":"Norte Portugal Regional Operational Programme","award":["NORTE2030-FEDER01786400"],"award-info":[{"award-number":["NORTE2030-FEDER01786400"]}]},{"name":"Norte Portugal Regional Operational Programme","award":["NORTE2030-FEDER-02705300"],"award-info":[{"award-number":["NORTE2030-FEDER-02705300"]}]},{"name":"FCT","award":["2022.11018.BD"],"award-info":[{"award-number":["2022.11018.BD"]}]},{"name":"FCT","award":["2021.02600.CEECIND"],"award-info":[{"award-number":["2021.02600.CEECIND"]}]},{"name":"Portuguese Cancer League\u2014North Branch","award":["LPCC-NRN 2025"],"award-info":[{"award-number":["LPCC-NRN 2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Bladder cancer (BC), particularly muscle-invasive urothelial bladder carcinoma (UBC), remains a clinical challenge due to frequent recurrence, chemoresistance, and limited treatment options. This study investigates the functional and mechanistic insights of 3-hydroxybutyrate (3-OBA), a ketone body with known metabolic and epigenetic roles, in muscle-invasive UBC models. 3-OBA significantly inhibited cell viability, proliferation, migration, and invasion in T24 and HT1376 cell lines in a dose-dependent manner. In vivo, 3-OBA impaired tumor growth and angiogenesis in the chick chorioallantoic membrane model. Mechanistically, 3-OBA did not alter the expression of the G-protein-coupled lactate receptor GPR81 or associated markers (phospho-ERK1\/2, LDHA, MCT1\/4, CD147), indicating its antitumor effects are GPR81-independent. Moreover, extracellular lactate modulation upon 3-OBA treatment varied between cell lines, with HT1376 cells showing reduced lactate production under nutrient deprivation, suggesting cell-specific metabolic responses to 3-OBA. These findings highlight 3-OBA\u2019s potential as a metabolic modulator with antitumor efficacy in UBC, particularly in metabolically constrained tumors. However, its dual role\u2014as both a potential energy source and therapeutic agent\u2014demands context-specific investigation. Future studies should focus on patient stratification and preclinical validation to clarify 3-OBA\u2019s therapeutic window and mechanism of action in bladder cancer.<\/jats:p>","DOI":"10.3390\/molecules30234624","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T16:47:37Z","timestamp":1764780457000},"page":"4624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Functional and Mechanistic Insights of 3-Hydroxybutyrate (3-OBA) in Bladder Cancer"],"prefix":"10.3390","volume":"30","author":[{"given":"Ana","family":"Silva","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mafalda","family":"F\u00e9lix","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3713-119X","authenticated-orcid":false,"given":"C\u00e9line S.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5779-9752","authenticated-orcid":false,"given":"Adhemar","family":"Longatto-Filho","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"},{"name":"Laboratory of Medical Investigation (LIM14), Faculty of Medicine, S\u00e3o Paulo State University, S\u00e3o Paulo 01049-010, SP, Brazil"},{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1770-4544","authenticated-orcid":false,"given":"F\u00e1tima","family":"Baltazar","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9748-3752","authenticated-orcid":false,"given":"Julieta","family":"Afonso","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,2]]},"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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