Abstract
Background Glioma is the most common primary malignant brain tumor in adults, with poor prognosis despite multimodal therapy. Circulating microRNAs offer potential as minimally invasive prognostic biomarkers. MicroRNA-15b and microRNA-221 have been implicated in glioma pathobiology, but no systematic review has synthesized the clinical evidence for their prognostic value in serum/plasma. Methods A systematic review was conducted in accordance with PRISMA 2020 guidelines and prospectively registered with PROSPERO (CRD420251230065). Four electronic databases were searched from inception to June 2026. Eligible studies enrolled adult glioma patients, measured serum or plasma microRNA-15b and/or microRNA-221 and reported quantitative prognostic outcome. Narrative synthesis was performed due to heterogeneity precluding meta-analysis. Results Five studies (357 participants, four countries) were included. Risk of bias was low in one study, moderate in two, and high in two. For circulating microRNA-15b, two studies reported contradictory associations: one found higher serum extracellular vesicle (EV) microRNA-15b-3p levels linked to inferior overall survival (Spearman R = −0.2746, p = 0.043), while the other reported higher serum microRNA-15b independently associated with improved two-year survival (HR = 0.62; 95% CI, 0.30–0.98; p = 0.049). For circulating microRNA-221, three studies consistently showed elevated expression associated with worse overall and progression-free survival. The only reported hazard ratio (univariate) for microRNA-221 was 2.40 (95% CI, 1.42–4.05). Conclusion Circulating microRNA-221 demonstrates a consistent but methodologically limited prognostic value in adult glioma, derived solely from univariate analyses with concerns about cohort independence. The prognostic role of circulating microRNA-15b remains inconclusive due to contradictory findings across non-equivalent measurement platforms. Prospective, adequately powered studies with standardized methodology and multivariable survival modelling are required before clinical application of either marker. PROSPERO; registration ID CRD420251230065.