Parkin inhibits iron overload-induced cardiomyocyte ferroptosis by ubiquitinating ACSL4 and modulating PUFA-phospholipids metabolism.
10.1016/j.apsb.2024.12.027
- Author:
Dandan XIAO
1
;
Wenguang CHANG
1
;
Xiang AO
1
;
Lin YE
1
;
Weiwei WU
2
;
Lin SONG
2
;
Xiaosu YUAN
1
;
Luxin FENG
3
;
Peiyan WANG
1
;
Yu WANG
1
;
Yi JIA
1
;
Xiaopeng TANG
2
;
Jianxun WANG
1
Author Information
1. Institute for Translational Medicine, the Affiliated Hospital of Qingdao University, Qingdao 266021, China.
2. School of Basic Medicine, Qingdao University, Qingdao 266071, China.
3. Department of Cardiovascular Medicine, the Affiliated Hospital of Qingdao University, Qingdao 266000, China.
- Publication Type:Journal Article
- Keywords:
ACSL4;
Ferroptosis;
Heart diseases;
I/R;
Iron overload;
Mitochondrial;
Parkin;
p53
- From:
Acta Pharmaceutica Sinica B
2025;15(3):1589-1607
- CountryChina
- Language:English
-
Abstract:
Iron overload is strongly associated with heart disease. Ferroptosis is a new form of regulated cell death indicated in cardiac ischemia-reperfusion (I/R) injury. However, the specific molecular mechanism of myocardial injury caused by iron overload in the heart is still unclear, and the involvement of ferroptosis in iron overload-induced myocardial injury is not fully understood. In this study, we observed that ferroptosis participated in developing of iron overload and I/R-induced cardiomyopathy. Mechanistically, we discovered that Parkin inhibited iron overload-induced ferroptosis in cardiomyocytes by promoting the ubiquitination of long-chain acyl-CoA synthetase 4 (ACSL4), a crucial protein involved in ferroptosis-related lipid metabolism pathways. Additionally, we identified p53 as a transcription factor that transcriptionally suppressed Parkin expression in iron-overloaded cardiomyocytes, thereby regulating iron overload-induced ferroptosis. In animal studies, cardiac-specific Parkin knockout mice (Myh6-CreER T2 /Parkin fl/fl ) fed a high-iron diet presented more severe myocardial damage, and the high iron levels exacerbated myocardial I/R injury. However, the ferroptosis inhibitor Fer-1 significantly suppressed iron overload-induced ferroptosis and myocardial I/R injury. Moreover, Parkin effectively protected against impaired mitochondrial function and prevented iron overload-induced mitochondrial lipid peroxidation. These findings unveil a novel regulatory pathway involving p53-Parkin-ACSL4 in heart disease by inhibiting of ferroptosis.
