SAV1 in Cooperation With FKBP52 Participates in Implantation

ABSTRACT Endometrial receptivity is restricted to an implantation window, during which progesterone (P 4 ) and estrogen (E 2 ) orchestrate uterine remodeling to support blastocyst attachment. While E 2 is indispensable for receptivity, the P 4 ‐primed uterus undergoes a transitional phase marked by luminal epithelial remodeling, stromal proliferation, and glandular differentiation, establishing competence for E 2 action. Precise coordination of P 4 ‐progesterone receptor (PR) signaling with estrogenic cues is essential; upstream regulatory mechanisms remain unclear. We identify Salvador homolog 1 (SAV1), a scaffold of the Hippo pathway, as a critical regulator of this temporal coordination. Deletion of Sav1 in endometrial cells impaired gland development, disrupted receptivity, and prevented implantation. SAV1 interacts with FKBP52), a progesterone receptor cochaperone, and promotes its mammalian STE20‐like kinase 1/2 (MST1/2)‐dependent phosphorylation, facilitating FK506‐binding protein 52 (FKBP52) nuclear localization and enhancing PR activation. Loss of SAV1 blunted progesterone signaling, delayed receptive phase, and disrupted competency for implantation. Hormonally induced reactivation after delayed implantation restored receptivity and implantation success in Sav1 ‐deficient mice. These findings identify the MST1/2‐SAV1‐FKBP52 axis as an integrator that couples Hippo signaling with steroid receptor activity. By ensuring the temporal precision of progesterone action, SAV1 orchestrates establishment of uterine receptivity and implantation, revealing a previously unrecognized role of noncanonical Hippo signaling in regulating P 4 ‐dependent responses that safeguard reproductive success.