{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:56:47Z","timestamp":1792180607055,"version":"4.4.0"},"reference-count":57,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":59,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82473081,82472903,82173195,82173229"],"award-info":[{"award-number":["82473081,82472903,82173195,82173229"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2024M753783,2025T180659"],"award-info":[{"award-number":["2024M753783,2025T180659"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,15]]},"abstract":"<jats:p>\n                    Gemcitabine-based chemotherapy is the standard treatment regimen for advanced intrahepatic cholangiocarcinoma (iCCA), but the frequent presence of chemoresistance limits its efficacy. Here, we identified isocitrate dehydrogenase 1 (IDH1) as the crucial target that confers chemoresistance of iCCA to gemcitabine using a druggable CRISPR\/Cas9 library. The positive association between IDH1 expression and chemoresistance was revealed in a gemcitabine-treated iCCA cohort and with cell-based drug sensitivity assays. Utilizing patient-derived organoids, cell line\u2013derived xenografts, and patient-derived xenografts, we demonstrated that IDH1 knockdown or IDH1 pharmacological inhibition facilitated gemcitabine efficacy in these preclinical iCCA models carrying wild-type IDH1 (wtIDH1). Mechanistically, wtIDH1 oxidizes isocitrate to generate \u03b1-ketoglutarate and NNADPH, thereby creating a mechanism to manage the oxidative stress induced by gemcitabine, maintaining cellular redox homeostasis, and, ultimately, leading to chemoresistance to gemcitabine. Significantly, ivosidenib, the FDA-approved allosteric IDH1 inhibitor, demonstrated synergistic antitumor efficacy with gemcitabine in wtIDH1 preclinical iCCA models through boosting intracellular oxidative stress under physiological conditions. The low level of Mg\n                    <jats:sup>2+<\/jats:sup>\n                    , an ion that competitively hinders binding of ivosidenib on wtIDH1, in the iCCA tumor microenvironment contributed to the expanded therapeutic window for use of ivosidenib in patients with iCCA. Our work revealed the potency of combining targeting IDH1 and chemotherapy against wtIDH1 iCCA and other tumors.\n                  <\/jats:p>\n                  <jats:p\/>\n                  <jats:p>The FDA-approved drug ivosidenib originally designed for mutant IDH1 is also effective in intrahepatic cholangiocarcinoma expressing wild-type IDH1<\/jats:p>","DOI":"10.1172\/jci199730","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T16:01:02Z","timestamp":1773763262000},"source":"Crossref","is-referenced-by-count":3,"title":["The allosteric IDH1 inhibitor ivosidenib overcomes chemoresistance in intrahepatic cholangiocarcinoma models expressing wild-type IDH1"],"prefix":"10.1172","volume":"136","author":[{"given":"Xiuxian","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biliary-Pancreatic Surgery,"},{"name":"Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tract Cancer,"},{"name":"Guangdong Provincial Key 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