Zbp1, also known as Z-DNA-binding protein 1, DAI or DLM-1, is a crucial innate immune sensor. It contains nucleic acid-binding domains for Z-form nucleic acids and receptor-interacting protein homotypic interaction motif (RHIM) domains for protein interactions. Zbp1 is involved in sensing viral RNA products and endogenous nucleic acid ligands, regulating cell death (pyroptosis, apoptosis, necroptosis, collectively PANoptosis), inflammasome activation, and pro-inflammatory responses [1,3,6]. It plays a significant role in host defense against viral infections and is also relevant in development [3]. Genetic models like KO/CKO mouse models are valuable for studying Zbp1's functions.

In influenza virus infection, Zbp1 senses Z-RNA produced, initiating PANoptosis through the formation of the ZBP1-NLRP3 inflammasome. Zbp1 recruits RIPK3 and caspase-8 for inflammasome activation, and host factors like those in the type I interferon signaling pathway and caspase-6, as well as viral proteins (M2, NS1, PB1-F2), regulate this process [1]. In addition, influenza virus-generated Z-RNAs activate Zbp1 in the nucleus, leading to RIPK3-mediated MLKL activation, nuclear envelope disruption, DNA leakage, and necroptosis. MLKL-deficient mice show reduced nuclear disruption in lung epithelia, decreased neutrophil recruitment, and increased survival after a lethal IAV dose [2]. Mice with RIPK1-related mutations (Ripk1mR/mR, RIPK1E-KO, FADDIEC-KO) have ZBP1-dependent perinatal lethality, skin inflammation, and colitis respectively, triggered by Zα-dependent sensing of endogenous ligands [6]. Adar1fl/flLysMcre mice (lacking ADAR1 in myeloid cells) are resistant to colorectal cancer and melanoma development, but deletion of ZBP1's Zα2 domain restores tumorigenesis in these mice [4]. Mice lacking ZBP1 are protected from Doxorubicin-induced cardiotoxicity as ZBP1 cooperates with cGAS in sensing mitochondrial DNA to promote IFN-I signaling and cardiotoxicity [5].

In conclusion, Zbp1 is a key regulator in innate immunity, cell death, and inflammation. Studies using KO/CKO mouse models have revealed its role in infectious diseases like influenza, and in conditions such as cardiotoxicity and tumorigenesis. Understanding Zbp1's functions provides potential therapeutic strategies for treating infectious, inflammatory, and neoplastic diseases.