{"doi":"10.1101/2025.10.29.685375","title":"Acetoacetate suppresses colon cancer via an MR1-MAIT axis","abstract":"<h4>ABSTRACT</h4>  Colorectal cancer (CRC) is a leading cause of cancer mortality and additional preventative, and therapeutic strategies are urgently needed. Ketogenic diets have mixed effects on tumorigenesis and compliance is challenging. Exogenous ketones, β-hydroxybutyrate (βHB) or acetoacetate (AcAc), offer an alternative approach. While βHB has been investigated, the anti-cancer effects of AcAc are poorly defined. Here, we show that orally administering ethyl AcAc (EAA) suppresses tumor growth in several pre-clinical CRC models. Single-cell RNA sequencing, flow cytometry, and genetic and antibody-mediated depletion studies reveal that EAA selectively expands and activates cytotoxic mucosal-associated invariant T (MAIT) cells in an MHC class I-related protein 1 (MR1)-dependent manner. EAA increases MR1 expression by tumor monocytes, which is recapitulated in human cell cultures, where AcAc and 5-amino-6-D-ribitylaminouracil (5-A-RU) induce MAIT cell expansion and tumor killing. Mechanistically, AcAc converts to methylglyoxal, combining with microbially-derived 5-A-RU to generate 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a potent MR1 ligand. These findings identify an AcAc-MR1-MAIT cell axis as a potential immunotherapy approach for CRC therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":9367,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0428,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-10-30","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":79194,"name":"Geniver El Tekle","orcid":"0000-0003-4772-1131","position":1,"is_corresponding":false},{"id":79195,"name":"Edrees H. Rashan","orcid":null,"position":2,"is_corresponding":false},{"id":79196,"name":"Diogo Fonseca-Pereira","orcid":null,"position":3,"is_corresponding":false},{"id":79197,"name":"Yern-Hyerk Shin","orcid":null,"position":4,"is_corresponding":false},{"id":79198,"name":"Natalia Andreeva","orcid":null,"position":5,"is_corresponding":false},{"id":79199,"name":"Geicho Nakatsu","orcid":"0000-0001-7239-2750","position":6,"is_corresponding":false},{"id":79200,"name":"Ayesha F. Lobo","orcid":null,"position":7,"is_corresponding":false},{"id":79201,"name":"Sway P. Chen","orcid":"0000-0002-1722-2473","position":8,"is_corresponding":false},{"id":79202,"name":"Sena Bae","orcid":null,"position":9,"is_corresponding":false},{"id":79203,"name":"Monia Michaud","orcid":null,"position":10,"is_corresponding":false},{"id":79204,"name":"Jonathan N. Glickman","orcid":"0000-0003-0910-2655","position":11,"is_corresponding":false},{"id":79205,"name":"Jon Clardy","orcid":"0000-0003-0213-8356","position":12,"is_corresponding":false},{"id":54230,"name":"Matthew G. Vander Heiden","orcid":"0000-0002-6702-4192","position":13,"is_corresponding":false},{"id":492,"name":"Wendy S. Garrett","orcid":"0000-0002-5092-0150","position":14,"is_corresponding":false},{"id":79206,"name":"Diogo Fonseca‐Pereira","orcid":"0000-0002-7400-9804","position":15,"is_corresponding":false},{"id":79207,"name":"Yern‐Hyerk Shin","orcid":null,"position":16,"is_corresponding":false},{"id":79208,"name":"Anna Beatriz Alves Pereira Lôbo","orcid":"0000-0003-1353-0863","position":17,"is_corresponding":false},{"id":79193,"name":"Slater L. Clay","orcid":"0000-0002-1966-892X","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","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":[]}