{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:50:28Z","timestamp":1792036228473,"version":"4.4.0"},"reference-count":57,"publisher":"Wiley","issue":"57","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"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":["52573296"],"award-info":[{"award-number":["52573296"]}],"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":["82372690"],"award-info":[{"award-number":["82372690"]}],"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":["82173027"],"award-info":[{"award-number":["82173027"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People's Republic of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Glioblastoma (GBM), one of the most lethal human cancers, faces a major therapeutic challenge due to drug resistance. Temozolomide (TMZ), a standard first\u2010line drug for clinical GBM treatment, benefits only a subset of patients, leaving an urgent need for strategies that can restore its efficacy. Herein, we propose that cuproptosis, a recently identified regulated cell death (RCD), is capable of reversing TMZ resistance in GBM. We design copper\u2010TMZ (Cu\u2010TMZ) prodrugs, assembled via the coordination of Cu\n                    <jats:sup>2+<\/jats:sup>\n                    with TMZ and, in optimized formulations, co\u2010loaded with metformin (MET) as an AMPK activator, to exploit cuproptosis for overcoming TMZ resistance. Upon glutathione\u2010triggered disassembly, the prodrugs release Cu\n                    <jats:sup>+<\/jats:sup>\n                    and TMZ, inducing mitochondrial proteotoxic stress and initiating a self\u2010amplifying cuproptosis loop characterized by ATP depletion, AMPK\u2010p53 activation, and glycolysis inhibition. Beyond self\u2010reinforcement, cuproptosis directly potentiates TMZ activity by suppressing drug efflux, impairing DNA repair, and aggravating metabolic and redox stress. Both in vitro and in vivo experiments demonstrate that Cu\u2010TMZ\/MET prodrugs markedly restore TMZ responsiveness and suppress TMZ\u2010resistant GBM progression. More broadly, this study illustrates how RCD pathways can be engineered into therapeutics to convert drug resistance into vulnerability, highlighting a generalizable strategy for improving the efficacy of frontline chemotherapy in otherwise intractable cancers.\n                  <\/jats:p>","DOI":"10.1002\/advs.76677","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:55:56Z","timestamp":1784552156000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reversing Temozolomide Resistance in Glioblastoma Based on Cuproptosis\u2010Mediated Positive Feedback Loop"],"prefix":"10.1002","volume":"13","author":[{"given":"Wenjie","family":"Feng","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine The First Hospital of Jilin University  Changchun P. R. China"},{"name":"Department of Neurosurgery The First Hospital of Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Weng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Hospital of Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanrui","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0548-6073","authenticated-orcid":false,"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine The First Hospital of Jilin University  Changchun P. R. China"},{"name":"State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Hospital of Jilin University  Changchun P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2373-1100","authenticated-orcid":false,"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine The First Hospital of Jilin University  Changchun P. R. China"},{"name":"State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University  Changchun P. R. 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