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Itaconate is an immunometabolite that drives two distinct protein modifications: cysteine itaconation (S-itaconation) and lysine itaconylation (K-itaconylation). S-itaconation was first characterized in 2018 as an electrophilic cysteine modification involved in inflammatory regulation. In 2023, K-itaconylation was identified as a novel lysine acylation modification. Despite sharing the same metabolic origin, these modifications are mediated through distinct chemical mechanisms and contribute to different biological processes.