Cysteine proteases in oral potentially malignant disorders: Molecular drivers, diagnostic signatures, and therapeutic opportunities.

Cysteine proteases are crucial enzymes regulating protein turnover, apoptosis, signalling, and tissue remodelling, and have emerged as important regulators of the oral epithelial microenvironment with increasing evidence implicating them in the progression of oral potentially malignant disorders (OPMDs) and their potential contribution to malignant transformation toward oral squamous cell carcinoma (OSCC). Dysregulated expression of these enzymes influences key molecular pathways, notably NF-κB, MAPK, protease-activated receptor (PAR) signalling, and apoptotic cascades, although the extent to which individual cysteine proteases act as primary drivers, facilitators of tumour-associated microenvironmental remodelling, or biomarkers of disease progression remains incompletely defined, which govern extracellular matrix remodelling, inflammation, proliferation, migration, and immune evasion, processes associated with malignant progression. Their diagnostic potential is evident through distinct expression patterns in saliva and tissue, suggesting potential utility as adjunct salivary biomarkers for early detection; however, their diagnostic performance relative to established approaches such as toluidine blue staining, autofluorescence imaging, and cytopathological assessment remains to be systematically evaluated. On the therapeutic front, approaches such as selective inhibitors, plant-derived proteases, prodrugs, and multifunctional theranostic agents have been explored experimentally for modulating inflammation, fibrosis, and tumour invasion, while innovative drug delivery strategies aim to increase specificity and reduce systemic toxicity. Nevertheless, most cysteine-protease-targeted interventions remain at preclinical or early translational stages, and clinical validation in oral diseases is currently limited. However, challenges including resistance mechanisms, lack of absolute selectivity, and potential off-target effects necessitate refined computational and experimental strategies for rational inhibitor design. Furthermore, the relative contribution of individual cysteine proteases across different OPMD subtypes remains insufficiently characterized. Future advances lie in validating protease-based biomarkers across diverse populations and embedding them into personalized medicine frameworks.