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  • miRNA-Mediated Regulation of the NRF2/KEAP1 Pathway in Glioblastoma

  • Sheida Azarm,1 Sorayya Ghasemi,2,*
    1. Shahrekord University of Medical Sciences, Shahrekord, Iran
    2. Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran


  • Introduction: Glioblastoma (GBM) is an aggressive and multifactorial primary brain tumor that exhibits rapid growth, extensive genetic and epigenetic heterogeneity, and resistance to conventional therapies. Oxidative stress and consequent disruption of cellular redox homeostasis are among the key contributors to therapeutic resistance in GBM. The NRF2/KEAP1 pathway regulates the cellular antioxidant response and mediates cellular adaptation to oxidative stress. As an important layer of post-transcriptional regulation, microRNAs (miRNAs) can influence the NRF2/KEAP1 pathway and cellular responses to oxidative stress, while influencing cancer progression. Despite growing evidence that miRNAs regulate NRF2 signaling in cancer, their role in the NRF2/KEAP1 axis in GBM remains poorly characterized. Therefore, we explored candidate miRNAs associated with the upstream regulation of the NRF2/KEAP1 pathway in GBM using a literature-based approach and publicly available bioinformatic resources.
  • Methods: A literature-based and in silico approach identified 30 candidate miRNAs targeting NFE2L2 and/or KEAP1 genes. These were screened against published evidence for glioma/GBM relevance. Experimentally supported miRNA-target interactions were assessed using miRNet based on the miRTarBase database. The expression of the selected miRNAs was examined in 436 TCGA-GBM samples accessible via Glioma-BioDP, presented as heatmap-based clustering.
  • Results: After screening 30 candidate miRNAs based on published evidence, 5 candidates showed higher relevance to glioma/GBM and the NRF2/KEAP1 pathway. Interactions of miR-144-3p, miR-153-3p, and miR-27a-3p with the NFE2L2 gene, along with miR-141-3p with KEAP1, were identified using the miRNet/miRTarBase database, whereas miR-200a-3p did not yield a corresponding interaction in the queried database. All 4 miRNAs were represented in the TCGA-GBM expression dataset, and their expression patterns were visualized using heatmap-based clustering.
  • Conclusion: These findings reveal that miRNAs are promising regulators of the NRF2/KEAP1 pathway in glioblastoma. Our findings provide a foundation to explore the functions of these miRNA candidates and their gene targets in redox homeostasis regulation in GBMs, which might contribute to drug-resistance development.
  • Keywords: Glioblastoma; miRNAs; NRF2/KEAP1 pathway; Oxidative stress; Therapeutic resistance

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