特定的RNA序列通过甲基化腺苷N6-甲基腺苷（m6A）的修饰对基因表达进行后转录调节。m6A在RNA中的数量由编写和抹除它的酶编排，而它的效应则由结合并读取这种修饰的蛋白质介导。这种后转录调节过程的功能失调与人类疾病有关。尽管最初的焦点是药物靶向编写和抹除酶，但读取蛋白质的兴趣受到了其功能作用和分子机制缺乏明确了解的挑战。m6A修饰RNA（m6A-RNA）的读取者 - YTH（YT521-B同源）结构域含蛋白家族副本1-3（YTHDF1-3，此处称为DF1-DF3） - 正在作为治疗靶点出现，因为它们与癌症和炎症等病理过程的联系以及它们在调节m6A-RNA命运中的作用变得清晰。我们提供了对DF1-DF3作用模式的更新理解，并回顾了它们的结构，以解锁DF副本选择性抑制的药物设计方法。版权所有 ©2023 The Authors。由 Elsevier Ltd. 出版。保留所有权利。

Specific RNA sequences modified by a methylated adenosine, N6-methyladenosine (m6A), contribute to the post-transcriptional regulation of gene expression. The quantity of m6A in RNA is orchestrated by enzymes that write and erase it, while its effects are mediated by proteins that bind to read this modification. Dysfunction of this post-transcriptional regulatory process has been linked to human disease. Although the initial focus has been on pharmacological targeting of the writer and eraser enzymes, interest in the reader proteins has been challenged by a lack of clear understanding of their functional roles and molecular mechanisms of action. Readers of m6A-modified RNA (m6A-RNA) - the YTH (YT521-B homology) domain-containing protein family paralogs 1-3 (YTHDF1-3, referred to here as DF1-DF3) - are emerging as therapeutic targets as their links to pathological processes such as cancer and inflammation and their roles in regulating m6A-RNA fate become clear. We provide an updated understanding of the modes of action of DF1-DF3 and review their structures to unlock insights into drug design approaches for DF paralog-selective inhibition.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.