动脉粥样硬化斑块铁沉积现象普遍，然而铁沉积的具体致病机制远未阐明。本项目拟以NLRP3炎性小体信号通路调控为切入点，结合斑块巨噬细胞铁代谢的病生特点，将动物整体与细胞分子水平的机制研究相结合，借助基因沉默、通路激动与阻断等分子生物学研究手段，聚焦于TLR4/MyD88信号通路激活和可变铁池稳态失衡促生的氧化型线粒体DNA水平增加等现象，对巨噬细胞铁沉积微环境中NLRP3炎性小体异常激活的潜在调控机制进行层层剖析与验证。在此基础上，选择可靶向富集于斑块巨噬细胞，并具有良好AS保护效应和铁稳态调控作用的槲皮素作为干预物，分析其对铁沉积微环境中NLRP3炎性小体异常激活的潜在调控机制及主要作用靶点，从全新的角度揭示其拮抗AS的分子作用机制。本项目的实施不仅有助于进一步阐明AS的发病机制，丰富AS“铁假说”，还将为AS的营养干预及槲皮素等植物化学物的开发应用提供新的线索。

Iron deposits has been frequently found in atherosclerotic lesions, especially in macrophages, but its pathological roles in atherogenesis remain unknown. Based on the regulatory mechanisms of NLRP3 inflammasome pathway, our present project is designed to explore the pathophysiological significance and the potential molecular mechanisms involved in the abnormal activation of NLRP3 inflammasome in the presence of atherosclerotic iron deposition. Our research will focus on iron deposition-induced TLR4/MyD88 signaling pathway activation and the labile iron pool disequilibrium-triggered ox-mtDNA production, which is realized by the combination of animal and cell experiment with the help of gene silencing, pathway activation and blocking and other molecular biology techniques. In addition, quercetin is selected as an intervention for atherosclerosis (AS) because it can specifically target and enriched in atherosclerotic plaque macrophages, and play protective roles in atherogenesis and iron homeostasis regulation. Clarifying the potential regulatory mechanism of quercetin in the iron deposition-initiated abnormal activation of inflammasome pathway, would be helpful to reveal the molecular mechanism of quercetin in antagonizing AS from a new perspective. Thus, this project will not only help to further clarify the pathogenesis of AS, enrich the "iron hypothesis" of AS, but also provide new clues for the nutritional intervention of AS and the development and application of phytochemicals such as quercetin.