MODIFIED PROJECT SUMMARY/ABSTRACT Liver transplantation is the definitive treatment for patients with end-stage liver disease, including some liver cancers. However, a significant proportion of patients, particularly those with the Model for End-stage Liver Disease (MELD) score ??24 and debilitating liver diseases, such as hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and colorectal liver metastases, do not receive this life-saving surgery due to a shortage in donor livers. Delayed liver transplantation not only affects the mortality risk and quality of life but also increases health care costs. The current donor utilization practice will exacerbate the existing organ shortage. Many livers are declined for transplantation because a surgeon doubts its viability based on his/her subjective assessment of the organ. Also, many additional livers are never even recovered because of similar concerns. A reliable and objective testing to assess the viability of marginal livers before transplant will help surgeons make informed decisions on the usability of marginal donor livers. Accumulating evidence from our group and others supports that normothermic machine perfusion (NMP) that pumps oxygenated blood with nutrients and medications at normal body temperature to maintain normal metabolic activity of the organ is a safe and feasible means of reconditioning marginal livers. In addition, NMP provides a unique opportunity for the transplant team to test viability of livers by assessing hemodynamic state and metabolic function of the liver graft. Building upon our single center phase 1 trial (NCT04483102), we propose to conduct a phase 2 single-arm multicenter trial (mRESTORE) that will transplant NMP-treated previously declined orphan livers after objective viability testing. The study will evaluate patient and graft survival and secondary transplant outcomes, including biliary complications, for the duration of the study funding period (up to 4 years), conduct mechanistic studies, and evaluate the cost-effectiveness of transplantation of NMP-treated livers that would otherwise have been discarded. Nine liver transplant centers and their OPOs that serve race/ethnically diverse patients will participate in this study. During the planning phase, we will finalize the study design and protocol, obtain regulatory approvals and build the operational infrastructure (e.g., case report forms, protocol monitoring plan) to enable timely implementation of the mRESTORE. After the transition to the full study, we will transplant NMP-treated previously declined marginal livers to patients and study their transplant outcomes. In addition, we will investigate hepatocellular injury mechanisms that are affected by NMP of previously declined marginal donor livers, identify liver dysfunction phenotypes of NMP with associated transplant outcomes, and evaluate the cost-effectiveness of the utilization of NMP-treated liver transplantation. Our study findings will info...