FGF21 overexpression upregulates SIRT1/GPX4 to inhibit ferroptosis and relieve CCl4 mouse acute liver injury
10.19405/j.cnki.issn1000–1492.2026.06.010
- VernacularTitle:FGF21过表达上调SIRT1/GPX4并抑制铁死亡缓解CCl4小鼠急性肝损伤
- Author:
Xutao LING
1
;
Qianqian HUANG
2
;
Lun ZHANG
2
;
Fang XIE
1
;
Nan BAI
1
;
Yingxia WANG
1
;
Haoran HUA
1
;
Haoze WANG
1
;
Wenjing DAI
3
;
Kexin LI
1
;
Jianqing WANG
1
Author Information
1. School of Pharmaceutical Sciences， Anhui Medical University， Hefei 230032
2. Department of Pharmacy， The First Affiliated Hospital of Anhui Medical University， Hefei 230022
3. Anhui No.2 Provincial People's Hospital， Hefei 230041
- Publication Type:Journal Article
- Keywords:
acute liver injury;
carbon tetrachloride;
ferroptosis;
fibroblast growth factor 21;
oxidative stress;
SIRT1/GPX4 pathway
- From:
Acta Universitatis Medicinalis Anhui
2026;61(6):1053-1060
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo investigate the protective effect of liver-targeted fibroblast growth factor 21 （FGF21） overexpression against CCl₄-induced acute liver injury （ALI） and its association with silent information regulator 1/glutathione peroxidase 4 （SIRT1/GPX4） expression and ferroptosis-related markers. MethodsFemale ICR mice （8 weeks old） were randomly divided into Control， CCl₄， adeno-associated virus （AAV）-FGF21， and AAV-FGF21 + CCl4 groups. Liver-targeted FGF21 overexpression was achieved via tail vein injection of AAV8-FGF21 virus with green fluorescent protein （GFP） labeling. ALI was induced by intraperitoneal injection of CCl₄ （0.3 mL/kg）， with sample collection at 12 hours. Body weight and liver weight were recorded to calculate the liver weight/body weight. Alanine aminotransferase （ALT） and aspartate aminotransferase （AST） levels were measured using a biochemical analyzer. FGF21 expression in liver tissues was detected by immunofluorescence. Hepatic histopathology was evaluated by HE staining. RT-qPCR was performed to assess mRNA expression of ferroptosis and iron metabolism-related genes （ACSL4， PTGS2， HJV， FPN， GPX4）， FGF21， and SIRT1. Protein expression of FGF21， SIRT1， and GPX4 were determined by Western blot. Iron content， malondialdehyde （MDA）， glutathione （GSH）， and superoxide dismutase （SOD） activity in liver homogenate were quantified using assay kits. ResultsCompared with the Control group， the FGF21 mRNA and protein expression elevated in CCl4 group； serum ALT/AST levels and liver weight/body weigh increased. The HE staining results showed that the liver cell membranes were ruptured. The mRNA levels of ACSL4 and PTGS2， the iron content and MDA levels all increased （P<0.01）. The mRNA levels of SIRT1， GPX4， HJV， and FPN， the GSH level and SOD activity all decreased （P<0.05）， and the protein levels of SIRT1 and GPX4 both decreased （P<0.05）. Compared with the CCl4 group， the serum levels of ALT and AST in the AAV-FGF21 + CCl4 group were decreased （P<0.01）， and the liver/body ratio of mice decreased （P<0.01）. The results of HE staining showed that the degree of liver injury was alleviated. The mRNA levels of ACSL4 and PTGS2， iron content and MDA level all decreased （P<0.01）， while the mRNA levels of SIRT1， GPX4， HJV， FPN， GSH level and SOD activity all increased （P<0.05）. The protein levels of SIRT1 and GPX4 both increased （P<0.05）. ConclusionFGF21 overexpression is associated with enhanced SIRT1/GPX4 expression and suppression of ferroptosis features， thereby contributing to the alleviation of CCl4-induced ALI.
