Machine perfusion improves outcomes of liver recipients via non-immunomodulatory effects

Liver transplantation (LT) is limited by organ shortage, increasingly relying on extended criteria donors (ECD) and donation after circulatory death (DCD) grafts, which are particularly vulnerable to ischemia-reperfusion injury (IRI). Beyond immune activation, IRI is driven by non-immunological mechanisms, including mitochondrial dysfunction, oxidative stress, endothelial injury and biliary damage, which critically affect graft quality. Machine perfusion (MP) offers a mean to directly target these upstream events. Hypothermic oxygenated perfusion/dual-hypothermic oxygenated perfusion (HOPE/D-HOPE) provides controlled mitochondrial reoxygenation, prevents succinate-driven reactive oxygen species (ROS) bursts, activates antioxidant pathways and protects the biliary epithelium, thereby reducing ischemic cholangiopathy (IC). Normothermic machine perfusion (NMP) sustains aerobic metabolism, maintains adenosine triphosphate (ATP) generation and microcirculatory homeostasis, and stimulates autophagy and regenerative pathways. Both strategies consistently reduce early allograft dysfunction (EAD) and improve graft outcomes, particularly in high-risk grafts. In addition, MP enables real-time viability assessment. Known markers, such as lactate clearance and bile composition, are complemented by emerging mitochondrial biomarkers, including flavin mononucleotide (FMN) and nicotinamide adenine dinucleotide (NADH), which directly reflect respiratory chain function and predict post-transplant outcomes. Sequential protocols combining HOPE and NMP maximize both protection and assessment, increasing safe utilization of marginal livers. Altogether, MP represents a therapeutic and diagnostic platform, improving metabolic stability, reducing biliary complications and expanding the donor pool, while moving beyond traditional static preservation.