Emerging roles of m⁶A modification in endodontic diseases: a systematic review

This review aims to synthesize and evaluate the evidence on the role of N⁶-methyladenosine (m⁶A) modification in pathogenesis, progression, and tissue repair of endodontic diseases, focusing on its regulatory functions in dental stem cells.

Two reviewers independently searched four databases for studies published by May 2025. The protocol was registered with PROSPERO (CRD420251233698). The certainty of findings was assessed using the CERQual approach.

Of 680 initial records, 27 studies were included. Findings demonstrated that m⁶A modification dynamically regulates enamel/root development, osteogenic/odontogenic differentiation of dental stem cells, and inflammatory responses in endodontic diseases. Five key themes were identified: pulpitis pathogenesis and repair, apical periodontitis pathogenesis and repair, and tooth development/pulp regeneration. Mechanistically, in pulpitis, METTL3 exacerbates inflammation via NF-κB/MAPK pathways, whereas FTO aggravates bone destruction in apical periodontitis. M⁶A regulates stem cell differentiation by modulating osteogenic/odontogenic gene expression and lncRNA/miRNA networks. METTL3 promotes tissue repair by stabilizing target mRNAs, while FTO enhances RUNX2 splicing. M⁶A regulates tooth morphogenesis through WTAP-SHH and METTL3-NFIC pathways.

This review establishes m⁶A modification as an important epitranscriptomic regulator that modulates inflammation and repair in endodontic diseases. Further clinical studies are needed to validate these mechanisms and their therapeutic potential.