{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T18:19:33Z","timestamp":1778005173922,"version":"3.51.4"},"reference-count":287,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Center of IPO Porto","award":["PI 27\u2014CI-IPOP-27-2016-CBEG"],"award-info":[{"award-number":["PI 27\u2014CI-IPOP-27-2016-CBEG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a dismal prognosis despite advances in multimodal treatment. Conventional therapies fail to achieve durable responses due to GBM\u2019s molecular heterogeneity and capacity to evade therapeutic pressures. Epigenetic alterations have emerged as critical contributors to GBM pathobiology, including aberrant DNA methylation, histone modifications, and non-coding RNA (ncRNA) dysregulation. These mechanisms drive oncogenesis, therapy resistance, and immune evasion. This scoping review evaluates the current state of knowledge on epigenetic modifications in GBM, synthesizing findings from original articles and preclinical and clinical trials published over the last decade. Particular attention is given to MGMT promoter hypermethylation status as a biomarker for temozolomide (TMZ) sensitivity, histone deacetylation and methylation as modulators of chromatin structure, and microRNAs as regulators of pathways such as apoptosis and angiogenesis. Therapeutically, epigenetic drugs, like DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis), appear as promising approaches in preclinical models and early trials. Emerging RNA-based therapies targeting dysregulated ncRNAs represent a novel approach to reprogram the tumor epigenome. Combination therapies, pairing epigenetic agents with immune checkpoint inhibitors or chemotherapy, are explored for their potential to enhance treatment response. Despite these advancements, challenges such as tumor heterogeneity, the blood\u2013brain barrier (BBB), and off-target effects remain significant. Future directions emphasize integrative omics approaches to identify patient-specific targets and refine therapies. This article thus highlights the potential of epigenetics in reshaping GBM treatment paradigms.<\/jats:p>","DOI":"10.3390\/ijms26125634","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T06:42:48Z","timestamp":1749710568000},"page":"5634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Epigenetic Alterations in Glioblastoma Multiforme as Novel Therapeutic Targets: A Scoping Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6938-7189","authenticated-orcid":false,"given":"Marco","family":"Meleiro","sequence":"first","affiliation":[{"name":"Integrated Master\u2019s in Medicine, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Centre Raquel Seruca (Porto.CCC), Rua Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Cancer Biology & Epigenetics Group-Research Center of IPO Porto (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Centre Raquel Seruca (Porto.CCC), Rua Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1002\/cac2.12361","article-title":"An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment","volume":"42","author":"Verdugo","year":"2022","journal-title":"Cancer Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3322\/caac.21613","article-title":"Management of glioblastoma: State of the art and future directions","volume":"70","author":"Tan","year":"2020","journal-title":"CA Cancer J. 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