TFAP2A-mediated downregulation of UBE2C is crucial for endometrial decidualization and embryo implantation.

Decidualization triggered by human endometrial stromal cells (HESCs) is a critical step in the establishment of endometrial receptivity, which provides an ideal environment for embryo implantation. However, the specific regulatory networks and core genes involved in the decidualization process remain incompletely characterized. Here, we identified ubiquitin-conjugating enzyme 2C (UBE2C), a key cell cycle regulator, as a pivotal factor in decidualization through comprehensive in vitro and in vivo investigations. RNA sequencing revealed UBE2C as a potential hub gene in the human endometrium. We found UBE2C expression was significantly downregulated in secretory-phase endometrium and in vitro decidual HESCs. Functional studies demonstrated that UBE2C overexpression attenuated decidual marker expression and disrupted normal proliferation in HESCs, mechanistically linked to NF-κB signaling pathway. Consistent with in vitro findings, mice studies showed UBE2C downregulation in peri-implantation uterine tissue, with uterine-specific UBE2C overexpression impairing both embryo implantation and decidualization. Further mechanistic exploration identified transcription factor AP-2 alpha (TFAP2A) as a novel mediator of UBE2C. Decidual stimulation promoted TFAP2A degradation via the ubiquitination pathway. Clinical relevance was established through the observation of elevated UBE2C and TFAP2A expression in secretory endometrium from recurrent implantation failure (RIF) patients. In conclusion, for endometrial decidualization and embryo implantation, TFAP2A-mediated downregulation of UBE2C is required. Dysregulation of this axis may compromise endometrial receptivity, suggesting UBE2C and TFAP2A as promising therapeutic targets for decidualization-related disorders such as RIF.