{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:55:57Z","timestamp":1790672157927,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82573129"],"award-info":[{"award-number":["82573129"]}],"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":["82273164"],"award-info":[{"award-number":["82273164"]}],"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>\n                    Therapy\u2010resistant glioblastoma stem cells (GSCs) drive tumor progression and recurrence in glioblastoma (GBM). Cuproptosis is a copper\u2010dependent form of regulated cell death triggered by aggregation of lipoylated mitochondrial proteins, but the mechanisms underlying cuproptosis resistance in GSCs remain unclear. Lactylome profiling identifies dihydrolipoamide dehydrogenase (DLD) as a key lactylation target regulating cuproptosis. Mechanistically, lactate\u2010dependent alanyl\u2010tRNA synthetase 2 (AARS2) catalyzes DLD K445 lactylation, while SIRT5 reverses this modification via NAD\n                    <jats:sup>+<\/jats:sup>\n                    \u2010dependent delactylation. DLD K445 lactylation does not disrupt pyruvate dehydrogenase (PDH) complex assembly or DLD stability, but suppresses PDH activity and DLAT lipoylation, limiting copper\u2010triggered DLAT aggregation and cuproptosis. Genetic disruption of DLD K445 lactylation restores DLAT lipoylation and sensitizes GSCs to elesclomol\u2010copper (ES\u2010Cu). Inhibiting lactate metabolism, activating SIRT5, or a cell\u2010penetrating peptide targeting DLD K445 all boost ES\u2010Cu efficacy in patient\u2010derived glioblastoma organoids and intracranial xenografts. Our work establishes DLD K445 lactylation as a metabolic driver of cuproptosis resistance and validates the AARS2\u2013DLD\u2013SIRT5 axis as a druggable therapeutic target for GBM.\n                  <\/jats:p>","DOI":"10.1002\/advs.78046","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:55:27Z","timestamp":1790668527000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AARS2\u2010SIRT5\u2010Driven DLD K445 Lactylation Promotes Cuproptosis Resistance in Glioblastoma Stem Cells"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5975-2329","authenticated-orcid":false,"given":"Mingtian","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5130-2629","authenticated-orcid":false,"given":"Haibiao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyin","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9786-213X","authenticated-orcid":false,"given":"Jun","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huibo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University  Nanjing China"},{"name":"Institute for Brain Tumors Jiangsu Key Laboratory of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043330"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010022\u201000486\u2010x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.024"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf0529"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2025.10.028","article-title":"Inhibition of Heme Biosynthesis Triggers Cuproptosis in Acute Myeloid Leukemia","volume":"189","author":"Lewis A. 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