Targeting non-coding RNAs to overcome resistance and improving outcomes in glioblastoma

Dhruv Parikh; Manan Shah

doi:10.1016/j.gmg.2025.100075

Global Medical Genetics ›› 2025, Vol. 12 ›› Issue (04) :100075 DOI: 10.1016/j.gmg.2025.100075

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Targeting non-coding RNAs to overcome resistance and improving outcomes in glioblastoma

Dhruv Parikh ^a^,^b^,^c^,^*
, Manan Shah ^d

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Abstract

Glioblastoma (GB) remains the most aggressive and treatment-resistant primary brain tumor, characterized by extensive heterogeneity, therapeutic resistance, and dismal prognosis. In this comprehensive review, we aimed to synthesize emerging insights into the roles of non-coding RNAs (ncRNAs)—including microRNAs, long non-coding RNAs, circular RNAs, and PIWI-interacting RNAs—in the regulation of glioblastoma progression, resistance mechanisms, and potential therapeutic strategies. We critically evaluated the molecular functions of ncRNAs in key oncogenic processes such as proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), and immune evasion. Additionally, we reviewed current detection methods, delivery technologies, and clinical trials targeting these ncRNAs. A central goal of this review was to bridge a notable gap in the literature by highlighting underrepresented ncRNA classes such as circRNAs and piRNAs, which exhibit regulatory complexity and potential as biomarkers and therapeutic agents in GB. We further discussed delivery challenges posed by the blood-brain barrier and explored promising nanocarrier and exosome-based approaches to enhance therapeutic targeting. Through curated case studies, we showcased the translational potential of targeting specific ncRNAs to reverse multiple resistance types and improve immunotherapy response. This review provides a consolidated framework for understanding the dynamic role of ncRNAs in glioblastoma and proposes an expanded toolkit for precision oncology approaches. Our findings not only underscore the therapeutic promise of ncRNAs but also call for future investigations into the lesser-known subclasses that could redefine the landscape of GB management.

Keywords

Glioblastoma / Non-coding RNAs / Therapeutic resistance / Improved outcomes / MicroRNAs (miRNAs) / Long non-coding RNAs (lncRNAs) / Circular RNAs (circRNAs) / PIWI-interacting RNAs (piRNAs) / Cancer / Neurobiology / Epigenetics

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Dhruv Parikh, Manan Shah. Targeting non-coding RNAs to overcome resistance and improving outcomes in glioblastoma. Global Medical Genetics, 2025, 12(04): 100075 DOI:10.1016/j.gmg.2025.100075

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Authors contribution

All the authors make substantial contribution to this manuscript. DP, and MS participated in drafting the manuscript. DP wrote the main manuscript, and all the authors discussed the results and implications on the manuscript at all stages.

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All relevant data and material are presented in the main paper.

Declaration of Competing Interest

The authors declare that they have no competing interests.

Acknowledgments

The authors are grateful to the Department of Neurology Johns Hopkins Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, the Biochemistry, Cell and Developmental Biology Graduate Program at Emory University, and the Department of Chemical Engineering, School of Energy Technology, Pandit Deendayal Energy University for the permission to publish this research.

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