LINC00520 Regulates VDAC1 Oligomerization to Promote Cisplatin Resistance in Lung Adenocarcinoma

Background: Platinum-based chemotherapy remains the primary treatment for lung adenocarcinoma (LUAD), although its efficacy is frequently limited by acquired cisplatin resistance. The involvement of long non-coding RNAs (lncRNAs) in this resistance is not well understood. Methods: Differentially expressed lncRNAs were identified through bioinformatics analysis. LINC00520 expression was further validated in LUAD clinical specimens and cisplatin (CDDP)-resistant A549 cells. MS2-tagged RNA affinity purification (MS2-TRAP) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to screen for LINC00520-interacting proteins, which were subsequently validated by RNA immunoprecipitation (RIP). Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, and apoptosis analysis, were conducted. Voltage-dependent anion-selective channel protein 1 (VDAC1) oligomerization and mitochondrial apoptosis were assessed by western blotting and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining. In vivo xenograft models were used to corroborate key findings. Results: LINC00520 was markedly upregulated in LUAD tissues and A549/CDDP-resistant cells, and elevated expression correlated with poor prognosis. Functionally, LINC00520 promoted proliferation, suppressed apoptosis, and enhanced cisplatin resistance, whereas its knockdown restored chemosensitivity. Mechanistically, LINC00520 directly bound VDAC1 and inhibited its oligomerization, thereby suppressing mitochondrial apoptosis. In vivo, LINC00520 silencing suppressed tumor growth and partially restored cisplatin sensitivity. Conclusions: LINC00520 drives cisplatin resistance in LUAD by modulating VDAC1-mediated mitochondrial apoptosis, suggesting that LINC00520 may represent a potential prognostic biomarker and therapeutic target for reversing cisplatin resistance in LUAD.