Cardiomyocyte-derived USP20 mitigates myocardial ischemia/reperfusion injury through deubiquitinating GRP78.
Z, C., L, Z., M, Y., Z, H., Z, Y., W, Z., Z, H., N, Z., X, C., & X, F. (2026). Cardiomyocyte-derived USP20 mitigates myocardial ischemia/reperfusion injury through deubiquitinating GRP78.. Theranostics. https://doi.org/10.7150/thno.132067
Z C, L Z, M Y, Z H, Z Y, W Z, et al. Cardiomyocyte-derived USP20 mitigates myocardial ischemia/reperfusion injury through deubiquitinating GRP78.. Theranostics. 2026; doi: 10.7150/thno.132067
Z C, L Z, M Y, et al. Cardiomyocyte-derived USP20 mitigates myocardial ischemia/reperfusion injury through deubiquitinating GRP78.[J]. Theranostics. 2026. DOI: 10.7150/thno.132067.
@article{z2026,
author = {Cheng Z and Zhong L and Ying M and Huang Z and Yang Z and Zhang W and Huang Z and Zhang N and Chen X and Fan X},
title = {Cardiomyocyte-derived USP20 mitigates myocardial ischemia/reperfusion injury through deubiquitinating GRP78.},
journal = {Theranostics},
year = {2026},
doi = {10.7150/thno.132067},
note = {PMID: 42370198},
}
TY - JOUR AU - Cheng Z AU - Zhong L AU - Ying M AU - Huang Z AU - Yang Z AU - Zhang W AU - Huang Z AU - Zhang N AU - Chen X AU - Fan X TI - Cardiomyocyte-derived USP20 mitigates myocardial ischemia/reperfusion injury through deubiquitinating GRP78. T2 - Theranostics PY - 2026 DO - 10.7150/thno.132067 AN - PMID:42370198 ER -
UNLABELLED: Myocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge characterized by cardiomyocyte loss and adverse remodeling after reperfusion. Ubiquitin-Specific Peptidase 20 (USP20), a deubiquitinase involved in cellular stress responses, has not been fully characterized in the ischemic heart. This study aimed to investigate the function and mechanism of cardiomyocyte-derived USP20 in myocardial I/R injury. METHODS: Myocardial I/R models and hypoxia/reoxygenation (H/R)-treated cardiomyocytes were used to evaluate USP20 expression and function. Single-cell transcriptomic analysis, cardiomyocyte-specific USP20 knockout, and USP20 overexpression models were applied. Co-immunoprecipitation, LC-MS/MS, ubiquitination assays, site-directed mutagenesis, and rescue experiments were performed to define the underlying mechanism. RESULTS: USP20 expression was markedly decreased in I/R-injured mouse hearts and H/R-treated cardiomyocytes, and USP20 was predominantly localized in cardiomyocytes. Cardiomyocyte-specific USP20 deletion aggravated myocardial injury, adverse cardiac remodeling, and cardiac dysfunction after I/R, whereas USP20 overexpression conferred significant cardioprotection. Mechanistically, USP20 directly interacted with glucose-regulated protein 78 (GRP78) and removed K63-linked polyubiquitin chains from GRP78 at K602 through its C154 active site. This deubiquitination activated GRP78, promoted adaptive endoplasmic reticulum stress responses, and reduced myocardial injury. CONCLUSIONS: These findings identify a previously unrecognized USP20-GRP78 regulatory axis that regulates endoplasmic reticulum stress responses and limits myocardial damage during I/R. USP20 may represent a potential therapeutic target for myocardial I/R injury.