Translated Circular RNAs in Glioblastoma: Emerging Regulators of Tumor Progression, Molecular Heterogeneity and Therapeutic Resistance

Glioblastoma (GBM) is the most common and highly malignant primary brain tumor in adults. Even with advances in surgery, radiotherapy, and systemic therapies, patient outcomes remain poor due to extensive intratumoral heterogeneity and the development of therapeutic resistance. Circular RNAs (circRNAs) are a class of covalently closed RNA molecules that are highly abundant in the central nervous system and frequently dysregulated in cancer. While originally considered non-coding transcripts, current evidence demonstrates that a subset of circRNAs contain functional open reading frames and can undergo cap-independent translation to generate biologically active proteins and peptides. Recent studies have identified a growing number of translated circRNAs in GBM encoding proteins implicated in diverse processes such as receptor tyrosine kinase signaling, DNA repair, metabolism, stemness, invasion, and therapeutic resistance. These findings expand the coding potential of the GBM transcriptome and highlight an additional layer of post-transcriptional regulation. In this review, we summarize our current understanding of circRNA translation, discuss the biological functions of translated circRNAs in GBM, and examine their potential roles in tumor progression, therapeutic resistance, and clinical management. Additionally, we consider the opportunities and challenges associated with targeting translated circRNAs and their encoded proteins for the treatment of GBM.