As host’s first line of defense, innate immune cells not only recognize various pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) through different pattern recognition receptors (PRRs), but also eliminate pathogens to restore host homeostasis through initiating rapid immune response and generating long-lasting adaptive immunity[1], [2]. To date, six kinds of PRRs have been described as follows: toll-like receptors (TLRs), retinoic acid-inducible gene I (RIGI)-like receptors (RLRs), nucleotide-binding domain and leucin-rich repeat-containing receptors (NLRs), C-type lectin receptors (CLRs), cyclic GMP-AMP synthase (CGAS)-stimulator of interferon response CGAMP interactor 1 (STING1) pathway, and AIM2-like receptors (ALRs)[2]. Nucleic acids, which serve as the fundamental genetic components of all organisms, possess considerable immunostimulatory properties. Nucleic acids derived from pathogens are mainly recognized by TLRs, RLRs, and cytosolic DNA sensors, thereby initiating type I interferons (IFN-I)-dependent antiviral responses and inducing inflammation[3], [4]. In addition, nucleic acids derived from host cells in the context of tissue or cell damage are also recognized by PRRs, which initiates sterile inflammatory responses[5]. Compelling evidence demonstrates that aberrant activation or dysregulation of nucleic acid-sensing systems contributes to the pathogenesis of inflammatory disorders and autoimmune diseases[6], [7].

Nucleic acids are composed of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), which are highly flexible biomolecules and have a wide range of specific conformations. DNA is a double-stranded helix molecule that has a long chain of nucleotides. The right-handed B helix conformation (B-DNA) is the dominant biological conformation of DNA in vivo[8]. In addition to the dominant right-handed B-type DNA, there are several forms of DNA structure, such as A-form, C-form, and Z-form. Among these secondary structures, Z-DNA is the only left-handed helical form of DNA in which the double helix winds to the left in a zigzag pattern[9]. The biological functions of Z-DNA are gradually clarified with the discovery of several Z-DNA binding domain (ZDBD)-containing proteins, such as Z-DNA-binding protein 1 (ZBP1), adenosine deaminase RNA specific (ADAR1), RNA-binding protein E3 (E3L), and protein kinase Z (PKZ). It is now established that Z-DNA exerts essential roles in various cell activities, such as recruitment of specific transcription activators or repressors, regulation of gene expression, control of genome instability, and eliciting immunogenic responses[10]. Z-form RNA (Z-RNA), a left-handed alternative conformation for the RNA double helix, resembles to Z-DNA. It is also favored by a sequence composed of purine/pyrimidine repeats and especially CG repeats. Aberrant immune responses induced by Z-RNAs are associated with the development of various human diseases.

ZBP1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM1, is dramatically upregulated in tumor, and surrounding stromal tissue as well as activated macrophages[11]. It is initially reported as an IFN-inducible tumor-associated protein and has been identified as the first innate immune activator that senses cytosolic DNAs, especially double-stranded nucleic acids adopting Z conformation[12]. ZBP1 initiates PANoptosome assembly to drive inflammasome activation and subsequent immunogenic cell death[13]. Thereby, ZBP1-mediated excessive or aberrant cell death can result in adverse inflammation in infected or non-infected contexts. It has emerged as a therapeutic target for the treatment of a variety of diseases.

This review outlines the structure and expression pattern of ZBP1, discusses its roles in human diseases through immune-dependent (e.g., the production of IFN-I and pro-inflammatory cytokines) and -independent (e.g., the activation of cell death) functions, and highlights the attractive prospect of manipulating ZBP1 as a promising therapeutic target in diseases.