Salivary Biomarkers as Prognostic Tools in Oral Squamous Cell Carcinoma: A Systematic Review of Survival and Progression Outcomes

Background/Objectives: Oral squamous cell carcinoma (OSCC) remains associated with poor survival, and conventional prognostic indicators such as TNM staging provide limited accuracy. Saliva has emerged as a promising liquid biopsy, but evidence regarding its prognostic role is limited. This review systematically assessed salivary proteomic, transcriptomic, and metabolomic biomarkers with prognostic value for survival and disease progression in OSCC patients. Methods: A systematic literature search was performed across PubMed, Scopus, Web of Science, Embase, and Cochrane Library up to 7 June 2025, following PRISMA 2020 and JBI guidelines. Human studies evaluating associations between salivary biomarkers and prognosis in OSCC were included. Risk of bias was assessed with the QUIPS tool. The review protocol was registered on PROSPERO (CRD42024535737). Results: Fifteen studies were included, involving 872 OSCC patients and 548 healthy controls. Biomarkers were identified using proteomic (n = 9), transcriptomic (n = 4), and metabolomic (n = 2) approaches. Among the most promising, miR-423-5p was independently associated with shorter disease-free survival (DFS), AKR1B10 levels above 646 pg/mL predicted worse overall survival (OS), and 3-methylhistidine was validated as a metabolomic marker of reduced OS. Additionally, miR-1307-5p correlated with nodal metastasis and chemoresistance, Cyfra 21-1 with recurrence and grade, and a low apoptotic/non-apoptotic salivary microvesicle ratio with poorer outcomes. However, heterogeneity in methods, small sample sizes, and lack of external validation limit clinical applicability. Conclusions: Salivary biomarkers show potential as non-invasive tools for prognostic stratification in OSCC. Among the identified candidates, miR-423-5p, AKR1B10, and 3-methylhistidine provide the most robust evidence. Future multicenter, longitudinal studies with standardized protocols and validation are essential.