Network-Guided Drug Repurposing for Hantaan Virus Infection in Endothelial Cells: Pathway Analysis, Target...

Hantaviruses cause haemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome, which are together the cause of more than 200,000 human cases every year. However, no specific antiviral therapy is approved. Here, we develop a three-stage computational framework for systematic drug repurposing. Transcriptome-wide analysis of hantavirus-infected human endothelial cells showed a response dominated by interferon pathways. A STRING protein-protein interaction network and a composite network centrality score identified 15 hub genes, including ISG15, IRF1, CXCL10, STAT1, and DDX58. Druggability and literature analysis of these hubs provided 12 repurposing candidates across four priority tiers. An ordinary differential equation (ODE) model of type I interferon signalling then evaluated eight drug perturbations. Early IFN-β achieved the fastest viral clearance (3.5 days) with reduced CXCL10 output. Early JAK inhibition delayed clearance (4.9 days) and increased IRF1-driven CXCL10. Our simulation showed that IFN-β combined with an anti-CXCL10 monoclonal antibody produced the best balance between antiviral effect and CXCL10 output. A structural sensitivity analysis showed the antiviral predictions to hold under an alternative network topology, while the chemokine predictions depended on it. This computational pipeline prioritises candidate therapies and phase-specific combinations for preclinical hantavirus studies.