Context-dependent roles of microRNA-21 in oral medicine: Established oncogenic relevance in OSCC and emerging regenerative potential in MRONJ

Objective: To critically examine the context-dependent role of microRNA-21 (miR-21) in medication-related osteonecrosis of the jaw (MRONJ), oral potentially malignant disorders (OPMDs), and oral squamous cell carcinoma (OSCC), focusing on its biological functions, biomarker potential, therapeutic implications, and translational challenges. Design: A narrative literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science from database inception to September 2026. Experimental, preclinical, clinical, and evidence-synthesis studies addressing the biological and clinical significance of miR-21 across regenerative and oncogenic oral contexts were considered. Results: miR-21 showed context-dependent effects supported by different evidence bases. In MRONJ, emerging preclinical evidence suggests that miR-21 restoration may counteract antiresorptive-induced osteoclast dysfunction and support bone regeneration. By contrast, broader experimental and clinical evidence supports its oncogenic relevance in OPMDs and OSCC, where overexpression promotes tumor progression and therapeutic resistance. Evidence also supports its diagnostic and prognostic potential, although its clinical utility as a standalone biomarker remains limited. These opposing effects raise safety concerns regarding regenerative miR-21 supplementation, particularly in oncologically susceptible tissues and in patients receiving antiresorptive therapy for skeletal metastatic disease. Conclusions: Current evidence supports an asymmetric, context-dependent framework: miR-21 restoration in MRONJ remains an emerging preclinical regenerative strategy, whereas its oncogenic relevance in OPMDs and OSCC has a broader evidence base. Clinical translation requires tissue-specific, controlled modulation and careful consideration of oncological risk.