Ninjurin-1 mediates hepatic ischemia-reperfusion injury
Bibliographic record
Abstract
Background: Ischemia-reperfusion injury (IRI) is a major clinical challenge during liver transplantation that can lead to early allograft dysfunction (EAD), graft rejection, and even death of the recipient. Induced lytic cell death (LCD) decreases functional cell mass and triggers a harmful pro-inflammatory immune response. Rupture of the plasma membrane, the final stage of several LCD pathways, could recently be shown to be an active and highly regulated process mediated by the transmembrane protein Ninjurin-1 (NINJ1). The role NINJ1 plays during hepatic IRI remains unknown. Aims: To investigate the role of Ninjurin-1 activation on hepatic IRI. Methods: A model of 70% segmental warm hepatic IRI was used in mice and rats with conventional whole-body ( Ninj1 -/- ) knockout and mice with hepatocyte-specific ( Ninj1 fl/fl Alb-Cre + ) and myelomonocyte/Kupffer cell (KC)-specific ( Ninj1 fl/fl LysM-Cre + ) knockout as well as their respective controls. The resulting injury was assessed using serum (AST, ALT, LDH) and histopathological (Suzuki score, TUNEL staining) markers for hepatic IRI. Treatment of WT mice with glycine or clone D1, an antagonizing antibody, both known to preserve plasma membrane integrity in a NINJ1-dependent manner, was used to assess pharmacological inhibition in vivo. To mimic IRI in vitro , we cultivated isolated and purified murine hepatocytes and KCs under hypoxia/reoxygenation conditions (H/R) and quantified LCD. Non-denaturing gel electrophoresis (BN-PAGE) was used to assess NINJ1 activation in liver samples from IRI- and sham-treated mice and biopsies from human liver grafts (hLG) pre-implantation and post-reperfusion. Results: NINJ1 deficiency in both mice and rats led to a significant reduction of all assessed parameters for hepatic IRI. Accordingly, pharmacological inhibition protected mice against IRI in vivo . Both hepatocytes and KCs undergo H/R-induced LCD contributing to hepatic IRI in vivo . Moreover, NINJ1 activation in post-reperfusion biopsies from hLG was markedly increased in recipients with EAD (peak AST>5,000 U/l postoperatively) compared to recipients with low AST levels (<200 U/l). Conclusion : Across species, we demonstrate that NINJ1 mediates hepatic IRI, which can be prevented by pharmacological targeting of NINJ1. Moreover, in hLG recipients, EAD was associated with increased NINJ1 activation. Thus, we propose NINJ1 as a new target to treat hepatic IRI and improve patient outcomes during liver transplantation. Publication History Article published online: 04 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".