Nucleic acids serve not only as carriers of genetic information but also as potent immunological signals that shape innate and adaptive immune responses. Their immunogenicity is determined by their origin, subcellular localization, structural conformation, and the host sensors that detect them. Within this landscape, Z-nucleic acids, including Z-RNA and Z-DNA, have emerged from biological noise to key regulators of immune activation, particularly through their ability to induce inflammatory cell death pathways. Both host and pathogens can generate Z-nucleic acids, yet the mechanisms governing their formation and regulation remain incompletely understood. In mammals, ZBP1 and ADAR1 are the only known Z-nucleic acid sensors, while some pathogens encode Z-binding proteins to evade detection. Although critical for host defense, dysregulated Z-nucleic acid signaling can drive autoimmunity and chronic inflammation. This review synthesizes current structural and functional principles of Z-nucleic acid recognition and highlights emerging therapeutic opportunities across infectious diseases, inflammatory disorders, and cancer. This review summarizes the mechanisms underlying the generation and regulation of Z-nucleic acids and discusses their sensing by ADAR1 and ZBP1 in cell death and inflammatory signalling, with broad implications for infection, inflammation, and cancer.
Thapa et al. (2026) studied this question.