MEK1/2 inhibition prevents DENV and ZIKV infection via disrupting the cytoskeletal vimentin cage required for viral replication.

Flaviviridae Dengue virus (DENV) and Zika virus (ZIKV) have posed significant threats to global public health in the past decades. Despite extensive study on therapeutic strategies against these viruses, effective treatment options are still lacking. Within host cells, the cytoskeletal vimentin intermediate filament network facilitates viral replication during DENV and ZIKV infection by shrinking and forming a cage-like structure. Our previous work indicated that MEK1/2 inhibitors can induce the dispersion of vimentin, but their potential impact on flavivirus infection remains unclear. Here, we observed that the MEK1/2 signaling pathway is activated in host cells infected with DENV and ZIKV. Treatment with MEK1/2 inhibitors significantly impaired the replication of both viruses. Further mechanistic studies revealed that MEK1/2 inhibitors prevent viral infection by promoting the dispersion of intracellular vimentin network, thereby disrupting the cytoskeletal structure required for viral replication. Our findings not only expand the understanding of vimentin regulatory mechanisms from a cellular biology perspective but also provide a new perspective on MEK1/2 inhibition as a potential anti-DENV and anti-ZIKV strategy.