Despite zygotic genome activation (ZGA) is crucial for early embryonic development, its regulatory mechanism is still unclear in mammals. In the present study, we demonstrate that TRPS1, a maternal factor, plays an essential role in mouse early embryogenesis by regulating the transition from 2-cell to 4-cell embryos during preimplantation development. The absence of Trps1 could leads to impaired ZGA through AKT/CREB signaling pathway. Furthermore, our findings suggest that TRPS1 may modulate the transcription of Pde4d to influence AKT and CREB phosphorylation. Interestingly, compared to Trps1 knockdown alone, co-injection of Trps1 siRNA and Pde4d mRNA significantly enhances the development rate of 4-cell embryos. Collectively, these results indicate a negative involvement of Trps1 in mouse preimplantation embryo development by targeting the PDE4D/AKT/CREB pathway to regulate ZGA.