bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–07–20
57 papers selected by
Dylan Ryan, University of Cambridge
  1. CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients.
  2. Metabolic regulation of the immune cell in psoriasis: mechanisms and interventions.
  3. Spectroscopic method for measuring activity of cis-aconitate decarboxylase, an important metabolic regulator of immune responses.
  4. Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage.
  5. Metabolic regulation of tissue-resident immune cells: Molecular mechanisms and therapeutic implications.
  6. Ensemble quantitation of absolute metabolite concentrations in T cells reveals conserved features of immunometabolism.
  7. Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.
  8. Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.
  9. Mycobacterium bovis frd operon phase variation hijacks succinate signaling to drive immunometabolic rewiring and pathogenicity.
  10. Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling.
  11. Hypoxia and immunometabolism in the tumor microenvironment: insights into mechanisms and therapeutic potential.
  12. Metabolic Programming Drives Protective and Inflammatory Monocyte Fates in Viral Encephalitis.
  13. Bi-directional metabolic reprogramming between cancer cells and T cells reshapes the anti-tumor immune response.
  14. HIF-1α-mediated glycolytic reprogramming facilitates decapod iridescent virus 1 pathogenesis in Macrobrachium rosenbergii: Central role of hexokinase in viral metabolic hijacking.
  15. Role of Macrophage PARP1 in the Regulation of Crosstalk between Adipose Immune Cells and Adipocytes during Diet-induced Obesity.
  16. Salicylic Acid Engages Central Metabolic Regulators SnRK1 and TOR to Govern Immunity by Differential Phosphorylation of NPR1.
  17. Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate.
  18. Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
  19. Deep metabolic profiling of immune cells by spectral flow cytometry-A comprehensive validation approach.
  20. Interferon gamma rebalances immunopathological signatures in Chronic Granulomatous Disease through metabolic rewiring.
  21. CD38 expression by neonatal human naïve CD4 + T cells shapes their distinct metabolic state and tolerogenic potential.
  22. Direct Peritoneal Resuscitation and Melatonin in the Treatment of Abdominal Sepsis-Induced Lung Injury via Macrophage Metabolic Reprogramming.
  23. Immunometabolic modulators alleviate vascular dysfunction in mice with systemic lupus erythematosus.
  24. An Anaerobic Pathogen Rewires Host Metabolism to Fuel Oxidative Growth in the Inflamed Gut.
  25. Lactate and lactylation: emerging roles in autoimmune diseases and metabolic reprogramming.
  26. B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity.
  27. The NF-κB-SLC7A11 axis regulates ferroptosis sensitivity in inflammatory macrophages.
  28. Obesity-Associated Metabolomic and Functional Reprogramming in Neutrophils from Horses with Asthma.
  29. Personalized Gut-Liver Microphysiological System Maps Donor-Specific Tissue-Resident Immunity and Reveals a Conserved Metabolic Crosstalk.
  30. DRP1/DMNL-1-mediated mitochondrial fission augments Rickettsia parkeri replication in macrophages.
  31. miR-182-Mediated Dysregulation of Histidine Metabolism Compromises T Cell Immunity in Sepsis.
  32. Mechanisms of Sepsis from a Metabolic Immunology Perspective: A Bidirectional Mendelian Randomization and Single-Cell Sequencing Study of CD39+ Cells.
  33. Macrophage clock of pregnancy: circadian and metabolic control of decidual macrophage.
  34. Natural killer cells from endurance-trained older adults show improved functional and metabolic responses to adrenergic blockade and mTOR inhibition.
  35. Inhibition of formate production blocks CD8 + T-cell responses and delays disease onset in a mouse model of type 1 diabetes.
  36. MEK-dependent bioenergetic demand drives terminal CD8 + T cell exhaustion.
  37. Intratumoral amino acid insufficiency limits CD8 + T-cell effector function.
  38. The FOXO1-SIRT1 axis in ankylosing spondylitis: A cross-platform regulator linking immunometabolism, oxidative stress, and bone remodeling.
  39. Hyperglycemia-Suppressed Acod1 Expression Contributes to Innate Immune Deficiency in Pseudomonas aeruginosa Keratitis.
  40. Altered immunometabolic response to fasting in humans living with obesity.
  41. Narirutin treatment accelerates the process of diabetic wound repair by regulating phenotype switching of macrophages through affecting metabolic reprogramming.
  42. Glycometabolic reprogramming of immune cells in autoimmune diseases.
  43. Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages.
  44. Characterization of hyperoxia-induced senescent lung macrophages in neonatal mice.
  45. Developmental programming by maternal obesity alters offspring lifespan and immune responses in a diet- and sex-specific manner.
  46. Protocol for identifying immune mediators during Leishmania infection in mice using metabolomic analysis.
  47. Treatment Resistant Persister Cells Exploit Macrophage Lipid Metabolism to Sustain Glioblastoma Growth.
  48. Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer.
  49. cGAS: Bridging Immunity and Metabolic Regulation.
  50. MCT1-mediated Lactate Shuttle to Mitochondria Governs Macrophage Polarization and Modulates Glucose Homeostasis by Affecting β Cells.
  51. Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL.
  52. Differentiation, ageing and leukaemia alter the metabolic profile of human bone marrow haematopoietic stem and progenitor cells.
  53. Clostridioides difficile meets the adenosine system: the art of manipulating host homeostasis.
  54. Serum untargeted metabolomics alterations in systemic lupus erythematosus patients with elevated serum ferritin.
  55. Metabolomics and lipidomics of plasma biomarkers for tuberculosis diagnostics using UHPLC-HRMS.
  56. Gut microbiota and brain-resident CD4+ T cells shape behavioral outcomes in autism spectrum disorder.
  57. GDF15 attenuates sepsis-induced acute lung injury by suppressing the HIF-1α/LDHA pathway.
  1. Cell Rep. 2025 Jul 11. pii: S2211-1247(25)00744-2. [Epub ahead of print]44(7): 115973
    CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients.
    Molly S Cook, Ellen King, Katie R Flaherty, Khadiza Siddika, Sophie Papa, Reuben Benjamin, Anna Schurich.
      Chimeric antigen receptor (CAR)-T cell therapy has led to unprecedented success in treating relapsed/refractory diffuse large B cell lymphoma (DLBCL). The most common CAR-T cell products currently in the clinic for DLBCL differ in their co-stimulation moiety, containing either CD28 or 4-1BB, which initiate distinct signaling pathways. Previous work has highlighted the importance of T cell metabolism in fueling anti-cancer function. We have studied the metabolic characteristics induced by CD28 versus 4-1BB co-stimulation in patient CAR-T cells ex vivo. Our data show that in patients, CD28 and 4-1BB drive significantly divergent metabolic profiles. CD28 signaling endows T cells with preferentially glycolytic metabolism supporting an effector phenotype and increased expansion capacity, while 4-1BB co-stimulation preserves mitochondrial fitness and results in memory-like differentiation. Despite the differences in metabolic programming, T cells in patients responding successfully to therapy were metabolically similar, irrespective of co-stimulator. In contrast, in non-responders, CD28- and 4-1BB-co-stimulated CAR-T cells were metabolically distinct from each other.
    Keywords:  4-1BB; CAR-T cells; CD28; CP: Cancer; CP: Metabolism; DLBCL; co-stimulation; glycolysis; lymphoma; metabolism; mitochondria; translational
    DOI:  https://doi.org/10.1016/j.celrep.2025.115973
  2. Curr Opin Immunol. 2025 Jul 16. pii: S0952-7915(25)00090-1. [Epub ahead of print]96 102614
    Metabolic regulation of the immune cell in psoriasis: mechanisms and interventions.
    Dan Hong, Hui Xiong, Siyao Lu, Jianchi Ma, Zhenrui Shi.
      Psoriasis is increasingly recognized as a metabolically regulated inflammatory skin disease. Aberrant glycolysis, oxidative phosphorylation, lipid metabolism, and amino acid metabolism reshape T cell, dendritic cell, macrophage, and neutrophil responses, driving chronic inflammation. Keratinocyte-derived metabolites further amplify immune dysfunction, establishing a reciprocal metabolic-immune circuit. Targeting immunometabolic checkpoints, including glucose transporter transporters, mammalian target of rapamycin signaling, and amino acid transporters, offers promising strategies to modulate pathogenic immune responses. This review highlights the metabolic reprogramming of key immune subsets in psoriasis and outlines future directions for developing selective metabolic interventions to improve therapeutic outcomes in this disease context.
    DOI:  https://doi.org/10.1016/j.coi.2025.102614
  3. Anal Biochem. 2025 Jul 11. pii: S0003-2697(25)00183-6. [Epub ahead of print]706 115944
    Spectroscopic method for measuring activity of cis-aconitate decarboxylase, an important metabolic regulator of immune responses.
    Kevin Knowlan, Cody L Hoop, Nadya I Tarasova.
      Cis-aconitate decarboxylase (ACOD1) is a key enzyme converting cis-aconitate to itaconate, which has therapeutic potential for inflammatory diseases. Existing methods to measure ACOD1 activity and itaconate are often expensive and complex. We developed a novel, high-throughput spectrophotometric assay using the Fürth-Herrmann reaction. Our method quantifies ACOD1-catalyzed itaconate production by leveraging distinct absorbance ratios of cis-aconitate and itaconate at 386 nm and 440 nm. We optimized parameters, characterized human ACOD1 kinetics, and determined an IC50 for citraconate consistent with previous reports. This simple, fast, and reliable assay, requiring only a UV-Vis spectrophotometer, will accelerate screening for ACOD1 modulators, speeding up therapeutic development.
    Keywords:  Immune-Responsive Gene 1 (IRG1); Itaconate; Spectrophotometry; cis-aconitate decarboxylase (ACOD1)
    DOI:  https://doi.org/10.1016/j.ab.2025.115944
  4. Clin Transl Med. 2025 Jul;15(7): e70419
    Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage.
    Shuchen Huangfu, Chaoting Lan, Sitao Li, Huijuan Wang, Chun Yan, Yuling Yang, Bowen Tian, Yide Mu, Peizhi Zhao, Yan Tian, Yijia Wang, Wei Zhong, Limei Zhong, Yongyan Shi, Yufeng Liu.
       BACKGROUND: Necrotizing enterocolitis (NEC) is a rapidly progressive and severe gastrointestinal disorder in neonates that is marked by an inflammatory cascade initiated by mechanisms that remain incompletely understood, resulting in intestinal necrosis and systemic infections. This study demonstrated that itaconate (ITA) exerts a protective effect in NEC by regulating macrophage reprogramming.
    METHODS: Changes in ITA expression were investigated using immunofluorescence staining and liquid chromatography-mass spectrometry, and their effect on immune cell differentiation was verified through single-cell sequencing. In vivo experiments were performed using ACOD1-/- and ACOD1fl/flLysMcre NEC mouse models.
    RESULTS: We detected changes in ITA expression in clinical NEC samples and confirmed the effect of these changes on immune cell differentiation. In vivo experiments confirmed the therapeutic role of ITA in regulating macrophage differentiation in NEC, and we further investigated the mechanism by which ITA regulates macrophage metabolic reprogramming. The depletion of ITA in NEC correlates with an increased frequency of pro-inflammatory macrophage polarization, thereby exacerbating intestinal inflammatory injury. Importantly, our in vivo experiments revealed that treatment with 4-octyl itaconate (4OI) significantly mitigated intestinal symptoms associated with NEC in murine models. Mechanistic investigations showed that 4OI effectively suppressed M1 macrophage polarization by rescuing mitochondrial function and upregulating oxidative phosphorylation in macrophages.
    CONCLUSIONS: Our results highlight ITA as a metabolic checkpoint of macrophage differentiation in NEC and suggest the therapeutic efficacy of 4OI in NEC.
    KEY POINTS: Itaconate alleviates NEC by reprogramming M1 macrophage metabolism ACOD1 deficiency exacerbates NEC severity 4OI maintains intestinal barrier integrity. 4OI rescues NEC by regulating macrophage mitochondrial activity.
    Keywords:  itaconate; macrophage; metabolic reprogramming; necrotizing enterocolitis; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/ctm2.70419
  5. Metabolism. 2025 Jul 09. pii: S0026-0495(25)00218-5. [Epub ahead of print]171 156349
    Metabolic regulation of tissue-resident immune cells: Molecular mechanisms and therapeutic implications.
    Zixiang Chen, Fan Xiao, Xiaoxia Zhu, Wenhao Zhou, Ke Rui, Liwei Lu, Jie Tian.
      Many innate and adaptive immune cells are resident in non-lymphoid tissues and do not participate in peripheral circulation. These tissue-resident immune cells not only rapidly recognize and respond to local infections or injuries but also contribute to the maintenance of tissue homeostasis and immune balance. Immune cell function is closely associated with their metabolic state. Recent studies reveal that tissue-resident immune cells undergo unique metabolic reprogramming to adapt to their specific tissue microenvironment. This metabolic adaptation is crucial for their long-term survival, differentiation, and function. In this review, we systematically elaborate on the metabolic characteristics and tissue-specific regulatory mechanisms of CD8+ tissue-resident memory T cells (TRM) and tissue-resident macrophages (TRMφs). Based on an in-depth analysis of the critical role of immunometabolic pathways in infection, cancer, and autoimmune diseases, we further summarize therapeutic strategies targeting these metabolic pathways and discuss their efficacy, potential side effects, and the challenges facing clinical translation.
    Keywords:  Metabolism; Targeting therapy; Tissue-resident immune cell; Tissue-resident macrophage; Tissue-resident memory CD8(+) T cell
    DOI:  https://doi.org/10.1016/j.metabol.2025.156349
  6. bioRxiv. 2025 Jun 12. pii: 2025.06.09.658709. [Epub ahead of print]
    Ensemble quantitation of absolute metabolite concentrations in T cells reveals conserved features of immunometabolism.
    Samantha O'Keeffe, Harin Sim, Elle McCue, Junyoung O Park.
      Cells regulate metabolite levels to efficiently utilize metabolic networks and avoid toxic buildup. In turn, metabolites dictate metabolic activity by acting as substrates, products, and effectors. Despite their foundational role in cell physiology, kinetics, and thermodynamics, absolute metabolite concentrations are seldom known. Here we develop an ensemble method for absolute metabolite quantitation and quantify 84 metabolites in T cells. Liquid chromatography-mass spectrometry of metabolites co-extracted from T cells and 13 C-labeled reference cells reveals absolute concentrations en masse . Across subtypes and individuals, T cell metabolomes resemble one another. T cells possess high adenylate energy charge and favorable redox ratios for energy and biomass production without compromising the forward driving force in glycolysis. Across metabolism, metabolite concentrations exceed their associated Michaelis constants and inhibitor constants two thirds and half of the time, respectively. The conserved features of T cell metabolomes underlie a design principle: metabolite levels prime cells for adaptive immune response.
    DOI:  https://doi.org/10.1101/2025.06.09.658709
  7. Nat Chem Biol. 2025 Jul 15.
    Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.
    Guinevere L Grice, Eleanor Minogue, Hudson W Coates, Mekdes Debela, Richard J Stopforth, Niek Wit, Zongyu Li, Joseph P Crowley, Arthur Kaser, Nicole Kaneider-Kaser, P Robin Antrobus, Marcia C Haigis, Randall S Johnson, James A Nathan.
      Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity. Glutarate exerts its effects either by directly inhibiting metabolite-dependent enzymes or through conjugation to substrates. Intriguingly, glutarylation can occur on protein and nonprotein substrates, but our understanding of these distinct glutaryl modifications is in its infancy. Here we uncover ABHD11 as a noncanonical deglutarylating enzyme critical for maintaining the tricarboxylic acid (TCA) cycle. Mechanistically, we find ABHD11 removes glutaryl adducts from lipoate-an essential fatty acid modification required for the TCA cycle. Loss of ABHD11 results in the accumulation of glutaryl-lipoyl adducts that drive an adaptive program, involving 2-oxoglutarate accumulation, that rewires mitochondrial metabolism. Functionally, this role of ABHD11 influences the metabolic programming of human CD8+ T cells. Therefore, our findings reveal lipoyl glutarylation as a reversible modification that regulates the TCA cycle.
    DOI:  https://doi.org/10.1038/s41589-025-01965-6
  8. J Exp Med. 2025 Sep 01. pii: e20241426. [Epub ahead of print]222(9):
    Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.
    Xiaoyun Li, Sofie Hedlund Møller, Jaeoh Park, Yu-Ming Chuang, Pei-Chun Hsueh, Tzu-Hsuan Chang, Kung-Chi Kao, Hector Gallart-Ayala, Yi-Hao Wang, Jhan-Jie Peng, Alessio Bevilacqua, Yi-Ru Yu, Zhiyu Li, Yann Kieffer, Domitille Peigney, Hugo Croizer, Yingxi Xu, Alfred Zippelius, Isabel C Lopez-Mejia, Lluis Fajas, Fatima Mechta-Grigoriou, Julijana Ivanisevic, Zhengtao Xiao, Ming-Chih Ho, Ying-Chun Shen, Ping-Chih Ho.
      In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared with normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs) and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME. Mechanistically, we found that tumor-derived palmitic acid activates a signaling cascade involving TLR4, Syk, and NF-κB in fibroblasts, leading to inflammatory CAF polarization and IL-6-induced glutamine synthesis. These findings uncover a novel metabolic symbiosis whereby tumor cells manipulate TAM polarization through CAF-mediated glutamine metabolism, presenting potential therapeutic targets for cancer immunotherapy.
    DOI:  https://doi.org/10.1084/jem.20241426
  9. Nat Commun. 2025 Jul 16. 16(1): 6538
    Mycobacterium bovis frd operon phase variation hijacks succinate signaling to drive immunometabolic rewiring and pathogenicity.
    Yuhui Dong, Xin Ge, Qingbin Guo, Xichao Ou, Chunfa Liu, Yuanzhi Wang, Ziyi Liu, Ruichao Yue, Weixing Fan, Yanlin Zhao, Xiangmei Zhou.
      Tuberculosis (TB), caused by Mycobacterium tuberculosis complex (MTBC) pathogens, remains a global health threat. While bacterial genetic adaptations during host infection are poorly understood, phase variation in genomic homopolymeric tracts (HT) may drive pathogenicity evolution. Here, we demonstrate that M. bovis exploits HT insertion mutations in the fumarate reductase-encoding frd operon to subvert host immunometabolism. In macrophages, wild-type M. bovis secretes FRD-catalyzed succinate, stabilizing hypoxia-inducible factor-1α (HIF-1α) to drive glycolytic reprogramming and IL-1β production. This activates IL-1R-dependent Th1 immunity, restraining bacterial replication. Conversely, M. bovis frd HT insertion mutants impair succinate secretion, suppressing HIF-1α/IL-1β signaling and redirecting immunity toward pathogenic Th17 responses that promote neutrophil infiltration and tissue necrosis. Mice infection models reveal that M. bovis frd mutants exhibit enhanced pathogenicity, with higher pulmonary bacterial burdens. IL-1R blockade phenocopies frd HT insertion mutation effects, exacerbating lung pathology. Crucially, conserved frd HT polymorphisms in clinical M. tb isolates suggest shared immune evasion strategies across MTBC pathogens. Our work uncovers the bacterial gene phase variation mechanism of hijacking the succinate/HIF-1α/IL-1β axis to operate host immunity, providing a framework for targeting host metabolic checkpoints in TB therapy.
    DOI:  https://doi.org/10.1038/s41467-025-61824-9
  10. bioRxiv. 2025 May 09. pii: 2025.05.05.652119. [Epub ahead of print]
    Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling.
    Sung Hoon Cho, Shawna K Brookens, Ariel L Raybuck, Kaylor Meyer, Yeeun C Paik, Jennie Hamilton, Jingxin Li, Karel Kalecky, Chloe Park, Sakeenah L Hicks, John Karijolich, Teodoro H Bottiglieri, Jeffrey C Rathmell, Denis Mogilenko, Chris D Scharer, Mark R Boothby.
      The efficiencies with which activated B lymphocytes proliferate and develop into antibody (Ab)- secreting plasma cells are critical determinants of adaptive humoral immunity and central to sustaining certain autoimmune diseases. Increasing evidence indicates that specific pathways in intermediary metabolism, or their substrate supply, influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases proliferation and differentiation of B cells into plasma cells, glutaminolysis - a major means of metabolism of this amino acid - was only conditionally crucial in B cells and the Ab responses derived from them. Strikingly, Gls , the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases only when either glucose uptake into B cells or pyruvate into their mitochondria was also impaired. This synthetic auxotrophy involved support to a progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel not only decreased the coupling of IL-21 stimulation to STAT3 induction, but also interferon stimulation of STAT1 activation. Together, our findings establish not only a powerful collaboration of metabolic pathways in promoting increased respiration and the development of Ab-secreting cells, but also a capacity of metabolism to modulate cytokine receptor signaling.
    DOI:  https://doi.org/10.1101/2025.05.05.652119
  11. Cancer Lett. 2025 Jul 11. pii: S0304-3835(25)00481-1. [Epub ahead of print]631 217913
    Hypoxia and immunometabolism in the tumor microenvironment: insights into mechanisms and therapeutic potential.
    Cen Wu, Tianhua Xu, Heyang Zhang, Yile Hu, Jinghua Jiao, Kun Qiu, Jia Gu, Wenya Li, Lei Sun.
      The tumor microenvironment (TME), regulated by both intrinsic oncogenic factors and immune metabolic processes, has become an increasing focus of research in recent years. Typical features of the TME include hypoxia, metabolic dysregulation, and immunosuppression. Metabolic reprogramming provides tumors with energy and biosynthetic compounds to meet the nutritional requirements for proliferation. Meanwhile, immune metabolism influences tumor cells to shape the tumor immunosuppressive microenvironment by altering immune cell function and phenotype. Tumor hypoxia signaling specifically fosters the development of immunosuppressive TME by regulating immune metabolism, which, in turn, supports the progression of malignant tumors through modulation of their biological behaviors. This review comprehensively explores the metabolic regulation of hypoxia and immune metabolism during the dynamic evolution of tumor-adapted TME. In the context of the intricate interplay between hypoxia and immunometabolism, the prospects and challenges associated with immunometabolism in the clinical management of tumors are systematically addressed.
    Keywords:  Immune evasion; Immunosuppressive microenvironment; Metabolic competition; Tumor hypoxia; Tumor-targeted therapy
    DOI:  https://doi.org/10.1016/j.canlet.2025.217913
  12. Adv Sci (Weinh). 2025 Jul 14. e05844
    Metabolic Programming Drives Protective and Inflammatory Monocyte Fates in Viral Encephalitis.
    Claire L Wishart, Alanna G Spiteri, Jian Tan, Laurence Macia, Nicholas J C King.
      Infiltrating monocytes can exert both protective and pathogenic effects during central nervous system (CNS) inflammation. However, the metabolic mechanisms that govern these divergent roles remain poorly understood, limiting opportunities for therapeutic intervention. Single-cell RNA-sequencing and metabolic flow analysis of brain and bone marrow (BM) is used to map the metabolic signatures of monocyte-derived cells (MCs) during lethal West Nile virus encephalitis. Trajectory analysis shows that BM monocytes progress through three metabolic profiles before migrating to the brain and differentiating into a pro-inflammatory HIF1-α⁺ MC population. This population further diverges into an inflammatory, iNOS⁺ MC subset with high glycolysis and amino acid metabolism, and a protective, glycolytically quiescent, antigen-presenting MC subset. Daily in vivo glycolysis inhibition reduces neuroinflammation and disease signs without increasing viral load. This effect does not reflect a broad reduction in myelopoiesis but rather a selective decrease in iNOS⁺ MC migration, revealing distinct glycolytic dependencies among MC subsets. HIF1-α activity remains independent of glycolysis, enabling functional differentiation of antigen-presenting MCs without impairing antiviral responses by cervical lymph node T cells. This study identifies key metabolic drivers of MC function in viral CNS disease, in which selective metabolic reprogramming reduces severe neuroinflammation, demonstrating a promising therapeutic strategy.
    Keywords:  Immunometabolism; West Nile virus; glycolysis; monocytes; monocyte‐derived cells; viral encephalitis
    DOI:  https://doi.org/10.1002/advs.202505844
  13. PLoS Biol. 2025 Jul 14. 23(7): e3003284
    Bi-directional metabolic reprogramming between cancer cells and T cells reshapes the anti-tumor immune response.
    Yajing Qiu, Yihan Xu, Xinyuan Ding, Congcong Zhao, Hongcheng Cheng, Guideng Li.
      Cancer cells and T cells engage in dynamic crosstalk within the tumor microenvironment (TME), shaping tumor progression and anti-tumor immunity. While cancer cells reprogram metabolism to support growth and immune evasion, T cells must adapt their metabolic states to maintain effector functions. Tumor-driven metabolic perturbations, such as nutrient depletion and accumulation of immunosuppressive metabolites, profoundly impair T cell function and fate. Conversely, metabolically reprogrammed T cells can modulate the TME and influence tumor growth. This reciprocal metabolic crosstalk represents both metabolic competition and intercellular communication, offering promising therapeutic targets.
    DOI:  https://doi.org/10.1371/journal.pbio.3003284
  14. Dev Comp Immunol. 2025 Jul 12. pii: S0145-305X(25)00103-X. [Epub ahead of print]169 105414
    HIF-1α-mediated glycolytic reprogramming facilitates decapod iridescent virus 1 pathogenesis in Macrobrachium rosenbergii: Central role of hexokinase in viral metabolic hijacking.
    Yu-Kun Jie, Jing-Wen Hao, Cui Liu, Jun-Jun Yan, Tian-Tian Ye, Ji-Lun Meng, Guo Li, Yu-Tong Zheng, Hong-Tuo Fu, Zhi-Min Gu.
      Decapod iridescent virus 1 (DIV1) poses a severe threat to global aquaculture, yet the mechanisms underlying its metabolic hijacking of host pathways remain poorly understood. Here, we demonstrate that DIV1 infection in Macrobrachium rosenbergii induces a hypoxia-inducible factor 1α (HIF-1α)-mediated Warburg-like metabolic reprogramming, with hexokinase (MrHK) serving as a central metabolic hub. Proteomic profiling of DIV1-infected shrimp hemocytes identified 902 differentially expressed proteins (DEPs), revealing striking upregulation of glycolysis pathway. The temporal analysis confirmed stage-specific induction of MrHK and synchronized activation of downstream glycolytic enzymes, mirroring full-pathway metabolic hijacking. Evolutionary and structural analyses revealed MrHK's conservation across crustaceans and identified two functional HK domains. Targeting MrHK with the inhibitor 2-deoxy-D-glucose (2-DG) reduced viral copies and improved survival rates from 21.21 % to 43.33 %. Mechanistically, DIV1 stabilizes HIF-1α under normoxia to transactivate MrHK via three hypoxia-response elements (HREs), with mutagenesis of the core HRE motif abolishing promoter activity. Silencing MrHIF-1α attenuated MrHK expression and activity, viral copies, and improved survival, highlighting the axis's therapeutic potential. These findings establish HIF-1α-driven glycolytic reprogramming as a deliberate viral strategy, advancing our understanding of the molecular mechanisms behind DIV1 infection and offering actionable targets for metabolic interventions and host-directed therapies to combat DIV1 outbreaks in aquaculture.
    Keywords:  DIV1; HIF-1α; Hexokinase; Proteomics; Warburg effect
    DOI:  https://doi.org/10.1016/j.dci.2025.105414
  15. bioRxiv. 2025 Jun 22. pii: 2025.06.20.660762. [Epub ahead of print]
    Role of Macrophage PARP1 in the Regulation of Crosstalk between Adipose Immune Cells and Adipocytes during Diet-induced Obesity.
    Jingbo Zhu, Rebecca Gupte, Tulip Nandu, Kai Huang, W Lee Kraus, Dan Huang.
      Adipose tissue consists of heterogeneous cell populations, including macrophages, which play a key role in maintaining adipose tissue homeostasis. We previously identified PARP1 as a critical regulator of proadipogenic gene expression in preadipocytes and proinflammatory gene expression in macrophages. To investigate the role of macrophage PARP1 in regulating adipose tissue homeostasis, we generated myeloid lineage-specific Parp1 knockout mice ( Parp1 KO LysM ). When subjected to a high fat diet for 12 weeks, the Parp1 KO LysM mice exhibited an obese phenotype accompanied by white adipose tissue (WAT) dysfunction, characterized by altered metabolite profile, pronounced adipocyte hypertrophy, and increased macrophage infiltration. Coculture of primary preadipocytes with the conditioned medium from bone marrow-derived macrophages (BMDMs) isolated from Parp1 KO LysM or control mice demonstrated that macrophage PARP1 depletion inhibited LPS-induced proinflammatory gene expression in BMDMs, but enhanced differentiation of preadipocytes into mature adipocytes. Single cell RNA-sequencing using CD45 + -sorted WAT resident immune cells showed that macrophage PARP1 depletion increased the fraction of macrophages and NK cells, altered gene expression in both cell populations, and promoted intercellular communications. Taken together, our studies demonstrate a key role for macrophage PARP1 in the maintenance of adipose tissue inflammatory and metabolic homeostasis. Macrophage PARP1 depletion promotes cell-cell crosstalk among macrophages, fat cells, and other immune cell populations in adipose tissue, which cooperatively drives the development of obesity.
    Significance: In this study, we characterized a role for macrophage PARP1 in regulating adipose tissue homeostasis. Depletion of PARP1 in macrophages enhances cell-cell crosstalk among immune cells and fat cells, which exacerbates adipose dysfunction and drives obesity and adverse metabolic outcomes.
    DOI:  https://doi.org/10.1101/2025.06.20.660762
  16. bioRxiv. 2025 Jun 18. pii: 2025.06.17.660129. [Epub ahead of print]
    Salicylic Acid Engages Central Metabolic Regulators SnRK1 and TOR to Govern Immunity by Differential Phosphorylation of NPR1.
    Yixuan Chen, John Withers, Tianyuan Chen, Sargis Karapetyan, Jan Draken, Yezi Xiang, Wolfgang Dröge-Laser, Xinnian Dong.
      Immunity is a delicate balance between combating infection and preserving the metabolic functions vital for host survival. However, the mechanisms by which immune responses are coordinated with cellular metabolism remain largely unknown. Here, we show that NONEXPRESSER OF PR GENES 1 (NPR1), the central plant immune regulator of salicylic acid (SA)-mediated defense responses, is controlled by a cascade of posttranslational modifications (PTMs) involving two master nutrient-sensing kinases. Under normal growth conditions, TARGET OF RAPAMYCIN (TOR) inhibits NPR1 through phosphorylation at Ser-55/59. During defense responses, elevated SA enhances SNF1-RELATED KINASE 1 (SnRK1) activity, which in turn inhibits TOR signaling and phosphorylates NPR1 at Ser-557. This phosphorylation event activates NPR1 and facilitates its subsequent PTMs. Together, our results reveal an integral role of SA (the active metabolite of aspirin) in controlling central metabolic regulators SnRK1 and TOR to coordinate immune responses and growth through antagonistic modifications of NPR1.
    DOI:  https://doi.org/10.1101/2025.06.17.660129
  17. Nat Immunol. 2025 Jul 16.
    Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate.
    Elizabeth M Steinert, Beatriz Furtado Bruza, Veronika D Danchine, Rogan A Grant, Karthik Vasan, Arjun Kharel, Yuqi Zhang, Weiguo Cui, Marten Szibor, Samuel E Weinberg, Navdeep S Chandel.
      Mitochondrial electron transport chain (ETC) function is linked to the generation of ATP, signaling molecules including reactive oxygen species (ROS), pyrimidines and tricarboxylic acid cycle metabolites1. Mitochondrial electron transport is required for T cell proliferation2-4. However, which mitochondrial ETC functions are necessary for each dynamic state of CD8+ T cell responses is unknown. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production and superoxide production, decreases peripheral naive numbers, antigen-induced CD8+ T cell proliferation and memory formation. Acute stimulation of mitochondrial complex III-deficient CD8+ T cells induced an exhausted-like phenotype. Expression of Ciona intestinalis alternative oxidase (AOX) in mitochondrial complex III-deficient CD8+ T cells restores respiration without generating ROS or proton pumping, and rescues proliferation and the exhausted phenotype but not naive or memory formation. Thus, T cell development, proliferation and memory formation have distinct requirements for mitochondrial complex III ROS.
    DOI:  https://doi.org/10.1038/s41590-025-02202-x
  18. bioRxiv. 2025 Jun 11. pii: 2025.06.09.658561. [Epub ahead of print]
    Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
    Peter Georgiev, Sheila Johnson, Kiran Kurmi, Song-Hua Hu, SeongJun Han, Dillon Patterson, Thao H Nguyen, Linglin Huang, Dan Liang, Naomi Goldman, Thomas Conway, Hannah Creasey, Jared Rowe, Marcia C Haigis, Arlene H Sharpe.
      Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4 + T cells. We demonstrate that asparagine depletion at different time points after CD4 + T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4 + T cell differentiation reduces cytokine production in multiple CD4 + T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4 + T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.
    DOI:  https://doi.org/10.1101/2025.06.09.658561
  19. iScience. 2025 Jul 18. 28(7): 112894
    Deep metabolic profiling of immune cells by spectral flow cytometry-A comprehensive validation approach.
    Claire L Wishart, Alanna G Spiteri, Jian Tan, Claudio Counoupas, James A Triccas, Laurence Macia, Nicholas J C King.
      The advancing field of immunometabolism requires tools that link single-cell metabolism with immune function. Metabolic flow cytometry provides this capability, but its broad adoption has been limited by costly custom reagents and a lack of standardized methods for validating metabolic targets. Here, we present a standardized and user-friendly spectral flow cytometry panel that profiles eight key metabolic pathways at single-cell resolution using only commercially available antibodies, enabling simultaneous analysis of immune phenotype and metabolic activity . Applying this approach to lung myeloid and T cells following intranasal adenoviral CD40L vaccination revealed distinct metabolic phenotypes between resident and infiltrating myeloid cells, as well as functionally divergent metabolic programs in naive, effector, and tissue-resident memory T cells. Additionally, leveraging NAD(P)H autofluorescence allowed label-free detection of glycolysis and expanded the panel's utility. This standardized approach reduces cost and experimental complexity, enabling researchers to elucidate how metabolism drives immune function across broader immunological and clinical contexts.
    Keywords:  Biocomputational method; Immune response; Immunological methods; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2025.112894
  20. Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016213. [Epub ahead of print]
    Interferon gamma rebalances immunopathological signatures in Chronic Granulomatous Disease through metabolic rewiring.
    Mariolina Bruno, Charlotte Kröger, Anaísa V Ferreira, Bowen Zhang, Rutger J Röring, Ruiqi Liu, Caspar I van der Made, Norman van Rhijn, Lazslo Groh, Viola Klück, Nico A F Janssen, Wenchao Li, Diletta Rosati, Ahmed Alaswad, Helin Tercan, Jorge Saiz, Carolina Gonzalez-Riano, Martina van Uelft, Orsi Gaal, Sophie Müller, Humberto J Ferreira, Stefanie Warnat-Herresthal, Matthias Becker, Lisa Holsten, Michael Kraut, Jonas Schulte-Schrepping, Lorenzo Bonaguro, Kristian Händler, Cristina Cunha, Manfred Schmolz, Joachim L Schultze, Leo Joosten, Coral Barbas, Mihai G Netea, Yang Li, Anna C Aschenbrenner, Agostinho Carvalho, Frank L van de Veerdonk.
      Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent life-threatening infections and hyperinflammatory complications. It is caused by mutations in the NADPH oxidase complex and the consequent loss of reactive oxygen species (ROS) production. Recombinant human interferon gamma (rIFN-γ) prophylaxis reduces the risk of severe infections, but the mechanisms behind its efficacy in CGD are still an open question, as it does not restore NADPH oxidase-dependent ROS production. Here, we show that innate immune cells of CGD patients are transcriptionally and functionally reprogrammed to a hyperactive inflammatory status, displaying an impaired in vitro induction of trained immunity. CGD monocytes have reduced intracellular amino acids concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatment with IFN-γ restored these metabolic defects and reduced excessive IL-1β and IL-6 production in response to fungal stimuli in CGD monocytes. These data suggest that prophylactic rIFN-γ modulates the metabolic status of innate immune cells in CGD. These data shed light on the effects of NADPH-oxidase-derived ROS deficiency to the metabolic programs of immune cells and pose the basis for targeting this immunometabolic axis, potentially beyond CGD, with IFN-γ immunotherapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016213
  21. bioRxiv. 2025 Jun 28. pii: 2025.01.02.631038. [Epub ahead of print]
    CD38 expression by neonatal human naïve CD4 + T cells shapes their distinct metabolic state and tolerogenic potential.
    Laura R Dwyer, Andrea M DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E Rogers, Scott P Oltman, Laura L Jelliffe-Pawlowski, Susan V Lynch, Rachel L Rutishauser, Allon Wagner, Alexis J Combes, Tiffany C Scharschmidt.
      Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naïve CD4 + T cells into regulatory T cells (Tregs). Here, we demonstrate heighted capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4 + T cells and that this is linked to their unique metabolic profile and elevated expression of the NADase, CD38. Early life naïve CD4 + T cells demonstrate a metabolic preference for glycolysis, which directly facilitates their differentiation trajectory. We reveal an age-dependent gradient in CD38 levels on naïve CD4 + T cells and show that high CD38 expression contributes to both the glycolytic state and tolerogenic potential of neonatal CD4 + T cells, effects that are mediated at least in part via the NAD-dependent deacetylase SIRT1. Thus, the early life window for peripheral tolerance in humans is critically enabled by the immunometabolic state of the naïve CD4 + compartment.
    DOI:  https://doi.org/10.1101/2025.01.02.631038
  22. J Pineal Res. 2025 Jul;77(4): e70066
    Direct Peritoneal Resuscitation and Melatonin in the Treatment of Abdominal Sepsis-Induced Lung Injury via Macrophage Metabolic Reprogramming.
    Zhirong Zhao, Jiamin Ji, Lan Ming, Zhaofeng Luo, Mingyi Li, Yuan Chen, Ran Sun, Weiting Lu, Weiliang Tian, Fan Yang, Qian Huang.
      Abdominal sepsis and the resultant lung injury lead to high mortality rates, with macrophage metabolic dysfunction and subsequent immune dysregulation being key contributing factors. The clarification of the therapeutic value of direct peritoneal resuscitation (DPR) combined with melatonin in regulating macrophage metabolic reprogramming is crucial for the development of potential treatment strategies. Lipopolysaccharide exposure led to a decrease in mitochondrial membrane potential (MMP) of macrophage, morphological changes in mitochondria, and a substantial accumulation of reactive oxygen species (ROS) within the cells. Melatonin protects the stability of the mitochondrial electron transport chain (ETC) by enhancing the synthesis of Uqcrc1, thereby restoring macrophage function. Silencing Uqcrc1 effectively blocked this protective effect. In the rat sepsis model, DPR combined with melatonin enhanced the survival of alveolar macrophages (AMs) and reduced lung tissue damage. Importantly, in the DPR combined with melatonin treated group, the macrophage metabolic reprogramming was evident through enhanced oxidative phosphorylation and increased adenosine triphosphate (ATP) synthesis, both of which contributed to improved immune function and reduced inflammation. It is found that melatonin promotes the synthesis of Uqcrc1, stabilizing the ETC in macrophages. The combination of DPR and melatonin alleviated sepsis-induced lung injury in rats by modulating macrophage metabolic reprogramming.
    Keywords:  direct peritoneal resuscitation; macrophage; melatonin; metabolic reprogramming; sepsis
    DOI:  https://doi.org/10.1111/jpi.70066
  23. Biochem Pharmacol. 2025 Jul 12. pii: S0006-2952(25)00419-8. [Epub ahead of print]241 117154
    Immunometabolic modulators alleviate vascular dysfunction in mice with systemic lupus erythematosus.
    Sofía Miñano, Javier Moleón, Cristina González-Correa, Rosario Jiménez, Manuel Gómez-Guzmán, Natividad Martín-Morales, Francisco O'Valle, Miguel Romero, Marta Toral, Juan Duarte.
      Hypertension (HTN) is a prominent cardiovascular risk factor frequently observed in patients with systemic lupus erythematosus (SLE). This study explores whether pharmacological interventions targeting dysfunctional immune cell metabolism can confer vascular protection in a genetic mouse model of SLE. Female NZBWF1 lupus mice, aged 29 weeks, were treated for 4 weeks with either a vehicle (SLE group), a combination of 2-deoxy-D-glucose (2DG) and metformin (Met), or rapamycin. NZW/LacJ mice served as controls.The treatment with 2DG + Met inhibited splenic glycolysis and mitochondrial metabolism, enhanced AMP-activated protein kinase (AMPK) activity, and suppressed mammalian target of rapamycin (mTOR) activity. These effects resulted in a reduction in activated T helper (Th) cells and Th17 cells. The treatment managed to prevent the onset of HTN and ameliorated aortic dysfunction, as evidenced by reduced vascular contraction to the thromboxane A2 receptor agonist U46619, improved endothelium-dependent relaxation to acetylcholine, and attenuation of vascular thickening along with diminished collagen and proteoglycan accumulation. This intervention also decreased aortic Th17 cell infiltration in SLE mice, mitigating the profibrotic, proinflammatory, and oxidative stress within the vasculature, primarily via the IL-17/Rho kinase/NADPH oxidase and Rho kinase/serum response factor/myocardin pathways. Moreover, the activation of AMPK in the vascular wall by 2DG + Met improved endothelial dysfunction. Similarly, rapamycin suppressed splenic mTORC1 activity, reducing Th17 differentiation and aortic Th17 infiltration, which subsequently alleviated vascular oxidative stress and endothelial dysfunction. In conclusion, immune metabolic modulators improved vascular abnormalities in SLE mice, highlighting the potential therapeutic applications of these interventions in hypertensive SLE patients.
    Keywords:  Endothelial dysfunction; Glycolysis; Hypertension; Immune system; Mitochondrial metabolism; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.bcp.2025.117154
  24. bioRxiv. 2025 May 31. pii: 2025.05.31.657111. [Epub ahead of print]
    An Anaerobic Pathogen Rewires Host Metabolism to Fuel Oxidative Growth in the Inflamed Gut.
    Luisella Spiga, Ryan T Fansler, Alexandra Grote, Madison Langford-Butler, Asia K Miller, Maxwell Neal, Owen F Hale, Yifan Wu, Deepanshu Singla, M Wade Calcutt, Abigail E Rose, Madeline M Bresson, Alexandra C Schrimpe-Rutledge, Brittany Berdy, Simona G Codreanu, Mary Kay Washington, Benjamin P Bratton, Stacy D Sherrod, John A McLean, Karsten Zengler, Cynthia L Sears, Megan G Behringer, Andreas Gnirke, Jonathan Livny, Danyvid Olivares-Villagómez, Ashlee M Earl, Wenhan Zhu.
      To colonize their host and cause disease, enteric pathogens must deploy their virulence factors to establish distinct nutrient niches. How obligate anaerobic pathogens construct nutrient niches in the densely populated large intestine remains poorly understood. Enterotoxigenic Bacteroides fragilis (ETBF) is considered an obligate anaerobic bacterium and has been implicated in inflammation-associated diseases, including colitis and colorectal cancer. Here we show that ETBF uses its virulence factor, Bacteroides fragilis toxin, to reprogram colonic epithelial cell metabolism to colonize the inflamed gut. Bacteroides fragilis toxin activates colonic epithelial signaling and hijacks the host bile acid recycling pathway, inducing a metabolic shift in the epithelium from oxidative phosphorylation to glycolysis. This shift increases local concentrations of lactate and oxygen, nutrients that support an oxidative metabolism in ETBF. These findings reveal an unexpected strategy by which a pathogenic organism, previously considered to be an obligate anaerobic bacterium, generates and exploits an oxidative niche in the inflamed gut.
    DOI:  https://doi.org/10.1101/2025.05.31.657111
  25. Front Immunol. 2025 ;16 1589853
    Lactate and lactylation: emerging roles in autoimmune diseases and metabolic reprogramming.
    Wenjun Liu, Ruhui Yang, Yuxin Zhan, Xuanyu Yang, Haimin Zeng, Bofan Chen, Jiahao Zeng, Tianheng Hu, Jie Hu, Qi Xiao, Yinjin Shao, Xiang Chen.
      Autoimmune diseases are a set of conditions in which the immune system incorrectly identifies and attacks the body's own healthy tissue, severely compromising patient health. While current treatments can somewhat control disease progression, their long-term effectiveness remains limited, necessitating the development of more effective therapeutic approaches. Lactate and lactylation are critical links between metabolic reprogramming and epigenetics. As an emerging epigenetic modification, lactylation induced by lactate is closely associated with the onset of autoimmune diseases. Lactylation can be categorized into histone and nonhistone modifications, both of which play pivotal roles in cellular functions and pathophysiological processes through distinct regulatory mechanisms. Lactylation impacts immune cell function by regulating metabolic reprogramming and signaling pathways. In autoimmune diseases, immune cell metabolic reprogramming controls lactylation levels through metabolic byproducts, and lactylation, in turn, modulates the cellular metabolism by altering the transcription and structure of key enzymes. These interconnected processes collectively drive disease progression. To better understand the role of lactate and lactylation in the pathogenesis of autoimmune diseases, this review synthesizes the effects on specific immune cells, examining their dual effects on immune system function and their particular impacts on two common autoimmune diseases-rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). By combining the established role of lactate in immune metabolic reprogramming with the emerging understanding of the influence of lactate-induced lactylation on epigenetic regulation, this paper explores the relationship between lactylation and the progression of autoimmune diseases. This approach aims to enhance the understanding of the interplay between epigenetics and metabolism in autoimmune disease development, providing new perspectives for future therapeutic strategies. Studies collectively indicate that treatment can be improved through regulating key enzymes involved in lactylation, targeting lactate production pathways, integrating innovative approaches with current therapies, and adopting personalized treatment strategies.
    Keywords:  autoimmune diseases; epigenetics; lactate; lactylation; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2025.1589853
  26. iScience. 2025 Jul 18. 28(7): 112819
    B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity.
    Stephanie C Puente-Ruiz, Leona Ide, Julia Schuller, Adel Ben-Kraiem, Anne Hoffmann, Adhideb Ghosh, Falko Noé, Christian Wolfrum, Kerstin Krause, Martin Gericke, Nora Klöting, Jens C Brüning, F Thomas Wunderlich, Matthias Blüher, Alexander Jais.
      Immune-derived opioid peptides have been implicated in immune regulation and inflammatory processes. Here, we investigate the effects of nociceptin/orphanin FQ (N/OFQ) on metabolic function and inflammation in obesity. Selectively targeting N/OFQ, encoded by the Pnoc gene, in B cells mitigates the adverse metabolic effects of diet-induced obesity and enhances insulin sensitivity and glucose tolerance. Notably, B cell-specific Pnoc knockout mice display a marked reduction in markers of immune cell migration and diminished macrophage recruitment in adipose tissue and liver. Mechanistically, we identify that N/OFQ promotes macrophage recruitment and metabolic inflammation, exacerbating glucose intolerance and insulin resistance during obesity. Overall, the immunomodulatory properties exhibited by the N/OFQ-NOP system render it a promising therapeutic target for mitigating metabolic inflammation.
    Keywords:  Biological sciences; Endocrinology; Natural sciences; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2025.112819
  27. Cell Insight. 2025 Aug;4(4): 100257
    The NF-κB-SLC7A11 axis regulates ferroptosis sensitivity in inflammatory macrophages.
    Mengjie Yang, Xiaowei Chen, Xiran Hu, Hexiang Li, Hao Huang, Yingzhe Fang, Jue Jiang, Hudan Liu, Yuan Wang, Guoliang Qing.
      M1-polarized macrophages exhibit remarkable resistance to ferroptosis, a form of regulated cell death driven by excessive lipid peroxidation. Yet the underlying mechanisms remain to be defined. Through CRISPR-based functional screen of metabolic genes combining transcriptomics analysis, we herein identified the cystine/glutamate antiporter SLC7A11 as a pivotal mediator of ferroptosis resistance in M1 macrophages. Mechanistically, lipopolysaccharide (LPS) engagement with the Toll-like receptor 4 (TLR4) resulted in NF-κB activation, leading to RELA-dependent transcriptional upregulation of Slc7a11 expression. SLC7A11 in turn promoted cystine uptake and subsequent glutathione (GSH) synthesis. Genetic ablation of Slc7a11 reduced GSH production, sensitizing M1 macrophages to RSL3-induced ferroptosis. In aggregate, our findings unveil the RELA-SLC7A11 axis as a critical metabolic checkpoint dictating macrophage ferroptosis sensitivity, which might be employed to modulate macrophage functions in inflammatory diseases.
    Keywords:  Ferroptosis; Immune metabolism; Macrophage; RELA; SLC7A11
    DOI:  https://doi.org/10.1016/j.cellin.2025.100257
  28. Animals (Basel). 2025 Jul 07. pii: 1992. [Epub ahead of print]15(13):
    Obesity-Associated Metabolomic and Functional Reprogramming in Neutrophils from Horses with Asthma.
    Alejandro Albornoz, Beatriz Morales, Valentina Bernal Fernandez, Claudio Henriquez, John Quiroga, Pablo Alarcón, Gabriel Moran, Rafael A Burgos.
      Equine asthma is a chronic respiratory disease characterised by neutrophilic inflammation, airway hyperresponsiveness, and impaired pulmonary function. Obesity, increasingly prevalent among domestic horses, has been identified as a potential risk factor for exacerbating inflammatory conditions. This study aimed to explore whether obesity modifies neutrophil metabolism and inflammatory responses in horses affected by asthma. Six asthmatic horses in clinical remission were categorised into two groups: obese and non-obese, based on body condition score. Serum levels of interleukin-1β (IL-1β) and peripheral blood neutrophil counts were significantly higher in obese horses, indicating a heightened systemic inflammatory state. Neutrophils from obese horses displayed a stronger oxidative burst following zymosan stimulation and elevated IL-1β gene expression in response to lipopolysaccharide, suggesting a hyperinflammatory phenotype. Metabolomic profiling of neutrophils identified 139 metabolites, with notable differences in fatty acids, branched-chain amino acids, and tricarboxylic acid (TCA) cycle intermediates. Pathway enrichment analysis revealed significant alterations in fatty acid biosynthesis, amino acid metabolism, and glutathione-related pathways. Elevated levels of itaconate, citraconic acid, and citrate in obese horses indicate profound metabolic reprogramming within neutrophils. These results suggest that obesity promotes a distinct neutrophil phenotype marked by increased metabolic activity and heightened responsiveness to inflammatory stimuli. This altered profile may contribute to the persistence or worsening of airway inflammation in asthmatic horses. The findings underscore the importance of addressing obesity in the clinical management of equine asthma and open avenues for further research into metabolic-targeted therapies in veterinary medicine.
    Keywords:  equine asthma; metabolomics; neutrophils; obesity
    DOI:  https://doi.org/10.3390/ani15131992
  29. bioRxiv. 2025 Jun 27. pii: 2025.05.05.652244. [Epub ahead of print]
    Personalized Gut-Liver Microphysiological System Maps Donor-Specific Tissue-Resident Immunity and Reveals a Conserved Metabolic Crosstalk.
    Merve Uslu, Ran Ran, Mohd Farhan Siddiqui, Jing Liang, Luther Raechal, Matjaz Dogsa, Carole Perrot, Linda Lieberman, Douglas K Brubaker, Martin Trapecar.
      Tissue-resident immune (TRI) niches are unique to tissues and greatly vary between individuals. We built a personalized gut-liver microphysiological system (MPS) to recapitulate these profiles, combining primary colon epithelium, hepatocytes, and autologous CD45⁺ TRI cells of two donors. Single-cell RNA-seq of colon and liver revealed distinct TRI profiles and predicted responses distinct between donors. Co-culture established organ and donor-specific immune programs: colonic epithelium induced Th1/Th17 polarization in Donor 1 but B cell differentiation in Donor 2. Gut-liver crosstalk in all donors converged on a retinoid-bile acid metabolic axis with a muted inflammatory set-point, indicating that circulating metabolites can override baseline immune differences. Microbial agonist challenges of gut compartments revealed distinct liver responses: Poly(I:C) induced a uniform type-I/III interferon burst, LPS triggered a stronger response in Donor 1, and 5-OP-RU selectively activated Donor 2. Our personalized, immune-competent gut-liver MPS demonstrates that a conserved metabolic dialogue coexists with and is modulated by TRI profiles. This work provides a blueprint for exploring immunometabolic diseases and precision therapeutics in multi-organ models reflecting human immune diversity.
    DOI:  https://doi.org/10.1101/2025.05.05.652244
  30. bioRxiv. 2025 Jun 25. pii: 2025.06.25.661470. [Epub ahead of print]
    DRP1/DMNL-1-mediated mitochondrial fission augments Rickettsia parkeri replication in macrophages.
    Natasha Kelly, Elliott Collins, Basel Abuaita, Juan J Martinez.
      Pathogenic Spotted Fever Group (SFG) Rickettsia species, including Rickettsia parkeri replicate in endothelial cells, monocytes, and macrophages in vitro and during infections in murine models of disease. We demonstrated that R. parkeri survives and proliferates within phagocytes and avoids intracellular killing within lysosomal compartments. We found that infection of human macrophage-like cells with a related SFG Rickettsia , R. conorii , resulted in a significant increase in mitochondria-associated proteins, suggesting that mitochondrial functions are involved in Rickettsia pathogenesis. Several intracellular bacterial pathogens manipulate host cell mitochondrial networks and stimulate mitochondrial fission mediated by a GTP-binding regulatory protein, DRP1/DMNL1, to promote intracellular replication. Here, we investigated the contribution of DRP1 in the growth of R. parkeri in macrophages. Murine immortalized bone marrow derived macrophages (iBMDMs) and primary human monocyte derived macrophages were infected with R. parkeri and mitochondrial dynamics (fission and network) were assessed by immunofluorescence microscopy. R. parkeri proliferated in macrophages, which coincided with a significant increase in mitochondria content and fission compared to uninfected cells. R. parkeri infection led to increases in host cell ATP production primarily due to mitochondrial respiration and bacteria were often found co-localized with mitochondrial fragments. Importantly, R. parkeri growth was significantly impacted in DRP1 deficient macrophages. These results suggest that the modulation of mitochondria content and dynamics are essential for replication and survival of pathogenic SFG Rickettsia species in macrophages and suggest that the metabolic requirements for obligate intracellular pathogens may differ from other pathogenic Gram-negative intracellular bacteria.
    DOI:  https://doi.org/10.1101/2025.06.25.661470
  31. Inflammation. 2025 Jul 17.
    miR-182-Mediated Dysregulation of Histidine Metabolism Compromises T Cell Immunity in Sepsis.
    Yaolu Zhang, Jie Lian, Lujia Zhu, Yamei Wei, Kaikai Wang, Zhongqiu Lu, Longwang Chen.
      MicroRNA-182 (miR-182) exhibits immunomodulatory effects in regulating inflammatory responses to bacterial infection. However, the involvement of miR-182 in regulating T-cell immune function and differentiation in sepsis remains unknown. This study investigated the role of miR-182 in regulating T cell immune function and its mechanism in sepsis-induced immunosuppression. Using the cecum ligation and puncture model to mimic experimental sepsis, we found a significant reduction in splenic lymphocyte numbers and dysregulated T cell differentiation in septic mice. miR-182 expression was elevated in septic mice. Its knockout improved T cell immune function, ameliorated organ damage and improved survival rates in septic mice. Metabolomic and proteomic profiling revealed that histidine catabolism was attenuated and histidine was increased after miR-182 knockout. L-histidine supplementation alleviated T-cell immunosuppression in vivo. In addition, elevated plasma miR-182 levels were correlated with poor clinical prognosis in sepsis patients. Our findings demonstrate that miR-182 deficiency ameliorates the immunosuppression of T cells through the modulation of histidine metabolism, offering novel insights into the molecular mechanisms underlying T-cell dysfunction in sepsis.
    Keywords:  Histidine Metabolism; Immunity.; MicroRNA-182; Sepsis; T Cell
    DOI:  https://doi.org/10.1007/s10753-025-02333-1
  32. Shock. 2025 May 27.
    Mechanisms of Sepsis from a Metabolic Immunology Perspective: A Bidirectional Mendelian Randomization and Single-Cell Sequencing Study of CD39+ Cells.
    Jinfang Xue, Ning Zhou, Quan Li, Ruijie Wang, Yan Li, Huadong Zhu, Chuanzhu Lv.
       BACKGROUND: Interactions between immune phenotypes and metabolites in sepsis pathogenesis remain poorly defined. We integrated Mendelian randomization (MR) and single-cell transcriptomics to investigate metabolic mediation in immune-sepsis associations.
    METHODS: Bidirectional two-sample MR analyzed sepsis GWAS (11,643 cases), 1,400 metabolites, and 731 immune phenotypes. Single-cell analysis of GSE167363 (sepsis vs. controls) included clustering, differential expression, and pathway enrichment.
    RESULTS: CD39 expression was upregulated in sepsis immune cells. MR identified CD3 + CD39 + CD8+ T cells as risk factors for sepsis incidence (OR = 1.053, P = 0.008) and 28-day mortality (OR = 1.108, P = 0.037). These cells correlated with 73 metabolites, notably androsterone sulfate, which mediated 4.97% of sepsis risk (P = 0.026).
    CONCLUSION: CD39 + CD8+ T cells drive sepsis progression through metabolic intermediates like androsterone sulfate, highlighting immunometabolic crosstalk as a therapeutic target.
    Keywords:  CD39+ cells; Mendelian randomization; Sepsis; androsterone sulfate; immune cell phenotypes; metabolites; single-cell transcriptomics
    DOI:  https://doi.org/10.1097/SHK.0000000000002633
  33. Semin Immunopathol. 2025 Jul 18. 47(1): 30
    Macrophage clock of pregnancy: circadian and metabolic control of decidual macrophage.
    Dongyong Yang, Kristin Thiele, Tailang Yin, Lianghui Diao.
      The temporal regulation of immune responses during pregnancy is crucial for successful gestation. Yet, the specific mechanisms controlling macrophage function across gestational stages remain poorly understood. Here, we introduce the concept of the "macrophage clock of pregnancy", describing how molecular clock and cellular metabolism coordinate macrophage function across gestational stages. The molecular mechanisms underlying circadian control of macrophage function are examined, as well as hormones secreted by the pineal gland and their relevance to pregnancy-related processes. These pathways orchestrate key macrophage functions in pregnancy: modifying the uterine epithelium during implantation, supporting spiral artery remodeling, maintaining fetal tolerance, and initiating labor. Recent evidence shows that environmental factors such as shift work and extension of artificial light exposure can disturb macrophage function. The temporal regulation of macrophages also depends on metabolic signals, with distinct patterns of glycolysis, oxidative phosphorylation, and fatty acid metabolism corresponding to different gestational phases. Disruption of these temporal and metabolic signals - whether through circadian misalignment or metabolic dysfunction - correlates with pregnancy complications including recurrent pregnancy loss, preeclampsia, and preterm birth. We propose that monitoring macrophage temporal dynamics could provide early indicators of pregnancy complications, while targeting clock-controlled pathways may offer new therapeutic strategies. Understanding the temporal aspects of macrophage function opens new approaches for treating pregnancy disorders through precise immunological timing.
    Keywords:  Circadian rhythms; Decidual macrophage; Maternal-fetal interface; Metabolic dysfunction; Molecular clock; Pregnancy complications
    DOI:  https://doi.org/10.1007/s00281-025-01057-6
  34. Sci Rep. 2025 Jul 14. 15(1): 25380
    Natural killer cells from endurance-trained older adults show improved functional and metabolic responses to adrenergic blockade and mTOR inhibition.
    Luciele Guerra Minuzzi, Helena Batatinha, Christopher Weyh, Vidya Srokshna Balasubramanian Lakshmi, Carmen Fiuza-Luces, Beatriz G Gálvez, Alejandro Lucia, Ana Maria Teixeira, Natascha Sommer, José Cesar Rosa-Neto, Fabio Santos Lira, Karsten Krüger.
      Aging is associated with immune dysfunction, but long-term endurance training may confer protective effects on immune cell function. This study investigates how natural killer (NK) cell phenotypes, functional markers, and metabolism differ between endurance-trained and untrained older adults. Ex vivo expanded NK cells from endurance-trained (63.6 ± 2.1 years) and untrained (64.3 ± 3.3 years) males were exposed to adrenergic blockade (propranolol; 0-200 ng/mL) or mTOR inhibition (rapamycin; 10-100 ng/mL), both with or without PMA-induced inflammatory stimulation. Flow cytometry assessed NK subsets, activation (CD38, CD57, CD107a, NKG2D), senescence (KLRG1), and inhibitory markers (PD-1, LAG-3, TIM-3, NKG2A). Seahorse analysis measured metabolic parameters. Trained participants displayed healthier immune profiles (lower NLR, SII) and higher effector NK cells with lower cytotoxic subsets. Propranolol at 100 ng/mL blunted PMA-driven increases in CD57, CD107a, and NKG2D, while potentiating regulatory markers KLRG1, LAG-3, and PD-1 in the trained group, indicating stronger immunoregulation. With rapamycin, trained NK cells preserved NKG2D and CD107a at 10 ng/mL, maintaining cytotoxicity and degranulation. In contrast, at 100 ng/mL rapamycin plus PMA, trained NK cells shifted toward an effector phenotype with higher CD57 and CD107a, yet a blunted PMA-increased LAG-3 and TIM-3, suggesting resistance to exhaustion. PD-1 and KLRG1 remained elevated, reflecting balanced immune control. Mitochondrial analysis revealed that trained NK cells exhibited higher basal and maximal OCR, greater spare respiratory capacity, and OCR/ECAR ratio, reflecting superior metabolic fitness. These findings indicate that endurance-trained older adults have NK cells with greater functional adaptability, reduced senescence, and enhanced metabolism under inflammatory and pharmacological stress.
    Keywords:  Metabolic reprogramming; Mitochondrial function; Natural killer; Physical exercise; Propranolol; Rapamycin
    DOI:  https://doi.org/10.1038/s41598-025-06057-y
  35. bioRxiv. 2025 Jul 08. pii: 2025.07.04.663229. [Epub ahead of print]
    Inhibition of formate production blocks CD8 + T-cell responses and delays disease onset in a mouse model of type 1 diabetes.
    Gabriela Ramirez-Hernandez, Micah Bell, Byungsoo Kong, Samuel Block, Matthew G Vander Heiden, Nora Kory.
      The one-carbon metabolic pathway is essential for proliferating cells and has recently been identified as an immunomodulatory target in CD4⁺ T cells. However, its role in other immune cell types has not been fully established. We investigated the function of the one-carbon pathway in CD8⁺ T cells, which are the primary effectors responsible for the destruction of pancreatic beta cells that causes type 1 diabetes. Enzymes involved in the one-carbon pathway, as well as levels of formate-a critical intermediate-were upregulated during CD8⁺ T-cell activation. Pharmacological inhibition of MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, suppressed CD8⁺ T-cell activation, proliferation, and effector function. Mechanistically, this effect was mediated by reduced signaling through KRAS and the mTORC1 downstream targets HIF1α, S6, and STAT3. As previously shown in CD4⁺ T cells, formate supplementation reversed the effects of MTHFD2 inhibition on activation, proliferation, and function of CD8 + T cells, and prevented the reduction of the TCF1 high CD8⁺ progenitor cell population, which has been shown to drive anti-beta cell autoimmunity. Formate levels were elevated in the immune cells isolated from pancreatic lymph nodes during the insulitis stage in non-obese diabetic mice. Treatment of euglycemic non-obese diabetic mice with an MTHFD2 inhibitor during the insulitis stage delayed CD8⁺ T-cell infiltration into pancreatic islets and postponed the onset of type 1 diabetes. These findings reveal a new paradigm for preventing and delaying the onset of type 1 diabetes.
    DOI:  https://doi.org/10.1101/2025.07.04.663229
  36. bioRxiv. 2025 May 05. pii: 2025.04.30.651453. [Epub ahead of print]
    MEK-dependent bioenergetic demand drives terminal CD8 + T cell exhaustion.
    Tanmana Mitra, Jahan Rahman, Madeline Hwee, Ruben Jose Jesus Faustino Ramos, Hui Liu, Travis Hartman, Justin Cross, Miguel de Jesus, Morgan Huse, Valerie Longo, Pat Zanzonico, Santosha A Vardhana.
      Loss of mitochondrial function contributes to CD8 + T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEK inhibition uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo . MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II CTD phosphorylation, reducing transcription rates at effector- and terminal-exhaustion associated genes while maintaining transcription of memory-associated genes. These findings establish MEK-dependent metabolic demand as a driver of T cell exhaustion and elucidate the role of MEK inhibition in enhancing immunotherapy efficacy.
    DOI:  https://doi.org/10.1101/2025.04.30.651453
  37. bioRxiv. 2025 May 01. pii: 2025.04.28.651077. [Epub ahead of print]
    Intratumoral amino acid insufficiency limits CD8 + T-cell effector function.
    Yan-Ting Chen, Ya-Hui Lin, Jahan Rahman, Justin Cross, Natalya N Pavlova, Santosha A Vardhana.
      Loss of effector function is a hallmark of tumor-infiltrating CD8 + T-cells that have lost therapeutic efficacy. This impaired capacity occurs despite expression of transcripts encoding cytotoxic proteins, raising the possibility that post-transcriptional suppression of cytotoxic protein synthesis limits anti-tumor immunity. Whether altered protein synthesis contributes to CD8 + T-cell dysfunction has not been explored. Here we show that intratumoral amino acid availability restricts the cytotoxic capacity of CD8 + TILs by perturbing their ability to sustain protein synthesis. mRNA translation rates in antigen-specific CD8 + T-cells were rapidly and specifically suppressed within tumors but not tumor-draining lymph nodes, due to a combination of increased amino acid demand and reduced amino acid availability. Mechanistically, amino acid-dependent uncharging of tRNA Gln in T-cells persistently exposed to antigen was sufficient to suppress protein synthesis in a manner that is independent of either activation of the integrated stress response or suppression of mTORC1 activation. Finally, suppressing intracellular glutaminase activity or ectopically overexpressing the amino acid transporter SLC6A15 was sufficient to restore CD8 + T-cell effector function. These results establish a novel mechanism by which nutrient availability in the tumor microenvironment limits T-cell function and demonstrate how enhancing T cell-specific amino acid availability can sustain T-cell effector function and potentiate anti-tumor immunity.
    DOI:  https://doi.org/10.1101/2025.04.28.651077
  38. Autoimmun Rev. 2025 Jul 14. pii: S1568-9972(25)00138-7. [Epub ahead of print] 103878
    The FOXO1-SIRT1 axis in ankylosing spondylitis: A cross-platform regulator linking immunometabolism, oxidative stress, and bone remodeling.
    Xuhong Zhang, Lu Jia, Xueni Lin, Lamei Zhou.
      Ankylosing spondylitis (AS) is a chronic immune-mediated disorder defined by the paradoxical coupling of inflammatory bone erosion and ectopic new bone formation. Recent studies implicate the Forkhead box O1 (FOXO1)-Sirtuin 1 (SIRT1) signaling axis as a systems-level regulator integrating immune metabolism, redox balance, and skeletal remodeling. FOXO1 and SIRT1 cooperatively regulate immune tolerance, redox balance, and skeletal homeostasis via transcriptional, epigenetic, and metabolic pathways. This review delineates the cross-platform roles of the FOXO1-SIRT1 axis across three interrelated modules: regulation of immune cell metabolism and polarization; redox sensing and organelle quality control via autophagy and mitophagy; and coordination of osteoblast - osteoclast dynamics in inflammatory microenvironments. Dysregulation of this axis disrupts immuno-metabolic equilibrium and promotes pathological ossification, contributing to the dual pathology of AS. We further discuss emerging therapeutic strategies - ranging from SIRT1 activators and anti -Interleukin-17 A (IL-17 A) biologics to histone deacetylase inhibitors - that converge mechanistically on FOXO1-SIRT1 signaling. These translational approaches underscore the axis's potential as a cross-domain integrator of immune and skeletal homeostasis, and as a promising target for precision intervention in AS.
    Keywords:  Ankylosing spondylitis; Autophagy; Bone remodeling; FOXO1; Immunometabolism; Oxidative stress; SIRT1
    DOI:  https://doi.org/10.1016/j.autrev.2025.103878
  39. Invest Ophthalmol Vis Sci. 2025 Jul 01. 66(9): 51
    Hyperglycemia-Suppressed Acod1 Expression Contributes to Innate Immune Deficiency in Pseudomonas aeruginosa Keratitis.
    Nan Gao, Rao Me, Sukhvinder Singh, Ashok Kumar, Fu-Shin X Yu.
       Purpose: Diabetes mellitus (DM) patients are at higher risk for infections, which are often more severe. This study investigated the role of aconitate decarboxylase 1 (Acod1) and its product, itaconate, in innate defense against bacterial keratitis and its impairment in type 1 DM mice.
    Methods: Wild-type or normal (NL), streptozotocin-induced DM, and Acod1-/- mice were inoculated with Pseudomonas aeruginosa (Pa) with or without 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate. Keratitis severity was determined by photography, clinical scores, Pa burden (cfu), and myeloperoxidase (MPO) activity. Gene expression was determined by quantitative PCR. Immune and Acod1-positive cells were determined by immunohistochemistry.
    Results: DM mice expressed lower levels of Acod1 in B6 mouse corneas, and Pa infection triggered its upregulation, mostly in infiltrated cells. Acod1 deficiency increased the severity of Pa keratitis and significantly augmented the expression of Il-1β, Il-1ra, and Ccl3, but not Ccl2, at 1 day post-infection (dpi). Acod1-/- increased neutrophil but decreased macrophage infiltration. 4-OI prevented Pa infection in NL corneas (P = 6.7E-05) and alleviated Pa keratitis in DM corneas (P = 0.000204) at 3 dpi. Hyperglycemia augmented Pa infection-induced Il-1β, Il-1ra, and particularly Ccl3, but not Ccl2. In DM corneas, 4-OI greatly dampened the expression of CCL3 but not CCL2, compared to DM corneas without the treatment. The presence of 4-OI significantly reduced the severity of Pa keratitis in Acod1-deficient mice.
    Conclusions: Acod1/itaconate is crucial for mediating protective immune responses against Pa infection in both NL and DM corneas. Acod1 activation and/or itaconate-based therapies may offer promising adjunctive treatments for microbial keratitis in patients with diabetes.
    DOI:  https://doi.org/10.1167/iovs.66.9.51
  40. iScience. 2025 Jul 18. 28(7): 112872
    Altered immunometabolic response to fasting in humans living with obesity.
    Helena Neudorf, Roderick E Sandilands, Spencer Ursel, Hillary Shaba, Darren Barg, Takeshi Tsusaka, María Dolores Moya-Garzón, Erica Vaz, Patricia Schimweg, Emily L Goldberg, Jonathan Z Long, Karsten Krüger, Hashim Islam, Jonathan P Little.
      Fasting and ketosis are gaining interest for treating obesity-related immunometabolic dysfunction. We aimed to (1) characterize systemic and T cell immunometabolic responses to a 48-h fast in humans and (2) determine if responses differed between individuals with (O-BMI) and without (L-BMI) obesity (n = 16 per group). Despite similar increases in systemic fat oxidation, increases in blood β-hydroxybutyrate (BHB), BHB-amino acid conjugates, and lysine β-hydroxybutyrylation were blunted in obesity. T cells from the L-BMI group upregulated their relative capacity for fat oxidation while the O-BMI group did not. The O-BMI group had a greater proportion of Th17 cells and secreted more interleukin-17 (IL-17), even after fasting. CD8 expression decreased in both groups and CD4 expression only decreased in the L-BMI group. The balance of anti-to pro-inflammatory cytokines increased less in the O-BMI group. Collectively, these findings show that humans living with obesity have a blunted systemic and T cell immunometabolic response to fasting. NCT05886738.
    Keywords:  human metabolism; immunology
    DOI:  https://doi.org/10.1016/j.isci.2025.112872
  41. Front Pharmacol. 2025 ;16 1614967
    Narirutin treatment accelerates the process of diabetic wound repair by regulating phenotype switching of macrophages through affecting metabolic reprogramming.
    Liang Liu, Han Wang, Juan Zhou, Jing Lu, Yan Zhang, Haiyan Liu, Li Lu.
       Introduction: Diabetic foot ulcer (DFU) is one of the most common complications of diabetes, with substantial morbidity and mortality. Narirutin (Nar), a bioactive phytochemical derived from citrus peel, has been suggested to possess anti-inflammatory abilities. However, the involvement of Nar in DFU development remains poorly understood.
    Methods: The polarization traits of bone marrow derived macrophages (BMDMs) with indicated treatments were determined by flow cytometry, immunofluorescence staining, western blot and qRT-PCR. Levels of lactate and α-ketoglutarate were measured for investigating the metabolic profiles. The cutaneous wounds of diabetic mice were established for evaluating the promotive roles of Nar in wound healing in vivo.
    Results: We found that high glucose treatment significant elevated the contents of TNF-α and IL-1β and lactate and reduced the levels of TGF-β1 and IL-4 and α-ketoglutarate in BMDMs. Then, Nar intervention effectively induced BMDMs repolarization from M1 to M2 state and the molecular mechanism was ascribed to drug-elicited activation of AMPK, which in turn increased the expression of downstream Mfn2, thereby enhancing the activity of oxidative phosphorylation and GATA3 cascade activation and disrupting the progress of glycolysis and NF-κB axis activation. Subsequently, we discovered that Nar injection effectively enhanced the healing rate of skin wounds in diabetic mice. Histological analysis showed that Nar dose-dependently induced dermis growth and collagen deposition in the wound area. Via activating AMPK/Mfn2 axis, Nar inhibited the activity of glycolysis and enhanced the extent of oxidative phosphorylation, accompanied by inflammation repression and angiogenesis promotion in the damaged tissue.
    Discussion: Our study discovered that macrophages repolarization to M2 phenotype was required for Nar-induced promotive effects on diabetic wound repair by regulating reprogramming of glucose metabolism via mediating AMPK/Mfn2 pathway, providing a promising strategy for DFU management.
    Keywords:  AMPK; diabetic foot ulcer; inflammation; macrophage; metabolic reprogramming; narirutin
    DOI:  https://doi.org/10.3389/fphar.2025.1614967
  42. Autoimmun Rev. 2025 Jul 14. pii: S1568-9972(25)00136-3. [Epub ahead of print]24(10): 103876
    Glycometabolic reprogramming of immune cells in autoimmune diseases.
    Jin Lin, Fan Yang, Yanyi Zheng, Xianglin Wang, Xiaoli Fan, Li Yang.
      Autoimmune diseases (ADs) are a classification of disorders that occur owing to the breakdown of immunological tolerance to self-antigens, leading to an immune response to these antigens and associated bodily harm. The pathogenesis and etiology of these diseases remain unclear. A growing body of research indicates that metabolic reprogramming of immune cells is crucial for immunological control. In particular, glycolysis, a crucial metabolic process in cells, is reconfigured to influence the phenotypic and function of immune cells, therefore playing a role in the onset and progression of ADs. This review elaborates on the involvement of glycometabolic reprogramming in ADs and explores the function of glycometabolic reprogramming in immune cells throughout disease progression. Furthermore, we examine the principal targets implicated and their influence on disease advancement. Finally, we provide a brief summary and outlook of studies related to glycometabolic reprogramming of immune cells in ADs, aiming to guide therapeutic strategies for these diseases.
    Keywords:  Autoimmune diseases; Glycometabolic reprogramming; Immune cell; Mechanism; Targets
    DOI:  https://doi.org/10.1016/j.autrev.2025.103876
  43. Vet Res. 2025 Jul 15. 56(1): 150
    Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages.
    Weili Feng, Yu Han, Wanyun Zhang, Lei Wu, Ao Zhou, Liangyu Shi, Jing Zhang.
      Glaesserella parasuis, the causative agent of Glässer's disease in swine, triggers severe systemic inflammation; however, the molecular mechanisms underpinning its pathogenesis remain incompletely understood. This study investigated the cellular and metabolic responses of porcine alveolar macrophage 3D4/21 cells to G. parasuis infection. Exposure to the pathogen significantly reduced cell viability and up-regulated pro-inflammatory cytokines (IL-6, IL-8, IL-1β, and TNF-α). Mechanistically, G. parasuis-induced apoptosis via up-regulation of Bcl-2-associated X protein (Bax) and cleaved Caspase-3, coupled with down-regulation of B-cell lymphoma-2 (Bcl-2). By contrast, pyroptosis was characterised by activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, Caspase-1 cleavage, and gasdermin D (GSDMD)-mediated membrane pore formation. Notably, infection provoked endoplasmic reticulum (ER) stress through the PERK/eIF2α/ATF4/CHOP pathway, as evidenced by ER expansion, ribosomal detachment, and mitochondrial damage. Treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA) mitigated these alterations. Inhibition of PERK with GSK2656157 suppressed pyroptosis-related proteins (NLRP3, GSDMD, and Caspase-1) without altering apoptosis markers, indicating the existence of distinct regulatory pathways. Untargeted metabolomic profiling revealed extensive metabolic reprogramming, identifying 419 differentially expressed metabolites associated with pathways such as glutathione metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism, underscoring their involvement in G. parasuis infection and immune modulation. Collectively, these findings demonstrate that G. parasuis undermines host defences by activating PERK-mediated ER stress to drive pyroptosis, while simultaneously inducing apoptosis and metabolic dysregulation through independent mechanisms. This study provides novel insights into G. parasuis pathogenesis and highlights the PERK pathway and metabolic regulators as potential therapeutic targets for mitigating Glässer's disease.
    Keywords:   Glaesserella parasuis ; apoptosis; endoplasmic reticulum stress; metabolic reprogramming; porcine alveolar macrophages; pyroptosis
    DOI:  https://doi.org/10.1186/s13567-025-01580-2
  44. bioRxiv. 2025 May 10. pii: 2025.05.09.652066. [Epub ahead of print]
    Characterization of hyperoxia-induced senescent lung macrophages in neonatal mice.
    Fanjie Lin, Wenju Lu, Phyllis A Dennery, Hongwei Yao.
      Bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants, results from mechanical ventilation and hyperoxia amongst other factors. We and others have shown that neonatal hyperoxia, known to lead to a BPD-like phenotype in rodent models, causes lung cellular senescence. In our 3-day hyperoxia model, the majority of senescent cells were lung macrophages, and these peaked at postnatal day (pnd) 7. The features of these senescent macrophages are not characterized. Here, we reanalyzed scRNA-seq datasets (GSE207866) of senescent lung cells from mice exposed to hyperoxia as neonates at pnd7 (SD7), and characterized their gene express profiling and compared them with air control (AirD7) and hyperoxia-exposed group without isolation of senescent cells at pnd7 (O2D7). We first classified the cells into epithelial, endothelial, immune, and mesenchymal cells to extract immune cells. By employing the workflow to the immune clusters, mixed populations of macrophages, monocytes, and dendritic cells and pure population of macrophages, we finally identified seven clusters of macrophages. In SD7 group, 65.9% senescent cells were macrophages, and comprised M1 (64%) and alveolar (62.8%) macrophages. Clusters 0 and 1 were M1 and alveolar macrophages, which were composed of 49.2% of senescent macrophages. These two clusters highly expressed genes involved in innate immunity, inflammation, DNA repair response and phagocytosis. Metabolic switch from mitochondrial respiration to glycolysis and pentose phosphate pathway was observed in these two clusters. Conclusively, senescent macrophages are heterogenous with distinct tissue compartments and metabolic dysregulation.
    DOI:  https://doi.org/10.1101/2025.05.09.652066
  45. Cells Dev. 2025 Jul 11. pii: S2667-2901(25)00047-6. [Epub ahead of print] 204040
    Developmental programming by maternal obesity alters offspring lifespan and immune responses in a diet- and sex-specific manner.
    Seyhmus Bayar, Lea Seep, Karolina Doubková, Jelena Zurkovic, Margret H Bülow, Katrin Kierdorf, Reinhard Bauer, Christoph Thiele, Gaia Tavosanis, Jan Hasenauer, Elvira Mass.
      Maternal obesity is a growing health concern that predisposes offspring to metabolic dysfunction, immune system alterations, and neurodegenerative disorders. To investigate the intergenerational effects of maternal obesity, we used Drosophila melanogaster exposed to high-sugar (HSD) and high-fat diets (HFD) before mating. We found that maternal diet-induced obesity significantly altered offspring lifespan, immune responses, and neuronal health in a sex- and diet-specific manner. Male offspring were particularly susceptible, exhibiting reduced lifespan, impaired climbing ability, and increased axonal degeneration, especially following maternal HFD exposure. Transcriptomic analyses revealed age-dependent and diet-specific changes, with males showing pronounced alterations at 50 days of age. Developmental programming of hemocytes (blood-like cells) played a crucial role in these outcomes, as knockdown of key immune pathways such as Relish and upd3 in hemocytes further influenced lifespan in a diet-specific manner. These findings highlight the complex interplay between maternal diet and immune function, underscoring the impact of maternal obesity-induced imprinting on immune cells and subsequent long-term health consequences. Our study provides new insights into conserved mechanisms linking maternal metabolic health to offspring outcomes and emphasizes the continued need for animal models to understand intergenerational health impacts.
    Keywords:  Developmental reprogramming; Drosophila melanogaster; Hemocytes; Lifespan; Macrophages; Maternal obesity; Metabolism; Neurodegeneration; Plasmatocytes
    DOI:  https://doi.org/10.1016/j.cdev.2025.204040
  46. STAR Protoc. 2025 Jul 16. pii: S2666-1667(25)00223-0. [Epub ahead of print]6(3): 103817
    Protocol for identifying immune mediators during Leishmania infection in mice using metabolomic analysis.
    Thalia Pacheco-Fernandez, Laura Klenow, Nazli Azodi, Hannah Markle, Matthew Bernier, Greta Volpedo, Timur Oljuskin, Parna Bhattacharya, Shinjiro Hamano, Greg Matlashewski, Hira L Nakhasi, Abhay R Satoskar, Sreenivas Gannavaram.
      Here, we present a protocol for identifying immune mediators during Leishmania infection in mice using metabolomic analysis. We describe steps for Leishmania infection, harvesting infected tissues, and performing liquid chromatography-mass spectrometry (LC-MS) to identify enriched metabolic pathways and altered metabolites. We then detail procedures for verifying the metabolite role in immune response via PCR and ELISA. This protocol focuses on cutaneous leishmaniasis models, but the analyses here are applicable to other infection models. For complete details on the use and execution of this protocol, please refer to Volpedo et al.1 and Oljuskin et al.2.
    Keywords:  mass spectrometry; metabolomics; microbiology; model organisms; molecular biology
    DOI:  https://doi.org/10.1016/j.xpro.2025.103817
  47. bioRxiv. 2025 Jun 10. pii: 2025.06.07.658345. [Epub ahead of print]
    Treatment Resistant Persister Cells Exploit Macrophage Lipid Metabolism to Sustain Glioblastoma Growth.
    Avirup Chakraborty, Changlin Yang, Aryeh Silver, Diana Feier, Guimei Tian, Avinash Pittu, Christina Von Roemeling, Nagheme Thomas, Michael Andrews, Cole Conforti, Olusegun O Sobanjo, Nyla T Searl, Miruna N Anica, Raquel McTiernan, Maryam Rahman, Jianping Huang, Jeffrey K Harrison, Duane A Mitchell, Matthew Sarkisian, Loic P Deleyrolle.
      Glioblastoma (GBM) displays pronounced intratumoral heterogeneity, posing significant challenges to understanding its biology and developing effective treatments. Using spatial multi-omics, in vivo functional assays, and systems-level analysis, we delineate the diverse metabolic and immune architecture of GBM. We identify a lipid-dependent lineage of treatment-resistant persister cells (TRPCs) that engage tumor-associated macrophages (TAMs) in a spatially organized, metabolically specialized crosstalk. TRPCs co-opt CCR2⁺, CSF1R⁺, CD163 + TAMs for lipid scavenging and acquisition, promoting a pro-tumorigenic and immunosuppressive microenvironment. This cooperative axis is critically dependent on lipid chaperones like FABPs, whose targeting disrupts TAM recruitment, remodels immune composition, and suppresses tumor growth. Retrospective clinical analyses reveal that elevated TRPC-associated transcriptome may serve as stratification criteria to identify patients benefiting from lipid-lowering therapies like statins. Our findings uncover a targetable immunometabolic circuit between TRPCs and TAMs and support the development of precision therapies that disrupt lipid-fueled tumor-immune cooperation in GBM.
    In brief: Treatment-resistant persister cells (TRPCs) in glioblastoma spatially engage TAMs to facilitate lipid transfer, thereby sustaining tumor growth and promoting immune evasion. Targeting this TRPC-TAM metabolic axis reprograms the immunosuppressive microenvironment and improves therapeutic outcomes, revealing a clinically actionable metabolic vulnerability with potential for precision immune-metabolic interventions in GBM.
    Highlights: GBM exhibits spatially resolved heterogeneity revealing correlative metabolic and immune micro-nichesTRPC lineage promotes a pro-tumorigenic and immunosuppressive microenvironment by recruiting lipid-specialized TAMsTRPC lineage hijacks TAMs for metabolic support via stimulating lipid transfer and acquisitionDisruption of the TRPC-TAM lipid axis, including through FABP3 targeting, reprograms the immune landscape, limits TAM recruitment, and impairs tumor progressionTRPC lineage and associated micro-niche transcriptomic profiles can serve as criteria for patient stratification and identification of responders to lipid-lowering therapies, such as statins.
    DOI:  https://doi.org/10.1101/2025.06.07.658345
  48. J Transl Med. 2025 Jul 17. 23(1): 803
    Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer.
    Jiannan Chen, Lianfeng Zhao, Wenying Li, Shuai Wang, Jiayi Li, Zhongyuan Lv, Yaoyao Zhao, Junqing Liang, Zhigang Hu, Feiyan Pan, Lingfeng He, Lili Gu, Zhigang Guo.
       BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy holds promise for cancer treatment, but its efficacy is often hindered by metabolic constraints in the tumor microenvironment. This study investigates the role of glutamine in enhancing CAR-T cell function against ovarian cancer.
    METHODS: Metabolomic profiling of blood samples from ovarian cancer patients treated with MSLN-CAR-T cells was conducted to identify metabolic changes. In vitro, glutamine pretreatment was applied to CAR-T cells, and their proliferation, CAR expression, tumor lysis, and cytokine production (TNF-α, IFN-γ) were assessed. Mechanistic studies focused on the mTOR-SREBP2 pathway and its effect on HMGCS1 expression, membrane stability and immune synapse formation. In vivo, the antitumor effects and memory phenotype of glutamine-pretreated CAR-T cells were evaluated.
    RESULTS: Elevated glutamine levels were observed in the blood of ovarian cancer patients who responded to MSLN-CAR-T cell treatment. Glutamine pretreatment enhanced CAR-T cell proliferation, CAR expression, tumor lysis, and cytokine production. Mechanistically, glutamine activated the mTOR-SREBP2 pathway, upregulating HMGCS1 and promoting membrane stability and immune synapse formation. In vivo, glutamine-pretreated CAR-T cells exhibited superior tumor infiltration, sustained antitumor activity, and preserved memory subsets.
    CONCLUSIONS: Our findings highlight glutamine-driven metabolic rewiring via the mTOR-SREBP2-HMGCS1 axis as a strategy to augment CAR-T cell efficacy in ovarian cancer.
    TRIAL REGISTRATION: NCT05372692.
    Keywords:  CAR-T cell therapy; Glutamine; HMGCS1; MTOR-SREBP2 Axis; Ovarian cancer; T cell exhaustion
    DOI:  https://doi.org/10.1186/s12967-025-06853-0
  49. J Mol Cell Biol. 2025 Jul 17. pii: mjaf018. [Epub ahead of print]
    cGAS: Bridging Immunity and Metabolic Regulation.
    Jing Wang, Wen Meng.
      Recent advances have revealed that cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS), classically recognized as a cytosolic DNA sensor, plays crucial roles beyond innate immunity. Particularly in the adipose tissue, cGAS functions as a metabolic sentinel, responding to mitochondrial stress and contributing to inflammation, insulin resistance, and energy imbalance. These effects occur through both stimulator of interferon genes (STING)-dependent and STING-independent pathways, involving autophagy, chromatin remodeling, and transcriptional reprogramming. Here, we propose a paradigm shift positioning cGAS at the intersection of immunity and metabolism. We explore its multifaceted roles in adipocytes and other metabolic tissues, highlighting emerging therapeutic opportunities and future research directions.
    DOI:  https://doi.org/10.1093/jmcb/mjaf018
  50. Adv Sci (Weinh). 2025 Jul 14. e14760
    MCT1-mediated Lactate Shuttle to Mitochondria Governs Macrophage Polarization and Modulates Glucose Homeostasis by Affecting β Cells.
    Lingling Chen, Yijun Lin, Xinyu Zhu, Shixuan Zhuo, Zixuan Li, Cheng Guo, Xiaoyi Ye, Jinzhu Chen, Shuying Wang, Yan Chen.
      As a major fuel source for the tricarboxylic acid cycle, lactate controls energy metabolism through cell-to-cell or tissue-to-tissue lactate shuttles via monocarboxylate transporters (MCTs). Although lactate is shown to influence macrophage functions via histone lactylation, the specific functions of MCTs in macrophages remain incompletely understood. This study discovers that MCT1 and MCT4 have contrasting effects on regulating macrophage polarization. M1 polarization is associated with increase of MCT4 while M2 polarization is accompanied with increase of MCT1. MCT1 is mainly localized in mitochondria while MCT4 is localized on the plasma membrane. M1 polarization elevates lactate efflux from the cytoplasm to extracellular space, while M2 polarization increases intracellular lactate flux to mitochondria. At cellular level, blocking MCT1 exacerbates LPS-induced M1-like polarization and impairs mitochondria function. At animal level, deletion of MCT1 in macrophages exacerbates glucose intolerance, suppresses insulin secretion and increases islet cell death in high-fat diet fed mice. Mechanistically, lactate reduces insulin secretion through GPR81-cAMP-PKA signaling pathway. These findings not only disclose that the MCT1-mediated intracellular lactate shuttle to the mitochondria plays a pivotal role in governing macrophage polarization but also uncovers a functional interplay between macrophages and β cells in maintaining glucose homeostasis.
    Keywords:  MCT1; glucose homeostasis; lactate shuttle; macrophage; mitochondria; pancreatic islet
    DOI:  https://doi.org/10.1002/advs.202414760
  51. Cell. 2025 Jul 08. pii: S0092-8674(25)00728-7. [Epub ahead of print]
    Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL.
    Cai-Yuan Wu, Chun-Xiang Huang, Xiang-Ming Lao, Zi-Wen Zhou, Jia-Hong Jian, Zheng-Xi Li, Yong-Yi Wu, Zheng-Yu Liu, Lei Chen, Lianxin Liu, Limin Zheng, Yuan Wei, Dong-Ming Kuang.
      Targeting glucose metabolism has emerged as a promising strategy for inhibiting tumor growth. However, we herein uncover an unexpected paradox: while glucose deprivation through a low-carbohydrate diet or impaired in situ metabolism suppresses primary tumor growth, it simultaneously promotes lung metastasis by depleting natural killer (NK) cells via lung macrophages. Mechanistically, glucose deprivation induces endoplasmic reticulum (ER) stress, activating HMG-CoA reductase degradation protein 1 (HRD1) to catalyze K63-linked ubiquitination of TRAIL, which is then packaged into exosomes via the endosomal sorting complex required for transport (ESCRT) complex. These exosomal TRAIL molecules polarize PVR+ macrophages, triggering NK cell exhaustion and establishing a pre-metastatic niche. Notably, TIGIT blockade not only prevents metastasis induced by glucose deprivation but also enhances its anti-tumor effects. Clinically, low glucose metabolism correlates with higher 2-year postoperative recurrence across 15 cancer types. Furthermore, plasma exosomal TRAIL outperforms traditional markers, such as α-fetoprotein (AFP) and tumor size, in predicting early postoperative lung metastasis, revealing both the risks and therapeutic potential of targeting glucose metabolism.
    Keywords:  NK cell; exosomal TRAIL; low-carbohydrate diet; lung metastasis; macrophage
    DOI:  https://doi.org/10.1016/j.cell.2025.06.027
  52. Nat Cell Biol. 2025 Jul 15.
    Differentiation, ageing and leukaemia alter the metabolic profile of human bone marrow haematopoietic stem and progenitor cells.
    Maria-Eleni Lalioti, Mari Carmen Romero-Mulero, Noémie Karabacz, Julian Mess, Helen Demollin, Jasmin Rettkowski, Konrad Schuldes, Michael Mitterer, Carolin Wadle, Khalid Shoumariyeh, Mirijam Egg, Carlos Alfonso-Gonzalez, Karin Jäcklein, Katharina Schönberger, Nikolaos Karantzelis, Gregor Reisig, Philipp Aktories, Isabella M Mayer, Ioanna Tsoukala, Alexander Schäffer, Irene Tirado-Gonzalez, Aurélien Dugourd, Lukas M Braun, Beatriz Silva-Rego, Michael-Jason Jones, Katrin Kierdorf, Julio Saez-Rodriguez, Kilian Reising, Sebastian Gottfried Walter, Hind Medyouf, Valérie Hilgers, Gabriel Ghiaur, Robert Zeiser, Darja Karpova, Simon Renders, Sascha Gravius, Joerg Buescher, Nina Cabezas-Wallscheid.
      Metabolic cues are crucial for regulating haematopoietic stem and progenitor cells (HSPCs). However, the metabolic profile of human HSPCs remains poorly understood due to the limited number of cells and the scarcity of bone marrow samples. Here we present the integrated metabolome, lipidome and transcriptome of human adult HSPCs (lineage-, CD34+, CD38-) upon differentiation, ageing and acute myeloid leukaemia. The combination of low-input targeted metabolomics with our newly optimized low-input untargeted lipidomics workflow allows us to detect up to 193 metabolites and lipids from a starting material of 3,000 and 5,000 HSPCs, respectively. Among other findings, we observe elevated levels of the essential nutrient choline in HSPCs compared with downstream progenitors, which decline upon ageing and further decrease in acute myeloid leukaemia. Functionally, we show that choline supplementation fuels lipid production in HSPCs and enhances stemness. Overall, our study provides a comprehensive resource identifying metabolic changes that can be utilized to promote and enhance human stem cell function.
    DOI:  https://doi.org/10.1038/s41556-025-01709-7
  53. J Biomed Sci. 2025 Jul 11. 32(1): 66
    Clostridioides difficile meets the adenosine system: the art of manipulating host homeostasis.
    Katia Fettucciari, Luigi Cari, Andrea Spaterna, Rachele Del Sordo, Filippo Tavanti, Pierfrancesco Marconi, Gabrio Bassotti.
       BACKGROUND: Adenosine is a ubiquitous endogenous molecule capable of influencing several pathophysiological aspects. The adenosine system is extremely complex, starting from the generation of intracellular and extracellular adenosine, the regulation of its levels, and its action on four different receptors that vary in affinity and distribution in the different cell types and tissues. The most relevant effects of adenosine during infections and inflammation are documented on all types of immune cells, including those of adaptive immunity (T lymphocytes, B lymphocytes, regulatory cells) and of natural immunity (macrophages, polymorphonuclear cells, dendritic cells, natural killer). Of interest, the adenosine system is also strongly involved in the pathophysiology of colonic cells. Clostridioides difficile (C. difficile), responsible for 15-20% of all cases of antibiotic-associated diarrhea, is an infection that has been evolving over the past two decades due to the unstoppable spread of C. difficile in the anthropized environment and the progressive human colonization. The pathological activity of C. difficile is due to toxin A (TcdA) and B (TcdB) which profoundly alter the homeostasis of the adenosine system, acting both at the level of its generation and on the expression and regulation of adenosine receptors. The final effect consists in an attenuation of the inflammatory response to favor the persistence of the C. difficile infection.
    CONCLUSION: This review highlights a new ability of C. difficile, through its Tcds, of manipulating the host to its advantage.
    Keywords:   Clostridioides difficile infection; Clostridioides difficile toxin B; Clostridioides difficiletoxin A; Adenosine; Anti-inflammatory response; Colon pathophysiology; Enteric glial cells; Immune cells; Inflammation
    DOI:  https://doi.org/10.1186/s12929-025-01160-8
  54. Sci Rep. 2025 Jul 15. 15(1): 25481
    Serum untargeted metabolomics alterations in systemic lupus erythematosus patients with elevated serum ferritin.
    Na Li, Rui Chai, Xue Xu, Qian Xu, Jun Liang, Dandan Wang, Huayong Zhang, Xuebing Feng, Linyu Geng, Lingyun Sun.
      This study investigated the alterations in serum metabolic profile in systemic lupus erythematosus (SLE) patients with increased levels of serum ferritin. 52 SLE patients were divided into two groups based on their ferritin levels. The metabolomic profile was identified using non-targeted metabolomics technology (UHPLC-MS/MS), and analyzed by Principal Component Analysis (PCA), Orthogonal Partial Least Squares Discrimination Analysis (OPLS-DA), ROC analysis, and pathway analysis. Results showed that SLE patients with high ferritin levels had increased hematologic involvement and elevated levels of inflammatory markers, including procalcitonin (PCT), alanine transaminase (ALT), and aspartate transaminase (AST). Additionally, there was decreased levels of albumin and CD4+ T cell counts. A distinct metabolic profile was found in the high-ferritin SLE group, with significant changes in metabolites and metabolic pathways. Potential correlations between differential metabolites and clinical features were identified, including associations with PCT, interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, ALT, AST, immunoglobulin G (IgG), and CD3+CD4+ T cell. The findings confirm elevated serum ferritin is associated with hematology involvement and offer insights into the pathology and targeted therapeutic strategies of SLE.
    Keywords:  Metabolomics; Serum ferritin; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1038/s41598-025-06170-y
  55. Front Cell Infect Microbiol. 2025 ;15 1526740
    Metabolomics and lipidomics of plasma biomarkers for tuberculosis diagnostics using UHPLC-HRMS.
    Gaofeng Sun, Quan Wang, Xinjie Shan, Maierheba Kuerbanjiang, Ruiying Ma, Wensi Zhou, Lin Sun, Qifeng Li.
       Introduction: Determining metabolic profiles during host-pathogen interactions is crucial for developing novel diagnostic tests and exploring the mechanisms underlying infectious diseases. However, the characteristics of the circulating metabolites and their functions after Mycobacterium tuberculosis infection have not been fully elucidated. Therefore, this study aimed to identify the differential metabolites in tuberculosis (TB) patients and explore the diagnostic value of these metabolites as potential biomarkers.
    Methods: Seventy-two TB patients and 78 healthy controls (HCs) were recruited as the training set, while 30 TB patients and 30 HCs were enrolled as the independent validation set. Metabolites in plasma samples were analyzed by high-resolution mass spectrometry. Differential metabolites were screened using principal component analysis and machine learning algorithms including LASSO, Random Forest, and XGBoost. The diagnostic accuracy of the core differential metabolites was evaluated. Pearson correlation analysis was performed.
    Result: The metabolic profiling of TB patients showed significant separation from that of the HCs. In the training set, 282 metabolites were identified as differentially expressed in TB patients, with 214 metabolites validated in the independent validation cohort. KEGG pathway enrichment analysis showed that the differential metabolites were mainly enriched in lipid metabolism. Seven core differential metabolites were identified by the three machine learning algorithms. Receiver operating characteristic analysis revealed that Angiotensin IV had high accuracy in diagnosing TB.
    Conclusion: These newly identified plasma metabolites are expected to serve as potentially valuable biomarkers for TB, potentially facilitating the diagnosis of the disease and enhancing the understanding of its underlying mechanisms.
    Keywords:  Tuberculosis; UHPLC-HRMS; biomarker; diagnosis; machine learning; metabolite
    DOI:  https://doi.org/10.3389/fcimb.2025.1526740
  56. Nat Commun. 2025 Jul 11. 16(1): 6422
    Gut microbiota and brain-resident CD4+ T cells shape behavioral outcomes in autism spectrum disorder.
    John Chulhoon Park, Min-A Sim, Changhon Lee, Hye-Eun Park, Juhun Lee, Seung Yeon Choi, Seohyun Byun, Haeun Ko, Haena Lee, Seung Won Kim, Jaegyun Noh, Geon Park, Solji Lee, Tae-Kyung Kim, Sin-Hyeog Im.
      Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by alterations in social, repetitive, and anxiety-like behaviors. While emerging evidence suggest a gut-brain etiology in ASD, the underlying mechanisms remain unclear. To dissect this axis, we developed a germ-free BTBR mouse model for ASD. The absence of gut microbiota in male mice ameliorates ASD-associated behaviors and reduces populations of inflammatory brain-resident T cells. Additionally, CD4+ T cell depletion mitigates neuroinflammation and ASD behaviors, suggesting a gut-immune-brain axis. We identify several microbial and metabolic regulators of ASD, particularly those relevant to the glutamate/GABA ratio and 3-hydroxyglutaric acid. Using an in silico metabolite prediction model, we propose Limosilactobacillus reuteri IMB015 (IMB015) to be a probiotic candidate. Administration of IMB015 reduces the glutamate/GABA ratio and neuroinflammation, resulting in improved behaviors. Here we report a gut-immune-brain axis in which the gut microbiota and its metabolites can modulate brain-resident immune cells and ASD-associated behaviors.
    DOI:  https://doi.org/10.1038/s41467-025-61544-0
  57. Int Immunopharmacol. 2025 Jul 15. pii: S1567-5769(25)01188-9. [Epub ahead of print]163 115198
    GDF15 attenuates sepsis-induced acute lung injury by suppressing the HIF-1α/LDHA pathway.
    Xiandong Kuang, Zhili Niu, Zhaoyang Huang, Xin Cai, Li Wang, Ye Zhang, Jialong Luo, Xincan Zhao, Li Shuo, Pingan Zhang.
       BACKGROUND: Sepsis-associated acute lung injury (ALI) is characterized by endothelial inflammation and metabolic reprogramming. Growth Differentiation Factor 15 (GDF15), a stress-inducible cytokine, may regulate immunometabolic crosstalk, but its endothelial-specific role remains undefined.
    METHODS: Using LPS-induced septic mice and human endothelial cells, GDF15 expression was dysregulated via AAV-mediated overexpression or siRNA knockdown. Pharmacological modulators included: HIF-1α inhibitor BAY 87-2243, HIF-1α activator 1,4-DPCA, LDHA inhibitor FX-11, and sodium lactate. Endothelial inflammation was evaluated through adhesion molecules (ICAM-1, VCAM-1, VEGF-A) and cytokines (TNF-α, IL-6) at protein levels.
    RESULTS: GDF15 was upregulated in pulmonary endothelia of septic mice and contributed to endothelial dysfunction, evidenced by elevated adhesion molecules (ICAM-1/VCAM-1/VEGF-A), cytokines (TNF-α/IL-6), and impaired barrier repair. GDF15 overexpression alleviated lung injury and inflammation, while its knockdown aggravated pathology. Mechanistic studies revealed that GDF15 inhibits the HIF-1α/LDHA glycolytic axis activated by LPS, reducing cytokine storm and leukocyte adhesion. Critically, HIF-1α inhibitor (BAY 87-2243) and LDHA inhibitor (FX-11) phenocopied GDF15 protection, whereas HIF-1α activator (1,4-DPCA) and sodium lactate negated it, establishing HIF-1α/LDHA as the primary effector pathway.
    CONCLUSION: GDF15 emerges as a critical endothelial protector in sepsis by suppressing HIF-1α/LDHA-mediated immunometabolic dysregulation. Its synergistic interplay with glycolytic inhibitors highlights a novel therapeutic strategy to target both inflammatory and metabolic drivers of ALI.
    Keywords:  Acute lung injury; Endothelial dysfunction; GDF15; HIF-1α/LDHA axis; Immunometabolic crosstalk; Vascular hyperpermeability
    DOI:  https://doi.org/10.1016/j.intimp.2025.115198
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