Programmed cell death (PCD) is a fundamental biological process by which cells undergo self-destruction through tightly regulated mechanisms. This self-elimination is crucial for maintaining organismal homeostasis, development, and immune defense, and it plays a pivotal role in both health and disease. Among the various forms of PCD—such as apoptosis, necroptosis, pyroptosis, and ferroptosis—emerging research has highlighted the integral role of the Z-DNA binding protein 1 (ZBP1) as a critical molecular sensor and regulator. A recently published comprehensive review by researchers at West China Hospital of Sichuan University offers groundbreaking insights into ZBP1’s multifaceted involvement in programmed cell death pathways and its therapeutic implications across a spectrum of diseases.
ZBP1 is characterized by its unique domain architecture, including the Zα domain, which binds to Z-conformation nucleic acids, and the RIP homotypic interaction motif (RHIM) domain, which mediates interactions with other key signaling molecules. These domains confer ZBP1 with the ability to detect both endogenous nucleic acids released during cellular stress and exogenous nucleic acids introduced by pathogens, particularly viruses. Upon recognition of aberrant nucleic acids, ZBP1 orchestrates downstream signaling cascades that activate various programmed cell death pathways, thereby modulating cellular fate in response to infection and injury.
The review elucidates the critical immunological function of ZBP1 as an intracellular nucleic acid sensor that triggers antiviral immune responses by inducing cell death pathways that eliminate infected cells and restrict viral propagation. This antiviral function positions ZBP1 as a pivotal component in host defense, enhancing the clearance of cytoplasmic viral genomes and contributing to innate immunity. Furthermore, ZBP1’s ability to sense nucleic acids explains its involvement not only in viral infections but also in sterile inflammatory conditions and autoimmune pathologies where endogenous nucleic acids accumulate abnormally.
ZBP1-mediated PCD encompasses a spectrum of mechanistically distinct but interconnected pathways. During apoptosis, ZBP1 engages apoptotic caspases through RHIM-dependent interactions, facilitating programmed cell dismantling that preserves tissue integrity. Conversely, in contexts of inflammation or infection where apoptosis may be inhibited, ZBP1 triggers necroptosis—a form of programmed necrosis characterized by membrane rupture and the release of intracellular contents, which acts as a potent pro-inflammatory signal. This switch between apoptosis and necroptosis underscores ZBP1’s dynamic regulatory role in cell fate decisions.
Another area of emerging interest in the review is ZBP1’s involvement in pyroptosis and ferroptosis, newer forms of PCD that contribute to inflammation and cellular metabolic dysfunction, respectively. Pyroptosis, driven by inflammasome activation and gasdermin-mediated pore formation, can be initiated downstream of ZBP1 signaling, amplifying immune responses to intracellular pathogens. Ferroptosis, characterized by iron-dependent lipid peroxidation, is also influenced by ZBP1-mediated signaling networks, linking metabolic stress responses with immune regulation.
At the molecular level, the interaction networks involving ZBP1 are intricate. Binding partners and downstream effectors recruited via the RHIM domain include receptor-interacting protein kinases RIPK1 and RIPK3, which assemble into signaling complexes that dictate cell death outcomes. The review presents a detailed analysis of these molecular complexes, highlighting how the modulation of RHIM motif interactions can tip the balance toward survival or death, inflammation or resolution, which is central in disease pathogenesis.
The pathological relevance of ZBP1 extends to diverse diseases beyond infections. Inflammatory disorders, neurodegenerative diseases, and various cancers exhibit aberrant regulation of ZBP1-mediated cell death pathways. For instance, dysregulated necroptosis driven by excessive ZBP1 activity contributes to chronic inflammation and tissue damage, while in cancer, ZBP1’s role can be context-dependent, either suppressing tumor growth through cell death induction or promoting tumor progression by fostering an inflammatory tumor microenvironment.
Given its central role, ZBP1 represents a promising therapeutic target. The review emphasizes advances in drug development targeting PCD pathways, particularly the modulation of ZBP1 and its interacting partners. Small molecules designed to inhibit or enhance ZBP1 function could offer novel treatments for autoimmune diseases, viral infections, and cancers that currently lack effective therapies. Moreover, technological strides such as artificial intelligence-driven drug discovery are accelerating the identification of potential candidates that modulate ZBP1 signaling with high specificity.
The review also underscores the importance of experimental disease models in elucidating ZBP1’s pathological functions. Animal models of viral infection, inflammatory diseases, and cancer have greatly expanded our understanding of how ZBP1-mediated cell death contributes to disease mechanisms, offering valuable platforms for preclinical testing of targeted therapies. Insights from these models underscore the therapeutic potential of fine-tuning ZBP1 activity to restore immune balance and prevent excessive tissue injury.
Looking forward, researchers highlight the necessity of delineating the precise molecular determinants that govern ZBP1’s specificity in activating distinct PCD pathways. Such mechanistic insights will be critical for designing strategies that selectively target pathological processes without disrupting physiological cell turnover. Furthermore, integrating multi-omics approaches and systems biology will enhance the ability to map ZBP1-centered regulatory networks within complex biological contexts.
In summary, the comprehensive review by Professor Xian Jiang, Dr. Gu He, and colleagues provides a pivotal synthesis of current knowledge on ZBP1-mediated programmed cell death. It unveils the molecular intricacies by which ZBP1 senses nucleic acid stress and directs cell fate, linking fundamental cellular processes with clinical pathologies. The elucidation of these pathways opens promising avenues for targeted therapeutics that modulate ZBP1 activity, potentially transforming the management of infectious, inflammatory, and neoplastic diseases.
As the field advances, the therapeutic modulation of ZBP1 stands as an exciting frontier in medicine, bridging basic molecular biology with translational research. Interdisciplinary efforts combining immunology, cell biology, and pharmacology will be paramount to harnessing the full potential of ZBP1-targeted interventions. This emerging paradigm reflects a broader recognition that programmed cell death is not merely a consequence of disease but a crucial regulatory node amenable to precise clinical control.
The scientific community awaits continued discoveries on ZBP1 as ongoing research sheds light on its nuanced roles in health and disease. The implications extend beyond therapy, offering deeper insights into immune regulation, cellular homeostasis, and the fundamental biology of cell death. This comprehensive understanding promises to catalyze innovations that redefine therapeutic strategies and improve patient outcomes worldwide.
Subject of Research: Not applicable
Article Title: Z-DNA-binding protein 1-mediated programmed cell death: Mechanisms and therapeutic implications
News Publication Date: 25-Aug-2025
Web References: https://doi.org/10.1097/cm9.0000000000003737
References: DOI: 10.1097/cm9.0000000000003737
Image Credits: Professor Xian Jiang from West China Hospital of Sichuan University
Keywords: Health and medicine, Cell biology, Cellular physiology, Cell death, Cellular necrosis, Cell apoptosis, Medical specialties, Human health, Health care, Clinical medicine, Medical treatments, Pharmacology
