Glioblastoma multiforme (GBM) confers a poor prognosis, largely due to frequent resistance to Temozolomide (TMZ), the cornerstone of adjuvant chemotherapy. Elucidating molecular mechanisms of TMZ resistance is essential for developing biomarkers for improved patient stratification and targeted therapies that overcome resistance. This study integrates a literature review of microRNAs (miRNAs) implicated in TMZ resistance with in-silico transcriptomic miR analyses to elucidate novel biomarkers. miRNAs, small non-coding RNAs, regulate gene expression, including O6-methylguanine-DNA methyltransferase (MGMT), a key mediator of TMZ resistance. We reviewed literature on miRNA-mediated TMZ resistance, identifying miRNAs such as hsa-miR-142-3p and hsa-miR-181d as regulators of MGMT with translational potential. In parallel, we analyzed DepMap transcriptomic data using DESeq2, identifying 17 differentially expressed miRNAs between TMZ-resistant (LN18, LN229) and TMZ-sensitive (U87MG, U251MG) GBM cell lines with p-value < 0.05. Interestingly, two miRs known to regulate MGMT expression demonstrated clinical relevance: high expression of hsa-miR-142-3p was associated with poorer overall survival (p = 0.025), whereas high expression of hsa-miR-181d correlated with improved survival outcomes (p = 0.0095) in the TCGA cohort, highlighting their roles as mechanistic regulators and prognostic biomarkers. Among these miRNAs, hsa-miR-181d, hsa-miR-181c, and hsa-miR-195 showed a significant negative correlation with MGMT expression, suggesting their potential regulatory role in MGMT-mediated TMZ resistance in glioblastoma. While the in-silico analysis elucidates cell line-based resistance mechanisms. This integrative approach provides a foundation for advancing miRNA-based strategies to overcome TMZ resistance.
