MassIVE MSV000085812

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MetaboLights MTBLS1140 - GNPS 4-octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects

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Description

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 recently been reported to regulate macrophage function, but its precise mechanism is not fully understood. Here, we showed that 4-octyl itaconate (OI, a cell-permeable itaconate derivative) directly alkylated cysteine residue 22 on the glycolytic enzyme GAPDH and decreased its enzyme activity. Glycolytic flux analysis by U13C?glucose tracing also provided evidence that OI generated a blockade of glycolytic flux at GAPDH. OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of OI were replicated by heptelidic acid, 2-DG and reversed by increasing wild-type but not C22A mutant GAPDH expression. OI protected against lipopolysaccharide-induced lethality in vivo and significantly inhibited cytokine release. These findings showed that itaconate is a critical immunometabolite that exerts anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: GNPS Metabolomics MetaboLights

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Principal Investigators:
(in alphabetical order) 		Shan-Ting Liao, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Submitting User: caceves
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