2. Academic Validation
  3. IL-18 potentiates platelet activation and thrombosis through IL-18Rα-dependent MAPKs and PI3K/Akt signaling

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

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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