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Research Article

Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD

Yunjing Zhang1,2,§, Jicheng Wu2,3,§, Quanlin An4, Huanhuan Zhu5,6, Xinwan Su1, Ying Wang1, Xishao Xie5,6, Jian Zhang5,6, Xi Yao5,6, Chunhua Weng5, Shi Feng5, Jianhua Mao7, Xianghui Fu8, Fei Han5( ), Xin Cao4( ), Ben Wang2,3( ), Weiqiang Lin1( )
International Institute of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Jinhua 322000, China
Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai 200032, China
Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Hangzhou 310003, China
Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou 310000, China
Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China

§ Yunjing Zhang and Jicheng Wu contributed equally to this work.

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Graphical Abstract

Renal tubule-targeted dexrazoxane (DXZ) inhibits ferroptosis by suppressing the catalytic activity or transcription of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) and Fenton reaction, thus inhibiting the mitochondrial tricarboxylic acid (TCA) cycle and reactive oxygen species (ROS) production and ultimately suppressing ferroptosis.

Abstract

Acute kidney injury (AKI) is a heterogeneous clinical complication with no existing definite or particular therapies. Therefore, molecular mechanisms and approaches for treating acute kidney injury are in urgent need. Herein, we demonstrated that dexrazoxane (DXZ), a U.S. Food and Drug Administration (FDA)-approved cardioprotective drug, can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically. This effect is characterized by decreasing lipid peroxidation, shown by the biomarker of oxidative stress 4-hydroxynonenal (HNE) and prostaglandinendoperoxide synthase 2 (Ptgs2), while reversing the downregulation of glutathione peroxidase 4 (GPX4) and ferritin 1 (FTH-1). Mechanistically, the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressing α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). Furthermore, the conjugation of dexrazoxane and polysialic acid (DXZ-PSA) is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney, especially retention and targeting in the renal tubules. This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZ-PSA with the enhanced renal distribution.

Keywords

dexrazoxanedexrazoxane-polysialic acidacute kidney injuryischemia-reperfusion injuryferroptosisα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD)

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Nano Research
Volume 16 Issue 7,
July 2023
Pages 9701-9714
DOI: 10.1007/s12274-023-5547-8
Cite this article:
Zhang Y, Wu J, An Q, et al. Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD. Nano Research, 2023, 16(7): 9701-9714. https://doi.org/10.1007/s12274-023-5547-8
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Received: 10 November 2022
Revised: 03 February 2023
Accepted: 06 February 2023
Published: 18 April 2023
© Tsinghua University Press 2023
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