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To design a multifactorial biological modulation approach targeting ischemia reperfusion injury to augment viability of porcine liver grafts from non–heart-beating donors (NHBD).Liver Transplantation (LTx) from NHBD is associated with an increased risk of primary nonfunction (PNF) and biliary complications. In porcine NHBD-LTx, we previously reported a 50% risk of PNF and toxic bile formation in grafts exposed to ≥30′ warm ischemia (WI).Porcine livers exposed to 45′ WI were cold stored, transplanted and either modulated (n = 6) or not (controls, n = 9). In the modulation group, donor livers were flushed with warm Ringers (avoiding cold-induced vasoconstriction), streptokinase (eliminating stagnating thrombi), and epoprostenol (vasodilator, platelet aggregation inhibitor) prior to cold storage. In recipients, glycine (Kupffer cell stabilizer), α1-acid-glycoprotein (anti-inflammatory protein), MAPKinase-inhibitor (pro-inflammatory cytokine generation inhibitor), α-tocopherol and glutathione (anti-oxidants), and apotransferrin (iron chelator) were administrated intravenously. PNF, survival, lactate, transaminase, TNF-α, redox-active iron, and biliary bile salt-to-phospholipid ratio were monitored.No PNF was observed in modulated versus 55% in control pigs (P = 0.025). Survival was 83% in modulated versus 22% in control pigs (P = 0.02). At 180′ postreperfusion, lactate was lower in modulated (5.4 ± 1.9 mmol/L) versus control pigs (9.4 ± 2.2 mmol/L; P = 0.011). At 60′ postreperfusion, there was a trend for lower AST in modulated versus control pigs at 60′ (939 ± 578 vs. 1683 ± 873 IU/L; P = 0.089). Postreperfusion, TNF-α remained stable in modulated pigs (49 ± 27 pg/mL at 15′ and 85 ± 26 pg/mL at 180′; P = 0.399) but increased in control pigs (107 ± 36pg/mL at 15′ and 499 ± 216 pg/mL at 180′; P = 0.023). At 180′ postreperfusion, redox-active iron was higher in control pigs versus modulated pigs (0.21±0.18 vs. 0.042±0.062 μm; P = 0.038). Biliary bile salt-to-phospholipid ratio post-LTx was lower in modulated versus control pigs (1128 ± 447 vs. 4836 ± 4619; P = 0.05).A multifactorial biological modulation eliminates PNF, improves liver function and increases survival. Biochemically, TNF-α and redox-active iron are suppressed and biliary bile salt toxicity is reduced. Translating this strategy clinically may lead to wider and safer use of NHBD.