Glioblastoma (GBM) is the most lethal and aggressive primary brain tumor in adults. Despite a standard-of-care regimen involving surgical resection, radiotherapy and temozolomide (TMZ), median overall survival typically hovers between 12 and 15 months. This poor prognosis is driven by profound intratumoral heterogeneity, glioma stem cell populations, and an immunosuppressive microenvironment that collectively fuel resistance to traditional apoptosis-centric therapies. Ferroptosis—a form of regulated cell death driven by iron-dependent phospholipid peroxidation and the collapse of antioxidant defenses—has emerged as a compelling alternative for eliminating therapy-refractory GBM cells. This review examines the molecular machinery of ferroptosis in glioma and explores how an additional regulatory layer, noncoding RNAs (ncRNAs), modulates this process. We highlight key experimentally validated axes where microRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) orchestrate iron handling and antioxidant thresholds. These include sensitizers like miR-147a and circLRFN5, which promote iron overload, and resistors like circCDK14 and TMEM161B-AS1, which act as “ferroptosis brakes”. Furthermore, we discuss how integrative analyses of TCGA and CGGA cohorts have yielded ferroptosis-related lncRNA signatures that robustly predict patient survival. Finally, we outline the clinical potential of these ncRNAs as biomarkers and therapeutic targets while addressing the delivery challenges, such as the blood–brain barrier, that must be overcome to achieve precision, ferroptosis-oriented GBM therapy.
Seerapu et al. (2026) studied this question.