Itaconate: A Potent Macrophage Immunomodulator

Li, Zeyu; Zheng, Wenbin; Kong, Wen; Zeng, Tianshu

doi:10.1007/s10753-023-01819-0

Cited by 21 publications

(10 citation statements)

References 142 publications

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“…There is another mechanism for increasing the levels of succinate in the cell, which is described in detail in macrophages (M1), that, upon activation, rearrange metabolism so that a certain analogue of succinate, itocanate, can be formed from cis-aconitate [ 74 , 75 ] (see Figure 2 ); and itocanate has powerful anti-inflammatory potency [ 76 ]. Two populations of macrophages are known to be proinflammatory and anti-inflammatory (M1 and M2, respectively), and both populations are present in the tumor microenvironment.…”

Section: Succinate and Cancermentioning

confidence: 99%

Targeting Mitochondria for Cancer Treatment

Zorova,

Abramicheva,

Andrianova

et al. 2024

Pharmaceutics

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There is an increasing accumulation of data on the exceptional importance of mitochondria in the occurrence and treatment of cancer, and in all lines of evidence for such participation, there are both energetic and non-bioenergetic functional features of mitochondria. This analytical review examines three specific features of adaptive mitochondrial changes in several malignant tumors. The first feature is characteristic of solid tumors, whose cells are forced to rebuild their energetics due to the absence of oxygen, namely, to activate the fumarate reductase pathway instead of the traditional succinate oxidase pathway that exists in aerobic conditions. For such a restructuring, the presence of a low-potential quinone is necessary, which cannot ensure the conventional conversion of succinate into fumarate but rather enables the reverse reaction, that is, the conversion of fumarate into succinate. In this scenario, complex I becomes the only generator of energy in mitochondria. The second feature is the increased proliferation in aggressive tumors of the so-called mitochondrial (peripheral) benzodiazepine receptor, also called translocator protein (TSPO) residing in the outer mitochondrial membrane, the function of which in oncogenic transformation stays mysterious. The third feature of tumor cells is the enhanced retention of certain molecules, in particular mitochondrially directed cations similar to rhodamine 123, which allows for the selective accumulation of anticancer drugs in mitochondria. These three features of mitochondria can be targets for the development of an anti-cancer strategy.

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Section: Succinate and Cancermentioning

confidence: 99%

Targeting Mitochondria for Cancer Treatment

Zorova,

Abramicheva,

Andrianova

et al. 2024

Pharmaceutics

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“…Obesity-related hormones are mostly secreted by adipocytes and have a direct impact on cytokine expression in CRC cells, as well as on M1/M2 macrophage polarization [14,41,45]. These TAMs, including both M1 and M2 macrophages, are key regulators of inflammatory signaling that have been found to affect CRC progression and patient survival.…”

Section: Obesity and The Tumor Microenvironmentmentioning

confidence: 99%

“…Itaconate is produced by the expression of IRG1, a gene that encodes the protein aconitate decarboxylase 1 (ACOD1). ACOD1 is an enzyme of the tricarboxylic acid (TCA) cycle that produces the metabolite itaconate from cis-aconitate [45]. It serves as a regulator of cellular metabolism via the regulation of glycolysis and leads to succinate accumulation through the inhibition of succinate dehydrogenase.…”

Section: Itaconatementioning

confidence: 99%

“…Itaconate also works to mediate anti-inflammatory effects by inducing anti-inflammatory transcription factors, such as nuclear factor erythroid-2 related factor 2 (NRF2), and oxidative stress reduction. It influences numerous transcription factors as well, including NF-κB, hypoxiainducible factor 1α (HIF1α), signal transducer and activator of transcription 3 (STAT3), and activator protein 1 (AP-1) [14,15,41,45].…”

Section: Itaconatementioning

confidence: 99%

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Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer

Jones,

Scheurlen,

Macleod

et al. 2024

Cancers

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Metabolic dysfunction associated with obesity leads to a chronic pro-inflammatory state with systemic effects, including the alteration of macrophage metabolism. Tumor-associated macrophages have been linked to the formation of cancer through the production of metabolites such as itaconate. Itaconate downregulates peroxisome proliferator-activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Similarly, leptin and adiponectin also influence macrophage cytokine expression and contribute to the progression of colorectal cancer via changes in gene expression within the PI3K/AKT pathway. This pathway influences cell proliferation, differentiation, and tumorigenesis. This work provides a review of obesity-related hormones and inflammatory mechanisms leading to the development and progression of early-onset colorectal cancer (EOCRC). A literature search was performed using the PubMed and Cochrane databases to identify studies related to obesity and EOCRC, with keywords including ‘EOCRC’, ‘obesity’, ‘obesity-related hormones’, ‘itaconate’, ‘adiponectin’, ‘leptin’, ‘M2a macrophage’, and ‘microbiome’. With this concept of pro-inflammatory markers contributing to EOCRC, increased use of chemo-preventative agents such as aspirin may have a protective effect. Elucidating this association between obesity-related, hormone/cytokine-driven inflammatory effects with EOCRC may help lead to new therapeutic targets in preventing and treating EOCRC.

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“…Our perspective first undertakes an in-depth examination of itaconate (Figure 1a)-arguably one of the most popular mt-REM with extensive broad-spectrum immunomodulatory operations [13,14]. We discuss the biosynthesis, feedback regulation, and functional ramifications of itaconate on representative targets/pathways.…”

Section: Introductionmentioning

confidence: 99%

Precision Immuno-Chemical Biology: Toward Decoding Spatiotemporal Signaling Activities of Reactive Immunometabolites

Huang,

Aye

2024

Preprint

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Immune-cell reprogramming driven by mitochondria-derived reactive electrophilic immunometabolites (mt-REMs—e.g., fumarate, itaconate) is an emerging phenomenon of major biomedical importance. Despite their localized production, mt-REMs elicit significantly-large local and global footprints within and across cells, through mechanisms involving electrophile signaling. Burgeoning efforts are being put into profiling mt-REMs’ potential protein-targets and phenotypic mapping of their multifaceted inflammatory behaviors. Yet, precision indexing of mt-REMs’ first-responders with spatiotemporal intelligence and locale-specific function assignments remains elusive. Highlighting the latest advances and overarching challenges, this perspective aims to stimulate thoughts and spur interdisciplinary innovations to address these unmet chemical-biotechnological needs at therapeutic immuno-signaling frontiers.

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Itaconate: A Potent Macrophage Immunomodulator

Cited by 21 publications

References 142 publications

Targeting Mitochondria for Cancer Treatment

Targeting Mitochondria for Cancer Treatment

Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer

Precision Immuno-Chemical Biology: Toward Decoding Spatiotemporal Signaling Activities of Reactive Immunometabolites

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