作为一种非常重要的甲基化修饰，5-甲基腺苷（m5C）修饰可以通过调节RNA的转录、结构和稳定性来深刻影响RNA。随着高通量技术的不断发展，差异表达的环状RNA（circRNA）越来越多地被发现，并且circRNA在肿瘤的发生和发展中发挥着独特的作用。然而，circRNA m5C修饰的调控机制尚未被揭示。本研究通过circRNA的差异表达谱初步鉴定了在肺癌组织中高表达且与肺癌临床进展显着相关的circERI3。组合的 m5C 微阵列分析显示 circERI3 含有 m5C 修饰，并且 NSUN4 介导的 circERI3 的 m5C 修饰可以增加其核输出。阐明了circERI3在体外和体内促进肺癌进展的重要功能。此外，我们还阐明了circERI3靶向DNA结合蛋白1（DDB1）、调节其泛素化、增强其稳定性，进而通过DDB1促进过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α）转录以影响线粒体功能和能量代谢，最终促进肺癌的发展。该研究不仅从甲基化角度揭示了circERI3在肺癌组织中分布异常的原因，阐明了circERI3在肺癌进展中的重要作用，还描述了circERI3通过线粒体能量代谢促进肺癌发生发展的新机制。 ，为肺癌 circRNA 研究提供新见解。版权所有 © 2024 Elsevier B.V. 保留所有权利。

As a highly important methylation modification, the 5-methyladenosine (m5C) modification can profoundly affect RNAs by regulating their transcription, structure and stability. With the continuous development of high-throughput technology, differentially expressed circular RNAs (circRNAs) have been increasingly discovered, and circRNAs play unique roles in tumorigenesis and development. However, the regulatory mechanism of the m5C modification of circRNAs has not yet been revealed. In this study, circERI3, which is highly expressed in lung cancer tissue and significantly correlated with the clinical progression of lung cancer, was initially identified through differential expression profiling of circRNAs. A combined m5C microarray analysis revealed that circERI3 contains the m5C modification and that the NSUN4-mediated m5C modification of circERI3 can increase its nuclear export. The important function of circERI3 in promoting lung cancer progression in vitro and in vivo was clarified. Moreover, we elucidated the novel mechanism by which circERI3 targets DNA binding protein 1 (DDB1), regulates its ubiquitination, enhances its stability, and in turn promotes the transcription of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) through DDB1 to affect mitochondrial function and energy metabolism, which ultimately promotes the development of lung cancer. This study not only revealed the reasons for the abnormal distribution of circERI3 in lung cancer tissues from the perspective of methylation and clarified the important role of circERI3 in lung cancer progression but also described a novel mechanism by which circERI3 promotes lung cancer development through mitochondrial energy metabolism, providing new insights for the study of circRNAs in lung cancer.Copyright © 2024 Elsevier B.V. All rights reserved.