A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1<i>β</i> and IL-6.

Liping Liao; Wenzhen Dang; Tingting Lin; Jinghua YU; Tonghai Liu; Wen LI; Senhao Xiao; Lei Feng; Jing Huang; Rong FU; Jiacheng LI; Liping Liu; Mingchen Wang; Hongru Tao; Hualiang Jiang; Kaixian Chen; Xingxing Diao; Bing Zhou; Xiaoyan Shen; Cheng Luo

Return

A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1β and IL-6.

Author: Liping LIAO ¹ ; Wenzhen DANG ² ; Tingting LIN ¹ ; Jinghua YU ¹ ; Tonghai LIU ¹ ; Wen LI ¹ ; Senhao XIAO ¹ ; Lei FENG ¹ ; Jing HUANG ¹ ; Rong FU ¹ ; Jiacheng LI ¹ ; Liping LIU ¹ ; Mingchen WANG ¹ ; Hongru TAO ¹ ; Hualiang JIANG ¹ ; Kaixian CHEN ¹ ; Xingxing DIAO ¹ ; Bing ZHOU ¹ ; Xiaoyan SHEN ² ; Cheng LUO ²
Author Information

1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
2. Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
Publication Type:Journal Article
Keywords: Glycolysis; Inflammation; Macrophages; NRF2; Phosphoglycerate kinase1
From: Acta Pharmaceutica Sinica B 2022;12(11):4180-4192
CountryChina
Language:English
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-1β 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.