Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, 2001 Longxiang Blvd., Longgang District, Shenzhen, 518172, Guangdong, China.
Shenzhen Bay Laboratory, Shenzhen, 518055, China.
Cell Commun Signal. 2024 Sep 6;22(1):431. doi: 10.1186/s12964-024-01798-1.
Recently we have shown that protein disulfide isomerase (PDI or PDIA1) is involved in mediating chemically-induced, glutathione (GSH) depletion-associated ferroptotic cell death through NOS activation (dimerization) and NO accumulation. The present study aims to determine the role of PDI in mediating chemically-induced hepatocyte injury in vitro and in vivo and whether PDI inhibitors can effectively protect against chemically-induced hepatocyte injury. We show that during the development of erastin-induced ferroptotic cell death, accumulation of cellular NO, ROS and lipid-ROS follows a sequential order, i.e., cellular NO accumulation first, followed by accumulation of cellular ROS, and lastly cellular lipid-ROS. Cellular NO, ROS and lipid-ROS each play a crucial role in mediating erastin-induced ferroptosis in cultured hepatocytes. In addition, it is shown that PDI is an important upstream mediator of erastin-induced ferroptosis through PDI-mediated conversion of NOS monomer to its dimer, which then leads to accumulation of cellular NO, ROS and lipid-ROS, and ultimately ferroptotic cell death. Genetic manipulation of PDI expression or pharmacological inhibition of PDI function each can effectively abrogate erastin-induced ferroptosis. Lastly, evidence is presented to show that PDI is also involved in mediating acetaminophen-induced liver injury in vivo using both wild-type C57BL/6J mice and hepatocyte-specific PDI conditional knockout (PDI Alb-cre) mice. Together, our work demonstrates that PDI is an important upstream mediator of chemically-induced, GSH depletion-associated hepatocyte ferroptosis, and inhibition of PDI can effectively prevent this injury.
最近我们发现，蛋白二硫键异构酶（PDI 或 PDIA1）通过 NOS 激活（二聚化）和 NO 积累，参与介导化学诱导的、与谷胱甘肽（GSH）耗竭相关的铁死亡细胞死亡。本研究旨在确定 PDI 在体外和体内介导化学诱导的肝细胞损伤中的作用，以及 PDI 抑制剂是否能有效预防化学诱导的肝细胞损伤。我们发现，在依拉司琼诱导的铁死亡细胞死亡过程中，细胞内 NO、ROS 和脂质-ROS 的积累遵循一个顺序，即细胞内 NO 首先积累，随后是细胞内 ROS 的积累，最后是细胞内脂质-ROS 的积累。细胞内 NO、ROS 和脂质-ROS 各自在介导培养的肝细胞中依拉司琼诱导的铁死亡中发挥关键作用。此外，研究表明，PDI 是依拉司琼诱导铁死亡的一个重要上游调节因子，通过 PDI 介导的 NOS 单体转化为二聚体，从而导致细胞内 NO、ROS 和脂质-ROS 的积累，最终导致铁死亡细胞死亡。PDI 表达的基因操作或 PDI 功能的药理学抑制都可以有效地阻断依拉司琼诱导的铁死亡。最后，研究结果表明，PDI 还参与介导体内对乙酰氨基酚诱导的肝损伤，分别使用野生型 C57BL/6J 小鼠和肝细胞特异性 PDI 条件性敲除（PDI Alb-cre）小鼠。总之，我们的工作表明，PDI 是化学诱导的、与 GSH 耗竭相关的肝细胞铁死亡的一个重要上游调节因子，抑制 PDI 可以有效预防这种损伤。
