Bimodal regulation and precision therapy of neutrophil extracellular traps in liver ischemia-reperfusion injury: recent advances

Liver transplantation is the definitive therapy for end-stage liver disease, yet hepatic ischemia-reperfusion injury (HIRI) remains a leading cause of early graft dysfunction. Neutrophil extracellular traps (NETs) can support host defense, but dysregulated NET formation during HIRI amplifies sterile inflammation, endothelial injury, and microvascular thrombosis-making NETs an attractive, pharmacologically tractable target. This review integrates recent evidence that NET responses in HIRI are bimodally regulated and stage dependent, with distinct release programs and molecular signatures across ischemia, early reperfusion, and late repair. We summarize key biochemical control nodes governing NET generation and persistence-oxidant signaling, calcium-dependent chromatin remodeling, protease-oxidase feed-forward loops, and platelet-endothelial crosstalk that promotes intravascular NET deposition. We further discuss how NETs reshape the hepatic immune microenvironment, driving inflammatory amplification, immune suppression, and coupling to regulated cell-death circuits, thereby sustaining tissue injury and impairing graft recovery. Translational implications are highlighted through NET-related biomarkers and intervention strategies spanning NET dismantling, inhibition of NET formation, modulation of upstream priming pathways, and liver-directed delivery, including ex vivo machine perfusion as a precision platform. NETs represent a druggable hub linking inflammation, thrombosis, and cell death in HIRI, but timing and selectivity are crucial to avoid compromising antimicrobial defense. Progress requires standardized NET readouts to define therapeutic windows and mechanism-guided combination regimens that selectively suppress pathogenic NET programs to improve graft preservation and post-transplant outcomes.