The study, led by Simona Nicolì and Biagio Solarino of the Section of Legal Medicine at the University of Bari, together with colleagues in Rome and Bari, screened 152 medico-legal autopsies performed between November 2020 and November 2024. Of these, 122 cases met the inclusion criteria and formed the final cohort. The researchers reviewed autopsy reports alongside whatever clinical documentation was available, including records of anticoagulant and antiplatelet therapy, vasoactive amines, corticosteroids, ongoing infections, and laboratory measurements such as total leukocyte count, neutrophil percentage, and absolute neutrophil count. Because premortem laboratory data were frequently unavailable, particularly in traumatic deaths, the team turned to a different strategy: they analyzed lung tissue samples from all 122 decedents directly.

The technical core of the study lies in digital pathology. Rather than eyeballing histological slides and grading neutrophil presence subjectively, the investigators scanned whole-slide images of lung tissue and quantified pulmonary intravascular neutrophil density using QuPath, an open-source digital pathology platform widely used for quantitative image analysis. This approach allowed the team to count neutrophils within vascular spaces per unit area, expressed as neutrophils per square millimeter, and to treat that density as a continuous variable amenable to statistical testing. The association between intravascular neutrophil density and the presence of chicken-fat clots was then analyzed using receiver operating characteristic curves, chi-squared tests, and odds ratios, the standard toolkit for evaluating diagnostic discrimination and association strength in retrospective cohorts.

The results were unambiguous. Chicken-fat clots were present in 34 of the 122 cases, a prevalence of 27.9 percent. Among the CFC-positive cases, septic shock represented the largest cause-of-death group, accounting for 29.4 percent of that subset, a distribution that itself hints at an inflammatory contribution. When the researchers compared lung tissue from cases with and without chicken-fat clots, they found that increased pulmonary intravascular neutrophil density was significantly associated with CFC presence, with an odds ratio of 21.0 and a p-value below 0.001. In practical terms, cases with high intravascular neutrophil density in the lungs had roughly twenty-one times the odds of showing chicken-fat clots compared with cases of low density.

The quantitative analysis went further. A threshold of 2286 neutrophils per square millimeter showed good discrimination for the presence of chicken-fat clots, with an area under the ROC curve of 0.840. An AUC of 0.840 sits well above the 0.5 that would indicate random guessing and approaches the range generally considered indicative of good diagnostic performance. This means that a single histological measurement, neutrophil density inside pulmonary vessels, could separate CFC-positive from CFC-negative cases with reasonable accuracy in this cohort. Notably, no significant associations were identified between chicken-fat clots and anticoagulants, antiplatelet agents, or the other evaluated blood parameters, suggesting that the clot morphology is not simply an artifact of antemortem medication or routine hematological variation.

Why would neutrophils matter for postmortem clot appearance? The answer may lie in what immunologists have learned about thrombosis as an innate immune effector. Neutrophils are the first responders of the immune system, and in sepsis and systemic inflammation they accumulate in microvascular beds, where they can release neutrophil extracellular traps, web-like structures of DNA studded with antimicrobial proteins. These traps are known to promote deep vein thrombosis in experimental models, and thrombosis is increasingly understood as an intravascular arm of innate immunity rather than a purely hemodynamic phenomenon. If neutrophils and their traps participate in the formation of intravascular coagula during the final hours of life, then the lipid-rich chicken-fat clot may carry an immunological signature that reflects the inflammatory state of the decedent, not merely the tempo of dying.

The authors are careful to frame what the study does and does not establish. Their conclusion states that chicken-fat clots were associated with increased pulmonary intravascular neutrophil density in this retrospective autopsy cohort, suggesting a possible relationship with systemic inflammatory or neutrophil-mediated processes. But they explicitly caution that these findings do not establish pulmonary intravascular neutrophil density as a validated marker of antemortem neutrophilia. Nor do they exclude the contribution of agonal duration or postmortem processes to CFC formation. The traditional slow-death concept, in other words, is not overturned; it is complemented. Further studies incorporating well-defined agonal timing and closely timed premortem laboratory data are needed to clarify the biological and temporal determinants of chicken-fat clot formation.

The methodological choices reveal why the team avoided relying on clinical blood counts. In forensic cohorts, particularly those dominated by traumatic deaths, decedents often arrive without any recent laboratory workup, so antemortem neutrophil counts are simply unavailable. By measuring neutrophil density directly in lung tissue, the investigators sidestepped this data gap, but they also introduced a new interpretive question: does intravascular neutrophil density in pulmonary vessels reflect antemortem neutrophilia, agonal neutrophil trapping, or postmortem cellular redistribution? Previous forensic work has explored small vessel neutrophils as a marker for sepsis at autopsy, and the present study extends that quantitative logic to clot morphology, but the temporal ambiguity remains an acknowledged limitation.

The historical arc of this research question is long. Giovanni Battista Morgagni, the eighteenth-century father of pathologic anatomy, described cadaveric clots of varying appearance, and forensic textbooks from Saukko and Knight onward have treated chicken-fat clots as a recognized agonal phenomenon. Japanese investigators in the 1980s linked postmortem fibrinolysis and plasma catecholamine levels to the fluidity of cadaveric blood after sudden death, and German researchers in 1988 examined the roles of coagulation, fibrinogenolysis, and fibrinolysis in the development of fluid and clotted cadaver plasma. More recently, a 2023 immunohistochemical study investigated the formation mechanism of chicken-fat clots, and a 2025 systematic review of cadaver clots by members of the same Bari group consolidated the literature. The new study adds a quantitative, neutrophil-centered dimension to this accumulating body of work.

For forensic practice, the implications are intriguing but preliminary. If a threshold of 2286 neutrophils per square millimeter in pulmonary vessels can be replicated in larger cohorts with well-characterized agonal timing, digital pathology could offer pathologists an objective histological parameter that correlates with a recognizable gross finding, potentially sharpening the interpretation of autopsy coagula in cases of septic shock and other inflammatory deaths. The association with septic shock as the leading cause of death among CFC-positive cases fits coherently with the neutrophil hypothesis, since sepsis drives both neutrophil mobilization and microvascular neutrophil accumulation. What the study ultimately delivers is a measurable bridge between a centuries-old gross observation and a modern immunological framework, and it sets the stage for the prospective studies that will determine whether the chicken-fat clot can graduate from descriptive curiosity to informative forensic marker.

Subject of Research: Chicken-fat clots linked to neutrophil buildup in lung vessels, autopsy study finds

Article Title: Chicken-fat clots and pulmonary intravascular neutrophil density: a retrospective autopsy study

Article References: Nicolì, S., Ambrosi, L., Mercuri, G., Oliva, A., Ferorelli, D., Ingravallo, G., & Solarino, B. (2026). Chicken-fat clots and pulmonary intravascular neutrophil density: a retrospective autopsy study. International Journal of Legal Medicine. https://doi.org/10.1007/s00414-026-04048-w

Image Credits: AI Generated

DOI: 10.1007/s00414-026-04048-w

Keywords: Chicken-fat, clots, pulmonary, intravascular, neutrophil, density, retrospective, autopsy, scientific research

Adipose tissue in mammals is broadly divided into subcutaneous depots, found under the skin, and visceral depots, which pad the abdominal organs. Although both store energy in the form of lipid droplets, they differ dramatically in their behavior and their consequences for health. Subcutaneous fat is comparatively benign and can undergo thermogenic remodeling, a process in which ordinary white adipocytes acquire features of brown fat cells, becoming packed with mitochondria that burn fuel to produce heat. Visceral fat, by contrast, resists this transformation, known as beiging, and instead tends to enlarge, release fatty acids into the portal circulation, and secrete inflammatory signals that promote insulin resistance. Why visceral fat refuses to beige has long been an open question.

The concept of beiging itself has a rich experimental history. Work from several laboratories over the past two decades, including studies by Rosenwald and colleagues and by Chitraju and colleagues, established that cold exposure and sympathetic nervous system activation recruit new adipocyte precursors in subcutaneous fat that differentiate into thermogenically competent beige adipocytes. Drugs such as beta-adrenergic agonists can induce similar remodeling. Yet when researchers apply the same stimuli to visceral depots, the response is muted or absent. Yuan and colleagues set out to identify what actively enforces this depot specificity, suspecting that the local tissue microenvironment, rather than an intrinsic defect in visceral adipocyte precursors, might be responsible.

The investigative trail led the researchers to neutrophils, the most abundant white blood cells in the human body and classic first responders to infection. Neutrophils are armed with an arsenal of serine proteases, including neutrophil elastase, proteinase 3, and cathepsin G, which they normally deploy to destroy pathogens and remodel extracellular matrix. Earlier work had already implicated neutrophil enzymes in metabolic regulation: Talukdar and colleagues showed in 2012 that neutrophil elastase deficiency protects mice from obesity-associated insulin resistance, and Mansuy-Aubert and colleagues demonstrated in 2013 that neutrophils modulate insulin sensitivity in adipose tissue. What remained unknown was whether these proteases could gate a specific developmental program within fat tissue.

Yuan and colleagues now show that they can. In their model, serine proteases released by neutrophils that reside in or traffic to visceral fat cleave key signaling components required for the beiging program, effectively putting the brakes on thermogenic differentiation before it can begin. When the researchers depleted neutrophils or blocked their proteases, visceral adipose tissue regained some capacity for beiging, acquiring multilocular lipid droplets, elevated mitochondrial content, and increased expression of thermogenic genes. The effect was depot-specific: subcutaneous fat, which hosts fewer of these protease-releasing neutrophils under resting conditions, was largely unaffected, providing a mechanistic explanation for the natural dichotomy between the two depots.

The technical logic of the study is notable for the way it integrates cellular, molecular, and physiological levels of analysis. Single-cell and population-level transcriptomic profiling allowed the authors to map the immune composition of visceral versus subcutaneous depots and to quantify the enrichment of neutrophil signatures and protease transcripts in visceral fat. Genetic and pharmacological perturbations, including protease-deficient models and pharmacologic inhibitors of the sort previously characterized by Korkmaz and colleagues in their comprehensive pharmacological reviews of neutrophil serine proteases, established causality rather than mere correlation. Functional readouts of thermogenesis, including respiratory measurements and gene expression panels anchored on canonical markers such as Ucp1, confirmed that the histological and molecular shifts translated into genuine changes in adipose tissue function.

Why would the body actively suppress heat production in its visceral fat? The authors and the commentary authors offer several evolutionary and physiological interpretations. Thermogenesis is metabolically expensive, and skeletal and cardiac muscle plus brown fat already serve as principal heat-generating organs during cold defense. Restricting beiging to subcutaneous depots may allow the body to preserve the mechanical and structural integrity of visceral fat, which cushions organs, while avoiding the wasteful combustion of a fuel depot located in the abdominal cavity. At the same time, neutrophils are recruited in greater numbers to visceral fat during obesity, as demonstrated classically by Weisberg and Xu and their colleagues in 2003, suggesting that a system designed to restrain thermogenesis in lean animals may become maladaptive when inflammation drives excessive neutrophil accumulation and further locks visceral fat into an metabolically unfavorable state.

The translational implications are considerable. Pharmacological strategies to induce beiging have struggled precisely because systemically administered thermogenic stimuli produce off-target effects, particularly on the cardiovascular system, through beta-adrenergic activation. A pathway that actively suppresses beiging in one specific depot offers an alternative therapeutic logic: relieve the brake rather than press the accelerator. If neutrophil serine protease activity in visceral fat could be selectively inhibited, patients with obesity or type 2 diabetes might regain some of the thermogenic and insulin-sensitizing capacity that their subcutaneous fat already possesses. Protease inhibitors exist for related enzymes, and neutrophil elastase inhibitors have been tested in inflammatory lung disease, providing a medicinal chemistry starting point, although the challenge of targeting protease activity specifically within visceral adipose tissue without impairing antimicrobial immunity remains substantial.

The study also carries conceptual weight for immunometabolism as a field. Over the past two decades, adipose tissue macrophages and T cells have been established as central players in obesity-associated inflammation, following foundational observations linking immune infiltration to metabolic dysfunction in fat. Neutrophils, by contrast, were long treated as short-lived, terminally differentiated cells with narrow antimicrobial functions. The new work joins a growing body of evidence, including the 2026 study by Son and colleagues in Nature on neutrophil heterogeneity, that neutrophils are functionally versatile cells whose granule contents can reprogram the behavior of surrounding tissues. Tol and Stienstra emphasize in their commentary that the identification of protease-gated depot specificity fundamentally reframes neutrophils as custodians of adipose tissue identity, not merely as inflammatory mercenaries.

Important questions remain. The precise molecular targets of the proteases within the beiging pathway, whether they act on adipocyte precursors directly, on extracellular matrix cues, or on paracrine signals from other stromal cells, will require further dissection. It is also unclear whether chronic pharmacological inhibition of these enzymes in adult animals produces durable, safe increases in visceral thermogenesis, or whether the brake exists to prevent pathology of its own. Human relevance, as always in mouse-first immunometabolism, must be established: visceral fat biopsies from people with varying degrees of obesity and metabolic health could test whether neutrophil protease abundance correlates with impaired beiging capacity in our own species. Nevertheless, by identifying a concrete, druggable class of enzymes that explains why visceral fat refuses to become a furnace, Yuan and colleagues have converted a long-standing observational puzzle into a tractable therapeutic opportunity, and have added an unexpected chapter to the story of how the immune system writes the metabolic rules of our bodies.

Subject of Research: Depot-specific suppression of visceral fat beiging by neutrophil-derived serine proteases

Article Title: Neutrophil proteases put the brakes on visceral beiging

Article References: Tol, M. J., & Stienstra, R. (2026). Neutrophil proteases put the brakes on visceral beiging. Nature Metabolism. https://doi.org/10.1038/s42255-026-01606-9

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01606-9

Keywords: neutrophils, serine proteases, visceral adipose tissue, beiging, thermogenesis, immunometabolism, obesity, insulin resistance, adipose tissue plasticity, innate immune cells, metabolism, Neutrophil