Gene-edited porcine liver xenotransplantation: advances and key clinical translation barriers

Liver allotransplantation constitutes a vital organ-replacement therapy for end-stage liver disease, yet the global shortage of donor livers severely limits treatment capacity. Porcine liver xenotransplantation, which employs genetically edited pig livers as grafts, holds promise for alleviating donor scarcity and providing bridging organ support for patients with acute liver failure. In recent years, considerable progress has been achieved in preclinical non-human primate (NHP) models and human clinical studies. Benefiting from multi-gene editing, optimized immunosuppressive regimens, and refined surgical techniques, this approach can now effectively avert hyperacute rejection (HAR) and achieve short-term graft functional compensation. Nevertheless, clinical translation of liver xenotransplantation still faces multiple obstacles. Technical bottlenecks include delayed immune injury mediated by non-α-1,3-galactose (α-Gal) antigens, intractable coagulopathy, cross-species incompatibility in metabolism and drug disposition, lack of standardized surgical protocols, and risks of cross-species transmission of porcine viruses. Non-technical challenges encompass inconsistent global regulatory standards, informed-consent issues, animal welfare, and medical equity. Risks posed by exogenous viruses such as porcine cytomegalovirus (PCMV) can be mitigated by establishing designated pathogen-free (DPF) donor pig breeding systems combined with pre-transplant pathogen screening; however, such strategies cannot eliminate porcine endogenous retroviruses (PERV) integrated within the porcine genome, which carry risks of latent reactivation, recombination-mediated mutation, and potential cross-species infection. This review summarizes research progress and core limiting factors in liver xenotransplantation, aiming to provide theoretical references for optimizing donor gene-editing targets, improving immune-coagulation disorder prevention and control, standardizing surgical procedures, and constructing ethical supervision frameworks, so as to facilitate safe and orderly clinical translation of liver xenotransplantation.