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). Mice were administrated with DOX (accumulative dosage of 20 mg/kg) repeatedly to establish a chronic DIC model. Cardiomyocyte-specific conditional 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. DOX led to increased levels in mA modification and METTL3 expression in cardiomyocytes in a c-Jun-dependent manner. -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 overexpression exerted the opposite effects. Mechanistically, METTL3 promoted mA modification of 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. METTL3 plays a cardinal role in the etiology of DIC by regulating cardiac iron metabolism and ferroptosis through mA modification. Inhibition of METTL3 might be a potential therapeutic avenue for DIC.

中文翻译：

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抑制 METTL3 通过抑制 TFRC 介导的铁死亡来改善阿霉素诱导的心脏毒性

阿霉素（DOX）是一种化疗药物，但其临床使用因危及生命的心脏毒性而受到极大限制。 N-甲基腺苷 (mA) RNA 修饰参与多种细胞过程。尽管如此，m6A 修饰及其甲基转移酶 METTL3 是否参与 DOX 诱导的心脏毒性 (DIC) 的进展仍不清楚。小鼠重复给予DOX（累积剂量20 mg/kg）建立慢性DIC模型。采用心肌细胞特异性条件敲除小鼠来评估 m6A RNA 修饰改变对 DIC 的影响。还检查了 METTL3 对 DOX 刺激反应对心肌细胞铁死亡的影响。 DOX 以 c-Jun 依赖性方式导致心肌细胞中 mA 修饰和 METTL3 表达水平增加。 -敲除小鼠在DOX损伤后表现出改善的心脏功能、重塑和损伤。此外，抑制 METTL3 可以减轻 DOX 诱导的心肌细胞铁积累和铁死亡，而过度表达则产生相反的效果。从机制上讲，METTL3 促进 mRNA（控制铁吸收的关键基因）的 mA 修饰，并通过识别 mA 阅读器蛋白 IGF2BP2 增强其稳定性。此外，高选择性 METTL3 抑制剂 STM2457 的药理学给药可有效改善小鼠的 DIC。 METTL3 通过 mA 修饰调节心脏铁代谢和铁死亡，在 DIC 的病因学中发挥重要作用。 METTL3 的抑制可能是 DIC 的潜在治疗途径。