ADAR1 orchestrates the ZBP1-mediated PANoptosis and heart transplant rejection

Abstract

Background: PANoptosis is an integrated form of cell death that combines features of pyroptosis, apoptosis, and necroptosis and is regulated by a complex network of signaling proteins. The roles of ADAR1 (adenosine deaminase acting on RNA 1) and RIPK1 (receptor-interacting serine/threonine-protein kinase 1) in orchestrating the ZBP1 (Z-DNA binding protein 1)-RIPK3 complex to mediate PANoptosis is not fully understood, particularly in the context of heart transplantation. Objective: This study investigated how ADAR1 and RIPK1 coordinate the activation of the ZBP1-RIPK3 complex to mediate PANoptosis and its implications in mouse heart transplantation. Methods: Using both in vitro and in vivo models, we analyzed the interactions between ADAR1, RIPK1, ZBP1, and RIPK3. We employed western blotting, and siRNA to elucidate the dynamics of these interactions. Additionally, we assessed the impact of ZBP1 on mouse heart transplantation outcomes. Results: Our studies revealed that ADAR1 regulates the activation of the ZBP1-RIPK3 complex for PANoptosis. The interaction of ADAR1 with ZBP1 protected against Z-DNA-induced cell death by limiting activations of ZBP1 and RIPK3. In mouse heart transplantation study, we found that ZBP1 and its ligand Z-DNA/Z-RNA were significantly increased in the graft post-transplantation. Furthermore, ZBP1 deficiency in the heart graft inhibited cardiac PANoptosis, attenuated acute graft injury, and induced long-term graft survival. Conclusion: This study elucidates the role of ADAR1 in ZBP1-mediated PANoptosis. Inhibition of ZBP1 can prevent heart graft injury and rejection. Understanding these mechanisms provides valuable insights into the regulation of cell death and may inform the development of novel therapeutic strategies to improve transplant outcomes.