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<p>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 &gt; I), which correlates with advanced metastatic stages and reduced patient survival. Functional studies demonstrated that edited SNHG3 (SNHG3<sup>ED</sup>) exhibits significantly greater pro-metastatic activity compared to its wild-type counterpart (SNHG3<sup>WT</sup>). Mechanistically, SNHG3<sup>ED</sup> 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 SNHG3<sup>ED</sup> effectively restored DTX sensitivity and suppressed tumor growth. Our findings demonstrate that SNHG3 c.1746 A &gt; I editing serves both as a novel prognostic biomarker for NSCLC and as a mechanistically defined therapeutic target to overcome DTX resistance, which offers a potential therapeutic target to improve DTX efficacy.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月2日

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  • Shizhen Chen,
  • Amei Zhuo,
  • Renyu Tang,
  • Siming Su,
  • Binbin Wen,
  • Wujun Wei,
  • Jianjiang Xie,
  • Ziqi Yu,
  • Boqi Rao,
  • Jiachun Lu,
  • Yibin Deng,
  • Zhili Zhang,
  • Lei Yang

摘要

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 therapeutic target to overcome DTX resistance, which offers a potential therapeutic target to improve DTX efficacy.