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Despite advances in organ preservation, marginal graft utilization, and xenotransplantation, a scalable source of functional liver tissue has not been realized. Blastocyst complementation has emerged as a novel strategy to generate exogenic organs, enabling the development of human derived hepatocytes within a xenogeneic host. The approach introduces a distinct biological paradigm where human parenchymal cells coexist with partial xenogeneic non-parenchymal compartments, resulting in compartmentalized immunogenicity. Efficient human-porcine blastocyst complementation remains an evolving technology, and functional exogenic humanized livers have yet to be demonstrated in large-animal transplant models. We examine exogenic liver transplantation through an immunology-first, clinical framework with emphasis on early graft injury driven predominantly by innate immune mechanisms at the vascular interface, including complement activation, macrophage mediated clearance, thrombocytopenia, and coagulation dysregulation as a major barrier observed in liver xenotransplantation. While adaptive immune responses may be attenuated due to reduced antigenic burden, residual xenogeneic endothelial and stromal compartments remain critical drivers of immune activation. We highlight exogenic hepatocyte transplantation as a potential translational bridge, enabling functional validation of chimerism-derived human hepatocytes\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    while bypassing the vascular incompatibility inherent to whole organ transplantation. This cell-based therapy could offer a platform before the clinical realization of whole exogenic liver transplantation. We propose a phased immunomodulatory approach centered on early control of innate and humoral injury using induction therapy, plasmapheresis, and complement modulation, followed by tolerance-oriented tapering of maintenance immunosuppression. Finally, we outline a translational pathway incorporating preclinical validation,\n                    <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                    perfusion, and human decedent transplant models, while addressing ethical, biosafety, and logistical considerations. Exogenic liver transplantation has the potential to represent a transformative strategy to generate scalable, immunologically optimized grafts and redefine the future of liver transplantation.\n                  <\/jats:p>","DOI":"10.1177\/09636897261479189","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T14:13:31Z","timestamp":1787408011000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["An Immunological and Translational Framework for Interspecies Exogenic Liver Transplantation"],"prefix":"10.1177","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0197-6107","authenticated-orcid":false,"given":"Joseph Sushil","family":"Rao","sequence":"first","affiliation":[{"name":"University of Minnesota"},{"name":"University of 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