Preclinical Evaluation of mTORC1 Inhibition via Rapamycin in Machine-Perfused Rodent Livers

Normothermic machine perfusion (NMP) enables real-time liver viability assessment and therapeutic intervention during preservation. Rapamycin, an mTORC1 inhibitor known to induce autophagy and promote cellular resilience, represents a promising candidate for mitigating ischemic injury during NMP. We developed a rat model of warm ischemia followed by NMP to evaluate whether rapamycin improves liver graft quality. Livers were subjected to 90 minutes of warm ischemia and then perfused for three hours with or without 50nM rapamycin. While no significant differences were observed in perfusate oxygen consumption, lactate clearance, or transaminase release, histological analysis revealed that rapamycin-treated livers had improved cellular architecture and reduced necrosis compared to untreated controls. These findings suggest that rapamycin may confer structural protection independent of immediate metabolic changes. This model provides a platform to further study targeted therapies during NMP and supports the potential role of mTORC1 modulation in enhancing liver graft preservation.