NINJ1 mediates hepatic ischemia-reperfusion injury through plasma membrane rupture in hepatocytes and Kupffer cells, and its genetic deletion or pharmacologic inhibition diminishes acute liver injury, positioning NINJ1 as a potential new therapeutic target with important implications for liver transplantation.
NINJ1 is highly expressed in human liver tissue and its up-regulation and activation correlate with early allograft dysfunction in liver transplant patients.
Ninj1 genetic deletion diminished acute hepatic injury in a segmental hepatic IRI model in mice and rats.
Pharmacologic inhibition of NINJ1 diminished acute hepatic injury following ischemia-reperfusion.
Hepatocyte-specific Ninj1 knockout reduced hepatocellular injury following IRI, indicating that NINJ1 within hepatocytes contributes to liver injury.
Macrophage-specific Ninj1 knockout reduced hepatocellular injury following IRI, indicating that NINJ1 within macrophages (Kupffer cells) also contributes to liver injury.
Hepatocytes and Kupffer cells are susceptible to hypoxia-induced NINJ1-mediated plasma membrane rupture, which can be pharmacologically prevented.
NINJ1 mediates plasma membrane rupture during multiple lytic cell death pathways implicated in hepatic IRI.
When the liver is deprived of blood flow and then has blood flow restored — a process called ischemia-reperfusion injury (IRI) — liver cells die in large numbers. This is a major problem in liver transplantation, where it can cause the transplanted organ to fail early. This research suggests that a protein called NINJ1, found on the surface of liver cells, plays a central role in causing this damage. NINJ1 works by clustering together on the cell membrane and physically tearing it open, killing the cell. The researchers found that NINJ1 is highly active in human liver tissue and that patients whose livers showed higher NINJ1 activity after transplant were more likely to experience early organ dysfunction. Using animal models in both mice and rats, the researchers showed that either removing the gene for NINJ1 or blocking NINJ1 with a drug significantly reduced liver injury after IRI. Importantly, removing NINJ1 specifically from liver cells (hepatocytes) or from liver immune cells called Kupffer cells each independently reduced injury, suggesting that NINJ1 drives damage through both cell types. In laboratory experiments, they confirmed that oxygen deprivation (mimicking ischemia) triggers NINJ1-mediated cell membrane rupture in both hepatocytes and Kupffer cells, and that this can be stopped with a pharmacologic inhibitor. This research suggests that NINJ1 is a promising new drug target for preventing liver damage during transplantation and other situations involving IRI. Because NINJ1 acts as a final common step in multiple types of cell death, blocking it could potentially protect the liver regardless of which specific death pathway is activated. The findings open the door to developing NINJ1-targeting therapies that could improve outcomes for liver transplant patients.
Mossemann J, Martins B, Zhao Y, Aguilar F, Taskina D, Hur C, et al.. (2026). Ninjurin-1 mediates hepatic ischemia-reperfusion injury.. Science advances. https://doi.org/10.1126/sciadv.aeg9496