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In this study, we uncover a precise metabolic vulnerability in ARID1A-deficient DGC driven by a specific transporter defect. Through integrated metabolomic and transcriptomic analyses, we demonstrate that ARID1A loss transcriptionally represses the high-affinity nucleoside transporter SLC28A3. Our profiling revealed a critical lack of redundancy in the concentrative transporter family in DGC, establishing a strict reliance on SLC28A3 for maintaining intracellular deoxycytidine (dC) pools. Consequently, ARID1A deficiency creates a severe \u201clow-dCTP\u201d metabolic bottleneck. We show that the dC analogue gemcitabine exploits this state through a distinct functional dichotomy: it enters via intact equilibrative transporters to target cells that have lost their competitive dC barrier. Mechanistically, gemcitabine exerts a \u201cdual- hit\u201d effect by outcompeting the scarce dC pool for DNA incorporation while simultaneously inhibiting ribonucleotide reductase, thereby blocking de novo nucleotide synthesis. This synergistic collapse of pyrimidine metabolism was validated in patient-derived ex vivo cultures and in vivo peritoneal dissemination models. Our findings provide a robust mechanistic basis for repurposing gemcitabine as a precision therapy for ARID1A-deficient DGC, offering a potent strategy for this intractable malignancy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Implications:<\/jats:title>\n                    <jats:p>This work uncovers a metabolic vulnerability in ARID1A-deficient gastric cancer caused by SLC28A3 loss. It provides a compelling rationale for repurposing gemcitabine as a targeted therapy for this intractable malignancy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/1541-7786.mcr-25-1069","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T13:50:38Z","timestamp":1772200238000},"page":"518-532","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ARID1A Deficiency in Diffuse-Type Gastric Cancer Promotes a Pyrimidine Metabolic Vulnerability"],"prefix":"10.1158","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4723-6235","authenticated-orcid":false,"given":"Harumi","family":"Hirano","sequence":"first","affiliation":[{"name":"1Division of Cancer Therapeutics, National Cancer Center Research Institute, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8181-6241","authenticated-orcid":false,"given":"Hideki","family":"Makinoshima","sequence":"additional","affiliation":[{"name":"2Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0860-1807","authenticated-orcid":false,"given":"Hideaki","family":"Ogiwara","sequence":"additional","affiliation":[{"name":"1Division of Cancer Therapeutics, National Cancer Center Research Institute, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1086","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"2026060303064912800_bib1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 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