The METTL3-PGR-WNT4 axis is critical for human endometrial stromal cell decidualization

Mouse studies have established the crucial role for uterine m⁶A modification in embryo implantation and decidualization. Nevertheless, the importance of this epigenetic modification in the analogous biological process in humans remains incompletely understood. Here, we show that methyltransferase-like 3 [METTL3; N(6)-adenosine-methyltransferase catalytic subunit METTL3], the core component of the m⁶A writer complex, was significantly decreased in the endometrium of women with recurrent implantation failure during the window of implantation. Furthermore, we demonstrated that small interfering RNA (siRNA)-mediated knockdown of METTL3 in cultured human endometrial stromal cells (HESCs) resulted in impaired decidualization, which was primarily attributed to the downregulation of WNT4, a crucial factor for decidualization. Mechanistically, we discovered that METTL3 positively regulates the expression of the Progesterone Receptor (PGR) protein through m⁶A modification at the 5' untranslated region (5'-UTR) of PGR mRNA. In turn, WNT4 functions downstream of PGR, serving as a secondary target of METTL3. In conclusion, this study provides evidence that the METTL3-PGR-WNT4 pathway is essential for human decidualization. Our findings offer novel insights into the molecular mechanisms underlying human decidualization, potentially paving the way for future therapeutic strategies in reproductive medicine.

METTL3; WNT4; decidualization; progesterone receptor; recurrent implantation failure.