Inhibition of adenosine kinase alleviates hypertrophic cardiomyopathy by ameliorating coronary microvascular dysfunction.

Hypertrophic cardiomyopathy (HCM) remains challenging with limited treatment options; the identification of novel therapeutic targets is urgently needed. We performed Mendelian randomization and colocalization analyses using HCM genome-wide association data (FinnGen: 1376 cases/210 300 controls; IEU OpenGWAS: 507 cases/489 220 controls) to identify causal druggable genes. The lead candidate gene was validated in HCM mice and endothelial cells (EC). Drug repurposing with molecular docking, dynamics simulations, and cellular thermal shift assay identified potential drugs, followed by in vitro and in vivo functional verification. Adenosine kinase (ADK) was identified as a causal gene for HCM (Mendelian randomization: odds ratio (OR) = 1.10, 95%CI 1.02-1.19, P = .015; validation: OR = 1.28, 1.01-1.61, P = .039; colocalization: PP.H4 = 82.0%). In HCM mice, ADK inhibition attenuated cardiac hypertrophy, fibrosis, and microvascular dysfunction. ADK inhibition rescued the impaired function of ECs induced by Ang II stimulation in vitro. Drug repurposing identified the anticoagulant dabigatran as the high-affinity ADK binder with the highest binding energy (-9.3 kcal/mol), as confirmed using molecular dynamics simulations and cellular thermal shift assay. Consistently, dabigatran improved EC function in vitro and, in HCM mice, ameliorated microvascular dysfunction and pathological cardiac remodelling. Our study established ADK as a therapeutic target for HCM treatment. Targeting ADK is a promising strategy for ameliorating microvascular dysfunction in HCM. Drug repurposing findings suggest that dabigatran may confer benefits in HCM via ADK inhibition.