Sometimes you can solve a mystery with a fish but not a mouse.
Sometimes you can see a biochemical process happening, but you can’t study it in detail until you identify the underlying players.
Sometimes separate streams of inquiry turn out to actually be part of the same story.
All three of these were the case for a team of scientists at Memorial Sloan Kettering Cancer Center (MSK). Their new study, published October 7 in Nature , solves a decades-old scientific puzzle and reveals that a critical inflammatory signaling pathway doesn’t just summon immune cells to the place where they’re needed — it also protects healthy cells from being damaged by the immune response.
The findings open new avenues for understanding diseases where inflammation runs amok, including cancer, inflammatory bowel disease, and asthma.
The story begins in 1992, when scientists at McGill University were studying a fatty signaling molecule that summons immune cells to the site of an infection. The name of this important molecule is a bit of a mouthful: 5-oxoETE, which is short for 5-oxo-6,8,11,14-eicosatetraenoic acid.
The scientists could see that an enzyme — a biological helper that speeds up chemical reactions — was assembling 5-oxoETE and breaking it back down again. But they didn’t know which human gene carried the blueprint for making the enzyme.
Without being able to identify the gene — and therefore to manipulate it in the lab — they were limited in their ability to study the enzyme further, to investigate its role in disease, and to understand what happens when it malfunctions.
So the McGill scientists gave the enzyme a functional name based on the chemical reaction it performs. And that functional name remained in place for more than 30 years. That is, until Yanan Ma, PhD , a postdoctoral researcher in MSK’s Sloan Kettering Institute — building on initial work by former lab mate King Lam Hui, PhD — unmasked the enzyme by establishing which human gene encodes it, opening the door to additional study.
Dr. Ma is a member of the lab of cell biologist Philipp Niethammer, PhD , whose work investigates wound healing, inflammation, and regeneration — all of which are important in cancer and many other diseases. A major focus of that research has been to understand how cells detect and then respond to an injury or the presence of harmful microorganisms.
When dangerous bacteria are detected, for example, the body sounds a chemical alarm — our old friend 5-oxoETE — that summons specialized white blood cells to the site. These immune cells rush in and deploy their weaponry against the invaders, causing inflammation.
“They flood the site with toxic substances to kill the bacteria,” Dr. Niethammer says. “But this can cause damage to healthy cells if it gets out of control.”
The lab has been studying aspects of the 5-oxoETE pathway for years — following the chain of molecular interactions and mapping the body’s inflammatory response step by step, player by player. But without the identity of the critical enzyme, there was only so far the research could advance.
Where other labs had zigged, Dr. Ma and her colleagues decided to zag. Instead of pursuing the pathway in mice, they turned to a less common research model: zebrafish.
“Mice and rats are the primary model used in biomedical research,” says Dr. Ma, who received a prestigious Marie-Josée Kravis WISE Fellowship in 2023 for her work on the pathway. “It makes sense — they’re mammals, and there’s about an 80% overlap between their genes and ours.”
But in mice, there’s no known receptor on their immune cells that the alarm signal — 5-oxoETE — can bind to.
“This means that you can’t study the pathway in mice,” Dr. Ma says. “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.”
The new detective work on the enzyme actually started with human cells in a dish. Dr. Ma and Dr. Hui screened a shortlist of candidate genes, silencing them one by one to see if the enzyme’s activity stopped.
When Dr. Ma silenced a gene called DHRS7 , the enzyme went dark — meaning she had found the gene that makes the enzyme. And when she tested the rodent version of the same gene, it also showed almost no activity — which is exactly what you would expect since mice have lost the receptor needed to detect the 5-oxoETE signal that the enzyme produces.
And just like that, the mystery enzyme’s true identity was laid bare.
Moreover, the discovery dovetailed with another project in the lab led by postdoc Miklos Lengyel, MD, PhD .
“Typically, when you have a paper with two first authors like Yanan and Miklos, there is just one story that two people contributed to equally,” Dr. Niethammer says. “But this paper is not like that. In this paper, there are two separate projects led by two different authors that came together as one larger discovery. And I think that’s extremely important to note.”
Dr. Lengyel had been working with a zebrafish model of colitis, silencing different genes of interest to understand their effects.
When he knocked out a gene called hcar1-4 (the zebrafish version of the human gene OXER1 ), something unexpected happened — there was inflammation when there shouldn’t have been any. The result was surprising because hcar1-4 is the gene that encodes the receptor that detects the alarm signal 5-oxoETE. Without the receptor, the signal can’t be received and acted upon.
“So if you remove the receptor that detects the signal, you’d expect less inflammation, not more,” Dr. Lengyel says.
Yet fish lacking the Hcar1-4 protein developed spontaneous gut inflammation when no infection was present. And the cause wasn’t neutrophils — the immune cells that rush in when the alarm is sounded — because depleting them didn’t solve the problem.
The findings left the scientists scratching their heads. Somehow this system meant to sound the alarm that triggers inflammation was also involved in preventing inflammation.
This is where the two separate projects converged.
Dr. Ma had established DHRS7’s true identity as the enzyme that makes 5-oxoETE. When Dr. Lengyel silenced the DHRS7 gene in zebrafish — preventing the fish from making the enzyme — then logically the fish should have had less inflammation: No enzyme, no alarm signal.
But once again, the changes led to more inflammation.
“It made absolutely no sense,” Dr. Lengyel says. “I had to prove using several different methods before the rest of the lab was convinced.”
These paradoxical results led the team to the study’s major finding: This inflammatory signaling pathway doesn’t just summon immune cells to the place where they’re needed, it also protects healthy cells from being damaged by the immune response.
“This makes sense when you think about it,” Dr. Niethammer says. “These immune cells unleash chemical warfare against a pathogen, and organisms have evolved an elegant way of protecting healthy cells at the same time.”
Scientists saw increased inflammation when this pathway was silenced because they had removed the protection it provided.
Without the 5-oxoETE signal — or Hcar1-4 to receive it — the zebrafish’s intestinal cells lost critical protection from the low-level chemical stress caused by normal gut bacteria. Ultimately, the researchers traced this protection to a family of enzymes — called NUDIX hydrolases — that act as a cleanup crew, getting rid of damaged DNA building blocks before they can cause problems.
So even in the absence of an outside invader, the loss of the pathway caused intestinal cells to die from chemical stress, triggering the inflammation the scientists saw in their experiments.
“As it turns out, this signal isn’t just an alarm, it’s also a shield,” Dr. Niethammer says.
The findings have the potential to inform future treatments because this critical inflammation pathway is known to break down in diseases like cancer, inflammatory bowel disease (IBD), and asthma, the researchers note.
In the context of cancer in people, mutations in DHRS7 and OXER1 (the human version of hcar1-4 ) have been found in gastrointestinal and uterine tumors. And mutations leading to nonfunctional versions of OXER1 have been correlated with poorer patient outcomes in colorectal, pancreatic, and kidney cancers.
“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,” Dr. Lengyel says.
The findings are also relevant to IBD and asthma, which both involve inflammation of the body’s protective mucosal linings. In IBD, lower levels of 5-oxoETE in intestinal tissue have been linked to worse outcomes. And in an independent study of asthma in primates , blocking OXER1 reduced the immune cells’ response and also led to the disappearance of protective mucus-producing cells that line the airway.
Still, the new study, in all its biochemical complexity, captures just one side of the lab’s investigation into this critical pathway. The same inflammatory machinery is triggered when tissues suffer physical damage and injury. And it’s this physical and mechanical side of the system that doctoral student Zaza Gelashvili, MS , has been studying.
The mechanical stress from an injury affects cell membranes and can set the entire inflammatory chain in motion.
Mechanical stress on cell membranes releases a fatty molecule called arachidonic acid — which becomes the raw material from which 5-oxoETE is ultimately built.
“There’s a mechanical component to the pathway that’s upstream of what Yanan and Miklos have been studying,” explains Gelashvili, a co-author on the study who led a separate study on physical wound signals that was published in Nature Communications earlier this year; his work was also recognized with the 2026 Chairman’s Prize from the Gerstner Sloan Kettering Graduate School of Biomedical Sciences. “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.”
In other words, when something goes wrong in the body, your cells receive several types of input, and these signals are brought together in the 5-oxoETE pathway.
“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,” Dr. Niethammer says.
Additional authors of the study include Yohannes Ambaw, Leehyeon Kim, Ritchie Ly, Siyang Peng, Meysoon Quraishi, Tobias Walther, and Robert Farese Jr., all of MSK.
The research was supported by the National Institutes of Health (R35GM140883); an MSK Basic Research Innovation Award; a Starr Foundation Program for Discovery Science grant; a Tow Foundation fellowship; a Marie-Josée Kravis Women in Science Endeavor (WISE) fellowship; a Crohn’s Colitis Foundation Research Fellows Award (1268111); an Experimental Immuno-Oncology Scholars fellowship; and core facility services funding in part by MSK’s National Cancer Institute Cancer Center Support grant (P30CA008748).
The authors declare no conflicts of interest.
Read the study: “ 5-oxoETE links redox control of epithelial damage detection and resilience ,” Nature . DOI: 10.1038/s41586-026-11121-2
Nature
Experimental study
Animals
5-oxoETE links redox control of epithelial damage detection and resilience
7-Oct-2026