{"doi":"10.3390/molecules30234624","title":"Functional and Mechanistic Insights of 3-Hydroxybutyrate (3-OBA) in Bladder Cancer","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’s potential as a metabolic modulator with antitumor efficacy in UBC, particularly in metabolically constrained tumors. However, its dual role—as both a potential energy source and therapeutic agent—demands context-specific investigation. Future studies should focus on patient stratification and preclinical validation to clarify 3-OBA’s therapeutic window and mechanism of action in bladder cancer.</jats:p>","journal":"Molecules","year":2025,"id":649887,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1694372,"name":"Ana Mafalda Félix","orcid":null,"position":1,"is_corresponding":false},{"id":1694373,"name":"Céline S. 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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’s potential as a metabolic modulator with antitumor efficacy in UBC, particularly in metabolically constrained tumors. However, its dual role—as both a potential energy source and therapeutic agent—demands context-specific investigation. Future studies should focus on patient stratification and preclinical validation to clarify 3-OBA’s therapeutic window and mechanism of action in bladder cancer.</jats:p>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41375220","pmcid":"PMC12693350","openalex_id":"https://openalex.org/W4416956576","authors":[],"funders":[{"funder_name":"Foundation for Science and Technology","grant_id":"UID/06304/2025","title":null},{"funder_name":"Foundation for Science and Technology","grant_id":"LA/P/0050/2020","title":null},{"funder_name":"Norte Portugal Regional Operational Programme","grant_id":"NORTE2030-FEDER01786400","title":null},{"funder_name":"Norte Portugal Regional Operational Programme","grant_id":"NORTE2030-FEDER-02705300","title":null},{"funder_name":"FCT","grant_id":"2022.11018.BD","title":null},{"funder_name":"FCT","grant_id":"2021.02600.CEECIND","title":null},{"funder_name":"Portuguese Cancer League—North Branch","grant_id":"LPCC-NRN 2025","title":null},{"funder_name":"Fundação para a Ciência e Tecnologia","grant_id":"UID/06304/2023; LA/P/0050/2020","title":null}],"total_grants":8,"fwci":1.3283,"citation_percentile":0.8338954,"influential_citations":0,"citation_trend":[{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1420-3049/30/23/4624/pdf?version=1764666446","host_type":"journal"},{"url":"https://www.mdpi.com/1420-3049/30/23/4624/pdf?version=1764666446","host_type":"publisher"},{"url":"https://www.mdpi.com/1420-3049/30/23/4624/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/molecules30234624","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41375220","host_type":"repository"},{"url":"https://doaj.org/article/48d7ec12632f414aaab9975d88ff30f2","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12693350/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12693350","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12693350?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Diet and metabolism studies","Cancer, Hypoxia, and Metabolism","Diet, Metabolism, and Disease","Urinary Bladder Neoplasms","Humans","3-Hydroxybutyric Acid","Cell Line, Tumor","Cell Proliferation","Animals","Cell Movement","Cell Survival","Antineoplastic Agents"],"mesh_terms":["Animals","Antineoplastic Agents","Urinary Bladder Neoplasms","Cell Movement","Cell Survival","Humans","3-Hydroxybutyric Acid","Cell Line, Tumor","Cell Proliferation"],"keywords":["Bladder cancer","Angiogenesis","Chorioallantoic membrane","Epigenetics","Mechanism of action","Cancer cell","Cancer","Cell culture","Cell","Lactate","Gpr81","Monocarboxylate Transporters","3-Hydroxybutyrate"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T04:28:23.749120Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}