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

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 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.

INSTRUMENT(S): Liquid Chromatography MS - negative - hilic

SUBMITTER: Shanting Liao

PROVIDER: MTBLS1140 | MetaboLights | 2019-10-02

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS1140	Other
	FILES	Other
	a_MTBLS1140_NEG_HILIC_mass_spectrometry.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS1140_NEG_HILIC_mass_spectrometry_v2_maf.tsv	Tabular

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

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