LINC00973/DTX3L Axis Promotes Non‐Small Cell Lung Cancer Progression and Serves as a Therapeutic Target

Long non-coding RNAs (lncRNAs) constitute a critical class of regulatory molecules involved in cancer biology and play pivotal roles in tumor initiation and progression. Nevertheless, the biological functions of many newly identified lncRNAs in non-small cell lung cancer (NSCLC), as well as their potential therapeutic relevance, remain insufficiently characterized. In this study, high-throughput sequencing analysis of paired NSCLC tumor tissues and adjacent non-tumorous samples revealed that LINC00973 is significantly upregulated in tumor specimens. Moreover, elevated LINC00973 expression was found to be closely associated with poor clinical outcomes in patients with NSCLC. Functional assays showed that LINC00973 knockdown inhibits NSCLC cell proliferation, migration, and invasion while inducing apoptosis, whereas overexpression produces opposite effects. These observations were confirmed in vivo, where LINC00973 depletion markedly suppressed tumor growth and metastasis. Mechanistically, LINC00973 interacts with and stabilizes deltex E3 ubiquitin ligase 3L (DTX3L), preventing its ubiquitination-mediated degradation and activating the AKT signaling pathway. Therapeutically, RGD-modified exosome-mediated delivery of LINC00973 siRNA significantly inhibited NSCLC progression in mouse models. Moreover, a synthetic biology-based strategy enabling hepatic production of exosomes carrying LINC00973-targeting siRNA achieved robust anti-tumor effects. Together, these findings establish LINC00973 as an oncogenic lncRNA that promotes NSCLC progression via DTX3L stabilization and highlight LINC00973 as a promising therapeutic target.