USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L

Qing-Qing Wu; Yang Xiao; Ying-Ying Hu; Xiang-Yu Yang; Xin-Yi Yan; Ke-Qiong Deng; Zhi-Li Jin; Wei Zhang; Jian-Lei Cao; Li-Hua Ni; Yong-Zhen Fan; Zhi-Bing Lu; Xiao-Rong Hu

doi:10.1016/j.mmr.2026.100004

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USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L

RESEARCH | Updated：2026-05-11

- USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L
- Military Medical Research (2026)
- Affiliations：
  
  Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430062, China
  Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430062, China
  Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Author bio：
  
  *Zhi-Bing Lu, luzhibing@whu.edu.cn;
  Xiao-Rong Hu, huxrzn@whu.edu.cn
- Funds：
- DOI：10.1016/j.mmr.2026.100004
  CLC：
- Received：17 June 2025，
  
  Revised：2026-03-05，
  
  Published：2026-03
- Accepted：
Scan QR Code
Wu QQ, Xiao Y, Hu YY, Yang XY, Yan XY, Deng KQ, et al. USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L. Mil Med Res. 2026;13(1):100004.
DOI：

Wu QQ, Xiao Y, Hu YY, Yang XY, Yan XY, Deng KQ, et al. USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L. Mil Med Res. 2026;13(1):100004. DOI： 10.1016/j.mmr.2026.100004.

摘要

Abstract

Background:

Mitochondrial quality control is essential for limiting myocardial injury induced by ischemia/reperfusion(I/R)

a major contributor to adverse outcomes after reperfusion therapy. This study aimed to determine whether the deubiquitinase ubiquitin-specific protease 18 (USP18) regulates mitophagy during cardiac I/R injury and thereby represents a potential therapeutic target to attenuate myocardial I/R injury.

Methods:

Cardiac-specific

USP18

knockout mice were subjected to cardiac I/R injury. To elucidate the role of USP18 in mitophagy regulation and cardiac I/R injury

we performed RNA sequencing

proteomic mass spectrometry

transmission electron microscopy

and mitophagy assays. In parallel

adeno-associated virus serotype 9 (AAV9)-mediated overexpression of USP18

knockdown of

Parkin

and phosphatase and tensin homolog-long (

PTEN-L

)

and administration of an anti-PTEN-L neutralizing antibody were used to elucidate the underlying mechanisms. Additionally

serum samples from patients with ST-segment elevation myocardial infarction (STEMI) were collected to assess clinical relevance.

Results:

USP18 expression was upregulated in mouse hearts following I/R injury and in ischemic human heart tissue. Cardiac-specific

USP18

deficiency mitigated I/R-induced acute myocardial injury

mitochondrial dysfunction

and adverse cardiac remodeling

whereas USP18 overexpression exacerbated these pathological changes. Mechanistically

USP18 interacted with PTEN-L

which in turn bound to and inhibited the phosphorylation and translocation of Parkin to mitochondria

thereby suppressing mitophagy.

Parkin

knockdown abolished the cardioprotective effects conferred by

USP18

deficiency

whereas

PTEN-L

knockdown reversed the detrimental effect of USP18 overexpression. Moreover

PTEN-L also exerted pathogenic effects via a paracrine mechanism

as neutralizing PTEN-L with an antibody attenuated cardiac I/R injury. Serum PTEN-L levels were elevated in STEMI patients

particularly postintervention.

Conclusions:

USP18 impairs mitophagy and exacerbates cardiac I/R injury through a PTEN-L-Parkin axis

involving both intracellular and paracrine mechanisms. Targeting the USP18-PTEN-L pathway may represent a novel therapeutic strategy to alleviate myocardial I/R injury.

关键词

Keywords

references

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