Itaconate, an endogenous mitochondrial metabolite produced by the enzyme aconitate decarboxylase 1 (ACOD1), has emerged as a central regulator of inflammation, innate immunity, and cellular stress responses. In a comprehensive review published in the Journal of Intensive Medicine by Yang et al, researchers summarize the rapidly expanding field of itaconate biology—highlighting its chemical reactivity, protein modification mechanisms, and therapeutic potential across infectious, inflammatory, autoimmune, and neurodegenerative diseases.
Itaconate and its electrophilic derivatives, such as 4-octyl itaconate (4-OI) and dimethyl itaconate (DMI), exert their biological effects primarily through two types of post-translational modifications: cysteine-directed S-itaconation and lysine-targeted K-itaconation. S-itaconation occurs through Michael addition, enabling itaconate derivatives to covalently modify key inflammatory regulators—including KEAP1, STING1, JAK1, NLRP3, GSDMD, and TBK1. These modifications alter protein activity, disrupt protein–protein interactions, and reshape downstream signaling pathways, thereby limiting oxidative injury, inflammasome activation, antiviral signaling, and pyroptotic cell death. In contrast, K-itaconation is a reversible acylation event mediated by the intermediate itaconyl-CoA, which modifies multiple glycolytic enzymes and reprograms cellular metabolism toward an anti-inflammatory state.
“By integrating chemical biology, immunometabolism, and systems-level signaling, the review provides a mechanistic framework explaining how itaconate acts as a master regulator of macrophage activation. It suppresses glycolytic flux, inhibits succinate dehydrogenase, reduces mitochondrial respiration, and stabilizes the transcription factor NFE2L2 through KEAP1 modification. Collectively, these actions shift immune cells away from a pro-inflammatory phenotype and promote the resolution of inflammation,” mentions Dr. Yang.
The review also emphasizes the important distinction between endogenous itaconate and its more electrophilic derivatives. Endogenous itaconate can paradoxically amplify interferon signaling by promoting mitochondrial RNA release and activating MAVS-dependent antiviral pathways. In contrast, derivatives such as 4-OI predominantly suppress antiviral and inflammatory pathways through STING1 and JAK1 modification. This context-dependent duality underscores the need for careful interpretation when translating itaconate-based interventions.
Preclinical models demonstrate broad therapeutic potential for itaconate derivatives. In sepsis, 4-OI protects against lethal inflammation by inhibiting inflammasome activation, pyroptosis, and thrombosis. In inflammatory bowel disease, 4-OI blocks GSDMD- and GSDME-mediated cell death, preserving epithelial integrity and reducing colitis severity. In models of Alzheimer’s and Parkinson’s disease, itaconate derivatives attenuate microglial activation and oxidative stress by stabilizing NFE2L2, thereby improving neuronal survival and functional outcomes.
Furthermore, the review highlights emerging applications in autoimmunity and cancer. In systemic lupus erythematosus, 4-OI reduces type I interferon signatures and inflammatory cytokines. In rheumatoid arthritis, itaconate reprograms synovial fibroblast metabolism and suppresses invasive activity. In the tumor microenvironment, itaconate modulates dendritic-cell antigen presentation, immune-checkpoint stability, and tumor cell metabolism—revealing opportunities for combinatorial immunotherapy.
Technological advances, including chemoproteomic platforms such as ITalk, 1-OH-Az, and thermal proteome profiling, have accelerated the identification of itaconate-modified proteins, uncovering hundreds of modification sites across diverse pathways. These tools now enable precise mapping of S- and K-itaconation events and provide the foundation for developing targeted itaconate-based therapeutics.
The authors conclude that “itaconate biology represents a paradigm shift: redefining metabolic intermediates not as passive byproducts, but as active regulators of immune cell fate and inflammatory homeostasis. Continued discovery in this field is expected to yield new strategies for treating infectious diseases, sepsis, autoimmunity, neuroinflammation, and cancer”.
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Reference
DOI: https://doi.org/10.1016/j.jointm.2025.10.002
Journal of Intensive Medicine
Literature review
Not applicable
Itaconate modifications: Mechanisms and applications
1-Dec-2025
The authors declare no conflicts of interest or financial interests. Given his role as Editorial Board Member, Daoling Tang had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to another journal editor