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Currently, 80% of grafts are taken from brain-dead (BD) donors. However, BD markedly reduces the tolerance of liver grafts to preservation/reperfusion injury and reduces graft survival. In addition, steatosis is currently estimated to be present in up to 50% of deceased donor livers and is recognized as a key donor variable predicting post-transplant outcome. HMGB1 has been described in different inflammatory disorders, and the deleterious effects of brain death may counteract the protection conferred by ischemic preconditioning. Therefore, our study examined how HMGB1 may affect preconditioned and un-preconditioned steatotic liver grafts from brain death donors undergoing transplantation.Steatotic grafts from non-BD and BD donors were cold stored for 6 hours and then transplanted. HMGB1 was pharmacologically modulated in liver grafts from brain death donors alone or in combination with ischemic preconditioning. Before the implantation of liver grafts in the recipient and after transplantation, hepatic damage and inflammatory response was analyzed and HMGB1-underlying mechanisms was characterized.We report that BD reduces HMGB1 in preconditioned and un-preconditioned livers, which is associated with inflammation and damage. Exogenous HMGB1 in BD donors activates PI3k/Akt and reduces hepatic inflammation (neutrophil accumulation, oxidative stress) and hepatic damage, altogether increasing the survival of recipients. Combination of exogenous HMGB1 and preconditioning shows additional benefits and stronger protection against damage, oxidative stress and neutrophil accumulation than HMGB1 treatment alone. This superior beneficial effect may derive from the anti-oxidant and anti-inflammatory properties of different mediators generated by preconditioning, which may act dependently of HMGB1.We show the injurious effects of BD in steatotic liver transplantation, which was associated with reduced HMGB1 expression. Pharmacological interventions to activate the HMGB1 signaling pathway in combination with ischemic preconditioning could be useful to reduce the incidence of postoperative complications in steatotic liver transplantation from deceased donors.