Embryo‐Derived Cathepsin B Promotes Implantation and Decidualization by Activating Pyroptosis

Abstract Embryo implantation and decidualization are crucial for a successful pregnancy. How the inflammatory response is regulated during these processes is undefined. Pyroptosis is an inflammatory form of cell death mediated by gasdermin D (GSDMD). Through in vivo, cultured epithelial cells and organoids, it is shown that pyroptosis occurs in epithelial cells at the implantation site. Compared with those on day 4 of pseudopregnancy and delayed implantation, pyroptosis‐related protein levels are significantly increased on day 4 of pregnancy and activated implantation, suggesting that blastocysts are involved in regulating pyroptosis. Blastocyst‐derived cathepsin B (CTSB) is stimulated by preimplantation estradiol‐17β and induces pyroptosis in epithelial cells. Pyroptosis‐induced IL‐18 secretion from epithelial cells activates a disintegrin and metalloprotease 12 (ADAM12) to process the epiregulin precursor into mature epiregulin. Epiregulin (EREG) enhances in vitro decidualization in mice. Pyroptosis‐related proteins are detected in the mid‐secretory human endometrium and are elevated in the recurrent implantation failure endometrium. Lipopolysaccharide treatment in pregnant mice causes implantation failure and increases pyroptosis‐related protein levels. Therefore, the data suggest that modest pyroptosis is beneficial for embryo implantation and decidualization. Excessive pyroptosis can be harmful and lead to pregnancy failure.