GAS1 Promotes Ferroptosis of Liver Cells in Acetaminophen-Induced Acute Liver Failure.
Int J Med Sci
; 20(12): 1616-1630, 2023.
Article
in En
| MEDLINE
| ID: mdl-37859699
ABSTRACT
Purpose:
Acute liver failure (ALF) is a clinically fatal disease that leads to the rapid loss of normal liver function. Acetaminophen (APAP) is a leading cause of drug-induced ALF. Ferroptosis, defined as iron-dependent cell death associated with lipid peroxide accumulation, has been shown to be strongly associated with APAP-induced liver injury. Growth arrest-specific 1 (GAS1) is a growth arrest-specific gene, which is closely related to the inhibition of cell growth and promotion of apoptosis. However, the functional role and underlying mechanism of GAS1 in APAP-induced ferroptosis remain unknown.Methods:
We established liver-specific overexpression of GAS1 (GAS1AAV8-OE) mice and the control (GAS1AAV8-vector) mice by tail vein injection of male mice with adeno-associated virus. APAP at 500 mg/kg was intraperitoneally injected into these two groups of mice to induce acute liver failure. The shRNA packaged by the lentivirus inhibits GAS1 gene expression in human hepatoma cell line HepaRG (HepaRG-shNC and HepaRG-shGAS1-2) and primary hepatocytes of mice with liver-specific overexpression of GAS1 were isolated and induced by APAP in vitro to further investigate the regulatory role of GAS1 in APAP-induced acute liver failure.Results:
APAP-induced upregulation of ferroptosis, levels of lipid peroxides and reactive oxygen species, and depletion of glutathione were effectively alleviated by the ferroptosis inhibitor, ferrostatin-1, and downregulation of GAS1 expression. GAS1 overexpression promoted ferroptosis-induced lipid peroxide accumulation via p53, inhibiting its downstream target, solute carrier family 7 member 11.Conclusion:
Collectively, our findings suggest that GAS1 overexpression plays a key role in aggravating APAP-induced acute liver injury by promoting ferroptosis-induced accumulation of lipid peroxides.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Liver Failure, Acute
/
Ferroptosis
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Int J Med Sci
Journal subject:
MEDICINA
Year:
2023
Document type:
Article
Affiliation country:
China