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A human study reveals how naturally occurring fat-derived molecules help switch off inflammation.
Researchers at University College London (UCL) have identified an important biological process that helps the body bring inflammation to an end, a finding that may eventually support new treatments for chronic illnesses that affect millions of people worldwide.
Inflammation is the body’s frontline defense against infection and injury. But if this response fails to shut down at the right time, it can contribute to serious conditions, including arthritis, heart disease, and diabetes. Scientists have long known that the immune system must shift from fighting to repairing, yet the signals that guide this transition have not been fully understood.
In a study published in Nature Communications, the team reports that small fat-derived molecules called epoxy-oxylipins can act as natural brakes on immune activity. The researchers found that these molecules help prevent the buildup of a specific immune cell type, intermediate monocytes, which can promote long-lasting inflammation – linked to tissue damage, illness, and disease progression.
Studying Inflammation in Humans
To examine this process in people, the researchers triggered a controlled, temporary inflammatory response in healthy volunteers. Participants received a small injection of UV-killed E. coli bacteria into the forearm, producing a short-lived reaction marked by pain, redness, heat, and swelling – similar to what can occur after infection or injury.
Volunteers were assigned to one of two groups: prophylactic arm and therapeutic arm.
At set time points, participants were given a drug called GSK2256294. The drug blocks an enzyme known as soluble epoxide hydrolase (sEH), which normally breaks down epoxy-oxylipins.
- Prophylactic arm: Participants received the drug two hours before inflammation began to test whether raising epoxy-oxylipins early could limit harmful immune changes. In this group, there were 24 volunteers – 12 were treated, 12 untreated (placebo).
- Therapeutic arm: Participants received the drug four hours after inflammation started, reflecting treatment after symptoms appear. In this group there were 24 volunteers – 12 were treated, 12 untreated (placebo).
In both groups, blocking sEH with GSK2256294 increased epoxy-oxylipin levels, helped pain resolve more quickly, and markedly lowered intermediate monocytes in blood and tissue – the immune cells linked to chronic inflammation and disease. The drug did not significantly change outward signs such as redness and swelling.
Pinpointing the Molecular Mechanism
Further tests revealed that one epoxy-oxylipin, 12,13-EpOME, works by shutting down a protein signal called p38 MAPK, which drives monocyte transformation. This was confirmed in lab experiments and in volunteers given a p38-blocking drug.
First author Dr Olivia Bracken (UCL Department of Aging, Rheumatology and Regenerative Medicine) said: “Our findings reveal a natural pathway that limits harmful immune cell expansion and helps calm inflammation more quickly.
“Targeting this mechanism could lead to safer treatments that restore immune balance without suppressing overall immunity.
“With chronic inflammation ranked as a major global health threat, this discovery opens a promising avenue for new therapies.”
Corresponding author Professor Derek Gilroy (UCL Division of Medicine) said: “This is the first study to map epoxy-oxylipin activity in humans during inflammation.
“By boosting these protective fat molecules, we could design safer treatments for diseases driven by chronic inflammation.”
He added: “This was an entirely human-based study with direct relevance to autoimmune diseases, as we used a drug already suitable for human use – one that could be repurposed to treat flares in chronic inflammatory conditions, an area currently bereft of effective therapies.”
Why epoxy-oxylipins?
Scientists chose to study epoxy-oxylipins because these fat-derived molecules were known from animal research to reduce inflammation and pain, but their role in humans remained unknown.
Unlike well-studied inflammatory mediators, such as histamine and cytokines, epoxy-oxylipins are part of an underexplored pathway that scientists believed could naturally calm the immune system.
Next steps
The discovery opens the door to clinical trials exploring sEH inhibitors as potential therapies for conditions like rheumatoid arthritis and cardiovascular disease.
Dr Bracken said: “For instance, rheumatoid arthritis is a condition in which the immune system attacks the cells that line your joints. sEH inhibitors could be trialled alongside existing medications to investigate if they can help prevent or slow down joint damage incurred by the condition.”
Dr Caroline Aylott, Head of Research Delivery at Arthritis UK, said: “The pain of arthritis can affect how we move, think, sleep, and feel, along with our ability to spend time with loved ones. Pain is incredibly complex and is affected by many different factors. We also know that everybody’s pain is different.
“That is why it is important that we invest in research like this, which helps us understand what causes and influences people’s experience of pain.
“We are excited to see the results of this study, which has found a natural process that could stop inflammation and pain. We hope in the future that this will lead to new pain management options for people with arthritis.”
Reference: “Epoxy-oxylipins direct monocyte fate in inflammatory resolution in humans” by Olivia V. Bracken, Parinaaz Jalali, James R. W. Glanville, Larrissa Benvenutti, Emma S. Chambers, Hugh Trahair, Madhur Motwani, Karen T. Feehan, Jamie G. Evans, Jhonatan de Souza Carvalho, Roel P. H. De Maeyer, Arne N. Akbar, Fred B. Lih, Darryl C. Zeldin, David Bishop-Bailey, Matthew L. Edin and Derek W. Gilroy, 16 January 2026, Nature Communications.
DOI: 10.1038/s41467-025-67961-5
The study was funded by Arthritis UK and involved researchers at UCL, King’s College London, University of Oxford, Queen Mary University of London, and National Institute of Environmental Health Sciences, USA.
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