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METTL16通过mA修饰促进ATF4来抑制胆管癌中的铁死亡。

METTL16 suppresses ferroptosis in cholangiocarcinoma by promoting ATF4 via mA modification.

作者信息

Zhao Senfeng, Cao Jiahui, Liang Ruopeng, Peng Tingting, Wu Shitao, Liu Zhipu, Wu Yahui, Song Liming, Sun Chenguang, Liu Yin, Gu Junmou, Wang Libo, Zhu Rongtao, Wang Weijie, Sun Yuling

机构信息

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.

出版信息

Int J Biol Sci. 2025 Jan 1;21(1):189-203. doi: 10.7150/ijbs.97886. eCollection 2025.

DOI:10.7150/ijbs.97886
PMID:39744432
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11667817/
Abstract

N6-methyladenosine (mA) modification is the most common post-transcriptional modifications, which is critical for the metabolism of ferroptosis-related RNAs. Yet, the impact of mA modification on ferroptosis in cholangiocarcinoma (CC) is far from clear. Public databases and tissue arrays were applied to explore the clinical relevance of METTL16 in CC. Then, the effects of METTL16 on growth and ferroptosis were studied and . Mechanistically, RNA-sequencing, methylated RNA immunoprecipitation, dual-luciferase reporter assays and RNA stability assays were used to identify the METTL16/ATF4 axis in ferroptosis in CC. Clinically, we find that METTL16 is overexpressed and associated with a poor prognosis in patients with CC. Functionally, METTL16 protects against ferroptosis by maintaining mitochondrial homeostasis, including mitochondrial structure, membrane potential and energy products. It also decreases cellular metabolism of Fe and lipid peroxide, thereby promoting cell growth and . Mechanistically, ATF4 is a novel target of METTL16 and METTL16 enhances the m6A level and expression of ATF4 mRNA by inhibiting its decay, which further prevented ferroptosis in CC via m6A modification. Our findings highlighted the role of METTL16/ATF4 in ferroptosis, which sheds light on potential therapeutic strategies for CC.

摘要

N6-甲基腺苷（mA）修饰是最常见的转录后修饰，对铁死亡相关RNA的代谢至关重要。然而，mA修饰对胆管癌（CC）中铁死亡的影响尚不清楚。利用公共数据库和组织芯片来探究METTL16在CC中的临床相关性。然后，研究了METTL16对生长和铁死亡的影响。机制上，采用RNA测序、甲基化RNA免疫沉淀、双荧光素酶报告基因检测和RNA稳定性检测来确定CC铁死亡中的METTL16/ATF4轴。临床上，我们发现METTL16在CC患者中过表达且与预后不良相关。功能上，METTL16通过维持线粒体稳态来保护细胞免受铁死亡，包括线粒体结构、膜电位和能量产物。它还降低细胞内铁和脂质过氧化物的代谢，从而促进细胞生长。机制上，ATF4是METTL16的一个新靶点，METTL16通过抑制ATF4 mRNA的降解来提高其m6A水平和表达，进而通过m6A修饰进一步阻止CC中的铁死亡。我们的研究结果突出了METTL16/ATF4在铁死亡中的作用，为CC的潜在治疗策略提供了线索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e025/11667817/3adff50c7f30/ijbsv21p0189g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e025/11667817/3adff50c7f30/ijbsv21p0189g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e025/11667817/8f4f070a396d/ijbsv21p0189g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e025/11667817/1c9557e9b339/ijbsv21p0189g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e025/11667817/3adff50c7f30/ijbsv21p0189g007.jpg

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