bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–09–06
47 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. SDH inhibition quenches rheumatoid arthritis flare-associated IL-1β+IFN-γ+ macrophages via NF-κB/STAT4.
  2. Oxygen-responsive bacterial glycosphingolipid links symbiont fitness and immune development in neonatal host.
  3. Mitochondrial succinate sensing promotes macrophage inflammation in RA.
  4. ACOD1-dependent succinate signalling acts as a metabolic checkpoint for osteoclast differentiation.
  5. The Immunometabolic Architecture of Sepsis: Bridging Cellular Bioenergetics and Systemic Immune Dysregulation.
  6. Sepsis as CNS-governed metabolic triage.
  7. Pseudomonas aeruginosa Impairs Mitochondrial Function During Infection of Corneal Epithelial Cells.
  8. Itaconate and its derivatives in human health and diseases.
  9. Revisiting macrophage metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: mechanisms, regulation, and therapeutic breakthroughs.
  10. α-Ketoglutarate Promotes Ciprofloxacin Tolerance in Methicillin-Resistant Staphylococcus aureus via Glutamate-Mediated Metabolic Remodeling.
  11. Neutrophil NADPH oxidase breaks the inflammatory IL-1β/IL-17A circuit to enhance pathogen clearance during respiratory virus infections.
  12. Stearoyl-CoA desaturase 1 regulates antiviral innate immunity in zebrafish via PPARα-IRF3 axis.
  13. Local lactate-driven H3K18 lactylation impairs anti-influenza immunity through NRF2-dependent dendritic cell dysfunction.
  14. Inhibition of 3-mercaptopyruvate sulfurtransferase enhances CD8+ T-cell antitumor immunity.
  15. The IL-9R/Arg1 pathway promotes polyamine metabolism in human airway macrophages.
  16. ACLY palmitoylation reprograms macrophages histone acetylation rewiring to repress hepatocellular carcinoma.
  17. Cross-tissue single-cell atlas reveals Id2 promotes sepsis-induced tissue damage by mediating macrophage metabolic reprogramming via Pkm2.
  18. Acute immunometabolic reprogramming following clade C HIV immunization in rhesus macaques.
  19. SIRT1 deacetylates GAPDH to drive microglial glycolysis and neuroinflammation.
  20. Uridine and pyruvate supplementation is associated with Th1 polarization during mitotoxic antibiotic therapy.
  21. Recent understanding of immunometabolic remodeling in pulmonary macrophages: homeostasis, chronic respiratory diseases, and therapeutic targeting.
  22. Measles virus reprograms CD4+ T-cell sphingolipid and fatty acid metabolism to facilitate infection.
  23. Candida albicans reprograms Staphylococcus aureus glycolytic metabolism to drive enhanced virulence.
  24. Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
  25. Human CD4+ iNKT cells have highly oxidative metabolism and use glycogen reserves to sustain IFN-γ production in nutrient-limited environments.
  26. Guanine promotes acute lung injury by repressing H3K27me3 in sepsis.
  27. Immunometabolic Control of Neutrophil Plasticity in Tuberculosis.
  28. From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.
  29. Tumors steal a signal from T cells.
  30. Salmonella lipopolysaccharide stimulates uptake of long-chain fatty acids in the small intestine.
  31. Metabolite and lipid profiling of human vitreous reveals purine metabolic dysregulation and inflammatory lipid remodeling as the drivers of bacterial endophthalmitis.
  32. Glycolysis Drives TLR Ligand-Induced Maturation and Immune Activation of Liver Sinusoidal Endothelial Cells.
  33. C646-loaded mesenchymal stromal cell extracellular vesicles alleviate lactate-driven immunoparalysis in sepsis-associated ARDS through the p300-H3K18la-PSMD14 axis.
  34. Aging microenvironment induces CD8+ T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis.
  35. Metabolic shifts driven by host-microbial interactions.
  36. MAP17 Orchestrates SGLT2-Dependent Glycolytic Reprogramming to Drive Trained Immunity and Accelerate Atherosclerosis.
  37. PLA2G7-Mediated Pro-Inflammatory Activation of Lipid-Associated Macrophages Drives Pulpitis.
  38. Methacrylated hyaluronic acid hydrogel enables CD44-mediated local berberine delivery to reprogram macrophage immunometabolism and promote alveolar bone repair in periodontitis.
  39. Proteins as Regulators of Metabolic Changes in Sepsis: Alterations in Body Fluids, Immune Cells, and Organs through the Eyes of Proteomics.
  40. Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species.
  41. SIRT1/PGC-1α Axis and CPT1A-Mediated Metabolic Reprogramming Reshape Macrophage Polarization to Ameliorate Intervertebral Disc Degeneration.
  42. Metabolic Reprogramming of NSUN2-Mediated m5C Modification Promotes the Progression of Hepatocellular Carcinoma by Restricting Natural Killer Cell-Mediated Cytotoxicity.
  43. Nutritional regulation of gut-brain immune crosstalk across the lifespan.
  44. Lactylation in sepsis-associated acute kidney injury: regulatory mechanisms and therapeutic prospects.
  45. Oxidative stress-driven epigenetic reprogramming of immune cells in COPD: from epitranscriptomic and metabolic crosstalk to treatable traits.
  46. Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives.
  47. Bacillus subtilis exopolysaccharide enhances Lactobacillus johnsonii-kynurenic acid to restore intestinal T helper 17/regulatory T cell balance via aryl hydrocarbon receptor.
  1. Ann Rheum Dis. 2026 Sep 04. pii: S0003-4967(26)00483-8. [Epub ahead of print]
    SDH inhibition quenches rheumatoid arthritis flare-associated IL-1β+IFN-γ+ macrophages via NF-κB/STAT4.
    Stephanie R Zack, Neha Satoeya, Víctor Andrés Sosa Hernández, Sania Deen, Wes Nijim, Brian Zanotti, Michael V Volin, Adel Burgos, Joseph A Karam, Yinglin Xia, Diana C Umali, Shiva Arami, Pim Jetanalin, Miriam Friedman, Luke A J O'Neill, Cornelia M Weyand, Nadera Sweiss, Shiva Shahrara.
       OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease in which distinct macrophage (MΦ) endotypes can guide therapy. TLR5, upregulated during disease flares, drives an IL-1β+NFKB1+IFN-γ+STAT4lo MΦ phenotype in blood and synovium that is refractory to tumour necrosis factor (TNF) and IL-6R blockade. This study aimed to identify an alternative strategy to correct inflammation and metabolic dysfunction in these pathogenic MΦs.
    METHODS: Peripheral blood-derived MΦs and synovial tissue from patients with RA, together with a localised arthritis model, were used to assess responses to succinate dehydrogenase (SDH) inhibition following TLR5 stimulation. We performed bulk RNA sequencing, Seahorse extracellular flux assays, flow cytometry, and multiscale immunofluorescence microscopy spanning whole RA synovium to individual mitochondria.
    RESULTS: TLR5, SDH, and p65/NFKB1 colocalised in synovial CD14⁺ MΦs and were upregulated in circulation during disease flares. IL-1β+NFKB1+IFN-γ+STAT4lo MΦs elicited by TLR5 stimulation exhibited biphasic metabolic reprogramming, with an early increase in mitochondrial adenosine triphosphate (ATP) production followed by tricarboxylic acid (TCA) cycle disruption, compensatory glycolysis, and SDH upregulation. In contrast to HK2 inhibition, which targets the first step of glycolysis, SDH inhibition within the TCA cycle intercepted TLR5-induced NF-κB/STAT4 signalling and oxidative stress, restoring TCA enzyme expression and mitochondrial function. In localised TLR5-driven synovitis, SDH inhibition attenuated joint inflammation by reducing the population of F4/80⁺IL-1β+iNOS⁺SDH⁺ MΦs and restoring metabolic balance.
    CONCLUSIONS: SDH functions as a metabolic-immune checkpoint in pathogenic IL-1β+NFKB1+IFN-γ+STAT4lo MΦs in RA. Targeting SDH may concurrently resolve mitochondrial dysfunction and inflammation in patients experiencing disease flares, with synovial enrichment of TLR5, SDH, IL-1β, NFKB1, and IFN-γ serving as predictive biomarkers.
    DOI:  https://doi.org/10.1016/j.ard.2026.07.025
  2. Cell. 2026 Sep 01. pii: S0092-8674(26)00938-4. [Epub ahead of print]
    Oxygen-responsive bacterial glycosphingolipid links symbiont fitness and immune development in neonatal host.
    Kyoo Heo, Da-Jung Jung, Ji-Sun Yoo, Byoungsook Goh, Dennis L Kasper, Sungwhan F Oh.
      Symbiotic gut bacteria must re-establish themselves in every host generation, yet the molecular strategies enabling this inheritance remain poorly understood. Here, we show that Bacteroides fragilis uses a membrane glycolipid, alpha-galactosylceramide (BfaGC), to colonize the neonatal gut. Genome-wide fitness profiling revealed that BfaGC biosynthesis is selectively required during early life, when transient oxygenation creates a physiological bottleneck for strict anaerobes. Mechanistically, BfaGC reduces membrane proton permeability, sustaining the proton-motive force that supports aerobic respiration. This oxygen-responsive adaptation simultaneously generates a host-facing immunomodulatory signal that calibrates neonatal natural killer T (NKT) cell development, linking bacterial fitness to immune maturation through a single metabolite. The same mechanism also enables niche expansion by enterotoxigenic strains, revealing context-dependent consequences. Notably, this strategy is distinct among gut Bacteroidales: other prominent members synthesize a different sphingolipid subclass supporting broader fitness, implying divergent evolutionary strategies. Our findings provide time-resolved insight into how bacterial metabolites shape host-microbiota symbiosis across development.
    Keywords:  Bacteroides fragilis; alpha-galactosylceramide; host-microbe coadaptation; neonatal colonization; vertical transmission
    DOI:  https://doi.org/10.1016/j.cell.2026.08.011
  3. Nat Rev Rheumatol. 2026 Sep 03.
    Mitochondrial succinate sensing promotes macrophage inflammation in RA.
    Jessica McHugh.
      
    DOI:  https://doi.org/10.1038/s41584-026-01434-x
  4. Biol Chem. 2026 Sep 07.
    ACOD1-dependent succinate signalling acts as a metabolic checkpoint for osteoclast differentiation.
    Yue Gao, Genyang Xin, Elisabeth Seebach, Dominik Schaack, Markus A Weigand, Katharina F Kubatzky.
      Immune cells undergo metabolic reprogramming in response to inflammatory stimuli. The immuneresponsive gene 1 (Irg1) encodes aconitate decarboxylase (ACOD1), which generates itaconate from cis-aconitate in the TCA cycle. Itaconate inhibits succinate dehydrogenase, resulting in succinate accumulation. Stable ACOD1 overexpression in RAW264.7 cells shifted cellular metabolism towards glycolysis, as indicated by enhanced mTOR activation, increased 4E-BP1 phosphorylation, and reduced ATP levels. ACOD1 cells displayed impaired osteoclastogenesis with reduced expression of osteoclast-associated genes and fewer TRAP-positive multinucleated osteoclasts. Unexpectedly, NFATc1 was constitutively present in the nucleus of untreated ACOD1 cells, resulting in residual NFAT activity and induction of inflammatory genes. Upon RANKL stimulation, these pre-activated cells showed delayed osteoclastogenic signalling accompanied by sustained expression of the transcriptional repressors BCL6, MafB, and IRF8. Using a GPR91 antagonist and a Gαq inhibitor, we demonstrate that extracellular succinate activates NFATc1 via GPR91-Gαq signalling. RNA sequencing further revealed that ACOD1 overexpression promotes an innate immune transcriptional program rather than osteoclast differentiation. Together, our findings identify succinate-GPR91 signalling as a regulator of the transition between inflammatory activation and osteoclastogenesis.
    Keywords:  ACOD1; GPR91; Gαq; metabolism; osteoclast; succinate
    DOI:  https://doi.org/10.1515/hsz-2026-0168
  5. Crit Care Clin. 2026 Oct;pii: S0749-0704(26)00038-2. [Epub ahead of print]42(4): 857-874
    The Immunometabolic Architecture of Sepsis: Bridging Cellular Bioenergetics and Systemic Immune Dysregulation.
    Valentim Rodrigues, Duarte Abecasis, Luis F Moita.
      Sepsis continues to be a leading public health challenge, accounting for almost 20% of annual global deaths. Here, we review the evolving pathophysiological understanding of this syndrome by highlighting the central role of immunometabolism. We move beyond the biphasic model to argue that hyperinflammation and immunosuppression coexist across different biological compartments. Recognition of danger through the signal triad of pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostasis-altering molecular processes induces profound intracellular metabolic reprogramming toward a predominantly aerobic glycolysis pattern. This shift supports early effector functions but leads to bioenergetic insufficiency, cytopathic hypoxia, and mitochondrial dysfunction.
    Keywords:  Immunometabolism; MODS; Mitochondrial dysfunction; PICS; Sepsis-3
    DOI:  https://doi.org/10.1016/j.ccc.2026.05.009
  6. Front Immunol. 2026 ;17 1842915
    Sepsis as CNS-governed metabolic triage.
    Barış Yurtsever, Demet Demirkol.
      Sepsis remains the leading cause of death in intensive care, yet decades of trials targeting individual inflammatory mediators have failed to reduce mortality. This failure may reflect a fundamental misunderstanding: sepsis may not be a disease of immune dysregulation but a centrally governed metabolic program, an evolved conservation response functionally analogous to bacterial sporulation. We bring together three lines of work. Two are established: the Selfish Brain Theory of hierarchical energy allocation and the Metabolic Shutdown Hypothesis of adaptive organ hibernation. The third is developed here from a preprint by one of the authors: the proposal that cortisol is a candidate driver of the septic state rather than an anti-inflammatory brake, and that, as a consequence, the systemic immune response can be read as an active-inference process governed by the central nervous system (CNS). These describe one phenomenon from different vantage points. The convergence yields what we call a sporulation-like conservation program: we propose that, when the CNS detects an existential threat, it activates a coordinated program of peripheral shutdown, resource centralization, and innate-dominant immune reconfiguration, mediated primarily through the hypothalamic-pituitary-adrenal axis. This response is adaptive when self-limiting but becomes pathological when the organism cannot terminate the program, a state we recognize as sepsis - specifically, the high-cortisol, catabolic, insulin-resistant sepsis phenotype to which this framework is limited. Drawing on the Free Energy Principle as an interpretive lens, we describe this governance as a pathological attractor state: the sporulation-like policy generates its own confirmatory sensory input, creating an immunometabolic echo chamber that leaves the CNS no reason to revise its model. Breaking this lock-in requires a signal the model cannot predict: a genuine metabolic surprise. We propose that insulin can serve as this termination signal, acting not through glucose control but as a CNS-directed anabolic signal that conveys metabolic safety. This reframing reinterprets the existing insulin trial literature and yields testable predictions, which we set out in full. This framework would shift the therapeutic objective from suppressing inflammation to providing the metabolic evidence the CNS needs to terminate its own emergency program, from fighting the response to persuading the controller.
    Keywords:  HPA axis; active inference; cortisol; free energy principle; insulin signaling; metabolic shutdown; organ dysfunction; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1842915
  7. Invest Ophthalmol Vis Sci. 2026 Sep 01. 67(11): 9
    Pseudomonas aeruginosa Impairs Mitochondrial Function During Infection of Corneal Epithelial Cells.
    Rajalakshmy Ayilam Ramachandran, Joelle T Abdallah, Abigail M Blanton, Mahad Rehman, Hamid Baniasadi, Danielle M Robertson.
       Purpose: Pseudomonas aeruginosa (PA) is a Gram-negative opportunistic bacterial pathogen that can infect the cornea as a result of trauma or contact lens wear. Mitochondria, originally derived from bacteria, play important roles in host defense. This study investigated the effect of PA on mitochondrial structure and function during the early stages of infection in corneal epithelial cells.
    Methods: Telomerase-immortalized human corneal epithelial cells and primary cultured human corneal epithelial cells were infected with a standard invasive test strain of PA (strain PAO1). Changes in mitochondrial dynamics, mitophagy, and metabolic proteins were assessed by Western blot. Mitochondrial polarization was quantified using JC-1 labeling. Mitochondrial metabolism was measured in real time using Seahorse, and mass spectrometry was performed for metabolomic analysis. Mitochondrial morphology was assessed by transmission electron microscopy.
    Results: PA infection induced rapid mitochondrial fission, followed by PINK1-mediated mitophagy. PA infection also reduced NADH-linked respiration through a reduction in complex I and impaired dihydroorotate and glycerolipid metabolism. Other changes in the metabolite profile included an increase in arginine biosynthesis, purine metabolism, and the pentose phosphate pathway, all pathways that can be readily exploited by bacteria. Following treatment with gentamicin to kill all extracellular bacteria, metabolic flux analysis showed that corneal epithelial cells were able to restore mitochondrial function despite the continued presence of intracellular PA.
    Conclusions: Taken together, these data demonstrate that extracellular PA triggers mitochondrial dysfunction and metabolic rewiring in corneal epithelial cells. This may represent a potential mechanism whereby PA disables host cell mitochondria to facilitate invasion.
    DOI:  https://doi.org/10.1167/iovs.67.11.9
  8. Signal Transduct Target Ther. 2026 Sep 04. pii: 363. [Epub ahead of print]11(1):
    Itaconate and its derivatives in human health and diseases.
    Jianyou Gu, Wenying Zhang, Junfeng Zhang, Silue Zeng, Renpei Xia, Lei Cai, Xiaosheng Zhong, Shixiang Guo, Huaizhi Wang, Zhe-Sheng Chen.
      Metabolic reprogramming forms the foundation of immune effector functions and the regulation of inflammation. As a pivotal node connecting the tricarboxylic acid cycle to immune signaling, the IRG1/ACOD1 and itaconate axes play a central role in coordinating inflammatory tone and redox balance. Itaconate, generated through the decarboxylation of cis aconitate, acts as an immunometabolic brake that engages multiple regulatory pathways to sustain the dynamic equilibrium between inflammation and tissue homeostasis. Across a broad spectrum of pathological conditions, including infectious diseases, metabolic disorders, ischemia‒reperfusion injury, neurodegenerative diseases, autoimmune disorders, and cancers, itaconate and its derivatives generally exert anti-inflammatory and cytoprotective effects. However, within specific microenvironments, these molecules may also be exploited by pathogens to evade immune clearance or promote immunosuppressive and protumorigenic responses. Future studies should further elucidate tissue- and lineage-specific functions, define bidirectional regulatory mechanisms, and optimize the pharmacokinetic properties of itaconate derivatives. With the advancement of multiomics integration, systems immunology, rational drug design, and engineered itaconate delivery technologies, the IRG1/ACOD1-itaconate axis and derivative-based therapeutic strategies are poised to emerge as key metabolic checkpoints and therapeutic targets in inflammatory-, metabolic-, immune-, and cancer-related diseases.
    DOI:  https://doi.org/10.1038/s41392-026-02936-6
  9. Front Immunol. 2026 ;17 1899587
    Revisiting macrophage metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: mechanisms, regulation, and therapeutic breakthroughs.
    Li Zhu, Bo Wu.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults globally, yet therapeutic options remain limited. Macrophage metabolic reprogramming is increasingly recognized as an important contributor to disease progression. Hepatic macrophages from resident Kupffer cells (KCs) to infiltrating monocyte-derived macrophages (MoMFs) and triggering receptor expressed on myeloid cells 2 (TREM2) + lipid-associated macrophages (LAMs) shift their bioenergetic profile from fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) toward aerobic glycolysis. This review maps the metabolic circuits driving macrophage-mediated inflammation in MASLD. We delineate how tricarboxylic acid (TCA) cycle disruption generates signaling metabolites that enforce glycolytic commitment through hypoxia-inducible factor stabilization, how metabolic-epigenetic coupling perpetuates inflammatory programs, and how the failure of repair mechanisms and mitochondrial quality control accelerates tissue damage. Notably, the IRG1-itaconate axis exhibits a dynamic U-shaped trajectory across MASLD stages: itaconate levels decrease during early steatosis due to Kupffer cell loss, but subsequently rise markedly during MASH as infiltrating macrophages upregulate IRG1 expression, representing a compensatory yet insufficient anti-inflammatory response. We further examine how these metabolic states evolve across disease stages, from simple steatosis through steatohepatitis and fibrosis to cirrhosis, and assess the therapeutic potential of metabolic interventions. Recent FDA accelerated approvals of resmetirom and semaglutide for selected adults with non-cirrhotic MASH and F2-F3 fibrosis have expanded the therapeutic landscape. Their clinical benefits are primarily supported by histological endpoints; whether modulation of hepatic macrophage metabolism contributes directly to these benefits remains to be established. Emerging evidence indicates that macrophage metabolic states retain plasticity and can be pharmacologically reprogrammed, with single-cell metabolomics poised to guide precision therapeutic strategies.
    Keywords:  HIF-1α; MASLD; TCA cycle; macrophage metabolism; metabolic therapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1899587
  10. J Proteome Res. 2026 Sep 04. 25(9): 4636-4650
    α-Ketoglutarate Promotes Ciprofloxacin Tolerance in Methicillin-Resistant Staphylococcus aureus via Glutamate-Mediated Metabolic Remodeling.
    Qing-Qiang Xu, Lv-Yuan Fan, Jing-Yun Wu, Ting Zhang, Zhuo-Ying Cao, Wen-Ting Zhang, Yu-Bin Su, Jiao Fei.
      Methicillin-resistant Staphylococcus aureus (MRSA) is a globally significant pathogen causing severe infections. The chronicity and recurrence of its infection pose serious challenges to public health. In this study, we reported that intracellular accumulation of α-ketoglutarate (α-KG) significantly increased ciprofloxacin (CIP) tolerance in MRSA. Using integrated metabolomic and functional genomic approaches, we demonstrated that both exogenous α-KG and genetic knockout of α-KG dehydrogenase (ΔsucA, ΔsucB) induced CIP tolerance in MRSA. Mechanistically, elevated α-KG levels drive the accumulation of glutamate (Glu), which in turn reduced bacterial membrane potential and cellular ATP content. Furthermore, Glu accumulation raised intracellular osmotic pressure, leading to decreased CIP uptake. These metabolic alterations enable MRSA to sustain high tolerance toward ciprofloxacin. Our findings reveal a key role of the α-KG-Glu metabolic axis in driving antibiotic tolerance and provide novel insights into the metabolic adaptations underlying drug persistence in MRSA.
    Keywords:  antibiotic tolerance; ciprofloxacin; metabolic regulation; methicillin-resistant Staphylococcus aureus; α-ketoglutarate/glutamate
    DOI:  https://doi.org/10.1021/acs.jproteome.6c00131
  11. Nat Commun. 2026 Aug 05. pii: 9425. [Epub ahead of print]17(1):
    Neutrophil NADPH oxidase breaks the inflammatory IL-1β/IL-17A circuit to enhance pathogen clearance during respiratory virus infections.
    Aderonke Sofoluwe, Angelos Petropoulos, Zehra Fatima Ali-Khan, Abhilesh Salil Goomanee, Simon J Cleary, Annika Warnatsch.
      Respiratory virus infections are invariably accompanied by an increase in oxidative stress through elevated production of Reactive Oxygen Species (ROS), which contribute to both host defence and pathogenesis. Using mouse models, we identify neutrophil NADPH Oxidase 2 (Nox2) as the major early source of ROS during Influenza A Virus (IAV) infection. Surprisingly, neutrophil Nox2-derived ROS display multifaceted effects, not only unleashing oxidative stress but also limiting pro-inflammatory IL-1β signalling. Absence of neutrophil Nox2 enhances IL-1β production, promoting the proliferation of IL-17-producing gamma delta (γδ) T cells. This early self-amplified augmentation of the IL-1β/IL-17 axis is associated with increased viral burden and reduced IFNα expression in the lung. We extend our findings to humans. Similar patterns of ROS production and cytokine regulation are observed in human neutrophils when exposed to IAV and the viral RNA analogue poly(I:C). Our discovery highlights that ROS, often associated with harm, play a dual role by regulating cytokine signalling and thus influencing the immune response against respiratory viruses.
    DOI:  https://doi.org/10.1038/s41467-026-76327-4
  12. Fish Shellfish Immunol. 2026 Sep 01. pii: S1050-4648(26)00590-5. [Epub ahead of print] 111686
    Stearoyl-CoA desaturase 1 regulates antiviral innate immunity in zebrafish via PPARα-IRF3 axis.
    Zengjie Liu, Wencong Lai, Han Hu, Wanxuan Zhang, Jinwei Duan, Kangsen Mai, Qinghui Ai.
      Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme that catalyzes the desaturation of saturated fatty acids to monounsaturated fatty acids. Although lipid metabolism is increasingly recognized to influence antiviral innate immunity, the role of SCD1 in host defense, particularly in teleost fish, has not been fully explored. Here, we show that viral infection markedly suppresses SCD1 expression in zebrafish. Overexpression of zebrafish SCD1 significantly suppresses antiviral gene expression and enhances viral replication. Pharmacological inhibition of SCD1 desaturase activity enhances antiviral gene expression, reduces viral replication, and protects zebrafish larvae from viral lethality, indicating that SCD1 suppresses antiviral immunity in an enzymatic activity-dependent manner. Mechanistically, palmitic acid (PA), the saturated fatty acid substrate of SCD1, acts as a potent enhancer of antiviral innate immunity. PA treatment upregulates antiviral gene expression in vivo and in vitro, and restricts viral replication in ZFL cells. We demonstrate that PA exerts its immunostimulatory effects by inhibiting the two zebrafish isoforms of peroxisome proliferator-activated receptor α, PPARαa and PPARαb, as overexpression of either isoform attenuates PA-induced antiviral responses while a PPARα antagonist mimics the effects of PA. Furthermore, we show that PPARαa and PPARαb physically interact with interferon regulatory factor 3 (IRF3) and suppress IRF3-induced antiviral gene expression, thereby inhibiting type I interferon signaling. Collectively, our findings establish an SCD1-PA-PPARα-IRF3 regulatory axis in which SCD1 consumes its substrate PA to sustain PPARα-mediated negative regulation of IRF3-dependent antiviral gene expression, thereby restraining antiviral innate immunity.
    Keywords:  IRF3; PPARα; SCD1; antiviral innate immunity; palmitic acid; zebrafish
    DOI:  https://doi.org/10.1016/j.fsi.2026.111686
  13. Cell Rep. 2026 Sep 03. pii: S2211-1247(26)01021-1. [Epub ahead of print]45(9): 117943
    Local lactate-driven H3K18 lactylation impairs anti-influenza immunity through NRF2-dependent dendritic cell dysfunction.
    Chen Lyu, Jiuyang Xu, Yulin Zhang, Fei Zhu, Di He, Weiwei Ge, Congcong Shang, Qi Wang, Wenting Zuo, Yingying Yuan, Yawen Ni, Yitian Xu, Ziyao Li, Yuxian Mu, Rongling Zhang, Bin Cao.
      Metabolic alterations are increasingly recognized during influenza virus infection, but how local lactate accumulation shapes antiviral immunity remains poorly characterized. By integrating time-series targeted energy metabolomics, single-cell RNA sequencing, flow cytometry, and functional perturbation, we show that influenza virus infection preferentially increases lactate within the lung microenvironment, where it restrains pulmonary CD8+ T cell response. Mechanistically, extracellular lactate enters dendritic cells through monocarboxylate transporter (MCT)-dependent transport and induces a tolerogenic-like state marked by impaired maturation, reduced costimulation, and diminished CD8+ T cell-priming capacity. Direct experimental evidence identifies H3K18la as a prominent lactate-responsive histone lactylation mark, while multi-omics integration links it to enhancer accessibility and NRF2 pathway activation. Functional studies further show that NRF2 promotes dendritic cell suppression by reinforcing tolerogenic programs and limiting mtROS-dependent XBP1 splicing. Together, these findings reveal a lactate-driven histone lactylation-NRF2 pathway that modulates antiviral immunity during influenza infection.
    Keywords:  CD8(+) T cells; CP: immunology; dendritic cells; histone lactylation; influenza virus; lactate
    DOI:  https://doi.org/10.1016/j.celrep.2026.117943
  14. Redox Biol. 2026 Aug 28. pii: S2213-2317(26)00372-1. [Epub ahead of print]97 104373
    Inhibition of 3-mercaptopyruvate sulfurtransferase enhances CD8+ T-cell antitumor immunity.
    Muriel Urwyler, Marietta Margareta Korsos, Eloise Dupuychaffray, Nikita Markov, Kelly Ascenção, Maria Petrosino, Karim Zuhra, Darko Stojkov, Sara Barcos, Jérémie Tachet, Pragallabh Purwar, Montserrat Alvarez, Aurélien Pommier, Mohamed Z Gad, Reham M Abdel-Kader, Csaba Szabo, Carole Bourquin.
      Hydrogen sulfide (H2S) is a redox-active gasotransmitter implicated in tumor progression and immune regulation. The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is a key contributor to endogenous H2S and polysulfide production, but its role in tumor-immune interactions remains poorly defined. Here, we show that 3-MST is the most abundantly expressed H2S-synthesizing enzyme in human renal cell carcinoma cells (RCC) and that high 3-MST expression correlates with reduced patient survival. Pharmacological inhibition of 3-MST lowered intracellular H2S levels in Renca renal carcinoma cells, suppressed proliferation, induced apoptosis, disrupted cellular metabolism, and increased expression of immune-related genes and proteins. In immune cells, partial inhibition of 3-MST promoted T cell activation, as evidenced by increased CD69 expression on CD3+, CD4+, and CD8+ T cells. In contrast, complete inhibition of 3-MST, achieved by high concentrations of the inhibitor, modestly reduced CD8+ T cell proliferation. Functionally, 3-MST inhibition potentiated antigen-specific CD8+ T cell-mediated killing of tumor cells, an effect further amplified by PD-L1 blockade. These results establish 3-MST as a redox-sensitive metabolic driver of tumor growth and immune evasion in RCC and demonstrate that its inhibition can boost antitumor immune responses, offering a potential avenue for combination immunotherapy.
    Keywords:  3-mercaptopyruvate sulfurtransferase (3-MST); Hydrogen sulfide (H(2)S); Immune checkpoint inhibition; Renal cell cancer; Tumor immunotherapy
    DOI:  https://doi.org/10.1016/j.redox.2026.104373
  15. J Allergy Clin Immunol. 2026 Sep 03. pii: S0091-6749(26)00625-1. [Epub ahead of print]
    The IL-9R/Arg1 pathway promotes polyamine metabolism in human airway macrophages.
    Wenwu Zhang, In Su Cheon, Abigail Pajulas, Anthony L Sinn, Maya Shraddha Krishnan, Jilu Zhang, Ahmed M Abdelaal, Xin Liu, Kaitlyn G Jackson, Jayden Zhang, Karen E Pollok, Kirsten M Kloepfer, Homer L Twigg, Benjamin Gaston, W Gerald Teague, Jie Sun, Mark H Kaplan.
       BACKGROUND: Lung macrophages are central regulators of inflammatory responses in the airways and lung parenchyma. Macrophages function as conduits for cytokine function in the inflammatory milieu. We previously demonstrated that IL-9-responsive macrophages are essential for allergic lung inflammation in an arginase 1 (Arg1) pathway.
    OBJECTIVE: Define the IL-9/Arg1/polyamine pathway in human macrophages from model systems and asthmatic patient samples.
    METHODS: Using humanized NSG-Quad mice treated with intranasal IL-9 and patient bronchoalveolar lavage (BAL) samples, we evaluated macrophage phenotypes via flow cytometry, bulk RNA sequencing, and metabolic assays.
    RESULTS: Two distinct human lung macrophage populations were defined by the expression of CD43. IL-9 promoted the expansion of IL-9R+/Arg1+ CD43- macrophages in humanized mice. In parallel, greater proportions of IL-9R+/Arg1+ CD43- macrophages were observed in asthmatic patient BAL samples compared with healthy control patients. Higher concentrations of polyamines, downstream metabolites of Arg1 function, were detected in BAL of IL-9-treated humanized mice. There were increased concentrations of polyamines in asthmatic patient BAL, compared to control samples, and concentrations were positively correlated to BAL IL-9 concentration and increases of IL-9R+ and Arg1+ CD43- macrophages.
    CONCLUSIONS: IL-9-responsive CD206+ CD43- macrophages alter the metabolites present in the lung milieu. These data provide evidence for an IL-9R/Arg1/polyamine lung macrophage axis that is active in asthma patients.
    Keywords:  Allergic lung inflammation; Arginase; Asthma; CD43; Cytokine signaling; IL-9; Macrophage; Polyamine
    DOI:  https://doi.org/10.1016/j.jaci.2026.08.016
  16. Cell Rep. 2026 Sep 03. pii: S2211-1247(26)01000-4. [Epub ahead of print]45(9): 117922
    ACLY palmitoylation reprograms macrophages histone acetylation rewiring to repress hepatocellular carcinoma.
    Junlong Zhao, Dongkun Xie, Jingwen Si, Fan Fan, Chunchen Gao, Zhiwei Yang, Hengchao Yu, Huan Zhang, Yiyang Hu, Liang Wang, Xiuli Cao, Shiqian Liang, Shilin Cheng, Lan Feng, Feng Guan, Xiaodi Zhao, Lei Shang, Yongzhan Nie, Lei Liu, Hongyan Qin.
      The tumor microenvironment (TME) domesticates macrophage function by decreasing chromatin accessibility. The activation and nuclear translocation of ATP-citrate lyase (ACLY) convert citrate to acetyl-CoA, providing a substrate necessary for histone acetylation. However, the underlying mechanisms in macrophage remodeling are poorly understood. Here, we found that saturated fatty acids (sFA), especially palmitic acid (PA), were lower in TAMs of patients with hepatocellular carcinoma (HCC). Scd1 knockout promoted PA accumulation, resulting in both primary and metastatic liver cancer retardation and overall survival improvement. Mechanisms indicated that ACLY-C893 palmitoylation via PA maintained tetramer stability against CUL3-mediated degradation, facilitating histone acetylation of M1-related genes. Notably, both dietary PA with Scd1KO macrophage infusion and TAM-targeted in vivo PA/shSCD1 reprogramming improved the TME to repress HCC progression. Collectively, our research highlights the crucial role of ACLY palmitoylation in the connection between macrophage FA metabolism and histone acetylation reprogramming, which sheds light on the strategy of macrophage-based HCC immunotherapy.
    Keywords:  ACLY; CP: cancer; CP: metabolism; SCD1; hepatocellular carcinoma; histone acylation; macrophage; palmitoylation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117922
  17. Int J Biol Sci. 2026 ;22(13): 7471-7486
    Cross-tissue single-cell atlas reveals Id2 promotes sepsis-induced tissue damage by mediating macrophage metabolic reprogramming via Pkm2.
    Xiaodan Wang, Yiyan Liu, Yuanqun Zhou, Liyong Zou, Xiaowei Zhou, Zhongyuan Du, Daiqin Bao, Yibo Zhao, Yu Zhu, Yue Wu, Xingnan Ouyang, Li Wang, Liangming Liu, Tao Li.
      As important immune cells, macrophage polarization is directly related to tissue damage in sepsis, and the polarization of macrophages is associated with their metabolic patterns. Previous studies exploring macrophage function in sepsis mainly focused on specific tissues, lacking comprehensive comparisons between tissues. Herein, we performed single-cell RNA sequencing (scRNA-seq) to systematically profile macrophages derived from the brain, heart, intestine, lung, spleen, and peripheral blood mononuclear cells (PBMCs) under homeostatic and septic conditions. Under steady-state, we detected the markers of macrophages in different tissues, classified the macrophages into 10 functional subtypes and compared the differences in their distribution among tissues. In sepsis, we found that Pkm2 and Id2 played important roles in macrophage glycolysis. Mechanistically, Id2 mediated the metabolic reprogramming of macrophages by regulating the chromatin accessibility of Pkm2. Helichrysetin, an inhibitor of Id2, could significantly alleviate tissue damage and increase the survival of septic mice. In summary, our research depicted a cross-tissue macrophage landscape at the single-cell level that encompasses both homeostasis and sepsis. We also provided a new target and a potential drug for the treatment of sepsis by inhibiting macrophage metabolic reprogramming.
    Keywords:  Id2; Pkm2; macrophages; metabolic reprogramming; sepsis
    DOI:  https://doi.org/10.7150/ijbs.136855
  18. Vaccine. 2026 Sep 04. pii: S0264-410X(26)00924-2. [Epub ahead of print]92 129115
    Acute immunometabolic reprogramming following clade C HIV immunization in rhesus macaques.
    Laura Arroyo, Reben Raeman, Smita S Iyer.
      Immunometabolism shapes vaccine immunogenicity, yet how HIV vaccine platforms affect metabolic programs and whether those programs predict immunogenicity remain poorly understood. We applied untargeted serum metabolomics to nine rhesus macaques receiving an HIV-1 DNA-prime/protein-boost regimen, sampling at weeks 0, 1, 2, and 8 after first protein boost. Vaccination induced acute and sustained metabolic changes. Lipid metabolism showed the broadest perturbation: free fatty acids were transiently depleted during the effector phase, while acylcholines, lysophospholipids, and endocannabinoid-like ethanolamides remained elevated through week 8. Glutamate, γ-glutamyl amino acids, and glycylvaline were elevated through week 8, with continued nitrogen recycling, glutathione turnover, and proteolytic activity. High antibody responders showed greater mitochondrial fatty acid oxidation and lower bile acid levels at baseline, and greater membrane lipid remodeling at the effector phase. These data define metabolic signatures of HIV vaccination and identify serum correlates of immunogenicity for prospective validation.
    Keywords:  Antibody; HIV; Metabolomics; Tfh cells
    DOI:  https://doi.org/10.1016/j.vaccine.2026.129115
  19. Front Immunol. 2026 ;17 1883095
    SIRT1 deacetylates GAPDH to drive microglial glycolysis and neuroinflammation.
    Chou-Yi Hsu, Ibrokhim Sapaev, Ozodbek Nematov, Rustam Turakulov, Sarmad S Abdullah, Zeina T Khaleel, Enas R Alwaily, Majid S Jabir.
       Introduction: Microglial activation drives neuroinflammation through a metabolic switch from oxidative phosphorylation to aerobic glycolysis; however, the molecular mechanisms governing this transition remain poorly defined. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), sirtuin 1 (SIRT1), lipopolysaccharide (LPS), and interferon-gamma (IFN-γ) are central to this study; GAPDH plays plays a key regulatory role in this switch, and its activity is modulated by reversible acetylation at lysine 254 (K254). It remains unclear whether sirtuin deacetylases regulate this modification in microglia.
    Methods: Here, we demonstrate that SIRT1 physically associates with GAPDH in murine microglia and deacetylates K254 under basal conditions. Inflammatory activation using LPS/IFN-γ reduced SIRT1 protein levels and deacetylase activity by approximately 50%, leading to a 2.5-fold increase in K254 acetylation. Pharmacological activation of SIRT1 (SRT1720) reversed this modification and enhanced glycolytic output, mimicking the effects of the deacetylation-mimetic K254R mutant. To isolate the causal role of K254, we replaced endogenous GAPDH with K254R or acetylation-mimetic (K254Q) mutant proteins.
    Results: K254R microglia exhibited approximately 35% higher GAPDH enzymatic activity, 40% greater glycolytic flux, and 1.6- to 2.2-fold higher secretion of TNF-α, IL-1β, IL-6, and IL-12p70 than K254Q cells. Glycolytic inhibition with 2-deoxyglucose reduced most of the excess cytokines, confirming enhanced flux as the causal factor in K254-driven inflammatory amplification.
    Discussion: Thus, SIRT1-GAPDH signaling represents a post-translational axis linking sirtuin activity directly to glycolytic enzyme function, distinct from SIRT1's traditional transcriptional roles and serving as a viable molecular checkpoint in microglial immunometabolism.
    Keywords:  Sirtuin 1; glyceraldehyde-3-phosphate dehydrogenase; glycolysis; lysine acetylation; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1883095
  20. iScience. 2026 Sep 18. 29(9): 117230
    Uridine and pyruvate supplementation is associated with Th1 polarization during mitotoxic antibiotic therapy.
    Stefania De Santis, Monica Rutigliano, Federica Simone, Letizia Larocca, Maria Laura Matrella, Martina Milella, Antonio Vavallo, Pasquale Ditonno, Nicola Marrano, Anna Mestice, Stefano Battaglia, Michele Battaglia, Antonio Moschetta, Peter Seibel, Elena Piccinin, Gaetano Villani.
      Antibiotics with off-target mitochondrial toxicity can impair host immunity, yet their impact on human adaptive immunity in vivo remains unclear. Because T cell activation and differentiation depend on mitochondrial metabolism, antibiotic-induced mitochondrial stress may alter T helper cell function. We investigated whether uridine and pyruvate (UP) supplementation modulates immune responses in patients receiving mitotoxic antibiotics. In a pilot observational study, 67 patients undergoing prophylactic antibiotic therapy received either antibiotics alone or antibiotics plus daily UP supplementation. Antibiotic exposure increased circulating growth differentiation factor-15 (GDF15), indicating mitochondrial stress, and altered T cell response. UP supplementation was associated with immune features consistent with preserved inflammatory competence, including a trend toward Th1 polarization. These findings suggest that mitotoxic antibiotics can influence human T cell programs and support the hypothesis that UP supplementation may preserve pro-inflammatory T cell responses during antibiotic therapy, representing a potential metabolic strategy to mitigate antibiotic-induced immunotoxicity.
    Keywords:  GDF15; OXPHOS; T cells; antibiotics; immunometabolism; mitochondria; pyruvate; uridine
    DOI:  https://doi.org/10.1016/j.isci.2026.117230
  21. Front Pharmacol. 2026 ;17 1890878
    Recent understanding of immunometabolic remodeling in pulmonary macrophages: homeostasis, chronic respiratory diseases, and therapeutic targeting.
    Zhenli Yuan, Ahmad Alhaskawi, Yejiang Tang, Bing Ruan.
      Pulmonary macrophages are essential regulators of immune surveillance, tissue homeostasis, and inflammatory responses within the respiratory microenvironment. Emerging evidence indicates that chronic environmental stress and persistent injury induce profound immunometabolic remodeling in these cells, thereby contributing to the development and progression of chronic lung diseases. Under physiological conditions, pulmonary macrophages maintain metabolic homeostasis primarily through oxidative phosphorylation and fatty acid oxidation. However, pathological conditions drive metabolic reprogramming characterized by altered glycolysis, mitochondrial dysfunction, oxidative stress, lipid dysregulation, and disturbed iron homeostasis, leading to persistent inflammation, impaired tissue repair, and progressive remodeling. Recent studies have further highlighted the critical interplay between metabolic pathways, redox signaling, and immune regulation in shaping macrophage phenotypes and functions. Importantly, therapeutic strategies targeting macrophage metabolism and redox balance, together with advances in macrophage-directed drug delivery systems, have emerged as promising approaches for modulating pulmonary inflammation and tissue injury. This review summarizes recent understanding of immunometabolic remodeling in pulmonary macrophages under homeostatic and pathological conditions and discusses emerging therapeutic perspectives targeting macrophage metabolism in chronic respiratory diseases.
    Keywords:  chronic respiratory diseases; immunometabolism; metabolic reprogramming; oxidative stress; pulmonary macrophages
    DOI:  https://doi.org/10.3389/fphar.2026.1890878
  22. Front Cell Dev Biol. 2026 ;14 1938931
    Measles virus reprograms CD4+ T-cell sphingolipid and fatty acid metabolism to facilitate infection.
    Maria Fernanda Grijalva Yépez, Yann Loïc Cordes, Agnes Fekete, Fabian Schumacher, Burkhard Kleuser, Elita Avota.
       Introduction: CD150-positive (CD150+) lymphocytes are the primary targets of measles virus (MV) infection during the acute phase. The depletion of infected CD150+ memory cells leads to a profound suppression of immune memory, resulting in increased susceptibility to secondary infections and severe complications in infected individuals. While lipids are known to be critical for viral life cycles, the specific lipid metabolic conditions facilitating MV replication in immune cells remain poorly understood.
    Methods and Results: In this study, a comprehensive lipidomic analysis of MV-infected primary CD4+ T cells revealed significant alterations in three major lipid classes: sphingolipids, triacylglycerols, and glycerophospholipids. Specifically, MV infection increased the abundance of ceramides, dihydroceramides and triacylglycerols, while significantly reducing the levels of glucosylceramides and glycerophospholipids. Pharmacological intervention in the pathways of de novo sphingolipid synthesis, triacylglycerol synthesis and lipolysis significantly impaired measles virus replication in activated CD4+ CD150+ T cells.
    Discussion: Mechanistically, we demonstrate that MV glycoprotein-mediated membrane fusion, essential for viral entry and cell-to-cell spread, requires glucosylceramide synthase (GCS) activity and is further promoted by plasma membrane triacylglycerol content. Collectively, these findings highlight the essential role of MV-modulated triacylglycerol and sphingolipid metabolism in viral entry, dissemination, and intracellular replication within CD4+ T cells.
    Keywords:  CD4+CD150+ T cell; ceramide (CER); dihydroceramide (dhCer); hexosylceramide (HexCer); measles virus (MV); signaling lymphocytic activation molecule family member 1 (SLAMF1/CD150); sphingolipids; triacylglycerol (TG)
    DOI:  https://doi.org/10.3389/fcell.2026.1938931
  23. Virulence. 2026 Dec;17(1): 2728465
    Candida albicans reprograms Staphylococcus aureus glycolytic metabolism to drive enhanced virulence.
    Xueting Wan, Yuan Wu, Qi Yang, Ruolan Wu, Ti Chen, Zhen Luo.
      The synergistic interaction between Staphylococcus aureus and Candida albicans exacerbates polymicrobial infection severity and mortality compared to monomicrobial infections. C. albicans metabolism is known to enhance S. aureus virulence, whereas the role of S. aureus metabolic reprogramming in this cross-species synergy remains poorly defined. In this study, we demonstrate that C. albicans remodels S. aureus glycolytic pathways, thereby increasing its virulence in glucose-rich environments. C. albicans triggers metabolic reprogramming in S. aureus, characterized by a reduction of lactate and accumulation of upstream glycolytic intermediates, including 3-phosphoglycerate, 2-phospho-D-glycerate, and phosphoenolpyruvate. The metabolic reprogramming phenotype is glycolysis-dependent, which is evidenced by 2-deoxy-D-glucose-mediated inhibition of virulence enhancement. Addition of exogenous lactate lowers extracellular pH and reduces the hemolytic activity of S. aureus-C. albicans co-cultures. Inhibition of lactate dehydrogenase by oxamate or extracellular alkalinization with sodium hydroxide significantly increases hemolysis in S. aureus mono-cultures. S. aureus-C. albicans co-infections promote inflammatory cell infiltration but do not affect the quantity of S. aureus, indicating that increased toxin levels, rather than bacterial quantity, drive the enhanced virulence. Collectively, these findings indicate that C. albicans enhances S. aureus virulence through metabolic reprogramming. Targeting lactate metabolism or glycolytic intermediates may disrupt this cooperative interaction, offering a novel therapeutic strategy against these polymicrobial infections.
    Keywords:  Candida albicans; Staphylococcus aureus; glycolysis; hemolysis; lactate; virulence
    DOI:  https://doi.org/10.1080/21505594.2026.2728465
  24. Cancer Discov. 2026 Sep 01. 16(9): 1727-1729
    Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
    Silvia Tiberti, Katayoun Rezvani, May Daher.
      Zhou and colleagues identify mitochondrial complex I activity, mediated through NDUFA9, as a critical determinant of natural killer (NK) cell metabolic fitness and antitumor function in glioblastoma. Their study links impaired oxidative phosphorylation to glutamine dependence, epigenetic repression of effector programs, and loss of NK cell activity, highlighting mitochondrial fitness as an actionable axis for improving cellular immunotherapy in solid tumors. See related article by Zhou et al., p. 1924.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1267
  25. Front Immunol. 2026 ;17 1894113
    Human CD4+ iNKT cells have highly oxidative metabolism and use glycogen reserves to sustain IFN-γ production in nutrient-limited environments.
    Niharika M Patankar, Kelsey A Smith, Nidus Jacobsen, Nikhila S Bharadwaj, Jenny E Gumperz.
      Invariant natural killer T (iNKT) cells are promising candidates for allogeneic cellular immunotherapy, but the metabolic pathways that support their effector function in nutrient-limited tumor microenvironments remain poorly defined. Human iNKT cells segregate into CD4+ and CD4⁻CD8⁻ double-negative (DN) subsets with distinct functional profiles, yet whether they use divergent metabolic strategies to sustain IFN-γ production is unknown. Here we show that in vitro-expanded human CD4+ and DN iNKT cells employ distinct metabolic programs that differentially support IFN-γ secretion under nutrient stress. DN iNKT cells exhibit higher Glut1 expression and a more glycolytic phenotype, with IFN-γ production that is sensitive to extracellular glucose withdrawal and glycolytic inhibition. In contrast, CD4+ iNKT cells display high spare respiratory capacity, preferentially engage glutamine-supported mitochondrial respiration, and maintain IFN-γ production despite glucose deprivation or 2-DG inhibitor treatment. CD4+ iNKT cells generated excess ATP through oxidative metabolism, accumulated intracellular glycogen stores during expansion in vitro, and subsequently mobilized this glycogen to support IFN-γ production in tumor-exhausted media. Using a xenograft model of EBV-driven B cell lymphoma, we show that adoptively transferred human CD4+ iNKT cells infiltrate tumors in vivo and are associated with elevated intratumoral IFN-γ. These findings identify a distinctive combination of high mitochondrial oxidative capacity, glutamine utilization, and glycogen storage that endows human CD4+ iNKT cells with exceptional metabolic resilience, suggesting that CD4+ iNKT-based products may provide a particularly valuable platform for adoptive cellular immunotherapy.
    Keywords:  glucose independence; glycogen stores; interferon-gamma (IFN-g); invariant natural killer T (iNKT) cell; metabolic resilience; oxidative phosphorylation (OXPHOS); spare respiratory capacity (SRC)
    DOI:  https://doi.org/10.3389/fimmu.2026.1894113
  26. Protein Cell. 2026 Sep 03. pii: pwag065. [Epub ahead of print]
    Guanine promotes acute lung injury by repressing H3K27me3 in sepsis.
    Chao-Qun Wang, Hui-Juan Wang, Yue-Yu Kong, Xiayila Abulaiti, Xiao-Hui Zhang, Liu Liu, Rui-Feng Shi, Sheng Hu, Xu Li, Mei-Xin Li, Lu Wang, Jia-Xi Lei, Jing Zhang, Li-Min Xiang, Long-Fei Wang, Tao Long, Hai-Ning Du, Li-Ying Zhan, Wei Yan.
      Sepsis is systemic inflammation with high mortality, accompanied by multi-organ failure including acute respiratory distress syndrome. Extracellular vesicles (EVs) encapsulating bioactive cargoes, mediate cell-cell communication to exert systemic regulation. However, whether and how host lung tissue responds quickly to plasma bacterial infection through EVs in sepsis is poorly understood. Here, we identify that peripheral blood macrophages secrete more exosomal G6PD protein to induce lung injury by rewiring purine metabolism during sepsis. Guanine accumulation reduces H3K27 trimethylation and subsequently induces Nos2, Ccl6 and Il6 expression by suppressing de novo EZH2 synthesis. Macrophage-specific Rab27a or G6pd knockout mice had low exosomal G6PD protein in serum, and failed to exert lung injury upon bacterial infection. Beyond, targeting macrophage-derived G6PD by G6PD inhibitors or engineered EVs delivering si-G6pd relieves lung injury in septic mice. In summary, our findings reveal that circulating G6PD promotes lung injury by rewiring purine metabolism and remodeling the epigenetic profile in sepsis, shedding light on the critical role of EVs as a pro-inflammatory signal and targeting G6PD for future sepsis diagnosis and treatment.
    Keywords:  epigenetic remodeling; extracellular vesicles; lung injury; purine metabolism; sepsis
    DOI:  https://doi.org/10.1093/procel/pwag065
  27. Cell Biol Int. 2026 Sep;50(9): e70205
    Immunometabolic Control of Neutrophil Plasticity in Tuberculosis.
    Khaldoun Hamdan, Jasur Rizaev, Dhara N Patel, Swayamsidha Mangaraj, Ahmed Faisal Mutee, Urazbaeva Yulduz, Erdonov Bekmurod, Shefali.
      The development of tuberculosis (TB) is dictated by a complicated interplay between antimicrobial defense and host-mediated immunopathology. Neutrophils are known to exhibit striking functional plasticity with phenotypes associated with both bacterial containment and tissue damage. However, the mechanisms that connect the granuloma microenvironment to neutrophil fate remain poorly understood. This review aims to fill this gap by integrating emerging evidence that defines immunometabolic adaptation as a key determinant of neutrophil plasticity in TB. The core of this analysis delineates how the spatially organized granuloma characterized by hypoxia, nutrient limitation, iron dysregulation, and extracellular acidosis imposes metabolic pressures that remodel neutrophil function. Environmental signals converge on regulatory networks, including HIF-1α, mTOR/AMPK signaling, glycolytic pathways, the pentose phosphate pathway, and redox control systems, thereby affecting the switch between antimicrobial activity and pathological inflammation. This paradigm presents metabolic rewiring as a potentially important determinant of neutrophil fate in TB and offers a mechanistic view of how protective antimicrobial programs could evolve into dysfunctional states characterized by excessive NETosis, matrix destruction, ferroptotic stress, and tissue injury. Ultimately, a better understanding of these metabolic checkpoints may provide opportunities for the development of host-directed therapeutic approaches to enhance protective neutrophil functions while limiting immunopathology.
    Keywords:  granuloma microenvironment; host‐directed therapy; immunometabolism; metabolic reprogramming; neutrophil plasticity; tuberculosis
    DOI:  https://doi.org/10.1002/cbin.70205
  28. Front Mol Neurosci. 2026 ;19 1921079
    From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.
    Qiaoqiao Cui, Ke Zheng, Qiyun Liu, Lizhen Wang, Yixin Liu, Ruifang Bai, Wei Zhang, Junhong Guo, Xueli Chang, Juan Wang.
      Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.
    Keywords:  amino acid metabolism; disease-associated microglia; glucose metabolism; immunometabolism; lipid metabolism; microglia; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnmol.2026.1921079
  29. Science. 2026 Sep 03. 393(6815): 978-979
    Tumors steal a signal from T cells.
    Navdeep S Chandel.
      An antioxidant released by tumors dampens T cell immunity.
    DOI:  https://doi.org/10.1126/science.aek5854
  30. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2618255123
    Salmonella lipopolysaccharide stimulates uptake of long-chain fatty acids in the small intestine.
    Eugene Koo, Gabriella Quinn, Cassie L Behrendt, Brian Hassell, Katie N Kang, Kelly A Ruhn, Gonçalo Vale, Jeffrey G McDonald, Wenhan Zhu, Sebastian E Winter, Lora V Hooper.
      Enteric bacterial pathogens profoundly alter intestinal physiology during infection, yet their effects on host lipid metabolism remain poorly understood. Using mass spectrometry lipidomics, we found that infection of the mouse intestine with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) stimulates uptake of long-chain fatty acids by small intestinal epithelial cells. This response coincided with increased expression of epithelial genes involved in lipid uptake and transport and required the long-chain fatty acid transporter CD36. Fatty acid uptake was triggered by S. Typhimurium lipopolysaccharide (LPS) and was impaired by bacterial mutations that alter LPS acyl chains. Mechanistically, S. Typhimurium induced lipid absorption through myeloid cell Toll-like receptor 4, a receptor for LPS. Escherichia coli, a related commensal bacterium, also induced intestinal lipid absorption through LPS, although to a lesser extent than S. Typhimurium. Finally, disruption of long-chain fatty acid absorption impaired host defense during bacterial stimulation, suggesting that bacteria-induced lipid uptake contributes to protection against enteric infection. Together, these findings identify LPS from Gram-negative intestinal bacteria as a key regulator of dietary lipid uptake by the intestinal epithelium.
    Keywords:  Salmonella Typhimurium; fatty acids; intestinal epithelial cells; lipid metabolism; lipopolysaccharide
    DOI:  https://doi.org/10.1073/pnas.2618255123
  31. Microbiol Spectr. 2026 Sep 03. e0078826
    Metabolite and lipid profiling of human vitreous reveals purine metabolic dysregulation and inflammatory lipid remodeling as the drivers of bacterial endophthalmitis.
    Dhanwini Rudraprasad, Agimanailiu Khapuinamai, Sreyasi Maiti, Satyashree Gagan, Joveeta Joseph.
      Bacterial endophthalmitis, an intraocular infection and inflammation, often progresses rapidly and leads to irreversible vision loss, especially in culture-negative cases where the diagnosis is delayed. We profiled infection-associated metabolomic and lipidomic alterations in the vitreous of patients with microbiological and clinically confirmed bacterial endophthalmitis to understand pathogenesis and identify distinct markers that drive infection and retinal injury. Untargeted metabolomic and lipidomic profiling of vitreous samples from affected patients and non-infectious retinal controls was performed using liquid chromatography coupled to tandem mass spectrometry. Metabolites and lipids with P-value < 0.05 were considered for further pathway-specific analysis. Metabolomic profiling distinctly segregated infected from control samples, revealing dysregulation in purine metabolism, amino acid turnover, polyamine synthesis, redox regulation, and vitamin pathways. Key metabolites, xanthine, hypoxanthine, spermine, seryl-valine, seryl-isoleucine, thymine, O-methyltyramine, and phenyltrimethylammonium, were significantly elevated. These elevations were accompanied by enhanced nucleotide degradation and increased proteolytic activity. Markers of immune activation and oxidative stress were concurrently upregulated, reflecting the broader biochemical disruption characteristic of bacterial endophthalmitis. Antioxidant seleno-L-methionine was downregulated, indicating redox imbalance. Purine, glutathione, vitamin B6, beta-alanine, and arginine-proline metabolism were broadly disrupted. Complementary lipidomics showed extensive vitreous remodeling. Alongside, fatty acids, bile acid derivatives, and membrane lipids were also dysregulated. Bacterial endophthalmitis triggers strong and consistent changes in metabolite and lipid profiles within vitreous, which reflect alterations in immune activation, oxidative stress, tissue breakdown, and metabolic reprogramming. The persistence of these biomolecular signatures in the vitreous highlights host response to infection and subsequent mechanistic elucidation of the specific drivers of retinal inflammation and progressive tissue damage.IMPORTANCEThe study highlights that bacterial endophthalmitis is not only driven by microbial burden but also by host metabolic and lipidomic reprogramming, transforming the understanding of disease pathogenesis. This study reveals metabolite-lipid networks in ocular infections, laying a critical foundation for precision medicine strategies in endophthalmitis management. Specifically, we found significant increases in key metabolites including xanthine, hypoxanthine, spermine, seryl-valine, seryl-isoleucine, thymine, O-methyltyramine, and phenyltrimethylammonium, together reflecting increased nucleotide degradation, proteolytic activity, and immune metabolic reprogramming. These molecular signatures not only provide deeper mechanistic insights into ocular infection but also provide potential biomarkers that could aid in diagnosis and monitoring of infection when conventional microbiological methods are inconclusive. The results highlight the clinical importance of metabolic profiling as a powerful tool to optimize visual outcomes, guide adjunctive therapeutic decisions, and enhance prognostic evaluation in patients affected by the condition.
    Keywords:  bacterial endophthalmitis; infection; lipidomics; metabolomics; vitreous
    DOI:  https://doi.org/10.1128/spectrum.00788-26
  32. Liver Int. 2026 Oct;46(10): e70864
    Glycolysis Drives TLR Ligand-Induced Maturation and Immune Activation of Liver Sinusoidal Endothelial Cells.
    Yiwen Shu, Hu Yan, Hang Sun, Xin Gu, Elisabeth Littwitz-Salomon, Jia Liu, Jun Wu, Dongliang Yang, Xin Zheng, Mengji Lu, Yanqin Du.
       BACKGROUND AND AIMS: Liver sinusoidal endothelial cells (LSECs) are liver-resident antigen-presenting cells that induce immune tolerance, a feature exploited by persistent viruses. Toll-like receptor (TLR) ligands can override this tolerance, but whether metabolic reprogramming underlies LSEC activation remains unknown. We investigated whether TLR ligand-induced functional changes in LSECs require glycolysis and explored the underlying mechanisms.
    METHODS: LSECs from wild-type and chronic hepatitis B virus (HBV) replication mice were stimulated with TLR2 ligand P3C or TLR9 ligand ODN1826. LSEC maturation, cytokine production and T cell-priming capacity were assessed. Glycolytic flux was measured by metabolomics and Seahorse analysis. The glycolysis inhibitor 2-deoxy-D-glucose (2-DG) was used, and mTORC1 pathway involvement was examined.
    RESULTS: The TLR2 ligand P3C promoted LSEC maturation, while the TLR9 ligand ODN1826 enhanced IL-12 production. Both ligands potentiated LSEC-induced T cell responses. In LSECs isolated from a mouse model of chronic HBV replication, P3C and ODN1826 also induced maturation and enhanced T cell-activating capacity, albeit to a weaker extent. Metabolomics and Seahorse analyses revealed that TLR2/9 ligands enhanced glycolysis and oxidative phosphorylation in LSECs, accompanied by activation of the mTORC1/HIF-1α/c-Myc axis. Blocking glycolysis with 2-DG significantly reduced co-stimulatory molecule expression on P3C-stimulated LSECs and IL-12 production by ODN1826-stimulated LSECs in both wild-type and chronic HBV models. Mechanistically, 2-DG suppressed the mTORC1 pathway, thereby attenuating TLR ligand-induced responses.
    CONCLUSIONS: TLR ligand-induced activation and pro-inflammatory functions of LSECs critically depend on glycolysis via the mTORC1 signalling pathway. This reveals a key metabolic mechanism underlying LSEC immune regulation during innate stimulation.
    Keywords:  TLR ligands; glycolysis; liver sinusoidal endothelial cells
    DOI:  https://doi.org/10.1111/liv.70864
  33. Int Immunopharmacol. 2026 Aug 31. pii: S1567-5769(26)01193-8. [Epub ahead of print]188 117346
    C646-loaded mesenchymal stromal cell extracellular vesicles alleviate lactate-driven immunoparalysis in sepsis-associated ARDS through the p300-H3K18la-PSMD14 axis.
    Yuanyuan Zhang, Jiaxu Guo, Jiamin Zhang, Yiqun Zheng, Hao Wang, Shi Zhang.
      Sepsis-associated acute respiratory distress syndrome (S-ARDS) is often followed by immunoparalysis, leaving patients vulnerable to secondary infection and adverse outcomes. Lactate is widely used as a severity marker in sepsis, but its direct contribution to immune paralysis remains unclear. We examined lactate-driven immune dysfunction in mouse models, bone marrow-derived macrophages and human CD14+ monocyte-derived macrophages, and tested C646-loaded mesenchymal stromal cell-derived extracellular vesicles (EVs-C646) as an experimental intervention. Lactate elevation blunted cytokine responses after rechallenge, reduced macrophage phagocytosis, shifted macrophages toward an M2-like phenotype, expanded regulatory T cells and decreased interferon-γ (IFN-γ) responses in CD8+ T cells. Mechanistically, lactate activated a p300-histone H3 lysine 18 lactylation (H3K18la) program and upregulated proteasome 26S subunit, non-ATPase 14 (PSMD14). Integrated RNA sequencing, H3K18la chromatin immunoprecipitation sequencing, public sepsis transcriptomic analysis and perturbation experiments identified PSMD14 as a lactylation-linked effector that strengthened AKT/mTOR signalling and promoted macrophage dysfunction. EVs-C646 decreased H3K18la and PSMD14 expression, restored macrophage inflammatory responsiveness, improved bacterial clearance, reduced lung injury and increased survival in experimental S-ARDS-related immunoparalysis models. These findings define a lactate-p300-H3K18la-PSMD14-AKT/mTOR pathway in immunoparalysis and support further preclinical evaluation of lactylation-targeted extracellular vesicle therapy.
    Keywords:  Extracellular vesicles; Histone lactylation; Immunoparalysis; PSMD14; Sepsis-associated ARDS
    DOI:  https://doi.org/10.1016/j.intimp.2026.117346
  34. Cell Metab. 2026 Sep 03. pii: S1550-4131(26)00334-7. [Epub ahead of print]
    Aging microenvironment induces CD8+ T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis.
    Yifeng Xiao, Yanling Zhang, Zihao Zhao, Zijian Zhang, Xiaohui Zhang, Pengju Chen, Jin Gu, Haichuan Zhu, Peng Jiang, Jie Cheng.
      The metabolic mechanisms by which aging blunts CD8+ T cell antitumor and pathogen defense remain unknown. We demonstrate that the aged microenvironment induces CD8+ T cell exhaustion by reducing β-hydroxybutyrate (3HB) bioavailability. Aging represses hepatic BDH1-dependent 3HB synthesis, restricting SLC16A1-mediated 3HB uptake. Hepatic BDH1 ablation recapitulates age-associated CD8+ T cell dysfunction, compromising antiviral and antitumor immunity, whereas 3HB supplementation reverses these deficits via protein β-hydroxybutyrylation. Using a 3HB-derived chemical probe, 3Halk, together with functional screening, we identify PRKAR1B as a primary effector of 3HB signaling. PRKAR1B β-hydroxybutyrylation inhibits the transcription factor cyclic AMP (cAMP)-responsive element modulator (CREM), which activates T cell exhaustion-related gene expression. Age-associated 3HB depletion enhances CREM-dependent transcription, sustaining CD8+ T cell exhaustion. Consistently, the aged microenvironment compromises chimeric antigen receptor (CAR) T antitumor activity, which is substantially restored by 3HB treatment. Collectively, this study uncovers a hepatic metabolism-derived 3HB-CREM axis governing CD8+ T cell immunosenescence, highlighting 3HB as a viable immunorestorative strategy to improve immunotherapy outcomes in aged individuals.
    Keywords:  3HB; CD8(+) T cell exhaustion; aging; liver metabolism; β-hydroxybutyrylate
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.009
  35. FEBS J. 2026 Sep 01.
    Metabolic shifts driven by host-microbial interactions.
    Tripti Nair, Nicole L Stuhr, Brandy A Weathers, Sean P Curran.
      Host-microbe interactions within the gut have been extensively reviewed in the context of host immune response. Emerging evidence, however, highlights that these inflammatory and immune outcomes are often deeply intertwined with the microbiome-derived secondary metabolites. The gut microbiota functions in concert with the host by providing an extensive repertoire of metabolic enzymes that enhance digestion and capacity to assimilate a broad spectrum of ingested food sources. This symbiotic metabolism generates a diverse array of bioactive metabolites that shape local and systemic physiology, adaptive immune responses, and neuroimmune responses. Here, we focus on microbial metabolism as a central organizing principle of host-microbiota symbiosis. Microbiota-derived metabolites, including short-chain fatty acids, secondary bile acids, tryptophan-derived indoles, sphingolipids, and gaseous byproducts, signal through downstream molecular partners like nuclear receptors, transcriptional regulators, and redox-sensitive homeostatic pathways to regulate host energy homeostasis, but also alter immune functions like gut epithelial integrity, immune tolerance, and neuroimmune crosstalk. Finally, we discuss emerging therapeutic strategies that target microbial metabolic functions-including dietary interventions, engineered probiotics, postbiotics, and receptor-directed approaches-that position microbial metabolism as a tractable axis for modulating immunometabolism homeostasis and potentially mitigating metabolic and inflammatory diseases.
    Keywords:  host–microbe; immunometabolism; metabolic signaling; metabolism; microbiome
    DOI:  https://doi.org/10.1111/febs.70704
  36. Arterioscler Thromb Vasc Biol. 2026 Sep 03.
    MAP17 Orchestrates SGLT2-Dependent Glycolytic Reprogramming to Drive Trained Immunity and Accelerate Atherosclerosis.
    Jianjin Wu, Lei Wang, Fukang Zou, Fangbing Liu, Guanyu Fang, Kai Cheng, Haochen Gao, Kangkang Zhi, Lefeng Qu.
       BACKGROUND: Atherosclerosis is driven by metabolic-immune crosstalk, in which trained immunity sustains vascular inflammation. MAP17 (membrane-associated protein 17), a redox- and metabolism-regulating adaptor protein, functions as a potential upstream driver of SGLT2 (sodium-glucose cotransporter 2). We aimed to determine whether MAP17 links hyperglycemia to glycolytic activation, inflammatory polarization, and plaque progression in atherosclerosis.
    METHODS: MAP17 expression and its correlations with clinical risk factors were analyzed in serum from 30 patients with atherosclerosis. A trained immunity model was established in bone marrow-derived macrophages via sustained high glucose and IFN-γ (interferon-γ)/lipopolysaccharide stimulation. Functional assays were performed after MAP17 overexpression/knockdown, SGLT2 silencing, or glycolysis inhibition.
    RESULTS: MAP17 was significantly coupregulated in patients with atherosclerosis, with the highest levels observed in those with concomitant diabetes or metabolic syndrome, and closely associated with elevated proinflammatory M1-like cytokines. Immunohistochemistry of carotid plaques confirmed its colocalization with SGLT2 within CD68+ macrophage-rich, lipid-laden, and inflamed regions. In bone marrow-derived macrophages, high glucose robustly induced MAP17 expression, which unidirectionally upregulated SGLT2, enhanced glycolytic flux, increased lactate production, and promoted M1-like polarization and foam cell formation. MAP17 knockdown markedly suppressed SGLT2 expression, glycolysis, and TNF-α (tumor necrosis factor-α)/IL (interleukin)-1β secretion, whereas MAP17 overexpression restored glycolytic activity, proinflammatory phenotype, and foam cell generation even in SGLT2-deficient cells. In diabetic chimeric Apoe-/- mice, MAP17 activation correlated with increased glycolytic marker expression, higher proinflammatory M1-like macrophage ratios, aggravated vascular inflammation, and greater plaque burden; these effects were mitigated by MAP17 or SGLT2 silencing, or by glycolysis inhibition.
    CONCLUSIONS: MAP17 is a key upstream controller of the SGLT2-glycolysis axis that promotes trained immunity and accelerates atherosclerosis. Targeting MAP17 may disrupt the metabolic-inflammatory feedback loop and represents a promising therapeutic strategy for diabetic atherosclerosis.
    Keywords:  atherosclerosis; glycolysis; oxidative stress; reactive oxygen species; trained immunity
    DOI:  https://doi.org/10.1161/ATVBAHA.126.324585
  37. Int Endod J. 2026 Sep 04.
    PLA2G7-Mediated Pro-Inflammatory Activation of Lipid-Associated Macrophages Drives Pulpitis.
    Xinyi Chen, Xiaoyuan Huang, Congxiao Lian, Yulian Zhang, Wenzhi Wu, Zhuo Chen.
       AIM: Pulpitis is a common and painful disease characterised by complex and dynamic immune responses and may lead to irreversible tissue damage or tooth loss. Macrophages act as key sentinels that exhibit differential metabolic reprogramming, tightly orchestrating the immune microenvironment. However, the specific metabolic mechanisms governing macrophage-driven inflammatory activation in pulpitis remain unclear. Here, we reveal a specific lipid metabolism-driven immune pathway within macrophages in pulpitis.
    METHODOLOGY: An integrative analysis of single-cell RNA sequencing (scRNA-seq), lipidomics and bulk RNA sequencing (RNA-seq) was employed to characterise macrophage subpopulations and metabolic alterations in pulpitis. Western blot and immunofluorescence staining were performed to validate the expression of phospholipase A2 group VII (PLA2G7) in human pulp tissues. In vitro, an inflammatory THP-1 macrophage model was established to investigate the effects of PLA2G7 inhibition and lysophosphatidylcholine (LPC) supplementation, and macrophage inflammatory activation was assessed by RT-qPCR, Western blot, ELISA and immunofluorescence staining. Bioinformatic analyses and fluorescence recovery after photobleaching (FRAP) experiments were conducted to identify the upstream transcriptional regulator of PLA2G7 and explore its regulatory mechanism. A murine pulpitis model treated with the PLA2G7 inhibitor darapladib was used to evaluate the anti-inflammatory effects by ELISA, immunohistochemical and immunofluorescence staining.
    RESULTS: ScRNA-seq, lipidomics and RNA-seq analyses identified a distinct lipid-associated macrophage subset with high PLA2G7 expression in pulpitis. The abundance of this subset increased with inflammatory severity. Immunofluorescence and Western blot validated increased PLA2G7 expression in lipid-associated macrophages in pulpitis tissues. In vitro, inhibition of PLA2G7 significantly suppressed inflammatory responses, whereas supplementation with LPC attenuated this anti-inflammatory effect. In vivo, darapladib-mediated inhibition of PLA2G7 significantly attenuated pulpitis progression and reduced macrophage activation in mice. Mechanistically, integrative bioinformatic analysis identified JunD proto-oncogene (JUND) as a transcriptional regulator of PLA2G7, potentially via liquid-liquid phase separation (LLPS)-mediated transcriptional condensates.
    CONCLUSIONS: These findings identify PLA2G7 as a potential biomarker for pulpitis and reveal a JUND-PLA2G7-LPC signalling axis linking lipid metabolism to macrophage-mediated inflammatory responses, providing a novel perspective for preserving dental pulp vitality.
    Keywords:  PLA2G7; lipid metabolism; macrophages; pulpitis
    DOI:  https://doi.org/10.1111/iej.70264
  38. Int J Biol Macromol. 2026 Sep 02. pii: S0141-8130(26)04260-1. [Epub ahead of print] 154314
    Methacrylated hyaluronic acid hydrogel enables CD44-mediated local berberine delivery to reprogram macrophage immunometabolism and promote alveolar bone repair in periodontitis.
    Xiaolei Lv, Yi Zhang, Xiaomeng Zhang, Junyu Shi, Xinxin Ding, Jianxu Wei, Xue Jiang, Yijie Yang, Xindi Wei, Lian Cen, Hongchang Lai, Shichong Qiao.
      Periodontitis is a chronic inflammatory disease characterized by persistent immune dysregulation and progressive alveolar bone loss. Here, reanalysis of single-cell transcriptomic data from human gingival tissues identified CD44+ macrophages as an expanded macrophage subset in periodontal lesions with proinflammatory and glycolytic features. To therapeutically modulate this population without relying on conventional antibiotics, we developed a local immunometabolic delivery platform (MHA-B@Lipo) by incorporating berberine-loaded liposomes into a methacrylated hyaluronic acid (MHA) hydrogel. Through localized hydrogel retention, inflammatory microenvironment-responsive network degradation, and HA-CD44-mediated cellular uptake, MHA-B@Lipo improved berberine delivery to CD44+ macrophages. Intracellularly, berberine reduced glycolytic activity and lactate accumulation, accompanied by suppression of the HIF-1α/GLUT1-related signaling and a metabolic shift toward mitochondrial oxidative phosphorylation. These changes promoted macrophage repolarization toward a reparative phenotype and established a pro-osteogenic microenvironment that supported the osteogenic responses of bone marrow stromal cells. In a rat ligature-induced periodontitis model, local administration of MHA-B@Lipo alleviated periodontal inflammation, preserved collagen tissue architecture, and promoted alveolar bone repair with efficacy comparable to minocycline. Together, these findings present a human tissue-informed, antibiotic-free strategy that couples localized biomaterial retention with immunometabolic rewiring for inflammatory bone repair.
    Keywords:  Hyaluronic acid; Immunometabolism; Macrophage reprogramming
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154314
  39. J Proteome Res. 2026 Sep 04. 25(9): 4380-4392
    Proteins as Regulators of Metabolic Changes in Sepsis: Alterations in Body Fluids, Immune Cells, and Organs through the Eyes of Proteomics.
    Giuseppe G F Leite, Felipe Dal-Pizzol, Tom van der Poll, Reinaldo Salomão.
      Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and profound metabolic alterations that contribute to immune dysfunction and organ failure. This Review synthesizes proteomic evidence on sepsis-associated alterations in proteins involved in metabolic pathways across circulating biofluids, immune cells, and organs. Across plasma and urine, proteomic studies identify disturbances in lipoprotein-associated pathways, redox homeostasis, mitochondrial function, and substrate metabolism, indicating that protein signatures of metabolic dysregulation are systemic and detectable across biofluids. In immune cells, monocytes and neutrophils, proteomic analyses reveal a shift toward glycolysis with concurrent impairment of mitochondrial pathways alongside phenotype-dependent differences in lipid and redox-related programs. Organ-level studies further show that metabolic responses are heterogeneous, with distinct trajectories in the kidney, heart, liver, lung, skeletal muscle, and brain. These observations support the concept that sepsis involves compartment-specific remodeling of metabolism-associated protein networks rather than a single convergent metabolic state. Proteomics also highlights potential translational opportunities by identifying metabolism-associated proteins linked to disease severity, clinical phenotypes, and biologically distinct patient subgroups, although the current evidence remains largely exploratory and context-dependent. Overall, proteomics provides a complementary framework for understanding the molecular regulation of sepsis-associated metabolic dysfunction and may refine biological stratification and therapeutic targeting, particularly when integrated with longitudinal sampling and multiomic data.
    Keywords:  immunometabolism; lipoproteins; mitochondria and biomarkers
    DOI:  https://doi.org/10.1021/acs.jproteome.6c00386
  40. Science. 2026 Sep 03. 393(6815): 1036-1044
    Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species.
    Alexander J Wesolowski, Ardon M Pillay, Panagiota Vardaka, Rabab Nasrallah, Randy Greaves, Housaiyin Li, Iliana Loffreda, Chelsea Jenkin, Andrew M James, Alica Nübling, Christopher J Ward, Teresa von Linde, Alberto G Conti, Sheue-Fen Tzeng, Layla Dahmani, Alexander C Evans, Sarah K Whiteside, Yumi Yamashita-Kanemaru, Charlotte J Imianowski, Jie Yang, Ignacio Moraga Gonzalez, Jack Chapman, Aws Al-Deka, Klaus Okkenhaug, Michael P Murphy, Bartlomiej Swiatczak, Geoffrey Guittard, Enrico Lugli, Lukas Flatz, Ping-Chih Ho, Robert L Eil, Rahul Roychoudhuri.
      Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes. Emerging data suggest that T cells depend on ROS for signal transduction. In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell-mediated antitumor immunity. The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor-driven kinase signaling and effector function. Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses. These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention.
    DOI:  https://doi.org/10.1126/science.adz8203
  41. Pharmacol Res. 2026 Sep 04. pii: S1043-6618(26)00348-8. [Epub ahead of print] 108433
    SIRT1/PGC-1α Axis and CPT1A-Mediated Metabolic Reprogramming Reshape Macrophage Polarization to Ameliorate Intervertebral Disc Degeneration.
    Shan-Xi Wang, Ren-Ji Wang, Kai-Yuan Lin, Ling-Jiang Li, Rong-Jin Luo, Jian-Bin Guan, Si-Bo Wang, Yuan-Ting Zhao, Liang Yan, Xiao-Jun Yu.
      Intervertebral disc degeneration (IDD) is a leading cause of chronic low back pain, and macrophages play a pivotal regulatory role through metabolic reprogramming that governs M1/M2 polarization. This study aimed to elucidate how the Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) axis and carnitine palmitoyltransferase 1A (CPT1A)-mediated metabolic reprogramming regulate macrophage polarization in IDD using single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (bulk RNA-seq), and isotope tracing. A puncture-induced IDD rat model was established. Exploratory scRNA-seq and bulk RNA-seq revealed an increased M1 macrophage trend and identified SIRT1, PGC-1α, and CPT1A as candidate regulators of glycolysis and fatty acid oxidation (FAO). Immunofluorescence, Western blot, and flow cytometry confirmed M1/M2 polarization changes. Lentiviral-mediated overexpression, PGC-1α/CPT1A knockdown rescue, and [¹³C]-glucose and [¹³C]-palmitate isotope tracing demonstrated that activation of the SIRT1/PGC-1α axis and CPT1A enhanced oxidative phosphorylation (OXPHOS) and FAO, reduced glycolytic activity, promoted M2 polarization, suppressed inflammatory cytokines, and mitigated extracellular matrix (ECM) degradation. In vivo administration of the SIRT1 agonist SRT1720 or CPT1A agonist C75 alleviated IDD progression. This study indicates that the SIRT1/PGC-1α/CPT1A axis regulates macrophage polarization through metabolic reprogramming and provides potential therapeutic targets for IDD.
    Keywords:  Carnitine Palmitoyltransferase 1A; Intervertebral Disc Degeneration; Macrophage Polarization; Metabolic Reprogramming; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha; Sirtuin 1
    DOI:  https://doi.org/10.1016/j.phrs.2026.108433
  42. Cancer Commun (Lond). 2026 ;46 0043
    Metabolic Reprogramming of NSUN2-Mediated m5C Modification Promotes the Progression of Hepatocellular Carcinoma by Restricting Natural Killer Cell-Mediated Cytotoxicity.
    Shengwei Mao, Yuan Fang, Jun Gao, Jiafeng Chen, Zhiqi Guan, Xuhui Zhao, Jinglei Wu, Xiaoling Wu, Guiqi Zhu, Xiangyu Zhang, Qianfu Zhao, Rui Yang, Yi Wang, Tianhao Chu, Yichao Bu, Jialu Fu, Hongxu Li, Zheng Tang, Yinghong Shi, Jian Zhou, Jia Fan, Jinling Jiang, Weiren Liu.
      Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with resistance to immunotherapy posing a major clinical challenge. Natural killer (NK) cells exhibit impaired infiltration and cytotoxicity in HCC; however, the mechanisms underlying NK cell-mediated immune evasion are still poorly understood. This study investigated how NOP2/Sun RNA methyltransferase 2 (NSUN2), a 5-methylcytosine (m5C) RNA methyltransferase, induces metabolic reprogramming and immunosuppression to drive HCC progression. Methods: We conducted a genome-wide CRISPR screen in HCC cells cocultured with NK cells. To delineate the downstream mechanisms, we integrated profiling of the m5C epitranscriptome, transcriptome, and chromatin landscape with metabolic characterization. The impact of NSUN2 on histone lactylation and programmed cell death 1 ligand 1 (PD-L1) transcription was further investigated. Functional assays in vitro and in vivo using syngeneic murine models and pharmacological inhibition validated these findings. Clinical relevance was assessed using patient tissues, The Cancer Genome Atlas dataset, and immunotherapy cohorts. Results: Genome-wide CRISPR screening in HCC cell-NK cell coculture models identified NSUN2 as a key suppressor of NK cell-mediated cytotoxicity. Mechanistically, NSUN2-mediated RNA m5C modification enhanced the messenger RNA stability and expression of glycolytic enzymes, including enolase 1 (ENO1), pyruvate kinase M1/2 (PKM), and lactate dehydrogenase A (LDHA), thereby increasing lactate production. Accumulated lactate promoted histone H3 lysine 18 lactylation (H3K18la), which enhanced chromatin accessibility at the CD274 (encoding PD-L1) promoter and recruited signal transducer and activator of transcription 3 (STAT3) to drive PD-L1 expression, ultimately inhibiting NK cell-mediated cytotoxicity. Clinically, high NSUN2 expression was associated with elevated PD-L1 levels, poor prognosis, and immunotherapy resistance in patients with HCC. In vivo, NSUN2 knockout increased NK cell infiltration and suppressed tumor growth, while the STAT3 inhibitor TTI-101 combined with anti-PD-L1 therapy enhanced NK cell cytotoxicity and inhibited HCC progression. Conclusions: Our data demonstrated that NSUN2 drove immune evasion in HCC by coupling m5C-dependent glycolytic reprogramming with H3K18la-mediated epigenetic activation of PD-L1. These findings suggest that NSUN2 could represent a critical nexus between m5C RNA methylation and immunosuppression, providing a therapeutic rationale for combination immunotherapy in HCC.
    DOI:  https://doi.org/10.34133/cancomm.0043
  43. Gut Microbes. 2026 Dec 31. 18(1): 2725371
    Nutritional regulation of gut-brain immune crosstalk across the lifespan.
    Yulin Zhou, Sebastian Del Toro, Melody Y Zeng.
      The gut-brain immune axis integrates microbial, immune, and neural signals to regulate neurodevelopment, homeostasis, and disease susceptibility. Early-life nutrition, particularly human milk oligosaccharides, shapes beneficial microbiota composition, enhances hippocampal plasticity, promotes anti-inflammatory microglia polarization, and fosters immune tolerance. Gut microbiota-derived metabolites, including short-chain fatty acids, tryptophan derivatives and secondary bile acids, regulate microglia maturation, astrocyte function, T cell differentiation, neurotransmitter production, and vagus nerve signaling. These processes influence synaptic pruning, neurogenesis, and neuroinflammation. Adaptive immune cells in the central nervous system, notably meningeal and infiltrating CD4 T cells, further connect peripheral immunity to neuronal responses through cytokines, such as IL-4, IFNγ, and IL-17A. Nutritional imbalances may exacerbate disease-associated microglia and pathogenic T cell activity in Multiple Sclerosis, Alzheimer's disease, and autism spectrum disorders. In aging, diet helps mitigate "inflammaging" by countering metabolic shifts in microglia and lymphocytes. This review examines how nutrition modulates bidirectional gut-brain immune crosstalk across the lifespan.
    Keywords:  Nutrition; aging; gut-brain axis; metabolites; microbiome; neuroimmunology
    DOI:  https://doi.org/10.1080/19490976.2026.2725371
  44. Front Mol Biosci. 2026 ;13 1899336
    Lactylation in sepsis-associated acute kidney injury: regulatory mechanisms and therapeutic prospects.
    Jiahui Zheng, Boyang Zheng, Qun Liang.
       Introduction: Sepsis-associated acute kidney injury (SA-AKI) is a prevalent, life-threatening sepsis complication with high mortality, prolonged organ support dependence, and scarce targeted therapies. Beyond being an anaerobic glycolysis byproduct, lactate serves as a critical circulating carbon source, mitochondrial fuel, redox regulator, signaling molecule, and lysine lactylation (Kla) substrate. Its multifaceted functions are vital to SA-AKI pathogenesis, which involves systemic lactate overload, impaired lactate clearance, renal metabolic reprogramming, and abnormal immune activation.
    Methods: This review synthesizes up-to-date evidence to systematically elucidate lactate and Kla mechanisms in SA-AKI. We hierarchically integrate findings from systemic sepsis metabolism and renal tubular lactate handling to cell-specific Kla modifications, aiming to clarify their distinct roles in SA-AKI progression.
    Results: Specific Kla sites (H3K18la, Fis1 K20la, LDHB K156la, Ezrin K263la, HMGB1 lactylation, ALDH2 K68la) mediate SA-AKI pathologies including mitochondrial dysfunction, tubular death, endothelial injury, and cGAS-STING/NLRP3-neutrophil extracellular trap activation. Lactate accumulation, acidosis, transport, oxidation, metabolic routing, and Kla are mechanistically distinct rather than uniformly harmful. Lactate/pyruvate metabolism exerts context-dependent injurious or adaptive effects across kidney disease models, modulated by cell type, injury phase, and metabolic reserve.
    Discussion: Lactate- and Kla-targeted strategies are promising for SA-AKI treatment yet require rigorous clinical validation. Blood lactate level and clearance are reliable clinical prognostic biomarkers, whereas Kla signatures remain investigational. Balanced understanding of lactate-Kla biology will refine precision diagnostic and therapeutic strategies for SA-AKI, advancing translational clinical application.
    Keywords:  AKI-to-CKD transition; immune regulation; lactate metabolism; lactylation; lysine lactylation; mitochondrial dysfunction; sepsis-associated acute kidney injury
    DOI:  https://doi.org/10.3389/fmolb.2026.1899336
  45. Front Immunol. 2026 ;17 1865051
    Oxidative stress-driven epigenetic reprogramming of immune cells in COPD: from epitranscriptomic and metabolic crosstalk to treatable traits.
    Chun Feng Pan, Qiong Wan, Feng-Xian Ni, Pan Xu, Dong-Hui Huang, Ze-Bo Jiang.
      Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by persistent oxidative stress and maladaptive immune responses, rather than a single disease entity. Oxidative stress not only damages lung tissue but also reprograms immune cells through both classical epigenetic mechanisms (DNA methylation, histone modifications) and epitranscriptomic regulation (m6A RNA methylation), shaping disease endotypes and treatment resistance. This review presents an integrated framework in which redox signals dynamically reshape the epigenetic and epitranscriptomic landscape, thereby locking immune cells into pathogenic states. Metabolic intermediates (S-adenosylmethionine, α-ketoglutarate, succinate, NAD+) serve as critical nodes that connect immunometabolism to both classical epigenetic enzymes and the m6A machinery, thereby linking redox status to RNA fate. Using NETosis as a paradigm, we illustrate how oxidative-epigenetic-metabolic loops sustain neutrophilic inflammation and resolution failure. Finally, we outline a treatable traits framework that integrates these mechanistic insights into precision combination therapies. This conceptual roadmap aims to shift COPD management from symptom control toward durable, mechanism-driven disease modification.
    Keywords:  COPD; NETosis; epigenetic reprogramming; immunometabolism; m6A modification; oxidative stress; treatable traits
    DOI:  https://doi.org/10.3389/fimmu.2026.1865051
  46. Immune Netw. 2026 Aug;26(4): e35
    Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives.
    Nan Chen, Xiangping Xie, Shuangyan He, Lifen Liang.
      Mitochondria have long been viewed as the "powerhouses" of the cell, but research over the past decade has established that they play a far more complex role in skin immune homeostasis beyond ATP production. The metabolic preferences of immune cells and skin parenchymal cells-glycolysis, oxidative phosphorylation, or fatty acid oxidation-determine their fate choices during inflammatory responses. When mitochondrial function is impaired, the release of damage-associated molecular patterns (DAMPs) such as mitochondrial DNA and mitochondrial ROS can activate the cGAS-STING and NOD-like receptor family pyrin domain-containing 3 inflammasome pathways, driving inflammatory cycles in various skin diseases including psoriasis, atopic dermatitis, lupus erythematosus, and vitiligo. This review systematically examines the key mechanisms of mitochondrial metabolic reprogramming in skin immune disorders, focusing on 3 typical scenarios: the metabolic preferences of immune cells, mitochondrial DAMP-mediated autoinflammation, and the impact of mitochondrial dynamics imbalance on tissue-resident memory T cell function. Furthermore, we evaluate clinical evidence for repurposing old drugs such as metformin and thiazolidinediones, and discuss the translational prospects of emerging strategies including Nrf2 agonists, mitophagy inducers, and targeted nanocarriers. Understanding the "dual identity" of mitochondria in skin immunity-as both metabolic regulators and signaling sensors-will lay the foundation for developing precise metabolic immunomodulatory therapies.
    Keywords:  Atopic dermatitis; Metabolic reprogramming; Mitochondria; Psoriasis
    DOI:  https://doi.org/10.4110/in.2026.26.e35
  47. Carbohydr Polym. 2026 Oct 15. pii: S0144-8617(26)00885-4. [Epub ahead of print]390 125768
    Bacillus subtilis exopolysaccharide enhances Lactobacillus johnsonii-kynurenic acid to restore intestinal T helper 17/regulatory T cell balance via aryl hydrocarbon receptor.
    Ge Zhang, Li Cao, Gang Zhang, Rongrong Fu, Yujun Wu, Jinbiao Zhao, Zeyu Zhang.
      Weaning-induced intestinal dysfunction remains a significant challenge, characterized by microbial dysbiosis and immune suppression. However, the precise molecular mechanisms by which specific structural features of levan-fructans influence host homeostasis through microbial metabolic pathways are not fully understood. Here, a branched levan-type exopolysaccharide from Bacillus subtilis BS21 (BS21EPS), characterized by a β-(2 → 6)-D-fructofuranosyl backbone and β-(2 → 1) linkages, reduces colonic damage and systemic inflammation. Metagenomic sequencing shows that BS21EPS supplementation selectively increases Lactobacillus johnsonii 428 in the colon, which contains specialized GH32 enzymes for levan degradation. Integrative metabolomics identifies kynurenic acid (KYNA) as the primary microbial metabolite consistently increased both in vivo and in vitro, which mechanistically serves as a potent endogenous ligand for the aryl hydrocarbon receptor (AhR). In a mouse colitis model, supplementation with L. johnsonii 428 or KYNA enhances intestinal barrier function and reduces inflammation by influencing T-cell lineage decisions, especially by promoting Treg expansion while inhibiting Th17 differentiation. Notably, AhR antagonism with CH223191 abrogates these immunomodulatory effects, confirming the crucial role of the KYNA-AhR axis in maintaining immune balance. Collectively, these findings reveal a structural-functional link between dietary levans, providing a targeted nutritional strategy for managing weaning-related dysfunction and inflammatory bowel diseases.
    Keywords:  AhR-Th17/Treg axis; Bacillus subtilis BS21 exopolysaccharide; Intestinal barrier; Kynurenic acid; Lactobacillus johnsonii; Weaned piglets
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125768
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