Circular RNAs in Oral Squamous Cell Carcinoma: A Systematic Review of Emerging Diagnostic and Prognostic Biomarkers

Abstract: Oral squamous cell carcinoma (OSCC) remains a major global health burden, with poor survival rates due to late diagnosis and limited prognostic precision. Circular RNAs (circRNAs) are a novel class of non-coding RNAs characterized by their covalently closed loop structure, conferring stability and tissue specificity. Recent evidence suggests circRNAs hold promise as diagnostic and prognostic biomarkers in OSCC. This article aims to systematically evaluate the diagnostic accuracy, prognostic value, and expression profiles of circRNAs in OSCC. We searched PubMed, Scopus, EBSCO, and Google Scholar databases (inception-August 2025) for studies assessing circRNAs in OSCC. Eligible studies reported diagnostic metrics (sensitivity, specificity, and AUC), prognostic outcomes (hazard ratios [HRs]), or differential expression data. Risk of bias was assessed using QUADAS-2 and NOS. Data were synthesized qualitatively. A total of 29 studies were included. Tissue-based circRNAs showed moderate diagnostic performance (AUC: 0.74-0.81), while saliva- and plasma-derived circRNAs demonstrated higher accuracy (AUC up to 0.922). Prognostic studies revealed oncogenic circRNAs were associated with poor overall survival (pooled OS HR ≈ 2.38), whereas tumor-suppressor circRNAs predicted favorable outcomes (pooled OS HR ≈ 0.43). Exosomal circRNAs, particularly circ-0000199, emerged as independent predictors of recurrence and mortality. CircRNAs exhibit strong potential as diagnostic and prognostic biomarkers in OSCC, particularly in liquid biopsy applications. However, heterogeneity, small sample sizes, and lack of multicenter validation limit immediate clinical translation. Larger, standardized studies are warranted to confirm their utility.