By Budi Oetomo Narendra 
A groundbreaking discovery by scientists at Memorial Sloan Kettering Cancer Center (MSK) has resolved a biological enigma that has persisted for more than three decades, revealing an unexpected dual role for a key chemical signal in the immune system. This breakthrough illuminates how the body not only marshals its defenses to fight infections but simultaneously safeguards healthy tissues from the very inflammation it triggers, offering profound implications for understanding and treating a spectrum of diseases, including cancer, inflammatory bowel disease (IBD), and asthma.
The Genesis of a 30-Year Scientific Enigma
The intricate dance of the human immune system, while essential for survival, is a double-edged sword. Its potent responses, designed to eradicate pathogens, can inadvertently inflict collateral damage on healthy host cells if left unchecked. Understanding the precise mechanisms that regulate this balance has been a paramount challenge in immunology.
The specific mystery at the heart of this discovery dates back to 1992. Researchers at McGill University were investigating a fatty signaling molecule known as 5-oxoETE (5-oxo-6,8,11,14-eicosatetraenoic acid). This molecule acts as a critical chemical beacon, efficiently recruiting immune cells—specifically neutrophils, a type of white blood cell—to sites of infection or injury. Neutrophils are the body’s first line of defense, engulfing invading microorganisms and releasing a barrage of toxic substances to neutralize threats.
During their early investigations, scientists observed an enzyme that possessed a peculiar ability: it could both synthesize 5-oxoETE and break it down. Enzymes are biological catalysts, proteins that accelerate specific chemical reactions in the body. While the enzyme’s function was clear, its genetic identity remained elusive. Despite its crucial role in modulating a potent inflammatory signal, the human gene responsible for producing this enzyme could not be identified. This missing genetic information posed a significant roadblock. Without knowing the gene, researchers were unable to manipulate the enzyme effectively in experimental settings, nor could they definitively link its dysfunction to specific disease pathologies. For over 30 years, this enzyme was referred to by its descriptive chemical function, its genetic origins shrouded in mystery.
An Unconventional Path to Discovery: The Zebrafish Advantage
The long-standing puzzle finally began to unravel through the innovative research conducted at MSK. A pivotal decision by the research team, led by cell biologist Philipp Niethammer, PhD, was to deviate from the conventional choice of laboratory animals. While mice and rats are the undisputed workhorses of biomedical research, sharing approximately 80% of their genes with humans and offering well-established experimental models, they presented a critical limitation for this specific investigation.
As Yanan Ma, PhD, a postdoctoral researcher at MSK’s Sloan Kettering Institute and a recipient of the prestigious Marie-Josée Kravis WISE Fellowship, explained, "Mice and rats are the primary model used in biomedical research… It makes sense – they’re mammals, and there’s about an 80% overlap between their genes and ours." However, this broad genetic similarity did not extend to the precise pathway under scrutiny. Crucially, mice lack a known immune cell receptor capable of recognizing 5-oxoETE. Without this receptor, the complete signaling process of 5-oxoETE could not be accurately studied in murine models.
This is where the humble zebrafish (Danio rerio) emerged as an unexpected hero. Zebrafish, small freshwater fish native to South Asia, have become increasingly valuable in biomedical research due to their genetic tractability, optical transparency, and rapid external development. More importantly for this study, zebrafish have retained the necessary biological machinery, including the specific receptor for 5-oxoETE. "This means that you can’t study the pathway in mice," Dr. Ma noted. "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." This strategic choice allowed the MSK team to observe the 5-oxoETE signaling pathway in a living organism, a critical step toward uncovering its previously hidden functions.
Unmasking DHRS7: The Missing Genetic Link
The initial breakthrough in identifying the elusive enzyme came through Dr. Ma’s meticulous work, building upon earlier investigations by former lab colleague King Lam Hui, PhD. Using cultured human cells, Ma and Hui systematically screened candidate genes that might be responsible for producing the mysterious enzyme. Their approach involved selectively disabling genes and observing the impact on the enzyme’s activity.
The decisive moment arrived when Dr. Ma disabled a gene known as DHRS7 (Dehydrogenase/Reductase SDR Family Member 7). Upon deactivating DHRS7, the enzyme’s function ceased entirely. This experiment unequivocally established DHRS7 as the long-sought gene that scientists had been searching for since the early 1990s.
Further tests corroborated the zebrafish’s utility and the mouse model’s limitations. When the rodent version of the DHRS7 gene was examined, it showed almost no enzyme activity. This finding was perfectly consistent with the known absence of the 5-oxoETE receptor in mice, strongly suggesting that rodents had lost key functions associated with this specific signaling system over evolutionary time. The identification of DHRS7 not only resolved a major scientific mystery but also provided researchers with a powerful new tool to investigate the enzyme’s precise functions and its role in health and disease.
The Unexpected Twist: When Suppressing a Signal Worsens Inflammation
The narrative of this discovery is particularly compelling because it involves two distinct but ultimately converging research projects within Dr. Niethammer’s laboratory. While Dr. Ma was painstakingly identifying DHRS7, postdoctoral researcher Miklos Lengyel, MD, PhD, was using zebrafish to study colitis, an inflammatory condition affecting the colon. His experiments involved manipulating specific genes to understand their influence on intestinal inflammation.
One particular experiment yielded an entirely counterintuitive result. Dr. Lengyel removed hcar1-4, the zebrafish equivalent of the human gene OXER1. This gene is responsible for producing the receptor that recognizes 5-oxoETE, allowing cells to respond to its chemical alert. Given that 5-oxoETE is known to attract immune cells and initiate inflammation, the logical expectation was that removing its receptor would weaken the inflammatory response.
"So if you remove the receptor that detects the signal, you’d expect less inflammation, not more," Dr. Lengyel stated. However, the zebrafish developed spontaneous intestinal inflammation, even in the absence of any infection. Initial investigations ruled out neutrophils as the primary cause, as their removal did not alleviate the inflammation. This puzzling observation strongly suggested that the 5-oxoETE pathway was involved in a far more complex regulatory role than previously understood, extending beyond mere immune cell recruitment.
The connection between Dr. Ma’s and Dr. Lengyel’s seemingly separate lines of inquiry became clear after DHRS7 was identified. Dr. Lengyel then disabled DHRS7 in zebrafish, effectively preventing the production of the enzyme and disrupting the 5-oxoETE signaling pathway. Again, contrary to expectations, inflammation increased. "It made absolutely no sense," Dr. Lengyel recalled. "I had to prove using several different methods before the rest of the lab was convinced."
These startling results forced a fundamental re-evaluation of the 5-oxoETE pathway. It was not merely an inflammatory trigger; it also appeared to play a crucial, previously unrecognized role in preventing unwarranted damage to healthy cells. The paradox was resolved: by disabling the pathway, scientists had inadvertently removed not only a signal that initiated inflammation but also a vital component of the body’s intrinsic cellular protection system.
The Immune System’s Hidden Protective Shield: An "Alarm and Shield" Mechanism
Further experiments meticulously dissected this newly discovered protective mechanism. When immune cells, such as neutrophils, launch their attack against pathogens, they release highly reactive oxygen species and other cytotoxic substances. While these compounds are essential for killing invaders, they can also induce significant "oxidative stress" on nearby healthy tissues, damaging DNA, proteins, and lipids. The MSK team discovered that the 5-oxoETE pathway helps tissues withstand this chemical assault, thereby reducing the risk of self-inflicted injury from the body’s own potent defenses.
"This makes sense when you think about it," Dr. Niethammer commented. "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 observed that zebrafish intestinal cells became particularly vulnerable to oxidative stress when either 5-oxoETE or its Hcar1-4 receptor was absent. Even the low-level chemical stress generated by the normal commensal bacteria residing in the intestine was sufficient to cause significant problems when this protective system was disabled. This vulnerability led to cell death, which, in turn, triggered an inflammatory response, even without an invading pathogen.
The team traced this cellular protection to a specific group of enzymes known as NUDIX hydrolases. These enzymes are crucial for maintaining genomic integrity and cellular health by identifying and removing damaged DNA building blocks (nucleotides) before they can interfere with normal biological processes like DNA replication and repair. In essence, the 5-oxoETE pathway, through its signaling, enhances the cell’s capacity to repair itself and withstand the chemical onslaught, allowing healthy cells to survive the inflammatory storm.
The profound implication of these findings is that the body employs the same molecular system for a dual purpose: to call immune cells into action and to protect healthy tissue from the consequences of that action. As Dr. Niethammer succinctly summarized, "As it turns out, this signal isn’t just an alarm, it’s also a shield."
Broad Implications for Chronic Inflammatory Diseases and Cancer
The identification of this protective mechanism carries significant implications for a wide array of human diseases characterized by dysregulated or excessive inflammation. The 5-oxoETE signaling pathway is known to be perturbed in various conditions, including cancer, inflammatory bowel disease (IBD), and asthma. This new understanding provides a fresh perspective on how such disruptions might contribute to tissue damage and disease progression.
In the context of cancer, mutations affecting DHRS7 and OXER1 (the human counterpart of hcar1-4) have been identified in tumors of the gastrointestinal tract and uterus. Furthermore, research has linked mutations that impair OXER1 function to poorer outcomes in patients with colorectal, pancreatic, and kidney cancers. These associations suggest that a compromised "shield" mechanism could render healthy cells more susceptible to tumorigenesis or exacerbate existing cancerous conditions by failing to protect them from chronic inflammatory stress.
The findings open a tantalizing avenue for therapeutic development. Strengthening this protective pathway might help healthy tissues better tolerate damaging conditions. For instance, in cancer treatment, radiation therapy and chemotherapy often induce severe oxidative stress, particularly in rapidly dividing cells like those lining the gut, leading to debilitating side effects such as mucositis. Dr. Lengyel postulates, "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." This could lead to strategies that mitigate treatment side effects, improving patient quality of life and potentially allowing for more aggressive, effective cancer therapies.
The discovery also holds promise for diseases affecting mucosal tissues, the critical protective linings of organs like the intestines and respiratory tract. In individuals suffering from IBD, which affects millions globally and is characterized by chronic inflammation of the digestive tract, lower concentrations of 5-oxoETE in intestinal tissue have been previously correlated with worse disease outcomes. This new research suggests that these lower concentrations might not just reflect reduced immune cell recruitment, but a weakened protective shield, exacerbating tissue damage.
Further evidence from asthma research supports this dual role. An independent study in primates found that blocking OXER1 not only weakened the immune cell response but also led to the disappearance of protective mucus-producing cells in the airways. This indicates that the 5-oxoETE pathway might be crucial for maintaining the integrity and function of mucosal barriers, a critical defense against environmental irritants and pathogens.
Collectively, these observations underscore a crucial paradigm shift: attempts to suppress inflammation must now carefully consider the dual, protective roles that certain inflammatory signals perform. While inhibiting inflammatory pathways can reduce immune cell activity, it could inadvertently remove the body’s natural cellular protection, leading to unintended consequences. Extensive further research will be necessary to determine whether targeting this pathway can lead to safe and effective treatments in humans.
Integrating Stress Signals: Mechanical Damage and Coordinated Responses
The MSK team’s investigation extends beyond infection and chemical stress, exploring how this sophisticated signaling pathway responds to physical damage. Doctoral student Zaza Gelashvili, MS, a co-author of the Nature study, is spearheading this aspect of the research, focusing on how cells detect and respond to mechanical forces associated with tissue injury.
Physical stress on cell membranes can initiate the same molecular cascade involved in inflammation. An early and critical step in this process is the release of arachidonic acid from stressed cell membranes. This fatty molecule serves as the raw material for the production of 5-oxoETE, effectively linking mechanical injury to the inflammatory and protective pathway.
Gelashvili’s contributions to understanding these mechanical signals were recognized with the 2026 Chairman’s Prize from the Gerstner Sloan Kettering Graduate School of Biomedical Sciences, and his separate investigation into molecular signals associated with physical wounds was published in Nature Communications earlier in 2026. He explains the interconnectedness: "There’s a mechanical component to the pathway that’s upstream of what Yanan and Miklos have been studying. 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 view suggests that the body intelligently combines information from various forms of cellular stress – mechanical damage, oxidative stress, and metabolic cues – to orchestrate a single, coordinated protective response. Rather than operating as isolated systems, these processes appear to work in concert, enabling the body to effectively recognize danger while simultaneously minimizing self-inflicted 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 concludes. This holistic understanding of inflammation and protection represents a significant leap forward in immunology, promising new avenues for therapeutic intervention and a deeper appreciation for the elegant complexity of the human body’s defenses.
Study Authors and Funding
The collaborative research leading to this discovery involved additional researchers from MSK: Yohannes Ambaw, Leehyeon Kim, Ritchie Ly, Siyang Peng, Meysoon Quraishi, Tobias Walther, and Robert Farese Jr.
The study received substantial financial backing from several prestigious institutions and grants, including 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).
