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

  • Biochem Pharmacol. 2025 Dec 18:245:117656. doi: 10.1016/j.bcp.2025.117656.
Maieryemu Waresi  1 ,  Huili Zhou  1 ,  Can Jiao  2 ,  Jingjing Hu  1 ,  Mengsha Shi  1 ,  Xuanhan Lin  1 ,  Tianxin Ye  1 ,  Chaoyang Huang  3 ,  Wei Zhang  4 ,  Xiaogang Guo  5 ,  Haoxuan Zhong  6
Affiliations
  • 1. Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 3. Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected].
  • 4. Department of Hematology, Zhongshan Hospital (Qingpu Branch), Fudan University, Shanghai, China. Electronic address: [email protected].
  • 5. Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected].
  • 6. Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected].
PMID: 41421453 DOI: 10.1016/j.bcp.2025.117656
Abstract

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.

Keywords
IL-18; Platelet activation; Thrombosis.
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