The Imbalance of p53–Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin‐Challenged Cardiomyocytes

Author:

Pan Jianan1,Xiong Weiyao2,Zhang Alian1,Zhang Hui3,Lin Hao1,Gao Lin1,Ke Jiahan1,Huang Shuying1,Zhang Junfeng1,Gu Jun1,Chang Alex Chia Yu12,Wang Changqian1ORCID

Affiliation:

1. Department of Cardiology Shanghai Ninth People's Hospital Shanghai JiaoTong University school of Medicine Shanghai 200001 P. R. China

2. Department of Shanghai Institute of Precision Medicine Shanghai Ninth People's Hospital Shanghai JiaoTong University school of Medicine Shanghai 200135 P. R. China

3. Department of Echocardiography Zhongshan Hospital Fudan University Shanghai 200030 P. R. China

Abstract

AbstractDoxorubicin (DOX)‐induced cardiotoxicity (DoIC) is a major side effect for cancer patients. Recently, ferroptosis, triggered by iron overload, is demonstrated to play a role in DoIC. How iron homeostasis is dysregulated in DoIC remains to be elucidated. Here, the authors demonstrate that DOX challenge exhibits reduced contractile function and induction of ferroptosis‐related phenotype in cardiomyocytes, evidenced by iron overload, lipid peroxide accumulation, and mitochondrial dysfunction. Compared to Ferric ammonium citrate (FAC) induced secondary iron overload, DOX‐challenged cardiomyocytes show a dysfunction of iron homeostasis, with decreased cytoplasmic and mitochondrial iron–sulfur (FeS) cluster‐mediated aconitase activity and abnormal expression of iron homeostasis–related proteins. Mechanistically, mass spectrometry analysis identified DOX‐treatment induces p53‐dependent degradation of Parkinsonism associated deglycase (Park7) which results in iron homeostasis dysregulation. Park7 counteracts iron overload by regulating iron regulatory protein family transcription while blocking mitochondrial iron uptake. Knockout of p53 or overexpression of Park7 in cardiomyocytes remarkably restores the activity of FeS cluster and iron homeostasis, inhibits ferroptosis, and rescues cardiac function in DOX treated animals. These results demonstrate that the iron homeostasis plays a key role in DoIC ferroptosis. Targeting of the newly identified p53–Park7 signaling axis may provide a new approach to prevent DoIC.

Funder

National Natural Science Foundation of China

Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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