IL-18 potentiates platelet activation and thrombosis through IL-18Rα-dependent MAPKs and PI3K/Akt signaling

Arterial thrombosis is a leading cause of global cardiovascular mortality. Clinical evidence indicates that elevated IL-18 levels independently predict cardiovascular events, yet its direct role in thrombosis is poorly understood. Hence, targeting IL-18 could be a novel therapeutic strategy. This study investigated the mechanism of IL-18 in platelet activation and evaluated the antithrombotic efficacy of interleukin-18 binding protein (IL-18BP). Through in vitro and in vivo models, including Il18r1^-/- mice, we demonstrated that IL-18 enhances platelet activation and thrombus formation via its receptor interleukin-18 receptor alpha (IL-18Rα). This action was mediated through the potentiation of MAPKs and PI3K/Akt signaling. Strikingly, IL-18BP exhibited superior antiplatelet effects in both mouse models and human subjects, including those with coronary artery disease (CAD). Our findings reveal that IL-18 is a key promoter of thrombosis and identify IL-18BP as a highly effective, targeted therapy for cardiovascular disease.