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. Author manuscript; available in PMC: 2026 Jun 24.
Published in final edited form as: Immunity. 2025 Aug 4;58(8):1904–1921. doi: 10.1016/j.immuni.2025.07.012

Figure 4: Endogenous itaconate and fumarate function as electrophiles that directly modify immune signaling through cysteine alkylation of target proteins.

Figure 4:

Left) Following TLR4 or IFNAR activation, ACOD1 (IRG1) expression increases, catalyzing the conversion of cis-aconitate to itaconate. Itaconate modifies cysteines in GAPDH to reduce glycolytic flux and also inhibits peroxiredoxin-5 (PRDX5) through a non-covalent mechanism, elevating mitochondrial H2O2 levels that enhance cGAS-STING signaling and type I interferon production. Itaconate can also inhibit succinate dehydrogenase (SDH) activity preventing succinate oxidation to fumarate and potentially altering mitochondrial ROS production. Right) Like itaconate, endogenous fumarate acts as an electrophile capable of cysteine modification. Fumarate is known to inhibit GAPDH similarly to itaconate and can also inactive KEAP1, which induces NRF2 activity. Fumarate hydratase (FH) activity is reduced by TLR and IFNAR signaling, while fumarate accumulation promotes mitochondrial DNA and RNA release that activates type I interferon responses. Importantly, synthetic derivatives of these metabolites—including dimethyl itaconate (DI), 4-octyl itaconate (4-OI), dimethyl fumarate (DMF), and monomethyl fumarate (MMF)—act as significantly stronger electrophiles than their endogenous counterparts. Synthetic itaconate derivatives exerts anti-inflammatory effects through multiple pathways including directly alkylating cysteine residues on gasdermin D (GSDMD) to reduce late inflammasome activation, KEAP1 to activate NRF2-dependent antioxidant pathways and signaling, JAK1 to inhibit downstream signaling, and ATF3 to inhibit IκBζ activity. Chemical fumarate mimetics show similar effects on KEAP1 and NRF2 activity. However, their enhanced electrophilic activity and expanded protein targets distinguish them functionally from the more selective effects of endogenous itaconate and fumarate, highlighting the importance of distinguishing between physiological metabolite signaling and pharmacological electrophile effects in immune regulation.