FLT1 as a Protective Factor in Ischemic Stroke: Insights from Real-World Pharmacovigilance and Genetic Evidence.

Abstract

Ischemic stroke contributes substantially to global death and disability, yet effective molecular targets remain scarce. This study integrates real-world pharmacovigilance data, molecular databases, and genetic evidence to support the discovery and validation of novel therapeutic targets. A stepwise analytic pipeline combined adverse event signals from the FDA Adverse Event Reporting System (FAERS), drug-target data from DrugBank, and Mendelian randomization (MR) using proteomic instruments from the UK Biobank Pharma Proteomics Project (UKB PPP). Disproportionality analyses identified drugs with signals for ischemic stroke. The top 30 drugs were cross-referenced in DrugBank to identify molecular targets, which were subjected to protein interaction and pathway enrichment analyses. MR analysis assessed the causal effects of plasma proteins on ischemic stroke using GWAS data from GIGASTROKE (discovery) and FinnGen (validation). Among 88,313 ischemic stroke-related reports in FAERS, 701 drugs showed consistent signals, with the top 30 prioritized for target identification. FLT1 was the only overlapping protein between MR-significant proteins and FAERS-associated drug targets. MR analysis showed a significant inverse causal relationship between plasma FLT1 levels and ischemic stroke in both the discovery (OR, 0.864; 95% CI, 0.774-0.965) and validation (OR, 0.829; 95% CI, 0.788-0.871) datasets. FLT1 was enriched in pathways such as MAPK and PI3K-Akt, implicated in stroke-related molecular processes. FLT1 was identified as a potential protective factor against ischemic stroke through a triangulated approach combining pharmacovigilance, target bioinformatics, and MR analysis. These findings offer mechanistic insights and a promising direction for targeted intervention.