The numbers behind the argument are striking. Antiphospholipid syndrome, the archetypal autoimmune clotting disorder, affects roughly 40 to 50 per 100,000 people in western populations, with a four-to-one female predominance, and carries an annual incidence of one to two cases per 100,000. Around 20 to 30 percent of patients with systemic lupus erythematosus carry antiphospholipid antibodies, and about 40 percent of those go on to develop secondary antiphospholipid syndrome. Patients who have both lupus and antiphospholipid antibodies face significantly higher risks of clotting and of recurrence than either condition alone. Rheumatoid arthritis, giant cell arteritis, Takayasu’s arteritis, polyarteritis nodosa and ANCA-associated vasculitis all add to the burden, as do immune-driven syndromes such as heparin-induced thrombocytopenia and the vaccine-induced clotting disorder VITT that emerged during the COVID-19 pandemic.

What makes these conditions clinically treacherous is that, unlike inherited clotting tendencies, they can strike any part of the circulation. In antiphospholipid syndrome, venous thromboembolism accounts for 39 percent of first events, but stroke follows at nearly 20 percent, with transient ischaemic attacks and heart attacks behind it. Clots also form in unusual places: the cerebral venous sinuses, the splanchnic veins, even the retina. In a five-year international cohort, the single most frequent recurrent event was stroke, a sobering signal that standard anticoagulation incompletely protects these patients. Microvascular thrombosis and pregnancy complications complete a picture that disproportionately afflicts younger adults, especially women, precisely the people conventional cardiovascular screening tends to overlook.

At the mechanistic heart of the problem lies immunothrombosis, the ancient host-defence programme that uses clot formation to wall off circulating pathogens. When autoantibodies hijack this machinery, the result is pathological thrombo-inflammation. The best-characterised culprit is the family of antiphospholipid antibodies, particularly those directed against beta-2 glycoprotein I. These antibodies bind phospholipid-binding proteins on endothelial cells, monocytes and platelets, triggering tissue factor expression, thrombin generation and platelet aggregation, and creating a sustained hypercoagulable state that spans arteries, veins and the microcirculation.

Platelets themselves turn out to be immune sentinels, and the review places the platelet Fc gamma receptor IIa at the centre of the story. This receptor, the only Fc receptor on platelets, binds the tail of IgG immune complexes. When pathogenic antibodies cross-link it, a signalling cascade through Src family kinases, Syk and phospholipase C gamma 2 rapidly activates the platelet, spurring granule release, integrin activation and aggregation. Activated platelets shed phosphatidylserine-rich microparticles that serve as catalytic surfaces for thrombin generation and express P-selectin, recruiting neutrophils and monocytes. In antiphospholipid syndrome, heparin-induced thrombocytopenia and VITT alike, Fc gamma receptor IIa signalling is the common final pathway converting adaptive immune mischief into arterial thrombosis, a fact already exploited therapeutically through high-dose intravenous immunoglobulin.

Neutrophils add a second layer of amplification. Activated neutrophils cast out neutrophil extracellular traps, web-like lattices of DNA, histones and granular enzymes that normally ensnare microbes but in autoimmunity provide scaffolds for fibrin deposition, activate platelets and injure the endothelium. In lupus and antiphospholipid syndrome, impaired clearance of these traps sustains vascular inflammation. Meanwhile complement fragments C3a and C5a stoke cytokine release and thrombin generation, while the membrane attack complex punches holes in endothelial cells; experimental work shows complement activation is essential to clotting in antiphospholipid syndrome, making complement inhibition a promising strategy for severe disease.

The endothelium itself is transformed from a guardian into an accomplice. Healthy vessels secrete nitric oxide and prostacyclin and display anticoagulant proteins, but inflammatory cytokines such as tumour necrosis factor-alpha, interleukin-1 and interferon-alpha flip the switch: adhesion molecules appear, von Willebrand factor floods out, natural anticoagulants are downregulated, and plasminogen activator inhibitor-1 throttles fibrinolysis. Oxidative stress strips away nitric oxide bioavailability. In lupus and rheumatoid arthritis this same endothelial dysfunction accelerates atherosclerosis, so patients develop premature arterial disease years or decades ahead of schedule. Traditional risk factors then multiply the damage: smoking boosts autoantibody production, obesity feeds chronic low-grade inflammation, and long-term glucocorticoid therapy worsens blood pressure, lipids and insulin resistance.

Paradoxically, several of these conditions cause clotting despite depleting platelets. In immune thrombocytopenia, antibodies against platelet glycoproteins drive the count down, yet patients still clot more often, through microparticle formation, enhanced thrombin generation and endothelial dysfunction. In autoimmune haemolytic anaemia, antibodies destroy red cells, and the liberated iron, procoagulant microparticles, complement activation and nitric oxide depletion together conspire toward thrombosis. Even antibodies against the natural anticoagulants protein C and protein S have been described, producing catastrophic syndromes such as purpura fulminans and symmetrical peripheral gangrene. The lesson, the authors stress, is that thrombosis in strange contexts or without traditional risk factors should prompt a search for an immune cause.

Diagnosis and risk stratification remain stubbornly difficult because conventional tools are calibrated to ordinary populations. Framingham and SCORE2 scores systematically underestimate vascular risk in inflammatory disease, which is why several rheumatology societies recommend adjustment factors. Laboratory assessment centres on antiphospholipid antibody testing, where persistence on repeat testing after at least twelve weeks confirms clinical significance, and so-called triple positivity marks particularly high recurrence risk. Anticoagulation strategy is similarly nuanced: vitamin K antagonists remain the standard for thrombotic antiphospholipid syndrome because randomised trials showed rivaroxaban and other direct oral anticoagulants carry unacceptably high arterial recurrence rates in triple-positive patients, though carefully selected low-risk patients intolerant of warfarin may still qualify. Hydroxychloroquine, with its platelet-calming and endothelial-protecting effects, statins, aggressive inflammation control and rigorous management of blood pressure, lipids and glucose all form part of the preventive package, alongside minimising cumulative steroid exposure.

The review closes with a policy prescription that amounts to a cultural shift. The authors call for European health systems to designate autoimmune diseases as cardiovascular risk-enhancing conditions, embedding cardiovascular prevention within routine rheumatology and haematology care rather than leaving it to cardiology alone. Multidisciplinary pathways linking primary care, rheumatology, haematology, cardiology and obstetrics, supported by harmonised registries and autoimmune-specific risk prediction tools, would allow earlier detection of high-risk patients through blood pressure, lipid and glucose monitoring, vascular imaging and structured screening of carriers of antiphospholipid antibodies. The economic stakes are substantial: venous thromboembolism costs the United States an estimated seven to ten billion dollars annually, and stroke cost 32 European countries roughly 31 billion euros in 2017, with the autoimmune contribution disproportionately large because patients are young and comorbidities multiply. Emerging therapies, from CD19-directed CAR-T cells to bispecific antibodies that deplete the plasma cells making pathogenic antibodies, hint that in the future the source of the problem, not just its downstream clot, might finally be silenced.

Subject of Research: Mechanisms, epidemiology and prevention of autoimmune-associated thrombosis

Article Title: Autoimmune-associated thrombosis: mechanisms, population burden, and prevention strategies

Article References: Arachchillage, D. J., Preece, M. V., & Laffan, M. (2026). Autoimmune-associated thrombosis: mechanisms, population burden, and prevention strategies. The Lancet Regional Health – Europe, 70, Article 101850. https://doi.org/10.1016/j.lanepe.2026.101850

Image Credits: AI Generated

DOI: 10.1016/j.lanepe.2026.101850

Keywords: autoimmune disease, thrombosis, antiphospholipid syndrome, systemic lupus erythematosus, immunothrombosis, endothelial dysfunction, neutrophil extracellular traps, complement activation, VITT, heparin-induced thrombocytopenia, cardiovascular risk, anticoagulation

The research team, led by Gaoquan Zheng, Dianqing Li, and colleagues, set out to test whether a deliberate local pH signal built into the implant interface could guide neutrophil behavior and strengthen host antibacterial defense without adding any exogenous bactericidal agent. Neutrophils are among the first innate immune cells recruited to infected sites, and beyond phagocytosis and degranulation they can release neutrophil extracellular traps, or NETs, which are extracellular chromatin-based networks that capture pathogens and limit their spread. Prior work had hinted that extracellular pH regulates this process: bicarbonate-rich pancreatic fluid has been shown to promote PADI4-dependent aggregated NET formation, a high bicarbonate-to-CO2 ratio and moderately alkaline pH favor NET release, and extracellular acidosis suppresses ROS-dependent NETosis. What remained poorly understood was how such a physicochemical cue is converted into functional changes inside the neutrophil, and whether it could be harnessed at a biomaterial surface.

To create the alkaline interface, the researchers subjected titanium plates to a hydrothermal reaction in a mixed sodium hydroxide and hydrogen peroxide solution at 80 degrees Celsius for 24 hours, followed by hydrochloric acid-mediated ion exchange to remove excess sodium-containing alkaline species and a thermal treatment ramping to 450 degrees Celsius. The resulting material, designated Ti-A, developed a uniform nanoscale porous architecture visible by scanning electron microscopy, in contrast to the relatively smooth pristine titanium surface. X-ray diffraction confirmed a mixed anatase and rutile TiO2 crystalline structure, and X-ray photoelectron spectroscopy detected a distinct sodium signal reflecting the incorporation of sodium-related species during alkali treatment. Critically, pH measurements taken approximately two millimeters above the surface showed that Ti-A maintained a local pH of roughly 7.88 in ultrapure water and, importantly, remained within a mildly alkaline range of about 7.49 to 7.78 even under physiological buffering conditions in PBS and cell culture medium over 48 hours.

The team then verified that this modified surface was compatible with the cells that matter. Rat bone marrow mesenchymal stem cells cultured on Ti-A retained well-organized F-actin cytoskeletons and intact nuclear morphology, with metabolic activity remaining approximately 92 percent of that observed on pristine titanium despite a modest but significant reduction. Neutrophils exposed to Ti-A for six hours retained roughly 89 percent of their CCK-8 metabolic signal, indicating that the interface did not cause extensive loss of neutrophil viability during the NET-induction period. With biocompatibility established, the researchers turned to the central question of whether Ti-A could trigger bona fide NET formation rather than nonspecific DNA leakage. SYTOX Green staining revealed more extracellular DNA-positive structures on Ti-A than on pristine Ti, and DNase I treatment markedly reduced these networks, confirming their dependence on a DNA scaffold.

Further molecular evidence strengthened the case. Ti-A markedly increased signals of citrullinated histone H3, a chromatin modification closely associated with NET formation, which colocalized with extracellular chromatin regions. Enzyme-linked immunosorbent assays showed higher levels of MPO-DNA complexes in the Ti-A group, indicating co-release of extracellular chromatin with neutrophil granule proteins, a biochemical hallmark of genuine NETs. When neutrophils and S. aureus were co-incubated on the surfaces for six hours, Ti-A achieved an antibacterial rate of approximately 86.67 percent compared with 47.50 percent on pristine titanium. Even without neutrophils present, Ti-A reduced bacterial survival, demonstrating intrinsic surface antibacterial activity, but the addition of neutrophils revealed a substantial host-mediated enhancement on top of that direct effect.

To dissect the mechanism, the researchers applied two pharmacological tools. DNase I, which degrades the extracellular DNA backbone of NETs, caused colony formation on Ti-A to rise sharply and the antibacterial rate to fall to a level close to that of Ti-A alone, indicating that NET-associated extracellular DNA structures were a major contributor to the enhanced killing. Cytochalasin D, which inhibits actin-dependent phagocytosis, also reduced the antibacterial rate, but it remained higher than that of Ti-A alone, suggesting that phagocytosis contributed without fully accounting for the neutrophil-mediated advantage. Together, these experiments established that beyond directly restricting bacterial survival, the alkaline interface amplified neutrophil extracellular killing as the dominant antibacterial mechanism.

The deepest insight of the study came from untargeted metabolomic profiling of neutrophils stimulated on the two surfaces. Volcano plot analysis revealed 77 upregulated and 7 downregulated metabolites in the Ti-A group, with lipid metabolism dominating the differential profile. Sphingosine and N-palmitoyl-D-sphingosine were elevated and ranked among the most important metabolites distinguishing Ti-A-stimulated neutrophils from controls, while 6-phosphogluconic acid, a metabolite of the oxidative pentose phosphate pathway that supplies NADPH for reactive oxygen species generation, was also increased. KEGG enrichment analysis placed sphingolipid metabolism and sphingolipid signaling among the top enriched pathways. This metabolic signature pointed the investigators toward a specific signaling axis: sphingosine can be phosphorylated by sphingosine kinase 1, or SPHK1, to generate sphingosine-1-phosphate, which signals through receptors including S1PR2 and may engage calcium- and MAPK-related pathways linked to PAD4 activation, histone H3 citrullination, chromatin decondensation, and NET formation.

Subsequent molecular and pharmacological experiments supported this model. Neutrophils on Ti-A showed markedly stronger intracellular oxidative signals by DCFH-DA fluorescence and flow cytometry, and both SPHK1 and S1PR2 were significantly upregulated at the mRNA and protein levels. Notably, PMA, a standard positive NET-inducing stimulus, enhanced oxidative activity without inducing comparable SPHK1 or S1PR2 increases, indicating that this upregulation is not a generic consequence of NET induction but is more closely tied to the sphingolipid remodeling triggered by Ti-A. When the researchers blocked the pathway with PF-543, a selective SPHK1 inhibitor, or with DPI, which suppresses NADPH oxidase-derived ROS production, both the web-like extracellular DNA structures and the intracellular oxidative signal were significantly attenuated. Because neither inhibitor completely abolished NET formation, the authors conclude that the SPHK1-S1PR2/ROS axis makes a substantial contribution while operating alongside other signaling events initiated at the interface.

The strategy then faced its most demanding test in vivo. Titanium and Ti-A implants preloaded with S. aureus were inserted into femoral condyle defects in rats. At three days after surgery, fewer colonies were recovered from peri-implant bone tissues in the Ti-A group, accompanied by stronger Ly6G neutrophil staining, enhanced H3Cit signals indicating histone citrullination, and elevated SPHK1 and S1PR2 expression at the interface. At two months, bacterial burden remained significantly lower around Ti-A implants, and micro-CT reconstruction showed more newly formed bone with significantly higher bone volume fraction and bone mineral density. Histology revealed richer bone matrix and collagen deposition, stronger osteopontin staining, and milder inflammatory infiltration, while H&E staining of major organs showed no pathological damage, indicating no evident systemic toxicity.

Importantly, the modified interface did not trade immune-antibacterial activity for impaired osteogenic function. In vitro, Ti-A supported stronger alkaline phosphatase staining and activity, more extensive Alizarin Red S mineral deposition, and increased Runx2 and Col1a1 expression during osteogenic induction. The authors caution that the biological consequences of NET formation depend strongly on timing, magnitude, and clearance: early NETs can immobilize bacteria and assist macrophage-mediated killing, whereas persistent or excessive NETs may sustain inflammation and damage tissue. Their experiments did not track NET formation and clearance continuously, and serial measurements at intermediate time points will be needed to define how the response subsides as the interface shifts from infection control toward tissue repair. Nevertheless, the work positions mild interfacial alkalinity as a host-responsive design cue for anti-infective bone implants, offering a route to coordinate early infection control and subsequent bone regeneration that could hold particular translational value for patients facing infected bone defects where both problems must be solved concurrently.

Subject of Research: Mildly alkaline titanium implant interfaces regulating neutrophil sphingolipid immunometabolism and NET formation for antibacterial host defense and bone repair

Article Title: Interfacial mild alkalinity shapes Neutrophil immunometabolism through sphingolipid remodeling to enhance antibacterial host defense

Article References: Interfacial mild alkalinity shapes Neutrophil immunometabolism through sphingolipid remodeling to enhance antibacterial host defense. (n.d.). https://doi.org/10.1016/j.mtbio.2026.103691

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103691

Keywords: neutrophils, neutrophil extracellular traps, implant-associated infection, titanium implant, interfacial pH, sphingolipid metabolism, SPHK1, S1PR2, reactive oxygen species, Staphylococcus aureus, osseointegration, bone regeneration

At the center of the review is the observation that surgical trauma activates two major neuroendocrine systems. The hypothalamic–pituitary–adrenal axis floods the circulation with glucocorticoids, which suppress the synthesis of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha through their effects on transcription factors like nuclear factor kappa B, while also impairing antigen presentation and lymphocyte proliferation. In parallel, the sympathetic nervous system releases catecholamines that bind beta-adrenergic receptors expressed on tumor cells, endothelial cells and immune populations. These signals promote epithelial-mesenchymal transition, angiogenesis and metastatic dissemination, and they reshape immunity by suppressing natural killer cell cytotoxicity, expanding myeloid-derived suppressor cells and regulatory T cells, and even upregulating the CD47/SIRPalpha “don’t eat me” pathway that shields tumor cells from macrophage phagocytosis. With an estimated ninety percent of cancer-related deaths attributable to metastatic disease after tumor resection, the authors contend that this axis deserves far more clinical attention than it currently receives.

The inflammatory arm of the axis is equally intricate. Surgery triggers a cytokine surge dominated by IL-6 and TNF-alpha, which activate the JAK/STAT3 and NF-kappaB pathways respectively, driving tumor cell proliferation, survival and immune evasion. These cytokines can also endow tumor cells with cancer stem cell-like properties, enhancing resistance to chemotherapy and radiotherapy, and they bias tumor-associated macrophages toward a pro-tumor M2 phenotype that fosters angiogenesis and metastasis. The review also highlights neutrophil extracellular traps, or NETs, web-like structures of DNA, histones and neutrophil proteins released in response to inflammatory stimuli such as IL-8, TNF-alpha and damage-associated molecular patterns. NETs can capture circulating tumor cells, promote their adhesion and colonization at distant sites, and suppress NK and cytotoxic T cell activity. In metastatic hepatocellular carcinoma models, NET internalization activates TLR4/9-COX2 signaling in a feed-forward loop that amplifies both NET formation and metastatic potential, while DNase I combined with anti-inflammatory agents reduced metastasis in mouse models.

The review then details how surgery expands immunosuppressive cell populations. Myeloid-derived suppressor cells accumulate from the bone marrow under the influence of tumor-derived factors, including exosomal PD-L1 that stimulates MDSC proliferation via IL-6/STAT3 signaling. Once activated, MDSCs deplete L-arginine through arginase 1 and inducible nitric oxide synthase, reducing CD3-zeta expression and interferon-gamma and IL-2 secretion, while granulocytic MDSCs nitrate the T-cell receptor through reactive oxygen species. MDSCs also inhibit NK cell cytotoxicity in a cell contact-dependent manner reliant on the NKp30 receptor. In patients undergoing cancer surgery, this expansion has been linked to impaired Th1 immune function, higher postoperative infection risk and increased tumor recurrence. Regulatory T cells follow a parallel trajectory: peripheral Treg levels rise significantly one week after radical mastectomy, accompanied by enhanced inhibitory activity and upregulated checkpoint molecules such as CTLA-4 and PD-1, and propranolol can abolish this catecholamine-driven increase.

Against this mechanistic backdrop, the review systematically appraises anesthetic agents, and the picture that emerges is deliberately nuanced. Propofol emerges as the most frequently discussed “immune-friendly” option. It inhibits cyclooxygenase activity in monocytes and macrophages, lowering prostaglandin E2 production and thereby relieving constraints on NK cell interferon-gamma output. Preclinical work shows it does not reduce NK activity or increase metastatic seeding compared with ketamine, thiopental or halothane, and it suppresses hypoxia-inducible factor-1alpha and RhoA-linked invasion pathways. Clinical studies report more favorable postoperative NK-cell cytotoxicity and reduced VEGF-C release with propofol-based regimens, though a large multicenter randomized trial found no breast cancer recurrence benefit from paravertebral block plus propofol compared with sevoflurane plus opioids. Direct evidence that propofol independently improves long-term oncologic outcomes therefore remains inconclusive.

Other agents complicate any simple classification. Dexmedetomidine, a selective alpha2-adrenergic agonist, blunts sympathetic and neuroendocrine stress responses and reduced circulating stress hormones and IL-6 in tumor-bearing mice, yet rodent studies have reported both increased and decreased metastatic burden depending on dose and model, and clinical outcome data are similarly mixed. Etomidate suppressed PD-L1 expression and improved antitumor immunity in hepatocellular carcinoma models but enhanced migration in colorectal cancer models, underscoring lineage dependence. Opioids engage mu-opioid receptors on immune cells; morphine suppresses NK cytotoxicity in humans and may activate pro-angiogenic signaling, whereas tramadol appears comparatively immune-sparing. Observational studies linking opioid exposure to recurrence point in conflicting directions across cancer types, and associations between opioid use and poorer immunotherapy response are vulnerable to confounding by pain burden and disease severity. Volatile anesthetics have been associated with blunted interferon-driven NK augmentation, T and B cell apoptosis and higher pro-tumor cytokines and matrix metalloproteinases in breast surgery, yet a large population-based study of stage III breast cancer reported lower mortality with inhalational maintenance, illustrating how context can invert apparent signals.

Regional and neuraxial techniques, including epidural and paravertebral blockade, are framed not as standalone anti-recurrence interventions but as components of a stress-attenuating bundle. Combined general and epidural anesthesia has been associated with increased intratumoral CD8-positive T-cell infiltration, reduced FOXP3-positive cell accumulation and lower postoperative inflammatory markers in lung and gastric cancer studies, and thoracic epidural analgesia reduced IL-6, norepinephrine, cortisol and ACTH during esophagectomy. Local anesthetics add direct biological signals: ropivacaine suppressed invasion through NaV1.5 channel effects, bupivacaine inhibited mitochondrial respiration and RhoA/ROCK-mediated migration in gastric cancer cells, and perioperative lidocaine reduced lung metastases in a murine breast tumor model. Randomized evidence, however, has not shown a stable recurrence benefit from anesthetic technique alone, and the authors emphasize that analgesia and recovery remain the most reliable benefits of regional approaches.

Pharmacologic adjuncts targeting the axis itself are attracting growing interest. Because prostaglandin E2 signaling through EP2 and EP4 receptors drives myeloid immunosuppression, perioperative NSAIDs or COX-2 inhibitors may partially relieve constraints on effector T and NK cells, and in vivo work shows COX inhibition can restrain tumor growth and alter PD-L1 expression and myeloid composition within tumors, although a single preoperative ketorolac dose did not improve disease-free survival in high-risk breast cancer. Beta-blockade combined with COX-2 inhibition improved markers of malignant potential, reduced epithelial-to-mesenchymal transition and remodeled immune infiltrates in a phase II breast cancer trial, and the PROSPER trial in pancreatic surgery confirmed safety with preliminary favorable signals. Immunonutrition, particularly omega-3 fatty acids that serve as precursors for pro-resolving lipid mediators, may further support inflammatory control and tissue repair within enhanced recovery pathways.

The review closes with an executable framework for individualized anesthetic planning built around three phases. Preoperatively, clinicians are encouraged to stratify risk using inflammatory and nutritional trajectories such as CRP-to-albumin ratios, neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios, and, in selected cases, circulating tumor DNA with standardized sampling windows. Intraoperatively, priorities include high-quality opioid-sparing multimodal analgesia, appropriate regional techniques, stable hemodynamics, normothermia and balanced fluid management, while avoiding unnecessary anesthetic depth. Postoperatively, trend-based monitoring should prompt early pain reassessment, early enteral nutrition and mobilization to shorten the duration of stress and inflammatory exposure. Embedded within ERAS pathways, the authors argue, anesthetic management becomes an integrated component of perioperative oncologic care: no single drug or technique constitutes an anti-recurrence strategy, but reducing stress peaks, limiting avoidable immunosuppressive exposure and accelerating recovery may collectively narrow the biological window through which cancer can exploit its own surgery.

Subject of Research: The perioperative stress–inflammation–immunosuppression axis and its influence on tumor progression and anesthetic management in cancer surgery

Article Title: Perioperative stress–inflammation–immunosuppression axis and tumor progression: mechanistic integration and anesthetic management strategies

Article References: Ye, L., Shen, H., Lin, J., Pei, S., Lin, F., Li, X., Chang, E., & Pan, L. (2026). Perioperative stress–inflammation–immunosuppression axis and tumor progression: mechanistic integration and anesthetic management strategies. Holistic Integrative Oncology, 5(1), Article 63. https://doi.org/10.1007/s44178-026-00280-x

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00280-x

Keywords: perioperative stress, surgical inflammation, immunosuppression, tumor progression, anesthetic management, natural killer cells, myeloid-derived suppressor cells, regulatory T cells, neutrophil extracellular traps, regional anesthesia, opioid-sparing analgesia, ERAS pathways

The research team, led by investigators at the University Hospital Zurich, examined 112 patients who died or suffered a recurrent myocardial infarction within one year of their initial event, matching each case one-to-one with a control patient of the same age, sex, infarct subtype, symptom-onset timing, and recruiting site. All blood samples were drawn within 24 hours of symptom onset, capturing the inflammatory landscape at a moment when standard clinical markers had often not yet begun their climb. Compared with controls, the patients who later experienced adverse outcomes had significantly higher plasma concentrations of IL-8, cell-free DNA, and myeloperoxidase, along with a higher neutrophil-to-lymphocyte ratio.

These three soluble markers tell a coherent biological story. Interleukin-8, also known as CXCL8, is released by endothelial cells, monocytes, and macrophages at the first sign of injury and creates a chemical gradient that draws neutrophils to the damaged myocardium. Once there, neutrophils expel neutrophil extracellular traps, web-like structures composed of cell-free DNA studded with enzymes such as myeloperoxidase. Although these traps serve a protective purpose against pathogens, in the setting of atherosclerosis they can activate platelets and coagulation factors, potentially worsening the very thrombotic process that caused the infarction. The simultaneous elevation of IL-8, cfDNA, and MPO in patients who fared poorly points to a hyperactive IL-8 and NET axis operating in the hours immediately after coronary occlusion.

Perhaps the most striking finding concerns timing. When patients were stratified by how quickly they reached the hospital after symptoms began, IL-8 levels were already significantly elevated in those presenting within three hours, whereas high-sensitivity troponin T only became clearly discriminative in late presenters beyond six hours. Within the hyper-acute window, IL-8 outperformed troponin, NT-proBNP, C-reactive protein, and kidney function markers in distinguishing future events from stable outcomes. After adjusting for these confounders, the association between IL-8 and the combined endpoint of death or recurrent infarction was strongest among early presenters, with an odds ratio of 2.65 for patients arriving within six hours of symptom onset.

The temporal analysis extended to the prognosis itself. When the researchers focused on early adverse events occurring within thirty days, the association between IL-8 and risk strengthened markedly, reaching an adjusted odds ratio of 4.47. A formal statistical test confirmed a significant interaction between IL-8 levels and symptom-onset time, meaning that the predictive value of this chemokine is genuinely tied to how early in the disease course the measurement is taken. This finding carries practical implications, because the first hours after symptom onset have long been a diagnostic blind spot in which traditional biomarkers lag behind the rapidly evolving pathology.

Within the group of patients who experienced adverse outcomes, those who died had higher IL-8 and cfDNA levels than those who survived with a recurrent infarction, suggesting that fatal outcomes are characterized by an even more intense neutrophil-driven inflammatory response. The neutrophil-to-lymphocyte ratio, a simple calculation available from any standard blood count, was likewise higher in the death subgroup, echoing results from large trials such as CANTOS, where each quartile increase in this ratio corresponded to a roughly twenty percent rise in major adverse cardiovascular events.

Unsupervised clustering of the inflammatory data added another layer of insight. When patients were grouped according to their combined profiles of IL-8, cfDNA, neutrophil-to-lymphocyte ratio, and high-sensitivity C-reactive protein, one cluster was significantly enriched in patients presenting with acute heart failure, defined clinically as a Killip Class of two or higher, and in those who ultimately died. This overlap between systemic inflammation and acute heart failure suggests that high IL-8 levels may partly reflect the mechanistic basis of pump dysfunction rather than merely accompanying it, although the observational design of the study cannot resolve whether inflammation causes heart failure or simply mirrors it.

The researchers also tested whether adding IL-8 to the widely used GRACE 2.0 risk score would improve its predictive accuracy. After rigorous cross-validation, neither IL-8 alone nor the combined panel of inflammatory markers produced a statistically significant improvement over the existing score for the overall cohort, likely because the score already captures much of the relevant risk and because late presenters diluted the hyper-acute signal. The authors therefore frame IL-8 not as a universal upgrade to existing risk tools but as a precision-medicine candidate for the specific subgroup of patients who present within hours of symptom onset.

Several caveats temper the enthusiasm. The study was observational and matched by design, so it cannot establish causality, and the lack of an IL-8 gene in mice complicates experimental efforts to probe the chemokine’s role directly. Genetic association studies hint that polymorphisms in the IL-8 promoter influence both circulating levels and acute coronary syndrome risk, but larger studies will be needed to determine whether IL-8 drives worse outcomes or simply reports on them. The authors also note that no clinical cutoff value for IL-8 can be proposed from a case-control design, and external validation in an independent cohort remains essential.

Even so, the prospect of a point-of-care IL-8 test, paired with the humble neutrophil-to-lymphocyte ratio, offers a tantalizing vision for emergency cardiology: a rapid, early, and biologically grounded assessment of risk during the very first hours of a heart attack, when every clinical decision carries the greatest weight. Therapies targeting IL-8 signaling are already being explored in oncology, and this study adds urgency to investigating whether similar approaches might one day quiet the inflammatory storm that follows myocardial infarction.

Subject of Research: Interleukin-8 and neutrophil-related biomarkers as prognostic markers for one-year mortality after acute myocardial infarction

Article Title: Interleukin-8 and other neutrophil-related biomarkers are associated with 1-year mortality in patients with acute myocardial infarction

Article References: Wang, Y.-J., Matter, M. A., Rossi, V. A., Heg, D., Costantino, S., Paneni, F., Gallino, C., Stähli, B. E., Räber, L., Windecker, S., Mach, F., Gencer, B., Klingenberg, R., Rodondi, N., Nanchen, D., Levesque, M. P., Demler, O. V., Ruschitzka, F., & Matter, C. M. (2026). Interleukin-8 and other neutrophil-related biomarkers are associated with 1-year mortality in patients with acute myocardial infarction. Clinical Research in Cardiology. https://doi.org/10.1007/s00392-026-03026-x

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03026-x

Keywords: interleukin-8, acute myocardial infarction, neutrophils, neutrophil extracellular traps, cell-free DNA, myeloperoxidase, neutrophil-to-lymphocyte ratio, biomarkers, mortality, inflammation, GRACE 2.0, cardiology

The new particles, described in Bioengineering & Translational Medicine, were created by researchers at the University of Michigan who wanted to solve a persistent problem in corticosteroid therapy. Dexamethasone has shown real promise in recent clinical trials for ARDS, improving outcomes where older steroids failed. Yet those benefits typically require high doses over prolonged regimens, and they appear limited to certain patient subgroups, with some patients actually faring worse after treatment. Free dexamethasone circulating through the bloodstream also triggers well-documented systemic effects, including neutrophilia, an abnormal rise in blood neutrophil counts, and lymphopenia, the depletion of lymphocytes. The Michigan team reasoned that if the drug could be packaged so that it preferentially reached neutrophils themselves, the therapeutic effect would be concentrated at the source of tissue damage while the rest of the body would be spared.

The fabrication strategy is elegantly simple. The researchers added an iron sulfate solution dropwise into a stirred solution of dexamethasone phosphate, triggering a nucleation-and-growth process in which amorphous iron-phosphate particles form with dexamethasone incorporated throughout the particle matrix. The resulting nanoparticles, dubbed Dex NP, measured approximately 75 nanometers in diameter with a zeta potential between negative 10 and negative 20 millivolts. Scanning electron microscopy confirmed uniform particle morphology, and energy-dispersive X-ray spectroscopy mapping showed that iron and dexamethasone phosphate were evenly distributed across each particle rather than segregated into layers. There was just one problem: when these first-generation particles were incubated with human neutrophils in whole blood, the cells ignored them completely. No internalization occurred, which meant the drug delivery concept would fail before it even left the bench.

The breakthrough came from reconsidering the particle surface. Nanoparticle behavior in blood is governed largely by the protein corona, the layer of plasma proteins that adsorbs onto the particle within seconds of exposure. Albumin, the most abundant plasma protein, is a known dysopsonin, meaning its presence on a particle surface actively discourages phagocytes from engulfing it. The team hypothesized that the ionic iron within the particle matrix could be exploited to change the surface chemistry. Because iron oxide can form at temperatures as low as 200 degrees Celsius in open air, the researchers heated their particles to 200, 215, and 230 degrees and monitored how the protein corona changed. Only temperatures above 215 degrees altered protein adsorption, so 215 degrees became the standard oxidation step, transforming Dex NP into DexOx NP.

Characterization confirmed the transformation worked exactly as intended. X-ray photoelectron spectroscopy of the top 10 nanometers of the particle surface revealed a shift from ferrous to ferric iron, consistent with iron oxide formation, while Fourier transform infrared spectroscopy showed that the characteristic peaks of dexamethasone phosphate survived the heating intact. This mattered because dexamethasone begins to thermally degrade only above 200 degrees Celsius, with degradation onset at 256 degrees under controlled heating rates, and the brief oxidation window used here was measured in minutes rather than the hour-long exposures that have degraded the drug in prior polymer studies. Release assays in phosphate-buffered saline at physiological temperature showed that dexamethasone emerging from the particles remained as therapeutically active as the free drug, confirming the payload was not compromised during manufacturing.

The biological consequences of oxidation were striking. When FITC-labeled particles were incubated in whole human blood and mouse blood, flow cytometry showed a distinct fluorescence shift in the neutrophil population for DexOx NP but not for the unoxidized particles, and confocal microscopy visualized the oxidized particles sitting inside neutrophils. Protein corona analysis explained why: total adsorbed protein dropped after oxidation, with marked reductions in the albumin and transferrin bands at roughly 60 and 80 kilodaltons, proteins known to adsorb poorly to iron oxide. Meanwhile, a slight increase in bands between 150 and 200 kilodaltons suggested immunoglobulins, which activate complement and drive phagocytosis, had taken their place. Less albumin blocking the surface and more immunoglobulin flagging the particle combined to make DexOx NP irresistible to neutrophils.

Safety testing came next, and the particles passed cleanly. DexOx NP caused no hemolysis of red blood cells, did not activate platelets, and left unactivated neutrophils untouched, indicating the particles could be infused systemically without triggering the very inflammation they were designed to treat. In activated neutrophils, however, the therapeutic effect was dramatic. When lipopolysaccharide was used to simulate bacterial activation, DexOx NP preserved L-selectin, an adhesion molecule shed during neutrophil activation, reducing shedding by 68 percent. This outperformed both free dexamethasone phosphate and the poorly internalized Dex NP, neither of which changed L-selectin expression at all. The effect depended on the glucocorticoid receptor, since mifepristone, a receptor antagonist, blunted the benefit, and control experiments with plain iron oxide particles confirmed the activity came from the dexamethasone rather than the metal.

The particles also tamed NETosis, the explosive process by which activated neutrophils expel DNA and intracellular contents, which drives tissue damage in ARDS. In neutrophils stimulated with phorbol 12-myristate 13-acetate, DexOx NP reduced total NET formation by 21 percent over five hours, while free dexamethasone phosphate, unoxidized particles, and cargo-free polystyrene particles had no effect. The mechanism likely involves inhibition of NADPH oxidase, the enzyme complex that initiates NET formation and whose p47phox subunit is a known corticosteroid target. Because internalized particles release dexamethasone directly into the cytosol where the glucocorticoid receptor resides, the team suggests the intracellular delivery route accelerates and amplifies the drug’s action compared with diffusion of free steroid from the extracellular fluid.

The decisive test came in a mouse model of acute lung injury, where lipopolysaccharide was instilled into the airways and treatments were injected into the tail vein one hour later. Both DexOx NP and free dexamethasone significantly reduced immune cell infiltration into the lungs, cutting total bronchoalveolar lavage cells by 37 and 34 percent respectively and neutrophil counts by 41 and 39 percent. Both treatments lowered the inflammatory cytokines IL-6 and TNF-alpha, and DexOx NP significantly reduced KC, a chemokine that recruits neutrophils to inflamed tissue. Cargo-free polystyrene particles, which neutrophils also engulf, did nothing, proving the benefit came from the drug rather than from particle diversion alone. Crucially, the side-effect profiles diverged sharply: free dexamethasone raised blood neutrophil counts by 57 percent and increased the neutrophil-to-lymphocyte ratio by 64 percent, classic signs of systemic steroid exposure, while DexOx NP produced neither effect. Liver enzymes, leukocyte counts, and body weight remained normal in healthy mice given the particles.

The findings point toward a broader strategy for taming acute inflammation without the blunt instrument of systemic steroids. Because the particles are composed of iron and the drug itself, with no exogenous polymer carrier, they avoid the stability, reproducibility, and loading problems that plague conventional formulations such as liposomes and PLGA particles. The researchers, who have filed a patent on composite drug particles, note that the approach could extend beyond dexamethasone to other corticosteroids and inflammatory diseases driven by neutrophil dysregulation. For a condition like ARDS, where clinicians have long struggled to harness steroid power without immunological collateral damage, a nanoparticle that speaks directly to the immune system’s most volatile cells represents a meaningful step toward precision anti-inflammatory medicine.

Subject of Research: Targeted dexamethasone nanoparticles that modulate neutrophil activity to treat acute neutrophilic inflammation and acute lung injury

Article Title: Iron‐dexamethasone nanoparticles mitigate acute neutrophilic inflammation

Article References: Felder, M. L., Guevara, M. V., Kupor, D., & Eniola‐Adefeso, O. (2026). Iron‐dexamethasone nanoparticles mitigate acute neutrophilic inflammation. Bioengineering & Translational Medicine, Article e70173. https://doi.org/10.1002/btm2.70173

Image Credits: AI Generated

DOI: 10.1002/btm2.70173

Keywords: neutrophils, dexamethasone, nanoparticles, acute lung injury, ARDS, drug delivery, inflammation, NETosis, protein corona, iron oxide, corticosteroids, immunomodulation

The epidemiological data assembled in the review are striking. Active cancer is present in roughly 5 to 10 percent of patients presenting with ischemic stroke, a proportion that rises among those with embolic stroke of undetermined source, the cryptogenic category in which no conventional mechanism can be identified. In 3 to 5 percent of such patients, the stroke actually precedes the cancer diagnosis by up to two years, making it the first clinical manifestation of an occult malignancy. Occult cancer is detected in about 5.3 percent of patients with embolic stroke of undetermined source, with the highest detection rate occurring in the early period after the stroke, at 14.3 per 1,000 person-months. Among cancer patients who do stroke, cancer-associated coagulopathy is the most frequent cause, accounting for 39.8 percent of cases, while traditional mechanisms such as large-artery atherosclerosis and cardioembolism from atrial fibrillation are comparatively less common.

Timing emerges as one of the most consistent signatures of the condition. The risk of hypercoagulability-related stroke peaks within the first six months after a cancer diagnosis, and many patients have already reached metastatic disease by the time the stroke occurs. Arterial thromboembolism more broadly shows a characteristic temporal pattern, with incidence peaking in the first year after cancer diagnosis, and stroke represents the majority of these arterial events at 71.6 percent. Although the risk declines after the first year, it remains elevated above that of the general population for as long as a decade. Histologically, adenocarcinoma dominates, with lung and pancreatic cancer most frequently implicated, followed by colorectal, breast and prostate malignancies. The interval between cancer diagnosis and stroke is particularly short in pancreatic and colorectal cancer, underscoring their especially potent thrombotic potential.

The pathophysiology described in the review is a layered interplay of tumor biology and hemostasis. Adenocarcinomas produce mucin, a heavily glycosylated molecule that, although largely cleared by the liver, can engage the adhesion molecules P-selectin and L-selectin to trigger the formation of platelet-rich microthrombi. Tumor cells also overexpress tissue factor, a transmembrane receptor that activates the coagulation cascade through the extrinsic pathway, and this expression is upregulated by oncogenic events such as inactivation of the p53 tumor suppressor and activating mutations in the K-ras oncogene. More recently, alterations in K-ras and the STK11 tumor suppressor gene have been linked to arterial thromboembolism risk, with hazard ratios of 2.22 and 3.48 respectively for stroke among individuals carrying versus lacking these alterations. A recent in vitro study in human pancreatic cancer cell lines further showed that thrombosis induced by tissue factor-expressing microvesicles depends predominantly on coagulation factors VIII and IX, with von Willebrand factor playing a lesser role.

Beyond mucins and tissue factor, the review highlights two additional mechanisms that have reshaped understanding of cancer-driven thrombosis. Circulating extracellular vesicles secreted by tumor cells have been measured by flow cytometry, and levels of cancer cell-derived vesicles are higher in patients with cancer-related stroke than in other groups, correlating with D-dimer levels but not with vesicle-associated tissue factor, which points to prothrombotic pathways beyond the canonical tissue factor route. In vitro experiments also found that vesicles from adenocarcinoma cell lines shorten clotting times more than those from squamous cell carcinoma, consistent with the clinical predominance of adenocarcinoma. Separately, neutrophil extracellular trap formation, or NETosis, has emerged as a key mediator: cancers sensitize peripheral neutrophils toward NET release via granulocyte colony-stimulating factor, and in stroke patients with cancer, NET-specific biomarkers such as plasma DNA, nucleosomes and citrullinated histone H3 are significantly elevated and correlate with D-dimer and thrombin-antithrombin complex levels. A post-mortem histopathological study even demonstrated widespread microvascular thrombosis in the brain, with H3Cit-positive cells embedded in multiple cerebral thrombi.

Clots physically retrieved from patients during thrombectomy provide direct confirmation of this biology. Thrombi from stroke patients with active cancer are platelet-rich and erythrocyte-poor, a composition most pronounced in those with non-bacterial thrombotic endocarditis, and immunohistochemical analysis shows significantly higher content of von Willebrand factor and citrullinated histone H3 in clots from patients with cancer. Proteomic studies have added further markers, identifying elevated levels of proteins associated with active cancer and immune responses, such as IGHG1 and vitronectin, in cancer-related clots. This distinctive composition has a practical radiological consequence: the absence of the susceptibility vessel sign on susceptibility-weighted imaging in patients with large-vessel occlusion is associated with active cancer, with a reported sensitivity of 27 percent and specificity of 85 percent, reflecting the fibrin- and platelet-heavy, red-cell-poor nature of the thrombus.

On brain imaging, the review identifies a pattern that should raise immediate suspicion. The hallmark of cancer-associated coagulopathy stroke is multiple ischemic lesions spanning more than two vascular territories on diffusion-weighted MRI, with microembolic dispersion seen in 78 percent of patients and prior silent infarcts in half. The most specific finding is the so-called three territories sign, defined by simultaneous bilateral lesions in three vascular territories spanning both anterior and posterior circulation. In the absence of infective endocarditis, this sign is highly specific for cancer-related stroke, and among patients with three-territory infarcts and no identifiable embolic source, approximately 75 percent of cases are malignancy-related. The number of affected territories independently predicts occult malignancy in cryptogenic stroke. Cortical and subcortical regions are most frequently affected, followed by the cerebellar hemispheres and corpus callosum, while deep structures and the brainstem are rarely involved.

Biomarker evidence converges on D-dimer as the single most useful test, despite its lack of specificity. Proposed diagnostic thresholds vary, with one study suggesting a cutoff of 5.5 micrograms per milliliter yielding 99.7 percent specificity and 92.9 percent positive predictive value, and a later study proposing 2.785 micrograms per milliliter with 50.9 percent sensitivity and 98.5 percent specificity. The authors caution, however, that different analytical platforms and reporting units, fibrinogen-equivalent versus D-dimer units, preclude a universal cutoff. D-dimer remains the only biomarker consistently associated with recurrent stroke and mortality in this population, and elevated levels after anticoagulant therapy predict early recurrence. Supporting markers include C-reactive protein above 20 milligrams per liter and fibrinogen above 600 milligrams per deciliter, both highly specific for occult malignancy in cryptogenic stroke, along with CA-125, elevated neutrophil-to-lymphocyte ratio above 15, and transcranial Doppler microembolic signals, though the latter show limited specificity. The NORSTROKE score, combining age, D-dimer, hemoglobin and smoking status, offers a probabilistic approach, estimating a 53 percent probability of active cancer in a patient under 75 with cryptogenic stroke, D-dimer above 3 milligrams per liter, hemoglobin below 12 grams per deciliter and a smoking history.

Treatment remains the weakest link in the evidence chain. Low-molecular-weight heparin and direct oral anticoagulants are the most commonly used secondary prevention strategies, with low-molecular-weight heparin generally preferred in gastrointestinal malignancies because of the higher bleeding risk of direct oral anticoagulants in that setting, while vitamin K antagonists are less effective. Comparative studies have shown broadly similar outcomes between agents: enoxaparin versus aspirin, direct oral anticoagulants versus enoxaparin, apixaban versus aspirin in a post hoc analysis of the ARCADIA trial, and oral edoxaban versus subcutaneous enoxaparin all failed to show significant differences in major bleeding, thromboembolism or survival. A recent retrospective study found no mortality or recurrence difference between anticoagulant and antiplatelet therapy, and a 2026 American Heart Association scientific statement concluded there is insufficient evidence to choose between anticoagulation and antiplatelet therapy for this indication. Current guidelines for cancer-associated thrombosis recommend at least three to six months of anticoagulation, extended when cancer remains active.

The prognosis statistics explain why the authors frame this as an urgent, underrecognized problem. Thirty-day mortality ranges from 25 to 50 percent, compared with 14 percent in stroke patients without cancer, and more than half of deaths occur within six months. The median modified Rankin Scale score at discharge is 3, and at three months 75.6 percent of patients remain at least moderately disabled. Recurrence rates reach 13.6 percent, roughly three times that of patients without cancer, with cumulative rates of 7 percent at one month and 16 percent at six months. When stroke is the first manifestation of occult malignancy, median survival is only 58 days, and median survival in cancer patients with cryptogenic stroke ranges from 62 to 365 days, versus 590 days for stroke of other causes. In patients with non-bacterial thrombotic endocarditis, up to 90 percent die or suffer recurrent stroke within six months. The review’s authors acknowledge limitations, including the predominance of retrospective observational data, the absence of prospective protocol registration, marked heterogeneity that prevented meta-analysis, and language restrictions to English and Spanish. They call for prospective multicenter cohorts, standardized D-dimer assays, external validation of the NORSTROKE score and randomized trials comparing low-molecular-weight heparin, direct oral anticoagulants and antiplatelet therapy. As cancer incidence rises and survival improves, they warn, the burden of this devastating stroke subtype will only grow, making earlier recognition and personalized antithrombotic strategies a clinical imperative.

Subject of Research: Ischemic stroke caused by cancer-associated coagulopathy, including its epidemiology, mechanisms, biomarkers, imaging features and treatment

Article Title: Stroke secondary to cancer-associated coagulopathy: a systematic review

Article References: Stroke secondary to cancer-associated coagulopathy: a systematic review. (n.d.). https://doi.org/10.1007/s00415-026-14119-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14119-y

Keywords: stroke, cancer-associated coagulopathy, Trousseau syndrome, adenocarcinoma, D-dimer, hypercoagulability, three territories sign, anticoagulation, low-molecular-weight heparin, direct oral anticoagulants, neutrophil extracellular traps, tissue factor

SALI is defined as an acute, secondary hepatic dysfunction that arises during sepsis and is observed in roughly 34 to 46 percent of patients. At the bedside it announces itself through abnormalities in standard liver tests, which can follow hepatocellular, cholestatic, or mixed patterns and range from modest enzyme elevations to profound liver failure. Crucially, the authors insist that SALI be treated as an operational clinical syndrome rather than the signature of a single underlying mechanism. Abnormal liver biochemistry in a septic patient may reflect inflammatory injury, cholestasis, hypoxic hepatitis caused by insufficient oxygen delivery, right-sided cardiac congestion, drug toxicity, or pre-existing conditions such as metabolic dysfunction-associated steatotic liver disease and occult fibrosis. The question, they argue, is not whether SALI has uniform biology, because it does not, but whether routinely available data can flag the patients most likely to deteriorate.

On the mechanistic side, one of the most striking recent findings concerns the gut. In a mouse model of sepsis, Murao and colleagues identified a pathway in which gut-primed neutrophils drive hepatic injury. Gut intraepithelial lymphocytes interact with neutrophils through the molecule CD112, facilitating the formation of neutrophil extracellular traps, the web-like DNA structures that neutrophils eject to ensnare pathogens. These primed neutrophils migrate through the portal vein into the liver, where they release their traps and activate Kupffer cells, the liver’s resident macrophages, triggering the secretion of interleukin-6 and tumor necrosis factor-alpha. Notably, portal vein neutrophils from septic mice produced significantly more neutrophil extracellular traps and induced greater Kupffer cell activation than systemic neutrophils, an effect that disappeared entirely in mice lacking PAD4, the enzyme essential for trap formation. The implication is provocative: the gut does not merely spill inflammatory mediators into the portal circulation, it actively educates immune cells that then inflict damage on distant organs.

Although the authors caution that translation to human disease requires care, the concept has clear clinical resonance. The liver receives most of its blood supply from the portal circulation and is therefore continuously bathed in gut-derived inflammatory signals. During sepsis, disruption of the intestinal barrier allows bacterial translocation and the spillover of pathogen-associated molecular patterns, which activate hepatic Toll-like receptors. Supporting this mechanistic bridge, human data from Czaikoski and colleagues have shown that neutrophil extracellular traps accumulate in organ tissue during experimental and clinical sepsis and correlate with damage. Together, these findings nominate trap formation and downstream Kupffer cell activation as candidate precision-medicine targets in SALI.

A second biological pillar concerns the loss of hepatic immune tolerance. In health, the liver is a strikingly tolerant organ, and Kupffer cells orchestrate that tolerance through antigen clearance and the induction of regulatory T cells. Recent work shows that during hepatic inflammation this tolerogenic phenotype collapses: Kupffer cells lose their signature tolerance markers, and antigen presentation shifts to infiltrating monocyte-derived macrophages. Activated Kupffer cells then recruit further immune cells to the liver, amplifying injury. Evidence from viral hepatitis research suggests that the transition from tolerance to inflammation involves dysregulation of inhibitory pathways, such as the Toll-like receptor pathway inhibitor SHIP, that normally restrain receptor signaling and keep Kupffer cells quiescent. Hepatic stellate cells, likewise, depend on inhibitory signals to remain dormant; when stimulated by microbial products or damage-associated molecular patterns, they produce extracellular matrix proteins and profibrogenic cytokines, and their contractile activation can raise sinusoidal resistance and portal pressure. Toll-like receptor 4-dependent crosstalk between Kupffer cells and stellate cells converts inflammatory signals into profibrogenic activation.

Within sepsis specifically, the inflammatory polarization of Kupffer cells toward the M1 phenotype has emerged as a hallmark of SALI. Extracellular cold-inducible RNA-binding protein, a damage-associated molecular pattern released during stress, promotes this M1 polarization through Toll-like receptor 4 signaling, driving overproduction of inflammatory cytokines. In mouse sepsis models the ratio of M1 to M2 Kupffer cells rises sharply, indicating a decisive shift toward proinflammatory function, and this polarization is not merely a byproduct of inflammation but an active driver of hepatocyte injury through reactive oxygen species, cytokines, and the recruitment of more neutrophils. In parallel, regulated forms of cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, appear to contribute to hepatocyte dysfunction. These converging mechanisms point toward the restoration of hepatic immune tolerance as a promising future therapeutic strategy, though no SALI-targeted therapy has yet been established.

It is on the clinical side that the commentary delivers its most immediately practical message. In a retrospective cohort study spanning two large intensive care cohorts, Palmowski and colleagues examined how well routine biomarkers could stratify mortality risk among patients meeting operational criteria for SALI, defined as sepsis-associated liver-test abnormalities within seven days of sepsis onset, excluding pre-existing chronic liver disease. The criteria included alanine aminotransferase at five or more times the upper limit of normal, alkaline phosphatase at twice the upper limit, or elevated bilirubin combined with enzyme elevations. Their central finding was that the De Ritis ratio, the simple ratio of aspartate to alanine aminotransferase, outperformed both the conventional R-factor and alanine aminotransferase alone in predicting thirty-day mortality. A ratio of one or below indicated low risk, values between one and two indicated intermediate risk, and values of two or above flagged the highest risk, a pattern consistent across infection sources and admission types.

The authors of the commentary are careful to frame these strata correctly. The De Ritis ratio is not a liver-specific diagnostic marker or a mechanistic endotype, and elevated aspartate aminotransferase can also signal hypoxic hepatitis, shock, right-sided congestion, systemic inflammation, chronic kidney disease, alcohol-related injury, or cardiometabolic comorbidity. Its pragmatic value lies in risk enrichment among patients who already meet operational SALI criteria, complementing rather than replacing SOFA-bilirubin scoring. Interpreted alongside the SOFA score, lactate, hemodynamic status, cardiac context, and comorbidities, a rising ratio should trigger a structured reassessment: is infection control optimized, are hemodynamics adequate, is the lactate trajectory improving, is there occult congestion or biliary obstruction, are hepatotoxic drugs on board, and does the patient carry underlying fibrosis risk? In this framework, routine liver tests define the dominant biochemical injury pattern, whether hepatocellular, cholestatic, or mixed, and link prediction to the prevention of further hepatic and systemic deterioration and of iatrogenic harm.

The translational pathway forward, the authors suggest, will require prospective studies testing whether serial liver tests, the De Ritis ratio, SOFA scores, lactate, hemodynamic data, and immune readouts such as monocyte HLA-DR expression or ex vivo monocyte cytokine responses can identify reproducible SALI trajectories and clinically actionable phenotypes. Preclinical work has already nominated an unusually rich set of therapeutic targets, including neutrophil extracellular trap formation, Kupffer cell polarization, inflammasome activation, ferroptosis, necroptosis, and the restoration of hepatic immune tolerance. Until such approaches are validated, however, current clinical utility remains deliberately pragmatic: recognize SALI early, classify the dominant biochemical pattern, stratify mortality risk with the De Ritis ratio, hunt actively for reversible contributors, and intensify surveillance in high-risk patients.

For the authors, the larger significance of this work lies in adding an organ-specific decision layer to the 2026 Surviving Sepsis Campaign framework. New-onset liver-test abnormalities in septic adults, they argue, should no longer be treated as incidental laboratory noise. When detected, the humble ratio of two transaminases, a calculation older than modern critical care and available in every hospital on earth, may identify the patients who need intensified monitoring and protection from modifiable second hits, while the expanding immunobiology of the gut-liver axis steadily maps the routes toward genuine precision medicine for a complication that affects as many as one in two patients with sepsis.

Subject of Research: Sepsis-associated liver injury: immunobiology and bedside risk stratification with routine liver tests

Article Title: Sepsis-associated liver injury: from liver-test risk signals to immunobiology-guided precision medicine

Article References: Katsounas, A., Tsochatzis, E., & Rello, J. (2026). Sepsis-associated liver injury: from liver-test risk signals to immunobiology-guided precision medicine. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08593-1

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08593-1

Keywords: sepsis-associated liver injury, De Ritis ratio, Kupffer cells, neutrophil extracellular traps, gut-liver crosstalk, hepatic immune tolerance, risk stratification, intensive care, Toll-like receptors, precision medicine, Sepsis-associated, liver

The scale of neutrophil involvement in cancer is staggering. Neutrophils are the most numerous circulating leukocytes in humans, produced at a rate of roughly one hundred billion cells per day in the bone marrow, and they can constitute the dominant immune population within many solid tumors. Large-scale analyses of the tumor immune landscape across human cancers have repeatedly found that high intratumoral neutrophil content correlates with poor prognosis in numerous malignancies, including renal cell carcinoma, head and neck cancer and non-small cell lung cancer. The neutrophil-to-lymphocyte ratio, a simple blood measurement, has emerged as one of the most robust prognostic biomarkers in oncology, predicting outcomes across tumor types and even forecasting response to immune checkpoint inhibitors.

Why would the immune system’s first responders become cancer’s accomplices? The answer, the review argues, lies in the extraordinary plasticity of neutrophils and their exquisite sensitivity to environmental cues. Tumors are, in the words of a classic 1986 observation by Harold Dvorak, wounds that do not heal, and neutrophils are the cells that respond to wounds. Cancers exploit the same inflammatory programs that neutrophils deploy during tissue repair. Tumor-derived signals such as granulocyte colony-stimulating factor, transforming growth factor-beta, interleukin-8 and other chemokines reprogram both the production and the function of neutrophils, driving emergency granulopoiesis in the bone marrow and recruiting immature, immunosuppressive granulocytes into the circulation and the tumor bed.

Once inside the tumor microenvironment, neutrophils promote cancer through several mechanistically distinct pathways. They release vascular endothelial growth factor and, critically, matrix metalloproteinase-9, an enzyme that liberates sequestered VEGF from the extracellular matrix and triggers the angiogenic switch that transforms a dormant lesion into a growing tumor. Studies in mouse models of multistage carcinogenesis showed that infiltrating neutrophils mediate this initial angiogenic switch, and human neutrophils are unique in releasing MMP-9 free of its natural inhibitor TIMP-1, making it an especially potent driver of new blood vessel formation. Neutrophil elastase, another granule protease, can degrade insulin receptor substrate-1 in tumor cells to accelerate lung tumor growth, and myeloid cell-derived reactive oxygen species have been shown to induce mutagenesis in adjacent epithelial cells, directly fueling the genomic instability that drives malignant transformation.

Perhaps no neutrophil behavior has attracted more attention in recent years than the formation of neutrophil extracellular traps, or NETs. First described in 2004 as web-like structures of DNA, histones and granule proteins that ensnare bacteria, NETs have since been implicated in a remarkable range of tumor-promoting processes. Recent work published in Nature demonstrated that NETs drive vascular occlusion, tumor necrosis and metastasis, linking phenomena long thought to be independent. NETs can sequester circulating tumor cells, shielding them from cytotoxic lymphocytes and natural killer cells; NET-associated DNA can bind the receptor CCDC25 on cancer cells, directing their migration; and NETs produced during systemic inflammation can awaken dormant cancer cells, triggering metastatic relapse years after primary tumor removal. Strikingly, the metastatic spread of breast cancer has been shown to accelerate during sleep, when rhythmic fluctuations in circulating neutrophils and cancer cell dynamics converge.

Neutrophils also construct the pre-metastatic niche, the distant soil that primary tumors prepare to receive their disseminated seeds. Tumor-derived factors mobilize neutrophils and their progenitors to future metastatic sites, where they suppress natural killer cell activity, remodel the extracellular matrix and create an immunologically permissive environment. In breast cancer models, neutrophils support the lung colonization of metastasis-initiating cells, and chronic stress has been shown to increase metastasis through neutrophil-mediated changes to the microenvironment. Even glucocorticoids, widely used clinically, can promote breast cancer metastasis by acting on these cells. The circadian biology of neutrophils, governed by an intrinsic molecular timer that coordinates immune defense and vascular protection, adds another layer of complexity to how and when these cells enable metastatic spread.

Yet the story is emphatically not one-directional. The review devotes substantial attention to the antitumor capacities of neutrophils, which many of the same molecules can mediate depending on context. Neutrophil elastase, which promotes tumor growth in some settings, has been shown in other contexts to selectively kill cancer cells and attenuate tumorigenesis, with important differences between mouse and human neutrophils in the production of its inhibitor, secretory leukocyte proteinase inhibitor. Activated neutrophils exert direct cytotoxicity against melanoma cells through reactive oxygen species, and tumor-associated neutrophils in early-stage human lung cancer can stimulate T cell responses rather than suppress them. Tumor-entrained neutrophils have even been shown to inhibit metastatic seeding in the lung, providing early evidence of spontaneous antimetastatic function. The pro- versus antitumor polarization of neutrophils, famously framed as N1 versus N2 states, is now understood to reflect a continuum of environmentally determined functional states rather than fixed identities.

This dual nature is precisely what makes neutrophils such compelling therapeutic targets. The review highlights several promising strategies. Neutrophil-activating therapy, developed by the Stanford group, demonstrated that pharmacologically activated neutrophils can eradicate tumors and reduce metastases independently of adaptive immunity. CD40 agonist antibodies recruit a subset of neutrophils associated with tumor control, and T cell immunotherapies have been shown to engage neutrophils to eliminate antigen-escape variants that would otherwise survive checkpoint blockade. Bacille Calmette-Guerin, the century-old tuberculosis vaccine used to treat bladder cancer, works in part by reprogramming hematopoiesis so that neutrophils develop the capacity to attack tumor cells, and interferon-gamma induces NET formation with tumor-killing activity in colorectal cancer. On the inhibitory side, CXCR2 antagonists, peptidyl arginine deiminase 4 inhibitors that block NET formation, arginase inhibitors, and antibodies that block the NET-associated immunosuppressive enzyme arginase-1 are all in clinical development, several in combination with checkpoint inhibitors.

Antibody-based approaches represent another frontier. Neutrophils are extraordinarily potent mediators of antibody-dependent cellular cytotoxicity, and IgA antibodies in particular trigger superior neutrophil-mediated killing of cancer cells compared with conventional IgG, engaging the Fc-alpha receptor to produce vigorous respiratory bursts and trogoptosis, a process in which neutrophils progressively strip membrane fragments from antibody-coated targets. Combining IgA-based therapeutics with blockade of the CD47-SIRP-alpha innate immune checkpoint, which prevents phagocytosis, has shown enhanced neutrophil cytotoxicity against neuroblastoma and other malignancies. Even more ambitiously, researchers have engineered chimeric antigen receptor neutrophils derived from induced pluripotent stem cells, which possess potent activity against solid tumors and can serve as delivery vehicles for tumor-microenvironment-responsive nanodrugs in glioblastoma. Neutrophils bearing adhesive polymer micropatches have been proposed as a drug-free immunotherapy platform.

The authors caution that translating these findings into the clinic requires resolving fundamental questions about neutrophil heterogeneity, nomenclature and species differences. A consensus statement has established standards for myeloid-derived suppressor cell classification, and recent single-cell atlases have mapped neutrophil developmental trajectories across tissues and disease states, revealing that mature and immature neutrophils converge on similar transcriptional signatures within tumors. Human and mouse neutrophils differ in important ways, including their circadian rhythms, granule composition and lifespan, with human neutrophils surviving approximately five days rather than hours as once believed. Nevertheless, the convergence of mechanistic insight, biomarker validation and early clinical activity suggests that the field has reached an inflection point. Neutrophils, long dismissed as terminally differentiated foot soldiers, are now recognized as master regulators of the tumor ecosystem, and learning to command them, rather than simply deplete them, may define the next era of cancer immunotherapy.

Subject of Research: The roles of neutrophils in tumor progression, immunosuppression, metastasis and cancer therapy

Article Title: Neutrophils in cancer

Article References: Diehl, M. I., Basto, P. A., Abikenari, M. A., Linde, I. L., Okwan-Duodu, D., & Engleman, E. G. (2026). Neutrophils in cancer. Nature Reviews Cancer. https://doi.org/10.1038/s41568-026-00968-2

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00968-2

Keywords: neutrophils, cancer, tumor microenvironment, neutrophil extracellular traps, metastasis, immunosuppression, angiogenesis, tumor-associated neutrophils, immunotherapy, myeloid-derived suppressor cells, NETosis, granulopoiesis

The mechanistic heart of the review is the positive feedback loop it describes between cancer cells, tumor-associated neutrophils and NETs. Tumor cells orchestrate the reprogramming of neutrophils through paracrine signaling: they secrete chemokines such as CXCL1 and CXCL2, which recruit neutrophils via the CXCR1 and CXCR2 receptors, and cytokines including IL-1β, IL-8, granulocyte colony-stimulating factor and tumor-derived exosomes carrying mutant KRAS. Once in the tumor microenvironment, these neutrophils can be pushed toward NET formation by hypoxia, acidity, collagen signaling through DDR1, and stromal inputs from cancer-associated fibroblasts. The NETs themselves then feed back on the tumor, activating pro-growth pathways such as ERK and NF-κB, promoting epithelial-mesenchymal transition and reinforcing the very signals that recruit more neutrophils. This self-amplifying circuit explains why circulating and tumor-infiltrating NETs correlate so consistently with advanced disease in breast, pancreatic, gastric, colorectal and hepatocellular cancers, among others studied to date.

At the molecular level, NET formation, or NETosis, is a carefully choreographed demolition of the neutrophil’s own architecture. In the classical suicidal pathway, signaling through reactive oxygen species generated by the NADPH oxidase complex activates protein arginine deiminase 4, or PAD4, an enzyme that hypercitrullinates histone H3. Citrullination loosens the electrostatic grip of histones on DNA, driving chromatin decondensation, nuclear envelope breakdown and ultimately the explosive extrusion of decondensed DNA decorated with granule proteins. Neutrophil elastase and myeloperoxidase translocate to the nucleus to assist this dismantling, while cathepsin G and proteinase 3 join the final trap. Alternative routes exist as well: viable neutrophils can expel mitochondrial DNA to form traps without dying, and rapid, nuclear-based release has been documented within minutes of certain bacterial encounters. Which pathway dominates appears to depend on the stimulus, a specificity confirmed by comparative proteomic analyses showing that NETs induced by different triggers carry distinct protein cargoes.

As weapons of metastasis, NETs act on several fronts simultaneously. Their DNA scaffolds physically enmesh circulating tumor cells in the bloodstream, increasing adhesion to the vascular endothelium and creating a protective nidus in which disseminated cells can extravasate and colonize distant organs. Proteases embedded in the traps, notably matrix metalloproteinase-9 and neutrophil elastase, remodel the extracellular matrix and, in pancreatic cancer, activate quiescent stellate cells and cancer-associated fibroblasts that prepare fertile ground for micrometastases. Landmark work in mice showed that NETs produced during inflammation can rouse dormant cancer cells, explaining recurrences years after primary tumor removal. The traps also subvert immunity directly: NET-associated DNA can bind TMCO6 on T cells to impair CD8-positive cytotoxic function, upregulate the immunosuppressive enzyme CD73, decorate themselves with PD-L1, promote T cell exhaustion and foster T regulatory cell infiltration. In this sense, NETs function as both physical scaffolds for spread and chemical camouflage against the immune system, a dual role that the review identifies as central to immune evasion and distant metastasis.

The consequences extend to treatment resistance, one of oncology’s most stubborn bottlenecks. NETs generated during chemotherapy confer resistance by activating latent TGF-β, while the dense DNA matrix limits the diffusion of drugs such as doxorubicin, blunting its ability to trigger apoptosis in ovarian cancer cells. In bladder cancer, NETs contribute to radiation resistance, and low-dose ionizing radiation itself can provoke NET extrusion, an unsettling feedback. Immune checkpoint blockade suffers too: NET formation driven by IL-17 signaling mediates resistance in pancreatic cancer, cirrhotic extracellular matrix initiates immunosuppressive NETs that attenuate anti-PD-1 responses in hepatocellular carcinoma, and IGF2BP3-induced NETosis undermines oncolytic virotherapy in malignant glioma. Conversely, the review emphasizes that targeted disruption of the NET axis reverses these resistances and sensitizes tumors to radiotherapy, chemotherapy and checkpoint inhibitors, positioning NETs as genuinely novel therapeutic targets rather than mere biomarkers of misfortune.

A notable theme of the review is the breadth of candidate drugs capable of disarming the NET machinery, many of them repurposed from other fields. Anthracyclines suppress both NADPH oxidase-dependent and -independent NETosis; the antiparasitic ivermectin abrogates NETs and prevents melanoma metastasis in preclinical models; chloroquine and hydroxychloroquine reduce trap formation partly by inhibiting PAD4; and the glucagon-like peptide-1 receptor agonists liraglutide and exenatide enhance checkpoint blockade efficacy by attenuating NETs in lung and liver cancers. Metformin mitigates obesity-driven NET-driven tumor aggressiveness in mice, the nuclear export inhibitor selinexor blocks human NET formation in vitro, and histidine-rich glycoprotein suppresses hepatic metastatic seeding. Even traditional Chinese medicine formulations, from Huang Qin Decoction to Pi Ji Pills, and phytochemicals such as kaempferol, resveratrol, epigallocatechin-3-gallate and emodin, have been shown to interfere with the ROS-PAD4, STAT3-CXCL8 and PI3K-AKT pathways that drive trap formation. Biomaterials approaches, including NET-degrading enzyme hydrogels applied after surgery, and localized photoregulated enzyme delivery, offer physically targeted ways to dismantle traps at metastatic sites.

Translating these discoveries into the clinic depends on measuring NETs reliably, and the review devotes substantial attention to detection technology. The most widely used circulating markers are cell-free DNA, nucleosomes, myeloperoxidase-DNA and neutrophil elastase-DNA complexes, and citrullinated histone H3, the latter quantified by increasingly refined enzyme-linked immunosorbent assays validated in human plasma. Flow cytometric assays allow direct enumeration of NET-bearing structures in blood, atomic force microscopy has resolved the physical architecture of individual traps, and microfluidic chips can capture chromatin fibers from a single drop of blood, while computational image-analysis algorithms now standardize histological quantification. Clinically, peripheral blood NET biomarkers have been associated with diagnosis and progression of malignant tumors, trap-associated CEACAM1 has been proposed as a therapeutic target in metastatic colon cancer, and PD-L1-positive neutrophils releasing NETs in malignant ascites show promise as a hepatocellular carcinoma biomarker. Gene-expression signatures built around NET-related genes and long non-coding RNAs predict prognosis and immunotherapy response across gastric, breast, colon, lung, head-and-neck and soft-tissue cancers, although the review cautions that inconsistent findings and tumor heterogeneity still constrain their deployment.

The prognostic potential is especially striking. Tumor-infiltrating NETs predict post-surgical survival in pancreatic ductal adenocarcinoma, blood NETosis correlates with progression in head and neck cancer, pan-cancer signatures built from NET-associated genes stratify patient outcomes, and a NET-score has emerged as a prognostic marker in colorectal cancer. NETs also influence cancer-associated thrombosis, a major cause of morbidity: tumor-derived exosomes induce NETs that establish hypercoagulability, and IL-1β blockade attenuates thrombosis in NET-dependent breast cancer models. Yet the review is candid about limitations. Detection technologies remain imperfect and poorly standardized, prognostic modeling must contend with heterogeneous patient populations, and some research findings conflict, reflecting context-dependent roles of neutrophil subsets that range from antitumor to pro-tumor. Aging itself alters NET biology, complicating extrapolation from young animal models to elderly patients. Future work, the authors argue, should prioritize optimizing detection methods, conducting rigorous clinical validation and identifying tumor-type-specific therapeutic targets.

The broader message is that the immune defense once celebrated for strangling microbes has become a central hub in cancer biology, one that links inflammation, dormancy, metastasis, thrombosis and treatment failure within a single mechanistic framework. By mapping the regulatory factors, from PAD4 and neutrophil elastase to CXCL chemokines and TGF-β, and by cataloguing both the pharmacological and biomaterial tools that can interrupt them, the review provides a theoretical basis for bringing NETs into precision oncology. If the technical and validation challenges can be overcome, clinicians may one day read a patient’s NET profile the way they now read hormone receptor status, and use NET-disrupting agents to prevent metastasis and sensitize tumors to the therapies already at hand. For now, the convergence of mechanistic insight, assay development and drug repurposing suggests that a web once woven for defense is becoming an actionable thread in the fight against cancer.

Subject of Research: Neutrophil extracellular traps in tumor progression, detection and diagnosis

Article Title: Neutrophil extracellular traps in tumor progression: from mechanistic insights and regulatory factors to clinical detection and diagnosis

Article References: Neutrophil extracellular traps in tumor progression: from mechanistic insights and regulatory factors to clinical detection and diagnosis. (n.d.). https://doi.org/10.1007/s00109-026-02709-2

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02709-2

Keywords: neutrophil extracellular traps, tumor-associated neutrophils, metastasis, immune evasion, therapy resistance, PAD4, cancer biomarkers, tumor microenvironment, diagnosis, checkpoint blockade, NETosis, precision oncology

The research team, led by Yash Bisht and Ashok Kumar Ahirwar, drew on three publicly available datasets from the Gene Expression Omnibus repository. The discovery dataset, GSE102215, contained RNA sequencing data from neutrophils of nine seropositive antiphospholipid syndrome patients and nine healthy controls. Two additional datasets served as exploratory replication cohorts: GSE50395, a microarray study of monocytes from three patients and three controls, and GSE312344, which profiled plasma exosomal RNA from three women with obstetric antiphospholipid syndrome and three healthy donors. Because these datasets differed in cell type, platform, and sample size, the researchers describe their approach as a directional comparison rather than formal meta-analysis, and they are careful to frame all cross-dataset findings as preliminary.

Using the DESeq2 statistical framework, the team identified 2,425 significantly differentially expressed genes in antiphospholipid syndrome neutrophils, with 1,277 genes upregulated and 1,148 downregulated. Among the most striking signals was a robust interferon signature. The genes IFIT1, with a log2 fold change of plus 3.13, MX1 at plus 2.32, STAT1 at plus 1.12, and IRF7 at plus 1.14 were all strongly activated, echoing earlier transcriptomic studies of the syndrome. Additional dysregulated genes included LILRA5, ALPL, THBD, and the downregulated transcripts HEMK1, DYNC2H1, and AUTS2. A hierarchical clustering heatmap of the fifty most altered genes separated patients and controls completely, a sign that the transcriptional differences were consistent across all samples rather than driven by outliers.

Pathway enrichment analysis added biological texture to these numbers. Gene Set Enrichment Analysis revealed significant activation of the proteasome pathway, with a normalized enrichment score of 2.15 and immunoproteasome subunits such as PSMB9 among the leading-edge genes, and of neutrophil extracellular trap formation, with a score of 1.87. These DNA-histone-protein webs, expelled by activated neutrophils, are increasingly recognized as central drivers of thrombosis in antiphospholipid syndrome, where antiphospholipid antibodies can trigger their release through TLR4 and reactive oxygen species signaling. The authors caution, however, that enrichment of trap-associated transcripts does not confirm actual trap formation; functional assays measuring citrullinated histone H3, cell-free DNA, or PAD4 activity would be needed to demonstrate NETosis directly. KEGG analysis also flagged cytokine-cytokine receptor interactions, MAPK signaling, and Th17 cell differentiation as significantly enriched pathways.

The centerpiece of the study is its long non-coding RNA discovery. Of 171 candidate lncRNA-annotated genes identified by name-based pattern matching in the discovery dataset, twenty-four were significantly dysregulated in patient neutrophils. The most strongly downregulated was LINC00515, with a log2 fold change of minus 3.38. MIR155HG, the host gene from which the inflammatory microRNA miR-155 is processed, was downregulated at minus 2.25, a finding that dovetails with prior work showing reduced miR-155 in monocytes of antiphospholipid syndrome patients. MIR210HG, MIAT, and SNHG7 were also significantly reduced, while LINC00493 and WDFY3-AS2 stood out among the upregulated candidates. Five of the significant candidates showed very low expression abundance, and the authors flag them as requiring cautious interpretation.

To explore how these non-coding RNAs might interact with the microRNA landscape, the researchers submitted the dysregulated candidates to miRNet 2.0, a network analysis platform drawing on predicted interactions from the starBase database. Thirteen of the twenty-four candidates mapped into a network of 294 predicted lncRNA-microRNA pairs spanning 389 edges. SNHG7 emerged as the top hub, with a degree of 70 and a betweenness centrality of 19,264, suggesting it could theoretically connect to and regulate an unusually large share of the microRNA pool. In other disease contexts, SNHG7 has been shown to modulate inflammatory pathways, including the miR-425-5p/TRAF5/NF-kB axis in neuroinflammation and the miR-485-5p/FSP1 axis in osteoarthritis. Whether SNHG7 acts as a competing endogenous RNA sponge in antiphospholipid syndrome neutrophils cannot be determined from transcriptomic data alone, and the authors emphasize that their network captures predicted interactions only.

A protein-protein interaction network built from the full set of differentially expressed genes placed STAT1 at the center of the molecular conversation, with a degree of 160, ahead of UBC, GRB2, FYN, JUN, IL6, and TLR4. This finding reinforces the established role of interferon-driven STAT1 signaling in the syndrome and validates the technical quality of the underlying dataset. An exploratory machine learning analysis, reported in the supplementary material as a proof of concept, combined LASSO feature selection with a random forest classifier and produced a perfect leave-one-out cross-validation area under the curve on eighteen samples. The authors are refreshingly candid about this result: with nine features selected from eighteen samples, and feature selection performed outside the cross-validation folds, the classifier almost certainly overfits the data and must not be interpreted as diagnostic performance. They note only that two long non-coding RNAs appeared among the top features, a hypothesis-generating observation for future larger studies.

Cross-dataset comparison offered modest but informative support. Against the monocyte microarray dataset, six of nine prespecified genes showed concordant direction of change, a 67 percent directional agreement rate, with the interferon genes STAT1, MX1, IRF7, and IFIT1 all upregulated in patient monocytes as in neutrophils. Three genes, LILRA5, PSMB9, and JUN, were discordant, likely reflecting genuine cell-type-specific expression patterns. SNHG7 showed nominal downregulation in the obstetric exosomal dataset as well. The authors stress that these comparisons are qualitative and limited by tiny sample sizes of three per group and by cross-platform differences that make direct fold-change comparisons unreliable.

The study arrives at a moment when the field has explicitly called for this kind of work. A 2025 systematic review identified long non-coding RNA research in antiphospholipid syndrome as a major gap, and the only prior lncRNA study in the disease, by Guzman-Martin and colleagues, had reported dysregulation of FGD5-AS1, OIP5-AS1, and GAS5 in monocytes. The new findings extend the non-coding RNA map into neutrophils, the very cells whose extracellular traps drive much of the thrombotic burden. They also raise an intriguing, if entirely speculative, possibility relevant to seronegative antiphospholipid syndrome, the perplexing subset of patients who display all clinical hallmarks of the disease yet test persistently negative on standard antibody assays. No such patients were included in this study, and the authors are unambiguous that any implications for seronegative disease are untested. Still, the hypothesis that RNA-level dysregulation might operate independently of antibody production offers a testable framework for future cohorts.

The limitations of the work are numerous and openly acknowledged: small samples, datasets originally generated for other purposes, absent clinical metadata such as age, sex, and medication status, and a lupus NETosis origin for the discovery dataset that complicates attribution of disease-specific signals. The lncRNA identification strategy relied on gene symbol pattern matching rather than formal transcript biotype annotation, and the interaction network rests entirely on predictions without accompanying microRNA expression data. Yet the researchers lay out a clear path forward, proposing quantitative PCR profiling of candidate microRNAs, luciferase assays to validate SNHG7-microRNA interactions, knockdown and overexpression experiments in neutrophil models, and replication in large, prospectively recruited cohorts including seronegative patients. Until those experiments are done, the study stands as a carefully hedged but genuinely novel cartography of the non-coding RNA landscape in antiphospholipid syndrome, pointing investigators toward SNHG7 and its neighbors as candidate regulators worth pursuing in the hunt for the missing molecular layers of a thrombotic autoimmune disease.

The competing endogenous RNA framework underlying this work rests on a simple idea: because microRNAs silence messenger RNAs by binding complementary sequences, transcripts that share microRNA response elements can titrate one another’s repressors. Long non-coding RNAs, with lengths exceeding two hundred nucleotides and often multiple binding sites, are well suited to act as such molecular sponges. In autoimmune disease, this mechanism has already been implicated in inflammatory regulation, and the SNHG7-centered network identified here echoes a previously characterized miR-425-5p/TRAF5/NF-kB axis, lending biological plausibility to the computational predictions.

The interferon signature observed in the discovery dataset also fits a broader pattern. Type I interferon signaling is a recognized transcriptomic hallmark of antiphospholipid syndrome, and the prominence of STAT1 as the top protein interaction hub, with a degree of 160, aligns with the known biology of interferon-driven neutrophil priming. Because antiphospholipid antibodies can provoke neutrophil extracellular trap release through TLR4 and reactive oxygen species, the concurrent enrichment of trap formation pathways and dysregulated non-coding RNAs in the same cells suggests a regulatory layer worth testing experimentally. The 2023 ACR/EULAR classification criteria, meanwhile, continue to define the disease by antibodies alone, underscoring why transcriptomic approaches that operate independently of antibody status may prove valuable for patients who fall outside conventional serological detection.

Subject of Research: Identification of dysregulated long non-coding RNAs and predicted lncRNA-microRNA interactions in antiphospholipid syndrome through cross-dataset transcriptomic analysis

Article Title: Identification of candidate dysregulated lncRNAs and predicted lncRNA–miRNA interactions in antiphospholipid syndrome via cross−dataset transcriptomic analysis

Article References: Bisht, Y., Joshi, S. S., Yadav, K., Tiwari, H., Tyagi, S., Sangwan, H., & Ahirwar, A. K. (2026). Identification of candidate dysregulated lncRNAs and predicted lncRNA–miRNA interactions in antiphospholipid syndrome via cross−dataset transcriptomic analysis. Discover Informatics, 1(1), Article 14. https://doi.org/10.1007/s44564-026-00014-1

Image Credits: AI Generated

DOI: 10.1007/s44564-026-00014-1

Keywords: antiphospholipid syndrome, long non-coding RNAs, lncRNA-miRNA interactions, neutrophils, interferon signaling, neutrophil extracellular traps, SNHG7, MIR155HG, transcriptomics, seronegative APS, competing endogenous RNA, autoimmune thrombosis