Abstract
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.
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Abbreviations
- ALT :
-
Alanine aminotransferase
- AST :
-
Aspartate aminotransferase
- ALD :
-
Alcoholic liver disease
- AML12 :
-
Alpha mouse liver 12
- CLP :
-
Cecal ligation and puncture
- DILI :
-
Drug-induced liver injury
- ELISA :
-
Enzyme-linked immunosorbent assay
- GPX4 :
-
Glutathione peroxidase 4
- GPCRs :
-
G protein-coupled receptors
- GPR116/ADGRF5 :
-
G protein-coupled receptor 116/Adhesion G protein-coupled receptor F5
- GSH :
-
Glutathione
- GSH-PX :
-
Glutathione peroxidase
- H&E :
-
Haematoxylin and eosin
- IL-6 :
-
Interleukin-6
- IRI :
-
Ischemia/reperfusion-related injury
- MDA :
-
Malondialdehyde
- NAFLD :
-
Nonalcoholic fatty liver disease
- NET :
-
Neutrophil extracellular trap
- RIPA :
-
Radioimmunoprecipitation assay
- SD :
-
Standard deviation
- TEM :
-
Transmission electron microscope
- TNF-α :
-
Umor necrosis factor-α
- SLC7A11 :
-
Solute carrier family 7 member 11
- SLC3A2 :
-
Solute carrier family 3 member 2
- WT :
-
Wild-type
- 4-HNE :
-
4-Hydroxy-2-noneal
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This work was supported by grants from the National Natural Science Foundation of China (81871579, 82272205, and 82072220).
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Ying Wang: design of experiments, experimental studies, data cleansing and analysis, edit the first draft and revision. Ting Wang, Qian Xiang: experimental studies and manuscript revision. Na Li, Jun Wang, Yan Zhang: experimental guidance and suggestions for improvement. Jiahao Liu: data analysis. Tao Yang, Jinjun Bian: experimental guidance and suggestions for improvement, manuscript revision.
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Wang, Y., Wang, T., Xiang, Q. et al. GPR116 promotes ferroptosis in sepsis-induced liver injury by suppressing system Xc–/GSH/GPX4. Cell Biol Toxicol 39, 3015–3030 (2023). https://doi.org/10.1007/s10565-023-09815-8
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DOI: https://doi.org/10.1007/s10565-023-09815-8