Introduction: Acute liver failure requires urgent intervention, yet donor organ shortages remain a critical barrier to timely transplantation. Xenotransplantation using gene-edited pig livers has emerged as a viable bridge strategy. Recent advances have translated into first-in-human applications, including orthotopic and heterotopic pig liver transplantation in brain-dead human subjects in China, as well as auxiliary liver support in a living subject. In the United States, gene-edited pig livers have been perfused ex vivo in brain-dead human models for up to 72 hours, leading to FDA approval of a clinical trial using these organs as extracorporeal blood detoxification devices. While these clinical milestones mark significant progress, alternative approaches—including extracorporeal perfusion and cell-based therapies—are also being pursued to improve accessibility and reduce procedural invasiveness. Additionally, regenerative strategies such as generating humanized livers in pigs via interspecies chimerism are expanding the conceptual scope of xenogeneic liver support beyond transplantation.

Methods: We systematically reviewed five major strategies for xenogeneic liver support:

(1) orthotopic and heterotopic liver xenotransplantation using gene-edited pigs, (2) ex vivo perfusion of pig livers for extracorporeal support, (3) hepatocyte transplantation and encapsulated hepatocyte therapies, (4) bioartificial liver (BAL) systems incorporating porcine or stem cell–derived hepatocytes, and (5) interspecies blastocyst complementation using human iPSCs to generate humanized livers within porcine hosts.

These approaches were evaluated based on immune compatibility, metabolic function, reversibility, and translational readiness.

Results: Gene-edited pig livers have demonstrated short-term metabolic support and immunologic feasibility in both preclinical and early human studies. In one case, an auxiliary orthotopic pig liver xenograft was used to support native liver regeneration after extended right hepatectomy for a large benign tumor in a living subject who was not a candidate for allotransplantation. Ex vivo perfusion studies in brain-dead humans confirmed stable liver function and laid the foundation for clinical trials. In contrast, hepatocyte-based and BAL systems remain limited by cell maturity, immunogenicity, and lack of validation using gene-edited donors. Early-stage work in blastocyst complementation shows promise for autologous human liver generation in vivo.

Conclusion: Xenogeneic liver support is evolving into a clinically actionable and regenerative platform. While gene-edited whole-organ transplantation currently offers the most immediate impact, extracorporeal and cell-based strategies provide complementary avenues. Looking forward, interspecies chimerism may enable patient-specific liver regeneration, uniting xenotransplantation and regenerative medicine in transformative new directions.