Sun Hai-Jian, Lu Qing-Bo, Liu Shi-Jia, Fu Xiao, Yu Cheng-Li, Su Jia-Bao, Meng Xin-Yu, Guo Xi, Shao Xin, Li Jun-Hui, Sun Qing-Yi, Zhu Xue-Xue, Shan Jin-Jun, Zhou Wei
Departement of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214125, China.
Cell Rep Med. 2025 Aug 19;6(8):102241. doi: 10.1016/j.xcrm.2025.102241. Epub 2025 Jul 21.
Diabetic kidney disease (DKD) is characterized by abnormal metabolic profiles. Metabolomics reveals increased serum levels of 3-phosphoglycerate (3-PG) in DKD patients. The protein expression of phosphoglycerate kinase 1 (PGK1), a key rate-limiting enzyme for 3-PG synthesis, is concomitantly upregulated in DKD patients and mice. The development of DKD is significantly mitigated by renal tubular epithelial cell-specific knockout of PGK1 and robustly worsened by PGK1 overexpression. Mechanistically, PGK1-dependent enzymatic production of 3-PG facilitates DKD through inhibiting GPX1 to activate the NLRP3 inflammasome. PGK1 promotes UNC5CL-mediated inflammation by binding to aldehyde dehydrogenase-1 L1 (Aldh1l1) through its non-enzymatic activity. The transcription factor paired box protein 5 (PAX5) mediates the upregulation of PGK1 in DKD. High-throughput screening reveals that C-16 from ChemDiv, the natural product lirinidine, and the Food and Drug Administration (FDA)-approved oxantel pamoate are potent PGK1 antagonists and efficaciously prevent DKD. Overall, blocking PGK1 may be a promising avenue for DKD management.
糖尿病肾病（DKD）的特征是代谢谱异常。代谢组学研究表明，DKD患者血清中3-磷酸甘油酸（3-PG）水平升高。3-PG合成的关键限速酶磷酸甘油酸激酶1（PGK1）在DKD患者和小鼠中的蛋白表达也随之上调。肾小管上皮细胞特异性敲除PGK1可显著减轻DKD的发展，而PGK1过表达则会使其明显恶化。机制上，PGK1依赖的3-PG酶促生成通过抑制GPX1激活NLRP3炎性小体促进DKD发展。PGK1通过其非酶活性与醛脱氢酶-1 L1（Aldh1l1）结合，促进UNC5CL介导的炎症反应。转录因子配对盒蛋白5（PAX5）介导DKD中PGK1的上调。高通量筛选显示，ChemDiv公司的C-16、天然产物利尼定以及美国食品药品监督管理局（FDA）批准的奥克太尔帕莫酸盐是有效的PGK1拮抗剂，可有效预防DKD。总体而言，阻断PGK1可能是治疗DKD的一个有前景的途径。
