Exploring the evolutionary roots and physiological function of itaconate.

New small molecules are continuing to emerge as metabolically derived regulators of cell function. Itaconate is a recent example where endogenous mammalian synthesis was demonstrated only seven years ago. Since then, interest in the biochemistry and therapeutic potential of itaconate has grown dramatically. Itaconate is an unsaturated dicarboxylic acid that has antimicrobial properties and modulates metabolic pathways throughout the cell. Naturally occurring mutations of enzymes involved in human itaconate synthesis and degradation pathways are associated with disease susceptibility and immunity. Here, we highlight recent discoveries on itaconate metabolism and discuss the relevance of its evolutionary origin to its function in mammals. We also consider the therapeutic relevance of itaconate metabolism and its derivatives for treating metabolic and inflammatory diseases.