Integrative multi-omics and structural biology identify FOSB and KCNJ2 as shared therapeutic targets for Cerebral Cavernous Malformation and Ischemic Stroke

Cerebral cavernous malformation (CCM) and ischemic stroke (IS) are disabling cerebrovascular disorders with distinct clinical courses yet convergent mechanisms involving endothelial dysfunction and immune–vascular dysregulation. However, shared pathogenic networks and dual-target therapeutic opportunities remain poorly defined. Here, we integrated transcriptomic datasets for CCM (GSE130174, GSE123968) and IS (GSE22255, GSE58294, GSE16561) from the Gene Expression Omnibus and applied differential expression analysis with weighted gene co-expression network analysis (WGCNA) to delineate shared molecular architecture. Functional enrichment, protein–protein interaction (PPI) analysis, and immune deconvolution were used to map key pathways and immune features. To translate network findings into candidate therapeutics, we implemented a structure-guided pipeline comprising pharmacophore modeling, virtual screening, ADMET filtering, molecular docking, and 150-ns molecular dynamics (MD) simulations with MM/PBSA binding free-energy estimation. Integration of 69 shared WGCNA modules with 72 differentially expressed genes yielded 139 convergent genes, enriched for immune regulation, signal transduction, and proliferation-associated programs. PPI topology identified FOSB and KCNJ2 as central hubs with robust diagnostic performance across datasets (AUC > 0.75). Immune profiling revealed disease-specific shifts in neutrophils, monocytes, and T-cell subsets, indicating both shared immune involvement and divergent inflammatory contexts in CCM versus IS. Pharmacophore-based screening with ADMET prioritization nominated two blood–brain barrier–permeable compounds (E588-0461 and K284-4583) with favorable docking and sustained binding during MD. MM/PBSA indicated the most favorable complexes for E588-0461–KCNJ2 (–18.67 kcal/mol) and K284-4583–FOSB (–10.81 kcal/mol). Collectively, these results nominate FOSB and KCNJ2 as shared regulatory hubs linking CCM and IS and provide dual-target ligands supporting precision multi-target therapy development in cerebrovascular disease.