Mapping a therapeutic redox ceRNA network in alcohol use disorder: Systems biology insights for drug repurposing

Alcohol use disorder (AUD) is a chronic neuropsychiatric condition in which oxidative stress drives ethanol‑induced neurotoxicity and neuroimmune dysregulation. However, the post‑transcriptional roles of non‑coding RNAs (ncRNAs) in redox imbalance remain poorly understood. In this study, we integrated redox‑related gene signatures from published transcriptomic sources (meta‑analyses and original datasets) with lncRNA and miRNA expression profiles to identify differentially expressed redox‑associated mRNAs, lncRNAs, and miRNAs. Using these features, we constructed a redox‑centered competing endogenous RNA (ceRNA) network. This network revealed coordinated upregulation of lncRNAs and mRNAs alongside miRNA suppression, consistent with ceRNA‑mediated derepression. The final network comprised 12 lncRNAs, 9 miRNAs, and 13 mRNAs, and uncovered modules linked to oxidative stress, neuroinflammation, endoplasmic reticulum stress, and synaptic remodeling. Redox‑related miRNAs were significantly enriched in addiction‑associated neurotransmitter pathways (dopaminergic, glutamatergic, GABAergic, and endocannabinoid), indicating a systems‑level impact of redox imbalance on AUD neurocircuitry. Protein‑protein interaction analysis identified key redox hubs involved in antioxidant defense, reactive oxygen species production, and inflammasome activation. Independent proteomic validation in human AUD brain tissue confirmed concordant regulation of superoxidase 2, glutathione peroxidase, and NADH quinone dehydrogenase 1, directly supporting these hubs. Toxicogenomic and network pharmacology analyses further linked these redox‑sensitive nodes to alcohol‑induced oxidative damage and to clinically relevant compounds (disulfiram, cannabidiol, melatonin, carbamazepine, valproic acid). Collectively, this work establishes the first integrative framework for ceRNA‑mediated redox control in AUD, elucidates mechanisms of oxidative stress‑driven neuroinflammation, and identifies potential biomarkers and therapeutic targets.