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

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. Adenosine-to-inosine editing in SNHG3 (c.1746 A > I) drives non-small cell lung (NSCLC) cancer metastasis and docetaxel resistance by enhancing SSRP1 binding and altering fatty acid metabolism. Targeting this hyper-edited RNA may improve cancer therapy.