# Ubiquitin E3 Ligases and p53 in Doxorubicin-Induced Cardiotoxicity

## TL;DR

This paper reviews how ubiquitin E3 ligases and p53 contribute to heart damage caused by the chemotherapy drug doxorubicin and explores new treatment approaches.

## Contribution

The paper highlights recent findings on E3 ligase-mediated p53 regulation and novel cardioprotective agents for doxorubicin-induced cardiotoxicity.

## Key findings

- Dysregulation of ubiquitin E3 ligases is linked to p53 upregulation and cardiotoxicity.
- E3 ligases play a role in p53 degradation, which is critical in cardiomyocyte survival.
- New cardioprotective agents targeting E3 ligases may offer therapeutic potential for treating cardiotoxicity.

## Abstract

Doxorubicin (Dox) is a widely used anti-cancer drug. It has proven efficacy against various cancers, although the clinical application of Dox has been limited due to dose-dependent, irreversible, and fatal Dox-induced cardiotoxicity (DIC). The mechanism of DIC remains unclear. p53 plays a key role in DIC via cardiomyocyte loss due to cell death and oxidative stress. Its expression is strictly controlled by post-translational modifications, and its suppression in cardiomyocytes reportedly ameliorates DIC. The ubiquitin system regulates biological processes that are fundamental to the development of cardiovascular diseases. The dysregulation of several ubiquitin E3 ligases is reportedly associated with DIC development through the upregulation of p53. Ubiquitin E3 ligases are classified into four groups; all classes of E3 ligases are involved in p53 degradation. In this review, we focus on recently emerging topics regarding the role of E3 ligases in the regulation of p53 degradation. We also provide an overview of the functional roles of E3 ligases in DIC. Recent reports have identified cardioprotective agents for DIC through ubiquitin E3 ligase-mediated p53 suppression. Here, we present some findings regarding the current development of cardioprotective agents for DIC. These agents may serve as a novel therapeutic target for the treatment of DIC.