Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3–IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.

中文翻译：

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代谢物衣康酸在宿主免疫调节和防御中的作用

代谢状态极大地影响免疫细胞的功能和分化。调节免疫细胞的代谢可以有效调节宿主的免疫反应。衣康酸是免疫细胞三羧酸（TCA）循环中衍生的中间代谢产物，是通过线粒体中顺乌头酸脱羧酶对顺乌头酸脱羧产生的。编码顺乌头酸脱羧酶的基因被称为免疫反应基因 1 (IRG1)。为了响应外部促炎刺激，巨噬细胞表现出高 IRG1 表达。IRG1/衣康酸抑制琥珀酸脱氢酶活性，从而影响巨噬细胞的代谢状态。因此，衣康酸充当巨噬细胞代谢、氧化应激和免疫反应之间的纽带，最终调节巨噬细胞功能。研究表明，衣康酸作用于多种信号通路，包括Keap1-核因子E2相关因子2-ARE通路、ATF3-IκBz轴、干扰素基因刺激剂（STING）通路，发挥抗炎和抗氧化作用。此外，多项研究报道衣康酸通过多种信号通路影响癌症的发生和发展。在本文中，我们全面综述了IRG1/衣康酸及其衍生物在巨噬细胞代谢和功能调节中的作用。通过进一步了解衣康酸，我们打算揭示其治疗炎症性疾病的潜力，并提供该领域的新见解。