LncRNA NORAD Promotes Oxaliplatin Resistance in Adenocarcinoma of Esophagogastric Junction via Sponging miR-433-3p and Activating Autophagy

Objective Adenocarcinoma of esophagogastric junction (AEG) is a clinically aggressive malignancy with an increasing incidence worldwide. Although oxaliplatin-based chemotherapy represents a cornerstone of treatment, the development of drug resistance remains a significant clinical challenge. This study aims to explore the role and underlying mechanism of the long non-coding RNA NORAD in oxaliplatin resistance in AEG, focusing on the NORAD/miR-433-3p/autophagy regulatory axis, as well as to evaluate the potential of serum exosomal NORAD as a novel biomarker. Methods Paired tumor and adjacent normal tissues were obtained from 56 patients with AEG and analyzed. Differentially expressed lncRNAs were identified using lncRNA microarray profiling and validated by qRT-PCR. Oxaliplatin-resistant cell lines (PDC-R and OE19-R) were established through long-term drug exposure. Serum-derived exosomes were isolated and characterized in terms of morphology and marker expression. Bioinformatics tools predicted potential interactions between NORAD and miR-433-3p, which were subsequently confirmed using dual-luciferase reporter assays. NORAD knockdown was effectively achieved via lentiviral transduction with shRNA targeting NORAD. Cell viability was evaluated using the CCK-8 assay. The levels of autophagy-related proteins, including LC3B-II and p62, were assessed by western blot analysis. Results NORAD was markedly upregulated in AEG tissues and further increased in oxaliplatin-resistant cells, whereas miR-433-3p expression was downregulated. A strong inverse correlation was observed between NORAD and miR-433-3p levels ( r = -0.864, p  < 0.001). Luciferase assays confirmed that NORAD directly interacts with miR-433-3p. Serum exosomal NORAD levels were significantly elevated in AEG patients compared to those in healthy controls and showed a positive correlation with NORAD expression in tumor tissues ( r  = 0.8858, p  < 0.001). Knockdown of NORAD enhanced the sensitivity of AEG cells to oxaliplatin, as indicated by reduced IC₅₀ values and resistance indices. Furthermore, NORAD silencing impaired autophagic flux, as demonstrated by decreased LC3B-II levels and increased p62 accumulation. Conclusions LncRNA NORAD contributes to oxaliplatin resistance in AEG by acting as a sponge for miR-433-3p and subsequently promoting autophagy. Serum-derived exosomal NORAD holds promise as a non-invasive biomarker for AEG. Targeting the NORAD/miR-433-3p/autophagy axis may offer a novel therapeutic approach to counteract chemoresistance.