METTL3 Regulates the Senescence of Stem Cells From the Apical Papilla by Mediating the m⁶A Modification of E2F3

We aimed to investigate whether N6-methyladenosine (m⁶A) methylation modification mediated by METTL3 regulates the senescence of SCAPs, and to elucidate the underlying molecular mechanisms.

Gain- and loss-of-function assays were performed using METTL3 overexpression and knockdown models to evaluate their effects on SCAP senescence and proliferation. To identify downstream targets of METTL3, Me-RIP (methylated RNA immunoprecipitation) high-throughput sequencing was conducted. The functional role of the METTL3-m⁶A-E2F3 axis in SCAP cell cycle progression was further validated via rescue experiments.

SCAP senescence was accompanied by reduced m⁶A modification levels and downregulated METTL3 expression. Functional assays demonstrated that METTL3 overexpression attenuated SCAP senescence and enhanced proliferation, whereas METTL3 knockdown exerted the opposite effects. Me-RIP sequencing identified E2F3 as a potential downstream target gene of METTL3 in regulating SCAP senescence and proliferation. Rescue experiments confirmed that the METTL3-m⁶A-E2F3 axis modulated SCAP cell cycle progression, establishing a mechanistic link between METTL3-mediated m⁶A modification and SCAP fate.

The METTL3-E2F3 axis serves as a critical anti-senescence mechanism in SCAPs under in vitro culture conditions.

These findings lay the groundwork for the development of novel epigenetic therapies aimed at improving the therapeutic efficacy of SCAPs in regenerative endodontics.