ABSTRACT Zika virus (ZIKV) infection is known to cause microcephaly in newborns, and its outbreaks have previously emerged as a global public health crisis. The lack of a preventive vaccine or specific antiviral drugs underscores the urgency of investigating the detailed mechanisms of pathogenesis. We identified that interferon‐induced protein 44 (IFI44) is significantly upregulated following ZIKV infection, but its role in ZIKV pathogenesis remains unclear. Using A549 and 2FTGH cells, we established ZIKV‐infected cell models and employed quantitative real‐time PCR and Western blotting to demonstrate that IFI44 overexpression suppressed ZIKV replication, whereas IFI44 knockdown via specific small interfering RNA promoted viral replication. Mechanistically, IFI44 inhibited early‐stage ZIKV infection, including viral attachment and entry into host cells. Further analyses revealed that IFI44 promoted IFN‐β expression, triggering activation of the Jak/STAT signaling pathway—as evidenced by increased phosphorylated STAT1 (p‐STAT1), enhanced interferon‐stimulated response element activity, and upregulated the downstream interferon‐stimulated genes (MX1, OAS2, IFIT2, and RIG‐I). Collectively, these findings demonstrate that ZIKV infection induced IFI44 expression, which acts as a positive feedback regulator of the Jak/STAT pathway to restrict viral replication. Our results establish IFI44 as a key component of the host antiviral response against ZIKV, highlighting its potential as a therapeutic target.
Lai et al. (Sun,) studied this question.