Bai Lulu, Yu Hanghui, Cai Yiqing, Wu Runliu, Kang Rui, Jia Yuanyuan, Zhang Xinyue, Tang Daolin, Dai Enyong
2nd Ward of Oncology Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China.
Department of Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Biochem Biophys Res Commun. 2025 Feb 2;747:151292. doi: 10.1016/j.bbrc.2025.151292. Epub 2025 Jan 6.
Itaconate is a small-molecule metabolite generated by the enzyme aconitate decarboxylase 1 (ACOD1), which is upregulated during inflammation. Traditionally, itaconate has been recognized for its anti-inflammatory properties; however, this study reveals a pro-inflammatory mechanism of itaconate in macrophages. We demonstrate that itaconate promotes the proteasomal degradation of glyoxalase 1 (GLO1) via Cys139. GLO1 is crucial for detoxifying methylglyoxal (MGO), a glycolysis byproduct that leads to advanced glycation end-products (AGEs). Elevated concentrations of itaconate correlate with reduced GLO1 expression in peripheral blood mononuclear cells (PBMCs) from patients with sepsis, linking increased itaconate concentrations to heightened MGO and AGE production. Functionally, itaconate-induced degradation of GLO1 promotes the accumulation of MGO and AGEs, thereby exacerbating inflammatory responses. In vivo, itaconate-treated myeloid-specific Ager conditional knockout mice exhibited reduced inflammation and improved survival in experimental sepsis models compared to wild-type controls. Collectively, these findings reveal a novel function of itaconate in immunometabolism, shedding light on its complex involvement in lethal infections.
衣康酸是由乌头酸脱羧酶1（ACOD1）产生的一种小分子代谢产物，该酶在炎症过程中上调。传统上，衣康酸因其抗炎特性而被认可；然而，本研究揭示了衣康酸在巨噬细胞中的促炎机制。我们证明衣康酸通过半胱氨酸139促进乙二醛酶1（GLO1）的蛋白酶体降解。GLO1对于解毒甲基乙二醛（MGO）至关重要，MGO是一种糖酵解副产物，可导致晚期糖基化终产物（AGEs）。脓毒症患者外周血单核细胞（PBMCs）中衣康酸浓度升高与GLO1表达降低相关，这将衣康酸浓度增加与MGO和AGEs生成增加联系起来。在功能上，衣康酸诱导的GLO1降解促进了MGO和AGEs的积累，从而加剧炎症反应。在体内，与野生型对照相比，经衣康酸处理的髓系特异性Ager条件性敲除小鼠在实验性脓毒症模型中表现出炎症减轻和存活率提高。总的来说，这些发现揭示了衣康酸在免疫代谢中的新功能，为其在致命感染中的复杂作用提供了线索。
