A molecule first scraped from mouldy fungus in 1836 has turned out to control whether your immune system saves you or kills you. Itaconate, long dismissed as metabolic junk, physically grabs onto proteins inside immune cells and changes their shape. Sometimes that stops inflammation cold. Other times it fans the flames.
The contradiction has baffled researchers for years, but a review in the Journal of Intensive Medicine now offers an explanation: it depends on where the itaconate comes from and which proteins it touches. Yingyi Yang’s team at UT Southwestern Medical Center synthesised over a decade of experiments showing that this small metabolite acts less like a byproduct and more like a molecular dimmer switch.
Location matters
Synthetic itaconate derivatives, the kind chemists cook up in labs, almost always suppress inflammation. When 4-octyl itaconate latches onto a protein called KEAP1, it triggers a cascade of antioxidant defences that protect cells from oxidative damage. The same compounds block inflammatory pathways such as STING and JAK-STAT, which normally fuel antiviral responses and cytokine storms. In sepsis models, these derivatives prevent cell death, reduce clotting, and limit organ failure. They also preserve the gut lining in inflammatory bowel disease by stopping gasdermin proteins from punching holes in epithelial cells.
But the body’s own itaconate does something different.
When immune cells produce itaconate naturally inside mitochondria, using an enzyme called ACOD1, it can amplify interferon signalling during viral infections. The mechanism involves releasing mitochondrial RNA and reactive oxygen species, both of which ramp up antiviral defences. The review also describes a second type of modification targeting lysine residues, which is reversible and lets immune cells adjust their metabolism on the fly.
“Itaconate biology represents a paradigm shift: redefining metabolic intermediates not as passive byproducts, but as active regulators of immune cell fate,” Yang says.
A double-edged molecule
Itaconate’s effects ripple across disease models. In brains affected by Alzheimer’s and Parkinson’s, synthetic derivatives calmed overactive microglia and reduced oxidative stress, which improved neurone survival. Autoimmune conditions such as lupus and rheumatoid arthritis responded to metabolic reprogramming driven by itaconate, which dialled down destructive immune activity in both immune and stromal cells.
Cancer complicates the picture. Inside tumours, itaconate suppresses antigen presentation by immune cells whilst simultaneously starving cancer cells of metabolic fuel. That dual role means timing will be everything if itaconate-based drugs reach the clinic. Give it too early and you might cripple the immune response. Too late and the tumour adapts.
Yang’s team argues that metabolic intermediates are not just fuel or waste. They are signals that decide when inflammation resolves and when it spirals. Understanding that chemistry could reshape how we treat sepsis, autoimmunity, neurodegeneration, and cancer without simply shutting the immune system off.
DOI: https://doi.org/10.1016/j.jointm.2025.10.002
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