Therapeutic hyperthermia promotes lipid export and HSP70/90 during machine perfusion of human livers

Liver transplantation is the only curative option for end-stage liver disease. Donor shortages necessitate the use of higher risk donor livers, including fatty livers, which are more susceptible to ischemia-reperfusion injury. Machine perfusion has improved graft utilization and is typically performed at hypothermic (8-12°C) or normothermic (35-37°C) temperatures. Here we studied the impact of mild hyperthermia (40°C) as a therapeutic intervention for fatty livers using in-depth proteomic and lipoprotein profiling of whole organ perfusion and precision-cut liver slices. We observed proteomic changes with metabolic alterations over time, evidenced by a significant increase in lipid export in whole organ perfusions. Furthermore, PCLS showed significant upregulation of metabolic processes and heat shock protein response after 24 h of hyperthermia. Machine perfusion under hyperthermic conditions may be a potential strategy to improve the utilization of fatty liver grafts, ultimately expanding the donor pool and improving transplant outcomes.