MA Demethylase ALKBH5 Attenuates Doxorubicin-induced Cardiotoxicity Via Posttranscriptional Stabilization of Rasal3

Overview

Journal iScience

Publisher Cell Press

Date 2023 Mar 6

PMID 36876119

Authors

Ri-Feng Gao

Kun Yang

Ya-Nan Qu

Xiang Wei

Jia-Ran Shi

Chun-Yu Lv

Yong-Chao Zhao

Xiao-Lei Sun

Ying-Jia Xu

Yi-Qing Yang

Affiliations

Soon will be listed here.

Abstract

The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (mA) plays an essential role in numerous biological processes. However, the roles of mA and mA demethylase ALKBH5 in DOX-induced cardiotoxicity (DIC) remain unclear. In this research, DIC models were constructed using -knockout (KO), -knockin (KI), and -myocardial-specific knockout (ALKBH5) mice. Cardiac function and DOX-mediated signal transduction were investigated. As a result, both whole-body KO and myocardial-specific KO mice had increased mortality, decreased cardiac function, and aggravated DIC injury with severe myocardial mitochondrial damage. Conversely, ALKBH5 overexpression alleviated DOX-mediated mitochondrial injury, increased survival, and improved myocardial function. Mechanistically, ALKBH5 regulated the expression of Rasal3 in an mA-dependent manner through posttranscriptional mRNA regulation and reduced mRNA stability, thus activating RAS3, inhibiting apoptosis through the RAS/RAF/ERK signaling pathway, and alleviating DIC injury. These findings indicate the potential therapeutic effect of ALKBH5 on DIC.

Citing Articles

The Emerging Role of m6A and Programmed Cell Death in Cardiovascular Diseases.

Wang H, Han J, Kong H, Ma C, Zhang X Biomolecules. 2025; 15(2).

PMID: 40001550 PMC: 11853213. DOI: 10.3390/biom15020247.

Role of M6a Methylation in Myocardial Ischemia-Reperfusion Injury and Doxorubicin-Induced Cardiotoxicity.

Liu Y, Wu H, Zhou G, Zhang D, Yang Q, Li Y Cardiovasc Toxicol. 2024; 24(9):918-928.

PMID: 39026038 DOI: 10.1007/s12012-024-09898-7.

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