FTO Controls Endometrial Receptivity and Embryo Implantation through Regulating m⁶A and H3K27me3

Endometrial receptivity is essential for implantation and pregnancy, yet the role of the m⁶A demethylase FTO remains unclear. We examined epithelial Fto and Wnt signaling during the implantation window using CRISPR/Cas9 Fto knockout mice analyzed at gestational day 4.5 and an Ishikawa and BeWo co-culture model. Histology, TUNEL, Immunofluorescence, m⁶A meRIP-seq, CUT&Tag and qRT-PCR were applied. Fto^KO uteri showed reduced weight, glandular loss, altered Ck18, vimentin and Foxa2, and increased Muc1. Fto deficiency elevated Wnt5b and reduced canonical Wnt/β-catenin activity, coincident with diminished H3K27me3 at the Wnt5b locus. Mechanistically, FTO loss increased m⁶A on SUZ12 mRNA, lowering its stability, weakening PRC2 function and de-repressing WNT5B. Functionally, FTO depletion impaired spheroid adhesion and Wnt signaling, reversible by SUZ12 restoration or WNT5B inhibition. Thus, FTO preserves epithelial integrity and endometrial receptivity by stabilizing SUZ12 mRNA and maintaining H3K27me3 mediated repression of WNT5B, implicating the FTO/SUZ12/WNT5B axis in implantation failure.