TRIM25 Rescues Against Doxorubicin-Induced Pyroptosis Through Promoting NLRP1 Ubiquitination.

Abstract	Doxorubicin (DOX) is an antineoplastic agent that is widely employed in carcinomas, but it can cause cardiotoxicity in clinic. TRIM25 has E3 ubiquitin ligase activities and can ubiquitinate its target proteins. The role of TRIM25 in DOX-induced cardiotoxicity remains unknown. In this study, our results showed that DOX induced pyroptosis of H9c2 cells by TUNEL staining and Western blot assay. Interestingly, TRIM25 was downregulated in DOX-treated H9c2 cells in a time- and dose-dependent manner. TRIM25 attenuated DOX-induced pyroptosis of H9c2 cells. Furthermore, in vitro ubiquitination assay proved that TRIM25 decreased the stability of NLRP1 via promoting the ubiquitination of NLRP1. The rescue experiments confirmed that TRIM25 inhibited DOX-induced H9c2 cells pyroptosis by regulating NLRP1 stability. Animal experiments demonstrated that overexpression of TRIM25 attenuated DOX-induced cardiomyocyte pyroptosis in rats. In summary, TRIM25 exerts its cardioprotective effects by promoting the ubiquitination of NLRP1 in DOX-induced cardiomyocyte pyroptosis, which provides a novel therapeutic strategy for DOX-induced cardiotoxicity.
Authors	Xiaxia Wang, Zhexun Lian, Yiping Ge, Dongqiang Yu, Shan Li, Kai Tan
Journal	Cardiovascular toxicology (Cardiovasc Toxicol) Vol. 21 Issue 10 Pg. 859-868 (10 2021) ISSN: 1559-0259 [Electronic] United States
PMID	34313957 (Publication Type: Journal Article)
Copyright	© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Chemical References	Antibiotics, Antineoplastic DNA-Binding Proteins Nerve Tissue Proteins Nlrp1a protein, rat Transcription Factors Trim25 protein, rat Doxorubicin
Topics	Animals Antibiotics, Antineoplastic Cardiotoxicity Cell Line DNA-Binding Proteins (genetics, metabolism) Disease Models, Animal Doxorubicin Heart Diseases (chemically induced, metabolism, pathology, prevention & control) Myocytes, Cardiac (metabolism, pathology) Nerve Tissue Proteins (metabolism) Pyroptosis Rats Rats, Wistar Time Factors Transcription Factors (genetics, metabolism) Ubiquitination

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