{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T03:14:15Z","timestamp":1788146055620,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFA1300602"],"award-info":[{"award-number":["2021YFA1300602"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273256"],"award-info":[{"award-number":["82273256"]}],"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":["82472775"],"award-info":[{"award-number":["82472775"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Developing effective therapies for triple\u2010negative breast cancer (TNBC) requires the identification of key molecular regulators. Here, among the major m6A modulators, we find that only the reader YTHDC1 is specifically overexpressed in TNBC and correlates to unfavorable prognosis. Mechanistically, YTHDC1 orchestrates glucose and glutamine metabolism in an m6A\u2010dependent manner to confer robust adaptability to lethal metabolic stress in TNBC cells. It not only stabilizes GLUT3 mRNA to sustain glucose uptake and NADPH production, but also reduces the mRNA stability of ATF4, thereby suppressing the overexpression of the cystine\/glutamate antiporter SLC7A11 to prevent excessive cystine uptake and glutamate export. YTHDC1 knockdown simultaneously disrupts glucose metabolism and upregulates SLC7A11, triggering disulfidptosis in TNBC cells in vitro and in vivo. Leveraging this YTHDC1 knockdown\u2010induced metabolic vulnerability, we develop an ATF4 mRNA\u2010targeted nanotherapy, which delivers mRNA directly to the cytoplasm and bypasses m6A\u2010mediated destabilization by YTHDC1 in the nucleus. By promoting SLC7A11 expression, therapeutic overexpression of ATF4 sensitizes TNBC cells to disulfidptosis upon GLUT inhibitor BAY\u2010876 treatment, and to glutamate deprivation\u2010induced cell death upon GLS inhibitor CB\u2010839 treatment. Collectively, this work reveals YTHDC1 as a pivotal coordinator of the glucose\u2010glutamine\u2010cystine metabolic network and provides ATF4 mRNA nanomedicine\u2010based combination strategies to improve TNBC therapeutic efficacy.<\/jats:p>","DOI":"10.1002\/advs.77492","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:29:10Z","timestamp":1788143350000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["YTHDC1 Orchestrates Glucose and Glutamate Rewiring to Overcome Lethal Metabolic Stress in Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","author":[{"given":"Zheng\u2010Hao","family":"Lai","sequence":"first","affiliation":[{"name":"Medical Research Center, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9580-0235","authenticated-orcid":false,"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical Research Center, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na\u2010Na","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Research Center, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou 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University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenkui","family":"Fu","sequence":"additional","affiliation":[{"name":"Medical Research Center, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4505-5174","authenticated-orcid":false,"given":"Yingsen","family":"Tang","sequence":"additional","affiliation":[{"name":"Medical Research Center, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou 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