Itaconate: a dual-edged sword in immunometabolism and host-pathogen interactions.

Itaconate (ITA), a tricarboxylic acid (TCA) cycle-derived immunometabolite produced mainly by activated macrophages and other myeloid cells (e.g., neutrophils) through immune-responsive gene 1 (IRG1)/aconitate decarboxylase 1 (ACOD1), links host metabolism with immune regulation and antimicrobial defense. Initially recognized as an anti-inflammatory metabolite, ITA regulates immune responses through antioxidant signaling, lysosomal activation, inflammasome modulation, and metabolic remodeling. However, emerging evidence reveals context-dependent immunomodulatory effects across different cellular and tissue environments. ITA plays a dual role in host-pathogen interactions by regulating host immune responses while simultaneously serving as a metabolic interface between host defense and bacterial survival. Host-derived ITA restricts pathogens by targeting conserved metabolic enzymes, biosynthetic pathways, and redox homeostasis, whereas bacteria counteract ITA stress through enzymatic degradation, metabolic rewiring, stress adaptation, biofilm formation, and interference with ITA availability. This review summarizes recent advances in ITA-mediated immunometabolic regulation and highlights the reciprocal metabolic competition shaping host-pathogen interactions.