The disease sepsis is caused by an infection that damages organs. Liver injury, with ferroptosis playing a key role, is an early sign of sepsis. G protein-coupled receptor 116 (GPR116) is essential in the maintenance of functional homeostasis in various systems of the body and has been proven to play a protective role in septic lung injury. However, it’s role in septic liver injury remains unclear. In this study, we found that hepatic ferroptosis during sepsis was accompanied by GPR116 upregulation. Hepatocyte-specific GPR116 gene deletion can prevent hepatic ferroptosis, thereby alleviating sepsis-induced liver dysfunction and improving mouse survival, which was verified in vivo. Mechanistically, GPR116 aggravated mitochondrial damage and lipid peroxidation in hepatocytes by inhibiting system Xc^–/GSH/GPX4 in overexpression experiments. In conclusion, we have identified GPR116 as a vital mediator of ferroptosis in sepsis-induced liver injury. It is thus an attractive therapeutic target in sepsis.

败血症是由损害器官的感染引起的。肝损伤是脓毒症的早期征兆，铁死亡起着关键作用。G 蛋白偶联受体 116 (GPR116) 在维持身体各系统的功能稳态中必不可少，并已被证明在感染性肺损伤中发挥保护作用。然而，它在脓毒性肝损伤中的作用仍不清楚。在这项研究中，我们发现脓毒症期间的肝铁死亡伴随着 GPR116 上调。肝细胞特异性GPR116基因缺失可预防肝铁死亡，从而减轻脓毒症引起的肝功能障碍，提高小鼠存活率，并在体内得到验证。从机制上讲，GPR116 通过抑制 Xc 系统加重肝细胞线粒体损伤和脂质过氧化^-/GSH/GPX4 在过表达实验中。总之，我们已经确定 GPR116 是败血症引起的肝损伤中铁死亡的重要介质。因此它是脓毒症中有吸引力的治疗靶点。