同济大学梅馨予团队的一项最新研究研制了同型半胱甘酸盐通过重塑蛋氨酸代谢和N-同型半胱氨酸化来控制炎症。相关论文于2025年8月27日发表于国际顶尖学术期刊《细胞—代谢》杂志上。

该课题组研究人员鉴定了产生同型半胱氨酸的免疫代谢串，同型半胱氨酸和由S-腺苷-L-同型半胱氨酸水解酶（AHCY）催化的衣康酸内聚形成的代谢物。同半胱甘酸在炎症期间增加152倍，并表现出抗炎作用。机制上，同型半胱甘酸结合促炎蛋白蛋氨酸- tRNA合成酶（MARS）的D312残基，抑制其功能，重塑蛋氨酸代谢，反馈抑制N-同型半胱氨酸化途径的早期激活。这种代谢开关促进NLR家族含pyrin结构域3 （NLRP3）泛素化来控制炎症。高胱甘肽酸在脓毒症、高脂肪饮食引起的炎症和结肠炎模型中显示出治疗效果。通过烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖的AHCY激活（主题化烟酰胺核苷和丙酮酸）促进内源性高半胱甘酸合成也通过靶向MARS/NLRP3-N-同型半胱氨酸级联抑制炎症。本研究确立了同半胱甘肽酸作为一种抗炎代谢物，通过重编程蛋白质修饰开关作为一种体内平衡调节剂，引入代谢时间调节和临床策略来管理炎症并发症。

据介绍，炎症及其代谢网络相互作用产生具有翻译意义的新型调控分子。

附：英文原文

Title: Homocysitaconate controls inflammation through reshaping methionine metabolism and N-homocysteinylation

Author: Moubin Lin, Juan Wang, Yongshuai Chai, Xin Chen, Danyang Zhao, Zhangdan Xie, Jiebang Jiang, Hong Li, Li Huang, Siwei Xing, Dashi Qi, Xinyu Mei

Issue&Volume: 2025-08-27

Abstract: Inflammation and its metabolic-network interactions generate novel regulatory molecules with translational implications. Here, we identify the immunometabolic crosstalk that generates homocysitaconate, a metabolite formed by homocysteine and itaconate adduction catalyzed by S-adenosyl-L-homocysteine hydrolase (AHCY). Homocysitaconate increases 152-fold during inflammation and exhibits anti-inflammatory effects. Mechanistically, homocysitaconate binds to the D312 residue of the pro-inflammatory protein methionyl-tRNA synthetase (MARS), inhibiting its function and reshaping methionine metabolism to feedback-brake the early activation of the N-homocysteinylation pathway. This metabolic switch facilitates NLR family pyrin domain-containing 3 (NLRP3) ubiquitination to control inflammation. Homocysitaconate demonstrates therapeutic effects in sepsis, high-fat-diet-induced inflammation, and colitis models. Boosting endogenous homocysitaconate synthesis through nicotinamide adenine dinucleotide (NAD+)-dependent AHCY activation (using nicotinamide riboside and pyruvate) also inhibits inflammation by targeting the MARS/NLRP3-N-homocysteinylation cascade. This study establishes homocysitaconate as an anti-inflammatory metabolite that serves as a homeostatic governor by reprogramming protein modification switches, introducing both metabolic timing regulation and clinical strategies to manage inflammatory complications.

DOI: 10.1016/j.cmet.2025.08.001

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00357-2