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.