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

## TL;DR

A long non-coding RNA called LINC00973 promotes lung cancer growth by stabilizing a protein called DTX3L and could be a new target for cancer treatment.

## Contribution

This study identifies LINC00973 as a novel oncogenic lncRNA in NSCLC and proposes a therapeutic strategy using exosome-delivered siRNA.

## Key findings

- LINC00973 is upregulated in non-small cell lung cancer and linked to poor patient outcomes.
- LINC00973 stabilizes DTX3L, activates the AKT pathway, and promotes cancer progression.
- Exosome-mediated delivery of LINC00973 siRNA effectively inhibits NSCLC in mouse models.

## Abstract

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.

LINC00973 promotes NSCLC progression by interacting with DTX3L, leading to activation of the AKT signaling pathway. Therapeutically, LINC00973 can be targeted by siRNA delivery strategies, including engineered exosomes for in vitro inhibition and in vivo self‐assembly of siRNAs within endogenous liver‐derived exosomes, thereby offering a potential treatment approach for NSCLC.

LINC00973 plays an oncogenic role in NSCLC progression and its upregulation predicts poor prognosis.LINC00973 binds to and stabilizes DTX3L protein, activating the AKT signaling pathway.Targeted inhibition of LINC00973 via in vitro fabricated and in vivo self‐assembled exosome delivery of siRNA represents a promising therapeutic strategy in NSCLC.

LINC00973 plays an oncogenic role in NSCLC progression and its upregulation predicts poor prognosis.

LINC00973 binds to and stabilizes DTX3L protein, activating the AKT signaling pathway.

Targeted inhibition of LINC00973 via in vitro fabricated and in vivo self‐assembled exosome delivery of siRNA represents a promising therapeutic strategy in NSCLC.