This review aims to comprehensively summarize the roles and underlying mechanisms of Z-DNA-binding protein 1 (ZBP1) in the onset and progression of systemic inflammation. As a critical initiator of PANoptosis and a sensor of Z-nucleic acids (e.g., viral RNA replication intermediates), ZBP1 has garnered growing attention in recent years for its critical involvement in various inflammatory diseases. By integrating current research progress, this review further explores the functional roles of ZBP1 in distinct inflammatory diseases and its potential value as a novel therapeutic target. Through systematic collation and analysis of recent studies on the regulatory mechanisms of ZBP1 in systemic inflammation, this review covers a broad range of disease areas, including neuroinflammation, diseases of the digestive, musculoskeletal, circulatory, and endocrine systems, as well as autoimmune diseases, sepsis, and bone marrow failure. Comprehensive analysis of these studies further elucidates the common regulatory mechanisms and disease-specific roles of ZBP1 in diverse inflammatory diseases. ZBP1 exerts diverse functions in inflammatory diseases across multiple organ systems. In the nervous system, it exacerbates brain injury and neuroinflammation by activating the RIPK3 (receptor-interacting protein kinase 3)-MLKL (mixed lineage kinase domain-like protein)-dependent necroptosis pathway. In digestive system diseases, it contributes to the pathological processes of periodontal disease and non-alcoholic steatohepatitis by regulating pyroptosis and inflammatory responses. In the musculoskeletal system, it accelerates the progression of osteoarthritis by facilitating chondrocyte damage and inflammation. In the circulatory system, it mitigates inflammatory responses in myocarditis and heart failure by inhibiting the activation of RIPK3 and NF-κB signaling pathways. In the endocrine system, it is implicated in the development of type 2 diabetes by regulating inflammatory responses and insulin resistance. In the respiratory system, it mediates programmed cell death and inflammatory responses by activating pathways such as ZBP1-RIPK3-MLKL, thereby participating in lung injury processes in diseases such as asthma, ARDS, and COVID-19. In the immune system, it aggravates the pathological progression of systemic lupus erythematosus and rheumatoid arthritis by triggering inflammatory cell death and related signaling pathways. ZBP1 exerts a pivotal role in the onset and progression of systemic inflammation by regulating inflammatory responses and tissue damage through multiple cell death and inflammatory signaling pathways. These findings not only offer novel insights into the mechanistic underpinnings of ZBP1 in systemic inflammation but also lay a theoretical basis for developing ZBP1-targeted therapeutic strategies. Future research should further elucidate the disease-specific mechanisms of ZBP1 in distinct inflammatory disorders and assess its therapeutic potential, thereby providing novel directions and strategies for the management of systemic inflammation- associated diseases.
Xiao et al. (Tue,) studied this question.