Computational Insights into Ribavirin's Potential Impact on Major Depressive Disorder: A Network Toxicology Study

To elucidate potential molecular intersections between ribavirin and Major Depressive Disorder (MDD) and to generate testable hypotheses regarding neuropsychiatric safety and mechanism of action.

Ribavirin-associated targets were integrated from Swiss Target Prediction, TargetNet, and SuperPred (n = 163), and MDD-related genes were compiled from OMIM and GeneCards (n = 2035). Venn analysis identified 45 overlapping candidates. A STRING-based protein interaction network was analyzed in Cytoscape using CytoNCA to prioritize core targets. Functional interpretation included GO and KEGG enrichment via OmicShare, cell type annotation with PanglaoDB, molecular docking, and transcriptomic cross-validation using the GSE76826 peripheral blood dataset.

Five core targets emerged as central nodes, namely CCND1, SIRT1, NFKB1, EP300, and MAPK1, each linked to neurogenesis, synaptic plasticity, immune and inflammatory regulation, epigenetic control, and stress signaling. Enrichment analyses highlighted processes and pathways relevant to MDD, including responses to oxygencontaining compounds, cell death, HIF-1 signaling, neurotrophin signaling, cellular senescence, and ferroptosis. Cell type annotations associated core targets with fibroblasts, dendritic cells, natural killer cells, and neurons. Docking suggested plausible hydrogen- bonded interactions between ribavirin and core proteins. Cross-validation with GSE76826 supported overlap with differentially expressed genes, pathway concordance, and altered expression of select core targets in MDD compared with controls.

The convergence of targets and pathways with established MDD biology supports the plausibility that ribavirin intersects depression-relevant mechanisms. Limitations include reliance on curated databases, potential hub bias in network topology, limited tissue and cell-type specificity in enrichment, the approximate nature of docking, uncertain brain exposure at clinical doses, and tissue mismatch when using peripheral blood for validation. Clinical attribution is further complicated by co-therapy, underlying infection, and psychosocial factors. These findings are hypothesis-generating and should guide targeted experimental and clinical validation.

Ribavirin may engage key axes of MDD biology through core targets such as CCND1, SIRT1, NFKB1, EP300, and MAPK1. The results support risk assessment and focused monitoring of depressive symptoms in ribavirin-treated patients and outline priorities for mechanistic validation.