Regulatory Networks of ncRNAs and NF-κB in Glioblastoma: Implications for Therapeutics

Glioblastoma (GBM) is the most malignant form of primary brain tumor, exhibiting rapid growth, increased blood vessel growth, therapy resistance, and severe immune suppression. Constant activation of the nuclear factor κB- (NF-κB) signaling axis underlies many of these cancer traits. Concurrently, non-coding RNAs (ncRNAs), notably microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as critical modulators of GBM pathways. This review explains how specific ncRNAs use NF-κB signaling to regulate glioma cell survival, invasion, and therapeutic responses. We synthesized current evidence for miR-21 and miR-181 family members in promoting NF-κB-driven gene expression patterns, described lncRNAs, such as MALAT1 and HOTAIR, which support NF-κB complexes, and highlighted circRNAs, including circKPNB1 and circEZH2, that act as competing RNAs to modulate NF-κB activity. We evaluated preclinical strategies targeting ncRNA-NF-κB interactions, including antisense oligonucleotides, small interfering RNAs, locked nucleic acids, CRISPR-Cas approaches, and smallmolecule- inhibitors, with an emphasis on delivery systems, target specificity, and tumor diversity. Finally, we propose a comprehensive model of ncRNA-NF-κB crosstalk in GBM pathobiology and outline practical approaches to exploit these networks for personalized treatment.