bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–09–20
fifty-six papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Breathing and burning: metabolic control of alveolar macrophages by intracellular bacterial pathogens.
  2. Unraveling the pleiotropic roles of the mTOR-glycolytic axis in ulcerative colitis: from immunometabolic dysregulation to mucosal barrier remodeling.
  3. Compensatory pathways in tryptophan metabolism and immune regulation following IDO inhibition.
  4. Immune metabolic reprogramming in MASLD.
  5. Immunometabolic Plasticity in Sarcopenic Obesity: Toward a New Paradigm for Precision Immunonutrition.
  6. Temporal CRAC channel blockade modulates the MYC-MXD axis to attenuate autoimmune inflammation.
  7. Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.
  8. A Bioactive Constituent from Bazhen Decoction Alleviates Sepsis-Associated Liver Injury by Restoring SLC6A6-Mediated Taurine Transport to Reprogram Macrophage Immunometabolism.
  9. Ubiquitylation by the GID/CTLH complex regulates the metabolic and innate immune response of macrophages to infection by Mycobacterium tuberculosis.
  10. Metabolic reprogramming of myeloid antigen-presenting cells in the tumor microenvironment: mechanisms of antigen presentation failure and therapeutic opportunities.
  11. ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.
  12. Japanese encephalitis virus reprograms host pyrimidine metabolism to facilitate viral replication.
  13. In vivo CRISPR screens identify the glutamine transporter SLC1A5 as a metabolic barrier to antitumor immunity.
  14. Balancing lipid synthesis and oxidation promotes B cell response to vaccination during immunosuppression.
  15. Drugging trained immunity: immunometabolic and epigenetic control of maladaptive inflammatory memory in chronic inflammatory diseases.
  16. Glutamine metabolism as a rheostat of CD4+ T cell pathogenic function in metabolic dysfunction-associated steatotic liver disease.
  17. Peripheral-central inflammatory crosstalk in Alzheimer's disease: immunometabolic functions of circulating soluble metabolites under dynamic blood-brain barrier states.
  18. An H2A.Z-dependent epigenetic checkpoint in macrophages couples genetic risk to microbial metabolite signaling.
  19. Mitochondrial transfer via ADSC-EVs reprograms glucose/glutamine metabolism to restore TCA cycle-driven M2 polarization in diabetic wounds.
  20. TLR7/9 and type I interferon signaling reprogram neutrophil NET responses and impair antibacterial defense in systemic lupus erythematosus.
  21. Dose-dependent arginine availability is associated with metabolic remodeling and immune phenotypes during development.
  22. Targeting PKM2 Enhances the Anti-Tumor Function of CD8+ T Cells Through Metabolic Reprogramming.
  23. Macrophage HDAC3 drives obesity and adipose tissue metabolic maladaptation through GDF3-mediated inflammation and chromatin remodeling.
  24. Acute activation of Gq-signaling in pancreatic islet macrophages inhibits insulin secretion through AMPK-sphingolipid axis.
  25. Microbiota-derived tryptophan metabolites shape Th2 lymphocyte responses via the aryl hydrocarbon receptor and metabolic reprogramming.
  26. Mechanism and clinical relevance of metabolic-immune cross-talk in pancreatic tumor microenvironment.
  27. IFNAR1-dependent metabolic circuit drives pathogenic neutrophil activation in chronic mucosal inflammation.
  28. Lysophosphatidylcholine-induced macrophage polarization imbalance and functional dysregulation in immune thrombocytopenia.
  29. HBV induces immunosuppressive macrophages via metabolic and epigenetic reprogramming to facilitate the establishment of chronic persistent infection.
  30. Metabolic sensor AMPK licenses intestinal CD103+ DCs to induce Treg responses.
  31. Coenzyme A activates TLR4 and enhances alternative macrophage activation in line with MyD88 agonism.
  32. Nitrated fatty acids form membrane biochemical capacitors that restrain inflammation.
  33. Mitochondria-Targeted Nanozyme Reprograms Dendritic-Cell Immunometabolism via Microenvironment-Responsive CO Release to Treat Periodontitis.
  34. Mitophagy-pyroptosis-macrophage polarization crosstalk in cardiovascular diseases: mechanistic insights and therapeutic potential.
  35. The role of glutamine metabolism in the pathogenesis of idiopathic pulmonary fibrosis and its therapeutic potential.
  36. Hypercapnia Induces Mitochondrial Adaptations and Alters Glutamine Metabolism to Drive a Distinct Metabolic Phenotype in Monocytes.
  37. Scopolamine ameliorates psoriasis by blocking M1 receptor-mediated IL-23 production in dendritic cells.
  38. Multi-Omics Profiling Identifies Immune-Metabolic Signatures and Gut Microbial Biomarkers in a Murine Model of Mycoplasma pneumoniae Pneumonia.
  39. Hematopoietic HCAR2 attenuates atherosclerosis by enhancing efferocytosis via AMPK/ABCA1 signaling.
  40. Targeting the ChREBP/PKLR-lactate axis via Huachansu tablets restores CD8⁺T cell immunity in MASH-HCC.
  41. Intermittent theta-burst stimulation in ischemic stroke: a mitochondria-centered framework connecting microglial reprogramming and neuronal survival.
  42. Hippuric acid contributes to NK-cell activation with dependence on TLR2 in chronic hepatitis B complicated by MASLD.
  43. Alox15 restrains glycolysis to support M2 macrophage effector function during helminth immunity.
  44. Author Correction: Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.
  45. Drug-induced metabolic remodeling promotes antimicrobial activity in macrophages and extends longevity in vivo.
  46. Super-enhancer-driven SGK1 activates polyamine metabolism to promote autoimmune uveitis.
  47. GNPAT-driven plasmalogen biosynthesis regulates macrophage polarization and protects against obesity-induced inflammation by suppressing PKCδ-STAT1 signaling.
  48. Lipid-Associated Macrophages in Obesity: Immunometabolic Programs and Emerging Therapeutic Implications-A Narrative Review.
  49. Macrophage immunometabolic reprogramming in inflammatory repair failure in osteonecrosis of the femoral head.
  50. Polyunsaturated fatty acids: host-derived antimicrobials against glycolytic Staphylococcus aureus.
  51. Targeting the GPR183/EBI2‒oxysterol axis in tuberculosis: Immunometabolic regulation and prospects for host-directed therapy.
  52. Epigenetic training licenses naïve CD8+ T cell metabolic fitness and function.
  53. Inflammation-centered neurovascular-immune-metabolic remodeling in ischemic stroke: stage-dependent mechanisms, regulated cell death, and therapeutic translation.
  54. Macrophage source influences peritoneal persistence and immune cell dynamics in assays of reverse cholesterol transport.
  55. 4-Octyl Itaconate Inhibits Porcine Epidemic Diarrhea Virus Replication by Modulating the Ferroptosis Axis and the Autophagy Pathway.
  56. Cancer-associated fibroblast-derived POSTN as a metabolic "switch" shapes lipid-stressed macrophage polarization in gastric cancer.
  1. Front Physiol. 2026 ;17 1895061
    Breathing and burning: metabolic control of alveolar macrophages by intracellular bacterial pathogens.
    Het Adhvaryu, Daniel E Voth.
      Alveolar macrophages (AMs) are the lung's phagocytic immune sentinels, programmed to maintain homeostasis while defending against inhaled pathogens. AM metabolism is shaped by both developmental origin and the alveolar microenvironment. Embryonically-derived AMs populate the lungs early in life and develop into long-lived, self-renewing cells displaying lipid-centered, oxidative metabolism that restrains inflammation and preserves alveolar structure. When infection or injury disrupts homeostasis, circulating monocytes are recruited to the airspace and differentiate into monocyte-derived AMs, which adopt a glycolytic, short-lived, pro-inflammatory phenotype. Thus, differences in origin and transcriptional programming create two metabolically distinct AM populations with divergent roles in lung immunity. The intracellular bacterial pathogens Mycobacterium tuberculosis, Coxiella burnetii, Legionella pneumophila, and Francisella tularensis exploit these metabolic programs to facilitate intracellular growth and disease progression. By modulating glycolysis, remodeling mitochondria, manipulating lipid handling, or redirecting host metabolites, these pathogens evade immune insults and create growth niches. In this review, we discuss mechanisms by which AM metabolism shapes the tissue environment and pulmonary immunity, and we showcase intracellular pathogens to understand pro-bacterial reprogramming of AM metabolism.
    Keywords:  alveolar macrophages; immunometabolism; infection; intracellular pathogen; pulmonary; vacuole
    DOI:  https://doi.org/10.3389/fphys.2026.1895061
  2. Front Immunol. 2026 ;17 1889686
    Unraveling the pleiotropic roles of the mTOR-glycolytic axis in ulcerative colitis: from immunometabolic dysregulation to mucosal barrier remodeling.
    Yanjie Chen, JinYin Xiao, Limin Xiao, Anni Chen, Lizhi He, Zhenquan Wang.
      Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colonic mucosa, whose pathogenesis is intricately linked to metabolic reprogramming within both immune and epithelial compartments. The mechanistic target of rapamycin (mTOR) signaling pathway serves as a central immunometabolic hub that integrates nutrient availability, microbial cues, and inflammatory signals to orchestrate glycolytic flux, thereby profoundly shaping the functional plasticity of diverse intestinal cell populations. This review systematically delineates, from a cell-type-specific perspective, the divergent regulatory roles of the mTOR-glycolysis axis in intestinal immunity and mucosal barrier homeostasis. We first outline the core molecular architecture of mTORC1/mTORC2-driven glycolytic reprogramming, highlighting key regulatory nodes including GLUT1/3-mediated glucose uptake, HK2-dependent rate-limiting phosphorylation, and PKM2-governed metabolic-transcriptional switching. Subsequently, we examine how aberrant mTOR-glycolysis axis activation in neutrophils, macrophages, type 3 innate lymphoid cells, and CD4+ T effector subsets propagates a feed-forward inflammatory loop-exacerbating oxidative burst, NETosis, M1 polarization, and Th17 pathogenicity-while simultaneously undermining the metabolic fitness and suppressive integrity of regulatory T cells. Moreover, we discuss the metabolic rewiring of intestinal epithelial cells via the mTOR-glycolysis axis, which compromises barrier integrity, disrupts epithelial regeneration, and initiates a "metabolic-secretory" crosstalk that perpetuates mucosal inflammation. Collectively, this review positions the mTOR-glycolysis axis as a rheostat governing the transition from homeostatic immunosurveillance to pathogenic inflammation in UC, and proposes that cell-selective metabolic checkpoint targeting-rather than broad systemic inhibition-represents a promising precision strategy for future therapeutic intervention.
    Keywords:  glycolysis; immune metabolism; mTOR signaling pathway; mTOR-glycolytic axis; ulcerative colitis
    DOI:  https://doi.org/10.3389/fimmu.2026.1889686
  3. Mol Biol Rep. 2026 Sep 12. pii: 1567. [Epub ahead of print]53(1):
    Compensatory pathways in tryptophan metabolism and immune regulation following IDO inhibition.
    Isabela Gontijo, Mariana Camurça, José Roberto Kfoury.
      Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-dependent enzyme that catalyzes the initial oxidation of L-tryptophan into the kynurenine pathway, thereby linking tryptophan metabolism to immune regulation. IDO1 expression is mainly induced by interferon-γ during immune activation and inflammation, and its activity helps control immune responses through tryptophan depletion and the generation of immunomodulatory metabolites. Because of its central role in immunometabolism, IDO1 has been widely investigated as a therapeutic target, and several strategies have been developed to inhibit its enzymatic activity or reduce its functional contribution to immune suppression. However, increasing evidence indicates that IDO1 inhibition may not completely interrupt tryptophan catabolism or downstream immunoregulatory signaling. Instead, IDO1 blockade can be accompanied by compensatory mechanisms that preserve metabolic and immune regulatory outputs. These mechanisms may include activity or upregulation of alternative tryptophan-catabolizing enzymes such as TDO2, IDO2, and IL4I1; metabolic diversion toward serotonin and melatonin pathways; microbiota-derived indole production; and cell-type-specific metabolic rewiring. Therefore, understanding these adaptive responses is essential for interpreting the limited efficacy of IDO1-targeted approaches and for improving therapeutic strategies directed at tryptophan metabolism. This review discusses the main compensatory pathways that may emerge under IDO1 inhibition and their relevance to developing more effective immunometabolic interventions.
    Keywords:  Compensatory pathway; IDO1 inhibition; Immune regulation; Indoleamine 2,3 dioxygenase
    DOI:  https://doi.org/10.1007/s11033-026-12707-9
  4. JHEP Rep. 2026 Sep 12. pii: S2589-5559(26)00298-3. [Epub ahead of print] 102027
    Immune metabolic reprogramming in MASLD.
    Joanna Razafiarison, Nicolas Venteclef, Florent Ginhoux, Camille Blériot.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health challenge driven by the interplay between metabolic dysregulation and chronic low-grade inflammation. Beyond simple hepatic lipid accumulation, MASLD is characterized by extensive remodeling of the liver immune microenvironment in response to metabolic stress and persistent immunological activation. Recent advances in the field of immunometabolism have revealed that metabolic pathways not only shape immune cell identity and functions, but are also themselves influenced by immune responses, creating a reciprocal circuit that drives hepatic and systemic metabolism dysfunction. In this review, we examine how innate and adaptive immune cells, with an extensive focus on macrophages, undergo metabolic reprogramming during MASLD progression, and how these changes contribute to inflammation, fibrosis, and tissue injury. We also discuss how the hepatic immune niche is reshaped by the spatial distribution of parenchymal cells to promote disease progression. Finally, we highlight emerging therapeutic strategies targeting immunometabolic pathways, which hold promise for restoring liver homeostasis and preventing the progression of MASLD.
    Keywords:  Liver; immune cells; metabolic reprogramming; nutrient trafficking
    DOI:  https://doi.org/10.1016/j.jhepr.2026.102027
  5. Nutrients. 2026 Aug 26. pii: 2787. [Epub ahead of print]18(17):
    Immunometabolic Plasticity in Sarcopenic Obesity: Toward a New Paradigm for Precision Immunonutrition.
    Lucia Malaguarnera.
      Immunonutrition continues to generate heterogeneous and often contradictory clinical outcomes, suggesting that nutrients do not exert fixed immunological effects but interact with the biological context in which they operate. Sarcopenic obesity (SO) represents a paradigmatic clinical model of this complexity, where chronic low-grade inflammation, mitochondrial dysfunction, anabolic resistance, metabolic inflexibility, and microbiota remodeling converge to compromise the adaptive capacity of integrated immunometabolic networks. We propose that this condition may be interpreted as a state of impaired immunometabolic plasticity, which may help explain the context-dependent variability of nutritional responses. Within this perspective, micronutrients are viewed not simply as cofactors supporting immune competence but as dynamic regulators of interconnected immunometabolic pathways. Particular attention is devoted to vitamin D and resveratrol, presented as complementary regulators of immunometabolic plasticity. Within the proposed framework, vitamin D may contribute to immunometabolic competence, whereas resveratrol may act as a broader signaling modulator through the SIRT1/AMPK-PGC-1α axis, influencing mitochondrial function, inflammatory tone, metabolic flexibility, and epigenetic adaptation. Beyond isolated compounds, bioactive-rich food matrices, exemplified by Opuntia ficus-indica, are discussed as examples of systems-level modulators capable of coordinating inflammatory, metabolic, redox, and microbiota-dependent biological circuitry. This review introduces immunometabolic plasticity as a conceptual framework linking nutritional signals to the coordinated regulation of immune and metabolic adaptation across diverse biological contexts. Finally, we discuss how biomarker-guided phenotyping, multi-omics integration, and context-aware nutritional interventions may provide a foundation for precision immunonutrition, shifting the field from generalized supplementation strategies toward restoration of adaptive immunometabolic resilience.
    Keywords:  adaptive nutrition; bioactive compounds; immunometabolic plasticity; immunometabolism; precision immunonutrition; sarcopenic obesity; systems biology; whole-food matrices
    DOI:  https://doi.org/10.3390/nu18172787
  6. Cell Rep. 2026 Sep 16. pii: S2211-1247(26)01095-8. [Epub ahead of print]45(10): 118017
    Temporal CRAC channel blockade modulates the MYC-MXD axis to attenuate autoimmune inflammation.
    Beibei Wu, Spyridon Hasiakos, Shawn Cokus, Matthew Do, Elizabeth Kaplan, Matteo Pellegrini, Zuoming Sun, Reuben H Kim, Sonal Srikanth, Yousang Gwack.
      Effector T cell pathogenicity is strongly associated with the progression and severity of autoimmune diseases. Th17 cells are dependent on Ca2+ signaling mediated by the Ca2+ release-activated Ca2+ (CRAC) channels for their effector function. Here, we demonstrate that Th17 cells are uniquely sensitive to temporal inhibition of CRAC channels. Temporal CRAC channel block disturbed the effector functions and metabolic programming of Th17 cells, which were rescued by MYC expression. We uncovered a regulatory hierarchy in which CRAC channel activity during differentiation maintains MYC function by repressing Mxd genes, which antagonize MYC. In an animal model of autoimmunity, temporal CRAC channel block increased MXD expression to attenuate Th17 pathogenicity. These observations extend to human Th17 cells, where temporal CRAC channel blockade also impacts the MYC-MXD axis to impede cytokine production. Collectively, our study identifies a role for CRAC channels in regulating the MYC-MXD balance that governs Th17 effector function.
    Keywords:  CP: immunology; CP: metabolism; CRAC channels; Ca2(+) signaling; MYC-MXD axis; ORAI; autoimmunity; effector T cells; immunometabolism; mitochondrial function in effector T cells
    DOI:  https://doi.org/10.1016/j.celrep.2026.118017
  7. Nat Commun. 2026 Aug 15. pii: 9805. [Epub ahead of print]17(1):
    Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.
    Ya Chun Yu, Yulseung Sung, Seonghun Lim, Jeong Ah Kwon, Min Ju Lee, Hyeong Yun Kim, Sunghoon Kim, Kuglae Kim, Do Sik Min, Hee Chan Yoo, Jung Min Han.
      Trained immunity enables innate immune cells to acquire memory-like responses, offering a strategy to enhance antitumor immunity. However, the metabolic‒epigenetic mechanisms underlying this process remain poorly defined. Here, we show that lipopolysaccharide-induced macrophage training is encoded by a mitochondrial metabolic checkpoint. Integrated transcriptomic, metabolomic, and epigenomic profiling reveals that TLR4-NF-κB signaling represses SLC1A5_var, a mitochondrial glutamine transporter, limiting glutaminolysis and reducing α-ketoglutarate availability. This metabolic restriction limits removal of the activating histone mark histone H3 lysine 4 trimethylation by KDM5B, thereby maintaining inflammatory gene accessibility. Functionally, pharmacological inhibition or myeloid-specific knockdown of SLC1A5_var potentiates macrophage training and improves tumor control in murine cancer models, whereas enforced SLC1A5_var expression or α-ketoglutarate supplementation abrogates these effects. These findings define an SLC1A5_var-α-ketoglutarate-KDM5B metabolic-epigenetic axis that programs macrophage trained immunity and illustrate how targeted metabolic restriction can be leveraged to enhance innate immune responses against cancer.
    DOI:  https://doi.org/10.1038/s41467-026-76757-0
  8. J Ethnopharmacol. 2026 Sep 18. pii: S0378-8741(26)01244-4. [Epub ahead of print] 122389
    A Bioactive Constituent from Bazhen Decoction Alleviates Sepsis-Associated Liver Injury by Restoring SLC6A6-Mediated Taurine Transport to Reprogram Macrophage Immunometabolism.
    Shi Chen, Huimin Lu, Xinran Liang, Zhibo Zhang, Jiali Liu, Xiang Ji, Jiawen Chen, Pengfei Du, Haiyang Hu, Jialiang Du, Wangping Peng, Xiaohui Liang, Liming Lu, Xiaolan Lu, Wenkui Yu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Bazhen Decoction (BZD) is a classical formula first recorded in Ruizhu Tang Jing Yan Fang (14th century) and prescribed for centuries to replenish "Qi" and nourish "Blood". However, its bioactive constituents and immunometabolic mechanisms in sepsis-associated liver injury (SALI) remain unclear.
    AIM OF THE STUDY: To identify the key bioactive component of BZD and investigate its immunometabolic mechanism in SALI.
    MATERIALS AND METHODS: An integrated pipeline combining metabolomics, UPLC-Q-TOF-MS/MS, network pharmacology, and transcriptomics was followed by validation in septic mice induced by cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages using pharmacological modulation, including competitive inhibition of SLC6A6 transport with β-alanine and Seahorse XF metabolic flux analysis.
    RESULTS: Among 305 constituents, Suchilactone emerged as a key constituent. BZD treatment improved 7-day survival, reduced liver injury scores by 50-60%, and shifted hepatic macrophage polarization from M1 toward M2. Integrated omics profiling identified taurine as the central metabolic mediator. Suchilactone upregulated SLC6A6, restored intracellular taurine, and suppressed JAK1/STAT3 phosphorylation. It improved macrophage glycolytic and mitochondrial readouts, accompanied by increased PGC-1α, CPT1A, and ACOX1 expression consistent with enhanced fatty-acid-oxidation capacity. β-Ala co-treatment attenuated several Suchilactone-associated metabolic and polarization changes, providing supportive pharmacological evidence for possible involvement of taurine transport without establishing β-Ala specificity or causal SLC6A6 dependence. The liver-protective and macrophage-polarization findings were further observed in vivo.
    CONCLUSIONS: Suchilactone is associated with SLC6A6-mediated taurine transport to reprogram macrophage immunometabolism via JAK1/STAT3 suppression. These results indicate that the SLC6A6/taurine axis is a potential therapeutic target for sepsis-associated liver injury, and the causal contribution of this pathway requires further investigation.
    Keywords:  Bazhen Decoction; JAK1/STAT3 signaling; Macrophage immunometabolism; Metabolic reprogramming; Sepsis-associated liver injury; Suchilactone; Taurine transport
    DOI:  https://doi.org/10.1016/j.jep.2026.122389
  9. PLoS Pathog. 2026 Sep 18. 22(9): e1014196
    Ubiquitylation by the GID/CTLH complex regulates the metabolic and innate immune response of macrophages to infection by Mycobacterium tuberculosis.
    Nelson V Simwela, Luana Johnston, Christopher M Sassetti, David G Russell.
      The GID/CTLH E3 ligase complex is implicated in several biological processes, yet its full substrate repertoire remains poorly defined. We recently identified the complex as a broad modulator of macrophage responses to Mycobacterium tuberculosis (Mtb) infection. Here, we use label-free proteomics and diGly capture analysis of Mtb-infected macrophages to define the GID/CTLH-dependent ubiquitylome. We identify thousands of dynamically altered ubiquitylation sites, with strong enrichment among proteins involved in cellular metabolism and innate immune signaling. Concurrent proteome analysis revealed extensive rewiring in GID/CTLH-deficient macrophages, with >90% of enriched pathways among increased proteins consisting of metabolic targets. Notably, inhibitory phosphatases (PTEN, INPP5D) also emerged as candidate substrates. Functional studies revealed proteasome-dependent stabilization of PTEN and INPP5D in GID/CTLH-deficient macrophages with each phosphatase individually exerting an influence on Mtb intracellular survival. Together, our study defines a GID/CTLH-dependent ubiquitylome in macrophages and identifies the complex as a central regulator of metabolism and antimicrobial immunity.
    DOI:  https://doi.org/10.1371/journal.ppat.1014196
  10. Biochim Biophys Acta Rev Cancer. 2026 Sep 14. pii: S0304-419X(26)00188-5. [Epub ahead of print]1881(6): 189716
    Metabolic reprogramming of myeloid antigen-presenting cells in the tumor microenvironment: mechanisms of antigen presentation failure and therapeutic opportunities.
    Peishan Zhou, Yicun Han, Qing Ji.
      Antigen-presenting cells (APCs) translate tumor-derived signals into adaptive immune responses, yet their function is shaped by the metabolically hostile tumor microenvironment (TME). Hypoxia, acidosis, nutrient scarcity, and immunoregulatory metabolite accumulation can reprogram myeloid APC metabolism, impair antigen processing and presentation, weaken costimulatory signaling and cytokine production, and compromise antitumor T cell responses. In this review, we examine how glucose, lipid, amino acid, and mitochondrial metabolic perturbations drive subset-specific remodeling of dendritic cells and tumor-associated macrophages. We emphasize mechanistic links between defined metabolic stressors, discrete antigen-presentation defects, and downstream immune consequences, while framing APC dysfunction as context-dependent adaptive remodeling rather than passive metabolic collapse. We also distinguish impaired lymph-node priming from maladaptive intratumoral restimulation and discuss therapeutic strategies that remodel the TME, recalibrate APC-intrinsic metabolism, enhance targeted delivery, and engineer APC-like cellular functions. Together, these insights position APC immunometabolism as a potentially actionable determinant of tumor immune escape and therapeutic responsiveness.
    Keywords:  Cancer immunotherapy; Dendritic cells; Immunometabolism; Myeloid antigen-presenting cells; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189716
  11. Cell Rep. 2026 Sep 15. pii: S2211-1247(26)01087-9. [Epub ahead of print]45(10): 118009
    ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.
    Songnan Wang, Yingjie Guo, Weidong An, J Michelle Lee, Yu Li, Valentino Sudaryo, Jacqueline A Carozza, Gabriel Grenot, Gemini Skariah, Saranya C Reghupaty, Sonny Young, Xiaochen Bai, Katrin J Svensson, Lingyin Li.
      The mechanism underlying the role of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in metabolic disease remains unsolved. Using a 2'3'-cyclic GMP-AMP (cGAMP)-hydrolysis-deficient mouse (Enpp1H362A), we show that selective loss of this activity exacerbates high-fat diet (HFD)-induced weight gain and insulin resistance. An in vivo glucose-uptake screen identifies brown adipose tissue (BAT) as a key site of metabolic impairment, marked by extracellular cGAMP accumulation and defective insulin-stimulated glucose uptake. Mechanistically, nutrient excess drives mitochondrial DNA leakage in brown adipocytes, triggering cGAMP synthesis and export. Excess extracellular cGAMP directly suppresses glucose uptake in brown adipocytes via stimulator of interferon genes (STING) pathway. Furthermore, impaired cGAMP clearance acts as a paracrine signal that recruits and polarizes BAT macrophages toward a pro-inflammatory M1-like phenotype. Finally, the human ENPP1 K173Q variant associated with obesity and diabetes displays reduced cGAMP hydrolysis activity. Together, these findings establish ENPP1 as an immunometabolic checkpoint that buffers extracellular cGAMP to maintain metabolic homeostasis.
    Keywords:  CP: immunology; CP: metabolism; ENPP1; STING; brown adipose tissue; diabetes; extracellular cGAMP; immune checkpoint; immunometabolism; insulin resistance; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2026.118009
  12. Infect Med (Beijing). 2026 Sep;5(3): 100274
    Japanese encephalitis virus reprograms host pyrimidine metabolism to facilitate viral replication.
    Jun Gu, Chencheng Fan, Shengxian Xiang, Youhui Si, Bibo Zhu, Shengbo Cao, Jing Ye.
       Background: Pyrimidine metabolism is crucial for the replication of viruses and the functionality of host cells. However, the cell-type-specific organization of this metabolism in the central nervous system and its dysregulation during Japanese encephalitis virus (JEV) infection remain poorly understood. Here, we aimed to characterize the cell-type-specific landscape of pyrimidine metabolism in the CNS and uncover pyrimidine metabolic reprogramming during JEV infection.
    Methods: Single-cell RNA sequencing data from normal and JEV-infected mouse brains were analyzed to profile the expression of pyrimidine metabolic genes across neuronal, glial, and vascular cell types. Functional validation of these metabolic pathways on JEV replication was performed in Neuro-2a cells and primary mouse brain-derived mixed neuron/glia cultures using pharmacological inhibitors, metabolite supplementation, and virological assays, including quantitative reverse transcription polymerase chain reaction, immunoblotting, and plaque assay.
    Results: We defined a universal core program for pyrimidine homeostasis alongside specialized, function-oriented metabolic programs across neurons, glia, and vascular cells in the normal mouse brain. JEV infection triggered cell-intrinsic reprogramming of this metabolic network, with viral replication critically depending on the de novo pyrimidine biosynthesis pathway in neurons. Pharmacological inhibition of the key enzyme dihydroorotate dehydrogenase significantly suppressed JEV replication. Furthermore, JEV replication created a metabolic dependency on exogenous glutamine and enhanced glutamate oxaloacetate transaminase-mediated aspartate synthesis for precursor acquisition.
    Conclusions: JEV rewires host brain pyrimidine metabolism in a cell-type-specific manner, revealing distinct metabolic dependencies on de novo pyrimidine biosynthesis, exogenous glutamine uptake, and glutamate oxaloacetate transaminase-mediated aspartate synthesis in neurons and highlighting potential targets for future antiviral strategies. By resolving these alterations at single-cell resolution, this study also provides a cell-type-resolved pyrimidine metabolic landscape of both the normal and JEV-infected brain.
    Keywords:  Aspartate; Brain; Glutamine; Japanese encephalitis virus; Metabolic reprogramming; Pyrimidine metabolism
    DOI:  https://doi.org/10.1016/j.imj.2026.100274
  13. Sci Immunol. 2026 Sep 18. 11(123): eaea4179
    In vivo CRISPR screens identify the glutamine transporter SLC1A5 as a metabolic barrier to antitumor immunity.
    Wenlong Jia, Guanxing Yu, Shenqi Han, Zhibo Ma, Junnan Liang, Wei Yan, Xinling Zhang, Chenglong Zeng, Lin Xue, Feng Xia, Ganxun Li, Ran Tao, Peixiang Lan, Wei Yan, Wanguang Zhang, Huifang Liang, Xiaoping Chen, Zhao Huang, Bixiang Zhang.
      Tumor cells often evade immune pressure via metabolic reprogramming, yet the key metabolic regulators orchestrating this process remain incompletely defined. Here, using in vivo metabolic CRISPR screening under distinct immune pressures, we identified tumor cell-intrinsic solute carrier family 1 member 5 (SLC1A5) as a metabolic node that sustains an immunosuppressive tumor microenvironment. SLC1A5-mediated glutamine metabolism in tumor cells modulated CD8 T cell infiltration and effector function, reshaping tumor responses to immune checkpoint blockade therapy. Glucose deprivation up-regulated SLC1A5 isoforms in tumor cells, enhancing glutamine uptake and glutathione synthesis. This adaptation limited mitochondrial oxidative stress and cytosolic mitochondrial DNA release, thereby suppressing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, interferon-β production, and CD8 T cell antitumor responses. These findings define a glutamine-fueled metabolic program as a barrier to tumor immunogenicity, positioning SLC1A5 as a tumor-intrinsic metabolic regulator with potential therapeutic relevance.
    DOI:  https://doi.org/10.1126/sciimmunol.aea4179
  14. J Clin Invest. 2026 Sep 17. pii: e205170. [Epub ahead of print]
    Balancing lipid synthesis and oxidation promotes B cell response to vaccination during immunosuppression.
    Elizabeth A Thompson, Alexis Figueroa, Katerina Roznik, Nicole E Skinner, Santosh Dhakal, Shuai Li, Luca Biavati, Laura A Sena, Laila Stoddart, Karli Redinger, Samuel B Warner, Sabra L Klein, Nadine Rouphael, Joel N Blankson, Yolanda Eby, Robert D Leone, Peter S Heeger, Mark A Robien, Christian P Larsen, Erika L Pearce, Edward J Pearce, Hongkai Ji, Andrew H Karaba, Dorry L Segev, Aaron Ar Tobian, William A Werbel, Andrea L Cox, Justin R Bailey.
      Pharmacologic immunosuppression is essential for preventing organ rejection and controlling autoimmunity, but profoundly impairs humoral immunity, increasing the risk of vaccine failure and infection. The mechanisms by which immunosuppressive therapies disrupt human B cell responses remain poorly defined. Here, we identified dysregulated lipid metabolism as a central determinant of impaired vaccine response in solid organ transplant recipients (SOTRs). Using high-dimensional immune profiling, single-cell transcriptomics, and functional metabolic assays, we found that effective B cell responses required a homeostatic balance between lipid synthesis and fatty acid oxidation. The widely used immunosuppressive agent, mycophenolic acid (MPA) was strongly associated with vaccine non-response and induced excessive lipid synthesis, lipid accumulation, and mitochondrial stress in B cells. In contrast, CD11c+ B cells retained the capacity to differentiate into plasmablasts in the presence of MPA through elevated expression of CPT1A, a mitochondrial fatty acid transporter, and enhanced fatty acid oxidation. These cells were found to be a key feature of early effective vaccine responses in healthy individuals and SOTRs. Notably, pharmacologic inhibition of cholesterol synthesis partially restored plasmablast differentiation in the presence of MPA. These findings identify B cell lipid metabolism as a critical and targetable regulator of human humoral immunity during immunosuppression.
    Keywords:  Adaptive immunity; B cells; Fatty acid oxidation; Immunology; Metabolism
    DOI:  https://doi.org/10.1172/JCI205170
  15. Immunol Res. 2026 Sep 15. pii: 112. [Epub ahead of print]74(1):
    Drugging trained immunity: immunometabolic and epigenetic control of maladaptive inflammatory memory in chronic inflammatory diseases.
    Aziz Ullah, Wajid Zaman.
      Chronic inflammatory diseases are usually treated as persistent activation states, yet many disorders also contain a memory component: innate immune cells and their bone marrow progenitors can retain durable metabolic and epigenetic programs after infection, sterile injury, modified lipoproteins, crystals, diet or vaccination. This process, known as trained immunity, improves host defense when appropriately induced but may also amplify maladaptive inflammation in atherosclerosis, gout, rheumatoid arthritis, inflammatory bowel disease, neuroinflammation, chronic pain and metabolic disease. The pharmacological importance of trained immunity is increasing because its core mechanisms are druggable: glycolysis, mTOR-HIF-1 alpha signaling, the mevalonate pathway, tricarboxylic-acid-cycle metabolites, histone methylation and acetylation, chromatin accessibility, NLRP3 inflammasome activity and IL-1 beta signaling. This review critically synthesizes trained immunity as a disease-relevant inflammatory memory program and evaluates repurposed and emerging interventions, including colchicine, IL-1 blockers, statins, metformin, mTOR inhibitors, fumarate/itaconate-related metabolic modulators, BET/HDAC-directed epigenetic strategies and NLRP3 inhibitors. We propose a translational framework in which patients are stratified by inflammatory-memory phenotypes, interventions are matched to dominant metabolic-epigenetic modules, and treatment success is judged by durable resolution without excessive immunosuppression. This approach can help convert trained immunity from a descriptive immunological concept into a practical target class for inflammation pharmacology.
    Keywords:  Epigenetics; IL-1 beta; Immunometabolism; Inflammation pharmacology; NLRP3 inflammasome; Trained immunity
    DOI:  https://doi.org/10.1007/s12026-026-09845-4
  16. Cell Metab. 2026 Sep 18. pii: S1550-4131(26)00370-0. [Epub ahead of print]
    Glutamine metabolism as a rheostat of CD4+ T cell pathogenic function in metabolic dysfunction-associated steatotic liver disease.
    Keisuke Sawada, Jarren R Oates, Masaki Kimura, Traci E Stankiewicz, John Eom, Pablo C Alarcon, Hak Chung, Michelle S M A Damen, Cassidy J Ulanowicz, Jennifer L Wayland, Ethan S O Williams Fonner, Colin C Anderson, Hayde K Cuervo-Jimenez, Amelia M Pearson, Yunguan Wang, Nathan Salomonis, Ty D Troutman, Julie A Reisz, Jeffrey C Rathmell, Sara Szabo, Michael A Helmrath, Takanori Takebe, Maria E Moreno-Fernandez, Senad Divanovic.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) severity is independently linked with pathogenic CD4+ T cell responses and skewed hepatic glutamine (Gln) metabolism. Whether these processes interact to drive disease progression remains unclear. Here, we identify hepatic Gln depletion as a key feature of steatohepatitis that is linked with increased hepatic CD4+ T cell inflammation and hepatocellular damage in humans. In complementary mouse models, both total hepatic and hepatic CD4+ T cell Gln levels were similarly reduced. Restoration of hepatic Gln through supplementation selectively restrained hepatic CD4+ T cell inflammatory programs and alleviated hepatocellular damage and disease severity. Mechanistically, T cell-intrinsic Gls1-mediated glutaminolysis limited O-GlcNAcylation to dampen pathogenic CD4+ T cell inflammation. Importantly, Gln treatment dampened CD4+ T cell-mediated injury in human liver organoids. Together, these findings establish hepatic CD4+ T cell-intrinsic Gln metabolism as a critical rheostat of pathogenic inflammation in MASLD and invoke metabolism-targeted strategies to restrict disease progression.
    Keywords:  MASH; MASL; MASLD; NAFL; NAFLD; NASH; adaptive immunity; amino acid metabolism; immunometabolism; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.018
  17. Front Immunol. 2026 ;17 1939482
    Peripheral-central inflammatory crosstalk in Alzheimer's disease: immunometabolic functions of circulating soluble metabolites under dynamic blood-brain barrier states.
    Nannan Song, Huan Xing, Feng Liu, Wang Xi.
      Immunometabolic dysregulation orchestrating bidirectional peripheral-central inflammatory crosstalk has been increasingly recognized as a contributor to Alzheimer's disease (AD) pathogenesis, challenging the conventional view of AD as an isolated central disorder dominated by amyloid-beta (Aβ) and tau pathology. However, although central immune-metabolic disturbances are well established, this perspective largely overlooks peripherally derived regulatory signals from systemic circulation. Classical peripheral-to-central pathways, such as immune cell infiltration and cytokine leakage, depend on overt blood-brain barrier (BBB) damage and cannot account for the latent neuroinflammation characteristic of the prodromal stage, when neurovascular units remain largely intact. To address this gap, we review recent advances on circulating soluble metabolites (<500 Da)-key immunometabolic mediators linking systemic disturbances to central lesions-and organize them into three groups by biosynthetic origin (a heuristic, non-taxonomic classification): peripheral immune-derived, gut microbiota-derived, and systemic host metabolic intermediates. We outline the transmembrane transport shifts associated with progressive BBB dysfunction and the downstream intracellular cascades-such as mitochondrial redox disturbance, mTOR-NLRP3 inflammasome activation, and histone epigenetic remodeling-that mediate this crosstalk. Importantly, although these proposed associations are mechanistically informative, they remain largely unsupported by direct human evidence and require further validation in large AD cohorts; nevertheless, several individual metabolite biomarkers already show consistent clinical association. This framework clarifies the multi-stage immunometabolic axis and may inform the development of ultra-early fluid biomarkers and peripheral-targeted immunometabolic interventions.
    Keywords:  Alzheimer’s disease; blood-brain barrier; circulating soluble metabolites; immunometabolism; neuroinflammation; peripheral-central inflammatory crosstalk
    DOI:  https://doi.org/10.3389/fimmu.2026.1939482
  18. Protein Cell. 2026 Sep 15. pii: pwag069. [Epub ahead of print]
    An H2A.Z-dependent epigenetic checkpoint in macrophages couples genetic risk to microbial metabolite signaling.
    Zhaoran Sun, Fanyi Meng, Chunjian Piao, Yuqiao Fu, Yingying Zhao, Liangyu Xing, Yunzhi Liu, Fengqin Jia, Liyu Li, Jin Li, Hailong Cao, Xudong Wu.
      Inflammatory gene programs must be precisely controlled to maintain immune homeostasis, yet the chromatin mechanisms enforcing transcriptional shutdown remain unclear. Here we show that the histone variant H2A.Z is evicted from pro-inflammatory loci upon acute macrophage activation and re-deposited during resolution. Myeloid-specific H2a.z deletion in mice causes unrestrained inflammatory transcription, arrested macrophage maturation, exacerbates colitis and dysbiosis, depleting butyrate-producing bacteria. Consistently, gut short-chain fatty acids, particularly butyrate, promote H2A.Z deposition through histone acylation, and butyrate's anti-inflammatory effects require H2A.Z. Strikingly, human inflammatory bowel disease (IBD)-associated risk variants are linked to reduced expression of GAS41 and TIP60, which form a reader-writer module that senses acylation mark to direct H2A.Z deposition. Diminished GAS41/TIP60 expression in patient tissues correlates with IBD progression and poor response to anti-TNF therapy. Thus, H2A.Z deposition functions as an acylation-dependent epigenetic checkpoint that couples macrophage differentiation to inflammatory resolution, integrating host genetics and microbial metabolites to calibrate immune responses.
    Keywords:  H2A.Z; acute colitis; epigenetic regulation; immune homeostasis; inflammatory bowel disease; macrophages
    DOI:  https://doi.org/10.1093/procel/pwag069
  19. J Nanobiotechnology. 2026 Jul 28. pii: 859. [Epub ahead of print]24(1):
    Mitochondrial transfer via ADSC-EVs reprograms glucose/glutamine metabolism to restore TCA cycle-driven M2 polarization in diabetic wounds.
    Yue Zhang, Fei Han, Yixuan Yuan, Mengyang Li, Linbin Yi, Yujie Xiao, Dongliang Zhang, Zhi Zhang, Yunchuan Wang, Hongtao Wang, Dahai Hu.
      Chronic diabetic wounds are trapped in a persistent inflammatory state, largely due to macrophage failure to transition from pro-inflammatory (M1) to pro-reparative (M2) phenotypes. Here, we show that adipose-derived stem cell extracellular vesicles (ADSC-EVs) deliver functional mitochondria into diabetic wound macrophages, thereby restoring tricarboxylic acid (TCA) cycle-driven M2 polarization. Mechanistically, ADSC-EV-mediated mitochondrial transfer reactivates pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC), increases TCA cycle flux, and suggests enhanced glutamine anaplerosis, as evidenced by ¹³C-glucose isotope tracing. This metabolic rewiring restores oxidative phosphorylation (OXPHOS), elevates oxygen consumption rate (OCR) and suppresses glycolysis. Consequently, ADSC-EV treatment reduces M1 macrophages and increases M2 macrophages, lowers pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, MCP1, p < 0.0001), and upregulates IL-10 in vitro, p < 0.0001). In a diabetic mouse wound model, a single course of ADSC-EVs accelerates wound closure at day 14 (p < 0.05), enhances re-epithelialization and collagen deposition, and reduces local oxidative stress and inflammation. Mitochondria‑depleted Rho-ADSC-EVs show markedly diminished effects, confirming that functional mitochondrial transfer is the primary driver. Our findings establish ADSC-EV-mediated mitochondrial transfer as a central metabolic reprogramming strategy that breaks the inflammatory lock in diabetic wounds and promotes healing.
    Keywords:  ADSC-EVs; Diabetic wound; Macrophages; Metabolic remodeling; Mitochondrial transfer; TCA cycle
    DOI:  https://doi.org/10.1186/s12951-026-04846-9
  20. Cell Press Blue. 2026 Aug;1(5): 100080
    TLR7/9 and type I interferon signaling reprogram neutrophil NET responses and impair antibacterial defense in systemic lupus erythematosus.
    Eden G TenBarge, Ashley D Wise, Morgan L Hetzel, Helene A Hoover, Helia Esfandiari, Bailey E Holder, Eva Belevska, Ellie C Mennen, Sarah R McDaniel, Nicole M Vaccaro, Courtney C Lucca, Jonathan M Williams, Jennifer Ferris, Timothy E Sparer, Leslie J Crofford, Jeffry D Bieber, Andrew J Monteith.
      Patients with systemic lupus erythematosus (SLE) are susceptible to bacterial infections, but the mechanisms remain unclear. We found that Staphylococcus aureus triggers mitochondria-dependent suicidal neutrophil extracellular trap (NET)osis through lactate sensing in healthy neutrophils, whereas this response is defective in SLE. Sustained Toll-like receptor (TLR) 7/9 signaling reduced mitochondrial lactate dehydrogenase B (LDHB), thereby impairing lactate sensing and suicidal NETosis. Instead, SLE neutrophils were biased toward vital NET release, a less bactericidal, type I interferon (IFN)-driven process initiated by staphylococcal pore-forming toxins and amplified by elevated systemic IFNα. In lupus-prone mice, combined hydroxychloroquine (HCQ) and interferon-alpha/beta receptor (IFNAR) blockade restored LDHB expression, rebalanced suicidal and vital NET responses, and improved bacterial clearance. Neutrophils from SLE patients showed similar defects that were reversed by HCQ and the IFNAR-blocking antibody anifrolumab. These findings define an immunometabolic checkpoint linking chronic autoimmune signaling to defective antibacterial defense in SLE and identify therapeutic routes to restore innate immunity.
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100080
  21. Biomed J. 2026 Sep 18. pii: S2319-4170(26)00096-X. [Epub ahead of print] 101040
    Dose-dependent arginine availability is associated with metabolic remodeling and immune phenotypes during development.
    Yu-Tsun Su, Mao-Meng Tiao, Yun-Ju Lai, You-Lin Tain, Chien-Ning Hsu, I-Chun Lin, Chih-Hao Chang, Chih-Yung Chiu, Hong-Ren Yu.
       BACKGROUND: L-Arginine is a semi-essential, functional amino acid crucial for fetal growth, metabolic regulation, and early-life immune ontogeny. However, how variations in maternal arginine availability influence neonatal metabolic remodeling and long-term immune development remains incompletely understood.
    METHODS: Female Sprague-Dawley rats were fed amino acid-defined diets with graded arginine levels during gestation and lactation. Neonatal hepatic metabolism was profiled by 1H NMR-based metabolomics, and splenic immune responses and immune cell populations were evaluated in neonatal and adult offspring.
    RESULTS: Arginine availability was associated with differences in neonatal hepatic metabolite profiles. A physiological level (6 g/kg diet) was associated with a balanced metabolic state, whereas deficiency (0 g/kg) and higher intake (24 g/kg) were associated with altered metabolic profiles. Deficiency was associated with features consistent with a catabolic state, including increased ketone bodies. Higher intake was associated with altered amino acid metabolism, including elevations in branched-chain amino acids and lactate. These metabolic patterns were accompanied by coordinated alterations in immune parameters that persisted into adulthood.
    CONCLUSION: Arginine availability was associated with non-linear, dose-dependent metabolic alterations and coordinated immune phenotypes during development, providing insight into the association between early-life metabolic remodeling and long-term immune programming.
    Keywords:  amino acid metabolism; arginine; developmental programming; immune development; immunometabolism; maternal nutrition; metabolomics
    DOI:  https://doi.org/10.1016/j.bj.2026.101040
  22. Int J Mol Sci. 2026 Aug 27. pii: 7664. [Epub ahead of print]27(17):
    Targeting PKM2 Enhances the Anti-Tumor Function of CD8+ T Cells Through Metabolic Reprogramming.
    Junxiu Zhang, Shuyi Wu, Qin Yin, Yanglin Liu, Shuguo Zheng, Peiwei Yang.
      The efficacy of adoptive cell transfer (ACT) therapy in solid tumors is often limited by the functional exhaustion and insufficient persistence of infused CD8+ T cells within the tumor microenvironment. Through the integrated analysis of single-cell transcriptomic data, this study identified enolase 1 (ENO1), a key rate-limiting enzyme in glycolysis, as a core gene highly correlated with the superior anti-tumor phenotype of tumor-infiltrating lymphocytes (TILs). However, in vitro functional validation demonstrated that the overexpression of Eno1 failed to substantially enhance the anti-tumor efficacy of mouse T cells, suggesting the presence of a downstream metabolic regulatory node within the glycolytic cascade that restricts the conversion of carbon flux. To overcome this limitation, we introduced the small molecule activator TEPP-46 to target a crucial downstream metabolic hub, pyruvate kinase M2 (PKM2). Transcriptome sequencing confirmed that PKM2 activation successfully induced systemic metabolic rewiring in CD8+ T cells and broadly upregulated the expression of cytotoxicity- and memory-related genes. In an in vivo B16-OVA melanoma model, OT-1 T cells subjected to In vitro TEPP-46 pretreatment exhibited significantly enhanced tumor-suppressive capabilities and effectively promoted the preferential differentiation of T cells into central memory T cells (Tcm). In summary, this study highlights the importance of targeting downstream metabolic nodes to bypass intrinsic metabolic restrictions in T cells. It demonstrates that in vitro metabolic pretreatment via PKM2 activation represents an effective translational strategy for optimizing the anti-tumor efficacy of ACT cell products.
    Keywords:  CD8+ T cells; adoptive cell transfer; enolase 1; glycolysis; metabolic reprogramming
    DOI:  https://doi.org/10.3390/ijms27177664
  23. Int Immunopharmacol. 2026 Sep 12. pii: S1567-5769(26)01232-4. [Epub ahead of print]189 117385
    Macrophage HDAC3 drives obesity and adipose tissue metabolic maladaptation through GDF3-mediated inflammation and chromatin remodeling.
    Yulin Zhang, Ye Chen, Jia Liu, Yan Liu, Rongrong Zhan, Xinyi Tao, Haoran Chen, Hao Dong, Wenjie Lu, Qichao Luo, Shan Gao, Qin Kong.
      Chronic inflammation is a hallmark of obesity and its associated metabolic disorders. Adipose tissue macrophages (ATMs) play a crucial role in maintaining tissue homeostasis and orchestrating metabolic inflammation. Importantly, the regulation of proinflammatory gene translation is critical for macrophage activation, a process that has been closely linked to the onset of insulin resistance and type 2 diabetes. Histone deacetylase 3 (HDAC3) is a contributing factor of inflammatory gene expression; however, its precise role in modulating adipose tissue inflammation and type 2 diabetes remains poorly understood. This study demonstrates that metabolically stressed-induced HDAC3 mediates ATMs inflammation. HDAC3 deficiency in macrophages reduces adipose tissue macrophage infiltration and fibrosis, improves hyperglycemia, and reduced weight gain, adiposity in diet-induced obesity mice. HDAC3 deficiency mitigated the chronic inflammation and fibrosis in adipose tissue by suppressing inflammatory cytokine production via H3K4Me3/H3K27Ac-mediated chromatin remodeling. Mechanistically, growth differentiation factor 3 (GDF3) functions as a sensor of metabolic stress, interacts with HDAC3 through histone modification-mediated chromatin remodeling of inflammation genes. Critically, HDAC3 and GDF3 co-expression increased in adipose tissue/ATMs of obese humans, correlating positively with BMI, blood glucose, and proinflammatory gene levels. Our finding identifies HDAC3 as a molecular nexus connecting ATMs activation to systemic insulin resistance and type 2 diabetes. The GDF3-HDAC3 axis drives transcriptional reprogramming through H3K4Me3/H3K27Ac modifications, revealing a novel therapeutic target for obesity-associated metabolic disease.
    Keywords:  Adipose tissue; GDF3; HDAC3; Inflammation; Macrophage
    DOI:  https://doi.org/10.1016/j.intimp.2026.117385
  24. J Clin Invest. 2026 Sep 15. pii: e202344. [Epub ahead of print]
    Acute activation of Gq-signaling in pancreatic islet macrophages inhibits insulin secretion through AMPK-sphingolipid axis.
    Simran Singh, Ashish Kumar, Sudipta Paul, Mriganka Sarkar, Santhosh Duraisamy, Ganesh Timalsina, Raashidha Farhath, Harender Yadav, Seema Kuldeep, Soumita Bhaumik, Kunj Kumar Prajapati, Saahiba Thaleshwari, Anuj Gargya, Tamojit Santra, Sonal Amit, Rashmi Parihar, Santosh K Misra, Hamim Zafar, Luiz F Barella, Michael A Kalwat, Dharmaraja Allimuthu, Sai Prasad Pydi.
      Obesity-associated inflammation impairs pancreatic β-cell function, yet the mechanisms by which immune cells acutely regulate insulin secretion remain poorly defined. Here, we identify myeloid Gq signaling as an immunometabolic node linking macrophage lipid sensing to impaired insulin secretion. Using chemogenetic DREADD-mediated activation of myeloid Gq, we show that acute macrophage Gq activation impairs glucose-stimulated insulin secretion (GSIS) in vivo, whereas myeloid Gαq ablation enhances GSIS. Mechanistically, Gq activation rapidly induced AMPK phosphorylation and sphingolipid remodeling independently of canonical inflammatory cytokines. Macrophage-derived sphingolipids impaired β-cell insulin signaling and GSIS through CD36-PKCζ, while inhibition of CD36, AMPK, or sphingolipid metabolism restored β-cell function. We further identified GPR18, a Gq-coupled endocannabinoid-responsive GPCR, as an upstream regulator. GPR18 activation with N-arachidonoyl glycine (NAGly) recapitulated this phenotype, whereas myeloid Gαq deletion or Gpr18/AMPK silencing abolished it. GPR18 signaling predominantly engaged Gq rather than Gi pathways. In human tissues, GPR18 was enriched in islet macrophages, and NAGly suppressed GSIS in primary human islets. Thus, a conserved macrophage GPR18-Gαq-AMPK-sphingolipid axis dynamically regulates β-cell function and represents a potential therapeutic target in obesity and type 2 diabetes.
    Keywords:  Beta cells; Endocrinology; G protein-coupled receptors; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI202344
  25. Mucosal Immunol. 2026 Sep 18. pii: S1933-0219(26)00107-8. [Epub ahead of print] 100405
    Microbiota-derived tryptophan metabolites shape Th2 lymphocyte responses via the aryl hydrocarbon receptor and metabolic reprogramming.
    Lu Yao, Tanya Guevara Avella, Abhijeet J Kulkarni, Marlinde Waardenburg, Maria Isabel Delgado-Dolset, Tomasz Wypych, Avril Walters, Kristoff Nieves, Hannah Devotta, Songhui Kim, Emer Shannon, Nonhlanhla Lunjani, Jens Walter, Milena Sokolowska, Liam O'Mahony.
      Allergic diseases are linked with changes in gut microbiota composition and metabolism, but the direct mechanisms linking microbial metabolism to T helper 2 (Th2) lymphocyte differentiation are still poorly understood. Colonization of gnotobiotic animals with Bifidobacterium longum and Clostridium sporogenes resulted in high levels of tryptophan-derived indole-3-lactic acid (ILA), indole-3-acrylic acid (IA), and indole-3-propionic acid (IPA), which correlated with suppressed Th2 responses. Indoxyl-3-sulfate (I3S) and IA reduced interleukin (IL)-4, IL-5 and IL-13 secretion from human Th2 polarized lymphocytes in an aryl-hydrocarbon receptor (AHR)-dependent manner. IA and IPA induced broader metabolic rewiring by reducing Th2 cell mitochondrial oxidative phosphorylation and reactive oxygen species damage. Microbial tryptophan metabolism may modulate human Th2 cell polarization, differentiation and function thereby linking allergy development to microbial processes. In addition, we have identified novel links between mitochondrial metabolic programs and Th2 lymphocyte polarization that are impacted by the microbial Stickland pathway derived metabolites IA and IPA.
    Keywords:  Allergy; Indoles; Metabolism; Mitochondria; Th2; Tryptophan
    DOI:  https://doi.org/10.1016/j.mucimm.2026.100405
  26. Cytokine Growth Factor Rev. 2026 Sep 12. pii: S1359-6101(26)00064-X. [Epub ahead of print]92 101525
    Mechanism and clinical relevance of metabolic-immune cross-talk in pancreatic tumor microenvironment.
    Jonaid Ahmad Malik, Mamatha Jatavath, Melissa L Fishel, Rakesh Bhatia, Shailendra K Gautam.
      Metabolic stress-induced immunosuppression begins as early as the precancerous stage in pancreatic ductal adenocarcinoma (PDAC), increases with disease progression, and is characterized by the abundant suppressive myeloid and lymphoid cells. Metabolic adaptation and reprogramming are critical for the survival and function of tumor-infiltrating immune cells. In particular, cytotoxic T cells and natural killer (NK) cells, the stalwarts of cell-mediated immunity, often fail to adapt to the metabolically distinct pancreatic tumor microenvironment (TME) and thus perform antitumor activities poorly, leading to immune exhaustion, aggressive disease progression, metastasis, and poor immunotherapy outcomes. This review article explores the intricate metabolic-immune crosstalk, mediated by tumor microenvironment-associated factors, that impacts the metabolic fitness and effector functions of infiltrating immune cells, including cytotoxic T cells, NK cells, and myeloid cells that bridge innate and adaptive immunity. In addition, we discuss how genetic, molecular, and stromal factors drive metabolic alterations in nutrient-deficient pancreatic tumors, leading to immune cell dysfunction, impaired cytokine release, and poor antitumor immunity. This review further emphasizes the selective targeting of metabolic stress-driven immunosuppressive pathways, unresolved questions, and future directions, including how spatial nutrient gradients across the TME shape distinct regional immune phenotypes, how metabolic interactions with tumor and immune cells occur, and how tumor-selective metabolic therapies could be engineered to exploit features such as hypoxia and acidosis. Understanding these metabolic interactions is crucial for advancing personalized immunotherapy approaches, including immune checkpoint blockade therapies, CAR-T, and other adoptive immune cell therapies, which could improve clinical outcomes in PDAC patients.
    Keywords:  And T cell exhaustion.; CAR-T cells; Immune metabolism and metabolic reprogramming; Immunotherapy resistance; Pancreatic cancer; Stroma modulation
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.08.005
  27. Signal Transduct Target Ther. 2026 Sep 14. pii: 380. [Epub ahead of print]11(1):
    IFNAR1-dependent metabolic circuit drives pathogenic neutrophil activation in chronic mucosal inflammation.
    Cecilia Pessoa Rodrigues, Raquel R Calçada, Mafalda Arnaud, Lukas Kaltenbach, Mika Manser, Anja Scheidegger, Leon Sidney Strauss, Alina Gavrilov, Sharang Kulkarni, Ece Yildiz, Daniela Liberati, Mairene Coto-Llerena, Tamara Hoening, Markus Martin Kramberg, Julian Behr, Anna Mechling, Marvin Hering, Kara G Lassen, Oliver Soehnlein, Emma Doran, Daniel Regan-Komito.
      Neutrophils are double-edged effectors of the innate immune system: while essential for host defense, they can drive significant tissue damage in the context of chronic inflammatory diseases. Identifying strategies to selectively dampen their pathogenic functions without compromising antimicrobial immunity remains a major clinical challenge. Here, we define a conserved IFNAR1-driven circuit mediated by iron homeostasis that sustains neutrophil pathogenicity across distinct mucosal tissues. Using single-cell transcriptomics and a CRISPR-based functional screen, we identified the mitochondrial iron transporter Mitoferrin-1 (SLC25A37) as a key regulator of neutrophil inflammatory programming. Mechanistically, our data indicate that Mitoferrin-1 mediates a feedforward loop in which NET-derived histones activate toll-like receptor 9 (TLR9), which in turn sustains IFN-α/IFNAR1 signaling, rewires mitochondrial metabolism, and ultimately drives tissue damage through markedly increased of NETosis, reactive oxygen species production, and degranulation. Notably, this IFNAR1-driven inflammatory circuit operates entirely independently of antimicrobial function, as pharmacological IFNAR1 blockade fully preserves phagocytic activity against bacterial pathogens in vivo. Targeting this pathway selectively attenuates neutrophil-driven inflammation in both murine models of colitis and acute lung injury, as well as in primary human intestinal organoid systems. Together, these findings identify a targetable metabolic node for selectively disarming pathogenic neutrophil responses in the setting of chronic inflammatory disease.
    DOI:  https://doi.org/10.1038/s41392-026-02963-3
  28. Chin Med J (Engl). 2026 Sep 14.
    Lysophosphatidylcholine-induced macrophage polarization imbalance and functional dysregulation in immune thrombocytopenia.
    Nan Jiang, Zi Sheng, Shaoqiu Leng, Xiaoyu Zhang, Xinyue Liu, Rosa Ayala Diaz, Joaquín Martínez-López, Yanqi Zhang, Xiang Hu, Shuai Liu, Shuqian Xu, Jun Peng, Yan Liu, Shuwen Wang.
       BACKGROUND: The pathogenesis of immune thrombocytopenia (ITP) involves platelet destruction driven by immune dysregulation, notably macrophage dysfunction. Lysophosphatidylcholine (LPC), a class of bioactive lipid, can modulate inflammation and immunity. This study aimed to determine whether LPC (16:0/0:0) reprograms macrophage metabolism and function in ITP, and to evaluate the therapeutic efficacy of dexamethasone (DXM) and atorvastatin (AT).
    METHODS: Bone marrow (BM) samples were collected from 61 patients with ITP and 46 healthy controls (HCs) at Qilu Hospital of Shandong University between July 2023 and June 2025. Flow cytometry was used to assess macrophage subsets. Untargeted metabolomics and transcriptomics were performed on sorted BM macrophages. The in vitro effects of LPC (16:0/0:0) on interleukin-10 (IL-10) expression, phagocytosis, and T-cell differentiation, as well as the impact of DXM, AT, or their combination, were tested. Passive and active ITP murine models were used for in vivo validation.
    RESULTS: ITP patients had significantly elevated M1 macrophages and decreased IL-10 levels compared to HCs. Integrated metabolomic and transcriptomic analyses revealed enrichment in the glycerophospholipid metabolism pathway, identifying LPC (16:0/0:0) as the most significantly elevated metabolite. Elevated LPC (16:0/0:0) levels correlated with severe thrombocytopenia. In vitro , LPC (16:0/0:0) suppressed IL-10 secretion by macrophages and enhanced M1 macrophage phagocytosis of platelets. It also reduced regulatory T cells (Treg) proportions and increased helper T cell (Th) 1, Th2 and Th22 differentiation. Treatment with DXM or AT restored IL-10 levels and inhibited phagocytosis; DXM suppressed Th1 and Th2 differentiation, AT restored Treg proportions. In vivo , LPC (16:0/0:0) decreased platelet counts and promoted M1 macrophage polarization. DXM and AT promoted platelet recovery and macrophage repolarization, with combination therapy demonstrating superior efficacy.
    CONCLUSIONS: LPC (16:0/0:0) drives ITP pathogenesis by reprogramming macrophage metabolism and function, promoting inflammation and platelet destruction. The DXM-AT combination exerts synergistic therapeutic effects by complementary targeting of metabolic and immune pathways in the LPC-driven pathogenic axis, effectively restoring immune homeostasis.
    Keywords:  Atorvastatin; Dexamethasone; Immune thrombocytopenia; Lysophosphatidylcholine; Macrophage; Metabolic reprogramming
    DOI:  https://doi.org/10.1097/CM9.0000000000004172
  29. Gut. 2026 Sep 16. pii: gutjnl-2025-337367. [Epub ahead of print]
    HBV induces immunosuppressive macrophages via metabolic and epigenetic reprogramming to facilitate the establishment of chronic persistent infection.
    Zhengmin Wang, Nan Liu, Yongqi Li, Tianyang Li, Licong Ma, Zhongfeng Wang, Xinyang Li, Yun Dai, Tong Zhang, Zhiheng Guo, Yao Zhi, Faxiang Ma, Juan Lv, Yanhang Gao, Junqi Niu, Yang Yang, Zhengkun Tu.
       BACKGROUND: Hepatitis B virus (HBV) induces hepatic immunosuppressive macrophages to facilitate chronic infection but the mechanisms remain unclear. Metabolic and epigenetic reprogramming during monocyte differentiation into macrophages has also been observed in bacterial infection and Bacillus Calmette-Guerin (BCG) vaccination, shaping tolerant or trained macrophages.
    OBJECTIVE: To investigate whether HBV modulates monocyte-to-macrophage differentiation via metabolic-epigenetic reprogramming.
    DESIGN: Monocytes from chronic HBV-infected patients, healthy controls and cord blood were differentiated into macrophages (monocyte-derived macrophages and cord blood monocyte-derived macrophages). Cytokine expression and secretion, metabolic and epigenetic changes and immunomodulatory functions were characterised by qRT-PCR, ELISA, Western blotting, immunofluorescence, multiplexed immunohistochemistry, immunoprecipitation, metabolite measurements, ChIP-seq, ChIP-qPCR assay, plasmid transfection, reanalysed scRNA-seq and flow cytometry.
    RESULTS: MDMs from CHB patients showed higher IL-10 and lower TNF-α than healthy donors ex vivo. HBV employed its surface antigen (HBsAg) to strongly influence cord blood but not adult monocyte differentiation into such an immunosuppressive macrophage in vitro. This occurred via post-translational modification of histone H3 on residue K18 (H3K18). HBsAg-pyruvate kinase M2 (PKM2) dimer interaction promoted PKM2/LDHA-driven lactate production, enhancing H3K18 lactylation at the IL-10 promoter and increasing IL-10 secretion. Meanwhile, phosphorylation of STAT1 is shifted with increased serine 727-phosphate but decreased tyrosine 701-phosphate via the p38/AKT pathway. It triggers the CD38/NAD+/SIRT1 axis, reducing H3K18 acetylation at the TNF-α promoter and suppressing TNF-α synthesis. Moreover, HBV-educated immunosuppressive macrophages inhibited NK cell IFN-γ production and promoted HBV replication in hepatocytes.
    CONCLUSIONS: HBV controls monocyte-to-macrophage fate via HBsAg-mediated metabolic-epigenetic-immune cascades to facilitate chronic persistent infection. These metabolic-epigenetic axes represent potential therapeutic targets.
    Keywords:  EPIGENETICS; GLUCOSE METABOLISM; HEPATITIS B; LIVER IMMUNOLOGY; MACROPHAGES
    DOI:  https://doi.org/10.1136/gutjnl-2025-337367
  30. Sci Adv. 2026 Sep 18. 12(38): eaeb4813
    Metabolic sensor AMPK licenses intestinal CD103+ DCs to induce Treg responses.
    Thiago A Patente, Julian van Duijvenvoorde, Graham A Heieis, Eline C Brombacher, Leonard R Pelgrom, Joost Lambooij, Anna Zawistowska-Deniziak, Martina Erbì, Frank Otto, Arifa Ozir-Fazalalikhan, Sara Barnhoorn, José J Fernández, Johan van der Reijden, Alwin J van der Ham, Lukas J A C Hawinkels, Bruno A Guigas, José A M Barbuto, Rick M Maizels, Bart Everts.
      Intestinal dendritic cells (DCs) play a central role in maintaining gut tolerance through priming of peripheral regulatory T cells (pTreg cells). DC tolerogenicity has been linked to catabolic metabolism, but the role of AMP-activated kinase (AMPK), a key regulator of catabolic metabolism, in regulating intestinal tolerance remains unclear. We found high AMPK activation in intestinal DCs, and loss of AMPKα1 in CD11c-expressing cells (CD11cΔAMPKα1) led to reduced frequencies of intestinal RALDH+ CD103+ cDC2s. This was associated with reduced pTreg cell induction and consequently increased type 2 immunity in models of intestinal helminth infection. Correspondingly, CD103+ cDC2s from helminth-infected CD11cΔAMPKα1 mice failed to prime Treg cells ex vivo. Similarly, Treg cell induction by AMPK-deficient human retinoic acid (RA)-induced tolerogenic CD103+ DCs was compromised. Mechanistically, AMPK underpinned RA-driven tolerogenicity by promoting RALDH activity and TGF-β secretion in a FoxO3-dependent manner, independent from metabolic reprogramming. Our findings identify AMPK as a key regulator of intestinal DC-mediated tolerance and as a therapeutic target to counter intestinal inflammatory disease.
    DOI:  https://doi.org/10.1126/sciadv.aeb4813
  31. EMBO Rep. 2026 Sep 18.
    Coenzyme A activates TLR4 and enhances alternative macrophage activation in line with MyD88 agonism.
    Anthony E Jones, Amy Rios, Neira Ibrahimovic, Andréa B Ball, Carolina Chavez, Nicholas A Bayley, Natalie A Falta, Marisa Mekkittikul, Clarissa Carrillo, Wei Yuan Hsieh, Alessandro Sammarco, Amber B Reyes, Angel A Cortez, Thomas G Graeber, Richard L Watson, Alexander Hoffmann, Steven J Bensinger, Ajit S Divakaruni.
      Metabolites and metabolic cofactors can shape the innate immune response, though the pathways by which these molecules adjust inflammation remain incompletely understood. Here we show that the metabolic cofactor coenzyme A (CoA) enhances IL-4 driven alternative macrophage activation [M(IL-4)] in vitro and in vivo. Unexpectedly, we find that perturbations in intracellular CoA metabolism do not influence M(IL-4) differentiation. Rather, we discover that exogenous CoA is a weak TLR4 agonist which primes macrophages for increased receptivity to IL-4 signals and resolution of inflammation via MyD88. Mechanistic studies reveal MyD88-linked signals enhance IL-4 responsiveness, in part, by reshaping chromatin accessibility to enhance transcription of IL-4-linked genes. The results identify CoA as a host metabolic co-factor that influences macrophage function through an extrinsic TLR4-dependent mechanism and suggest that damage-associated molecular patterns (DAMPs) can prime macrophages for alternative activation and resolution of inflammation.
    DOI:  https://doi.org/10.1038/s44319-026-00925-y
  32. Cell Chem Biol. 2026 Sep 17. pii: S2451-9456(26)00289-8. [Epub ahead of print]33(9): 1252-1269.e5
    Nitrated fatty acids form membrane biochemical capacitors that restrain inflammation.
    Nicole Colussi, Sonia R Salvatore, Matias M Vazquez, Maria V Gutierrez, Scott Hahn, Karina Ricart, Felipe Vendrame, Matias Badino, Agustina L Schopfer, Dario A Vitturi, Luis Villacorta, Rakesh P Patel, Amit Gaggar, Carsten Skarke, Adam C Straub, Francisco J Schopfer.
      Nitrated fatty acids (NO2-FAs) are electrophilic lipid mediators that suppress inflammatory signaling, yet the sources, storage mechanisms, and physiological functions of endogenous NO2-FAs remain poorly understood. Here, we identify nitro-conjugated linoleic acid (NO2-CLA) as a diet-derived anti-inflammatory lipid that accumulates in membrane phospholipids and functions as a mobilizable biochemical reserve. Using cellular, murine, and human models, we show that phospholipids store NO2-CLA under basal conditions and rapidly release it during inflammatory stress through phospholipase-dependent remodeling. Mobilized NO2-CLA dampens cytokine production, limits inflammatory mediator formation, and preserves vascular homeostasis during endotoxemia. In both experimental inflammation and human sepsis, tissue and circulating pools of NO2-CLA become depleted, indicating that consumption exceeds endogenous replenishment during acute inflammatory responses. These findings establish membrane phospholipids as reservoirs of endogenous NO2-FAs and reveal a previously unrecognized mechanism by which diet, lipid metabolism, and redox signaling converge to regulate inflammation.
    Keywords:  anti-inflammatory; conjugated linoleic acid; endotoxemia; lipid mediator; nitrated fatty acids; phospholipids
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.002
  33. Adv Healthc Mater. 2026 Sep 18. e71727
    Mitochondria-Targeted Nanozyme Reprograms Dendritic-Cell Immunometabolism via Microenvironment-Responsive CO Release to Treat Periodontitis.
    Shangyan Shan, Chengyu Liu, Lina Ding, Weishu Zeng, Haoran Cui, Jia Liu, Meiqi Li, Xu Ding, Biao Dong, Liang Cheng, Manlin Qi, Lin Wang.
      Inflammatory diseases are characterized by overactivated immune responses and a disrupted metabolic equilibrium, particularly in dendritic cells (DCs), where mitochondrial reactive oxygen species (mtROS) burst and metabolic reprogramming drives pathological maturation. While modulating immunometabolism is a promising therapeutic avenue, achieving subcellular-targeted delivery of bioactive molecules remains a formidable challenge. Here, we report a mitochondria-targeted nanozyme designed to concurrently scavenge mtROS and reprogram DC metabolism for effective anti-inflammatory therapy in periodontitis. This system is constructed based on Prussian blue nanoparticles (PB NPs) loaded with manganese carbonyl, a high oxidative stress-responsive carbon monoxide (CO) donor, and further modified with triphenylphosphine for mitochondrial targeting. This nanozyme efficiently accumulates in the mitochondria of activated DCs, where it efficiently scavenges mtROS and concurrently delivers controlled CO release, synergistically modulating DC function. Metabolomics analysis reveals that CO suppresses DC maturation by reprogramming cellular metabolism, including inhibiting the tricarboxylic acid cycle, modulating glycolysis, and disrupting fatty acid synthesis. Consequently, the synergistic action of PB NPs and CO effectively reverses the pro-inflammatory phenotype of DCs, reshapes the immune microenvironment, and ultimately alleviates periodontal inflammation in vivo. This work presents a promising strategy for curing inflammatory diseases by targeting metabolic reprogramming at the subcellular level.
    Keywords:  chronic inflammation; dendritic cell maturation; immunometabolism; mitochondria targeting; nanozyme; stimulus‐responsive release
    DOI:  https://doi.org/10.1002/adhm.71727
  34. Front Cardiovasc Med. 2026 ;13 1886093
    Mitophagy-pyroptosis-macrophage polarization crosstalk in cardiovascular diseases: mechanistic insights and therapeutic potential.
    Jieying Yuan, Tingru Ji, Ruquan Chen, Yuesong Yuan, Lin Ji.
      Cardiovascular disease (CVD) is one of the leading causes of global morbidity and mortality. Its development and progression are closely associated with mitochondrial dysfunction, sterile inflammation, and immunometabolic dysregulation. Mitophagy, a key mechanism of mitochondrial quality control, maintains mitochondrial homeostasis by selectively removing damaged mitochondria. However, either insufficient or excessive mitophagy may disrupt cellular metabolism, promote ROS production and mitochondrial DNA (mtDNA) release, and activate inflammatory signaling pathways, thereby aggravating cardiovascular injury. Increasing evidence indicates that mitophagy is closely linked to pyroptosis and macrophage polarization. Impaired mitophagy can enhance inflammasome activation and gasdermin-mediated pyroptosis. In turn, inflammatory mediators released during pyroptosis may further impair mitochondrial quality control, forming a self-amplifying inflammatory loop. Meanwhile, mitophagy regulates macrophage metabolic reprogramming and phenotypic switching, thereby influencing the balance between pro-inflammatory M1-like responses and reparative M2-like functions. This review summarizes the molecular mechanisms underlying the crosstalk among mitophagy, pyroptosis, and macrophage polarization in CVD, with particular emphasis on myocardial infarction (MI) and myocardial ischemia-reperfusion injury. Current evidence suggests that restoring appropriate mitophagic flux, inhibiting aberrant pyroptosis, and reshaping macrophage phenotypes may help alleviate inflammatory injury and adverse cardiac remodeling. This review aims to provide a mechanistic framework for immunometabolic regulation in CVD and to support the development of precision therapeutic strategies targeting mitochondrial quality control and inflammatory cell responses.
    Keywords:  cardiovascular disease; immunometabolic regulation; macrophage polarization; mitochondrial quality control; mitophagy; pyroptosis
    DOI:  https://doi.org/10.3389/fcvm.2026.1886093
  35. Front Oncol. 2026 ;16 1873614
    The role of glutamine metabolism in the pathogenesis of idiopathic pulmonary fibrosis and its therapeutic potential.
    Junzi Li.
      Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease characterized by usual interstitial pneumonia, relentless decline in lung function and incomplete disease modification by available antifibrotic therapies. Beyond canonical profibrotic pathways, accumulating evidence identifies aberrant glutamine metabolism as a convergent metabolic feature of IPF pathogenesis. In structural cells, glutaminolysis fuels myofibroblast activation, de novo glycine and proline synthesis for collagen, whereas epithelial glutamine utilization may support antioxidant defence, mitochondrial adaptation and repair. In immune cells, glutamine shapes macrophage and T-cell polarization and may contribute to an inflammatory, profibrotic microenvironment. Glutamine-derived intermediates intersect with mTOR/AMPK and TGF-β/Smad signalling and act as cofactors for epigenetic regulators, thereby stabilizing apoptosis-resistant, profibrotic transcriptional programmes. Experimental models and human studies further demonstrate upregulation of glutamine transporters and glutaminase 1 (GLS1) in fibrotic lungs, protection from bleomycin-induced fibrosis after genetic or pharmacologic GLS1 inhibition, and a genetic association between lower circulating glutamine and increased IPF risk. Importantly, the effects of glutamine metabolism are context- and cell type-dependent: epithelial and immune glutamine utilization may support repair, barrier integrity and host defence, whereas excessive fibroblast-directed glutaminolysis promotes matrix accumulation. Building on these observations, this review synthesizes current knowledge on cell type-relevant glutamine metabolism in lung fibrosis, distinguishes direct lung-fibrosis evidence from extrapolated mechanistic evidence, delineates its integration with fibrogenic signalling, oxidative stress, mitochondrial stress and immunometabolism, and critically evaluates the therapeutic potential and caveats of targeting glutamine uptake, catabolism and nutrient-sensing pathways as adjuncts to existing antifibrotic regimens.
    Keywords:  glutamine metabolism; glutaminolysis; idiopathic pulmonary fibrosis; immunometabolism; mTOR/AMPK; myofibroblast
    DOI:  https://doi.org/10.3389/fonc.2026.1873614
  36. Immunol Cell Biol. 2026 Sep 16.
    Hypercapnia Induces Mitochondrial Adaptations and Alters Glutamine Metabolism to Drive a Distinct Metabolic Phenotype in Monocytes.
    Ben Reddan, David E Phelan, Xiaofei Yin, Lorraine Brennan, Martina Wallace, Eoin P Cummins.
      Carbon dioxide (CO2) is an ancient and ubiquitous physiological gas generated during aerobic respiration. Historically viewed as a simple metabolic waste product, CO2 has received far less research attention than oxygen (O2), the primary substrate of aerobic respiration. However, emerging evidence has revealed important roles for CO2 in immunometabolism, immunology, muscle physiology, and clinical medicine. While circulating pCO2 levels are tightly regulated, patients with lung diseases such as chronic obstructive pulmonary disease (COPD) frequently develop hypercapnia, pCO2 > 45 mmHg. Hypercapnia is associated with significantly increased mortality, higher risk of ICU admission, and a global prevalence estimated at 13-15 million patients. Its broader clinical consequences remain poorly understood and are inadequately integrated into current therapeutic paradigms. Here, we examined the impact of hypercapnia on the metabolic profile of monocytes. We demonstrate that 24 h of buffered hypercapnia induces a marked reduction in mitochondrial mass. This is accompanied by dysregulation of mitochondrial membrane potential and key bioenergetic substrates (NADH/NAD+ and ATP content). We further show that hypercapnia alters the abundance of metabolites and proteins associated with mitochondrial metabolism, with effects spanning glucose, glutamine, and lipid metabolism. Thus, we provide direct mechanistic evidence that hypercapnia directly alters the glutamine-glutamate-proline synthesis axis. Collectively, these findings establish the foundation for a discrete hypercapnic metabolic phenotype, that is, in several respects, distinct from the metabolic adaptations observed in hypoxia. We propose that hypercapnia triggers a cascade of metabolic adaptations with tissue-dependent consequences on cellular effector functions.
    DOI:  https://doi.org/10.1111/imcb.70162
  37. J Immunol. 2026 Aug 29. pii: vkag179. [Epub ahead of print]215(9):
    Scopolamine ameliorates psoriasis by blocking M1 receptor-mediated IL-23 production in dendritic cells.
    Yue Wu, Ziyang Zhang, Xiaojie Cai, Yang Sun, Fangzhou Lou, Zhikai Wang, Yan Li, Xichen Zheng, Xiuli Yang, Wenxiang Ding, Zilong Fang, Jing Zou, Zhenyao Xu, Siyu Deng, Aie Xu, Buwei Yu, Qifang Li, Honglin Wang.
      Psoriasis is a chronic inflammatory skin disease involving intricate neuroimmune crosstalk. However, the specific mechanisms and therapeutic targets remain elusive. In this study, a pilot clinical trial demonstrated that intravenous scopolamine, a muscarinic receptor antagonist, significantly ameliorated skin lesions in psoriasis patients. Consistently, scopolamine reduced inflammation in an imiquimod-induced mouse model. Metabolomic profiling identified acetylcholine (ACh) as a significantly upregulated neurotransmitter in psoriatic skin, and exogenous ACh exacerbated inflammatory phenotypes. To pinpoint the cellular target, single-cell RNA sequencing revealed that dendritic cells (DCs), unlike T cells or macrophages, uniquely coexpressed neurointeraction receptors and the pathogenic cytokine Il23a. Mechanistically, scopolamine competitively inhibited ACh binding to M1 muscarinic receptors (M1Rs) on DCs, suppressing interleukin (IL)-23 secretion. This therapeutic efficacy was recapitulated in mice with DC-specific M1R deletion. Crucially, the protective effect of M1R deficiency was abolished by recombinant IL-23 administration, whereas scopolamine failed to inhibit inflammation induced by direct IL-23 injection, confirming its action upstream of cytokine release. Collectively, our findings provide compelling evidence that scopolamine treats psoriasis by antagonizing elevated ACh and blocking M1 receptor-mediated IL-23 release in DCs.
    Keywords:  dendritic cells; neuroimmune crosstalk; psoriasis; scopolamine
    DOI:  https://doi.org/10.1093/jimmun/vkag179
  38. Biology (Basel). 2026 Aug 31. pii: 1469. [Epub ahead of print]15(17):
    Multi-Omics Profiling Identifies Immune-Metabolic Signatures and Gut Microbial Biomarkers in a Murine Model of Mycoplasma pneumoniae Pneumonia.
    Yun Li, Changbai Hu, Yunwei Liu, Jiawen Ye, Tong Zhou, Jiaoxu Shi, Lin Xiao, Lingyun Yang, Dongxuan Li, Lianyu Wang, Xiaoying Wen, Yongyao Yu, Jinghua Yang, Xiaolan Xiao.
      Mycoplasma pneumoniae pneumonia (MPP) is driven by excessive host immune responses and metabolic dysregulation, yet its systemic pathogenesis remains poorly understood. Here, we established a murine MPP via MP (1 × 108 CCU/mL), which faithfully recapitulates clinical features, including interstitial pneumonia, elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and increased alveolar macrophage abundance. Integrating lung transcriptomics and metabolomics, we found that MP infection activates pro-inflammatory cytokines (e.g., cytokine-cytokine receptor interaction, Th17 differentiation, NF-κB signaling) while disrupting fatty acid metabolism. Correlative analyses revealed that downregulated 3'-AMP and CMP-Neu5Ac correlated with elevated pro-inflammatory IL-18/IL-33, whereas upregulated 4-imidazoleacrylic acid correlated with reduced anti-inflammatory IL-12A base on transcriptomic data, suggesting that metabolic reprogramming may exacerbate pulmonary inflammation. Furthermore, 16S rRNA sequencing and fecal metabolomics revealed marked microbiota dysbiosis, enrichment of Marvinbryantia, and depletion of beneficial taxa, alongside altered fecal metabolites, with correlations linking gut microbial shifts and metabolite changes to lung transcript-level inflammatory cytokines, supporting a gut-lung axis involvement in MPP. Collectively, our multi-omics dissection provides a systems-level view of immune-metabolic crosstalk in MP infection, offering mechanistic insights and potential biomarkers for improved diagnosis and therapeutic targeting.
    Keywords:  Mycoplasma pneumoniae pneumonia; biomarkers; gut–lung axis; immune–metabolic crosstalk; multi-omics
    DOI:  https://doi.org/10.3390/biology15171469
  39. Int Immunopharmacol. 2026 Sep 17. pii: S1567-5769(26)01264-6. [Epub ahead of print]189 117417
    Hematopoietic HCAR2 attenuates atherosclerosis by enhancing efferocytosis via AMPK/ABCA1 signaling.
    Jiacheng Chen, Li Jiang, Fengying Zhang, Yan Luo, Bibiao Shen, Zhao Pan, Ping Zhang, ZhengYang Yuan, Yongjun Chen, Yangzhi Xie.
       BACKGROUND: Atherosclerotic plaque progression involves lipid accumulation, inflammation, and impaired efferocytosis, the macrophage mediated clearance of apoptotic cells. HCAR2, a metabolite sensing receptor highly expressed on macrophages, modulates immune metabolic responses, but its role in efferocytosis and atherosclerosis remains unclear.
    METHODS: APOE-/- and bone marrow chimeric mice were fed a high fat diet and treated with HCAR2 agonist MK-6892 or vehicle. Plaque size, composition, and efferocytic activity were assessed. Primary macrophages were evaluated for efferocytosis, lipid metabolism, cytokine release, and cholesterol efflux. Mechanistic studies included transcriptomics, immunoblotting, calcium imaging, and loss of function experiments.
    RESULTS: Compared to APOE-/- controls, APOE-/- mice lacking HCAR2 exhibited larger atherosclerotic plaques with increased lipid deposition, reduced collagen content, decreased smooth muscle cell coverage, and impaired efferocytosis. HCAR2 activation rescued the atherosclerotic phenotype and efferocytosis. Bone marrow transplantation confirmed that hematopoietic HCAR2 deficiency aggravated atherosclerosis. An in vitro study confirmed that HCAR2 restricted foam cell formation, inhibited the release of pro-inflammatory cytokines, promoted cholesterol efflux, and enhanced efferocytic activity. Mechanistically, HCAR2 signaling increased intracellular Ca2+ and cAMP levels, activating the downstream Ca2+/CAMKK2/AMPK and PKA/LKB1/AMPK pathways, which subsequently upregulated LXRα/ABCA1 signaling. Lentiviral knockdown of ABCA1 blocked HCAR2-induced enhancement of macrophage efferocytosis, cholesterol efflux, and inflammatory regulation in vitro, indicating that ABCA1 is required for these cellular effects of HCAR2 activation.
    CONCLUSION: HCAR2 activation is associated with enhanced macrophage efferocytosis and reduced atherosclerotic plaque burden, correlating with Ca2+/cAMP-mediated AMPK/ABCA1 pathway engagement. These findings suggest a potential mechanistic link between HCAR2 and efferocytosis, but the causal relationship remains to be established. Notably, the in vivo role of the ABCA1 pathway was not validated in this study.
    Keywords:  ATP-binding cassette transporter A1; Atherosclerosis; Efferocytosis; Hydroxycarboxylic acid receptor 2; Macrophage
    DOI:  https://doi.org/10.1016/j.intimp.2026.117417
  40. Pharmacol Res. 2026 Sep 14. pii: S1043-6618(26)00363-4. [Epub ahead of print]233 108448
    Targeting the ChREBP/PKLR-lactate axis via Huachansu tablets restores CD8⁺T cell immunity in MASH-HCC.
    Yueyue Li, Jingjing Ma, Weitong Peng, Zhengxiang Lv, Xinmeng Liang, Shanshan Li, Manman Wang, Jingjing Su, Shengyong Luo, Wei Gu, Hui Cheng, Chuan Luo, Meng Wang, Qinglin Li.
      The incidence of metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) continues to rise worldwide, highlighting an urgent need for effective therapies. Natural products represent a vital source for anticancer drug discovery. Huachansu tablets (HCS), a clinically approved adjunctive antitumor agent, remain poorly characterized regarding their therapeutic efficacy and molecular mechanisms in MASH-HCC. This study found that HCS markedly suppressed the initiation and progression of MASH-HCC, alleviated metabolic abnormalities within the tumor microenvironment, and restored the antitumor function of CD8⁺T cells. In MASH-HCC mouse models, HCS significantly suppressed tumor progression and reprogrammed the tumor immune microenvironment. Further investigation revealed that HCS substantially reduced the production of tumor derived lactate and associated metabolites, thereby alleviating lactate mediated immunosuppression and restoring CD8⁺T cell effector function and antitumor immunity. Mechanistic studies identified PKLR as a key target through which HCS regulates tumor lactate metabolism. HCS inhibited ChREBP nuclear translocation, thereby downregulating PKLR expression and enzymatic activity, which subsequently attenuated glycolytic flux and reduced lactate production. Rescue experiments confirmed that HCS exerts its immunometabolic reprogramming effects primarily by targeting the ChREBP/PKLR-lactate metabolic axis. Moreover, combining HCS with anti-PD-1 therapy further enhanced CD8⁺T cell function and sensitized MASH-HCC to ICIs. Collectively, our findings reveal that HCS suppresses MASH-HCC progression through the coordinated remodeling of tumor metabolism and the immune microenvironment. Furthermore, the ChREBP/PKLR-lactate axis represents a promising therapeutic target, providing a mechanistic rationale for the clinical application of HCS in this disease.
    Keywords:  Antitumor immunity; CD8(+)T cell; Huachansu tablets; Lactic acid metabolism; MASH-HCC; PKLR
    DOI:  https://doi.org/10.1016/j.phrs.2026.108448
  41. Exp Neurol. 2026 Sep 17. pii: S0014-4886(26)00395-X. [Epub ahead of print] 116028
    Intermittent theta-burst stimulation in ischemic stroke: a mitochondria-centered framework connecting microglial reprogramming and neuronal survival.
    Yue Liu, Yizhuo Zhang, Yingying Huang, Xia Bi.
      Ischemic stroke triggers a mitochondrial metabolic crisis that propagates secondary injury through neuroimmune and neuron-intrinsic mechanisms. Within minutes, collapse of oxidative phosphorylation (OXPHOS) drives succinate accumulation; upon reperfusion, rapid succinate re-oxidation generates a burst of mitochondrial reactive oxygen species (ROS) via reverse electron transport, triggering neuroinflammation, blood-brain barrier disruption, and regulated neuronal death. Intermittent theta burst stimulation (iTBS), a time-efficient repetitive transcranial magnetic stimulation protocol, targets this crisis at a systems level. Preclinical evidence indicates that iTBS restores neurovascular integrity, reprograms microglial activation by suppressing the succinate/hypoxia-inducible factor-1α (HIF-1α)-driven Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB)/ NLR family pyrin domain-containing 3 (NLRP3) inflammasome cascade, and promotes a reparative immune microenvironment. We further propose that restoration of microglial OXPHOS may couple inflammatory resolution to enhanced synthesis of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), forming a metabolic bridge between immune resolution and neuronal survival-a connection assembled from independently supported components but not yet tested as an integrated pathway in the iTBS context. At the neuron-intrinsic level, iTBS suppresses apoptosis via miR-34c-5p/p53/Bax signaling, attenuates ferroptosis by restoring iron homeostasis and antioxidant capacity, and reinforces mitochondrial quality control through transcription factor EB (TFEB)-mediated autophagy. We propose a mitochondria-centered framework wherein mitochondrial homeostasis serves as the central integrative hub linking microglial immunometabolic reprogramming to neuron-intrinsic survival programs. This framework is intended as a hypothesis-generating synthesis rather than a summary of established causal pathways; several of its central links, including the microglial succinate-itaconate axis and the OXPHOS-trophic bridge, remain to be tested directly in iTBS-treated tissue. Preliminary clinical studies report functional improvements across motor, cognitive, language, and swallowing domains, although sample sizes are limited and protocols heterogeneous. We discuss translational challenges including parameter heterogeneity, and note that peripheral markers such as plasma succinate and cell-free mitochondrial DNA warrant exploration as candidate pharmacodynamic indices rather than as a validated response-guided panel.
    Keywords:  Ferroptosis; Immunometabolism; Intermittent theta burst stimulation; Ischemic stroke; Microglial reprogramming; Mitochondrial dysfunction; Neuronal survival; iTBS
    DOI:  https://doi.org/10.1016/j.expneurol.2026.116028
  42. iScience. 2026 Sep 18. 29(9): 117362
    Hippuric acid contributes to NK-cell activation with dependence on TLR2 in chronic hepatitis B complicated by MASLD.
    Luyuan Zhang, Anqi Li, Ke Xu, Siyang Tao, Meijuan Zheng.
      The coexistence of chronic hepatitis B and metabolic dysfunction-associated steatotic liver disease (CHB-MASLD) has been linked to accelerated fibrosis progression and less favorable clinical outcomes, but the immunopathological mechanisms remain incompletely understood. In the present study, we observed that CHB-MASLD patients exhibited significantly increased peripheral natural killer (NK) cell frequency and activation, with transcriptomic analysis revealing enrichment of inflammatory effector gene signatures. Notably, TLR2 was found to be upregulated in NK cells from CHB-MASLD patients and the frequency of TLR2-expressing NK cells correlated with metabolic parameters and liver stiffness. In vitro, metabolic-stress modeling increased TLR2 expression and enhanced NK-cell cytokine production. Untargeted plasma metabolomics identified hippuric acid as a candidate metabolite enriched in CHB-MASLD, and its abundance was associated with metabolic parameters and liver stiffness. Hippuric acid was involved in promoting NK-cell activation, and this effect was partially attenuated by TLR2 blockade. Furthermore, co-culture with hippuric acid-stimulated NK cells was associated with increased activation-related readouts in LX-2 cells, which were partially attenuated by TLR2 blockade. Collectively, these findings support an immunometabolic link among metabolic dysfunction, peripheral NK-cell activation, and a partially TLR2-dependent response to hippuric acid in CHB-MASLD, offering new insights into the immunopathology of CHB-MASLD.
    Keywords:  MASLD; NK cells; chronic hepatitis B; hippuric acid; toll-like receptor 2
    DOI:  https://doi.org/10.1016/j.isci.2026.117362
  43. J Exp Med. 2026 Oct 05. pii: e20241620. [Epub ahead of print]223(10):
    Alox15 restrains glycolysis to support M2 macrophage effector function during helminth immunity.
    Dovran Ovezgeldiyev, Vanessa Trefzer, Rory Doolan, Mati Moyat, Gillian Coakley, Lakshanie C Wickramasinghe, Carmel Daunt, Beatrice Volpe, Fiona Henkel, Alex Serra, Maike Hartmann, Shirin Rezaei, Niki Ubags, Alana Butler, Roxanne Chatzis, Benjamin J Marsland, Adam Alexander T Smith, Deanna Deveson Lucas, Erin N S McGowan, Kathrina J Binger, Malcolm J McConville, Julia Esser-von Bieren, Nicola L Harris, Tiffany Bouchery.
      Macrophage polarization by type-2 cytokines is central to anti-helminth immunity and tissue repair. While some hallmark changes in macrophages are well-characterized and associated with protection against helminths, it is still unclear how macrophages exert their anti-helminth effects. In this context, we investigated arachidonate 15-lipoxygenase (LOX) (Alox15), a LOX well known for its role in macrophage polarization in the context of metabolic diseases, and a hallmark of type-2 macrophage (M2) human polarization. We show that in the absence of Alox15, M2 cannot trap and kill helminths. Surprisingly, expression of M2 markers was normal despite a loss of function. Instead, we found a concomitant increase in pro-inflammatory responses due to an uncontrolled activation of glycolysis. We further show that activation of Peroxisome proliferator-activated receptor-delta (PPAR-δ) by lipids downstream of docosapentaenoic acid (DPA) can restore normal glycolysis control, highlighting a novel role of lipids in the fine-tuning of the metabolic support required for optimal macrophage polarization.
    DOI:  https://doi.org/10.1084/jem.20241620
  44. Nat Metab. 2026 Sep 15.
    Author Correction: Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.
    Hsuan-Chia Chang, Chung-Ying Tsai, Cheng-Lung Hsu, Tzong-Shyuan Tai, Mei-Ling Cheng, Yu-Ming Chuang, Hsiang-Yu Tang, Kun-Ju Lin, Jia-Jin Chen, Szu-Han Chang, Yi-Ching Ko, Yu-Wen Chi, Hsuan Liu, Bertrand Chin-Ming Tan, Chia-Rui Shen, Chih-Wei Yang, Ping-Chih Ho, Huang-Yu Yang.
      
    DOI:  https://doi.org/10.1038/s42255-026-01633-6
  45. Life Sci Alliance. 2026 Dec;pii: e202603852. [Epub ahead of print]9(12):
    Drug-induced metabolic remodeling promotes antimicrobial activity in macrophages and extends longevity in vivo.
    Claudia Hollmann, Eun Chan Park, Zheng Liu, Faye Nourollahi, Emīls Edgars Bašēns, Jonathan Dietz, Trushnal S Waghmare, Mehul Vora, Georgy Nikolayshvili, Nanci S Kane, Tongbin Li, Fabian Imdahl, Kay F Macleod, Zaiga Nora-Krukle, Mohamed M Elashiry, Christopher Rongo, Bhupesh K Prusty.
      Multiple immune mechanisms must be coordinated to defend against a broad range of pathogens; however, the mechanisms by which broad-spectrum antipathogens act remain largely elusive. Here, we used systems biology approaches to understand the organization of human immune cells at the single-cell level and their reorganization in response to K21, a silane derivative effective against viral, bacterial, and fungal infections. K21 effectively reduced the infectivity of Enterococcus faecalis within macrophages while improving bacterial phagocytosis by human monocyte-derived macrophages, in a manner similar to that of known mitophagy inducers. K21 induced pro-inflammatory pathways in M1 and M2 macrophages without altering cytokine secretion, decreased a specific subtype of M1 macrophages and M2c macrophages, and improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the model organism C. elegans induced mitophagy and extended lifespan, suggesting an evolutionarily conserved mechanism. Our work demonstrates that a drug that remodels mitochondrial metabolism can reshape the immune cell repertoire, potentially aiding the development of more effective antimicrobials and helping to prevent the emergence of drug-resistant pathogens.
    DOI:  https://doi.org/10.26508/lsa.202603852
  46. Sci Adv. 2026 Sep 18. 12(38): eaea6376
    Super-enhancer-driven SGK1 activates polyamine metabolism to promote autoimmune uveitis.
    He Li, Lei Zhu, Zhaohuai Li, Genxian Zhang, Gengchen Jiang, Yihan Zhang, Jialing Tang, Xuling Chen, Yingying Wen, Shenqian Tian, Siyun Liu, Yue Peng, Qi Jiang, Xingyu Liu, Lian Han, Renbing Jia, Wenru Su.
      Uveitis, a leading cause of blindness, is driven by dysregulated immune responses, particularly autoreactive T cells. Despite advances in understanding its pathogenesis, key regulatory mechanisms remain elusive. Here, we integrate the cleavage under targets and tagmentation (CUT&Tag) and single-cell RNA sequencing (scRNA-seq) to delineate the super-enhancer (SE) landscape and transcriptional profiles of CD4+ T cells in Vogt-Koyanagi-Harada (VKH) disease. We identify serum/glucocorticoid-regulated kinase 1 (SGK1) as a key SE-associated gene, substantially up-regulated in CD4+ T cells of VKH patients. Pharmacological inhibition of SGK1 markedly alleviates uveitis in mice. Mechanistically, SE-driven SGK1 expression activates the MEK1-ERK1/2-ODC1 axis, leading to aberrant polyamine metabolism and a skewed T helper 17 (TH17)/regulatory T (Treg) balance, whereas polyamine supplementation negates these therapeutic benefits, confirming SGK1's role in driving disease progression. Notably, through molecular docking and molecular dynamics simulations, we identified herbacetin as a natural inhibitor of SGK1. Herbacetin restores immune balance and mitigates disease severity, highlighting SGK1 as a promising therapeutic target for autoimmune uveitis.
    DOI:  https://doi.org/10.1126/sciadv.aea6376
  47. Mol Metab. 2026 Sep 18. pii: S2212-8778(26)00124-9. [Epub ahead of print] 102440
    GNPAT-driven plasmalogen biosynthesis regulates macrophage polarization and protects against obesity-induced inflammation by suppressing PKCδ-STAT1 signaling.
    Ji-Young Yun, Myoung Seok Ko, Chung Hwan Hong, Ji Eun Yoon, Jaechan Leem, Mi-Ok Kim, Su Jung Kim, Hyun Ju Yoo, Yun-Kyung Cho, In-Jeoung Baek, Young-Bum Kim, Ki-Up Lee, Eun Hee Koh.
      Chronic inflammation in white adipose tissue (WAT) contributes to obesity-associated insulin resistance. Plasmalogens, ether phospholipids synthesized in peroxisomes, have been implicated in immune regulation. GNPAT (glyceronephosphate O-acyltransferase) is a peroxisomal enzyme that catalyzes the first and rate-limiting step of plasmalogen biosynthesis. Here, we show that dietary supplementation with alkyl glycerol (AG), a plasmalogen precursor, improves insulin sensitivity and reduces adipose inflammation in high-fat diet (HFD)-fed mice, independent of changes in body weight or invariant natural killer T cell activation. AG treatment reduced M1-like macrophage infiltration and proinflammatory gene expression in WAT without altering M2 macrophage polarization. Furthermore, AG supplementation restored levels of docosahexaenoic acid-enriched plasmalogen species that were reduced by HFD. In contrast, Gnpat+/- mice displayed impaired plasmalogen biosynthesis, elevated M1 polarization, and exacerbated insulin resistance upon HFD feeding. Mechanistically, GNPAT overexpression in macrophages inhibited protein kinase C delta (PKCδ) activation and downstream signal transducer and activator of transcription 1 (STAT1) signaling, attenuating lipopolysaccharide-induced inflammation. In vivo studies showed that AG supplementation reduced diacylglycerol accumulation, suggesting that altered lipid flux contributes to the modulation of PKCδ signaling observed in macrophages. Of translational relevance, GNPAT expression was decreased in the visceral adipose tissue of humans with type 2 diabetes. These findings establish GNPAT-driven plasmalogen biosynthesis as a key modulator of adipose immune homeostasis via suppression of PKCδ-STAT1 signaling. Thus, enhancing plasmalogen levels may have therapeutic potential for obesity-related metabolic disorders.
    Keywords:  Adipose tissue; Glyceronephosphate O-acyltransferase (GNPAT); Insulin resistance; Macrophage; Plasmalogens; Protein kinase Cδ (PKCδ); Signal transducer and activator of transcription 1 (STAT1)
    DOI:  https://doi.org/10.1016/j.molmet.2026.102440
  48. Diabetes Metab Syndr Obes. 2026 ;19 631555
    Lipid-Associated Macrophages in Obesity: Immunometabolic Programs and Emerging Therapeutic Implications-A Narrative Review.
    Wen Zhang, Bo Zhu, Jianan Xu, Xian Jin, Junfeng Cui.
      Obesity-associated adipose tissue inflammation is accompanied by the expansion of macrophage populations enriched in lipid-handling, lysosomal, and phagocytic programs, commonly referred to as lipid-associated macrophages (LAMs). Single-cell and spatial studies support their accumulation in crown-like structures and other lipid-rich adipose tissue niches, with partially conserved LAM-like populations also identified in humans. However, direct functional evidence, particularly in human adipose tissue, remains limited. Experimental studies suggest that LAMs may participate in lipid sequestration, efferocytosis, lysosomal processing, and inflammatory regulation, although their net effects appear to vary according to species, adipose depot, metabolic stage, and experimental model. The proposed transition from an adaptive lipid-buffering state to a chronically inflammatory state should therefore be regarded as a context-dependent working model rather than an established temporal sequence. This narrative review critically examines how LAMs are defined, distinguishes direct adipose LAM evidence from findings extrapolated from broader macrophage systems, and integrates lipid metabolism, bioenergetic remodeling, inflammatory signaling, and therapeutic evidence within an explicit evidence hierarchy. Current interventions act mainly through broader macrophage, adipose tissue, or systemic metabolic pathways, and no selective LAM-targeted therapy is currently available. Further translation will require robust human LAM definitions, longitudinal functional studies, reliable biomarkers, and strategies that modify detrimental LAM-associated functions without disrupting beneficial macrophage activities.
    Keywords:  adipose tissue; immunometabolism; lipid-associated macrophages; metaflammation; obesity; therapeutic implications
    DOI:  https://doi.org/10.2147/DMSO.S631555
  49. J Orthop Translat. 2026 Sep;60 101212
    Macrophage immunometabolic reprogramming in inflammatory repair failure in osteonecrosis of the femoral head.
    Yan Wang, LuLu Zhang, XueZhi Liu, Dong Wang, JianXiong Ma.
      The classical "vascular occlusion" model does not fully account for osteonecrosis of the femoral head (ONFH). Femoral head collapse may progress despite restored perfusion, and ischemia alone cannot adequately explain steroid-associated ONFH. We propose that ONFH involves disruption of bone-vascular-immune homeostasis, with macrophage immunometabolic reprogramming in response to hypoxic and lipotoxic stress acting as a potential driver of inflammatory repair failure. Among the metabolic mechanisms implicated in ONFH, the strongest disease-specific evidence supports roles for hypoxia, oxidative stress, disordered lipid metabolism, macrophage imbalance, and ferroptosis-associated injury. By contrast, macrophage-specific glycolytic reprogramming, remodeling of the tricarboxylic acid (TCA) cycle, epigenetic fixation, osteomac dysfunction, and cuproptosis remain less well established. Regulated cell death pathways, particularly ferroptosis and pyroptosis, may exacerbate local tissue injury by releasing damage-associated molecular patterns (DAMPs) and inflammatory mediators that disrupt type H vessel-osteogenesis coupling and shift repair toward fibrosis. Establishing causal relationships rather than correlative associations will require lineage-tracing experiments, spatial validation, metabolic flux analyses, and genetic loss-of-function studies in ONFH models.
    The translational potential of this article: Viewing ONFH as an immunometabolic disorder identifies experimentally tractable targets beyond conventional anti-inflammatory strategies, including SLC7A11/GPX4-dependent ferroptosis defense, NLRP3 inflammasome signaling, and HIF-1α-associated macrophage metabolic adaptation. Extracellular vesicle- or biomaterial-based delivery systems designed for prolonged local retention should currently be considered experimental platforms for assessing lesion-specific target engagement in early-stage ONFH. Their clinical relevance must be established through ONFH-specific studies evaluating efficacy, safety, biodistribution, manufacturability, and long-term structural outcomes.
    Keywords:  Ferroptosis; Immunometabolism; Macrophages; Osteoimmunology; Osteonecrosis of the femoral head (ONFH); Type H vessel
    DOI:  https://doi.org/10.1016/j.jot.2026.101212
  50. J Bacteriol. 2026 Sep 17. e0024926
    Polyunsaturated fatty acids: host-derived antimicrobials against glycolytic Staphylococcus aureus.
    Alex R Stackhouse, Asif Iqbal, D Grace Ross, Wyatt W Wittliff, Kirsten E Rico, Bennett J Blank, Brooke M LeBreton, Sara P Bucher, Michelle Y MacIntyre, William N Beavers.
      Metabolic flexibility allows Staphylococcus aureus to survive killing by antibiotics and antimicrobial immune molecules while infecting every niche of the mammalian host. Whether S. aureus is using glycolysis, aerobic respiration, or anaerobic respiration to generate energy, these cellular processes must be accurately attuned to the infected host tissue. Shifting from respiration to glycolysis lowers metabolic throughput, allowing the transition to a persistent S. aureus infection and avoiding killing by most antimicrobial molecules, which typically target rapidly dividing cells. Previously, we reported that arachidonic acid (AA), an abundant host polyunsaturated fatty acid (PUFA), kills S. aureus through a lipid peroxidation mechanism. Here, we report that the extent of PUFA killing of S. aureus can be predicted by the autoxidation rate constant, extending our previous AA findings to include all PUFAs. Contrasting many other antimicrobial molecules, AA kills glycolytic S. aureus more effectively than respiring S. aureus. Elevating cellular ATP levels protects S. aureus from PUFA killing, indicating that glycolytic S. aureus strains cannot sufficiently energize the ATP-dependent processes that allow S. aureus to survive PUFA toxicity. This report defines cellular metabolism as a key determinant in S. aureus PUFA resistance and demonstrates that PUFAs are effective antimicrobials against glycolytic S. aureus, including persister cells and small colony variants. Furthermore, identifying and validating the ATP-dependent processes that protect S. aureus from PUFA killing will define pathways that can be targeted to accentuate killing by the host immune system, leading to the clearance of persistent S. aureus infections.IMPORTANCEStaphylococcus aureus causes significant human morbidity and mortality. The metabolic diversity of this pathogen makes eradication challenging, leading to persistent infections in many patient populations. Polyunsaturated fatty acids (PUFAs) are host-derived antimicrobial molecules that are abundant at the host-pathogen interface. Here, we define the mechanism of killing by PUFAs in metabolically limited S. aureus strains. These strains are difficult to eradicate because most therapies target rapidly dividing cells. We demonstrate that PUFAs kill slow-growing S. aureus through a lipid peroxidation mechanism better than their normal growth counterparts. Restoring ATP levels in these strains protects against PUFA killing, demonstrating that the PUFA survival response is not fully energized in the low metabolic state.
    Keywords:  Staphylococcus aureus; arachidonic acid; glycolysis; lipid electrophiles; lipid peroxidation; persisters; polyunsaturated fatty acids; small colony variants
    DOI:  https://doi.org/10.1128/jb.00249-26
  51. Clin Transl Med. 2026 Sep;16(9): e70755
    Targeting the GPR183/EBI2‒oxysterol axis in tuberculosis: Immunometabolic regulation and prospects for host-directed therapy.
    Junfei Wang, Yingnan Zhou, Xunming Ji, Haiping Zhao, Lingjun Zhan.
       BACKGROUND: Tuberculosis (TB), caused predominantly by Mycobacterium tuberculosis (Mtb), remains a major global health challenge despite the availability of antimicrobial chemotherapy. Drug-resistant TB, latent infection, immunopathology and metabolic comorbidities such as diabetes continue to undermine treatment efficacy, highlighting the urgent need for host-directed therapeutic (HDT) strategies that complement antibacterial regimens. G protein-coupled receptors (GPCRs) are highly tractable drug targets that integrate immune and metabolic signals. Among them, GPR183, also known as Epstein‒Barr virus-induced gene 2 (EBI2), has emerged as an oxysterol-sensing receptor with growing relevance to TB pathogenesis.
    MAIN BODY: GPR183 is activated by oxysterol gradients, particularly 7α,25-dihydroxycholesterol (7α,25-OHC), which is generated via the CH25H‒CYP7B1‒HSD3B7 metabolic axis. This pathway regulates diverse immune functions, including immune-cell positioning, macrophage recruitment, dendritic-cell and lymphocyte localisation, type I interferon restraint and autophagy induction. In the context of TB, reduced GPR183 expression and impaired oxysterol signalling have been linked to disease severity, diabetes-associated susceptibility and defective macrophage antimicrobial responses.
    CONCLUSION: Collectively, these observations position the GPR183‒oxysterol axis as a potential immunometabolic checkpoint that coordinates macrophage trafficking with autophagic control of intracellular Mtb while simultaneously curbing excessive type I interferon-driven immunopathology. In this review, we summarise current evidence linking GPR183 biology with TB immunity, discuss available pharmacological modulators and GPCR-targeted drug-development challenges, and propose experimental frameworks to evaluate GPR183 as a candidate HDT target for TB.
    Keywords:  GPR183/EBI2; Mycobacterium tuberculosis; autophagy; host‐directed therapy; oxysterol; type I interferon
    DOI:  https://doi.org/10.1002/ctm2.70755
  52. Sci Adv. 2026 Sep 18. 12(38): eaee8251
    Epigenetic training licenses naïve CD8+ T cell metabolic fitness and function.
    Mengjie Lv, Jiyu Ding, Haizhen Long, Qian Chai, Lili Xu, Caiwei Jin, Wei Liang, Liwei Zhang, Bangmin Zhang, Zhihan Lv, Jicheng Zhao, Guohong Li, Mingzhao Zhu.
      Naïve T cells maintain quiescence yet must respond rapidly to antigens, but how they prime this capacity is unclear. We identify histone variant H2A.Z as a key regulator of an epigenetic training program that licenses quiescent naïve CD8+ T cells for future activation. H2A.Z deficiency disrupts naïve T cell homeostasis and effector responses. Multiomics reveals that H2A.Z is selectively deposited at oxidative phosphorylation (OXPHOS) gene promoters in quiescent naïve CD8+ T cells, priming the chromatin for rapid transcriptional induction. This training is developmentally instructed by tonic interleukin-7 (IL-7) signaling and regulated by transcription factor GABPα. Age-related decline in IL-7 signaling reduces H2A.Z occupancy and impairs T cell activation, while IL-7 supplementation or enforced H2A.Z expression rescues this defect. H2A.Z overexpression also enhances chimeric antigen receptor T cell stemness and antitumor efficacy. Our work defines an IL-7R-GABPα-H2A.Z-OXPHOS axis that epigenetically establishes metabolic and functional fitness in quiescent T cells, offering insights for immunotherapy targeting ageing and tumors.
    DOI:  https://doi.org/10.1126/sciadv.aee8251
  53. Front Immunol. 2026 ;17 1918327
    Inflammation-centered neurovascular-immune-metabolic remodeling in ischemic stroke: stage-dependent mechanisms, regulated cell death, and therapeutic translation.
    Linjing Song, Zijin Sun, Xuhui Zhang, Guojiao Shang, Shanyu Du, Fafeng Cheng, Wenxiu Xu.
      Ischemic stroke evolves beyond arterial occlusion through an inflammation-centered network linking neurovascular dysfunction, immune remodeling, metabolic reprogramming, and regulated cell death. These interactions are organized across the hyperacute, acute, subacute, and chronic phases. Hyperacute energy failure, excitotoxicity, thromboinflammation, pericyte contraction, and capillary stalling can sustain microcirculatory no-reflow despite recanalization. Acute injury is characterized by blood-brain barrier disruption, innate immune amplification, mitochondrial stress, as well as ferroptotic, necroptotic, pyroptotic, and proposed cuproptotic pathways. Subacute recovery involves debris clearance, immune resolution, angiogenesis, metabolic adaptation, and oligodendrocyte-lineage repair, whereas chronic outcomes reflect persistent inflammation, white-matter remodeling, and neural plasticity. Cell-specific metabolism and brain-border and systemic immune-metabolic communication further shape injury and recovery. Experimental evidence is distinguished from findings in human blood, thrombectomy-derived samples, imaging, and brain tissue. Therapeutic translation requires stage-matched interventions compatible with reperfusion and rehabilitation, clinically realistic post-onset dosing, mechanistic biomarkers, and appropriate safety evaluation. This framework links early microvascular rescue with immune resolution, metabolic recovery, and network repair.
    Keywords:  immunometabolism; ischemic stroke; neuroinflammation; neurovascular unit; regulated cell death
    DOI:  https://doi.org/10.3389/fimmu.2026.1918327
  54. J Lipid Res. 2026 Sep 15. pii: S0022-2275(26)00178-1. [Epub ahead of print] 101148
    Macrophage source influences peritoneal persistence and immune cell dynamics in assays of reverse cholesterol transport.
    Jordan M Bobek, Cade R Rahlf, Vera L Tarakanova, Daisy Sahoo.
      Assays to measure macrophage-to-feces reverse cholesterol transport (RCT) in mouse models are well-established, yet the immunologic consequences of injecting allogeneic versus syngeneic macrophages remain undefined in the context of this assay. In this study, we compared primary bone marrow-derived macrophages (BMDMs) and reticulosarcoma-derived J774 macrophages as cholesterol-loaded donor cells in a well-established in vivo RCT assay to determine whether macrophage origin influences host immune activation and cholesterol flux. Following intraperitoneal injection, J774 macrophages exhibited markedly reduced peritoneal persistence relative to BMDMs, with <1% of cells detectable at 24 or 48 hours post-injection, compared to sustained retention of the BMDMs. This was accompanied by distinct immune activation profiles where J774 macrophages induced prolonged innate immune activation, whereas BMDMs elicited coordinated and transient responses involving early B cell activation that resolved by 48 hours. Despite these differences in cellular persistence and immune response, RCT outcomes were comparable between groups under the conditions tested, with no major differences observed in hepatic uptake or fecal excretion of [3H]-cholesterol in BMDM-injected mice at 24 hours compared to J774-injected mice. Mechanistically, these findings suggest that the presence of macrophages to mediate cholesterol efflux in the early steps of RCT likely dominates total RCT measurements, potentially buffering the impact of later differences in macrophage persistence and immune activation. Together, these results demonstrate that macrophage source influences peritoneal persistence and immune cell dynamics, but does not substantially alter RCT outcomes under the conditions tested, underscoring the importance of considering macrophage source when designing and interpreting macrophage-to-feces RCT studies.
    Keywords:  BMDMs; Cholesterol/efflux; J774 macrophages; cholesterol/trafficking; cytokines; inflammation; innate immune activation; lipoproteins/metabolism; transport
    DOI:  https://doi.org/10.1016/j.jlr.2026.101148
  55. Antiviral Res. 2026 Sep 18. pii: S0166-3542(26)00194-4. [Epub ahead of print] 106535
    4-Octyl Itaconate Inhibits Porcine Epidemic Diarrhea Virus Replication by Modulating the Ferroptosis Axis and the Autophagy Pathway.
    Yueyi Lu, Shuqi Yang, Mengzhe Hou, Linyang Yu, Yixin Yuan, Yidan Geng, Yuchen Ma, Shuai Du, Fengxia Zhang, Dongliang Li, Wenjuan Du, Jianli Li, Shen Wang, Qinghua Shang, Yongtao Li.
      Porcine epidemic diarrhea virus (PEDV) continues to pose a significant threat to the swine industry, leading to high mortality in neonatal piglets and substantial economic losses. The emergence of antigenic variants often compromises vaccine efficacy, highlighting the need for novel antiviral strategies. This study investigates the potential of 4-octyl itaconate (4-OI) as a novel therapeutic agent against PEDV. In vitro studies demonstrated that 4-OI exhibits dose-dependent antiviral activity across multiple cell lines, directly reduces viral infectivity, and displays broad-spectrum inhibitory effects against enveloped viruses. In a piglet model, 4-OI administration (100 mg/kg) significantly reduced disease severity, as evidenced by decreased intestinal viral load and tissue damage, improved weight gain, reduced diarrhea, and enhanced survival. Mechanistically, 4-OI inhibits PEDV replication by modulating ferroptosis and autophagy pathways, thereby restricting viral exploitation of host autophagy-ferroptosis crosstalk. These findings suggest that 4-OI is a promising therapeutic candidate for PEDV infection, offering a novel host-targeted antiviral approach and opening up a promising new direction for antiviral therapy.
    Keywords:  4-Octyl itaconate; Autophagy; Ferroptosis; Porcine epidemic diarrhea virus
    DOI:  https://doi.org/10.1016/j.antiviral.2026.106535
  56. Redox Biol. 2026 Sep 09. pii: S2213-2317(26)00388-5. [Epub ahead of print]97 104389
    Cancer-associated fibroblast-derived POSTN as a metabolic "switch" shapes lipid-stressed macrophage polarization in gastric cancer.
    Qin Ding, Ziteng Li, Ruiwen Liu, Wanjing Feng, Jiayi Wei, Chengye Liu, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Shenglin Huang, Xiaodong Zhu.
       BACKGROUND: Cancer-associated fibroblasts (CAFs) foster an immunosuppressive tumor microenvironment (TME) and confer resistance to immune checkpoint blockade (ICB) in gastric cancer (GC). However, the mechanisms by which specific CAF subsets regulate metabolic crosstalk and immune evasion remain poorly defined.
    METHODS: We integrated bulk and single-cell RNA-sequencing data, spatial transcriptomics, and clinical cohorts of GC patients treated with immunotherapy. Functional validation was performed using in vitro co-culture systems, multiple murine models, and lipid nanoparticle (LNP)-encapsulated siRNA targeting Postn.
    RESULTS: We identified POSTN + CAFs as a key subset enriched in ICB non-responders and associated with poor prognosis. Mechanistically, POSTN secreted by CAFs engaged integrin β1 (ITGB1) on tumor cells and macrophages, activating the PI3K/AKT/mTOR signaling axis and upregulating PPARγ. This signaling cascade drove lipid metabolic reprogramming, characterized by increased lipid accumulation and oxidative stress, and promoted the polarization of macrophages toward an immunosuppressive, lipid-stressed M2 phenotype. Targeting POSTN signaling with LNP-formulated siPostn attenuated tumor growth, suppressed lipid metabolism, and reduced M2 macrophage infiltration in the TME.
    CONCLUSION: This work reveals that POSTN + CAFs establish an immunosuppressive TME and are associated with ICB non-response in GC by remodeling lipid metabolism through the ITGB1-PI3K/AKT/mTOR-PPARγ axis, a finding that underscores the therapeutic value of intervening in this specific CAF-macrophage metabolic crosstalk.
    Keywords:  Fatty acid metabolism; Gastric cancer; Immunotherapy response; Lipid-stressed macrophage; POSTN
    DOI:  https://doi.org/10.1016/j.redox.2026.104389
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