Decades-Old Biological Mystery Solved: Researchers Discover Immune System’s Dual Role as Both Alarm and Shield
Scientists at the Memorial Sloan Kettering Cancer Center (MSK) have unraveled a biological mystery that eluded the global scientific community for more than thirty years. Their breakthrough illuminates an unexpected mechanism by which the human immune system safeguards healthy tissue from collateral damage during inflammatory responses. Published in the October 7 issue of the prestigious journal Nature, the findings demonstrate that a well-known chemical signal responsible for recruiting immune cells to sites of infection simultaneously acts as a protective shield for vulnerable, healthy cells.
This monumental discovery challenges long-held medical assumptions regarding how the body manages inflammation. By utilizing an unconventional animal model—the zebrafish—researchers successfully identified a long-sought human gene and its corresponding enzyme, a critical missing puzzle piece that bridges mechanical and metabolic stress responses. The implications of this research extend far beyond basic immunology, potentially paving the way for novel therapeutics targeting inflammatory bowel disease (IBD), asthma, and various forms of cancer.
Chronology of a Decades-Long Scientific Mystery
The roots of this discovery stretch back to 1992, when biochemists and immunologists at McGill University began investigating a specific fatty signaling molecule known as 5-oxoETE, or 5-oxo-6,8,11,14-eicosatetraenoic acid. During acute infections or tissue injuries, the body generates this lipid mediator to act as a chemical siren, guiding specialized white blood cells—specifically neutrophils—directly to the compromised site to neutralize pathogens.
During their early investigations, 1990s researchers observed an enigmatic enzyme capable of both synthesizing and breaking down 5-oxoETE. Enzymes, which are vital proteins that accelerate biochemical reactions, were recognized as central players in this pathway. However, despite decades of technological advancement, the specific human gene responsible for encoding this enzyme remained unidentified.
This missing genetic information created a formidable bottleneck in biomedical research. Without knowledge of the underlying gene, scientists could not manipulate the enzyme in laboratory models to observe its physiological effects or determine how its dysfunction might drive human pathology. Consequently, while the molecule’s role as an inflammatory activator was well documented, the mechanics of its regulation remained shrouded in mystery for over thirty years.
Breaking Through the Model Organism Barrier
The tide turned when postdoctoral researcher Yanan Ma, PhD, working in the laboratory of renowned cell biologist Philipp Niethammer, PhD, at MSK’s Sloan Kettering Institute, decided to pivot away from traditional laboratory models. While mice and rats constitute approximately 95 percent of all mammalian models in biomedical research due to an 80 percent genetic overlap with humans, they proved fundamentally unsuited for this specific line of inquiry.
"Mice and rats are the primary models used in biomedical research because they are mammals, and there is a high degree of genetic conservation between them and us," explained Dr. Ma, recipient of the 2023 Marie-Josée Kravis WISE Fellowship. However, rodents lack a functional immune cell receptor capable of recognizing 5-oxoETE. Because mice do not express this critical receptor, the entire downstream signaling pathway is rendered inert, making them useless for studying this specific immunological axis.
Recognizing this limitation, the MSK team turned to zebrafish (Danio rerio). Unlike rodents, zebrafish retain the evolutionary machinery necessary to process 5-oxoETE signaling. By leveraging this alternative model, Dr. Ma and her colleagues bypassed the genetic dead end that had stalled research for decades, enabling them to observe the complete, intact pathway functioning within a living organism.
Identifying the Missing Genetic Link
Before validating their hypotheses in zebrafish, Dr. Ma and former lab colleague King Lam Hui, PhD, utilized cultured human cells to hunt for the elusive enzyme’s genetic source. They systematically screened a panel of candidate genes, switching them off one by one to monitor changes in enzymatic activity.
A definitive result emerged when the researchers disabled a gene designated as DHRS7. Upon the deactivation of DHRS7, the enzyme ceased functioning entirely, confirming that this was the exact genetic sequence researchers had sought since 1992. Subsequent analyses of the rodent version of DHRS7 revealed negligible enzymatic activity, neatly explaining why mice lack functional responses to the 5-oxoETE pathway and validating the researchers’ choice of zebrafish models.
This genetic identification coincided with a separate investigation conducted in the same laboratory by postdoctoral researcher Miklos Lengyel, MD, PhD, who was studying colitis—a severe inflammatory condition of the colon—using zebrafish. Dr. Lengyel was examining the effects of disabling hcar1-4, the zebrafish ortholog of the human receptor gene OXER1, which detects the 5-oxoETE signal.
Conventional immunological dogma dictated that removing a receptor responsible for driving inflammation should mitigate inflammatory symptoms. Instead, Dr. Lengyel observed the exact opposite: the zebrafish spontaneously developed severe intestinal inflammation in the absence of any pathogen or infection.
When Dr. Lengyel subsequently disabled the newly identified DHRS7 gene to disrupt the signaling pathway, the same paradoxical result manifested. Inflammation surged rather than subsided.
The Immune System’s Dual Nature: Alarm and Shield
Through rigorous validation across multiple experimental methods, the MSK team realized they had uncovered a profound, previously unrecognized biological principle. The 5-oxoETE pathway does not merely serve as an aggressive alarm system to summon destructive white blood cells; it simultaneously deploys a protective shield to preserve surrounding healthy tissue.
When immune cells swarm an infection site, they release reactive oxygen species and other potent toxins designed to annihilate invading microorganisms. However, this chemical warfare inherently threatens adjacent healthy host cells. The 5-oxoETE pathway mitigates this collateral damage by enhancing the resilience of nearby tissues against metabolic and oxidative stress.
The researchers traced this cellular protection to a family of housekeeping enzymes known as NUDIX hydrolases, which safeguard cellular health by clearing out damaged DNA building blocks. When either the 5-oxoETE signal or its receptor was deleted, intestinal cells lost their capacity to withstand the mild, chronic oxidative stress generated by normal, commensal gut bacteria. This cellular distress triggered widespread cell death, which in turn provoked a secondary, unregulated inflammatory response.
"As it turns out, this signal isn’t just an alarm, it’s also a shield," Dr. Niethammer noted. "Organisms have evolved an elegant way of protecting healthy cells at the exact same moment immune cells unleash chemical warfare against a pathogen."
Integrating Mechanical and Metabolic Stress Responses
Expanding upon these findings, doctoral student Zaza Gelashvili investigated how physical forces and mechanical tissue damage feed into this same signaling axis. In a related study published earlier in the year in Nature Communications—work that earned him the 2026 Chairman’s Prize from the Gerstner Sloan Kettering Graduate School of Biomedical Sciences—Gelashvili demonstrated that physical stress on cell membranes releases arachidonic acid, the direct biochemical precursor to 5-oxoETE.
This discovery unifies disparate physiological stress responses. Physical injury ruptures cell membranes to release raw material; metabolic and oxidative stress drive the conversion of that material; and DHRS7 amplifies the resulting signal. The body thus integrates mechanical and metabolic inputs into a single, cohesive, protective physiological response.
Broad Implications for Cancer, IBD, and Asthma
The discovery of the protective dimension of 5-oxoETE signaling holds profound translational potential for human medicine, particularly in conditions characterized by chronic or dysregulated inflammation.
In clinical oncology, mutations in DHRS7 and OXER1 have been identified in gastrointestinal and uterine tumors. Furthermore, clinical data links impaired OXER1 function with significantly poorer prognoses in colorectal, pancreatic, and renal cancers. Researchers hypothesize that pharmacologically activating this protective pathway could bolster the resilience of mucosal tissues against the oxidative stress induced by chemotherapy and radiation therapy.
Similarly, patients suffering from inflammatory bowel disease (IBD) often present with depleted levels of 5-oxoETE in intestinal tissues, correlating with more severe disease phenotypes. In the respiratory sphere, independent studies on primate models have demonstrated that blocking the OXER1 receptor not only dampens immune cell infiltration but also causes protective, mucus-producing airway cells to disappear—a finding of direct relevance to severe asthma management.
While pharmaceutical translation will require extensive preclinical and clinical validation, this discovery fundamentally alters how pharmacologists must approach anti-inflammatory drug design. Therapeutics aimed at suppressing harmful immune reactions must carefully preserve—or ideally augment—the endogenous protective shields that prevent the body from damaging itself.
Funding and Acknowledgments
This research was supported by grants from the National Institutes of Health (R35GM140883), an MSK Basic Research Innovation Award, the Starr Foundation Program for Discovery Science, the Tow Foundation, the Marie-Josée Kravis Women in Science Endeavor (WISE) fellowship, the Crohn’s Colitis Foundation Research Fellows Award (1268111), and an Experimental Immuno-Oncology Scholars fellowship. Additional contributions were made by MSK researchers Yohannes Ambaw, Leehyeon Kim, Ritchie Ly, Siyang Peng, Meysoon Quraishi, Tobias Walther, and Robert Farese Jr.
