Molecular Mechanisms of Zika Virus Entry into Host Cells

The World Health Organization classifies mosquito-borne viruses as a major global public health threat with pandemic risk and urges all nations to strengthen pandemic preparedness. As a representative mosquito-borne flavivirus, ZIKV bears prominent pandemic capacity. Its distinctive neurotropic property and capability of vertical transmission create unique pathogenic hazards and transmission risks. Owing to the absence of approved vaccines and targeted antiviral therapeutics, the prevention and management of ZIKV outbreaks remain extremely challenging. Viral entry into host cells marks the very first step of productive ZIKV infection, and mechanistic investigations into this entry process lay an essential theoretical foundation for developing small-molecule agents that block ZIKV cellular entry. This review summarizes recent advances concerning ZIKV host receptor usage, membrane fusion cascades, and entry-targeted inhibitor development; systematically discusses existing inconsistencies and core controversies in cell type-dependent entry pathways, functionally redundant host receptor usage, especially the disputed AXL receptor, and unresolved molecular details of membrane fusion resulting from diverse experimental models and technical limitations; and proposes targeted future research directions to resolve these bottlenecks and clarify the context-dependent ZIKV entry mechanisms.