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Doxorubicin-induced cardiomyopathy (DIC) remains a dose-limiting clinical challenge. This study reveals that cardiac vascular endothelial cells (CVECs) act as initial sensors of doxorubicin cardiotoxicity: circulating doxorubicin activates the cGAS‑STING pathway in CVECs, triggering NLRP3 inflammasome‑mediated pyroptosis and release of pathogenic extracellular vesicles that induce mitochondrial dysfunction in neighboring cardiomyocytes, establishing a self‑perpetuating injury loop. Leonurine (LEO), a natural alkaloid, is identified as a direct STING inhibitor that specifically binds the TYR261 residue, blocking both STING oligomerization and STING‑TBK1 heterodimer formation-a mechanism distinct from known STING inhibitors. LEO exerts hierarchical dual protection: directly preserving cardiomyocyte mitochondria while primarily inhibiting endothelial STING to disrupt the pathogenic loop. This endothelial‑centric strategy shifts the therapeutic paradigm from direct cardiomyocyte protection to upstream endothelial intervention, establishing LEO as a promising candidate for DIC.