The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases

Abstract

Endogenous small molecules are metabolic regulators of cell function. Itaconate is a key molecule that accumulates in cells when the Krebs cycle is disrupted. Itaconate is derived from cis-aconitate decarboxylation by cis-aconitate decarboxylase (ACOD1) in the mitochondrial matrix and is also known as immune-responsive gene 1 (IRG1). Studies have demonstrated that itaconate plays an important role in regulating signal transduction and posttranslational modification through its immunoregulatory activities. Itaconate is also an important bridge among metabolism, inflammation, oxidative stress, and the immune response. This review summarizes the structural characteristics and classical pathways of itaconate, its derivatives, and the compounds that release itaconate. Here, the mechanisms of itaconate action, including its transcriptional regulation of ATF3/IκBζ axis and type I IFN, its protein modification regulation of KEAP1, inflammasome, JAK1/STAT6 pathway, TET2, and TFEB, and succinate dehydrogenase and glycolytic enzyme metabolic action, are presented. Moreover, the roles of itaconate in diseases related to inflammation and oxidative stress induced by autoimmune responses, viruses, sepsis and IRI are discussed in this review. We hope that the information provided in this review will help increase the understanding of cellular immune metabolism and improve the clinical treatment of diseases related to inflammation and oxidative stress.

Keywords: Antioxidant therapeutics; COVID-19; IRG1; Inflammation; Itaconate; Metabolism.

Graphical abstract

Fig. 1

Timeline of itaconate milestones. The timeline is divided into two parts based on the main studies on itaconate. The first part shows the discovery of itaconate, and the second part depicts the exploration of its mechanisms of action.

Fig. 2

Metabolism of itaconate. Itaconate is a metabolite produced when the TCA cycle is bypassed during energy production, and IRG1/ACOD1 transforms cis-aconitate to itaconate in the mitochondrial matrix. Itaconate is converted to itaconate-CoA and is ultimately catalyzed to form acetyl-CoA, which re-enters the TCA cycle. The process in brown rectangle is part of TCA cycle. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Modulation of IRG1. Many stimuli can induce the expression of IRG1 by activating certain receptors.

Fig. 4

The structure of itaconate, similar metabolites, derivatives and bioactive materials. Itaconate is structurally similar to certain other metabolites, such as succinate, fumarate, and malonate, which exhibit similar biological functions given their similar structures. Researchers synthesized derivatives of itaconate to leverage their high membrane permeability. Since the rapid development of interdisciplinary studies, ItaCORM, P(NIPAM-IA), and ITA containing polymers have been synthesized to generate anti-inflammatory effects.

Fig. 5

The classical signaling pathways by which itaconate regulates the inflammatory response and oxidative stress. These classical signaling pathways by which itaconate regulates the inflammatory response and oxidative stress can be divided into three types: (1) transcriptional regulation, including the regulation of the ATF3/IκBζ axis, and type I IFN activation (① & ②); (2) protein modification regulation, including the regulation of the KEAP1, inflammasome, JAK1-STAT6 pathway, TET2 catalytic activity, and TFEB nuclear translocation (the specific methods of modification are shown in Fig. 6, ③-⑨); and (3) metabolic regulation, including inhibition of the activity of key glycolytic enzymes and SDH (⑨ & ⑩).

Fig. 6

Itaconate and its derivates modify proteins to regulate the inflammatory response and oxidative stress. The numbers in each box correspond to the numbers in Fig. 5. This figure shows detailed descriptions of the roles played by itaconate and its derivatives in protein modification regulation.

Fig. 7

The roles of itaconate in different inflammatory and oxidative stress-induced diseases and the animal and cell models used in these cited studies. Itaconate plays a significant role in many inflammatory and oxidative stress-induced diseases, and the references cited in this review are presented in the table after the listing of the related disease.