抑制 METTL3 通过抑制 TFRC 介导线粒体铁死亡改善阿霉素诱导的心脏毒性。

Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis.

机构信息

Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.

出版信息

Redox Biol. 2024 Jun;72:103157. doi: 10.1016/j.redox.2024.103157. Epub 2024 Apr 12.

DOI:10.1016/j.redox.2024.103157

PMID:38631119

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11033199/

Abstract

BACKGROUND

Doxorubicin (DOX) is a chemotherapeutic drug, while its clinical use is greatly limited by the life-threatening cardiotoxicity. N-methyladenosine (mA) RNA modification participates in varieties of cellular processes. Nonetheless, it remains elusive whether mA modification and its methyltransferase METTL3 are involved in the progression of DOX-induced cardiotoxicity (DIC).

METHODS

Mice were administrated with DOX (accumulative dosage of 20 mg/kg) repeatedly to establish a chronic DIC model. Cardiomyocyte-specific conditional METTL3 knockout mice were employed to evaluate the effects of altered mA RNA modification on DIC. The effects of METTL3 on cardiomyocyte ferroptosis were also examined in response to DOX stimulation.

RESULTS

DOX led to increased levels in mA modification and METTL3 expression in cardiomyocytes in a c-Jun-dependent manner. METTL3-knockout mice exhibited improved cardiac function, remodeling and injury following DOX insult. Besides, inhibition of METTL3 alleviated DOX-induced iron accumulation and ferroptosis in cardiomyocytes, whereas METTL3 overexpression exerted the opposite effects. Mechanistically, METTL3 promoted mA modification of TFRC mRNA, a critical gene governing iron uptake, and enhanced its stability through recognition of the mA reader protein, IGF2BP2. Moreover, pharmacological administration of a highly selective METTL3 inhibitor STM2457 effectively ameliorated DIC in mice.

CONCLUSION

METTL3 plays a cardinal role in the etiology of DIC by regulating cardiac iron metabolism and ferroptosis through TFRC mA modification. Inhibition of METTL3 might be a potential therapeutic avenue for DIC.

摘要

背景

阿霉素（DOX）是一种化疗药物，但由于其致命的心脏毒性，其临床应用受到极大限制。N6-甲基腺苷（m6A）RNA 修饰参与多种细胞过程。然而，m6A 修饰及其甲基转移酶 METTL3 是否参与阿霉素诱导的心脏毒性（DIC）的进展仍不清楚。

方法

用 DOX（累积剂量 20mg/kg）重复给小鼠给药，建立慢性 DIC 模型。使用心肌细胞特异性条件性 METTL3 敲除小鼠来评估改变 m6A RNA 修饰对 DIC 的影响。还检查了 METTL3 对 DOX 刺激下心肌细胞铁死亡的影响。

结果

DOX 以依赖 c-Jun 的方式导致心肌细胞中 m6A 修饰和 METTL3 表达增加。METTL3 敲除小鼠在 DOX 损伤后表现出改善的心脏功能、重构和损伤。此外，抑制 METTL3 减轻了 DOX 诱导的心肌细胞中铁积累和铁死亡，而 METTL3 过表达则产生相反的效果。机制上，METTL3 通过识别 m6A 读蛋白 IGF2BP2，促进 TFRC mRNA 的 m6A 修饰，该基因是控制铁摄取的关键基因，并增强其稳定性。此外，高选择性 METTL3 抑制剂 STM2457 的药理学给药有效改善了小鼠的 DIC。