The Role of Noncoding RNA in MGMT-Positive Glioblastoma: A Narrative Review

Glioblastoma (GBM) is the most aggressive primary malignant tumor of the central nervous system and is characterized by rapid progression, frequent recurrence, and poor survival outcomes. The current standard of care, comprising maximal safe surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ), has improved clinical management; however, the therapeutic benefit remains limited by both intrinsic and acquired resistance to TMZ. O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that removes TMZ-induced O6-methylguanine adducts, is a major determinant of TMZ responsiveness. In particular, methylation of the MGMT promoter is associated with reduced MGMT expression and improved sensitivity to TMZ, although this molecular marker alone does not fully explain interpatient variability in treatment response, which is further modulated by the immunosuppressive tumor microenvironment. Increasing evidence indicates that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), participate in the regulatory network controlling MGMT expression. These ncRNAs may regulate MGMT directly at the posttranscriptional level or indirectly through competing endogenous RNA networks, epigenetic mechanisms, and signaling pathways associated with DNA repair and chemoresistance. Consequently, dysregulated ncRNA expression may contribute to TMZ resistance and GBM progression. Moreover, ncRNAs have potential clinical value as biomarkers for molecular stratification and prognostic assessment, as well as therapeutic targets for restoring TMZ sensitivity. This narrative review summarizes current evidence regarding ncRNA-mediated regulation of MGMT in GBM and discusses the potential implications of targeting these regulatory mechanisms to overcome TMZ resistance.