When you get an infection or injure yourself, your immune system springs into action, causing inflammation to help you heal. That process is vital but it needs to know when to stop. When it doesn’t, the result can be chronic conditions like cardiovascular disease, arthritis, and Crohn’s disease. Now, scientists have discovered a molecular switch that helps control that response, opening up a potential new path to treatment, according to a study published in Nature Metabolism.
A Protein With a Secret
At the centre of the discovery is a protein called iNOS, which is short for inducible nitric oxide synthase. For years, scientists knew iNOS as the protein that produces nitric oxide during inflammation. Nitric oxide is a chemical signal that helps drive the immune response. That was thought to be its main job.
But the new research, conducted by researchers from the University of Surrey and the University of Oxford, UK, reveals iNOS has been keeping a second job hidden. It can physically latch onto another protein, called IRG1, inside the cell’s mitochondria. And when iNOS grabs hold of IRG1, it stops IRG1 from doing its own important work.
A Natural Brake on Inflammation
IRG1’s job is to produce a molecule called itaconate, which acts as a natural brake on the inflammatory response, essentially helping to calm things down once the immune system has done its work. When iNOS grabs IRG1 and holds it in place, that brake doesn’t get applied. Inflammation is left to run harder and longer than it should.
The researchers confirmed this dramatically: in cells without iNOS, IRG1 produced more than 15 times the normal amount of itaconate after immune stimulation. That’s a huge difference, and it shows just how powerfully iNOS can suppress IRG1’s calming role.
Shape Matters More Than Chemistry
One of the most surprising findings was how iNOS controls IRG1. It was believed to be through the nitric oxide it produces, but the study shows that’s not what’s happening here.
What matters is the physical shape of the iNOS protein. That shape is maintained by a helper molecule called BH4 (tetrahydrobiopterin). When BH4 is present, iNOS holds its correct form and can bind to IRG1. When BH4 is disrupted, the whole interaction falls apart and IRG1 is free again to do its job. Importantly, even versions of iNOS that couldn’t produce nitric oxide at all still blocked IRG1, as long as they had the right shape.
A More Precise Target for New Drugs
This distinction matters enormously for medicine. Most existing approaches for controlling inflammation work by blocking what iNOS produces. This new finding suggests it might be possible to target what iNOS physically does instead.
Dr. Mark Crabtree of the University of Surrey explained why that’s significant: “The reason this matters beyond the biology is that it points to a different way of intervening. Most approaches to controlling inflammation target what iNOS produces. This opens the possibility of targeting what iNOS physically does inside the cell – how it interacts with other proteins. That’s a more precise handle, and precision is what we need when the immune system is the thing causing harm.”
Rather than broadly suppressing the immune system, which comes with serious side effects, a drug could be designed to break up just the iNOS-IRG1 interaction, allowing the body’s own natural braking mechanisms to do their job.
Dr. Crabtree added: “The physical interface between iNOS and IRG1 is a potential drug target – and a precise one. Rather than dampening the immune response across the board, you could design something that disrupts just this interaction, freeing up the natural mechanisms that keep inflammation in check. That’s the direction we want to move in, and this work gives us a rational basis for doing it.”
What Comes Next
The researchers used a range of advanced techniques to confirm their findings, including tests in both mouse and human models, suggesting the interaction is preserved across species and likely has deep biological significance.
For the millions of people living with inflammatory conditions, this discovery represents a genuine reason for hope. It’s not a treatment yet, but a clear, scientifically grounded target to aim for.
Diotallevi, M., Outeiral, C., Patel, P. et al. iNOS modulates inflammatory responses in an NO-independent manner through direct interaction with IRG1 in mitochondria. Nat Metab8, 855–868 (2026). https://doi.org/10.1038/s42255-026-01492-1