Dear Editor,

Succinate (SA) is a classic intermediate metabolite of the TCA cycle and is produced in mitochondria under normal physiological conditions.¹ SA accumulates within cells and is secreted into the extracellular space, engaging in metabolic regulation and inflammatory response during conditions such as hypoxia, ischemia-reperfusion, and pro-inflammatory processes.² Excess SA functions as a paracrine signal through its extracellular G protein-coupled receptor, SUCR1,³ which senses extracellular metabolic stress signals and regulates energy homeostasis.⁴ SUCR1 couples to G_i and G_q signaling pathways,⁵ resulting in physiological effects closely tied to human health and diseases such as hypertension, diabetes, inflammation, atherosclerosis, sepsis, immune response, cancer, asthma, and adiposity.^3,6,7,8,9,10 Therefore, it is of great interest as a drug target. While the crystal structure of antagonist-bound rat SUCR1 complex has been resolved to clarify the inactivation mechanism of the receptor,¹¹ a comprehensive understanding of the detailed molecular activation mechanism triggered by SA sensation is impeded by the lack of experimental active-state SUCR1 structures.

 亲爱的编辑，

琥珀酸 (SA) 是 TCA 循环的经典中间代谢产物，在正常生理条件下在线粒体中产生。 ¹ SA 在细胞内积累并分泌到细胞外空间，在缺氧、缺血再灌注和促炎症过程等条件下参与代谢调节和炎症反应。 ²过量的 SA 通过其细胞外 G 蛋白偶联受体 SUCR1 充当旁分泌信号， ³可感知细胞外代谢应激信号并调节能量稳态。 ⁴ SUCR1 与 G 和 G _q信号通路结合， ⁵产生与人类健康和高血压、糖尿病、炎症、动脉粥样硬化、败血症、免疫反应、癌症、哮喘和肥胖等疾病密切相关的生理效应。 ^3,6,7,8,9,10因此，它作为药物靶点引起了人们的极大兴趣。虽然拮抗剂结合的大鼠 SUCR1 复合物的晶体结构已被解析，以阐明受体的失活机制， ¹¹由于缺乏实验活性状态 SUCR1 结构，阻碍了对 SA 感觉触发的详细分子激活机制的全面理解。