A-to-I edited SNHG3 promotes non-small cell lung cancer metastasis by promoting fatty acid oxidation and resisting ferroptosis

作者：Shizhen Chen, Amei Zhuo, Renyu Tang, Siming Su, Binbin Wen, Wujun Wei, Jianjiang Xie, Ziqi Yu, Boqi Rao, Jiachun Lu, Yibin Deng, Zili Zhang, Lei Yang · 发表于：Communications Biology · 年份：2025 · DOI：10.1038/s42003-025-08776-4 · 被引用次数：5 · 研究领域：Cancer-related molecular mechanisms research、RNA modifications and cancer、RNA Research and Splicing

Adenosine-to-inosine (A-to-I) RNA editing is a critical post-transcriptional modification that enhances tumor genome diversity and contributes to cancer progression. In non-small cell lung cancer (NSCLC), while specific A-to-I editing events have been identified, their functional mechanisms and clinical relevance remain poorly understood. Here, through whole-transcriptome analysis of NSCLC specimens, we discovered a hyper-editing event at position c.1746 in the long non-coding RNA SNHG3 (c.1746 A > I), which correlates with advanced metastatic stages and reduced patient survival. Functional studies demonstrated that edited SNHG3 (SNHG3ED) exhibits significantly greater pro-metastatic activity compared to its wild-type counterpart (SNHG3WT). Mechanistically, SNHG3ED shows enhanced binding affinity for the chromatin remodeler SSRP1, triggering SSRP1-mediated replication origin assembly and subsequent upregulation of fatty acid metabolism and ferroptosis-related genes. This molecular rewiring promotes fatty acid oxidation, confers resistance to ferroptosis, and importantly, drives docetaxel (DTX) chemoresistance. In DTX-resistant NSCLC cell lines, patient-derived organoids, and Nude mouse xenograft tumor model, antisense oligonucleotide-based targeting of SNHG3ED effectively restored DTX sensitivity and suppressed tumor growth. Our findings demonstrate that SNHG3 c.1746 A > I editing serves both as a novel prognostic biomarker for NSCLC and as a mechanistically defined therapeut...