Phosphodiesterase 4D protects against embryo loss via KLF4-IFITM3 axis during viral infection

Phosphodiesterase 4D (PDE4D), a cAMP-specific hydrolase, is a key regulator of intracellular cyclic nucleotide levels and plays a crucial role in modulating inflammation and immune responses. Emerging evidence suggests that the cAMP/PKA signaling pathway is closely associated with the regulation of viral infections. However, the mechanisms by which PDE4D influences viral pathogenesis remain poorly understood. In this study, we identify PDE4D as a positive regulator of antiviral immunity. Overexpression of PDE4D markedly inhibited viral replication, mitigated virus-induced cell death, and attenuated excessive inflammatory responses. Mechanistically, PDE4D enhances the expression of IFITM3 by downregulating the transcriptional repressor KLF4 during viral infection. Furthermore, we demonstrated that PDE4D rescued embryonic loss and restored the abnormal placental labyrinth structure induced by VSV infection. These findings highlight the critical function of PDE4D in antiviral innate immune responses.