The use of lysosomal acidification inhibitor NH<sub>4</sub>Cl significantly reversed S100A6-mediated downregulation of NS3 protein levels, suggesting that S100A6 degrades NS3 via the lysosomal pathway.<h4>Conclusion</h4>ZIKV infection upregulated host S100A6, which acted as an anti-infection factor by specifically targeting ZIKV-NS3 for degradation, thereby inhibiting viral replication. Here, S100A6 is linked to Zika virus infectious disease.