Itaconate, an immune cell metabolite, rewires inflammation by chemically tagging key proteins
Macrophages make itaconate, which tags inflammatory proteins like NLRP3, STING1 and GPX4. This review maps how it controls inflammation and cell death.
Summary
When immune cells called macrophages are activated, they make a small metabolite called itaconate. This review explains how itaconate and lab-made versions of it (4-octyl itaconate, dimethyl itaconate) physically attach to proteins and change how they work. Targets include KEAP1, STING1, NLRP3, GPX4 and GAPDH, which control inflammation, antioxidant defense and inflammatory cell death (pyroptosis and ferroptosis). In animal and cell models, the derivatives helped in sepsis, colitis, neurodegeneration, autoimmunity and cancer. Natural itaconate is more complicated: depending on context it can calm inflammation or boost interferon signaling. Human cells also make much less itaconate than mouse cells. So the promise is real but preclinical, and no human trials are described.
Detailed Summary
Inflammation that is poorly controlled underlies many age-related and immune-mediated conditions, so molecules that act as built-in brakes are of great interest. Itaconate is one such molecule. It is a small metabolite that activated macrophages make from the TCA cycle intermediate cis-aconitate using the enzyme ACOD1 (also called IRG1). This review from Yang, Kang, Zhou and Tang synthesizes how itaconate and its synthetic derivatives chemically modify proteins and thereby reshape immune signaling, cell death and metabolism.
The authors begin with biochemistry. Itaconate is an α,β-unsaturated dicarboxylic acid and a mild electrophile that can add to cysteine thiols (S-itaconation). It can also be converted to itaconyl-CoA, which supports reversible lysine acylation. Derivatives such as 4-octyl itaconate (4-OI) and dimethyl itaconate (DMI) are more cell-permeable and more electrophilic than itaconate itself. Some adducts seen with them may therefore not form at physiological itaconate levels. In LPS-stimulated macrophages, Acod1 mRNA rises within 2 hours, but itaconate accumulates only after about 6 hours. The review also covers regulation of ACOD1 by TLRs, MYD88, type I interferon, CDK2-JNK1-JUN signaling, BRD3-TRIM21-CREBBP-CREB1 and dopamine receptor D2.
The core of the paper is a catalog of more than 20 modified targets (Table 1). 4-OI and DMI modify KEAP1 at Cys151, Cys273 and Cys288, which stabilizes NRF2 and activates antioxidant genes. JAK1 is modified at Cys715, Cys816 and Cys943 by 4-OI and at Cys1130 by itaconate, which blunts IL-4 and interferon signaling. STING1 (Cys91 with 4-OI) and TBK1 (Cys605) are alkylated, which dampens type I interferon responses. 4-OI modifies NLRP3 at Cys548, blocking NEK7 binding and inflammasome assembly. Itaconate modifies GSDMD at Cys77, limiting pore formation. 4-OI modifies TFEB at Cys212, promoting autophagy and lysosomal biogenesis. 4-OI also modifies UBR5 at Cys2768, which promotes PADI4 degradation and limits NETosis in septic mice. Itaconate modifies GPX4 at Cys66, which the authors link to protection from ferroptosis.
The review stresses that endogenous itaconate is not simply anti-inflammatory. By inhibiting succinate dehydrogenase it can drive mitochondrial RNA release and MAVS-dependent type I interferon production. By inhibiting PRDX5 non-covalently it can raise mitochondrial peroxide and enhance interferon signaling. Species differences matter as well. Human ACOD1 has a 5.9-fold lower kcat and a 4.1-fold lower catalytic efficiency than the mouse enzyme, and human macrophages produce less itaconate. In vivo 13C-itaconate tracing in male mice showed rapid plasma clearance, urinary excretion and incorporation into liver and kidney TCA intermediates.
Preclinical work cited in the abstract shows benefit of itaconate derivatives in sepsis, colitis, neurodegeneration, autoimmunity and cancer. The review also covers detection technologies and translational prospects. Itaconate is positioned as a master regulator of immunometabolic reprogramming and a template for drug design.
Caveats are substantial. The evidence is almost entirely from cell lines, primary macrophages and mouse models, often using supraphysiologic doses of reactive derivatives. Some modifications have not been shown for endogenous itaconate. Human clinical data are essentially absent, apart from cell work on patient-derived cells in CAPS. Translation will require selectivity and safety work for electrophilic compounds.
Key Findings
- Table 1 catalogs more than 20 proteins modified by itaconate or its derivatives, including KEAP1, JAK1, STING1, TBK1, NLRP3, GSDMD, GPX4, TFEB, GAPDH and PD-L1
- 4-OI and DMI modify KEAP1 at Cys151, Cys273 and Cys288, which stabilizes NRF2 and drives antioxidant and anti-inflammatory gene expression
- 4-OI modifies NLRP3 at Cys548, blocking its interaction with NEK7 and suppressing inflammasome activation, including in PBMCs from CAPS patients
- Itaconate modifies GSDMD at Cys77 to inhibit pore formation and pyroptosis, and modifies GPX4 at Cys66 to enhance its activity against ferroptosis
- Human ACOD1 has a 5.9-fold lower kcat and a 4.1-fold lower catalytic efficiency than mouse ACOD1, so human macrophages make far less itaconate
- In LPS-stimulated macrophages, Acod1 mRNA rises within 2 hours, but intracellular itaconate becomes evident only after about 6 hours
- Endogenous itaconate can also boost type I interferon signaling by inhibiting SDH (mtRNA release, MAVS) or PRDX5, unlike the mostly suppressive derivatives
Methodology
This is a narrative review with no prespecified search strategy, sample size or pooled statistics. The authors integrate preclinical studies on itaconate biosynthesis, regulation of ACOD1, S-itaconation, K-itaconation, ferroptosis and pyroptosis, detection technologies and disease models. Evidence comes mainly from cell lines, primary macrophages, knockout mice (e.g., Acod1-/-) and disease models such as cecal ligation and puncture, with limited patient-derived cells. The supplied full text was truncated partway through the ferroptosis and pyroptosis section, so later sections on disease applications and detection methods were not available for this analysis.
Study Limitations
The authors note that derivatives are more electrophilic than itaconate, so adducts seen with 4-OI or DMI may not form under physiological itaconate levels, and direct KEAP1 or STING1 modification by endogenous itaconate has not been consistently shown. Human macrophages produce less itaconate than murine cells, limiting translation of mouse findings. Most evidence is preclinical, and no conflicts of interest were available in the supplied text.
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