GPR116 promotes ferroptosis in sepsis-induced liver injury by suppressing system Xc-/GSH/GPX4

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.

Automated summary

Sepsis is a disease caused by infection-induced organ damage. Liver injury, marked by ferroptosis, is an early indicator of sepsis. G protein-coupled receptor 116 (GPR116) has been shown to play a protective role in septic lung injury, but its role in septic liver injury is unknown. This study found that hepatic ferroptosis during sepsis is accompanied by upregulated GPR116. Deletion of hepatocyte-specific GPR116 gene can prevent hepatic ferroptosis, alleviate sepsis-induced liver dysfunction, and improve survival in mice, confirming it as a promising therapeutic target in sepsis.