Scientists have uncovered a biological mechanism that helps the body end inflammation, a discovery that could lead to new treatments for chronic inflammatory diseases that affect millions of people. Inflammation is a critical part of the immune system’s response to injury or infection, helping to fight pathogens and repair damaged tissue. However, if inflammation persists too long, it can harm healthy tissues and contribute to conditions such as arthritis, heart disease, and diabetes. While scientists have long understood how inflammation begins, the process by which the body determines when to shift from fighting a threat to repairing damage has remained unclear. The new study, published in Nature Communications, identifies a group of small fat-derived molecules called epoxy-oxylipins as part of the body’s natural process to shut down inflammation. These molecules act like a "brake" on the immune system, helping to prevent excessive growth of intermediate monocytes—white blood cells that support healing in the short term but can contribute to chronic inflammation if they remain active for too long. To study this process in humans, researchers gave healthy volunteers a small injection of UV-killed E. coli bacteria on their forearm. The bacteria could not cause infection but triggered a temporary inflammatory response, producing symptoms like pain, redness, and swelling similar to those after an injury. The volunteers were divided into two groups: one received a drug called GSK2256294 before the inflammation started (prophylactic arm), and the other received it after symptoms appeared (therapeutic arm). The drug blocks an enzyme called soluble epoxide hydrolase (sEH), which normally breaks down epoxy-oxylipins. By inhibiting sEH, the drug allows more of these protective molecules to remain in the body. Both approaches led to similar results: increased epoxy-oxylipin levels, faster resolution of pain, and a sharp decrease in intermediate monocytes in the blood and tissue. Although the treatment did not significantly reduce visible symptoms like redness or swelling, it appears to have affected deeper immune processes. Researchers also explored how the mechanism works at the molecular level. They found that one epoxy-oxylipin, called 12,13-EpOME, suppresses a protein signaling pathway known as p38 MAPK, which helps transform monocytes into a form linked to prolonged inflammation. This discovery was confirmed through lab experiments and in volunteers given a drug that directly blocks p38. Scientists believe targeting this pathway could lead to safer treatments that restore immune balance without broadly suppressing the immune system. As chronic inflammation is a major global health concern, this finding offers a promising new direction for developing therapies.