ZBP1 orchestrates dynamic transitions between cell death pathways in response to arsenic and hyperosmotic stress

Z-DNA binding protein 1 (ZBP1), a sensor of Z-form nucleic acids, plays a crucial role in cell death and inflammation. While its functions in infection and development are well-established, its involvement in environmental stress responses remains largely unexplored. In this study, we uncovered novel mechanisms by which ZBP1 mediates cell death under arsenic and hyperosmotic stress. We demonstrate that ZBP1 initiates necroptosis during the early stages of these stresses. As the stress persists, the cell death mode evolves, shifting towards apoptosis and pyroptosis in later stages. This transition is particularly pronounced when the necroptotic pathway is compromised. Interestingly, despite previous implications of stress granules (SGs) in arsenic-dependent cell death, we found that neither SGs formation inhibitors nor the ablation of SGs components significantly impacts cell death under arsenic or hyperosmotic stress. This suggests that environmental stress-induced necroptosis operates largely independent of SGs formation. Employing genome-wide CRISPR/Cas9 library screening, we identified that ZBP1-dependent cell death in response to arsenic is primarily driven by reactive oxygen species and the KEAP1-NRF2 signaling pathway. Notably, ZBP1 KO mice demonstrated resistance to arsenic-induced cell death and tissue injury, further substantiating our findings. Our research provides important new insights into ZBP1's role in environmental stress-induced cell death, expanding our understanding beyond its established functions in infection and development. These findings offer potential implications for comprehending stress-related tissue injury mechanisms.