{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:22:31Z","timestamp":1790619751452,"version":"4.1.0"},"reference-count":63,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["P01-CA233452-02"],"award-info":[{"award-number":["P01-CA233452-02"]}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"crossref","award":["I01BX001040-06"],"award-info":[{"award-number":["I01BX001040-06"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,20]]},"abstract":"<jats:p>\n                    Chemotherapy is often combined with surgery for muscle invasive and nonmuscle invasive bladder cancer (BCa). However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism that promotes cancer reprogramming via the metabolic enzyme OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in \u03b2-hydroxybutyrate (\u03b2HB) catabolism, was elevated in muscle invasive disease and in patients with chemoresistant BCa. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant BCa, knocking out\n                    <jats:italic>OXCT1<\/jats:italic>\n                    restored gemcitabine sensitivity, and administering the nonmetabolizable \u03b2HB enantiomer (S-\u03b2HB) only partially restored gemcitabine sensitivity. Suggesting an extrametabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor OVOL1 as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a cohort of patients with BCa who have been treated with chemotherapy. The KO of\n                    <jats:italic>OXCT1<\/jats:italic>\n                    restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of BCa supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.177840","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T12:55:25Z","timestamp":1730984125000},"source":"Crossref","is-referenced-by-count":9,"title":["Targeting ketone body metabolism in mitigating gemcitabine resistance"],"prefix":"10.1172","volume":"9","author":[{"given":"Krizia","family":"Rohena-Rivera","sequence":"first","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA."},{"name":"Samuel Oschin Cancer Center, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3513-1783","authenticated-orcid":true,"given":"Sungyong","family":"You","sequence":"additional","affiliation":[{"name":"Samuel Oschin 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