Phosphoglycerate kinase 1 contributes to diabetic kidney disease through enzyme-dependent and independent manners

  • Cell Rep Med. 2025 Aug 19;6(8):102241. doi: 10.1016/j.xcrm.2025.102241.
Hai-Jian Sun  1 ,  Qing-Bo Lu  2 ,  Shi-Jia Liu  3 ,  Xiao Fu  1 ,  Cheng-Li Yu  4 ,  Jia-Bao Su  5 ,  Xin-Yu Meng  1 ,  Xi Guo  6 ,  Xin Shao  7 ,  Jun-Hui Li  8 ,  Qing-Yi Sun  1 ,  Xue-Xue Zhu  9 ,  Jin-Jun Shan  10 ,  Wei Zhou  11
Affiliations
  • 1. Departement of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
  • 2. Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214125, China.
  • 3. Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China.
  • 4. School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5. Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214122, China.
  • 6. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 7. Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 8. Department of Nephrology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai 200060, China.
  • 9. Departement of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China. Electronic address: [email protected].
  • 10. Institute of Pediatrics, Jiangsu Key Laboratory of Pediatric Respiratory Disease, Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China. Electronic address: [email protected].
  • 11. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 40695289 DOI: 10.1016/j.xcrm.2025.102241
Abstract

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.

Keywords
3-phosphoglycerate; NLRP3; PGK1; diabetic kidney disease; drug screening; inflammation; metabolomics; oxidative stress.
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