GSTP1-mediated inhibition of ACSL4-dependent ferroptosis via JNK pathway in DOX-induced cardiomyopathy.
10.1097/CM9.0000000000003758
- Author:
Mingbo WU
1
;
Ye ZHAO
2
;
Dong LI
3
;
Xueli HU
4
;
Jiaojiao ZHOU
1
;
Siyi CHEN
3
;
Xin YANG
3
;
Zegang LI
3
;
Xiaomiao RUAN
1
;
Jingwen YANG
1
;
Wenwu LING
1
Author Information
1. Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
2. School of Bioscience and Biotechnology, Chengdu Medical College, Chengdu, Sichuan 610500, China.
3. Department of Oncology, General Hospital of Western Theater Command of PLA, Chengdu, Sichuan 610083, China.
4. State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
- Publication Type:Journal Article
- Keywords:
Cardiomyopathy;
Doxorubicin hydrochloride;
Ferroptosis;
Glutathione S-transferase P1;
Reactive oxygen species;
c-Jun N-terminal kinase pathway
- From:
Chinese Medical Journal
2025;138(19):2498-2510
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Doxorubicin hydrochloride (DOX) is extensively used in the treatment of various tumors. However, its clinical application is limited due to dose-dependent cardiotoxicity. Currently, few effective strategies exist to mitigate or eliminate DOX-induced cardiomyopathy (DIC). Although ferroptosis is implicated in DIC and its inhibition partially alleviates the condition, the direct targets of DOX in the progression of cardiotoxicity remain unclear. This study aimed to discover the direct targets of DOX in ferroptosis-mediated DIC.
METHODS:A DOX pulldown assay was performed to identify proteins specifically binding to DOX in murine hearts, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify candidate proteins. A cardiac injury mouse model was established by DOX treatment. Based on this, multiple ferroptosis biomarkers were detected by flow cytometry, quantitative real-time polymerase chain reaction, western blotting, immunochemistry, etc. Besides, specific activator and inhibitor of signaling pathways were applied to illuminate molecular mechanisms.
RESULTS:Glutathione S-transferase P1 (GSTP1) was identified as a DOX target. GSTP1 activity was inhibited in DOX-treated cardiomyocytes, while its overexpression significantly alleviated DIC. Moreover, GSTP1 overexpression inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. Mechanistically, GSTP1 overexpression suppressed c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing reactive oxygen species (ROS) production and inhibiting ferroptosis in DIC.
CONCLUSIONS:This study identifies the DOX/GSTP1/JNK axis as a critical pathway mediating ACSL4-dependent ferroptosis in DIC. GSTP1 is highlighted as a potential key mediator of ferroptosis and a promising therapeutic target for DIC.
