Work

USP8 protects rat-derived H9C2 cardiomyocytes from doxorubicin-triggered ferroptosis and cell death through deubiquitination-mediated stabilization of MDM4

Year: 2025

Type: article

Abstract: BACKGROUND: Acute heart failure (AHF) is a life-threatening clinical syndrome due to impaired cardiac function. Ferroptosis has emerged as a contributor to cytotoxicity in cardiomyocytes. However, the functional interplay between USP8 and ferroptosis during AHF has not been investigated. METHODS: , lipid ROS, MDA, and GSH levels in treated cells. Immunoprecipitation (IP), Co-IP, and protein stabilization assays were performed to validate the USP8/murine double minute 4 (MDM4) interaction and the regulation of USP8 in MDM4. Expression of mRNA and protein was quantified by quantitative PCR and immunoblot analyses, respectively. RESULTS: USP8 and MDM4 were downregulated in Dox-exposed H9C2 cardiomyocytes. USP8 overexpression alleviated Dox-triggered cytotoxicity and cell death in H9C2 cardiomyocytes. Moreover, USP8 overexpression mitigated H9C2 cardiomyocyte ferroptosis induced by Dox. Mechanistically, USP8 stabilized MDM4 via deubiquitination. Inhibition of MDM4 counteracted the ability of USP8 overexpression to attenuate Dox-triggered cell death and ferroptosis in H9C2 cardiomyocytes. CONCLUSION: Our findings indicate that USP8 overexpression protects H9C2 cardiomyocytes from Dox-induced ferroptosis by stabilizing MDM4 via deubiquitination.

Source: Hereditas

DOI: 10.1186/s41065-025-00527-z

Authors: Yixi Li, Xue Yang, Liang Zhang

Institutions: Tongde Hospital of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University

Language: English

Topic: Chemotherapy-induced cardiotoxicity and mitigation

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,590