Ticagrelor is the first reversibly binding oral P2Y₁₂ receptor antagonist to inhibit platelet activation and has been approved by the Food and Drug Administration for the treatment of coronary artery disease. At present, the other pharmacological functions of ticagrelor remain poorly understood. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune system, but its excessive activation also contributes to the pathogenesis of complex diseases. In this study, we systematically examined the effects of ticagrelor on the NLRP3 inflammasome and found that ticagrelor inhibits NLRP3 inflammasome activation in macrophages independent of its classic inhibitory effect on the P2Y₁₂ signaling pathway. Further mechanistic studies demonstrate that ticagrelor attenuates the oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) by blocking chloride efflux, an effect achieved through the degradation of chloride intracellular channel proteins (CLICs) and blockade of the translocation of CLICs to the plasma membrane. Moreover, experiments on lipopolysaccharide-induced sepsis and alum-induced peritonitis in mice confirmed that ticagrelor mitigates the severity of systemic inflammation independent of P2Y₁₂ receptor antagonism. Importantly, oral administration of ticagrelor rapidly and strongly inhibited NLRP3 inflammasome activation in peripheral blood mononuclear cells from patients with acute coronary syndrome. Overall, our study reveals a novel pharmacological function of ticagrelor in addition to its classic antiplatelet properties, which suggests that ticagrelor may serve as a potential therapeutic agent for use in NLRP3-associated diseases.

替格瑞洛是第一个可逆结合的口服 P2Y ₁₂受体拮抗剂，可抑制血小板活化，并已被美国食品和药物管理局批准用于治疗冠状动脉疾病。目前，替格瑞洛的其他药理功能仍知之甚少。 NOD、LRR 和 Pyrin 结构域蛋白 3 (NLRP3) 炎性小体在先天免疫系统中发挥着关键作用，但其过度激活也会导致复杂疾病的发病机制。在本研究中，我们系统地研究了替格瑞洛对NLRP3炎症小体的影响，发现替格瑞洛抑制巨噬细胞中NLRP3炎症小体的激活，独立于其对P2Y ₁₂信号通路的经典抑制作用。进一步的机制研究表明，替格瑞洛通过阻断氯离子流出来减弱含有 CARD (ASC) 的凋亡相关斑点样蛋白的寡聚化，这种作用是通过降解氯离子胞内通道蛋白 (CLIC) 和阻断 CLIC 易位到细胞内而实现的。质膜。此外，对小鼠脂多糖诱导的脓毒症和明矾诱导的腹膜炎的实验证实，替格瑞洛可减轻全身炎症的严重程度，而与 P2Y ₁₂受体拮抗作用无关。重要的是，口服替格瑞洛可快速而强烈地抑制急性冠脉综合征患者外周血单核细胞中 NLRP3 炎症小体的激活。总体而言，我们的研究揭示了替格瑞洛除了其经典的抗血小板特性外，还具有新的药理功能，这表明替格瑞洛可能作为治疗 NLRP3 相关疾病的潜在治疗剂。