Itaconate

Itaconate is a small dicarboxylic acid metabolite produced by certain immune cells, notably macrophages, in response to inflammatory stimuli. In mammals, it is generated from cis-aconitate in the mitochondria by the enzyme immune-responsive gene 1 (IRG1), as part of metabolic reprogramming during activation.

In biological systems, itaconate can act as a regulatory metabolite with anti-inflammatory effects. Through its electrophilic properties, itaconate-derived molecules can modify cysteine residues on KEAP1, leading to activation of the NRF2 transcription factor and upregulation of antioxidant and anti-inflammatory genes. It may also influence cellular metabolism by inhibiting enzymes of the TCA cycle, such as succinate dehydrogenase, thereby altering energy production in activated cells. The net effect on inflammation is context dependent and can involve both pro- and anti-inflammatory pathways.

Itaconate has antimicrobial activity in macrophages by inhibiting isocitrate lyase, an enzyme used by several bacteria in the glyoxylate shunt. Inhibiting this enzyme can restrict bacterial growth within host cells, contributing to host defense against pathogens such as Mycobacterium tuberculosis and Salmonella.

Derivatives of itaconate, including cell-permeable esters such as dimethyl itaconate, are commonly used in cell biology to study its effects. Research continues to define the physiological roles of endogenous itaconate, its potential as a biomarker in inflammatory diseases, and its prospects as a therapeutic target.