METTL3 Affects Endometrial Receptivity Through Modulation of P62-Mediated Autophagic Flux

Endometrial receptivity is a crucial factor in the successful implantation of embryos. Our previous study has proved that METTL3 acted as a key regulatory factor in endometrial receptivity. However, the regulatory relationship between METTL3-mediated modifications to m⁶A and autophagy in endometrial receptivity is not yet elucidated. Here, this study investigated the functions and essential processes of METTL3 in autophagy. In this study, METTL3 loss is linked to autophagy dysregulation in endometrial tissue with recurrent implantation failure, and METTL3 deletion reduced the attachment efficiency of BeWo cell spheres. Mechanically, down-expression of METTL3 increased H3K9me3 modification at the gene body of P62 by upregulating SUV39H1 expression, leading to the upregulation of P62 mRNA expression. Meanwhile, METTL3 absence enhanced the mRNA stability of P62 in a m⁶A-dependent manner. These alterations collectively lead to increased P62 expression, enhancing senescence, inflammation, apoptosis, and autophagy in endometrial cells. These findings elucidate the molecular underpinnings of endometrial receptivity and highlight potential therapeutic targets for recurrent implantation failure.