Neutrophil extracellular traps induce hepatocyte pyroptosis via CCDC25 in sepsis-associated liver injury

Clinical data reveal that elevated neutrophil extracellular traps (NETs) in sepsis-associated liver injury (SALI) patients strongly correlate with increased liver enzymes (NET-DNA vs. ALT/AST: r² = 0.6727/0.8884) and predict higher 90-day mortality. Critically, we identify a novel NETs-CCDC25-pyroptosis axis driving SALI pathogenesis: Lipopolysaccharide (LPS)-activated NETs upregulate the hepatocyte transmembrane receptor CCDC25, which synchronizes with liver injury severity and directly triggers hepatocyte pyroptosis and inflammatory cytokine release. This cascade is reversed by NETs disruption (DNase I or Cl-amidine) or CCDC25 silencing in vitro. Therapeutically, inhibiting NETs with Cl-amidine or knocking down CCDC25 with si-CCDC25 in vivo reduces liver enzymes, suppresses pyroptosis executors (e.g., GSDMD-N), and attenuates histopathological damage. This study clarifies the mechanism of the NETs-CCDC25-pyroptosis axis in SALI, offering a novel targeted therapeutic strategy for clinical practice.