"This means that you can't study the pathway in mice," Ma said. "But the pathway is intact in fish. So picking the right alternative model was critical to advancing our understanding of how the human body responds."

Consistent with that, the rodent version of DHRS7 showed almost no activity — exactly what you'd expect in an animal that has lost the receptor for the signal the enzyme produces.

Why did removing the alarm cause more inflammation?

The paper is unusual in another way: it fuses two separate projects. A second first author, postdoc Mikos Lengyel, M.D., Ph.D., had been working with a zebrafish model of colitis, knocking out genes to observe the effects.

When he disabled a gene called hcar1-4 — the zebrafish version of the human gene OXER1, which encodes the receptor that detects 5-oxoETE — something strange happened. The fish developed spontaneous gut inflammation with no infection present.

"So if you remove the receptor that detects the signal, you'd expect less inflammation, not more," Lengyel said.

It wasn't the neutrophils, the immune cells that normally rush in when the alarm sounds; depleting them didn't fix the problem. And when Lengyel silenced DHRS7 itself — no enzyme, no alarm signal — inflammation again increased.

"It made absolutely no sense," Lengyel said. "I had to prove it using several different methods before the rest of the lab was convinced."

What is the pathway's second job?

These paradoxical results led to the study's central finding: the pathway plays a protective role alongside its alarm function. Without the 5-oxoETE signal, or the Hcar1-4 receptor to receive it, the zebrafish's intestinal cells lost protection against low-level chemical stress caused by normal gut bacteria. The cells died, and that death triggered the inflammation the researchers observed.

The team traced this protection to a family of enzymes called NUDIX hydrolases, which work like a cleanup crew, removing damaged DNA building blocks before they cause harm.

"These immune cells unleash chemical warfare against a pathogen, and organisms have evolved an elegant way of protecting healthy cells at the same time," said lab leader Philipp Niethammer, Ph.D., who studies wound healing, inflammation and regeneration.

"As it turns out, this signal isn't just an alarm; it's also a shield," Niethammer said.

Could this lead to new treatments?

The researchers are cautious. The findings are preliminary and come largely from zebrafish, but the pathway is known to break down in several human diseases, and several hints connect it to patient outcomes:

• Mutations in DHRS7 and OXER1 appear in gastrointestinal and uterine tumors.
• Nonfunctional versions of OXER1 correlate with poorer outcomes in colorectal, pancreatic and kidney cancers.
• In IBD, lower levels of 5-oxoETE in intestinal tissue link to worse outcomes.
• In an independent primate study of asthma, blocking OXER1 dampened immune-cell responses but also wiped out protective mucus-producing cells lining the airway.

"More research is needed, but there's a possibility that activating the pathway could increase the resilience of the gut to oxidative stress — which might help counteract damage caused by radiation therapy or chemotherapy," Lengyel said.

What comes next?

The Nature paper captures only one side of the lab's work. Doctoral student Zaza Gelashvili, M.S., a co-author, studies the mechanical side: physical injury stresses cell membranes, releasing a fatty molecule called arachidonic acid — the raw material from which 5-oxoETE is built. His separate study on physical wound signals appeared in Nature Communications earlier this year.

"You can think of it as the first step in a chain reaction: Physical stress unlocks the raw material, oxidative stress drives the conversion, and DHRS7 amplifies the signal," Gelashvili said.

"What we are really studying is a pathway that integrates two completely different kinds of stress — mechanical and metabolic — and converts them into a single, coordinated, protective response," Niethammer said.

Publication details: Yanan Ma et al., "5-oxoETE links redox control of epithelial damage detection and resilience," Nature (2026). DOI: 10.1038/s41586-026-11121-2