Neutrophil extracellular traps prime the ZBP1-cGAS sensor complex, triggering necroptosis and inflammatory injury in acute pancreatitis.

Severe acute pancreatitis (SAP) involves dynamic interactions between immune dysregulation and inflammatory infiltration. Although elevated levels of neutrophil extracellular traps (NETs) are associated with SAP, the downstream mechanisms by which NETs exacerbate the inflammatory injury remain unclear. In this study, we demonstrate that NETs levels positively correlate with SAP severity, and pharmacological inhibition of NETs reduces pancreatic injury, and acinar cell death. Mechanistically, NETs activate the ZBP1-cGAS complex via mitochondrial DNA (mtDNA), triggering downstream necroptosis and inflammatory pathways, thereby driving pancreatic inflammatory injury. Specifically, NETs induce mitochondrial damage in acinar cells, leading to cytosolic accumulation of mtDNA. This recruits ZBP1 to form a complex with cGAS dependent on the RHIM domain, wherein ZBP1 stabilizes Z-form mtDNA and potentiates cGAS recognition of Z-mtDNA, thereby cooperatively promoting necroptosis and inflammation. Furthermore, cyclosporine A inhibits mtDNA release, thereby suppressing NETs-induced ZBP1-cGAS complex formation and mitigating pancreatic injury. Our findings establish the mtDNA-ZBP1-cGAS axis as a pivotal mechanism by which NETs exacerbate pancreatic inflammation, revealing new therapeutic targets for SAP.