z-bio 2025-10-29 3038

　　Professor Sun Beicheng of Anhui Medical University is mainly engaged in basic and clinical research on liver surgery and liver transplantation. Recently, he has published a number of research papers in the Journal of Hepatology, a top journal of hepatology, focusing on the molecular basis and clinical translation of chronic inflammatory immune microenvironment mediating the malignant progression of liver cancer.

　　Article 1 The world’s first case: Genetically engineered pig-to-human liver xenotransplantation

　　Liver transplantation is the most effective method to treat end-stage liver disease. Led by Academician Dou Kefeng's team, a study published in Nature introduced the world's first complete case of transplanting a gene-edited pig liver to a human recipient diagnosed as brain-dead. It verified the safety and effectiveness of multi-gene-edited pig organ transplantation and laid the foundation for the clinical application of xenotransplantation. ‌

　　Recently, Professor Sun Beicheng and Professor Wei Hongjiang of Yunnan Agricultural University published a research paper titled "Genetically engineered pig-to-human liver xenotransplantation" as co-corresponding authors.

　　The research team constructed 10 genetically modified pig models through CRISPR-Cas9 technology and successfully transplanted 514 g of pig liver into a 71-year-old patient with liver cancer and liver failure. Three major breakthroughs were achieved, namely the world's first living functional survival: the graft continued to secrete bile (peak 400 ml/d) and synthesized coagulation factors to control rejection; gene editing effectively avoided hyperacute rejection survival records and the patient's overall survival reached 171 days, significantly surpassing previous records.

　　The study achieved the first live gene-edited pig liver transplantation, successfully avoiding hyperacute rejection and maintaining functional survival for 31 days. However, on the 31st day of the operation, symptoms of xenograft-related thrombotic microangiopathy (xTMA) appeared, and antibody treatment was ineffective. Therefore, surgical removal of the pig liver relies on the regeneration function of the patient's left liver lobe. After staged antibody treatment, xTMA symptoms were relieved. Unfortunately, the patient suffered a sudden upper gastrointestinal bleeding on the 135th day after surgery. Despite multiple medical interventions, bleeding events continued to occur, eventually leading to the patient's death on the 171st postoperative day. Therefore, the revelation of xTMA's refractory nature requires optimization at the genetic level.　

　　Article 2 New breakthroughs in the treatment of steatohepatitis and liver fibrosis

　　Identifying the metabolic targets that drive liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) is critical to the development of effective preventive therapies. However, the metabolic pathways dysregulated in MASH and their molecular mechanisms are still poorly understood. The mitochondrial protease LON peptidase 1 (LONP1) plays a key role in maintaining mitochondrial protein quality control and executing highly regulated proteolytic reactions.

　　In this regard, Sun Beicheng's team found that the LONP1-DHODH metabolic axis affects liver fibrosis by regulating orotic acid levels in metabolic dysfunction-associated steatohepatitis (MASH). Studies have shown that LONP1 expression is significantly reduced in MASH patients and mouse models, leading to DHODH accumulation and increased orotic acid levels, exacerbating liver fibrosis. Overexpression of LONP1 or use of DHODH inhibitors attenuated fibrosis. Mechanistically, LONP1 selectively degrades DHODH in an ATP-dependent manner, reduces orotic acid and inhibits hepatic stellate cell activation. These findings provide new targets for the treatment of MASH liver fibrosis.

　　The study is titled Decreased LONP1 expression exacerbates MASH-induced liver fibrosis via elevated orotic acid levels.

　　Article 3 New discoveries in the treatment of intrahepatic cholangiocarcinoma

　　Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer, accounting for 10%-15%. It is an almost fatal malignant tumor.

　　Previous studies have found that although epidermal growth factor receptor (EGFR) is overexpressed and abnormally activated in intrahepatic cholangiocarcinoma (iCCA), the disease remains refractory to EGFR tyrosine kinase inhibitors (TKIs). Several clinical trials involving EGFR-targeting agents have been conducted; however, no clinically meaningful efficacy has been demonstrated.

　　The research team found through transcriptomic, proteomic and metabolomic analysis that plasma orotic acid levels were negatively correlated with liver LONP1 expression in patients with metabolic dysfunction-associated steatohepatitis (MASH), and positively correlated with fibrosis gene expression and fibrosis score.

　　This study clarifies the role of XOR in resistance to EGFR TKIs, advances the molecular understanding of iCCA, and identifies attractive targets for combination therapy with EGFR TKIs.

　　The study is titled Decreased LONP1 expression exacerbates MASH-induced liver fibrosis via elevated orotic acid levels.