A prospective human pregnancy requires successful implantation and decidualization, which are two critically orchestrated reproduction processes (Ochoa-Bernal and Fazleabas, 2020). Decidualization occurs in endometrial stroma and involves the proliferation and differentiation of endometrial stromal cells (ESCs) during early pregnancy (Liu et al., 2021a; Ticconi et al., 2021). The endometrium transforms into a robust decidual matrix that accommodates the fetal placenta during early pregnancy. The decidua provides a tolerant environment for placental development and embryo hatching during pregnancy(Bortoletto et al., 2022). Decidualization of ESCs is regulated by several factors, including immunity, angiogenesis, and hormones (Murata et al., 2022). A recent study showed that endocrine-disrupting chemicals reduced decidualization of human ESCs in vitro (Lavogina et al., 2022). A previous study has shown that the combined treatment with ovarian steroid hormone (E2 and medroxyprogesterone acetate) and thyroid hormone facilitates the in vitro decidual response of human ESCs and promotes the expression of progesterone receptor (PR) (Kakita-Kobayashi et al., 2020). Defective decidualization is a leading factor for recurrent implantation failure and early pregnancy loss (EPL) (Liu et al., 2021a).

Ubiquitin-specific protease 7 (USP7), also known as herpes virus-associated ubiquitin-specific protease (HAUSP), is one of the members of the ubiquitin-specific proteases in the deubiquitinating enzyme family, which disassembles ubiquitin-protein conjugates to protect substrates from degradation (Rawat et al., 2019). USP7 regulates various proteins involved in multiple cellular pathways, including Wnt, NOTCH1, and NF-κB (Nininahazwe et al., 2021; Lu et al., 2021; Zhou et al., 2021). USP7 is widely reported to interact with p53 and mediate its deubiquitination (Nininahazwe et al., 2021). A recent study suggested that gene variants of USP7 in the p53 pathway were associated with ongoing pregnancy rates and later pregnancy maintenance (Palomares et al., 2021). Abnormal USP7 gene expression might lead to unsuccessful pregnancy outcomes (Palomares et al., 2021). Nevertheless, the underlying mechanism by which USP7 modulates reproductive processes in early pregnancy remains to be elucidated.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor for signal transduction that regulates various cellular processes, including apoptosis, oxidative stress, and differentiation, in different cell types (Wu et al., 2022; Wei et al., 2022). A previous study demonstrated that progesterone-induced blocking Factor 1 (PIBF1) downregulated the expression of IL6 and p-STAT3 to inhibit ESC viability and decidualization in the mid-luteal phase of the menstrual cycle (Zhou et al., 2020). Another study revealed that the expression of STAT3 was increased during pregnancy in the endometrium (Liu et al., 2021b). Here, we report on the potential role of USP7 in normal decidual tissue and in that of women who miscarried and examined the possible role of this enzyme at the molecular and cellular levels. Our observations provide insight into a potential mechanism for USP7 in the decidualization of ESCs.