4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects

Shan-Ting Liao, Chao Han, Ding-Qiao Xu, Xiao-Wei Fu, Jun-Song Wang () and Ling-Yi Kong ()
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Shan-Ting Liao: China Pharmaceutical University
Chao Han: China Pharmaceutical University
Ding-Qiao Xu: China Pharmaceutical University
Xiao-Wei Fu: China Pharmaceutical University
Jun-Song Wang: Nanjing University of Science and Technology
Ling-Yi Kong: China Pharmaceutical University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U13C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.

Date: 2019
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DOI: 10.1038/s41467-019-13078-5

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