A molecule initially extracted from decayed fungus in 1836 has been found to determine whether your immune system aids in your survival or leads to your demise. Itaconate, previously regarded as metabolic residue, physically binds to proteins within immune cells and alters their configuration. At times, this halts inflammation abruptly. At others, it intensifies it.
This paradox has perplexed scientists for many years, but a review in the *Journal of Intensive Medicine* now provides clarification: it relies on the source of the itaconate and the specific proteins it interacts with. Yingyi Yang’s team at UT Southwestern Medical Center compiled over a decade of research demonstrating that this minor metabolite operates less as a byproduct and more like a molecular dimmer switch.
## Location is crucial
Synthetic derivatives of itaconate, the variants that chemists produce in laboratories, nearly always inhibit inflammation. When 4-octyl itaconate binds to a protein termed KEAP1, it initiates a series of antioxidant responses that shield cells from oxidative harm. These same compounds obstruct inflammatory pathways such as STING and JAK-STAT, which typically support antiviral responses and cytokine storms. In sepsis models, these derivatives prevent cell death, minimize clotting, and curtail organ failure. Additionally, they protect the gut lining in inflammatory bowel disease by halting gasdermin proteins from creating openings in epithelial cells.
However, the body’s endogenous itaconate behaves differently.
When immune cells generate itaconate naturally within mitochondria via an enzyme known as ACOD1, it can enhance interferon signaling during viral infections. This process involves the release of mitochondrial RNA and reactive oxygen species, both of which boost antiviral defenses. The review also outlines a second type of modification focusing on lysine residues, which is reversible and allows immune cells to dynamically adjust their metabolism.
> “Itaconate biology signifies a paradigm shift: redefining metabolic intermediates not as mere byproducts, but as active regulators of immune cell outcomes,” Yang states.
## A two-sided molecule
Itaconate’s impacts resonate throughout various disease models. In brains impacted by Alzheimer’s and Parkinson’s, synthetic derivatives soothed hyperactive microglia and decreased oxidative stress, improving neuronal survival. Autoimmune disorders such as lupus and rheumatoid arthritis benefited from the metabolic reprogramming induced by itaconate, which reduced harmful immune activity in both immune and stromal cells.
Cancer adds complexity to the scenario. Within tumors, itaconate inhibits antigen presentation by immune cells while simultaneously depriving cancer cells of metabolic resources. This dual function implies that timing will be critical if itaconate-based treatments make it to clinical use. Administering it too soon may impair the immune response. Delaying too long may allow the tumor to adapt.
Yang’s team contends that metabolic intermediates serve not merely as fuel or waste. They act as signals that dictate when inflammation resolves and when it escalates. Grasping this chemistry could transform our approach to treating sepsis, autoimmunity, neurodegeneration, and cancer without merely disabling the immune system.
DOI: [https://doi.org/10.1016/j.jointm.2025.10.002](https://doi.org/10.1016/j.jointm.2025.10.002)
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