Exosomal lncRNA NORAD drives oxaliplatin resistance in AEG via the miR-433-3p/autophagy axis: a novel mechanism and potential biomarker

Oxaliplatin resistance poses a substantial therapeutic challenge in adenocarcinoma of the esophagogastric junction (AEG). Although the lncRNA NORAD has been implicated in chemoresistance, its specific role, underlying mechanism, and clinical significance in AEG remain unclear. We hypothesize that exosome-derived NORAD promotes oxaliplatin resistance via a competing endogenous RNA network that modulates autophagy and may serve as a potential circulating biomarker. The expression levels of NORAD and miR-433-3p were analyzed in 56 paired AEG tumor and adjacent normal tissues, as well as in AEG cell lines (OE19, PDC) and their corresponding oxaliplatin-resistant derivatives (OE19-R, PDC-R), using quantitative real-time polymerase chain reaction. The direct interaction between NORAD and miR-433-3p was validated by dual-luciferase reporter assay. Functional consequences of NORAD knockdown were assessed: cell viability was determined by CCK-8 assay to calculate the half-maximal inhibitory concentration (IC₅₀); autophagic flux was evaluated by western blotting for the LC3B-Ⅱ/LC3B-I ratio and p62 degradation; and apoptosis was quantified by flow cytometry. Serum exosomal NORAD levels were measured in AEG patients and healthy controls. In AEG tissues, NORAD was significantly upregulated, whereas miR-433-3p was downregulated, and a strong inverse correlation was observed between them (r = −0.864, p < 0.001). NORAD directly bound to miR-433-3p, acting as a molecular sponge. Oxaliplatin-resistant cells exhibited elevated NORAD levels, enhanced autophagic flux—characterized by an increased LC3B-Ⅱ/I ratio and decreased p62 levels—and a higher IC₅₀ value. Silencing NORAD resensitized the resistant cells to oxaliplatin (e.g., IC₅₀ in PDC-R decreased from 22.27 to 2.51 µg/mL), inhibited autophagy, and promoted apoptosis. Clinically, serum exosomal NORAD levels were significantly elevated in AEG patients, and a strong positive correlation was observed between serum exosomal NORAD levels and tumor NORAD expression (r = 0.886, p < 0.001). Our study identifies a novel NORAD/miR-433-3p/autophagy axis driving oxaliplatin resistance in AEG. Targeting NORAD restores chemosensitivity, highlighting its therapeutic potential. Moreover, circulating exosomal NORAD serves as a promising non-invasive biomarker, supporting its application in liquid biopsy for AEG management.