NAC and DNase I synergistically reduce NETs to attenuate severe acute pancreatitis via suppressing the NETs/NF-κB/CXCL3 pathway.

Neutrophil extracellular traps (NETs) drive severe acute pancreatitis (SAP) progression by promoting pancreatic injury, duct obstruction, and systemic inflammation. Reactive oxygen species (ROS) are critical for NETs formation, while NETs degradation remains therapeutically challenging. This study investigates whether combined N-acetylcysteine (NAC) and deoxyribonuclease I (DNase I) therapy mitigates SAP and associated lung injury by suppressing NETs formation and degradation, respectively, and explores the underlying molecular mechanisms. NETs were elevated in SAP pancreatic tissue. In vitro, NAC reduced NETs formation by inhibiting oxidative stress, while DNase I degraded preformed NETs. Combined therapy surpassed monotherapy efficacy, synergistically attenuating NETs burden. In vivo, Early dual intervention degraded NETs, reduced neutrophil infiltration and apoptosis, and lowered inflammatory cytokines, thereby alleviating pancreatitis and lung injury. Mechanistically, dual therapy suppressed NF-κB activation in pancreatic tissue, decreasing CXCL3 release and subsequent CXCR2-positive neutrophil recruitment, ultimately ameliorating SAP. NAC and DNase I synergistically target NETs generation and clearance, offering a promising redox-based therapeutic strategy for SAP.