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

## TL;DR

This review discusses how neutrophil extracellular traps (NETs) contribute to liver injury during transplantation and explores targeted therapies to manage their harmful effects.

## Contribution

The paper highlights the bimodal regulation of NETs in liver ischemia-reperfusion injury and proposes precision therapeutic strategies.

## Key findings

- NETs have dual roles in liver injury, with distinct regulatory mechanisms across different stages.
- Pharmacological interventions like DNase I and PAD4 inhibition show promise in reducing NET-mediated damage.
- Ex vivo machine perfusion offers a precision platform for targeted NET modulation.

## Abstract

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.

Flowchart illustration detailing the process of ischemia in the liver leading to mitochondrial stress, ROS production, DAMPs, neutrophil priming, NET release, and DNA web formation, resulting in endothelial injury, microthrombosis, inflammation, persistent NETs, immune suppression, T cell exhaustion, and collagen scar fibrosis, with ex vivo perfusion, PAD4 inhibition, DNase I, and checkpoint blockade shown as therapeutic interventions.