2026/02/13 by Haitao Lu, Jifu Jiang, Xuyan Huang +5 · 1 voice
Immunology and Microbiology · Biochemistry, Genetics and Molecular Biology · #interferon and immune responses #RNA regulation and disease #Cell death mechanisms and regulation
paper · doi:10.1016/j.ajt.2026.02.003
openalex publication_date 2026/02/13 · openalex created_date 2026/02/14 · openalex updated_date 2026/07/30
PANoptosis integrates features of pyroptosis, apoptosis, and necroptosis. The roles of Z-DNA-binding protein 1 (ZBP1), adenosine deaminase acting on RNA 1 (ADAR1), RIPK1, and RIPK3 in PANoptosis are not fully understood, particularly in the context of heart transplantation. Our studies revealed that Z-DNA can induce PANoptosis in human microvascular endothelial cells via ZBP1. ADAR1 and RIPK1 collaboratively regulate the activation of the ZBP1-RIPK3 complex for PANoptosis in a time-dependent manner. The interaction of ADAR1 with ZBP1 protected against Z-DNA-induced cell death by limiting the activation of ZBP1 and RIPK3 at an early stage of cell death. As well, RIPK1 promoted the phosphorylation of RIPK3 and furthered ZBP1-RIPK3 interaction and cell death. Our in vivo studies showed that ZBP1 and its ligand, Z-DNA, were significantly upregulated in the grafts after mouse heart transplantation. Importantly, ZBP1 deficiency in the mouse heart graft inhibited cardiac PANoptosis, attenuated acute and chronic graft injury, antidonor immune responses, and induced long-term graft survival. In conclusion, this study elucidates the roles of ADAR1 and RIPK1 in regulating the ZBP1-RIPK3 complex and PANoptosis. Inhibition of ZBP1 can prevent heart graft injury and rejection. Our studies may inform the development of novel therapeutic strategies targeting multiple programmed cell death pathways to improve graft survival.