Xu Jinghong, Chen Shirui, Liu Di, Zhang Qi, Luo Tao, Zhu Jiaxing, Zhou Liang, Lin Yuan, Pan Hongyu, Chen Yichao, Zhao Qiang, Wang Tielong, Andrea Schlegel, Nashan Björn, Stefan Tullius G, Cai Changjie, Cui Jun, He Xiaoshun, Guo Zhiyong
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Adv Sci (Weinh). 2025 Feb;12(6):e2406200. doi: 10.1002/advs.202406200. Epub 2024 Nov 22.
Ischemia-free liver transplantation (IFLT) is developed as a novel clinical approach to avoid ischemia-reperfusion injury (IRI). This study aims to identify the most distinguished programmed cell death pathway in grafts undergoing IFLT versus conventional liver transplantation (CLT) and to explore the underlying mechanism. Ferroptosis is the most distinct programmed cell death form between IFLT and CLT grafts. Among various cell death inhibitors, the ferroptosis inhibitor (Ferrostain-1) is the most effective one to prevent hepatocytes from damage induced by oxygen deprivation/reoxygenation (OGD/R). Hepatocyte ferroptosis is significantly alleviated in IFLT versus CLT grafts in both human beings and pigs. Ubiquitination enzyme screening identifies augmented amounts of ubiquitin-specific protease 19 (USP19) in IFLT versus CLT grafts. The upregulation of USP19 in the grafts is correlated with reduced pathological Suzuki's score, lower post-transplant peak liver enzyme level, and less early allograft dysfunction in liver transplant recipients. USP19 overexpression mitigates post-transplant liver injury in mice. Mechanistically, USP19 inhibits the degradation of solute carrier family 7 member 11 (SLC7A11) by removing its K63-linked ubiquitin chains. Notably, USP19 overexpression reduces ferroptosis and IRI in a SLC7A11-dependent manner in mice. Collectively, USP19-mediated suppression of hepatocyte ferroptosis via deubiquitinating SLC7A11 is a key mechanism by which IFLT abrogates graft IRI.
无缺血肝移植（IFLT）是作为一种避免缺血再灌注损伤（IRI）的新型临床方法而开发的。本研究旨在确定在接受IFLT与传统肝移植（CLT）的移植物中最显著的程序性细胞死亡途径，并探索其潜在机制。铁死亡是IFLT和CLT移植物之间最明显的程序性细胞死亡形式。在各种细胞死亡抑制剂中，铁死亡抑制剂（Ferrostain-1）是预防缺氧/复氧（OGD/R）诱导的肝细胞损伤最有效的一种。在人类和猪中，与CLT移植物相比，IFLT移植物中的肝细胞铁死亡明显减轻。泛素化酶筛选发现，与CLT移植物相比，IFLT移植物中泛素特异性蛋白酶19（USP19）的含量增加。移植物中USP19的上调与肝移植受者的病理铃木评分降低、移植后肝酶峰值水平降低以及早期移植物功能障碍减少相关。USP19过表达减轻小鼠移植后肝损伤。机制上，USP19通过去除溶质载体家族7成员11（SLC7A11）的K63连接泛素链来抑制其降解。值得注意的是，在小鼠中，USP19过表达以SLC7A11依赖的方式减少铁死亡和IRI。总的来说，USP19通过去泛素化SLC7A11介导的对肝细胞铁死亡的抑制是IFLT消除移植物IRI的关键机制。
