ArticleJournal of the American Heart Association2026
Systematic Identification of Therapeutic Targets and Repurposed Drugs for Stroke: From Genome Causal Analysis to Multilevel Validation.
Article in Journal of the American Heart Association, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
6 authors.
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Abstract
backgroundStroke is a severe cerebrovascular disease characterized by narrow time windows and complications. This study aimed to identify novel drug targets and repurposed drugs for stroke.
methodsThis study used expression quantitative trait loci data from druggable genes in brain and blood as instrumental variables. Mendelian randomization, colocalization, and phenome-wide Mendelian randomization were applied to evaluate causal relationships and potential side effects, with stroke and ischemic stroke as primary outcomes. Preclinical validation used oxygen-glucose deprivation/reperfusion and middle cerebral artery occlusion/reperfusion models. Pharmacological and behavioral assessments evaluated the therapeutic potential of candidate targets and drugs. Additionally, proteomic sequencing was performed following GGCX (γ-glutamyl carboxylase) overexpression to explore its biological functions.
resultsElevated GGCX expression in brain and blood was potentially causally associated with reduced risk of stroke and ischemic stroke, supported by colocalization evidence, although potential cardiovascular risks could not be excluded. Drug repositioning identified ifenprodil as a candidate agent that reduced infarction volume, improved motor and cognitive functions, and reversed GGCX downregulation in mice. Ifenprodil treatment and GGCX overexpression alleviated oxygen-glucose deprivation/reperfusion-induced injury and upregulated GGCX expression. Mechanistically, GGCX conferred neuroprotection by regulating protein homeostasis, suppressing inflammation, promoting metabolic recovery, and modulating nuclear transcriptional regulation.
conclusionsThis study established a potential causal link between GGCX and stroke risk, particularly ischemic stroke. GGCX represents a promising therapeutic target for ischemic stroke. Targeted GGCX expression upregulation and drug repurposing, particularly ifenprodil, may offer novel therapeutic avenues. Further validation is warranted to assess clinical efficacy and safety.
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