Homo sapiens Raw sequence reads

Recurrent implantation failure (RIF), a challenging issue in reproductive medicine, has been associated with increased endometrial senescence by recent transcriptomic studies. Previously, we revealed downregulation of CDC42, an important molecule involved in various senescence-related diseases, in RIF endometria. However, the specific role of CDC42 in endometrial function of RIF patients remains unknown. We collected endometria from fertile control and RIF patients to explore the correlation between CDC42 expression and endometrial senescence. Additionally, we utilized a CDC42-knockdown adenovirus and primary endometrial stroma cells to verify the causal relationship between CDC42 deficiency and senescence, as well as its underlying mechanism. We observed a correlation between stromal CDC42 deficiency and senescence in RIF endometria. CDC42 Knockdown induced premature senescence of endometrial stromal cells, impairing decidualization and inhibiting trophoblast invasion. Transcriptomic analysis showed Wnt signaling activation in CDC42-deficient stromal cells. Further mechanistic studies suggested that CDC42 interacted with AKT competitively and impeded the binding of GSK3b to AKT. Knockdown of CDC42 increased phosphorylation and inhibition of GSK3b by AKT, leading to accumulation and nuclear translocation of b-catenin. Wnt signaling inhibitors partially ameliorated the endometrial senescence caused by CDC42 deficiency, and improved decidualization and trophoblast invasion ability. These findings underscore the significance of CDC42 in maintaining optimal endometrial function and propose its potential as a therapeutic target for enhancing endometrial receptivity in RIF patient. Furthermore, the development of Wnt signaling inhibitors holds promise as clinical interventions to ameliorate the implantation rate and clinical pregnancy outcomes among RIF patients with endometrial senescence.