lncRNA NAS1 Deficiency Drives Cisplatin Resistance via NR2F1-Mediated TGFB1/NF-κB Signaling Axis in NSCLC.

Background: Cisplatin resistance remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). Although long non-coding RNAs (lncRNAs) have been implicated in chemotherapy resistance, their specific roles and underlying mechanisms remain incompletely understood. This study aimed to identify lncRNAs associated with cisplatin resistance in NSCLC and to elucidate the role and mechanism of NR2F1-AS1 (NAS1) in this process. Methods: Cisplatin-resistant NSCLC cell lines were established and subjected to transcriptome-wide RNA sequencing. NAS1 expression was validated by quantitative real-time PCR, and its clinical relevance was assessed using The Cancer Genome Atlas (TCGA) dataset. NAS1 and NR2F1 knockdown, together with NR2F1 overexpression and rescue experiments, were performed to evaluate their effects on cisplatin sensitivity. Downstream mechanisms were investigated by public dataset analysis, qPCR, and Western blotting, and NF-κB signaling was functionally assessed using the inhibitor DHMEQ. Results:NAS1 was consistently downregulated in multiple cisplatin-resistant NSCLC cell lines and was also decreased in NSCLC tissues. NAS1 knockdown enhanced cisplatin resistance. Mechanistically, loss of NAS1 reduced NR2F1 protein expression without significantly affecting its mRNA level, indicating translational regulation. NR2F1 downregulation also conferred cisplatin resistance, phenocopying the effect of NAS1 loss, whereas NR2F1 re-expression restored cisplatin sensitivity. Further analyses identified TGFB1 as a downstream effector derepressed by loss of the NAS1-NR2F1 axis, leading to activation of NF-κB signaling. Inhibition of NF-κB partially reversed cisplatin resistance in resistant cells. Conclusions: Collectively, our findings delineate a NAS1/NR2F1/TGFB1/NF-κB signaling axis critical for cisplatin resistance in NSCLC, revealing a potential therapeutic target for overcoming platinum resistance.