Z-DNA binding protein 1 (ZBP1) is a cytosolic nucleic acid sensor that functions as a master regulator of innate immune responses and inflammatory cell death. ZBP1 recognizes pathogen-associated molecular patterns including bacterial DNA, viral Z-RNA, and Z-DNA through its Zα-containing domains 12. Upon activation, ZBP1 initiates type I interferon production and triggers RIPK3-mediated necroptosis and PANoptosis (a coordinated inflammatory cell death involving apoptosis, necroptosis, and pyroptosis) 123. ZBP1 operates within a multi-protein PANoptosome complex containing AIM2, pyrin, caspase-1, caspase-8, RIPK3, and FADD, providing coordinated host defense against infections including herpes simplex virus 1 and Francisella novicida 3. During influenza infection, ZBP1 senses viral Z-RNA in the nucleus, triggering nuclear MLKL activation that disrupts the nuclear envelope and activates neutrophils 2. ADAR1 negatively regulates ZBP1-mediated PANoptosis through Zα domain interactions, and this suppression promotes tumorigenesis 4. Beyond pathogenic sensing, ZBP1 mediates heat stress-induced cell death independent of nucleic acid sensing 5. These functions establish ZBP1 as a critical sentinel balancing host defense against infection with potential pathological consequences in severe disease and cancer development.