Identification of plasma exosomal VPS41 chr7:38764322A>I editing as a diagnostic biomarker in lung cancer via a pan-cancer screen

BACKGROUND: Plasma exosomal RNA has emerged as a promising source of tumor biomarkers for early cancer detection. However, conventional expression-based markers are often limited by the need for stable reference genes. RNA editing, as a sequence-specific modification, provides internal, reference-free molecular signals, offering a potential advantage for robust and reproducible biomarker development. METHODS: We performed a two‑stage screening across GEO and Synapse databases to identify candidate RNA editing sites with multi-cancer diagnostic potential. The lead candidate was validated in 30 paired lung cancer tissues. Then the editing was assessed in plasma exosomes from 100 pairs of early‑stage lung cancer patients and healthy controls, as well as an independent set of 172 pulmonary nodule cases (35 benign and 137 malignant). Diagnostic performance was assessed using ROC analysis and 10-fold cross-validation. Bioinformatics and functional experiments were employed to investigate the underlying regulatory mechanisms. RESULTS: We identified VPS41 chr7:38764322A>I as a dysregulated RNA editing site across lung, liver, and gastric cancers. Its editing level was consistently reduced in lung cancer tissues and patient plasma exosomes. This site demonstrated high diagnostic accuracy for early‑stage lung cancer (AUC = 0.763, 95%CI: 0.696-0.829) and effectively distinguished malignant from benign pulmonary nodules (AUC = 0.813, 95%CI: 0.727-0.899). Mechanistically, this editing event, mediated by ADAR2, potentially inhibits VPS41 expression by strengthening miR‑3170 binding. Furthermore, VPS41 was found to promote lung cancer cell proliferation. CONCLUSIONS: Our study identifies VPS41 chr7:38764322A>I as a promising exosomal biomarker with strong diagnostic utility for early lung cancer. By elucidating its potential role in miRNA-mediated regulation, we provide a novel, exosome‑based RNA editing tool for early lung cancer detection.