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Background  Dental pulp stem cells (DPSCs) are a promising cell source in endodontic regeneration and tissue engineering with limited self-renewal and pluripotency capacity.  N  6 -methyladenosine (m 6 A) is the most prevalent, reversible internal modification in RNAs associated with stem cell fate determination. In this study, we aim to explore the biological effect of m 6 A methylation in DPSCs.    Methods  m 6 A immunoprecipitation with deep sequencing (m 6 A RIP-seq) demonstrated the features of m 6 A modifications in DPSC transcriptome. Lentiviral vectors were constructed to knockdown or overexpress methyltransferase like 3 (METTL3). Cell morphology, viability, senescence, and apoptosis were analyzed by β-galactosidase, TUNEL staining, and flow cytometry. Bioinformatic analysis combing m 6 A RIP and shMETTL3 RNA-seq functionally enriched overlapped genes and screened target of METTL3. Cell cycle distributions were assayed by flow cytometry, and m 6 A RIP-qPCR was used to confirm METTL3-mediated m 6 A methylation.    Results  Here, m 6 A peak distribution, binding area, and motif in DPSCs were first revealed by m 6 A RIP-seq. We also found a relatively high expression level of METTL3 in immature DPSCs with superior regenerative potential and METTL3 knockdown induced cell apoptosis and senescence. A conjoint analysis of m 6 A RIP and RNA sequencing showed METTL3 depletion associated with cell cycle, mitosis, and alteration of METTL3 resulted in cell cycle arrest. Furthermore, the protein interaction network of differentially expressed genes identified Polo-like kinase 1 (PLK1), a critical cycle modulator, as the target of METTL3-mediated m 6 A methylation in DPSCs.    Conclusions  These results revealed m 6 A methylated hallmarks in DPSCs and a regulatory role of METTL3 in cell cycle control. Our study shed light on therapeutic approaches in vital pulp therapy and served new insight into stem cell-based tissue engineering.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13287-021-02223-x.

METTL3-mediated m6A modification regulates cell cycle progression of dental pulp stem cells