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Review
. 2021 May 12:9:669308.
doi: 10.3389/fchem.2021.669308. eCollection 2021.

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

Jiaqi Lin  1 , Jinxuan Ren  1 , Dave Schwinn Gao  1 , Yi Dai  1 , Lina Yu  1
Affiliations
Review

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

Jiaqi Lin et al. Front Chem. .

Abstract

Metabolites have recently been found to be involved in significant biological regulation and changes. Itaconate, an important intermediate metabolite isolated from the tricarboxylic acid cycle, is derived from cis-aconitate decarboxylation mediated by immune response gene 1 in mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component involved in the development and progression of inflammation and immunity. It could directly modify cysteine sites on functional substrate proteins which related to inflammasome, signal transduction, transcription, and cell death. Itaconate can be a connector among immunity, metabolism, and inflammation, which is of great significance for further understanding the mechanism of cellular immune metabolism. And it could be the potential choice for the treatment of inflammation and immune-related diseases. This study is a systematic review of the potential mechanisms of metabolite associated with different pathology conditions. We briefly summarize the structural characteristics and classical pathways of itaconate and its derivatives, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.

Keywords: immunometabolism; inflammation; itaconate; itaconate derivative; therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The Biosynthesis and Metabolism of Itaconate. Itaconate is produced by the decarboxylation of cis-aconitate encoded by aconitate decarboxylase 1. Itaconate inhibits SDH and accumulates Succinate. Pyruvate dehydrogenase complex catalyzes pyruvate into citrate precursor—acetyl-CoA.Itaconate is metabolized into itaconyl-coenzyme A. Itaconyl-coenzyme A inactivates mitochondrial CoA B12 thus inhibits methylmalonyl-CoA mutase and methylmalonyl-CoA conversion.
Figure 2
Figure 2
The classical signal pathways of itaconate that have been studied at present. The classical signal pathways of itaconate can be divided into five main types. (1) Itaconate mediated by IRG1 could inhibit due to structural similarity with succinate. (2) Itaconate covalently modify Keap1 cysteine 151 etc.to dissociate the combination of the Keap1-Nrf2, thus promote migration of Nrf2 to cell nuclei. (3) Itaconate increases the levels of ATF3 protein which translocated to the cell nuclei to inhibit IκBζ at the translational level. (4) Itaconate abolish NLRP3-NEK7 connection in a modification termed dicarboxypropylation on C548 of NLRP3 thus block NLRP3-dependent IL-1β release. (5) Itaconate inhibit glycolysis by alkylating cysteine 22 residues on GAPDH, cysteine 73, and 339 on ALDOA. Created with Biorender.
Figure 3
Figure 3
Itaconate can be involved in various types of diseases through a variety of regulatory ways.
See this image and copyright information in PMC

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