Scientists at Memorial Sloan Kettering Cancer Center have solved a 30-year-old biological mystery, revealing a dual role for a key inflammatory molecule that not only recruits immune cells to fight infection but also protects healthy tissue from damage. The discovery, published October 7 in Nature, was made possible in part by an unconventional model organism, the zebrafish, which provided the necessary biological tools that mice lack.
This breakthrough fundamentally alters our understanding of the immune response, reframing a long-studied signaling pathway as both an “alarm” and a “shield” against inflammatory damage. The finding has profound implications for developing new treatments for cancer, inflammatory bowel disease (IBD), and asthma by potentially strengthening the body’s natural defenses against tissue injury.
How a 30-Year-Old Mystery Finally Cracked
The story begins in 1992, when researchers at McGill University observed an enzyme that could both produce and break down a fatty signaling molecule called 5-oxoETE (5-oxo-6,8,11,14-eicosatetraenoic acid). 5-oxoETE acts as a chemical alert, attracting immune cells to sites of infection. Despite decades of effort, the genetic source of this enzyme remained elusive, creating a major roadblock for scientific investigation.
The missing piece of the puzzle was finally identified by Yanan Ma, PhD. Dr. Ma systematically identified DHRS7 as the gene responsible for producing the enzyme that generates 5-oxoETE. This established DHRS7 as the long-sought gene, resolving a mystery that had persisted for over three decades. Dr. Ma received a Marie-Josée Kravis WISE Fellowship in 2023 for her work on the pathway.
Zebrafish Offer Key to Uncovering a Hidden Function
While Dr. Ma focused on the enzyme, Miklos Lengyel, MD, PhD, another researcher in Dr. Philipp Niethammer’s laboratory, was using zebrafish to study colitis, an inflammatory bowel condition. This decision was important because, as Dr. Ma explained, mice and rats, the standard biomedical models, lack a key immune cell receptor for 5-oxoETE. “Mice and rats are the primary model used in biomedical research… but the pathway is intact in fish. So picking the right alternative model was critical,” Dr. Ma stated. This biological difference meant that the complete signaling process could not be fully studied in mice.
Dr. Lengyel’s experiments involved disabling a gene in zebrafish called hcar1-4, the zebrafish version of the human OXER1 gene, which codes for the 5-oxoETE receptor. The expectation was that removing this alarm signal would reduce inflammation. Instead, the fish developed intestinal inflammation without an infection being present. “So if you remove the receptor that detects the signal, you’d expect less inflammation, not more,” Dr. Lengyel said. “It made absolutely no sense. I had to prove using several different methods before the rest of the lab was convinced.”
Body Shields Cells from Damage
- Your body uses the same chemical signal, 5-oxoETE, to both call in the immune cavalry and to protect your healthy tissues from friendly fire during an infection.
- A 30-year-old scientific puzzle has been solved, revealing a gene (DHRS7) and a protective mechanism involving NUDIX hydrolase enzymes that shield cells from damage.
- This discovery opens the door to new treatments for diseases like inflammatory bowel disease, asthma, and complications from cancer, all of which involve uncontrolled inflammation.
The Immune System’s “Alarm and Shield” Mechanism
When the two research projects converged, the picture became clear. The team disabled the DHRS7 gene in zebrafish, which prevented the production of the 5-oxoETE-synthesizing enzyme. As expected, this disrupted the immune call-to-arms. But, as with disabling the receptor, inflammation paradoxically increased.
The team discovered that the 5-oxoETE pathway activates a protective process involving a group of enzymes known as NUDIX hydrolases. These enzymes act as cellular housekeepers, removing damaged DNA building blocks. When this protective signaling was absent, intestinal cells were left vulnerable to the chemical stress caused by the body’s own bacteria and its immune response. This vulnerability led to cell death and, ultimately, inflammation, even in the absence of a dangerous pathogen. “As it turns out, this signal isn’t just an alarm, it’s also a shield,” Dr. Niethammer summarized.
Implications for Cancer, IBD, and Asthma Treatment
Understanding this dual role is significant for a range of diseases characterized by dysregulated inflammation. Mutations affecting DHRS7 and OXER1 have been identified in certain cancers. The findings also shed light on conditions like IBD, where lower concentrations of 5-oxoETE in intestinal tissue have been associated with worse disease outcomes. In the context of cancer, this discovery could lead to strategies for protecting the gut from oxidative stress. “More research is needed, but there’s a possibility that activating the pathway could increase the resilience of the gut to oxidative stress,” Dr. Lengyel suggested. Evidence from asthma research further supports the pathway’s protective role, as a separate primate study found that blocking the OXER1 receptor weakened the immune cell response while also causing protective mucus-producing cells in the airways to die.
| Gene/Protein | Function | Associated Conditions |
|---|---|---|
| DHRS7 | Produces the enzyme that generates 5-oxoETE | Mutations identified in certain cancers |
| OXER1 | Receptor for 5-oxoETE, allowing cells to respond | Mutations identified in certain cancers; associated with IBD and asthma |
| 5-oxoETE | Signaling molecule with dual role: immune recruitment and tissue protection | Associated with cancer, IBD, and asthma |
Consult a Doctor for Symptoms
It is important to remember that this research is foundational and describes a biological mechanism. It does not constitute a specific new treatment available to patients. Therapies targeting this pathway are still in the preclinical research phase. Individuals experiencing symptoms of inflammatory conditions—such as persistent abdominal pain, blood in stool, chronic coughing, or shortness of breath—should consult their healthcare provider. These symptoms may indicate a serious underlying condition that requires established, evidence-based medical evaluation and treatment.
Two Projects Become One Discovery
The convergence of these two independent research projects highlights the power of collaborative science. As Dr. Niethammer noted, “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.” This foundational work, published in Nature, signals a significant discovery in the field.
The Marie-Josée Kravis WISE Fellowship mentioned for Dr. Ma is an example of philanthropic support.
References
- Memorial Sloan Kettering Cancer Center. “Scientists Solve a 30-Year Biological Mystery and the Discovery Could Change How We Treat Inflammation.” October 20, 2026.
- Nature. Published October 7.
