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A feature of the GBM microenvironment is hypoxia, which activates a wide range of adaptive responses orchestrated mainly by the hypoxia-inducible factor (HIF). The Von Hippel\u2013Lindau protein (pVHL) is a central regulator of HIF stability, inducing proteasomal degradation under physiological conditions. However, in GBM, the pVHL is frequently mutated or functionally inactivated by several mechanisms, including microRNA regulation, post-translational modifications, or degradation by specific E3 ubiquitin ligases. This loss of function results in persistent HIF activation, thereby enhancing the oncogenic and pro-angiogenic environment that contributes to the progression and aggressiveness of GBM. This review focuses on the multifaceted roles of the pVHL-HIF axis and proposes it as a key driver of GBM malignancy.<\/jats:p>","DOI":"10.3390\/ijms26209979","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T15:20:12Z","timestamp":1760973612000},"page":"9979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Von Hippel\u2013Lindau\/Hypoxia Inducible Factor Axis in Glioblastoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Itamar","family":"Flores","sequence":"first","affiliation":[{"name":"Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleli","family":"Salazar","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1451-8754","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"P\u00e9rez de la Cruz","sequence":"additional","affiliation":[{"name":"Neurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1851-6774","authenticated-orcid":false,"given":"Tamara","family":"Mena-Guerrero","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier Angel Navarro","family":"Cossio","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Mexico City 14269, Mexico"},{"name":"Laboratorio de Inmunorregulaci\u00f3n, Departamento de Inmunolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0271-7892","authenticated-orcid":false,"given":"Mario Eugenio","family":"Cancino-Diaz","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda Aplicada, Departamento de Inmunolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1455-312X","authenticated-orcid":false,"given":"Benjamin","family":"Pineda","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Mexico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Grochans, S., Cybulska, A.M., Simi\u0144ska, D., Korbecki, J., Kojder, K., Chlubek, D., and Baranowska-Bosiacka, I. 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