By Budi Oetomo Narendra 
Scientists at Memorial Sloan Kettering Cancer Center (MSK) have brought to a close a biological mystery that has puzzled researchers for more than three decades, revealing an unexpected and vital mechanism by which the immune system safeguards the body from the very inflammatory responses designed to protect it. This groundbreaking discovery illuminates that a chemical signal, previously known for its role in recruiting immune cells to combat infections, simultaneously functions as a critical defense, preventing those same potent immune defenses from inflicting damage on healthy tissues. Published in the esteemed journal Nature on October 7, these findings not only rewrite our understanding of immune regulation but also open promising new avenues for the development of treatments for a spectrum of diseases, including cancer, inflammatory bowel disease (IBD), and asthma, by potentially strengthening the body’s intrinsic defenses against inflammatory harm.
The Genesis of an Enduring Scientific Enigma: A 1992 Beginning
The scientific journey to this revelation began in 1992, when researchers at McGill University first investigated a crucial molecule involved in directing immune cells to sites of infection. This fatty signaling molecule, known as 5-oxoETE (or 5-oxo-6,8,11,14-eicosatetraenoic acid), acts as an urgent chemical alert, signaling the body’s need to mobilize its defenses against a perceived threat. During their investigations, scientists observed an enzyme capable of both producing and breaking down 5-oxoETE. Enzymes, as biological catalysts, facilitate chemical reactions, but in this particular instance, the scientific community was unable to identify the human gene responsible for its creation.
This missing genetic information presented a significant and persistent obstacle. Without knowing the specific gene that produced this enzyme, researchers were severely hampered in their ability to manipulate it experimentally or to ascertain how dysfunctions in its activity might contribute to disease pathologies. For over 30 years, despite assigning the enzyme a descriptive name based on its observed chemical function, its genetic identity remained an elusive piece of the immunological puzzle. This void in understanding underscored a fundamental gap in comprehending how the immune system managed its delicate balance of attack and protection.
The Breakthrough at MSK: Unmasking the Missing Link
The long-awaited breakthrough finally materialized through the dedicated work of Yanan Ma, PhD, a postdoctoral researcher at MSK’s Sloan Kettering Institute. Building upon earlier foundational investigations conducted by her former lab colleague, King Lam Hui, PhD, Dr. Ma successfully identified the human gene responsible for producing the mysterious enzyme. This pivotal identification, the gene DHRS7, provided researchers with the essential tool needed to delve much deeper into its function and significance within the immune system. The resolution of this three-decade-old mystery was a testament to persistent scientific inquiry and innovative research methodologies.
Dr. Ma’s work is conducted in the laboratory of cell biologist Philipp Niethammer, PhD, whose research program is dedicated to understanding how cells respond to various forms of stress, including injuries and infections. Dr. Niethammer’s team specifically focuses on the intricate processes of inflammation, tissue repair, and regeneration – biological phenomena that are critically implicated in the progression of cancer and numerous other diseases. Their long-standing interest in the molecular reactions governing 5-oxoETE signaling had already yielded significant insights into the system’s components, but the unidentified enzyme remained the crucial missing link that prevented a complete understanding of the pathway.
Beyond Conventional Models: The Zebrafish Advantage
A key factor in this discovery was an unusual departure from standard biomedical research practices. While most animal-based biomedical experiments traditionally utilize mice or rats due to their extensive biological similarities with humans, these familiar laboratory models presented a critical limitation for the specific question Dr. Ma and her colleagues sought to answer.
"Mice and rats are the primary model used in biomedical research," noted Dr. Ma, who was honored with a prestigious Marie-Josée Kravis WISE Fellowship in 2023 for her contributions to this pathway. "It makes sense – they’re mammals, and there’s about an 80% overlap between their genes and ours." However, despite these broad genetic commonalities, mice lack a known immune cell receptor capable of recognizing 5-oxoETE. This crucial absence meant that researchers could not fully investigate the complete signaling process in mice, rendering them unsuitable for this particular line of inquiry.
In contrast, zebrafish, a small freshwater fish widely used in developmental biology, have remarkably retained the necessary biological machinery, including the 5-oxoETE receptor. "This means that you can’t study the pathway in mice," Dr. Ma explained. "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 strategic decision to utilize zebrafish allowed the scientists to observe and explore how this intricate signaling pathway operates within a living organism, ultimately helping to uncover a vital function that had remained hidden for decades.
Identifying DHRS7: A Decisive Experimental Turn
Before transitioning to investigations in zebrafish, Dr. Ma and Dr. Hui initiated their search for the enzyme’s genetic origins using cultured human cells. They systematically selected several candidate genes that might be responsible for the enzyme’s production and then individually switched them off, carefully observing for any resultant changes in the enzyme’s activity. One particular candidate gene yielded a decisive and unambiguous result.
When Dr. Ma disabled a gene designated DHRS7, the enzyme’s function ceased entirely. This experiment definitively established DHRS7 as the gene that researchers had been diligently searching for since the early 1990s. Further confirmatory tests involving the rodent version of the gene showed almost no enzyme activity, a finding perfectly consistent with the known absence of the 5-oxoETE receptor in mice. This result strongly suggested that rodents had, over evolutionary time, lost key functions associated with this specific signaling system, further validating the choice of zebrafish as the appropriate model.
The identification of DHRS7 not only resolved the long-standing mystery but also serendipitously connected Dr. Ma’s research with a separate, yet complementary, investigation underway in the same laboratory. This parallel project was led by postdoctoral researcher Miklos Lengyel, MD, PhD. Dr. Niethammer underscored the unique synergy of this collaborative effort: "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. 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."
The Unexpected Turn: Disabling a Signal Worsens Inflammation
While Dr. Ma was meticulously investigating the mysterious enzyme, Dr. Lengyel was independently utilizing zebrafish to study colitis, an inflammatory condition affecting the colon. His experiments involved selectively disabling specific genes to understand their influence on intestinal inflammation. One particular experiment produced an outcome that was especially puzzling and counter-intuitive.
Dr. Lengyel removed a gene called hcar1-4 (the zebrafish homolog of the human gene OXER1). This gene is responsible for producing the receptor that recognizes 5-oxoETE, thereby allowing cells to respond to its signal. Given that 5-oxoETE is known to attract immune cells and initiate inflammation, the prevailing scientific expectation was that removing its receptor would theoretically weaken this inflammatory response.
"So if you remove the receptor that detects the signal, you’d expect less inflammation, not more," Dr. Lengyel explained. Instead, to the astonishment of the researchers, the zebrafish developed spontaneous intestinal inflammation, even in the complete absence of any infection. The team initially considered whether neutrophils, the white blood cells typically recruited by the 5-oxoETE signal, might be responsible. However, removing these immune cells did not alleviate the inflammation. This unexpected behavior strongly suggested that the 5-oxoETE pathway was performing a much more complex role than simply activating the immune system.
The Immune System’s Hidden Protective Shield: An "Alarm and a Shield"
The profound connection between the two research projects became strikingly clear after Dr. Ma successfully identified DHRS7 as the gene responsible for producing the enzyme involved in 5-oxoETE signaling. Dr. Lengyel then disabled DHRS7 in zebrafish, effectively preventing the enzyme’s production and disrupting the critical signaling process.
Based on the molecule’s established role in attracting immune cells, the researchers once again anticipated a decrease in inflammation. Instead, they observed the same surprising and paradoxical pattern seen when the receptor was removed: inflammation significantly increased. "It made absolutely no sense," Dr. Lengyel recounted, emphasizing the unexpected nature of the result. "I had to prove using several different methods before the rest of the lab was convinced."
These compelling findings pointed unequivocally to a previously unrecognized function. The 5-oxoETE signaling pathway did not merely help to initiate the immune response; it also appeared to actively prevent unnecessary damage to healthy cells. This newly discovered dual responsibility provided a comprehensive explanation for why eliminating the pathway had such an unexpected and detrimental effect. By disabling the system, scientists had inadvertently removed not only a signal that triggers inflammation but also a vital source of cellular protection.
Further meticulous experiments elucidated precisely how this protective mechanism operates. When immune cells launch an attack against dangerous microorganisms, they release highly reactive and often toxic substances designed to destroy pathogens. However, these powerful agents can inadvertently harm nearby healthy cells. The 5-oxoETE pathway, the researchers discovered, helps tissues withstand this intense chemical stress, significantly reducing the risk that the body’s own zealous defenses will cause collateral damage.
"This makes sense when you think about it," Dr. Niethammer reflected. "These immune cells unleash chemical warfare against a pathogen, and organisms have evolved an elegant way of protecting healthy cells at the same time." The researchers found that zebrafish intestinal cells became particularly vulnerable when either 5-oxoETE or its Hcar1-4 receptor was absent. Even the normal, commensal bacteria living in the intestine produced enough low-level chemical stress to trigger severe problems when this crucial protective system was disabled.
The team ultimately traced this cellular protection to a specific group of enzymes known as NUDIX hydrolases. These enzymes play a critical role in maintaining cellular health by diligently removing damaged DNA building blocks before they can interfere with normal biological processes and cellular integrity. Without the protective 5-oxoETE signaling pathway, intestinal cells could no longer adequately withstand the chemical stress associated with ordinary gut bacteria. Consequently, some cells died, initiating an inflammatory response despite the complete absence of an invading pathogen. The results unequivocally revealed that the body employs the same molecular system both to summon immune cells into action and to simultaneously shield healthy tissue from the potentially destructive consequences of that action. "As it turns out, this signal isn’t just an alarm, it’s also a shield," Dr. Niethammer concluded, encapsulating the profound nature of their discovery.
Profound Implications for Cancer and Inflammatory Diseases
Understanding this newly identified protective mechanism holds profound implications for a wide array of diseases characterized by excessive or poorly controlled inflammation, conditions that collectively affect millions globally and represent a significant public health burden. The 5-oxoETE signaling pathway is already known to be disrupted in prevalent conditions such as various cancers, inflammatory bowel disease (IBD), and asthma. By identifying its previously unknown protective role, researchers have gained a fresh and critical perspective on how these disruptions might directly contribute to tissue damage and disease progression.
In human cancers, mutations affecting DHRS7 and OXER1 (the human version of hcar1-4) have been identified in tumors of the gastrointestinal tract and uterus. Research has also established a concerning link between mutations that impair OXER1 function and poorer clinical outcomes in patients suffering from colorectal, pancreatic, and kidney cancers. These observations suggest that a compromised 5-oxoETE pathway might leave healthy cells more vulnerable to carcinogenic processes or the harsh environment within tumors.
The findings compellingly suggest that strengthening this pathway might eventually help healthy tissues tolerate damaging conditions more effectively. One promising potential application involves protecting the intestine from the severe oxidative stress frequently associated with cancer treatments, such as radiation therapy or chemotherapy. "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 posited, highlighting a tangible future therapeutic direction.
The discovery also has significant implications for diseases affecting mucosal tissues, the crucial protective linings found in areas such as the intestines and respiratory tract. In people with IBD, a chronic inflammatory condition affecting an estimated 1.6 million Americans and millions more worldwide, researchers have previously associated lower concentrations of 5-oxoETE in intestinal tissue with worse disease outcomes. This new understanding provides a mechanistic explanation for that correlation, suggesting that a weakened protective shield contributes to the ongoing tissue damage characteristic of IBD.
Evidence from asthma research points to another possible protective function. Asthma, affecting approximately 300 million people globally, is characterized by airway inflammation. An independent study involving primates found that blocking OXER1 not only weakened the immune cell response but also caused protective mucus-producing cells in the airways to disappear. This intricate interplay underscores the delicate balance required in immune regulation. Together, these observations underscore a critical consideration: attempts to suppress inflammation must carefully account for the integral protective roles certain inflammatory signals perform. However, further rigorous research will be indispensable to determine whether therapeutically targeting this pathway can produce safe and effective treatments in human patients, avoiding unintended consequences.
Integrating Stress Responses: The Role of Physical Injury
The researchers are also actively investigating how this multifaceted signaling pathway responds not just to infection or chemical stress, but also to physical damage. This crucial aspect of the work is being explored by doctoral student Zaza Gelashvili, MS, who studies how cells detect the mechanical forces inherently associated with tissue injury.
When cells experience physical stress, changes to their membranes can initiate the same complex chain of molecular reactions involved in inflammation. An early and critical step in this process occurs when stressed cell membranes release arachidonic acid, a fatty molecule that serves as the fundamental starting material for producing 5-oxoETE.
Gelashvili, a co-author of the Nature study, led a separate investigation into the molecular signals associated with physical wounds, research that was published in Nature Communications earlier in 2026. His significant contributions were also recognized with the 2026 Chairman’s Prize from the Gerstner Sloan Kettering Graduate School of Biomedical Sciences. "There’s a mechanical component to the pathway that’s upstream of what Yanan and Miklos have been studying," Gelashvili explained. "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."
This integrated research suggests that the body combines information about different forms of cellular stress – mechanical and metabolic – to coordinate its response effectively. Physical damage can initiate the process, chemical (oxidative) stress can influence the conversion of signaling molecules, and DHRS7 helps strengthen the resulting protective signal. Rather than operating as isolated responses, these intricate processes appear to work synergistically to help the body recognize danger while simultaneously limiting unnecessary harm to healthy cells. "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 summarized, highlighting the elegance and efficiency of biological systems.
Study Authors and Funding Acknowledgements
This groundbreaking study represents a collaborative effort involving numerous dedicated researchers. Additional contributors to the Nature study from MSK included Yohannes Ambaw, Leehyeon Kim, Ritchie Ly, Siyang Peng, Meysoon Quraishi, Tobias Walther, and Robert Farese Jr. Their collective expertise and commitment were instrumental in bringing this complex research to fruition.
The vital financial support that underpinned this extensive research came from a consortium of prestigious institutions and foundations. Key funding sources included 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 supported in part by MSK’s National Cancer Institute Cancer Center Support grant (P30CA008748). This diverse funding landscape underscores the broad scientific interest and potential impact of the research on human health.
