Authors
Jan Mossemann, Brunna X Martins, Yixuan Zhao, Fiorelle Aguilar, Daria Taskina, Claire J Hur, Diana Nakib, Allen Volchuk, Gang Ye, Danish M Ali, Ali Mirzaesmaeili, Iram Siddiqui, Ghazal Goodarzi, Philip J Bilan, Irma B Stowe, Nobuhiko Kayagaki, Sonya MacParland, Spencer A Freeman, Neil M Goldenberg, Benjamin E Steinberg, Blayne A Sayed
Published in
Science advances. Volume 12. Issue 35. Pages eaeg9496. Aug 28, 2026. Epub Aug 26, 2026.
Abstract
Lytic cell death pathways drive hepatic ischemia-reperfusion injury (IRI). The transmembrane protein ninjurin-1 (NINJ1) aggregates in the plasma membrane to permeabilize the cell during multiple cell death pathways implicated in hepatic IRI. We hypothesized that NINJ1 mediates liver IRI and that its inhibition would mitigate injury. We found that NINJ1 is highly expressed in human liver tissue and that its up-regulation and activation correlate with early allograft dysfunction in liver transplant patients. Using a segmental hepatic IRI model in mice and rats, Ninj1 genetic deletion or pharmacologic inhibition diminished acute injury. Mice with hepatocyte- or macrophage-specific Ninj1 knockout had reduced hepatocellular injury following IRI, suggesting that NINJ1 within both populations contributes to the resulting liver injury. Mechanistically, we found that hepatocytes and Kupffer cells are susceptible to hypoxia-induced NINJ1-mediated plasma membrane rupture, which can be pharmacologically prevented. We therefore position NINJ1 as a potential new therapeutic target to limit hepatic IRI, with important implications for liver transplantation.
PMID:
42647649
Bibliographic data and abstract were imported from PubMed on 27 Aug 2026.
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