Itaconate modifications: Mechanisms and applications

Itaconate is a mitochondrial metabolite generated from the tricarboxylic acid cycle intermediate cis-aconitate by the enzyme aconitate decarboxylase 1 (ACOD1). Beyond its metabolic role, itaconate has emerged as a critical regulator of immune and inflammatory signaling. Together with its electrophilic derivatives (e.g., 4-octyl itaconate, dimethyl itaconate), it modulates diverse cellular processes through covalent post-translational modifications. These include S-itaconation, a cysteine-directed Michael addition primarily mediated by electrophilic derivatives, and K-itaconation, a lysine-targeted, reversible acylation involving an itaconyl-CoA intermediate derived from itaconate. Such modifications influence multiple immune regulators - including Kelch-like ECH-associated protein 1 (KEAP1), stimulator of interferon response cGAMP interactor 1 (STING1), NLR family pyrin domain containing 3 (NLRP3), glutathione peroxidase 4 (GPX4), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) - thereby modulating inflammation, oxidative stress, and cell death pathways such as pyroptosis and ferroptosis. Preclinical studies demonstrate that itaconate derivatives confer therapeutic benefits in sepsis, colitis, neurodegeneration, autoimmunity, and cancer. By contrast, endogenous itaconate exhibits context-dependent effects, acting as either a pro-resolving or immunostimulatory metabolite. This review integrates current insights into itaconate biosynthesis, molecular targets, post-translational modifications, detection technologies, and translational potential, underscoring its emerging role as a master regulator of immunometabolic reprogramming and inflammatory control.