Targeting neutrophil extracellular traps in liver ischemia-reperfusion injury: From molecular mechanisms to pharmacological and translational opportunities

Hepatic ischemia-reperfusion injury (HIRI) remains a major determinant of adverse outcomes after liver transplantation, major hepatectomy, and other clinical settings involving the unavoidable interruption and subsequent restoration of hepatic blood flow. Rather than merely reversing ischemic stress, reperfusion rapidly transforms metabolic collapse into a sterile inflammatory response characterized by liver sinusoidal endothelial cell (LSEC) activation, platelet-neutrophil crosstalk, oxidative stress, and microcirculatory dysfunction. In this context, neutrophil extracellular traps (NETs), web-like structures composed of decondensed chromatin decorated with histones and granular enzymes, have emerged as more than a by-product of neutrophil activation. Although initially described as an antimicrobial defense mechanism, NETs are now recognized as potent amplifiers of sterile tissue injury when produced excessively or cleared inefficiently. Evidence from extrahepatic ischemia-reperfusion models suggests that NETosis is a conserved pathogenic program across organs, shaped by microbial conditioning, endothelial and platelet activation, and redox-dependent signaling. In the liver, NETs are particularly detrimental because they provide a scaffold for immunothrombosis, obstruct the sinusoidal microcirculation, expose tissues to cytotoxic histones and proteases, and reinforce regulated cell death pathways. The reperfused liver is especially susceptible to this process because danger signals released from stressed parenchymal and non-parenchymal cells promote sustained neutrophil activation within a low-pressure microvascular bed that is highly sensitive to intravascular obstruction. This review discusses the molecular regulation of NET formation and persistence in HIRI, the mechanisms by which NETs exacerbate hepatocellular and microvascular injury, and the pharmacological and translational opportunities for NET-targeted intervention.