核因子2-类似2（NFE2L2; NRF2）信号通路在人类癌症中经常发生失控。除了转录激活之外，NRF2在癌症中的关键功能尚不清楚。在这里，我们揭示了NRF2在RNA剪接调控中的以往未知角色。全局剪接分析发现，NSCLC A549细胞中NRF2敲除改变了485个基因中839个选择性剪接（AS）事件。机制研究表明，NRF2通过结合SMN1启动子中的两个抗氧化反应元件转录调控SMN mRNA表达。经络后，NRF2与SMN蛋白物理上相互关联。NRF2的Neh2结构域以及SMN的YG盒子和外显子7编码的区域对它们的相互作用是必需的。NRF2与SMN和Gemin2形成复合物，并存在于细胞核的颗粒体和Cajal小体中。此外，NRF2-SMN相互作用通过在NRF2敲除的HeLa细胞中表达SMN在某些改变的RNA剪接上产生调控作用。此外，在肺鳞状细胞癌的患者中，SMN的过表达与NRF2通路的改变明显相关。综上所述，我们的发现为包括异常NRF2通路的癌症提供了一种新的治疗策略。© 2023。作者通过Springer Nature Limited独家许可。

The nuclear factor erythroid 2-like 2 (NFE2L2; NRF2) signaling pathway is frequently deregulated in human cancers. The critical functions of NRF2, other than its transcriptional activation, in cancers remain largely unknown. Here, we uncovered a previously unrecognized role of NRF2 in the regulation of RNA splicing. Global splicing analysis revealed that NRF2 knockdown in non-small cell lung cancer (NSCLC) A549 cells altered 839 alternative splicing (AS) events in 485 genes. Mechanistic studies demonstrated that NRF2 transcriptionally regulated SMN mRNA expression by binding to two antioxidant response elements in the SMN1 promoter. Post-transcriptionally, NRF2 was physically associated with the SMN protein. The Neh2 domain of NRF2, as well as the YG box and the region encoded by exon 7 of SMN, were required for their interaction. NRF2 formed a complex with SMN and Gemin2 in nuclear gems and Cajal bodies. Furthermore, the NRF2-SMN interaction regulated RNA splicing by expressing SMN in NRF2-knockout HeLa cells, reverting some of the altered RNA splicing. Moreover, SMN overexpression was significantly associated with alterations in the NRF2 pathway in patients with lung squamous cell carcinoma from The Cancer Genome Atlas. Taken together, our findings suggest a novel therapeutic strategy for cancers involving an aberrant NRF2 pathway.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.