Abstract
Pathogenic viruses threaten fetal development by achieving vertical transmission and instigating placental immunopathology, while the pathobiological mechanisms and effective therapeutics remain critical gaps. Here, we reveal cyclophilin A (CypA) as a crucial host factor necessary for Zika virus (ZIKV) replication in human placental trophoblasts, acting independently of its canonical functions. ZIKV infection recruits CypA into the viral replication organelle and reconfigures its interactome, thereby subverting host RNA decay machinery and stress granule-mediated antiviral surveillance. Both genetic ablation of CypA and its pharmacological inhibition with clinically approved drug ciclosporin A (CsA) restrict ZIKV transplacental transmission and corresponding placental and fetal pathologies. Beyond its anti-ZIKV potency, CsA concurrently counteracts pathological type I interferon signaling by targeting the JAK1-STAT1/2 pathway, broadly ameliorating pregnancy-specific interferonopathies driven by viral infection or endogenous double-stranded RNA stress. Our findings elucidate CypA-governed ZIKV pathogenesis and license CsA as a promising dual-action therapeutic to counteract congenital viral infections.
Acknowledgements
We thank Drs. Jiahuai Han and Haibin Wang at Xiamen University for providing genetic mouse models.
Funding
This work was supported by grants from the National Natural Sciences Foundation in China (82130047 to B.C., 82401973 to W.Y., and 82571928 to X.H.), the National Key Research and Development Program of China (2022YFC2702400 to B.C. and 2022YFC2704702 to X.H.), Natural Science Foundation of Xiamen, China (3502Z202372001 to X.H.), Open Funding of State Key Laboratory of Reproductive Medicine and offspring health (SKLRM-K202401 to B.C.), Fundamental Research Funds for the Central Universities (20720240113 to X.H.).
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Yu, W., Cao, H., Deng, Z. et al. A dual-pronged host-directed therapeutic targeting cyclophilin A and pathogenic interferon response abrogates virus-triggered pregnancy pathologies. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73497-z
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DOI: https://doi.org/10.1038/s41467-026-73497-z
