The impact of YTHDF2-mediated NCOA4 methylation on myocardial ferroptosis

IF 8.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Apoptosis Pub Date : 2025-04-01 DOI:10.1007/s10495-025-02106-z

Xiaoqi Shao, Mengxian Sun, Ruonan Wang, Mingyang Leng, Hongtao Diao, Xu Li, Dongwei Wang, Kaili Wu, Liang Wang, Wen Lv, Xianglu Rong, Yue Zhang

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Abstract

The N6-Methyladenosine (m6A) modification is prevalent across various RNA species, including messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs), and has garnered significant interest due to its potential implications in cardiovascular disease. Despite extensive research, the precise relationship between m6A and myocardial infarction (MI) remains inadequately understood. The human YTH domain family 2 (YTHDF2) protein has emerged as a critical factor in this context, selectively recognizing m6A-modified RNAs and modulating their degradation. Our investigation revealed that the knockdown of YTHDF2 markedly enhanced ferroptosis in vitro, whereas the overexpression of YTHDF2 exhibited a significant protective effect. Mechanistically, it was elucidated that YTHDF2 suppresses the expression of nuclear receptor coactivator 4 (NCOA4) via m6A methylation. Furthermore, the inhibition of cardiomyocyte ferroptosis by YTHDF2 is contingent upon its regulation of NCOA4. Additionally, the enzyme methyltransferase-like 3 (METTL3) was identified as a pivotal factor in the m6A-mediated degradation of NCOA4 mRNA. Taken together, our results highlight the significant role of YTHDF2-mediated NCOA4 m6A methylation in the regulation of myocardial infarction and myocardial ferroptosis, suggesting that YTHDF2 may be a promising target for therapeutic interventions in myocardial infarction.

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ythdf2介导的NCOA4甲基化对心肌铁下垂的影响。

n6 -甲基腺苷（m6A）修饰普遍存在于各种RNA物种中，包括信使RNA （mrna）和长链非编码RNA (lncRNAs)，由于其在心血管疾病中的潜在意义而引起了极大的兴趣。尽管有广泛的研究，但m6A与心肌梗死（MI）之间的确切关系仍未充分了解。在这种情况下，人类YTH结构域家族2 （YTHDF2）蛋白作为一个关键因素出现，选择性地识别m6a修饰的rna并调节其降解。我们的研究发现，体外敲低YTHDF2可显著增强铁下垂，而过表达YTHDF2则具有显著的保护作用。机制上，YTHDF2通过m6A甲基化抑制核受体共激活因子4 （NCOA4）的表达。此外，YTHDF2对心肌细胞铁下垂的抑制取决于其对NCOA4的调节。此外，甲基转移酶样3 （METTL3）被确定为m6a介导的NCOA4 mRNA降解的关键因素。综上所述，我们的研究结果强调了YTHDF2介导的NCOA4 m6A甲基化在心肌梗死和心肌铁凋亡的调控中的重要作用，表明YTHDF2可能是心肌梗死治疗干预的一个有希望的靶点。

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来源期刊

Apoptosis 生物-生化与分子生物学

CiteScore

9.10

自引率

4.20%

发文量

审稿时长

1 months

期刊介绍： Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.