We conducted blood-based metabolomic profiling in ovarian cancer and determined its clinical relevance. NMR spectroscopy was performed on a total of n = 760 longitudinal plasma samples from n = 292 ovarian cancer patients, probing for n = 39 metabolites. At primary diagnosis, we revealed two distinguishable signatures, representing blood-based surrogates for a continuum of two metabolic states in ovarian cancer. These signatures shaped two subgroups of patients with differential surgical outcome and relapse risk (HR = 1.605, 95%CI:1.11-2.32, p = 0.009). Deconvolution of the metabolomic signatures identified acetoacetate, 3-hydroxybutyrate and alanine among the most relevant signature-determining metabolites. The acetoacetatelow/3-hydroxybutyratelow/alaninehigh-profile was a strong predictor for superior clinical outcome, independently of FIGO stage and surgical outcome (HR = 0.471, 95%CI:0.236-0.942, p = 0.033). A strong relative decline of the ketone bodies in the course of therapy indicated adverse clinical outcome (acetoacetate: OS: HR = 2.22, 95%CI:1.08-4.55, p = 0.02). We propose a 3-metabolite blood-based signature in ovarian cancer that could be used for independent prediction of relapse risk and survival.

Accumulation of senescent cells in the bone microenvironment, including bone marrow mesenchymal stromal cells (BM-MSCs), contributes to aging-related bone degeneration. Developmental endothelial locus-1 (DEL-1), the expression of which declines with old age is herein described as an endogenous secreted senolytic protein. DEL-1 promotes apoptosis of senescent BM-MSCs via a β3 integrin/CD73/adenosine/p38 mitogen-activated protein kinase (p38 MAPK)/B-cell lymphoma-2 (BCL-2) pathway, thereby leading to their clearance by macrophages. DEL-1-deficiency displays increased abundance of β3 integrin-rich CD73+ senescent BM-MSCs and higher chemotherapy-induced or aging-related senescence-associated bone loss. Conversely, mice with endothelial-specific overexpression of DEL-1 (EC-Del1) have decreased numbers of senescent BM-MSCs and diminish senescence-associated bone loss. CD73-deficiency reverses the reduction in senescent BM-MSC numbers in EC-Del1 mice. Administration of DEL-1 (or a DEL-1-inducing macrolide) causes a reduction in senescence markers and reverses aging-related periodontitis. Therefore, DEL-1 may be harnessed as an endogenous senolytic to prevent senescent cell buildup and senescence-associated bone loss.

Comparative analysis of urinary versus plasma-based metabolomic signature. A, Pairwise correlations between metabolite concentrations in matched plasma and urine samples (n = 161); r denotes Pearson’s coefficient. Asterisks indicate P < 0.05. B, Schematic of model comparisons using urinary metabolites and a previously established plasma signature. C, Time-dependent ROC curves of the urinary model, plasma signature, and combined model. AUC values indicate discriminatory performance for 60-month OS. To account for censoring before 60 months, AUC estimates were calculated using inverse probability of censoring weighting. Analysis was restricted to the complete-case cohort. (B, Image created with BioRender.com. Schwarz, F. [2026] https://BioRender.com/dy8x8k4.)

Identification of prognostically informative urinary metabolites. A, Overview of the analytic workflow used to identify urinary metabolites with prognostic relevance. B, Regularization path of Cox-LASSO regression across λ-values. C, Nonzero β-coefficients at optimal λ (λ_min) for retained metabolites. Here, β denotes the Cox regression model coefficient and is shown as the log HR for each metabolite, not the metabolite concentration. D, Pairwise Pearson correlations among retained metabolites (n = 190); all r < 0.28. (A, Image created with BioRender.com. Schwarz, F. [2026] https://BioRender.com/7oq101y.)

Abstract The term trained immunity (TRIM) was coined to describe a form of innate immune memory, whereby prior stimulation induces durable rewiring, mainly at the epigenetic level, in innate immune cells and their bone marrow precursors. In cancer, this concept has gained increasing relevance, as innate immune cells and myelopoiesis crucially modulate anti-tumor immune responses and immunotherapy outcome. TRIM can act at the level of mature myeloid cells, but also in hematopoietic stem and progenitor cells, thereby altering myeloid cell function over prolonged periods. In this context, microbial and fungal-derived TRIM agonists, including Bacillus Calmette-Guérin and β-glucan, can boost anti-tumor immunity by generating monocytes, macrophages, neutrophils and dendritic cells with enhanced anti-tumor actions. These trained innate immune cells can promote tumor cell killing, antigen presentation, T cell activation and improve responses to immune checkpoint blockade. In this review, we discuss the role of TRIM in cancer and highlight emerging translational strategies that exploit innate immune memory to enhance anti-tumor immunity.

Diseases associated with obesity and metabolic dysregulation, such as diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) promote chronic low-grade inflammation, which in turn, may enhance the risk for cardiovascular disease. Emerging evidence in recent years suggests that chronicity of inflammation involves alterations in bone marrow homeostasis. Obesity-related inflammation and metabolic stress, including hyperglycemia or hyperlipidemia, may trigger rewiring of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, driving production of myeloid cells with heightened inflammatory capacity that in turn fuel and sustain chronic inflammation. This process is akin to trained immunity and may promote an inflammatory memory that links metabolic disorders to their cardiovascular complications. Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by aging-related emergence of somatic mutations in hematopoietic cells that clonally expand and bear higher inflammatory potential. Importantly, a bidirectional link between CHIP and metabolic disorders as well as their cardiovascular sequelae emerges. Here, we review current concepts regarding the links between bone marrow biology and metabolic diseases and associated chronic inflammation.

PURPOSE:Reliable prognostic tools in ovarian cancer are urgently needed to guide risk-adapted treatment decisions, yet the clinical utility of urinary metabolites for noninvasive risk stratification remains largely undefined. Here, we define a clinically relevant urinary metabolite signature that enables noninvasive prognostic risk stratification in ovarian cancer. EXPERIMENTAL DESIGN:We used targeted 1H nuclear magnetic resonance spectroscopy to profile 149 metabolites related to energy metabolism, oxidative stress, mitochondrial function, nitrogen metabolism, amino acid degradation, gut microbiome activity, and inflammation. Metabolites were measured in preoperative urine samples from 199 consecutive patients with newly diagnosed ovarian cancer treated in routine clinical practice between 2013 and 2022. RESULTS:Unsupervised clustering revealed biologically heterogeneous subgroups but lacked prognostic resolution and alignment with overt clinical phenotypes. However, single-metabolite analysis identified a condensed three-metabolite prognostic signature comprising glycine, alanine, and citrate. A final parsimonious model integrating this metabolite signature with clinical covariates outperformed established risk factors alone (Fédération Internationale de Gynécologie et d'Obstétrique stage and surgical outcome), accurately predicted 60-month overall survival (AUC = 0.839), and stratified risk. Patients in the highest-risk quartile (Q4) had markedly shorter progression-free survival [Δmedian ≈ 56 months; HR, 2.63; 95% confidence interval (CI), 1.54-4.52; P < 0.001] and overall survival (Δmedian ≈ 86 months; HR, 2.49; 95% CI, 1.39-4.46; P = 0.009) compared with the lowest-risk group (Q1). CONCLUSIONS:We define a urinary three-metabolite signature that enables noninvasive identification of patients with high-risk ovarian cancer beyond established clinical factors. This signature may support molecular stratification and risk-adapted clinical decisions, thereby underscoring the clinical scalability of urine as a matrix for metabolic risk profiling in ovarian cancer.

Clonal haematopoiesis of indeterminate potential (CHIP) is an ageing-related condition associated with a substantial fraction of circulating leukocytes having descended from a single somatically mutated haematopoietic stem cell (HSC). CHIP increases the risk of haematological malignancies and several chronic diseases (for example, cardiovascular pathologies) and contributes to persistent, low-grade inflammation or inflammageing. Inflammageing, in turn, promotes functional impairment of normal HSCs, including reduced self-renewal potential. By contrast, CHIP-mutant HSCs not only are resistant to inflammageing-induced functional decline but also gain a selective expansion advantage in an inflammatory environment. A recent surge of discoveries has increased our understanding of the CHIP–inflammageing interplay, from a mechanistic and clinical perspective, highlighting its broader relevance to age-related diseases. In this Review, we discuss the molecular and cellular mechanisms that cause CHIP, its interplay with inflammageing, as well as the pathophysiological consequences and the translational implications for diseases that affect older individuals. Clonal haematopoiesis of indeterminate potential (CHIP) is an ageing-related condition associated with a substantial fraction of leukocytes descending from a single somatically mutated haematopoietic stem cell. This Review discusses the molecular and cellular mechanisms that cause CHIP, its interplay with inflammageing, and the pathophysiological consequences and translational implications for older individuals.

The 21st International Aegean Conference on Innate Immunity showcased advances that position innate immunity as a multiscale regulatory system integrating environmental, metabolic, epigenetic and genetic inputs.

Extramedullary organs such as the spleen can assume granulopoiesis as a supportive mechanism to cope with increased demands during persistent inflammation. However, the quantitative output of extramedullary granulopoiesis is limited, and whether the spleen provides neutrophils of a qualitative difference remains unclear. Here, we found that splenic stress granulopoiesis is associated with distinct neutrophil production and differentiation trajectories. Myeloid progenitors in the spleen engaged in accelerated production of neutrophils with an immature phenotype. Yet, neutrophils generated during persistent stress granulopoiesis were fully competent to exert antimicrobial functions and were necessary to contain bacterial invasion in the bladder. Activation of type I interferon signaling in the spleen was required for splenic neutrophil priming, and its loss impaired antibacterial host defense. Thus, the spleen provides an immunological environment for stress-induced rapid production and priming of highly active neutrophils to meet demands during infection.

With innate immunity at the core of the pathophysiology of atherosclerosis, the discovery of new mechanisms of immune cell activation can potentially identify novel pharmacological targets to prevent or treat cardiovascular disease (CVD). One of these mechanisms is trained immunity (TRIM), defined as a recallable long-term hyperinflammatory innate immune phenotype supported by changes of metabolic and epigenetic intracellular processes. TRIM can be induced in mature innate immune cells in tissues, including monocytes/macrophages, and natural killer cells, but also in non-immune cells such as endothelial and epithelial cells (peripheral TRIM). Bone marrow haematopoietic stem and progenitor cells can also be trained (central TRIM), which explains the long-term presence of trained cells, such as monocytes and neutrophils, in the circulation. Recent experimental studies in mice revealed that central TRIM can be induced by traditional CVD risk factors (including diet-induced obesity or intermittent high-fat diet, hyperglycaemia, and hypertension), inflammatory co-morbidities (such as periodontitis and arthritis), unhealthy life-style factors (psychosocial stress and sleep disturbance), and by mechanisms activated by experimental myocardial infarction and stroke. This leads to the long-term presence of hyperinflammatory monocytes and neutrophils that can subsequently accelerate atherosclerosis development. A key mechanism that drives the development of central TRIM in many of these conditions is IL-1β signalling in the bone marrow. In addition, rewiring of cellular metabolism (e.g. activation of glycolysis and glutaminolysis) and changes in histone methylation, acetylation, and lactylation mediate the development of central and peripheral TRIM. We propose that prevention of TRIM by pharmacological targeting of these pathways in myeloid cells represents a new avenue for the prevention and treatment of cardiovascular events.

Background: Myelodysplastic neoplasms (MDSs) are clonal hematopoietic stem cell disorders associated with ineffective hematopoiesis, chronic inflammation, and increased cardiovascular morbidity. Although metabolic dysregulation has been implicated in MDS pathogenesis, systemic metabolic alterations remain incompletely characterized. Methods: Plasma samples from treatment-naïve patients with MDS or chronic myelomonocytic leukemia (CMML) and age-matched healthy controls were analyzed using quantitative nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Metabolomic profiles were compared using unsupervised and supervised multivariate analyses, validated in an independent external MDS cohort, and integrated with re-analysis of publicly available RNA-sequencing datasets from purified CD14+ CMML monocytes. Results: Patients with MDS and CMML exhibited broad reductions in circulating lipoprotein-associated metabolites, including HDL-, LDL-, IDL-, and apolipoprotein-associated fractions, indicating disturbed systemic lipoprotein homeostasis. Within the discovery cohort, CMML samples showed higher concentrations of the ketone bodies 3-hydroxybutyrate and acetoacetate, as well as succinate. LC-MS analysis demonstrated selective increases in C18:1 acylcarnitine, oleic and isopalmitic acids, whereas free carnitine abundance remained unchanged. Elevated 3-hydroxybutyrate levels were not associated with mutational burden, hematologic parameters, disease risk, or immunophenotypic features. Re-analysis of public CMML monocyte transcriptomes demonstrated increased expression of genes involved in lipid uptake and intracellular lipid trafficking, including FABP5, APOE, LPL, and SLC27A2, without coordinated activation of fatty acid oxidation pathways. External cohort analysis confirmed the overall MDS-associated plasma metabolomic profile. Conclusions: MDSs and CMML are associated with reproducible alterations in systemic lipid metabolism characterized by reduced circulating lipoprotein-associated metabolites, while CMML showed more pronounced ketone body- and acylcarnitine-associated metabolic phenotype accompanied by changes in lipid-handling transcriptional programs. These findings support altered systemic lipid metabolism and carnitine-dependent fatty acid handling as characteristic features of myeloid neoplasms and provide a rationale for future functional studies investigating lipid metabolism in disease pathogenesis.

Itaconate is produced by inflammatory macrophages and promotes negative feedback on inflammation. It is synthesized by aconitate decarboxylase 1 (ACOD1) from cis-aconitate, a metabolite of the tricarboxylic acid cycle. Here, we focused on the role of ACOD1 in the immunometabolic reprograming of inflammatory microglia. Similar to macrophages, ACOD1 deficient microglia displayed a stronger inflammatory response to lipopolysaccharide (LPS) compared to their wild type counterparts. The proinflammatory effects of ACOD1 deficiency were associated with enhanced ATP citrate lyase (ACLY) activity and elevated acetyl-CoA amounts, and reprogramed arginine metabolism entailing enhanced argininosuccinate synthesis at the expense of polyamine biosynthesis. These effects of ACOD1 deficiency on arginine metabolism were reversed by ACLY inhibition. These findings provide new insights in the immunometabolic role of ACOD1.

Abstract Myelodysplastic neoplasms (MDSs) are clonal disorders characterized by ineffective hematopoiesis, dysplasia, and a risk of transformation into acute myeloid leukemia. MDS is also associated with a higher incidence of osteoporosis, suggesting a complex interplay between hematopoiesis, the bone marrow (BM) microenvironment, and bone homeostasis. Targeting inflammation has emerged as a promising therapeutic strategy, particularly in lower risk MDS. Tasquinimod (TASQ) is a small‐molecule inhibitor of the inflammatory alarmin S100A9, blocking its interaction with TLR4 and RAGE receptors. We investigated the efficacy of TASQ in modulating inflammation and improving disease phenotype using in vitro and in vivo MDS models. Immunofluorescence staining of human BM identified neutrophils and macrophages as primary S100A9 sources. Exposure of mesenchymal stromal cells (MSCs) to S100A9 induced Toll‐like receptor 4 (TLR4) downstream signaling, resulting in increased expression of IRAK1, NF‐κB‐p65, interleukin‐1β (IL‐1β), IL‐18, caspase 1, and PD‐L1. These effects were effectively abolished by TASQ. Additionally, TASQ restored the disturbed MSC‐mediated hematopoietic support, as demonstrated by increased numbers of cobblestone area‐forming cells and colony‐forming units. In NHD13 MDS mice, TASQ (30 mg/kg, 12 weeks) improved hemoglobin and red blood cell counts, but exerted no effect in wild‐type (WT) mice. Additionally, TASQ improved bone microarchitecture by increasing trabecular number and bone volume, likely a result of reduced osteoclast activity. Our findings suggest that TASQ mitigates inflammasome activation in the MDS BM, improving erythropoiesis and bone health. These results provide a necessary preclinical basis for clinical trials in lower risk MDS patients, in whom anemia and osteoporosis often coexist.

SUMMARY One of the enduring paradoxes of sepsis is that organs fail despite little evidence of irreversible tissue injury. Emerging evidence suggests that this state reflects a regulated metabolic shutdown within host tissues, yet whether such hypometabolism contributes to pathology or promotes survival remains unclear. This phenomenon resembles torpor, a physiological state of profound hypometabolism induced by environmental stress and mediated through reversible protein phosphorylation. Septic hypometabolism is identified here as a conserved tissue-specific metabolic adaptation which is characterized by transient activation of Glycogen Synthase Kinase (GSK)3β. This activation reduced disease severity of bacterial sepsis without affecting the hosts pathogen burden, indicating that GSK3β activity promotes disease tolerance to infection. Consistent with these findings, plasma signatures associated with GSK3β inhibition correlated with worse clinical outcomes in patients with sepsis. Together, these results define septic hypometabolism as a torpor-like response and identify reversible phosphorylation as a key mechanism governing host adaptation to severe bacterial infection.

Early detection of active melanoma metastasis is crucial. Serum metabolomics may offer non-invasive biomarkers, but real-world applicability needs validation. This study aimed to identify ¹H-NMR-based serum metabolic signatures for active metastasis in a large clinical cohort. Serum from 963 melanoma patients (1698 samples) underwent ¹H-NMR spectroscopy. Patients were classified by active metastasis status. OPLS-DA and RFE followed by logistic regression models were developed on a patient-level training/test split. Subgroup analyses assessed signatures related to Immune Checkpoint Inhibitor (ICI) therapy, brain metastases, and BRAF status. Models for active metastasis showed moderate test set discrimination (Area Under the Curve [AUCs]: OPLS-DA 0.609, RFE 0.630). The RFE-model highlighted seven significant metabolites: increased pyruvate, phenylalanine, acetoacetate, glutamate, glucose, and decreased histidine and citrate were associated with active metastasis. OPLS-DA yielded concordant metabolites. Subgroup analyses revealed distinct metabolic associations, e.g., for ICI therapy (citrate, RFE AUC 0.721) and BRAF status (acetate, RFE AUC 0.655), but limited performance for brain metastases (RFE AUC 0.553). ¹H-NMR serum metabolomics detects systemic metabolic alterations of active melanoma metastasis with moderate accuracy in a real-world setting. Identified disruptions in energy and amino acid metabolism offer pathobiological insights and warrant investigation for multimodal biomarker panels.

Neutrophil swarming has emerged as a conserved multicellular behaviour observed across tissues and pathological contexts. Yet, the molecular cues and the spatially coordinated cellular circuits that drive the process of neutrophil swarming leading to cluster formation remain poorly understood. Here, we combine spatial proteomics and lipid profiling in a model of urinary tract infection to define the epithelial-immune circuits driving neutrophil cluster formation. We identify thrombospondin-1 (TSP1)-mediated activation of transforming growth factor beta 1 (TGF-β1) as key epithelial signal licensing neutrophil clustering and enhancing bacterial control. Spatial lipid analysis further reveals that TSP1/TGF-β1 signalling locally activates arachidonic acid metabolism in epithelial neutrophils, with 5-lipoxygenase dependent leukotriene synthesis required for swarm formation and infection clearance. These findings uncover a spatially coordinated defence mechanism in which epithelial-derived TSP1/TGF-β1 engages neutrophil lipid metabolism to orchestrate neutrophil swarming behaviour and reinforce antibacterial immunity. ![Graphical abstract][1] Graphical abstract ### Competing Interest Statement The authors have declared no competing interest. Deutsche Forschungsgemeinschaft, TRR332 (449437943), A2, A3, A5, B4, C5, C6, Z1, FOR5427 (466687329), SP1, SP4, EN984 18-1 (539301313), TRR296 (424957847) P09, INST 20876/486-1 (504501554), 516868494, 518551069, 247354600, 247377969, 426788273 Bundesministerium für Forschung, Technologie und Raumfahrt, 01EW2503 Mildred Scheel Cancer Carrer Center Hamburg [1]: pending:yes

Metabolic flexibility is key for the function of myeloid cells. Arginine metabolism is integral to the regulation of myeloid cell responses. Nitric oxide (NO) production from arginine is vital for the antimicrobial and pro-inflammatory responses. Conversely, the arginase 1 (ARG1)-dependent switch between the branch of NO production and polyamine synthesis downregulates inflammation and promotes recovery of tissue homeostasis. Creatine metabolism is key for energy supply and proline metabolism is required for collagen synthesis. Myeloid ARG1 also regulates extracellular arginine availability and T cell responses in parasitic diseases and cancer. Cancer, surgery, sepsis and persistent inflammation in chronic inflammatory diseases, such as neuroinflammatory diseases or arthritis, are associated with dysregulation of arginine metabolism in myeloid cells. Here, we review current knowledge on arginine metabolism in different myeloid cell types, such as macrophages, neutrophils, microglia, osteoclasts, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). A deeper understanding of the function of arginine metabolism in myeloid cells will improve our knowledge on the pathology of several diseases and may set the platform for novel therapeutic applications.

Nanoparticles in physiological environments acquire a biomolecular corona that defines their biological identity, mediating immune system recognition and accelerating blood clearance of the nanoparticles. Typically, low-fouling materials are chosen to minimize protein adsorption and thereby immune system responses, contributing to stealth in blood. However, absolute prevention of the biomolecular corona remains tantalizingly out of reach. Herein, it is proposed to leverage the biomolecular corona rather than preventing its formation, in order to overcome immune responses toward nanoparticles. Low-fouling and stealthy poly(ethylene glycol)(PEG) nanoparticles are used, with a functional biomolecular corona enriched with anticoagulant heparin-antithrombin III (HEP-ATIII) complexes that can mitigate undesirable immune responses. Through immune response evaluations and proteomic analyses are used to ascertain the low-fouling, stealthy character of the nanoparticles, similar to that of PEG nanoparticles. However, PEG nanoparticles alone induce coagulation responses in human blood, which are mitigated by pre-enrichment of the biomolecular corona with HEP-ATIII complexes. This shows that coagulation is another factor to be considered in the design of materials for nanomedicine and that the low-fouling and stealthy properties do not directly translate to hemocompatibility. These findings highlight the potential of biomolecular corona engineering to address key challenges in the field, toward developing safer, efficacious therapeutic nanomaterials.