Zbp1, also known as DAI or DLM-1, is an interferon-inducible protein that functions as a critical innate immune sensor. It harbors nucleic acid-binding domains for left-handed helix (Z-form) and receptor-interacting protein homotypic interaction motif (RHIM) domains for protein homotypic interactions. Zbp1 is involved in sensing not only viral RNA products but also endogenous nucleic acid ligands, and it plays a key role in regulating cell death (such as pyroptosis, apoptosis, and necroptosis, also known as PANoptosis), inflammasome activation, and pro-inflammatory responses [1,4,6]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In Influenza A virus infection, Zbp1 senses the Z-RNA produced, initiating RIPK3-mediated necroptosis. This involves Zbp1-mediated activation of RIPK3 in the nucleus, leading to nuclear envelope disruption, DNA leakage, and eventual necroptosis. MLKL-deficient mice show reduced nuclear disruption, decreased neutrophil recruitment, and increased survival after a lethal dose of IAV, highlighting Zbp1's role in this process [2]. In addition, ADAR1, which interacts with Zbp1, suppresses Zbp1-mediated PANoptosis. Adar1fl/flLysMcre mice are resistant to colorectal cancer and melanoma development, and deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice, suggesting Zbp1's role in tumorigenesis regulation [3]. Mice lacking ZBP1 are protected from Doxorubicin-induced cardiotoxicity as ZBP1 cooperates with cGAS to sense mitochondrial DNA, sustain STAT1 phosphorylation and type I interferon signaling [5].

In conclusion, Zbp1 is a crucial innate immune sensor regulating cell death, inflammation, and immune responses. Studies using KO/CKO mouse models have revealed its significant roles in infectious diseases like influenza, tumorigenesis, and cardiotoxicity. Understanding Zbp1's functions provides potential avenues for developing therapeutic strategies against these diseases.