1. A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1β and IL-6.
- Author
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Liao, Liping, Dang, Wenzhen, Lin, Tingting, Yu, Jinghua, Liu, Tonghai, Li, Wen, Xiao, Senhao, Feng, Lei, Huang, Jing, Fu, Rong, Li, Jiacheng, Liu, Liping, Wang, Mingchen, Tao, Hongru, Jiang, Hualiang, Chen, Kaixian, Diao, Xingxing, Zhou, Bing, Shen, Xiaoyan, and Luo, Cheng
- Subjects
INTERLEUKIN-6 ,INFLAMMATORY bowel diseases ,DEXTRAN sulfate ,ENZYME metabolism ,FETAL hemoglobin ,HIGH throughput screening (Drug development) - Abstract
Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATP-competitive inhibitor of PGK1 with an affinity of K d = 99.08 nmol/L. DC-PGKI stabilizes PGK1 in vitro and in vivo , and suppresses both glycolytic activity and the kinase function of PGK1. In addition, DC-PGKI unveils that PGK1 regulates production of IL-1 β and IL-6 in LPS-stimulated macrophages. Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium (DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease. A potent PGK1 antagonist, DC-PGKI, suppresses glycolytic activity and Il-1 β and Il-6 genes through activating NRF2 signaling pathway in LPS-stimulated macrophages. Moreover, DC-PGKI ameliorates acute mouse UC model. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2022
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