Novel Insights Into Small Open Reading Frame-Encoded Micropeptides in Glioblastoma.

Glioblastoma is the most aggressive type of brain tumor, with a dismal prognosis, highlighting the urgent need for novel biomarkers and therapeutic targets. Recent advances in transcriptomics and proteomics have revealed the critical role of small open reading frame (sORF)-encoded micropeptides, a previously overlooked class of polypeptides derived from noncoding RNAs (ncRNAs), in glioblastoma pathogenesis. In this review, the current knowledge on the functional mechanisms of these micropeptides-including MP31, SHPRH-146aa, AKT3-174aa, and others-which regulate tumor metabolism, proliferation, angiogenesis, and therapeutic resistance, is synthesized. These micropeptides act as molecular switches by modulating key pathways or stabilizing tumor-suppressive proteins. We outline methods for identifying sORFs and validating their translation potential and functional characteristics. Emerging evidence highlights their diagnostic and prognostic value, as well as their therapeutic potential as peptide-based drugs or targets for precision oncology. Despite the challenges in detecting low-abundance micropeptides, their specificity and functional diversity make them promising candidates for improving glioblastoma management. Future studies should prioritize clinical translation and mechanistic exploration to harness their full potential in combating this lethal disease.