Colyn Leticia, Grube Julia, Wang Chaochao, Dietrich Jana, Kühnel Mark, Reinders Jörg, Edlund Karolina, Jonigk Danny, Gaßler Nikolaus, Hengstler Jan, Trautwein Christian
Department of Internal Medicine III, RWTH Aachen University, Aachen, Germany.
Institute of Pathology, RWTH Aachen University, Aachen, Germany.
Liver Int. 2025 Sep;45(9):e70210. doi: 10.1111/liv.70210.
BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening condition with limited treatment options beyond liver transplantation in non-acetaminophen cases. The extensive loss of liver function results from severe hepatocyte death, where elevated reactive oxygen species (ROS) play a significant role. Nuclear factor erythroid-2 like 2 (Nrf2) is crucial in ROS defence by regulating genes like glutathione peroxidase 4 (GPX4), which prevents lipid peroxidation (LPO). GPX4 is involved in several regulated cell processes, including apoptosis and ferroptosis.
GPX4 expression was measured in liver samples from healthy, ALF, and acute-on-chronic liver failure (ACLF) patients. To investigate GPX4's role, mice with hepatocyte-specific deletion of Gpx4 (Gpx4) and both Gpx4 and the Nrf2 repressor, Keap1, (Gpx4Keap1) were generated. ALF was induced in mice using carbon tetrachloride (CCl) and bile duct ligation (BDL) cholestasis models, each lasting 48 h.
ALF patients exhibited reduced GPX4 levels compared to healthy individuals and ACLF patients, consistent with observations in CCl-treated wild-type mice. ALF-induced Gpx4 mice exhibited increased hepatocyte death and liver dysfunction upon CCl, with increased apoptosis despite no changes in LPO markers. Activation of Nrf2 in Gpx4Keap1 mice reversed CCl-induced damage, reducing necrosis and apoptosis markers while inducing anti-apoptotic BCL2.
Our results demonstrate that Gpx4 plays a critical role in ALF as its absence exacerbates apoptosis. Activating Keap1-dependent pathways targeting antioxidant defence systems and upregulating BCL2 provides substantial protection against ALF in mice lacking Gpx4 in hepatocytes. Our findings suggest that the Keap1-Nrf2 axis is a promising therapeutic target in ALF.
急性肝衰竭（ALF）是一种危及生命的疾病，在非对乙酰氨基酚所致病例中，除肝移植外治疗选择有限。肝功能的广泛丧失是由严重的肝细胞死亡导致的，其中活性氧（ROS）水平升高起重要作用。核因子红细胞2样2（Nrf2）通过调节谷胱甘肽过氧化物酶4（GPX4）等基因在ROS防御中起关键作用，GPX4可防止脂质过氧化（LPO）。GPX4参与多种受调控的细胞过程，包括凋亡和铁死亡。
检测健康、ALF和慢加急性肝衰竭（ACLF）患者肝脏样本中GPX4的表达。为研究GPX4的作用，构建了肝细胞特异性缺失Gpx4（Gpx4-/-）以及同时缺失Gpx4和Nrf2抑制因子Keap1（Gpx4Keap1-/-）的小鼠。使用四氯化碳（CCl4）和胆管结扎（BDL）胆汁淤积模型诱导小鼠发生ALF，每个模型持续48小时。
与健康个体和ACLF患者相比，ALF患者的GPX4水平降低，这与CCl4处理的野生型小鼠中的观察结果一致。CCl4诱导的Gpx4-/-小鼠肝细胞死亡增加，肝功能障碍加重，尽管LPO标志物无变化，但凋亡增加。Gpx4Keap1-/-小鼠中Nrf2的激活逆转了CCl4诱导的损伤，降低了坏死和凋亡标志物，同时诱导了抗凋亡蛋白BCL2。
我们的结果表明，Gpx4在ALF中起关键作用，因为其缺失会加剧凋亡。激活靶向抗氧化防御系统的Keap1依赖性途径并上调BCL2可为肝细胞中缺乏Gpx4的小鼠提供对ALF的实质性保护。我们的研究结果表明，Keap1-Nrf2轴是ALF中一个有前景的治疗靶点。
