N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2
N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2
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DOI：
10.1038/s41418-023-01138-9
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发表时间：
2023-02
影响因子：
12.4
通讯作者：
Haibo Xia;Yan Wu;Jing Zhao;Cheng Cheng-Cheng;Jiaheng Lin;Yi Yang;Lu Lu-Lu;Q. Xiang;T. Bian;
中科院分区：
文献类型：
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作者：
Haibo Xia;Yan Wu;Jing Zhao;Cheng Cheng-Cheng;Jiaheng Lin;Yi Yang;Lu Lu-Lu;Q. Xiang;T. Bian;
上皮细胞损伤引发的慢性阻塞性肺疾病（COPD）涉及由复杂的基因-环境相互作用引发的调节性细胞死亡（RCD），包括铁凋亡。我们的数据表明，在COPD患者和实验性COPD中，铁超载和铁缺乏与COPD进展相关。此外，我们发现，在COPD患者的肺组织中，通过circRNA-seq筛选，circSAV 1与COPD进展相关。敲低circSAV 1逆转香烟烟雾提取物（CSE）诱导的铁凋亡。在机制上，m6 A修饰的circSAV 1形成了circSAV 1/YTHDF 1/IREB 2的RNA-蛋白质三元复合物，以促进IREB 2 mRNA的翻译。IREB 2蛋白水平升高破坏了铁稳态，导致不稳定铁库（LIP）的积累和脂质过氧化，这有助于铁凋亡。在这里，我们证明，通过使用由香烟烟雾（CS）诱导的实验性COPD模型，circSAV 1的沉默和去铁胺（DFO）的治疗阻断了CS诱导的肺上皮细胞的铁凋亡，这减弱了小鼠的COPD进展。我们的研究结果表明，N6-甲基腺苷修饰的circSAV 1通过募集YTHDF 1促进IREB 2的翻译而触发COPD中的铁凋亡，表明circSAV 1是铁凋亡的介导剂，并且circSAV 1依赖的铁凋亡是COPD的治疗靶点。在肺上皮细胞中，m6 A修饰的circSAV 1通过募集YTHDF 1诱导形成circSAV 1/YTHDF 1/IREB 2 mRNA蛋白三元复合物，其促进IREB 2 mRNA的翻译。此外，升高的IREB 2有助于不稳定铁池（LIP）的积累和脂质过氧化，然后触发肺上皮细胞的铁凋亡。气道上皮细胞和肺泡上皮细胞的铁凋亡分别诱导气道重塑和肺气肿，导致COPD。
Epithelial cell damage-initiated chronic obstructive pulmonary disease (COPD) is implicated in regulated cell death (RCD) including ferroptosis triggered by complex gene-environment interactions. Our data showed that iron overload and ferroptosis are associated with COPD progression in COPD patients and in experimental COPD. Furthermore, we found that, in lung tissues of COPD patients, circSAV1 was associated with COPD progression by circRNA-seq screening. Knockdown of circSAV1 reversed cigarette smoke extract (CSE)-induced ferroptosis. Mechanistically, m6A-modified circSAV1 formed an RNA-protein ternary complex of circSAV1/YTHDF1/IREB2 to facilitate the translation of IREB2 mRNA. Elevated protein levels of IREB2 disrupted iron homeostasis, resulting in accumulation of a labile iron pool (LIP) and lipid peroxidation, which contribute to ferroptosis. Here we demonstrate, by use of an experimental COPD model induced by cigarette smoke (CS), that silencing of circSAV1 and the treatment with deferoxamine (DFO) blocked CS-induced ferroptosis of lung epithelial cells, which attenuated COPD progression in mice. Our results reveal that N6-methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2, indicating that circSAV1 is a mediator of ferroptosis and that circSAV1-dependent ferroptosis is a therapeutic target for COPD.In lung epithelial cell, m6A-modified circSAV1, via recruiting YTHDF1, induces the formation of a circSAV1/YTHDF1/IREB2 mRNA protein ternary complex, which promotes translation of IREB2 mRNA. Further, elevated IREB2 contributes to the accumulation of a labile iron pool (LIP) and lipid peroxidation, then triggers ferroptosis of lung epithelial cells. The ferroptosis of airway epithelial cells and alveolar epithelial cells induces airway remodeling and emphysema, respectively, which causes COPD.