Itaconic acid (ITA) (ITA)

Itaconic acid is a dicarboxylic acid produced in the mitochondrial matrix by the enzyme ACOD1 (Aconitate decarboxylase 1) during the activation of myeloid cells, particularly macrophages (Michelucci et al., 2013, PNAS). It serves as a critical metabolic checkpoint that limits excessive inflammation by reprogramming cellular metabolism and signaling pathways. Its primary mechanisms include the competitive inhibition of succinate dehydrogenase (SDH), which leads to succinate accumulation and reduced mitochondrial reactive oxygen species (Lampropoulou et al., 2016, Cell Metabolism). It also acts as an electrophile, covalently modifying cysteine residues on target proteins like KEAP1 to trigger the NRF2-mediated antioxidant defense (Mills et al., 2018, Nature). Furthermore, itaconate inhibits glycolysis by targeting GAPDH, which suppresses the inflammatory phenotype of myeloid cells (Liao et al., 2019, Molecular Cell). Given its role in resolving inflammation, itaconate mimetics and derivatives are being explored as novel treatments for conditions such as sepsis, psoriasis, and rheumatoid arthritis. However, its electrophilic nature requires careful design of derivatives to ensure specificity and minimize off-target effects. Overall, it represents a key link between innate immune activation and metabolic regulation.

Other names

Itaconate2-methylidenebutanedioic acidMethylene succinic acidAconitate decarboxylase 1 product

Itaconate acts as an endogenous immunomodulator by inhibiting succinate dehydrogenase (SDH) and activating the NRF2 antioxidant pathway through the alkylation of KEAP1 cysteine residues. It also inhibits glycolysis by targeting GAPDH and modulates the NLRP3 inflammasome to reduce pro-inflammatory cytokine release.