Z‐nucleic acids: Uncovering the functions from past to present

Since Z‐nucleic acid was identified in the 1970s, much is still unknown about its biological functions and nature in vivo. Recent studies on adenosine deaminase acting on RNA 1 (ADAR1) and Z‐DNA‐binding protein 1 (ZBP1) have highlighted its function in immune responses. Specifically, Z‐RNAs, either endogenous or induced by viral infection, are sensed by ZBP1 and activate necroptosis. Z‐RNAs act as the stimuli that induce innate immune responses through various pathways, including melanoma differentiation‐associated protein 5 (MAD5)‐mitochondrial antiviral‐signaling protein (MAVS)‐mediated type I IFN activation and proteinase kinase R (PKR)‐dependent integrated stress response, and their immunostimulatory potential is curtailed by RNA editing conducted by ADAR1. Aberrant immune responses induced by Z‐RNAs are associated with human diseases. They also induce pathogenesis in mice. Unlike Z‐RNAs, the biological functions of Z‐DNAs were barely studied, especially in mammals. Moreover, the origin or sequence preference of Z‐nucleic acids requires further investigation. Such knowledge will expand our understanding of Z‐nucleic acids, including from which genomic loci and under which circumstances they form, and the mechanisms by which they participate in the physiological activities. In this review, we provide insights in Z‐nucleic acid research and highlight the unsolved puzzles.