{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:02:51Z","timestamp":1791925371337,"version":"4.3.4"},"reference-count":37,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T00:00:00Z","timestamp":1722556800000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31870805"],"award-info":[{"award-number":["31870805"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U20A20371"],"award-info":[{"award-number":["U20A20371"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373438"],"award-info":[{"award-number":["82373438"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7222023"],"award-info":[{"award-number":["7222023"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012401","name":"Beijing Science and Technology Planning Project","doi-asserted-by":"publisher","award":["D171100006517004"],"award-info":[{"award-number":["D171100006517004"]}],"id":[{"id":"10.13039\/501100012401","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Although it is traditionally believed that ATP binding cassette subfamily C member 2 (ABCC2) is a multidrug resistance\u2010associated protein correlated with a worse prognosis, our previous and several other studies demonstrated the contrary to be true in gastric cancer (GC). We aim to explore the underlying mechanism of this discovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Our study utilized whole\u2010exome sequencing (WES), RNA sequencing, and droplet digital PCR (ddPCR) analysis of 80 gastric cancer samples, along with comprehensive immunohistochemical (IHC) analysis of 1044 human GC tissue samples.By utilizing CRISPRCas9 to genetically modify cell lines with the ABCC2\u201024C &gt; T (rs717620) point mutation and conducting dual\u2010luciferase reporter assays, we identified that transcription factors SOX9 and ETS1 serve as negative regulators of ABCC2 expression. Seahorse assay and mass spectrometry were used to discover altered metabolic patterns. Gain and loss\u2010of\u2010function experiments in GC cell lines and preclinical models were carried out to validate ABCC2 biological function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ABCC2 high expression correlated with better prognosis, and rs717620 can influence ABCC2 expression by disrupting the binding of ETS1 and SOX9. Gain and loss\u2010of\u2010function experiments in GC cell lines demonstrated amino acid deprivation reduces proliferation, migration, and drug resistance in ABCC2\u2010high GC cells. ABCC2 leads to reduced intracellular amino acid pools and disruption of cellular energy metabolism. This phenomenon depended on ABCC2\u2010mediated GSH extrusion, resulting in alterations in redox status, thereby increasing the cell's susceptibility to ferroptosis. Furthermore, patient\u2010derived organoids and patient\u2010derived tumor\u2010like cell clusters were used to observe impact of ABCC2 on therapeutic effect. In the xenograft model with high ABCC2 expression, we observed that constricting amino acid intake in conjunction with GPX4 inactivation resulted in notable tumor regression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings demonstrate a significant role of ABCC2 in amino acid metabolism and ferroptosis by mediating GSH efflux in GC. This discovery underlines the potential of combining multiple ferroptosis targets as a promising therapeutic strategy for GC with high ABCC2 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>ABCC2 plays a crucial role in inducing metabolic vulnerability and ferroptosis in gastric cancer through enhanced glutathione efflux.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The ABCC2 24C &gt; T polymorphism is a key factor influencing its expression.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results highlight the potential of ABCC2 as a predictive biomarker and therapeutic target in gastric cancer.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1754","type":"journal-article","created":{"date-parts":[[2024,8,3]],"date-time":"2024-08-03T02:16:05Z","timestamp":1722651365000},"source":"Crossref","is-referenced-by-count":21,"title":["ABCC2 induces metabolic vulnerability and cellular ferroptosis via enhanced glutathione efflux in gastric cancer"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6984-0832","authenticated-orcid":false,"given":"Yiding","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Cancer Translational Research Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Peking University Cancer Hospital &amp; Institute  Beijing P.R. 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