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Inhibition of USP14 Suppresses ROS-dependent Ferroptosis and Alleviates Renal Ischemia/Reperfusion Injury

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Abstract

The ubiquitin-specific protease 14 (USP14) is a deubiquitinating enzyme, its inhibitor was reported could alleviate the ischemia/reperfusion (I/R)-stimulated cerebral neuronal damage. However, its specific role in I/R-induced acute kidney injury (AKI) remains unclear. We established hypoxia/reoxygenation (H/R)-induced HK-2 cell injury model in vitro and I/R-induced kidney injury mice model in vivo. The expression or activity of USP14 was inhibited by siRNA or IU1, a small molecule inhibitor of USP14. ROS were scavenged by N-acetyl-cysteine (NAC). Biochemical index analysis and hematoxylin & eosin (H&E) staining were performed to evaluate renal injury. The results indicated that USP14 was upregulated in H/R-induced HK-2 cells and kidney tissues of I/R mice. Inhibition of USP14 suppressed the cell death, inflammatory, oxidative stress and reactive oxygen species (ROS)-dependent ferroptosis of H/R-induced HK-2 cells. What’s more, IU1 and NAC effectively alleviated renal injury of I/R mice. In summary, this study suggested that inhibition of USP14 protected renal from I/R injury.

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Data availability

The data in the present study are available from the corresponding author on reasonable request.

Abbreviations

AKI:

acute kidney injury

I/R:

ischemia/reperfusion

H/R:

hypoxia/reoxygenation

USP14:

ubiquitin-specific protease 14

NAC:

N-acetyl-cysteine

ROS:

reactive oxygen species

GSH-Px:

glutathione peroxidase

LDH:

lactate dehydrogenase

SOD:

superoxide dismutase

COX2:

cyclooxygenase-2

NOX1:

NADPH oxidase 1,

ACSL4:

Acyl-CoA Synthetase Long Chain Family Member 4

GPX4:

glutathione peroxidase 4

FTH1:

ferritin heavy chain 1

BUN:

blood urea nitrogen

Scr:

serum creatinine

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Author contributions

W.L. and J.P. designed and performed most of the experiments, analyzed all data, prepared figures and wrote the manuscript; J.Z. and L.F. performed part of the experiments; XL.X. and ZT.H. contributed to experimental design, data interpretation, and writing the paper. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Internal Medicine, Ninth hospital of xi’an, Xi’an, Shaanxi, 710054, China

    Jie Pan, Jing Zhao, Ling Feng, Xiaoli Xu, Zhiting He & Wei Liang

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  1. Jie Pan
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  2. Jing Zhao
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  3. Ling Feng
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Correspondence to Wei Liang.

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The present study was approved by the Ethics Committee of the Ninth hospital of xi’an.

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Pan, J., Zhao, J., Feng, L. et al. Inhibition of USP14 Suppresses ROS-dependent Ferroptosis and Alleviates Renal Ischemia/Reperfusion Injury. Cell Biochem Biophys 81, 87–96 (2023). https://doi.org/10.1007/s12013-022-01107-y

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