Pig-to-human liver transplantation promises cure for hepatic diseases

A genetically engineered pig liver has been successfully transplanted in a living human, according to a recent study, noting the challenge posed by postoperative xenotransplantation-associated thrombotic microangiopathy (xTMA) to long-term success.

“[T]his groundbreaking auxiliary liver xenotransplantation case offers critical insights into the feasibility, challenges, and potential of xenotransplantation as a life-saving therapy for severe liver disease,” the investigators said.

“This study marks a pivotal advancement in tackling the worldwide organ scarcity crisis, establishing a crucial foundation for expediting clinical trial progression and facilitating the broader implementation of liver xenotransplantation in clinical settings,” they added.

A patient with large hepatocellular carcinoma initially deemed ineligible for curative resection underwent xenotransplantation with a genetically modified pig liver that served as an auxiliary organ. The investigators then closely monitored liver function, metabolic, and coagulation markers throughout the perioperative period.

No hyperacute or acute rejection, infections, or significant complications occurred during the first 31 days following transplantation. Furthermore, the patient’s hepatic and renal function remained stable. Early postoperative coagulopathy occurred, as shown by elevated D-dimer and fibrin degradation products, and was patched using anticoagulant therapy. [J Hepatol 2026;84:587-598]

On day 38 after the procedure, the auxiliary liver was removed due to xTMA, but this was successfully resolved through subsequent management with eculizumab and plasma exchange. Unfortunately, the patient died on day 171 following repeated upper gastrointestinal haemorrhage.

Organ rejection

“Our study provides the first evidence that a 10-gene-modified pig-to-human auxiliary liver xenotransplantation is feasible in a living recipient,” the investigators said.

“While hyperacute and acute rejection remain significant barriers in xenogeneic liver transplantation, the pathological and immunological analyses in this case revealed no evidence of either rejection type,” they added. [Int J Mol Sci 2021;22; Nature 2023;622:244-245]

To prevent organ rejection, a multifaceted approach was used, including knockout of three pig xenoantigen genes (GGTA1, CMAH, and β4GalNT2), preoperative administration of rituximab (an anti-CD20 monoclonal antibody for B-cell depletion), and basiliximab (an interleukin-2 receptor antibody to inhibit T-cell proliferation). [Nat Commun 2022;13:5174; JCI Insight 2019;4] 

The donor pig was maintained in designated-pathogen-free (DPF) facilities since its birth, and a comprehensive screening confirmed the absence of 47 pathogens (eg, PLHV-1, PCMV, and PRRSV-1/2), meeting the requirements for DPF pigs as specified by the International Xenotransplantation Association. [Xenotransplantation 2016;23:25-31; Xenotransplantation 2016;23:25-31; Sci Rep 2020;10:17531]

Several in vitro studies and animal models suggest theoretical risks for porcine endogenous retrovirus (PERV), which is characterized by permanent genomic integration in all porcine tissues and has shown potential for recombination into human-tropic, horizontally transmissible strains.

“However, there is no conclusive evidence that PERV transmission causes disease in nonhuman primates or clinical cases, likely owing to species barriers, immune control, and limited viral replication,” the investigators said. [Clin Microbiol Rev 2025;38:e0015023]

To address such risk, a systematic postoperative surveillance was conducted using high-sensitivity qRT-PCT for PERV RNA. All samples tested negative.

“This study underscores the necessity of advanced genetic modifications to reduce rejection risks, precise immunosuppressive strategies to control immune responses, and careful coagulation management to prevent thrombotic complications, all of which are vital for improving xenotransplantation outcomes,” the investigators said.

“Early detection and intervention for xTMA are essential to ensure the safety and efficacy of liver xenotransplantation,” they added.