METTL3/YTHDF3 m⁶A axis promotes ferroptosis in diabetic kidney disease by stabilizing TfR1.

IF 3.2 3区医学

Journal of Diabetes Investigation Pub Date : 2025-06-10 DOI:10.1111/jdi.70094

Jinmei Zhang, Xiaoping Zhou, Bin Wang, Yan Yin, Daihao Wei, Kun Li

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引用次数: 0

Abstract

Objective: Diabetic kidney disease (DKD) is a common complication of diabetes. N6-Methyladenosine (m⁶A) modification is a widely studied epigenetic mechanism. Methyltransferase-like (METTL) 3 is a well-studied methyltransferase. This study aimed to investigate the role of METTL3 in DKD and the underlying mechanism.

Methods: Thirty-five DKD patients and 28 control volunteers were recruited. Animal and cell DKD models were established. QRT-PCR and Western blot were performed to analyze the expression of METTL3 and fibrosis-related indicators. Cell viability and proliferation were assessed via a cell counting kit-8 and colony formation assays. Ferrous iron (Fe²⁺), malonaldehyde (MDA), and glutathione (GSH) contents were measured by commercial kits. The interaction between METTL3/YTH N6-methyladenosine RNA binding protein (YTHDF)3 and transferrin receptor-1 (TfR1) was examined through RNA immunoprecipitation and dual-luciferase reporter assays.

Results: Results showed that METTL3-mediated m⁶A modification was elevated in kidney tissues of DKD patients and in high glucose (HG)-treated human renal mesangial cells (HRMCs). Besides, HG-treated HRMCs showed increased ferroptosis. In addition, METTL3 inhibition increased cell proliferation and inhibited ferroptosis in HRMCs. Mechanically, the METTL3/YTHDF3 m⁶A axis enhanced the stability of TfR1 mRNA. Moreover, YTHDF3 inhibition increased cell proliferation and inhibited ferroptosis in HRMCs. Finally, in vivo study results indicated that METTL3 deficiency inhibited ferroptosis and improved pathological damages.

Conclusions: In summary, METTL3/YTHDF3 m⁶A axis promoted ferroptosis in DKD by stabilizing TfR1, which could provide a reference for DKD treatment.

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METTL3/YTHDF3 m6A轴通过稳定TfR1促进糖尿病肾病铁下垂。

目的：糖尿病肾病（DKD）是糖尿病的常见并发症。n6 -甲基腺苷修饰（m6A）是一种被广泛研究的表观遗传机制。甲基转移酶样（METTL） 3是一种被广泛研究的甲基转移酶。本研究旨在探讨METTL3在DKD中的作用及其机制。方法：招募35例DKD患者和28例对照志愿者。建立动物和细胞DKD模型。采用QRT-PCR和Western blot分析METTL3及纤维化相关指标的表达情况。通过细胞计数试剂盒-8和菌落形成试验评估细胞活力和增殖。用商用试剂盒测定亚铁（Fe2+）、丙二醛（MDA）和谷胱甘肽（GSH）含量。通过RNA免疫沉淀和双荧光素酶报告基因检测检测METTL3/YTH n6 -甲基腺苷RNA结合蛋白（YTHDF）3与转铁蛋白受体-1 （TfR1）的相互作用。结果：结果显示mettl3介导的m6A修饰在DKD患者肾脏组织和高糖（HG）处理的人肾系膜细胞（HRMCs）中升高。此外，hg处理的hrmc出现铁下垂增加。此外，METTL3抑制可增加hrmc细胞增殖并抑制铁下垂。机械上，METTL3/YTHDF3 m6A轴增强了TfR1 mRNA的稳定性。此外，抑制YTHDF3可增加hrmc细胞增殖并抑制铁下垂。最后，体内研究结果表明，METTL3缺乏抑制铁下垂，改善病理损伤。结论：综上所述，METTL3/YTHDF3 m6A轴通过稳定TfR1促进DKD铁下沉，可为DKD治疗提供参考。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Diabetes Investigation Medicine-Internal Medicine

自引率

9.40%

发文量

218

期刊介绍： Journal of Diabetes Investigation is your core diabetes journal from Asia; the official journal of the Asian Association for the Study of Diabetes (AASD). The journal publishes original research, country reports, commentaries, reviews, mini-reviews, case reports, letters, as well as editorials and news. Embracing clinical and experimental research in diabetes and related areas, the Journal of Diabetes Investigation includes aspects of prevention, treatment, as well as molecular aspects and pathophysiology. Translational research focused on the exchange of ideas between clinicians and researchers is also welcome. Journal of Diabetes Investigation is indexed by Science Citation Index Expanded (SCIE).