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可诱导的小岛β细胞功能障碍和铁死通过m-YTHDF2-依赖的CHAC1增强

Tianming Qiu¹, Jingyuan Zhang¹, Jinwei Song¹

¹Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China.

Ecotoxicology and environmental safety

|December 12, 2024

概括

暴露会通过通过m6A修饰增加CHAC1,从而损害小岛贝塔细胞,从而导致铁亡. 过度表达METTL3可以防止这种功能障碍,从而揭示了2型糖尿病的新型治疗点.

科学领域:

环境毒理学环境毒理学
分子生物学分子生物学
内分泌学在内分泌学.

背景情况:

是一种环境污染物,通过引起小岛β细胞功能障碍,与2型糖尿病 (T2D) 有关.
由GPX4调节的细胞死亡途径铁灭,与诱导的β细胞损伤有关,但机制尚不清楚.
谷氨水平极大地影响GPX4活性和铁亡.

研究的目的:

阐明了诱导的β细胞功能障碍和铁死背后的分子机制.
研究CHAC1和N6-甲基氨酸 (m6A) 修饰在这个过程中的作用.
确定与相关的T2D的潜在治疗点.

主要方法:

在体内和体外评估对GPX4,CHAC1和GCLC表达的作用.
利用CHAC1倒置和METTL3过度表达来评估它们对β细胞功能和铁亡的影响.
在CHAC1上确定了m6A修饰部位,并使用RIP测试分析了相互作用.
在METTL3过度表达后测量CHAC1 mRNA半衰期.

主要成果:

可以上调CHAC1 (>体内2倍,体外1.5倍) 和降低GPX4的表达,从而抑制依赖谷氨酸的铁亡.
降低CHAC1缓解了引起的β细胞功能障碍和铁亡.
治疗降低了METTL3/14表达 (~0.5倍),而METTL3过度表达保护了β细胞.
通过抑制METTL3/YTHDF2与CHAC1mRNA的相互作用,METTL3过度表达减少了CHAC1mRNA的半衰期 (约0.5倍).

结论:

会通过抑制由METTL3.3介导的m6A修饰来上调CHAC1表达来诱导β细胞功能障碍和铁亡.
这项研究揭示了毒性中一种新的m6A-CHAC1-ferroptosis途径.
针对m6A通路,特别是METTL3,为因暴露引起的T2D提供了潜在的治疗策略.

关键词:

亚是一种.这就是CHAC1的原因.铁化是铁化的一种.这是一种N6-甲基氨酸.的β细胞.

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