ZBP1 and IFI16: novel innate sensors and inflammation regulation under infection stress

The innate immune system is the first line of defense against infection, using pattern recognition receptors to sense pathogens and abnormal host-derived nucleic acids. Among these, Z-DNA-binding protein 1 (ZBP1) and interferon gamma-inducible protein 16 (IFI16) are two important nuclear and cytosolic nucleic acid sensors attracting recent attention. These sensors play key roles in detecting abnormal nucleic acids from viruses, bacteria, and damaged host cells. They trigger downstream innate immune responses to regulate inflammation. Despite much progress, key questions remain about how they are exactly activated under infection stress, the complexity of their signaling networks, and their dual roles in protective immunity and pathological inflammation. This review summarizes the structural features of ZBP1 and IFI16, how they recognize ligands, and their interactions with key signaling molecules (including RIPK1, RIPK3, MLKL, and caspase-1). We then emphasize cell fate decisions mediated by these sensors. Especially, ZBP1 is the core upstream regulator of PANoptosis (an integrated form of programmed cell death combining pyroptosis, apoptosis, and necroptosis via the PANoptosome complex), alongside classical cell death pathways. In addition, we review recent advances to highlight functional roles of ZBP1 and IFI16 in herpesvirus, influenza virus, and bacterial infections, and their dysregulation in autoimmune diseases. For IFI16, human studies and murine homolog-based evidence are analyzed. Further we review unique and overlapping functions, including a comparison with other canonical nucleic acid sensors (e.g., cGAS, AIM2, RIG-I) and analyze the ADAR1-ZBP1 axis in self-nonself nucleic acid discrimination. We cover the therapeutic potential of targeting ZBP1- and IFI16-mediated pathways for anti-inflammatory and anti-infective strategies and provide a balanced analysis of developmental challenges, potential toxicity, and risks of impaired immune surveillance.