{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kojima H"],"funding":["NIDDK NIH HHS","NIAID NIH HHS"],"pagination":["e174354"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10967411"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["9(3)"],"pubmed_abstract":["Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism."],"journal":["JCI insight"],"pubmed_title":["Cold stress-induced ferroptosis in liver sinusoidal endothelial cells determines liver transplant injury and outcomes."],"pmcid":["PMC10967411"],"funding_grant_id":["R01 DK102110","R01 DK107533","P01 AI120944","R01 DK062357"],"pubmed_authors":["Kitajima H","Torgerson T","Farmer DG","Ito T","Kadono K","Hirao H","Kojima H","Dery KJ","Kaldas FM","Yao S","Kupiec-Weglinski JW","Ogawa T"],"additional_accession":[]},"is_claimable":false,"name":"Cold stress-induced ferroptosis in liver sinusoidal endothelial cells determines liver transplant injury and outcomes.","description":"Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2025-04-04T23:52:52.13Z","creation":"2025-04-04T23:52:52.13Z"},"accession":"S-EPMC10967411","cross_references":{"pubmed":["38329125"],"doi":["10.1172/jci.insight.174354"]}}