Immunometabolism of Liver Xenotransplantation and Prospective Solutions

End-stage liver diseases, such as hepatocellular carcinoma or acute liver failure, critically necessitate liver transplantation. However, the shortage of available organ donors fails to meet the rapidly growing transplantation demand. Due to the high similarity of liver tissue structure and metabolism between miniature pigs and humans, xenotransplantation of pig livers is considered as a potentially viable solution to organ scarcity. In the 2024, teams from China first time have successfully transplanted a genetically modified Bama miniature pig liver into a clinically brain-dead man lasting for 10 days. This milestone in human xenotransplantation research not only confirms the feasibility of clinical application of xenotransplantation, but also underscores the daunting and protracted nature of this pathway. Despite advanced gene-editing technologies theoretically circumventing the occurrence of most transplant rejection reactions, patients still face challenges such as chronic immune rejection, coagulation disorders, and thrombotic microangiopathy after receiving xenografts. Moreover, prolonged use of immunosuppressive drugs may induce irreversible immune dysfunction, leading to opportunistic infections and metabolic disorders. This article compares the similarities and differences in livers between humans and pigs, summarizes the immunometabolism of xenotransplantation based on current findings, and provides research perspectives on pre-transplantation and post-transplantation strategies for prolonging the survival time of xenografts.