{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T06:07:47Z","timestamp":1788847667969,"version":"build-2803163510"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Temozolomide (TMZ) remains the first-line chemotherapeutic agent for glioblastoma (GBM), but its clinical efficacy is often limited by acquired resistance. This study aimed to investigate whether nectin-4 could serve as a target to sensitize GBM cells to TMZ and to determine whether resveratrol enhances TMZ efficacy through downregulation of nectin-4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Nectin-4 expression was evaluated in TMZ-treated GBM cell lines (U87, U251) and in an orthotopic GBM mouse model using qRT-PCR, Western blotting, and immunohistochemistry. Gain- and loss-of-function approaches were performed to assess the functional role of nectin-4 in GBM cell proliferation, tumor progression, and response to TMZ. The effects of resveratrol on nectin-4 expression and on the antitumor activity of TMZ were examined\n                      <jats:italic>in vitro<\/jats:italic>\n                      and in an intracranial orthotopic GBM model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TMZ treatment significantly upregulated nectin-4 expression at both mRNA and protein levels in GBM cells and in tumor tissues from orthotopic mouse models. Nectin-4 overexpression promoted GBM cell proliferation\n                      <jats:italic>in vitro<\/jats:italic>\n                      and accelerated intracranial tumor progression\n                      <jats:italic>in vivo<\/jats:italic>\n                      , whereas nectin-4 knockdown enhanced the antitumor activity of TMZ. Resveratrol alone effectively reduced nectin-4 expression and blocked the TMZ-induced upregulation of nectin-4. Consistent with these molecular findings, the combination of resveratrol and TMZ synergistically suppressed GBM cell proliferation, inhibited intracranial tumor growth, and significantly prolonged survival of tumor-bearing mice compared with either agent alone.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Targeting nectin-4 represents an effective strategy to overcome TMZ resistance in GBM. Resveratrol enhances TMZ efficacy at least in part through downregulating nectin-4, supporting its potential as a chemo-sensitizing adjunct to TMZ-based chemotherapy for GBM patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1908590","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:35:28Z","timestamp":1788845728000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Nectin-4 sensitizes glioblastoma to temozolomide"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiao-Guang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi Province, China"]},{"name":"Department of Neurosurgery, The First Affiliated Hospital of Henan University","place":["Kaifeng, Henan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Henan University","place":["Kaifeng, Henan Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Ning","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1158\/1078-0432.CCR-22-3882","article-title":"Scratching the surface: NECTIN-4 as a surrogate for enfortumab vedotin resistance","volume":"29","author":"Aggen","year":"2023","journal-title":"Clin. 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