{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:02:16Z","timestamp":1791810136226,"version":"4.3.4"},"reference-count":130,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"INNODOC-MED","award":["351058"],"award-info":[{"award-number":["351058"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Liver transplantation remains the definitive treatment for end-stage liver disease and acute liver failure, yet a critical and persistent shortage of donor organs results in thousands of preventable deaths annually worldwide. Xenotransplantation has emerged as a potential solution to this structural deficit. This narrative review traces the evolution of liver xenotransplantation, from early non-human primate trials in the 1960s through the application of CRISPR\/Cas9-driven multi-gene editing platforms in contemporary porcine donors. The immunological barriers that drove the transition from primate to porcine donors are examined, including hyperacute rejection mediated by anti-\u03b1-Gal antibodies, coagulation dysregulation and xenograft thrombotic microangiopathy. The genetic engineering strategies underlying current triple-knockout, ten-gene-edited donor pigs are reviewed alongside the preclinical non-human primate evidence establishing biological feasibility. The three pig-to-human liver xenotransplantation studies published between 2025 and 2026 are then analyzed, encompassing heterotopic auxiliary transplantation in a brain-dead decedent, extracorporeal liver cross-circulation and the first auxiliary liver xenotransplantation in a living recipient with a documented 171-day survival. These cases collectively provide preliminary evidence supporting proof-of-concept for porcine hepatic bridging therapy, with current evidence supporting a role for xenogeneic liver support as a temporary bridge to recovery or allotransplantation rather than definitive organ replacement. Xenograft thrombotic microangiopathy is identified as the principal remaining biological barrier, and the substantial translational challenges, including reproducibility, scalability and regulatory readiness that must be resolved before broader clinical application can be considered.<\/jats:p>","DOI":"10.3390\/jcm15083144","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T13:22:47Z","timestamp":1776691367000},"page":"3144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Liver Xenotransplantation: From Early Primate Trials to the First-in-Human Porcine Bridging Therapies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1032-608X","authenticated-orcid":false,"given":"Alexandru Grigorie","family":"Nastase","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"General Surgery and Liver Transplant Clinic, St. Spiridon University Hospital, 700111 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9865-5114","authenticated-orcid":false,"given":"Alin Mihai","family":"Vasilescu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"General Surgery and Liver Transplant Clinic, St. Spiridon University Hospital, 700111 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria","family":"Trofin","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"General Surgery and Liver Transplant Clinic, St. Spiridon University Hospital, 700111 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5072-8075","authenticated-orcid":false,"given":"Nicolae Florin","family":"Iftimie","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0565-3791","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"Segura-Sampedro","sequence":"additional","affiliation":[{"name":"Peritoneal, Retroperitoneal and Soft Tissue Oncological Surgery Service, Department of General and Digestive Surgery, Hospital Universitario La Paz (IdlPaz), 28046 Madrid, Spain"},{"name":"Faculty of Medicine, Universidad San Pablo CEU, 28040 Madrid, Spain"},{"name":"Translational Research and Innovation Group in General and Digestive Surgery, Research Institute, Hospital Universitario La Paz (IdIPaz), 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona","family":"Cadar","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"General Surgery and Liver Transplant Clinic, St. Spiridon University Hospital, 700111 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-2029","authenticated-orcid":false,"given":"Iulian","family":"Buzincu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"General Surgery and Liver Transplant Clinic, St. Spiridon University Hospital, 700111 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Davidescu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1486-1039","authenticated-orcid":false,"given":"Anda Lucia","family":"Nastase","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Advanced Research and Development Center for Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d-CEMEX, Grigore T. Popa University of Medicine and Pharmacy, 700454 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oana Georgiana","family":"Briceanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7539-9453","authenticated-orcid":false,"given":"Corina","family":"Lupascu-Ursulescu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Radiology Clinic, St. Spiridon University Hospital, 700111 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian Dumitru","family":"Lupascu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"General Surgery and Liver Transplant Clinic, St. Spiridon University Hospital, 700111 Iasi, Romania"},{"name":"Academy of Romanian Scientists, 050044 Bucharest, Romania"},{"name":"Romanian Academy of Medical Sciences, 030167 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","first-page":"659","article-title":"Homotransplantation of the Liver in Humans","volume":"117","author":"Starzl","year":"1963","journal-title":"Surg. Gynecol. Obstet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Khalil, A., Quaglia, A., G\u00e9lat, P., Saffari, N., Rashidi, H., and Davidson, B. (2023). New Developments and Challenges in Liver Transplantation. J. Clin. Med., 12.","DOI":"10.3390\/jcm12175586"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Toma, D., Lazar, O., and Bontas, E. (2019). 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