Secretoglobin family 2A member 1 downregulation impairs endometrial decidualization in recurrent implantation failure by disrupting protein kinase B interaction and forkhead box O1 nuclear translocation.

Embryo implantation requires precise endometrial receptivity, which is critically dependent on progesterone-induced stromal decidualization during the mid-secretory phase. In recurrent implantation failure (RIF), this process is impaired, yet the underlying mechanisms remain poorly understood. Here, by integrating bulk and single-cell transcriptomic data, we found that secretoglobin, family 2A, member 1 (SCGB2A1) was dynamically expressed in the human endometrium, with peak expression in the stromal compartment during the mid-secretory phase. This expression pattern was validated in samples from fertile control women, whereas in individuals with RIF, SCGB2A1 was significantly downregulated in both the endometrial stroma and uterine fluid during this critical window for decidualization. Functionally, SCGB2A1 was transcriptionally regulated by the progesterone signaling axis, and its knockdown in endometrial stromal cells impaired decidual marker expression and cytoskeletal remodeling. Mechanistically, we reported for the first time that SCGB2A1 physically interacted with protein kinase B (AKT), as demonstrated by RNA-seq, proteomic analyses, and co-immunoprecipitation assays. Loss of SCGB2A1 disrupts this interaction, resulting in aberrant AKT activation, increased AKT/forkhead box O1 (FOXO1) phosphorylation, and impaired FOXO1 nuclear translocation, ultimately suppressing decidual marker expression. Notably, treatment with an AKT inhibitor partially rescued the decidualization defects caused by SCGB2A1 deficiency. These findings reveal a previously unrecognized molecular defect in RIF, implying that SCGB2A1 may contribute to progesterone-mediated decidualization and could serve as a potential marker for assessing endometrial receptivity.