Background/Objectives: Volatile organic compounds (VOCs) are emerging as non-invasive biomarkers of metabolic and disease-related processes, yet their reliable detection from complex biological matrices such as urine remains analytically challenging. This study aimed to establish a robust, non-targeted headspace solid-phase microextraction gas chromatography–mass spectrometry (HS–SPME GC–MS) workflow optimized for very small-volume urinary samples. Methods: We systematically evaluated the effects of pH adjustment and NaCl addition on VOC extraction efficiency using a 75 µm CAR/PDMS fiber and a sample volume of only 0.75 mL. Method performance was further assessed using concentration-dependent experiments with representative VOC standards and by application to real human urine samples analyzed in technical triplicates. Results: Acidification to pH 3 markedly improved extraction performance, increasing both total signal intensity and the number of detectable VOCs, whereas alkaline conditions and additional NaCl produced only minor effects. Representative VOC standards showed compound-specific linear dynamic ranges with minimal carry-over within the relevant analytical range. Application to real urine samples confirmed high analytical reproducibility, with triplicates clustering tightly in principal component analysis and most metabolites exhibiting relative standard deviations below 25%. Conclusions: The optimized HS–SPME GC–MS method enables comprehensive, non-targeted urinary VOC profiling from limited sample volumes. This workflow provides a robust analytical foundation for exploratory volatilomics studies under sample-limited conditions and supports subsequent targeted method refinement once specific compounds or chemical classes have been prioritized.

Skeletal muscle and the immune system continuously exchange metabolites and signals that are essential for homeostasis. Disruption of this communication, such as during infection, inflammation, or cancer, triggers cachexia, a severe wasting syndrome characterized by altered amino acid flux, mitochondrial dysfunction, and systemic energy imbalance. By contrast, regular exercise activates overlapping pathways but directs them toward regeneration and hypertrophy, supported by controlled cytokine release and metabolite exchange. This review outlines the metabolic reprogramming that underlies muscle-immune crosstalk in cachexia and exercise, emphasizing how identical mediators, including interleukin-6, can promote either catabolism or adaptation depending on context. Understanding these shared yet divergent pathways opens avenues for therapeutic strategies that target metabolism and immune-metabolic communication.

Abstract Still’s disease (SD) is a chronic and systemic autoinflammatory disorder, with the possibility of resulting in life-threatening complications, including macrophage activation syndrome (MAS). The metabolic–immune interplay underlying the immunopathology of SD/MAS remains largely unexplored. In this study, we identified itaconate — a myeloid cell-specific metabolite derived from the tricarboxylic acid cycle via the enzyme ACOD1 — as a dual regulator of inflammation and chemokine-driven tissue injury in SD/MAS. Clinical metabolomics revealed elevated serum itaconate in patients with SD, attributable to peripheral blood monocytes and correlated with disease severity. This was consolidated by the identification of the Acod1–itaconate axis in monocytes and macrophages in both a mouse model of MAS and in vitro cell cultures. Although itaconate suppressed IL-1β, IL-6, CXCL1 and CCL2 in vitro, it paradoxically amplified CXCL10 secretion in vitro and in vivo. This was in line with the observations of elevated plasma CXCL10 levels in patients with MAS. In the CpG ODN 1826-induced MAS mouse model, ablation of Acod1 ameliorated disease manifestations and hepatic inflammation, accompanied by a reduced CXCL10 level as well as attenuated hepatic infiltration of CD8+ T cells. Collectively, our study reveals a previously unrecognized metabolic–immune crosstalk in AOSD/MAS, positioning monocyte/macrophage-derived itaconate as a dual regulator that suppresses canonical pro-inflammatory cytokines while licensing CXCL10-mediated CD8+ T cell-driven tissue injury. Therefore, discovery from this study calls for scrutiny of an itaconate-based anti-inflammatory strategy in chronic inflammatory diseases.

Abstract Introduction Peritoneal cavity (PC) tissue resident macrophages (TRM) are key players in immune defense and tissue homeostasis. The metabolite N-acetyl aspartate (NAA) is elevated in the PC. NAA is synthesized from acetate and aspartate by Nat8l and metabolized back to aspartate by Aspa. TRM depend on their tissue niche, PC TRM uniquely express Aspa, and NAA levels are associated with worse outcomes in ovarian cancer patients suggesting NAA is key in the biology of the PC. Methods The PC niche was examined by phenotype, metabolomics, 13C carbon tracing and single cell RNA sequencing in wild type and Aspa-/- or Nat8l-/- mice. In addition, multiple type 2 inflammatory models and orthotopic tumor models carried out in vivo and macrophage responses to NAA assessed in vitro. Results We reveal the expression of Nat8l by PC TRM, indicating the NAA metabolic loop can run within the PC. Moreover, PC NAA levels are dynamic in type 2 mouse models, however, there is low incorporation of metabolized NAA-derived aspartate into the TCA cycle. In vitro, NAA alters the intracellular metabolome and increases metabolic rates. These metabolic changes are also seen in vivo, where Aspa-/- mice display increased PC NAA levels and glycolytic intermediates following stimulation. The role of NAA is not only metabolic, as macrophages exposed to NAA have an increased pro-inflammatory gene signature. Lastly, in contrast with previous literature, genetic perturbation of the NAA metabolic loop within the PC leads to reduced growth in a murine intraperitoneal tumor challenge model. Conclusion This work shows a role for the NAA metabolic loop within the PC, anchored by the TRM. NAA within the PC serves as a metabolic and pro-inflammatory modulator rather than a fuel, leading to increased cellular energetics, and an altered metabolome. Therefore, the primary role of Nat8l and Aspa in PC TRM may be to modulate NAA levels and control the inflammatory potential of the peritoneal cavity. Funding Source NIH Project Number ZIA BC 010300 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

During perinatal development, liver metabolism is tightly regulated to ensure energy supply for the newborn. Before birth, glycogen is stored in hepatocytes and later metabolized to glucose, meeting neonatal energy demands. Shortly after birth, lipogenesis begins, driven by transcriptional activation of enzymes involved in fatty acid oxidation. These processes are thought to be largely regulated by systemic insulin and glucagon levels. However, the role of liver-derived local factors in neonatal hepatocyte metabolism remains unexplored. Kupffer cells (KCs), the liver's resident macrophages, colonize the fetal liver early in embryogenesis and support liver metabolism in adulthood. Yet whether KCs influence neonatal hepatocyte metabolism is unknown. Using conditional knockout mouse models targeting macrophages, we demonstrate that yolk sac-derived KCs play a crucial role in hepatocyte glycogen storage and function by regulating the tricarboxylic acid cycle, a role monocyte-derived KC-like cells cannot substitute. Newborn pups lacking yolk sac-derived KCs mobilize glycogen more rapidly, a process in part regulated by insulin-like growth factor 1 (Igf1) production. Our findings identify KCs as major source of Igf1, with local production essential for balanced hepatocyte metabolism at birth.

ABSTRACT Background Cancer cachexia exemplifies a high medical need condition without effective treatment. Recent studies implicated bacterial gut microbiome alterations to cancer cachexia. Whether the gut bacteriophage profile, an important microbiome component for health and disease, is also related to cancer cachexia remains unknown. We aimed to profile gut microbiome alterations in human cancer cachexia with attention on bacteriophages. Methods We performed shotgun metagenomic sequencing in stool samples from 78 cachectic and 42 noncachectic patients (53% male, mean age 67 ± 8 years) with newly diagnosed, advanced‐stage (UICC IV) gastrointestinal cancers. Cachexia was defined according to the main criterion agreed upon international consensus (weight loss [WL] adjusted to body mass index [BMI]). Obtained DNA short‐reads were used for k‐mers‐based, phage‐inclusive matching with reference databases, de novo phage assembly and inferring microbiome‐encoded functions. We replicated significance‐based statistical and prediction‐oriented machine‐learning analyses in 2022 and 2025 generated metagenome datasets to incorporate the recent change by the International Committee on Taxonomy of Viruses (ICTV) from morphology‐based (valid until 2022) to revised genome‐based phage taxonomy into microbiome findings of cachexia. Results Cachectic and noncachectic patients differed significantly regarding BMI (mean 20.9 vs. 26.4 kg/m2), WL (mean −6.5 vs. −0.2 kg), survival (median 5 vs. 13 months) and clinical cachexia domains (e.g., C‐reactive proteine and appetite loss) (all p < 0.001) but not for other clinical covariables (e.g., cancer type) (all p > 0.05). Read‐based mapping (2022/2025) identified 1.312/1.513 species (74/39 phage species), and de novo assembly resulted in 4.184/4.209 contigs (corresponding to 65/39 phage species). Concordantly, both analyses (2022 and 2025) showed that prevalent cachexia associated significantly with beta‐diversity (Bray‐Curtis distance, PERMANOVA, p < 0.05), but not to alpha‐diversity (Shannon‐Index, ANOVA, p > 0.05), reduced microbiome‐encoded detoxification functions (e.g., enriched microbial β‐glucuronidase and depleted bacterial efflux pumps) and lowered abundance of bacterial species with false‐discovery‐rate (FDR)‐corrected p < 0.05 (2022: Faecalibacterium prausnitzii, Roseburia intestinalis, Streptococcus species and Lachnospiraceae species; 2025: Faecalibacterium species, Ruminococcus gauvreauii and Intestinibacter bartlettii). Further, lowered abundance of bacteriophages associated with cachexia, predominantly affecting double‐stranded (2022: Caudovirales, Siphoviridae, FDR‐corrected p < 0.05; 2025: Myoviridae, Siphoridae, p < 0.05) but also single‐stranded (2022: Inoviridae, Microviridae, p < 0.05; 2025: Inoviridae; p < 0.05) DNA phage species. In machine‐learning models, bacteriophages were top‐ranked cachexia predictors (2022: Caudovirales, Siphoviridae; 2025: Myoviridae, Siphoridae). Accuracy was highest when only phage contigs were taken into account (correctly classified instances: 75.0%–85.8%; AUC: 0.703–0.916). Conclusions The previously unknown link between gut bacteriophages and human cancer cachexia expands the scope for basic, translational and clinical microbiome‐targeted research in an area of significant unmet medical need. Trial Registration Study Box of the German Cancer Society (Registration Number ST‐U069, Date: 29 May 2018)

IntroductionInfluenza A virus (IAV) infection is primarily associated with respiratory disease; however, accumulating evidence indicates that neurotropic strains can induce central nervous system (CNS) inflammation and contribute to persistent neurological dysfunction. Aberrant immune activation is thought to play a critical role in these outcomes, yet therapeutic approaches that effectively attenuate neuroinflammation while preserving antiviral immunity remain limited. Immunometabolic regulators, including the endogenous metabolite itaconate, have recently emerged as key modulators of innate immune responses, although their contribution to virus-induced CNS pathology remains incompletely understood.MethodsIn the present study, we investigated whether systemic administration of itaconate or its structural isomer mesaconate modulates neuroinflammatory responses and hippocampal synaptic integrity during infection with the neurotropic IAV strain rSC35M (mouse-adapted A/Seal/Mass/ 1/80, H7N7). Using a murine model, treatment was initiated at the onset of clinical symptoms, and both peripheral and central immune responses were assessed at the peak of disease.Results and discussionNeither itaconate nor mesaconate significantly altered overall disease severity, as assessed by body weight loss, although mesaconate attenuated infection-associated hypothermia. Pulmonary inflammatory responses were largely unaffected by treatment; in contrast, mesaconate selectively reduced IL-1β levels in the brain. At the cellular level, H7N7 infection induced pronounced microglial activation within hippocampal subregions, characterized by increased cell density and soma volume, altered process complexity, and enhanced engulfment of postsynaptic material. These infection-induced microglial alterations were partially prevented by mesaconate treatment and largely abrogated by itaconate treatment. Notably, attenuation of microglial density and reactivity during the acute phase was associated with long-term preservation of hippocampal synaptic plasticity. Collectively, these findings indicate that therapeutic administration of itaconate and mesaconate, potentially through distinct mechanisms, can modulate microglia-driven synaptic pathology during neurotropic IAV infection. Targeting immunometabolic pathways may therefore represent a promising strategy to prevent persistent neurological sequelae associated with viral disease.

Taurine is a non-proteinogenic β-amino acid that plays fundamental roles in cellular homeostasis. Although it is the most abundant free amino acid in many tissues, the full spectrum of its molecular functions has only recently begun to be elucidated. Taurine supplementation has shown promising outcomes in human studies, with emerging relevance in precision nutrition and the prevention of metabolic and age-related diseases. In this review, we summarize the current knowledge on taurine's molecular mechanisms, including its roles in antioxidant defense, anti-inflammatory signaling, calcium regulation, mitochondrial function, and lipid metabolism. We integrate mechanistic insights with evidence from clinical and nutritional studies examining taurine supplementation in the contexts of oxidative stress, inflammation, metabolic syndrome, and physical performance. Increasing data suggest that taurine can modulate key pathways linked to metabolism, inflammation, and healthy aging. Physiological synthesis and dietary intake appear sufficient to maintain basal health; however, human trials indicate that supplementation of 1-6 g day-1 may further promote metabolic resilience and mitochondrial function without adverse effects. Collectively, these findings position taurine as a promising dietary compound at the interface of metabolism, inflammation, and aging, highlighting its potential as a modulator of healthspan within precision nutrition strategies.

Skeletal muscle hypertrophy requires a substantial nutrient influx for biomass accretion, but global metabolite exchange during growth is poorly characterized. Therefore, we profiled the metabolite uptake and release in insulin-like growth factor-1 (IGF-1)-stimulated C2C12 myotubes and human muscle 24 h after resistance exercise. Differentiated C2C12 myotubes were stimulated to grow with IGF-1 (100 ng/mL, 24 h) or received vehicle control. To measure metabolite exchange, we analysed fresh and spent media by gas chromatography-mass spectroscopy metabolomics. In a second experiment, seven untrained adults (three males and four females; age 25.6 ± 3.2 years; body mass index 23.8 ± 2.8 kg/m2) performed single-leg hypertrophy-oriented resistance exercise, with the contralateral leg serving as the control. After 24 h, we obtained arteriovenous blood samples in the postabsorptive state and analysed plasma by untargeted liquid chromatography-mass spectroscopy metabolomics, characterizing the directionality of metabolite exchange across the human leg. In vitro, IGF-1 increased uptake of serine, arginine and pyridoxamine, while enhancing lactate release (all P < 0.05), reflecting anabolic, Warburg-like reprogramming. In vivo, 24 h postexercise there were modest global shifts (principal components analysis: PC1 8.8%, PC2 6.3% variance) and no significant essential amino acid uptake. Nominal differences (P < 0.05) included increased uptake of peptide-related metabolites (acisoga and 2-amino-4-CP) and α-ketoglutarate, alongside release of C12:0 and C16:0 acylcarnitines. No in vivo differences persisted after false discovery rate correction. Although IGF-1 stimulation in vitro promotes coordinated nitrogen-rich metabolite uptake and lactate release, human muscle 24 h postexercise in a postabsorptive state is characterized by increased peptide turnover and lipid release rather than net amino acid uptake. This indicates limited substrate accumulation and net biomass accretion in the absence of exogenous nutrients.

A bidirectional relationship exists between metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), and sarcopenia, with each worsening the prevalence and prognosis of the other. Hepatokines have recently been shown to affect skeletal muscle metabolism and function, both in the context of MASLD and wasting diseases. We here explored the possibility of targeting hepatokines to counteract MASLD-induced sarcopenia. Integrating mouse and human liver transcriptomics with muscle proteomics from MCD- and GAN-diet induced murine MASH models with sarcopenia, we identified three MASH-induced hepatokines, namely LCN2, LGALS3 and OPN. These hepatokines were elevated in the circulation of mouse MASH models with sarcopenia and in sarcopenic patients with advanced chronic liver disease. C2C12 myotubes treated with liver-secreted proteins as well as recombinant LCN2 and LGALS3 exhibited atrophy. Stable isotope tracing and mitochondrial respiration showed that liver-secreted proteins altered mitochondrial metabolism in C2C12 myotubes, which was recapitulated in primary human myotubes. Human 3D skeletal muscle organoids treated with recombinant proteins exhibited functional impairment. Virus-mediated knockdown of LCN2 in liver of mice with MASH improved muscle function and myotube size, whereas virus-mediated overexpression of LCN2 in the liver aggravated MASH-induced myotube atrophy. Targeting hepatokines may therefore be a feasible future therapeutic strategy against sarcopenia.

Summary The “Integrative Metabolic-Flux Platform for Analysis, Contextualization, and Targeting” (IMPACT) is a comprehensive, fully modular platform designed for both targeted and untargeted metabolomics analysis in stable-isotope labeling experiments. It facilitates the accurate calculation of mass isotopomer distributions (MIDs) and the annotation of unknown metabolites with a contextualization algorithm, addressing the challenges in metabolomics research. IMPACT integrates an entire preprocessing pipeline for LC-MS data, including peak picking, feature grouping, and peak filling, along with advanced features for isotope detection, MID calculation, and its core feature contextualization, enabling metabolite integration into biological pathway networks. The platform supports various file formats and offers user-friendly online access, making it accessible for researchers seeking to elucidate metabolic pathways and networks with precision and reliability. Availability and implementation IMPACT is implemented in Python 3.9 and R 4.3.2, with a front-end in Javascript utilizing the Cytoscape.js library for data visualization. It is available as a docker container and can be accessed online at https://impact.bioinfo.nat.tu-bs.de, providing a user-friendly interface for metabolomics data analysis.

The mono-ADP-ribosylhydrolase MacroD1 has been recently reported to localize to mitochondria exclusively. However, the extent and means by which MacroD1 regulates metabolic homeostasis remains unclear. Here we show that the absence of MacroD1 in mice decreased mitochondrial load and negatively impacted muscle function, reducing maximal exercise capacity. Knockdown of MacroD1 in C2C12 myoblast cells amplified the production of reactive oxygen species which ultimately resulted in increased mitochondrial fission. Proteomic and metabolomic profiling showed that loss of MacroD1 re-routed metabolite flux from glucose to the pentose-phosphate cycle instead of the tricarboxylic acid cycle to support the production of antioxidants, including glutathione and NADPH. This resulted in increased glucose uptake and dependency both in vitro and in vivo. Hence, our research establishes MacroD1 as a regulator of metabolic homeostasis, which ensures the coordination of cellular carbohydrate flux and optimal mitochondrial function.

Our laboratory has demonstrated that the NLRP3 inflammasome has a critical role in the microglial innate immune response to Alzheimer’s disease (AD)-related peptides, triggering the release of cleaved-caspase-1 and IL-1β. NLRP3 activation was found in post-mortem tissue from individuals with AD (Heneka et al., 2013) and in transgenic models of AD (APP/PS1 mice). However, APP/PS1 mice deficient for NLRP3 were protected from AD-pathology and neuroinflammation. We wanted to examine the wider implications of NLRP3 deficiency and uncover other pathways and mechanisms employed by microglia to protect the brain from the buildup of Aβ. Single cell RNA sequencing (scRNAseq) and ATAC sequencing was performed on CD11b + cells from the brains of wildtype, APP/PS1, NLRP3 −/− and APP/PS1.NLRP3 −/− mice. Microglia were prepared from wildtype and NLRP3 −/− mice to assess metabolic function, phagocytosis and for flow cytometric analysis. Targets were investigated in the post-mortem brain tissue of those with and without AD. In a separate experiment, APP/PS1 mice were treated with NLRP3-targeted inhibitors. ScRNAseq found a unique cluster of microglia in APP/PS1.NLRP3 −/− mice with pathways related to phagocytosis and glutamate metabolic signaling, with a specific increase in the glutamate transporter Slc1a3 . Metabolically, NLRP3 −/− microglia had increased mitochondrial and metabolic function with altered levels of the metabolite α-ketoglutarate. NLRP3 −/− microglia had greater Aβ phagocytosis than the wildtype cells, which was strictly associated with α-ketoglutarate availability and epigenetic regulation. Importantly, we were able to replicate these findings in human cells and using NLRP3-specific inhibitors in vitro and in vivo . We have identified a new mechanism where loss of NLRP3 influences glutamine/glutamate metabolism, which modulates α-ketoglutarate to affect epigenetic regulation and gene transcription, boosting downstream phagocytic activity (McManus et al., in revision). This pathway is conserved between murine and human cells. Critically, we can mimic this effect in vivo using NLRP3-specific pharmacological inhibition. Together, our data strengthens NLRP3 as a master-immune regulator and an important target in the treatment of AD and dementia.

Atherosclerosis is a chronic inflammatory disease of the arterial wall that causes cardiovascular disease. Monocyte-derived macrophages are an important contributor to atherogenesis. Monocytes can become primed for higher responsiveness to secondary, unrelated stimuli-a phenomenon known as trained immunity-a process driven by intracellular metabolic and epigenetic reprogramming. Oxidized low-density lipoprotein (oxLDL) induces trained immunity by enhancing glycolysis and oxidative phosphorylation (OXPHOS). Glutamine is known to enter the Krebs cycle through glutaminolysis where it can be used for ATP synthesis via OXPHOS. We therefore explored the role of the glutaminolysis pathway in oxLDL-induced trained immunity. Primary human monocytes from healthy donors were exposed to oxLDL for 24 h, followed by differentiation into macrophages over 6 days in culture medium. Thereafter, cytokine production capacity was assessed by stimulating them with Toll-like receptor agonist. Co-administration of the glutaminase inhibitor CB-839 during oxLDL exposure reduces glutamine anaplerosis. This prevented oxLDL-induced trained immunity, with diminished cytokine production capacity, associated with a reduced oxygen consumption rate (OCR), and glycolysis rate (ECAR). The role of glutaminolysis for induction of trained immunity was validated genetically, by showing significant associations between several single-nucleotide polymorphisms in genes related to glutaminolysis and ex vivo cytokine production in oxLDL-trained monocytes from 243 healthy volunteers. Finally, we identified a positive correlation between glutamate and Krebs cycle metabolites with inflammatory circulating biomarkers and monocyte counts in an independent cohort of 302 obese individuals. Altogether, these data suggest a crucial role of glutaminolysis in the establishment of oxLDL-induced trained immunity.

Excessive fibroblast proliferation and metabolic reprogramming are hallmarks of pathological cardiac remodeling, contributing significantly to impaired cardiac function. This study investigates the role of circular RNAs (circRNAs) in fibroblast metabolic reprogramming, an unexplored area with potential therapeutic implications. Through deep circRNA sequencing of cardiac tissue from heart failure (HF) patients and healthy individuals, we identified circIGF1R (hsa_circ_0005035), which exhibited dysregulation specifically in isolated cardiac fibroblasts derived from failing hearts. Silencing circIGF1R in patient-derived human cardiac fibroblasts (HCFs) led to accelerated proliferation, enhanced glycolytic activity, altered glucose trafficking, and increased glucose import. Conversely, administering recombinant circIGF1R inhibited the accelerated proliferation and enhanced glycolytic activity observed in HCFs from HF patients. Mechanistically, RNA pulldown assays and in silico analyses identified AZGP1 as a potential interaction partner facilitating the glycolysis-inhibitory and anti-proliferative functions of circIGF1R. Our findings identify circIGF1R as a pivotal regulator of fibroblast proliferation via metabolic reprogramming, particularly by glycolysis inhibition. Overexpression of circIGF1R demonstrated significant anti-fibrotic effects in cardiac fibroblasts derived from heart failure patients. These results underscore the therapeutic potential of circIGF1R in attenuating cardiac fibrosis by directly targeting fibroblast metabolism in the context of pathological cardiac remodeling.

Objective: Regulatory T cells (Tregs) are essential in maintaining immune tolerance and controlling inflammation. Treg stability relies on transcriptional and post-translational mechanisms, including histone acetylation at the Foxp3 locus and FoxP3 protein acetylation. Additionally, Tregs depend on specific metabolic programs for differentiation, yet the underlying molecular mechanisms remain elusive. We aimed to investigate the role of acetyl-CoA carboxylase 1 (ACC1) in the differentiation, stability, and function of regulatory T cells (Tregs). Methods: We used either T cell-specific ACC1 knockout mice or ACC1 inhibition via a pharmacological agent to examine the effects on Treg differentiation and stability. The impact of ACC1 inhibition on Treg function was assessed in vivo through adoptive transfer models of Th1/Th17driven inflammatory diseases. Results: Inhibition or genetic deletion of ACC1 led to an increase in acetyl-CoA availability, promoting enhanced histone and protein acetylation, and sustained FoxP3 transcription even under inflammatory conditions. Mice with T cell-specific ACC1 deletion exhibited an enrichment of double positive RORgt+FoxP3+ cells. Moreover, Tregs treated with an ACC1 inhibitor demonstrated superior long-term stability and an enhanced capacity to suppress Th1/Th17-driven inflammatory diseases in adoptive transfer models. Conclusions: We identified ACC1 as a metabolic checkpoint in Treg biology. Our data demonstrate that ACC1 inhibition promotes Treg differentiation and long-term stability in vitro and in vivo. Thus, ACC1 serves as a dual metabolic and epigenetic hub, regulating immune tolerance and inflammation by balancing de novo lipid synthesis and protein acetylation. (c) 2025 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Neonates primarily rely on innate immune defense, yet their inflammatory responses are usually restricted compared to adults. This is controversially interpreted as a sign of immaturity or essential programming, increasing or decreasing the risk of sepsis, respectively. Here, combined transcriptomic, metabolic, and immunological studies in monocytes of healthy individuals reveal an inverse ontogenetic shift in metabolic pathway activities with increasing age. Neonatal monocytes are characterized by enhanced oxidative phosphorylation supporting ongoing myeloid differentiation. This phenotype is gradually replaced during early childhood by increasing glycolytic activity fueling the inflammatory responsiveness. Microbial stimulation shifts neonatal monocytes to an adult-like metabolism, whereas ketogenic diet in adults mimicking neonatal ketosis cannot revive a neonate-like metabolism. Our findings disclose hallmarks of innate immunometabolism during healthy postnatal immune adaptation and suggest that premature activation of glycolysis in neonates might increase their risk of sepsis by impairing myeloid differentiation and promoting hyperinflammation.

Type 2 innate lymphoid cells (ILC2s) are essential for maintaining and protecting barrier tissues, but they also drive chronic inflammation, a process associated with altered metabolic activity. Identifying and targeting the metabolic pathways driving ILC2-mediated inflammation could restore tissue homeostasis. Here, we find that in allergic airway inflammation, pathogenic ILC2s rely on cystine for enhanced metabolic flexibility and survival. Cystine acquisition fuels glutathione (GSH) synthesis, which, together with increased expression of glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1), confers resistance to ferroptosis by counteracting lipid peroxidation and reactive oxygen species (ROS). This adaptation enables accelerated lipid acquisition and metabolism, fostering ILC2 and T helper type 2 (Th2) cell expansion. Conversely, ablation of GPX4 and TXNRD1 in ILC2s or pharmacological inhibition of TXNRD1 constrains lipid metabolism and prevents ILC2 accumulation in allergen-induced airway inflammation. This demonstrates that increased reliance on antioxidant systems represents a metabolic vulnerability that can be exploited therapeutically to treat asthma.