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Pharmacological ascorbate (P-AscH\u2212) exhibits anticancer activity through pro-oxidant mechanisms; however, its effects on GBM motility and invasion remain incompletely defined. Transcriptomic analyses revealed a strong association between glioma aggressiveness and gene programs governing migration and invasion. Here, we demonstrate that P-AscH\u2212 markedly suppresses migration and invasion of GBM cells. These phenotypic effects are accompanied by coordinated repression of epithelial\u2013mesenchymal transition (EMT) programs, characterized by reduced expression of mesenchymal markers (ZEB1, N-cadherin, Vimentin, Slug, and Twist1) and induction of the epithelial marker Claudin-1 at both transcriptional and protein levels. In parallel, P-AscH\u2212 significantly downregulates invasion-associated matrix metalloproteinases MMP2 and MMP9 at the mRNA level. Mechanistically, catalase rescue experiments establish extracellular hydrogen peroxide as an essential mediator of P-AscH\u2212-induced inhibition of GBM motility and EMT-associated gene and protein expression. In addition, P-AscH\u2212 attenuates mTOR signaling, and combination with a dual mTORC1\/2 inhibitor further reinforces suppression of migratory behavior and mesenchymal programs. Importantly, these phenotypic and molecular effects are conserved in a patient-derived glioblastoma model, underscoring translational relevance. Collectively, these findings identify extracellular hydrogen peroxide-driven redox signaling as a key mechanism by which pharmacological ascorbate suppresses EMT and invasive programs in GBM, providing mechanistic support for ongoing clinical evaluation and highlighting its potential utility as an invasion-targeted therapeutic strategy in GBM and other highly plastic malignancies.<\/jats:p>","DOI":"10.3390\/ijms27114964","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:45:08Z","timestamp":1780404308000},"page":"4964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological Ascorbate Restrains Epithelial\u2013Mesenchymal Transition and Invasion in Glioblastoma Cells via Extracellular H2O2 Generation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2208-0546","authenticated-orcid":false,"given":"Onsurang","family":"Wattanathamsan","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3946-1798","authenticated-orcid":false,"given":"Naphat","family":"Chantaravisoot","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Systems Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rungnapa","family":"Bootsri","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuttiya","family":"Kalpongnukul","sequence":"additional","affiliation":[{"name":"Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Napatsakon","family":"Youngsanbhu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia R.","family":"Oliva","sequence":"additional","affiliation":[{"name":"Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne E.","family":"Griguer","sequence":"additional","affiliation":[{"name":"Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3582-5980","authenticated-orcid":false,"given":"Visarut","family":"Buranasudja","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Natural Products for Ageing and Chronic Diseases, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iii1","DOI":"10.1093\/neuonc\/noab200","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014\u20132018","volume":"23","author":"Ostrom","year":"2021","journal-title":"Neuro Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11622","DOI":"10.1038\/s41598-020-68011-4","article-title":"Longer-term (\u2265\u20092 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: A systematic review and meta-analysis","volume":"10","author":"Poon","year":"2020","journal-title":"Sci. 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