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Beyond functioning as an alternative oxidative substrate,\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    engages in\n                    <jats:styled-content style=\"fixed-case\">HCAR2<\/jats:styled-content>\n                    \u2010mediated signaling,\n                    <jats:styled-content style=\"fixed-case\">HDAC<\/jats:styled-content>\n                    \u2010related regulation, redox coupling, and lysine \u03b2\u2010hydroxybutyrylation, thus influencing tumor cell metabolism, chromatin state, and the tumor immune microenvironment. The biological effects of\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    in cancer exhibit high context dependency. In certain models,\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    inhibits inflammation, angiogenesis, epithelial\u2010mesenchymal transition, or tumor growth, while in others, it promotes metabolic adaptation, survival, metastasis, or treatment resistance. These seemingly contradictory outcomes can be elucidated through two major mechanistic switch points. The first involves tumor cell ketolytic competence: cells exhibiting effective\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    uptake, functional\n                    <jats:styled-content style=\"fixed-case\">BDH1<\/jats:styled-content>\n                    \u2013\n                    <jats:styled-content style=\"fixed-case\">OXCT1<\/jats:styled-content>\n                    \u2010dependent ketolysis, and preserved mitochondrial respiration may utilize\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    as an adaptive substrate under nutrient or therapeutic stress. The second concerns cellular allocation within the tumor microenvironment, determining whether\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    preferentially supports malignant cells, antitumor lymphocytes, or other immune and stromal populations. Furthermore,\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    source and treatment context further modulate these responses. Notably, ketogenic diet, direct\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    supplementation, and tumor\u2010intrinsic ketogenesis represent biologically distinct experimental states and should not be interpreted interchangeably. This review integrates current evidence into a source\u2013access\u2013interpretation framework that differentiates tumor\u2010adaptive, signaling\u2010dominant, and immune\u2010supportive\n                    <jats:styled-content style=\"fixed-case\">BHB<\/jats:styled-content>\n                    states, emphasizing priorities for causal, cell\u2010resolved, and biomarker\u2010guided investigation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202603664rr","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:42:33Z","timestamp":1792593753000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b2\u2010Hydroxybutyrate in Cancer: From Alternative Fuel to a Context\u2010Dependent Metabolic Signal"],"prefix":"10.1096","volume":"40","author":[{"given":"Qihai","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy Anhui College of Traditional Chinese Medicine  Wuhu Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7468-6277","authenticated-orcid":false,"given":"Yaping","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Anhui College of Traditional Chinese Medicine  Wuhu Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-024-02119-3"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.115064"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.115206"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-025-02460-1"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70358"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.123.3191.309"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw5473"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202050635"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.01.007"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2014.12.002"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.60"},{"key":"e_1_2_14_14_1","article-title":"Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application","volume":"13","author":"Liang Z.","year":"2025","journal-title":"Biomedicine"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.019"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.12.022"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.08.011"},{"key":"e_1_2_14_18_1","article-title":"Emerging Pathophysiological Roles of Ketone Bodies","volume":"39","author":"Tsuruta H.","year":"2024","journal-title":"Physiology (Bethesda, Md.)"},{"key":"e_1_2_14_19_1","article-title":"Ketone Body Induction: Insights Into Metabolic Disease Management","volume":"13","author":"Yoo B. 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