Endometriosis is one of the most common and least satisfactorily treated chronic diseases affecting women, defined by the growth of endometrial-like tissue outside the uterine cavity. It causes pelvic pain, dysmenorrhea, subfertility and, in many patients, a progressive scarring process known as fibrosis that stiffens lesions and surrounding tissue. Current therapies largely rely on hormonal manipulation, which suppresses estrogen-driven growth but does not address the inflammatory and fibrotic machinery that makes the disease chronic. A new study published in the Journal of Translational Medicine now points to a surprising partnership between two cellular players, immune cells called neutrophils and the endometriotic cells themselves, and identifies a lipid signaling molecule as the chemical language they use to drive each other toward tissue scarring.
The research, led by teams at the University of Florence and the University of Pisa with international collaborators, focused on neutrophil extracellular traps, or NETs. NETs are web-like structures composed of DNA studded with toxic proteins that neutrophils normally release to immobilize and kill microbes. In recent years, however, biologists have recognized that inappropriate or excessive NET formation, a process called NETosis, contributes to autoimmune conditions, thrombosis and cancer progression. Earlier work had hinted that NETs are present in endometriotic lesions, but the molecular consequences of their presence, and the mechanisms that sustain their production in this disease, remained poorly defined.
To close that gap, the investigators first examined tissue from patients. Using immunofluorescence and immunohistochemistry, they compared endometriotic lesions from ten women with endometrial tissue from ten healthy controls. The lesions showed a marked increase in markers of NETs, including myeloperoxidase, an enzyme packaged into NET webs, and citrullinated histone H3, a chemical signature of the chromatin decondensation that precedes NET release. Masson’s trichrome staining, which dyes collagen blue, revealed significantly greater collagen deposition in the lesions, confirming that fibrosis accompanies the accumulation of these neutrophil-derived structures. The two phenomena, NET burden and scarring, appeared side by side in the same tissue.
The next question was whether the NETs were merely a bystander or an active driver of fibrosis. To find out, the researchers treated human endometriotic epithelial cells and stromal cells, the two main cell types within lesions, with isolated NETs in the laboratory. The response was striking. Epithelial cells underwent epithelial-mesenchymal transition, a developmental program in which tightly adherent epithelial cells lose their identity, gain motility and acquire the capacity to deposit extracellular matrix; this was visible as a loss of E-cadherin and a gain of mesenchymal markers. Stromal cells, meanwhile, shifted toward a myofibroblast-like phenotype, upregulating alpha-smooth muscle actin and fibronectin, hallmarks of activated, matrix-producing cells. In both compartments, NET exposure pushed the cells toward a pro-fibrotic state.
The mechanistic heart of the study lies in a lipid called sphingosine 1-phosphate, or S1P. S1P is a bioactive sphingolipid metabolite that signals through five cell-surface receptors and regulates immunity, vascular integrity and cell survival. The team found that when endometriotic cells were exposed to NETs, they reprogrammed their entire S1P signaling axis. Expression of sphingosine kinase-1, or SK1, one of the two enzymes that synthesize S1P, increased, as did the transporter Spns2, which exports S1P out of the cell, and two of the S1P receptors, S1P2 and S1P3. In other words, the cells not only made more of the lipid but also built the machinery to ship it out and to sense it once it returned.
To test whether this lipid circuit was actually responsible for the fibrotic response, the researchers used genetic silencing and pharmacological tools to interfere with SK1 or with Spns2. When either node of the pathway was disabled, the pro-fibrotic effect of NETs on endometriotic cells was abolished. This loss-of-function result is critical: it demonstrates that S1P synthesis and export are not incidental correlates of scarring but necessary links in the chain connecting neutrophil traps to collagen-producing behavior. The finding elevates S1P metabolism from a general inflammatory marker to a specific, testable driver of endometriosis-associated fibrosis.
Perhaps the most compelling discovery emerged when the direction of communication was reversed. The team collected conditioned media, the nutrient fluid in which endometriotic cells had been cultured, from cells in which S1P metabolism or export had been modulated, and applied these fluids to fresh neutrophils. The media potently influenced NETosis, showing that endometriotic cells stimulate neutrophils to release their traps through S1P-dependent signaling. Combined with the earlier results, this establishes a bidirectional feedback loop: neutrophils release NETs, which push endometriotic cells to produce and export S1P, and the exported S1P in turn drives neutrophils to form more NETs. Each turn of the loop amplifies both inflammation and fibrogenesis, providing a mechanistic explanation for why endometriotic lesions tend to become progressively more fibrotic over time.
To determine whether this circuit operates in the whole organism rather than only in culture dishes, the researchers measured circulating levels of S1P and myeloperoxidase, a NET marker, in the plasma of thirty patients and twenty healthy controls. In patients with endometriosis, the two molecules correlated positively, whereas in healthy women no such relationship existed. This correlation suggests that the S1P-NET axis is active systemically in the disease and raises the possibility that the pair could serve as a blood-based biomarker, offering a less invasive way to assess disease activity than surgery, which remains the gold standard for diagnosis today.
The therapeutic implications are considerable. Because the loop requires S1P synthesis by SK1 and its export through Spns2, both enzymes represent concrete points of intervention. Drugs that modulate S1P signaling already exist in other fields; fingolimod, a functional S1P receptor modulator, is an approved treatment for multiple sclerosis, and SK inhibitors are in development for cancer and inflammation. The present study does not report clinical trials of such agents in endometriosis, but it provides the preclinical rationale for evaluating them. Importantly, targeting S1P metabolism would be a non-hormonal strategy, addressing a major unmet need for patients who cannot tolerate or do not respond to existing hormonal therapy, and it could in principle dampen both NETosis and fibrogenesis simultaneously rather than merely suppressing lesion growth.
Caveats remain, as they do in any translational study. The patient tissue cohort was small, with ten lesions and ten controls in the histological analysis, and the plasma correlation, while statistically meaningful, does not by itself prove causation in humans. The mechanistic work relies on immortalized cell lines and isolated neutrophils, which capture key features of the disease but not its full complexity. Nonetheless, the convergence of patient tissue data, cell-based loss-of-function experiments and circulating biomarker correlations forms an unusually coherent evidence chain. The study also carries a poignant note: it is dedicated to the memory of co-author Asgerally T. Fazleabas, a distinguished reproductive biologist at Michigan State University who contributed to the project before his death. If future work confirms that breaking the S1P-NET loop slows fibrosis in patients, this research may mark the beginning of a shift in how endometriosis is understood, from a primarily hormonal disorder to one in which immune-lipid crosstalk is a central, and druggable, engine of disease progression.
Subject of Research: The role of sphingosine 1-phosphate signaling and neutrophil extracellular traps in fibrosis associated with endometriosis
Article Title: Sphingosine 1-phosphate-driven interplay between neutrophils and endometriotic cells fuels fibrosis in endometriosis: insights into the role of neutrophil extracellular traps
Article References: Prisinzano, M., Seidita, I., Bertilacchi, M. S., Giusti, M., Romeo, L., Nardi, E., Castiglione, F., Schumacher, F., Thomas, D., Kleuser, B., Fambrini, M., Fazleabas, A. T., Petraglia, F., Trincavelli, M. L., Bruni, P., Donati, C., Giacomelli, C., & Bernacchioni, C. (2026). Sphingosine 1-phosphate-driven interplay between neutrophils and endometriotic cells fuels fibrosis in endometriosis: insights into the role of neutrophil extracellular traps. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08971-9
Image Credits: AI Generated
DOI: 10.1186/s12967-026-08971-9
Keywords: endometriosis, neutrophil extracellular traps, NETosis, sphingosine 1-phosphate, sphingosine kinase-1, Spns2, fibrosis, epithelial-mesenchymal transition, myeloperoxidase, inflammation, non-hormonal therapy, biomarkers
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Ophelia Keating. (October 4, 2026). Immune Cell Traps and a Lipid Messenger Drive Scarring in Endometriosis. Scienmag. https://scienmag.com/immune-cell-traps-and-a-lipid-messenger-drive-scarring-in-endometriosis/
Ophelia Keating. “Immune Cell Traps and a Lipid Messenger Drive Scarring in Endometriosis.” Scienmag, 4 October 2026, https://scienmag.com/immune-cell-traps-and-a-lipid-messenger-drive-scarring-in-endometriosis/. Accessed 4 October 2026.
Ophelia Keating. “Immune Cell Traps and a Lipid Messenger Drive Scarring in Endometriosis.” Scienmag. October 4, 2026. https://scienmag.com/immune-cell-traps-and-a-lipid-messenger-drive-scarring-in-endometriosis/
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Tags: a lipid messenger called lysophosphatidic acid (LPA) was identified as a key factor in signaling between immune cells and endometrial tissueBiomarkersbut their precise role remained unclear. The study reveals that NETs promote fibrosis by activating endometriotic cells and recruiting more immune cellscreating a vicious cycle. Additionallydriving the fibrotic process. This research highlights potential new therapeutic targets to interrupt the immune cell trapping mechanism and lipid signaling pathways involved in endometriosisendometriosisendometriotic lesionsepithelial-mesenchymal transitionfibrosisinflammationmyeloperoxidaseNETosisneutrophil extracellular trapsnon-hormonal therapysphingosine kinase-1sphingosine-1-phosphateSpns2
