Scientists finally found the gene behind an immune signal that has puzzled researchers since 1992

Memorial Sloan Kettering Cancer Center researchers have identified DHRS7 as the gene behind an enzyme that scientists first characterized in 1992 without ever finding its gene. The enzyme makes and breaks down 5-oxoETE, a fatty signaling molecule that draws immune cells toward infection and injury. The work, led by cell biologist Philipp Niethammer, appeared in Nature on Oct. 7, 2026.

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For more than 30 years the enzyme carried only a name based on its chemistry.

Scientists at McGill University studied 5-oxoETE in 1992 and observed an enzyme that both builds it and breaks it down, but they could not name the human gene responsible. Memorial Sloan Kettering’s own account and a ScienceDaily repost describe how postdoctoral researcher Yanan Ma closed that gap, building on earlier work by King Lam Hui. The finding is published in Nature (DOI 10.1038/s41586-026-11121-2) as “5-oxoETE links redox control of epithelial damage detection and resilience”.

Why the gene stayed hidden so long is a story of method. The McGill researchers described the enzyme by its chemical reaction and gave it a functional name that stuck for more than three decades, while the matching gene went unidentified. Ma’s gene-by-gene silencing finally pinned it down, and the zebrafish work showed what it does in a living animal. Related coverage by Drug Target Review frames the result as a 30-year mystery in inflammation biology.

Silencing candidate genes until DHRS7 stood out

Ma’s team silenced candidate genes one at a time and watched whether the enzyme kept working. When DHRS7 was disabled, the activity stopped. In the paper, DHRS7 is described as an orphan short-chain dehydrogenase-reductase that converts 5(S)-HETE to 5-oxoETE and back, using NADP+ and NADPH as cofactors, and it is the long-sought 5-HEDH enzyme.

The authors also checked its relatives. DHRS7B, DHRS9 and RDH11 showed no significant 5-HEDH activity, which suggests the job belongs to DHRS7 alone. Memorial Sloan Kettering adds that DHRS7 mutations have been found in gastrointestinal and uterine tumors, a link the researchers present as context and not as a proven cause.

Zebrafish stand in for mice

Mice were the wrong animal for the question. They have no known receptor on immune cells that 5-oxoETE can bind, so the pathway cannot be studied in them. Zebrafish are tiny, transparent and quick to grow, and they keep the pathway intact. Their receptor, hcar1-4, is the counterpart of the human receptor OXER1.

The enzyme’s activity is conserved from zebrafish to human cells, according to the Nature abstract. That conservation is what lets findings in a fish tank carry over as a working model for human biology, though it falls well short of showing human benefit.

An alarm that doubles as a shield

Which way DHRS7 works depends on the cell’s NADP+ to NADPH balance. Under normal conditions, when NADPH is high, it mostly consumes 5-oxoETE and keeps inflammation in check. At wounds, where oxidative stress raises NADP+, it produces 5-oxoETE and alerts immune cells. Zebrafish mutants lacking the gene had higher baseline 5-oxoETE and weaker recruitment of neutrophils and macrophages to wounds.

The group has published a companion result as well. Gelashvili’s study of physical wound signals appeared in Nature Communications, and the two papers together sketch how a torn or stretched membrane starts a chemical chain that ends in immune recruitment. Both lines of work came out of the Niethammer laboratory, which studies wound healing, inflammation and regeneration.

Immune cells that rush to an infection release toxic substances to kill bacteria, Niethammer says, and those substances can harm healthy tissue as well. A molecule that both summons the cells and primes nearby epithelium to withstand the damage would be a neat piece of biological design, and the new data suggest 5-oxoETE does exactly that.

The surprise came in the gut. Removing either the receptor or DHRS7 produced intestinal inflammation even without infection, the opposite of what the team expected. Postdoctoral researcher Miklos Lengyel, who ran the colitis experiments, called the result something that made absolutely no sense at first. Niethammer summarized the resolution: this signal isn’t just an alarm, it’s also a shield.

The shield works by protecting intestinal cells from chemical stress, including stress from ordinary gut bacteria, and it involves NUDIX hydrolase enzymes that clear damaged DNA building blocks. Doctoral student Zaza Gelashvili studied the first step, in which physical stress on cell membranes releases arachidonic acid, the raw material for 5-oxoETE.

The practical reach is still distant. DHRS7 is now a named target with a known biochemistry, so chemists can ask whether its activity can be nudged up or down, and clinicians can ask whether tumors with DHRS7 mutations behave differently. Neither question has an answer in the reports.

The authors suggest the pathway could inform ways to protect the gut during chemotherapy or radiation and shed light on inflammatory bowel disease and asthma. They stress that much more research is needed before any human treatment exists, and no clinical trial is described in the reports.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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