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Review
. 2025 May;33(5):521-532.
doi: 10.1016/j.tim.2024.12.008. Epub 2025 Jan 13.

ZBP1-driven cell death in severe influenza

David F Boyd  1 , Summer Vaughn Jordan  2 , Siddharth Balachandran  3
Affiliations
Review

ZBP1-driven cell death in severe influenza

David F Boyd et al. Trends Microbiol. 2025 May.

Abstract

Influenza A virus (IAV) infections can cause life-threatening illness in humans. The severity of disease is directly linked to virus replication in the alveoli of the lower respiratory tract. In particular, the lytic death of infected alveolar epithelial cells (AECs) is a major driver of influenza severity. Recent studies have begun to define the molecular mechanisms by which IAV triggers lytic cell death. Z-form nucleic-acid-binding protein 1 (ZBP1) senses replicating IAV and drives programmed cell death (PCD) in infected cells, including apoptosis and necroptosis in AECs and pyroptosis in myeloid cells. Necroptosis and pyroptosis, both lytic forms of death, contribute to pathogenesis during severe infections. Pharmacological blockade of necroptosis shows strong therapeutic potential in mouse models of lethal influenza. We suggest that targeting ZBP1-initiated necroinflammatory cell lysis, either alone or in combination antiviral drugs, will provide clinical benefit in severe influenza.

Keywords: RIPK3; ZBP1; apoptosis; influenza A virus; necroptosis; pyroptosis.

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Conflict of interest statement

Declaration of interests S.B. is listed as co-inventor on patent applications related to the UH15 series of compounds filed by Tufts University, the University of Houston, and the Institute for Cancer Research, Fox Chase Cancer Center. S.B. holds equity in Vaayu Therapeutics. The other authors declare no competing interests.

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