A stress-responsive morphogenetic program of the uterine epithelium safeguards the establishment of early pregnancy

Successful embryo implantation requires coordinated interactions between the endometrial epithelium, stroma, and the embryo, yet underlying mechanisms have not been fully understood. Using three-dimensional histological reconstruction combined with single-cell and spatial transcriptomics, we identify a previously unrecognized phase of luminal architectural reorganization preceding embryo attachment. Within a narrow peri-implantation window, the luminal epithelium rapidly remodels from a highly folded structure into a flattened, organized architecture that provides a scaffold for embryo positioning. This morphogenetic transition is accompanied by activation of stress-responsive signaling across epithelial and stromal compartments. Functional analyses show that uterine-specific deletion of the stress-responsive MAP kinase p38 disrupts luminal remodeling, leading to persistent epithelial folding, failed embryo attachment, and infertility despite normal hormone levels and embryo development. Although combined progesterone and leukemia inhibitory factor supplementation rescues embryo attachment in p38-deficient uteri, luminal disorganization, abnormal stromal responses, and impaired pregnancy progression persist. These findings identify a p38-dependent, stress-responsive morphogenetic program that coordinates epithelial dynamics and epithelial-stromal communication to establish implantation-competent luminal architecture.