{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:49:08Z","timestamp":1791521348200,"version":"4.3.4"},"reference-count":35,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"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":["82573052"],"award-info":[{"award-number":["82573052"]}],"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":["82303346"],"award-info":[{"award-number":["82303346"]}],"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":["82472833"],"award-info":[{"award-number":["82472833"]}],"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":["82373342"],"award-info":[{"award-number":["82373342"]}],"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":["82403452"],"award-info":[{"award-number":["82403452"]}],"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":["82303837"],"award-info":[{"award-number":["82303837"]}],"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>Although anti\u2010angiogenic (anti\u2010VEGF) therapy is widely used for glioblastoma (GBM), its efficacy is severely limited by acquired resistance. Here, we identify endothelial\u2010mesenchymal transition (Endo\u2010MT) in brain endothelial cells as the primary driver of this resistance, fundamentally modulated by hexosaminidase B (HEXB). Mechanistically, HEXB directly binds and stabilizes heat shock protein 60 (HSP60) by inhibiting its ubiquitination and degradation. This stabilization upregulates insulin\u2010like growth factor binding protein 1 (IGFBP1), thereby promoting the Endo\u2010MT process. Addressing its clinical relevance, the combination of a HEXB inhibitor and anti\u2010VEGF therapy exerts potent synergistic therapeutic effects in GBM murine models. Overall, our study establishes HEXB as a key driver of Endo\u2010MT and provides a promising dual\u2010targeting strategy to overcome anti\u2010VEGF resistance in GBM.<\/jats:p>","DOI":"10.1002\/advs.78208","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:56:48Z","timestamp":1791518208000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor\u2010Intrinsic HEXB Drives Endothelial\u2010To\u2010Mesenchymal Transition and Confers Resistance to Anti\u2010Angiogenic Therapy in Glioblastoma"],"prefix":"10.1002","author":[{"given":"Tianqi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixu","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"},{"name":"Department of Neurosurgery The First Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongda","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"},{"name":"Department of Rehabilitation Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0689-1695","authenticated-orcid":false,"given":"Wen","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3402-1884","authenticated-orcid":false,"given":"Anhua","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Shengjing Hospital of China Medical University  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2018.01.053"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(19)30035\u2010X"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1056\/NEJMoa2214963","article-title":"Trifluridine\u2010Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer","volume":"388","author":"Prager G. W.","year":"2023","journal-title":"The New England Journal of Medicine"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJMoa1308573","article-title":"A randomized trial of bevacizumab for newly diagnosed glioblastoma","volume":"370","author":"Gilbert M.","year":"2014","journal-title":"The New England Journal of Medicine"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.11.021"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84876"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201011\u20103067"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2019.05.007"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201005982\u2010z"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noac033"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201008\u20101800"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201052888\u20100"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2022.2031499"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200804583"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.1904488"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202402450"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1158\/2159-8290.CD-23-1348","article-title":"Phosphocreatine Promotes Epigenetic Reprogramming to Facilitate Glioblastoma Growth Through Stabilizing BRD2","volume":"14","author":"Chen L.","year":"2024","journal-title":"Cancer Discovery"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201012001\u20102"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.01.041"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658\u2010020\u201000245\u20106"},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1093\/cvr\/cvt047","article-title":"Extracellular HSP60 induces inflammation through activating and up\u2010regulating TLRs in cardiomyocytes","volume":"98","author":"Tian J.","year":"2013","journal-title":"Cardiovascular Research"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2016.2643"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.22.10553"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2208787120"},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.drup.2022.100849","article-title":"New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects","volume":"64","author":"Huang M.","year":"2022","journal-title":"Drug Resistance Updates"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2014.06.003"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010018\u20100007\u20108"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010021\u201001485\u20106"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418\u2010020\u201000696\u20106"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102141"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418\u2010020\u20100523\u20102"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.011666"},{"key":"e_1_2_10_34_1","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/s41380-018-0285-0","article-title":"CircDYM ameliorates depressive\u2010like behavior by targeting miR\u20109 to regulate microglial activation via HSP90 ubiquitination","volume":"25","author":"Zhang Y.","year":"2020","journal-title":"Molecular psychiatry"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010020\u201001208\u20103"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.03.013"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78208","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.78208","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.78208","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:56:50Z","timestamp":1791518210000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.78208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,8]]},"references-count":35,"alternative-id":["10.1002\/advs.78208"],"URL":"https:\/\/doi.org\/10.1002\/advs.78208","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,8]]},"assertion":[{"value":"2025-12-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e78208"}}