Oral cancer is a common human malignancy that still maintains an elevated mortality rate despite scientific progress. Tumorigenesis is driven by altered gene expression patterns of proto-oncogenes and tumor-suppressor genes. MicroRNAs, a class of short non-coding RNAs involved in gene regulation, seem to play important roles in oral cancer development, progression, and tumor microenvironment modulation. As properties of microRNAs render them stable in diverse liquid biopsies, together with their differential expression signature in cancer cells, these features place microRNAs at the top of promising biomarkers for diagnostic and prognostic values. In this review, we highlight eight expression levels and functions of the most relevant microRNAs involved in oral cancer development, progression, and microenvironment sustainability. Furthermore, we emphasize the potential of using these small RNA species as non-invasive biomarkers for the early detection of oral cancerous lesions. Conclusively, we highlight the perspectives and limitations of microRNAs as novel diagnostic tools, as well as therapeutic models.

Background/Objectives: Oral potentially malignant diseases (OPMD) are a group of specific conditions characterized by a variable degree of progression to oral cancer. Although these lesions are generally easily recognizable, clinicians face a difficult challenge in predicting which lesions will undergo malignancy. This fact becomes more pressing when considering that early detection of OPMD significantly influences the survival toll. Our systematic review aims to evaluate current evidence of the mechanism through which salivary microRNAs are involved in OPMD and to study the possibility of using these molecules as a novel biomarker for predicting transition to oral cancer. Methods: A comprehensive search in PubMed, Google Academic, Cochrane and Scopus databases was performed, analyzing studies conducted between 2014 and 2025. The quality of studies was evaluated using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Results: A total of 1046 articles were found; 76 articles were thoroughly examined, but only 33 articles were included in this systematic review. Salivary microRNAs, such as miR-21, miR-34a or miR-320a, were found to be dysregulated in OPMD samples compared to healthy and oral squamous cell carcinoma samples (OSCC), contributing to malignancy through gene expression alteration. Conclusions: Salivary microRNAs were found to be intricately involved in the malignant transformation of OPMD, potentially being promising biomarkers for early detection of oral cancer.