Evaluating the Role of Nitric Oxide Synthase (NOS) Expression in Oral Submucosal and Mucosal Lesions: A Molecular Pathology Schematic Approach

Nitric oxide (NO) signaling is involved in inflammatory processes, epithelial homeostasis, vascular function, and tissue remodeling, making it possible that expression of nitric oxide synthase (NOS) could be involved in oral mucosal and submucosal lesions. The aim of this narrative review is to discuss the reported expression patterns of NOS isoforms, their underlying molecular mechanisms, and the possible diagnostic and prognostic use. Oral leukoplakia and oral squamous cell carcinoma (OSCC) studies suggest that in certain cohorts there is increased expression of inducible NOS (NOS2/iNOS); however, these studies are limited by small sample size, methodological heterogeneity, and predominantly cross-sectional study design. There is still inconclusive evidence for oral submucous fibrosis and other potentially malignant disorders having consistent associations or independent prognosis. The distribution of NOS protein can be characterized by immunohistochemistry, which should be complemented by molecular and functional assays. Importantly, expression of NOS does not necessarily denote enzymatic activity or bioavailability of NO. The use of standardized methods and the assessment of isoforms, spatial analysis, and prospective multicenter validation are required before the establishment of NOS-derived biomarkers in routine oral pathology.