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

  • Mil Med Res. 2026 Dec;13(1):100004. doi: 10.1016/j.mmr.2026.100004.
Qing-Qing Wu  1  2 ,  Yang Xiao  3 ,  Ying-Ying Hu  1  2 ,  Xiang-Yu Yang  1  2 ,  Xin-Yi Yan  1  2 ,  Ke-Qiong Deng  1  2 ,  Zhi-Li Jin  1  2 ,  Wei Zhang  1  2 ,  Jian-Lei Cao  1  2 ,  Li-Hua Ni  1  2 ,  Yong-Zhen Fan  1  2 ,  Zhi-Bing Lu  1  2 ,  Xiao-Rong Hu  1  2
Affiliations
  • 1. Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430062, China.
  • 2. Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430062, China.
  • 3. Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
PMID: 41953055 DOI: 10.1016/j.mmr.2026.100004
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.

Keywords
Mitophagy; Myocardial ischemia/reperfusion (I/R) injury; Parkin; Phosphatase and tensin homolog-long (PTEN-L); Ubiquitin-specific protease 18 (USP18).
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