2. Academic Validation
  3. Inhibition of PGK1 ameliorates acute kidney injury through inactivating the PKM2/ALOX12/ferroptosis pathway in a study with male mice

Inhibition of PGK1 ameliorates acute kidney injury through inactivating the PKM2/ALOX12/ferroptosis pathway in a study with male mice

  • Nat Commun. 2025 Oct 24;16(1):9436. doi: 10.1038/s41467-025-64480-1.
Xue-Xue Zhu # 1,  Xin-Yu Meng # 1,  Ao-Yuan Zhang # 1,  Chen-Yang Zhao # 1,  Yi-Ting Wei 1,  Yuan-Yuan Wen 1,  Jia-Bao Su 2,  Xiao Fu 1,  Guo Chen 1,  An-Jing Xu 1,  Meng-Yuan Wang 1,  Le-Ming Ji 1,  Neng Bao 3,  Zheng-Yang Bao 4,  Na Li 5,  Qing-Bo Lu # 1 6,  Hai-Jian Sun 7 8 9
Affiliations

Affiliations

  • 1 MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, China.
  • 2 Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China.
  • 3 Department of Nephrology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China.
  • 4 Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi, China. Txwdbzy9307@outlook.com.
  • 5 Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi, China. 9862023252@jiangnan.edu.cn.
  • 6 Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China.
  • 7 MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, China. haijian.sun@jiangnan.edu.cn.
  • 8 Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China. haijian.sun@jiangnan.edu.cn.
  • 9 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. haijian.sun@jiangnan.edu.cn.
  • # Contributed equally.
PMID: 41136411 DOI: 10.1038/s41467-025-64480-1
Abstract

Despite decades of studies into the mechanisms underlying acute kidney injury (AKI), the effective clinical therapies are still limited. Here we report that the development of AKI was attenuated by conditional knockout of phosphoglycerate kinase 1 (PGK1) in renal tubular epithelial cells (RTECs) and aggravated by specific overexpression of PGK1 and administration of 3-phosphoglycerate (3-PG) in male mice. PGK1 interacted with Pyruvate Kinase M2 (PKM2), inducing PKM2 phosphorylation, promoting the formation of the PKM2 dimer and the subsequent nuclear translocation of PKM2. In the nucleus, the interaction of PKM2 with Pknox1 potentiated the enrichment of Pknox1 within ALOX12 promoters, which resulted in ALOX12-mediated Ferroptosis in RTECs. Our drug screening experiments identified L7DG as a potential PGK1 inhibitor which exhibited protective effects against ischemic/reperfusion (I/R)-induced renal injury. Overall, we establish that genetic and pharmacological inhibition of PGK1 might be proposed as an avenue for managing AKI.

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