bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–06–21
fifty-nine papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Kiss and spit metabolomics highlight the role of host purine metabolism during pathogen infection.
  2. β-catenin-driven innate and metabolic reprograming in macrophages fuel T-cell-dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention.
  3. Microparticles synthesized from itaconate polyesters enable metabolite delivery and elicit immunoregulatory outcomes.
  4. Bovine rotavirus exploits host arginine metabolism to facilitate replication: A novel antiviral strategy targeting the arginase-iNOS axis.
  5. Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.
  6. Metabolic reprogramming of CD4⁺ T cells by Zaprinast induces HIV-1 latency reversal ex vivo.
  7. Effects of Metabolic Dysregulation on Macrophage Polarization in Rheumatoid Arthritis.
  8. The cardiovascular risk marker itaconate is sex-dependently associated with legume intake and immune-inflammatory competence in subjects with high BMI.
  9. Metabolic support of trained immune responses in myeloid cells.
  10. HSV-1-Driven Lipid Metabolic Reprogramming and Lipid Droplet Accumulation in Macrophages Impair Antiviral Immunity.
  11. The competition of amino acid among tumors, tumor-associated macrophages and T cells based on metabolic reprogramming.
  12. Metabolic reprogramming of glutamine is associated with M2 macrophage polarization in allergic rhinitis.
  13. HIF-1α in macrophage polarization: roles in immunometabolism and autoimmune diseases.
  14. Metabolic regulatory nodes of the inflammasome and inflammatory cell death.
  15. TIM3 signaling in effector T cells acts as an immunometabolic switch in the purine degradation pathway to suppress intestinal inflammation.
  16. Retiring M1/M2: a view from the succinate receptor.
  17. Immunometabolic Reprogramming: A New Frontier in Cancer Immunotherapy.
  18. Comparative Interactome Profiling of Itaconate and α-Ketoglutarate by the Peptide-Centric Local Stability Assay.
  19. RNF34 restrains endometriosis through SREBP1-dependent metabolic-immune crosstalk.
  20. 3-Hydroxypropionic acid converts inflammatory macrophage glycolysis into mitochondrial oxidation through GAPDH carboxyethylation.
  21. Dendrobine alleviates lung injury in septic mice by inhibiting mitochondrial-endoplasmic reticulum crosstalk-mediated NLRP3 inflammasome activation.
  22. Glycolytic reprogramming in cancer: tumour cell metabolism, immune modulation, and therapeutic opportunities.
  23. Editorial: Immunometabolic circuits in host-pathogen interaction.
  24. CD300e modulates metabolic programs in adipose tissue macrophages during obesity.
  25. Remodeling of the immune-metabolic landscape triggered by long-term high-altitude exposure.
  26. FCGR2B drives immunosuppressive M2 polarization of tumor-associated macrophages via metabolic reprogramming of fatty acid oxidation.
  27. Glycolytic reprogramming in ovarian cancer: mechanisms, immune crosstalk, and therapeutic implications.
  28. The SIRT1/STAT3 axis as a central regulator of immune, inflammatory, and lipid metabolic dysregulation in rheumatoid arthritis: therapeutic implications.
  29. Resveratrol derivative restores macrophage cholesterol homeostasis via stabilizing xanthine oxidoreductase in hepatocellular carcinoma.
  30. Glutamine metabolism shapes the phenotypic adaptation of uterine dendritic cells in response to early allogeneic pregnancy.
  31. Metabolic adaptations of inflammatory macrophages govern ferroptosis susceptibility via the GCH1-BH4-iNOS axis.
  32. Mechanisms and therapeutic advances of gut metabolites in the regulation of neuroimmune inflammatory diseases.
  33. Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.
  34. Plasmacytoid Dendritic Cells Exhibit High Transferrin Receptor Expression Without Iron Accumulation.
  35. Neuroglial P2Y1 receptor signalling differentially contributes to inflammatory neurodegeneration.
  36. Pam3Csk4 regulates glycolysis in PMN-MDSCs and attenuates their immunosuppressive effect on T cells.
  37. Nutrition as a regulator of hematopoietic stem cell biology and transplantation.
  38. Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.
  39. SARS-CoV-2 ORF3a blocks lysosomal cholesterol egress by disrupting VPS39-regulated NPC2 trafficking and BMP metabolism.
  40. The role of macrophage autophagy and mitochondrial metabolic reprogramming in the treatment of myocardial infarction.
  41. T cell dysfunction and metabolic disruption in chronic hepatitis C virus infection.
  42. Anakinra prevents high glucose-mediated potentiation of IL-1β-induced NLRP3 inflammasome activation, small extracellular vesicle release and vascular inflammation.
  43. Immunometabolic and immune regulatory functions of capsaicin in cancer: mechanistic insights and emerging perspectives.
  44. Cell-Resolved Mass Spectrometry Imaging Integrated with Isotope Tracing Elucidates Macrophage Polarization-Specific Metabolic Reprogramming.
  45. Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.
  46. A viral protein promotes host L-asparaginase activity and weakens the asparagine-induced resistance pathway for the benefit of virus infection.
  47. Labile iron starvation in embryonic Kupffer cells aggravates MASH via mitochondrial failure and macrophage dysfunction.
  48. The role of short-chain fatty acids as key mediators of gut microbiota - host crosstalk in athyroid diseases.
  49. Enhanced Respiratory Electron Dissipation by Immunometabolites Promotes Mycobacterial Biofilm Longevity.
  50. ARF-like GTPase 8B orchestrates lipophagy and exocytosis to drive single-stranded RNA virus replication.
  51. Microbial metabolites at the front line: Orchestrating gastrointestinal and systemic barrier immunity across the lifespan.
  52. A TIGIT nanotrapping-guided STING-activatable immunometabolic strategy overcomes innate immune silence and T cell exhaustion in breast cancer.
  53. Mucosal-associated invariant T (MAIT) cells are reduced and dysfunctional in acute melioidosis.
  54. Ma-Xing-Shi-Gan decoction alleviates allergic asthma by modulating the gut microbiota-tryptophan metabolism-ILC2 axis.
  55. Amplified inflammatory and immune responses in viral-associated pulmonary aspergillosis.
  56. Chronic hyperglycemia induces macrophage iron accumulation and promotes Mycobacterium tuberculosis virulence.
  57. Hyperglycemia aggravates vitiligo through succinate/SUCNR1-mediated T cell activation.
  58. Lonicera japonica polysaccharide restores mucosal integrity in ulcerative colitis by increasing microbiota-derived spermidine.
  59. Taurine supplementation at the crossroads of metabolism, inflammation and aging: mechanistic and nutritional perspectives.
  1. mSphere. 2026 Jun 15. e0025626
    Kiss and spit metabolomics highlight the role of host purine metabolism during pathogen infection.
    Gina M Gallego-Lopez, William J Olson, Andres M Tibabuzo-Perdomo, David Stevenson, Daniel Amador-Noguez, Grant Lawrence, James W Leahy, Emmanuel Contreras Guzman, Melissa C Skala, Laura J Knoll.
      Intracellular bacteria and protists rely on the host cell to supply many metabolites, but the mechanisms through which pathogens manipulate host metabolism to their benefit are not understood. Here, we demonstrate that when the obligate intracellular parasite Toxoplasma gondii secretes its rhoptry organelle contents into the host cytoplasm before invasion-a process called "kiss and spit"-host cell metabolite abundance is altered in nucleotide synthesis, the pentose phosphate pathway, glycolysis, and amino acid synthesis. U-13C6-labeling metabolomics confirmed that kiss and spit increased the flow of carbon through the pentose phosphate pathway and nucleotide synthesis. An increase in 2,3-bisphosphoglycerate abundance led us to investigate the activation of host cytosolic nucleosidase II (cN-II) to provide purines for the parasite. We found that T. gondii manipulates the host cN-II enzyme to dephosphorylate GMP and IMP that it needs for replication. Furthermore, we found that the approved anti-cancer drug fludarabine, which inhibits cN-II, also inhibits Toxoplasma replication. These results reveal Toxoplasma host cell manipulation and highlight potential therapies for toxoplasmosis.IMPORTANCEA fundamental challenge in parasitology is understanding how intracellular parasites rapidly reprogram host metabolism to support replication. This study reveals that Toxoplasma gondii initiates profound metabolic reprogramming through a "kiss-and-spit" mechanism, secreting effector molecules without invasion. We demonstrate that T. gondii specifically hijacks host cytosolic 5'-nucleotidase II (cN-II) by elevating 2,3-bisphosphoglycerate levels, which allosterically activates this enzyme to generate purines essential for parasite survival. Genetic deletion of host cN-II significantly impairs parasite replication, establishing cN-II as a critical host dependency factor. These findings have important implications for antiparasitic drug development while advancing our understanding of purine metabolism in apicomplexan parasites. More broadly, elucidating the molecular mechanism linking parasite effector secretion to specific host enzyme activation provides a framework for understanding metabolic manipulation across other intracellular pathogens.
    Keywords:  Toxoplasma gondii; cN-II enzyme; host–pathogen interaction; metabolomics; purines
    DOI:  https://doi.org/10.1128/msphere.00256-26
  2. Cell Death Dis. 2026 Jun 13. pii: 568. [Epub ahead of print]17(1):
    β-catenin-driven innate and metabolic reprograming in macrophages fuel T-cell-dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention.
    Geetika Kumari, Amit Kumar, Rasmiranjan Muduli, Mayami Das, Prithwik Bhowmik, Biplab Singha, Ankita Namdeo, Criss Dcosta, Neerja Wadhwa, Jaswinder Singh Maras, Rakesh Kundu, Nishith Gupta, Ruchi Anand, Dhanasekaran Shanmugam, Tanmay Majumdar.
      Toxoplasma gondii activates innate immunity via TLR11/12 in mice, but the lack of functional human counterparts leaves a gap in understanding parasite sensing in humans. Here, we bridge this gap by uncovering a host-intrinsic sensing mechanism, wherein β-catenin signaling mediates immune recognition of T. gondii. Notably, this parasite hijacks the PI3K-AKT-β-catenin pathway in macrophages to promote its replication. While β-catenin ablation, either genetically or pharmacologically (XAV939), disavows this process, thereby inhibiting replication. Phospho-β-catenin-TCF4 drives IRF4 transcription, followed by phosphorylation of IRF4, which regulates CYBB transcription. Augmented CYBB enhances mitochondrial-ROS and triggers mitophagy via PINK1/PARKIN, whereas ablation of β-catenin preserves mitochondrial fitness, thereby impeding parasite growth. Enhanced ROS can oxidize host mitochondrial DNA, which then functions as a host-associated molecular pattern (HAMP). This activates the cytosolic pathogen recognition receptor (PRR) AIM2, triggering the AIM2-NLRP3-ASC-caspase-1-IL-1β inflammasome cascade. This cascade leads to gasdermin-D-mediated pyroptosis, a process that critically depends on the phosphorylation of β-catenin. T. gondii's ASP5 protease plays an essential role in the phosphorylation of β-catenin-mediated inflammasome activation. Metabolically, β-catenin-dependent enhanced ROS stabilized HIF-1α, which stimulates the HKII-LDH-A axis, promoting the Warburg effect, histone acetylation and pro-inflammatory M1-macrophage polarization (IL-12/IL-6/IL-23/TNF-α). β-catenin ablation shifts metabolism to oxidative-phosphorylation, fostering M2-phenotype (IL-2/IL-10/TGF-β) that abrogates parasites survival. β-catenin also strengthens MHC-TCR avidity, driving Th1/Tc1, Th9/Tc9, and Th17/Tc17 paradigm, whereas β-catenin inhibition promotes anti-inflammatory Th2/Tc2/Threg/Tcreg differentiation. Additionally, macrophage intrinsic β-catenin dictates metabolic divergence in both CD4⁺ and CD8⁺T-cells. Notably, β-catenin-deletion in macrophages protects mice (β-catΔMΦ) against infection, highlighting that XAV939 has therapeutic potential against toxoplasmosis.
    DOI:  https://doi.org/10.1038/s41419-026-08953-1
  3. J Control Release. 2026 Jun 17. pii: S0168-3659(26)00518-3. [Epub ahead of print] 115115
    Microparticles synthesized from itaconate polyesters enable metabolite delivery and elicit immunoregulatory outcomes.
    Amanda N Brocki, Ryan A McIlvaine, Corinne A Martin, Lawrence R Sita, Christopher M Jewell, Senta M Kapnick.
      Metabolites directly influence immune cell function. Consequently, altering metabolite availability can regulate immunity and represents a window of opportunity for therapeutic manipulation. Itaconate (ITA) - a tricarboxylic acid cycle derivative generated intracellularly - has been shown to exert anti-inflammatory effects in models of autoimmunity. However, efficacy is dependent on systemic, frequent, high-dose treatments due to ITA's poor membrane permeability and rapid clearance from circulation. Thus, there is a need for metabolite delivery strategies that overcome these challenges. Here, we synthesized ITA-based polyesters that enable microparticle (MP) assembly entirely from the polymeric metabolite (pITA). Treatment with biocompatible pITA MPs, which hydrolyze to release unmodified ITA, reduced inflammatory cytokine secretion (e.g., IL-6, IL-1β) by both macrophages and dendritic cells. These data suggest MPs effectively deliver metabolite to the intracellular compartment for immunomodulation in an accessible form. Furthermore, pITA MPs inhibited polarization of inflammatory T cells (TH17) and promoted regulatory T cells (Treg), linking the effect of MPs on innate signaling to adaptive immunity. In a preclinical mouse model of multiple sclerosis (MS), pITA MPs reduced circulating serum IL-6 - a cytokine that drives inflammation in several autoimmune diseases. Together, this work advances a biomaterials-based strategy that overcomes hurdles to metabolite delivery and expands opportunities for intervention during autoimmunity and inflammation.
    Keywords:  Autoimmunity; Biomaterials; Immunometabolism; Inflammation; Itaconate; Metabolite; Polyesters
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115115
  4. Microb Pathog. 2026 Jun 18. pii: S0882-4010(26)00365-7. [Epub ahead of print]218 108639
    Bovine rotavirus exploits host arginine metabolism to facilitate replication: A novel antiviral strategy targeting the arginase-iNOS axis.
    Fengshi Xie, Ziwei Liu, Jiankun Huang, Xuhua Ran, Xiaobo Wen.
      Bovine rotavirus (BRV) is a leading cause of severe diarrhea in calves, resulting in significant economic losses globally. Viruses often reprogram host metabolism to support their replication; however, the metabolic interplay between BRV and host arginine metabolism remains unclear. In this study, untargeted metabolomics revealed that BRV infection significantly alters arginine biosynthesis pathways in MA104 cells, leading to a depletion of intracellular arginine and its precursors. We found that exogenous arginine supplementation promotes BRV replication, suggesting the virus exploits this amino acid. Further investigation showed that BRV infection upregulates both the activity and transcription of arginase (ARG) and inducible nitric oxide synthase (iNOS), the two key enzymes consuming arginine. While individual inhibition of ARG or iNOS showed limited or dose-dependent antiviral effects, simultaneous blockade of both enzymes significantly restricted BRV replication. Mechanistically, this dual inhibition restored intracellular arginine levels, which subsequently induced sustained activation of the mTORC1 signaling pathway to restrict viral replication. Notably, the specific mTORC1 inhibitor rapamycin reversed the antiviral effect of the dual blockade, indicating that the suppression of BRV is mTORC1-dependent. These findings demonstrate that BRV hijacks arginine metabolism to facilitate its own propagation and targeting the ARG/iNOS-mTORC1 axis represents a potential therapeutic strategy for controlling rotavirus infection.
    Keywords:  Arginase (ARG); Arginine; Inducible nitric oxide synthase (iNOS); Metabolic reprogramming; Rotavirus; Viral replication
    DOI:  https://doi.org/10.1016/j.micpath.2026.108639
  5. Infect Immun. 2026 Jun 15. e0017826
    Salmonella Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.
    Zachary M Powers, Michael J McFadden, Gi Young Lee, Tracey Schultz, Luiza A Castro Jorge, Daniel F Edwards, Simon Sanchez-Paiva, Jonathan Z Sexton, Katherine R Spindler, Jeongmin Song, Mary X O'Riordan.
      Many intracellular pathogens stimulate host cell stress by directly or indirectly causing an imbalance in host nutrients. Depletion of amino acid pools, in particular, can act as a danger signal to infected cells. Using a restrictive host model of Salmonella enterica serovar Typhi (S. Typhi) infection, we identify early induction of the integrated stress response (ISR) by viable bacteria, but not by heat-killed bacteria. Genetic deletion of the amino acid-sensing ISR kinase GCN2 (also known as EIF2AK4) prevented early ISR activation during S. Typhi infection and murine macrophages lacking GCN2 show impaired bacterial clearance and decreased cytokine output. Supplementation of wild-type C57BL/6 murine macrophages with only the non-essential amino acid asparagine was sufficient to suppress S. Typhi-induced ISR activation, and deletion of S. Typhi ansB, encoding an asparaginase, prevented ISR activation during infection. Pharmacological inhibition of mammalian target of rapamycin (mTOR), the other major amino acid-sensing pathway in eukaryotic cells, prevented GCN2 activation and ISR induction in murine macrophages, indicating an upstream role for mTOR in signaling to GCN2. These findings suggest a role for the ISR in macrophage innate immune responses to S. Typhi infection and highlight a potential difference in nutrient-dependent signaling between the S. Typhi-susceptible human host and the restrictive murine host centered around asparagine, mTOR, and GCN2.
    Keywords:  gram-negative bacteria; innate immunity; nutritional immunity
    DOI:  https://doi.org/10.1128/iai.00178-26
  6. Retrovirology. 2026 Jun 13.
    Metabolic reprogramming of CD4⁺ T cells by Zaprinast induces HIV-1 latency reversal ex vivo.
    V De Masson d'Autume, V LeDouce, A Dutilleul, S O'Reilly, N François, E Formiconi, M Angieladis, L Pilosio, M Bendoumou, A Garcia Leon, D Alalwan, E Moore, T McGinty, J C Valle-Casuso, A Macken, O Rohr, C Van Lint, A Sáez-Cirión, A Cotter, E Feeney, P W G Mallon, W V Gautier.
       BACKGROUND: HIV-1 latency and persistence of viral reservoirs within memory CD4+ T cells remain a fundamental obstacle to achieving a cure despite suppressive antiviral treatments. HIV-1 persistence is sustained by the dynamic interactions between viral regulatory mechanisms and the host cellular environment. At the intersection between immunometabolism and virology, the quiescent metabolic profile of resting CD4+ T cells, defined as the balance between oxidative phosphorylation (OXPHOS) and aerobic glycolysis, supports the long-term maintenance of latent viral reservoirs. Existing "Shock and Kill" strategies have shown limited clinical impact, partly due to the metabolic constraints that limit robust viral reactivation. Targeting metabolic junctions to overcome this barrier may provide a complementary therapeutic avenue.
    RESULTS: We evaluated Zaprinast, a mitochondrial pyruvate carrier inhibitor (MPCi), for its capacity to reprogramme CD4+ T cell metabolism and promote latency reversal. Across multiple primary T-cell based models of HIV-1 latency, Zaprinast induced a moderate yet reproducible increase in HIV-1 gene expression and viral particle production, including in circulating reservoirs from antiretroviral-treated individuals cultured ex vivo. Metabolic profiling revealed a biphasic response: an initial, transient inhibition of mitochondrial respiration followed by a shift from an OXPHOS-dominant to a more glycolytic metabolic state, while maintaining mitochondrial function. This metabolic reprogramming of resting CD4+ T cells by Zaprinast was reversible and did not impair cell viability, trigger non-specific T cell activation or proliferation, nor elevate reactive oxygen species levels.
    CONCLUSIONS: These results highlight that selective targeting of the quiescent metabolic state in resting CD4+ T cells can facilitate HIV-1 reactivation without compromising cellular integrity. This study identifies host metabolic reprogramming as a promising strategy to enhance latency reversal and complement existing cure strategies. Our work provides new insights into the importance of host metabolic states in governing viral persistence and underscores the translational potential of metabolic interventions in HIV-1 eradication research.
    DOI:  https://doi.org/10.1186/s12977-026-00680-x
  7. Arthritis Rheumatol. 2026 Jun 18.
    Effects of Metabolic Dysregulation on Macrophage Polarization in Rheumatoid Arthritis.
    Xinyue Zhang, Xiaoyue Deng, Shixiong Wei, Mengtao Li, Xiaofeng Zeng.
      Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by complex immune dysregulation, in which macrophages play a central pathogenic role. Macrophages accumulate extensively in RA synovium, and their abundance and functional phenotypes are correlated with disease activity and severity. Disturbed macrophage polarization is a key feature of RA progression, characterized by an increased proportion of classically activated (M1) macrophages and a reduced proportion of alternatively activated (M2) macrophages. M1 macrophages produce pro-inflammatory mediators that sustain synovial inflammation and contribute to progressive joint damage. Accumulating evidence indicates that immune cell functions are closely linked to metabolic programs. The synovial microenvironment in RA is marked by hypoxia, acidosis, and nutrient limitation, which lead to substantial metabolic reprogramming during macrophage polarization. Importantly, metabolic changes occur not merely secondary to polarization but actively shape the phenotypic transition of macrophages. In this review, we summarize current evidence on how dysregulation of glucose, lipid, and amino acid metabolism regulates the phenotype switching of macrophages in RA. We discuss the roles of key metabolic enzymes and intermediates in macrophage polarization, consider the diagnostic potential of metabolic biomarkers, and highlight therapeutic opportunities targeting metabolic pathways, thereby resolving macrophage imbalance and improving RA outcomes.
    DOI:  https://doi.org/10.1002/art.70253
  8. Front Immunol. 2026 ;17 1853371
    The cardiovascular risk marker itaconate is sex-dependently associated with legume intake and immune-inflammatory competence in subjects with high BMI.
    Amanda Cuevas-Sierra, Andrea Higuera-Gómez, Begoña de Cuevillas, Gabriela Paula-Buestan, María Martínez-Urbistondo, Raquel Castejón, J Antonio Vargas, José Moisés Laparra, J Alfredo Martínez.
       Background: Itaconate has received attention as a key immunometabolic mediator produced by activated macrophages, linking cellular metabolism to inflammatory responses. The determinants of circulating itaconate as a cardiovascular risk marker and putative relationships with diet, inflammation, and sex-specific immune responses were assessed given that it remains poorly characterized.
    Objectives: The aim of this investigation was to analyze the determinants of circulating itaconate concentrations involving metabolic associations, with markers of innate immune activation and systemic inflammation, as well as to evaluate the potential modulatory role of dietary patterns-particularly legume consumption-as well as sex-specific differences concerning these relationships in subjects with excessive adiposity.
    Methods: A total of 453 participants were screened in relation to dietary intake, and also anthropometric measurements, biochemical and inflammatory markers. Participants were categorized according to itaconate levels and legume consumption. Multivariable linear regression models were implemented to identify factors associated with circulating itaconate concentrations. Interaction analyses were performed to assess sex-specific associations.
    Results: Circulating itaconate concentrations did not differ across categories of legume intake or adherence to the Mediterranean diet. Baseline characteristics were comparable across groups, with a borderline inverse association with IL-6 levels (p = 0.053). Higher legume consumption was associated with a healthier lifestyle profile and lower adiposity, but not with circulating itaconate. In multivariable analyses, monocyte counts were independently associated with circulating itaconate, while IL-6 showed an independent inverse association. No associations were observed for age, sex, adiposity, dietary variables, or other inflammatory markers. A significant interaction between itaconate and sex was identified for monocyte counts (p = 0.025), with an inverse association observed in men but not in women.
    Conclusions: Circulating itaconate appears to reflect innate immune activation rather than dietary exposure per se. Association with monocyte-related phenotypes and systemic inflammation, together with marked sex-specific differences, supports a dependent role of itaconate within immunometabolic interactions. The findings highlight notable sex-specific immune responses, underscoring the importance of considering biological sex in understanding variations in immune function in the context of precision medicine.
    Keywords:  cardiovascular inflammation; immunometabolism; inflammation; itaconate; legume intake; monocytes; sex differences
    DOI:  https://doi.org/10.3389/fimmu.2026.1853371
  9. Elife. 2026 Jun 19. pii: e108814. [Epub ahead of print]15
    Metabolic support of trained immune responses in myeloid cells.
    Aitor Jarit-Cabanillas, Gillian Dunphy, Federico Virga, Jan Van den Bossche, David Sancho.
      Trained immunity (TI) is defined as a form of innate immune memory characterised by a long-lasting ability to develop enhanced responses to a secondary challenge, whether of the same or a different nature than the initial stimulus. This process is mediated by several established hallmarks, most prominently the existence of activating epigenetic marks and metabolic adaptations. The activating epigenetic marks prime the expression of immune-related genes and are a direct driving force behind the increased cytokine production after secondary stimulation of trained monocytes and macrophages. Training stimuli also induce specific metabolic adaptations, such as the upregulation of glycolysis and lactate production or the activation of glutaminolysis leading to fumarate accumulation, which in turn promotes epigenetic changes. However, the mechanisms linking these epigenetic and metabolic changes to a TI phenotype are varied, and not all stimuli that increase glycolysis promote training, whereas some stimuli such as lipopolysaccharide (LPS) display a non-monotonic induction of TI. In addition to metabolism directly driving epigenetic changes, early gene expression changes can also reshape cell metabolism to promote a trained phenotype. In this review we aim to separate two main types of metabolic rewiring that have not been previously uncoupled. Firstly, those primary metabolic changes occurring during the initial stimulation, which precede TI induction by altering the epigenomic landscape around inflammatory genes. Secondly, those metabolic adaptations arising later as a consequence of the first wave of epigenetic regulation, which support an enhanced functional state of macrophages.
    Keywords:  immunology; inflammation; metabolism; myeloid cells; trained immunity
    DOI:  https://doi.org/10.7554/eLife.108814
  10. Invest Ophthalmol Vis Sci. 2026 Jun 01. 67(6): 39
    HSV-1-Driven Lipid Metabolic Reprogramming and Lipid Droplet Accumulation in Macrophages Impair Antiviral Immunity.
    Junwen Ouyang, Yun He, Yaoyao Liu, Youmei Zheng, Changyu Wu, Jiaxuan Jiang, Kai Hu.
       Purpose: Herpes simplex virus type 1 (HSV-1) is a continuous health challenge, infecting 64% of the global population under the age of 50 years. Macrophages play a critical role in antiviral immunity by integrating metabolic status with effector functions. This study aimed to investigate how HSV-1 infection reshapes macrophage metabolism and to elucidate the consequent effects on innate and adaptive immune regulation.
    Methods: We isolated bone marrow-derived macrophages (BMDMs) and assessed HSV-1-induced metabolic alterations using transcriptome sequencing, metabolomic profiling, and flow cytometry. We further used pharmacological inhibitors targeting key metabolic enzymes and co-culture system to evaluate macrophage functions. The main findings were validated in an in vivo mouse model of HSV-1 infection.
    Results: We found that HSV-1 infection induced marked lipid droplet (LD) accumulation in BMDMs. Pharmacological inhibition of diacylglycerol acyltransferase 2 (DGAT2) significantly reduced LD accumulation, limited viral replication, and enhanced the antiviral effector functions of macrophages.
    Conclusions: Overall, our findings suggest that HSV-1-induced LD accumulation exerts a negative regulatory effect on macrophage immune function.
    DOI:  https://doi.org/10.1167/iovs.67.6.39
  11. iScience. 2026 Jun 19. 29(6): 116253
    The competition of amino acid among tumors, tumor-associated macrophages and T cells based on metabolic reprogramming.
    Chenyang Xianyu, Yuxiao Song, Ci Zhao, Qian Min, Zhixu Wang, Mingbo Zhang, Bicheng Zhang.
      Amino acids are important nutrients in the process of tumor proliferation. Dysregulated amino acid metabolism profoundly influences tumor growth and immune cell function. Within the tumor microenvironment (TME), metabolic reprogramming of amino acids modulates the polarization of tumor-associated macrophages (TAMs) and the differentiation of T cells, processes intimately linked to tumor immune evasion. Meanwhile, metabolic reprogramming leads to amino acid competition between tumor cells and immune cells, particularly TAMs and T cells. To meet their own amino acid needs, tumors carry out a series of optimized metabolic strategies by expressing specific enzymes, cytokines, and amino acid transporters, and so forth promoting the formation of an immunosuppressive microenvironment and hindering anti-tumor immunity. Notably, this metabolic competition may exhibit spatial heterogeneity and temporal dynamics. Given the central role of amino acid metabolism in tumor progression and immune evasion, targeting key metabolic pathways represents a promising therapeutic strategy for cancer treatment.
    Keywords:  Cancer; Cancer systems biology; Human metabolism; Immune response
    DOI:  https://doi.org/10.1016/j.isci.2026.116253
  12. Front Immunol. 2026 ;17 1815245
    Metabolic reprogramming of glutamine is associated with M2 macrophage polarization in allergic rhinitis.
    Shang Yan, Kai Xue, Yinan Wang, Desheng Jia, Yongchao Chen, Xueyou Lai, Chunrui Zhao, Guowei Chen, Yang Xu, Xiaoxu Wang, Hongguang Pan, Nan Zeng.
       Introduction: Allergic rhinitis (AR) is classically regarded as a type 2 immune-driven disease, yet its chronicity and heterogeneity suggest that additional regulatory layers shape the local immune microenvironment. Although immune cell function is closely linked to metabolic state, how specific metabolic cues are integrated into immune signaling in AR remains unclear.
    Methods: We combined human nasal mucosal metabolomic analysis, murine models, single-cell transcriptomics, bulk RNA sequencing, and protein assays to investigate the role of glutamine in AR pathophysiology.
    Results: We identified elevated glutamine levels in AR nasal mucosa and found that dietary glutamine supplementation was associated with altered nasal behavioral responses in experimental AR. Single-cell profiling revealed changes in immune cell composition, with macrophages displaying a shift toward an M2-like transcriptional state under high-glutamine conditions. Transcriptomic and pathway analyses positioned fibroblast growth factor receptor 1 (FGFR1) within differentially enriched signaling networks, and its expression increased under high-glutamine conditions. Protein-level assays further showed that aminoacylation-associated signals on FGFR1 varied with glutamine availability, together with coordinated changes in YARS and SIRT1.
    Discussion: These hypothesis-generating findings support an associative model in which metabolic alterations in AR are linked to non-canonical modification of FGFR1 and macrophage transcriptional polarization, suggesting a potential immunometabolic layer regulating the nasal mucosal microenvironment.
    Keywords:  fibroblast growth factor receptor 1; glutamine; immunometabolism; macrophage polarization; metabolomics; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2026.1815245
  13. J Leukoc Biol. 2026 Jun 18. pii: qiag082. [Epub ahead of print]
    HIF-1α in macrophage polarization: roles in immunometabolism and autoimmune diseases.
    Dongye Li, Xihao Pan, ZiJin He, Jingru Cui, Runhe Zhu, Dadong Guo.
      Hypoxia-inducible factor-1α (HIF-1α) is a central regulator of cellular responses to hypoxia and plays a pivotal role in immune cell activation and functional reprogramming. This review summarizes how HIF-1α modulates inflammatory responses through metabolic regulation and examines its mechanistic involvement in autoimmune diseases. Under normoxic conditions, HIF-1α is rapidly degraded, whereas hypoxia, inflammation, or metabolic stress stabilizes the protein, allowing its nuclear translocation and activation of glycolysis-related genes. This shift drives immune cells from oxidative metabolism to glycolysis, supporting rapid energy production and promoting inflammation-associated functional states. Consequently, HIF-1α enhances the production of inflammatory mediators and forms positive feedback loops with inflammatory signaling pathways, influencing immune cell migration, survival, and function. Aberrant activation of HIF-1α is closely associated with disease activity in autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis, contributing to immune imbalance and tissue damage. However, its effects are context-dependent; in conditions like inflammatory bowel disease and uveitis, moderate activation may exert protective roles. Therefore, therapeutic strategies require precise, context-specific modulation rather than simple inhibition or activation. Although current drug development targeting HIF-1α focuses mainly on oncology, emerging approaches-including small molecule inhibitors, nanodelivery systems, and gene therapy-highlight its potential in autoimmune disease treatment. Overall, HIF-1α serves as a key link between hypoxia, metabolism, and immune regulation.
    Keywords:  Autoimmune Disease; Energy Metabolism; HIF-1α; Immunometabolism; Inflammatory Response
    DOI:  https://doi.org/10.1093/jleuko/qiag082
  14. Trends Immunol. 2026 Jun 19. pii: S1471-4906(26)00139-0. [Epub ahead of print]
    Metabolic regulatory nodes of the inflammasome and inflammatory cell death.
    Ein Lee, Minh Quan Nguyen, Suyeong Im, Rajendra Karki.
      Inflammation is a metabolically intensive and tightly regulated process, driven primarily by innate immune cells. Cellular metabolism actively instructs immune signaling and cell fate decisions. Bioenergetic pathways, including glycolysis, mitochondrial respiration, and the tricarboxylic acid cycle, reshape cytokine production and regulate inflammatory cell death pathways. In this review, we synthesize emerging evidence on how metabolic intermediates and pathways regulate inflammasome signaling and the execution of diverse inflammatory cell death modalities, including pyroptosis, necroptosis, PANoptosis, and ferroptosis. We propose that metabolic inputs-including redox balance, mitochondrial dynamics, and lipid modifications-constitute an interconnected metabolic regulatory network that determines the threshold and outcome of inflammatory signaling. This framework offers new insights into immunometabolic dysregulation and therapeutic strategies in inflammatory, infectious, and neoplastic diseases.
    Keywords:  PANoptosis; ferroptosis; inflammation; metabolic nodes; necroptosis; pyroptosis
    DOI:  https://doi.org/10.1016/j.it.2026.06.002
  15. Gastroenterology. 2026 Jun 17. pii: S0016-5085(26)06976-3. [Epub ahead of print]
    TIM3 signaling in effector T cells acts as an immunometabolic switch in the purine degradation pathway to suppress intestinal inflammation.
    Annkathrin Knauss, Michael Gabel, Cora Kaufmann, Laura Loges, Timo Rath, Raja Atreya, Daniel Radtke, Hendrik Grapp, Katharina Gerlach, Oana-Maria Thoma, Markus Eckstein, Arne Gessner, Nora Bartels, Benjamin Schmid, Philipp Tripal, Benno Weigmann, Markus F Neurath.
       BACKGROUND AND AIMS: Effector T lymphocytes have been shown to play a key role in inflammatory bowel diseases (IBD). However, the molecular pathways controlling their metabolism and functional activity remain poorly defined. We aimed to elucidate the role of the immune checkpoint receptor TIM3 for T cell signalling in IBD.
    METHODS: We combined experimental colitis models in TIM3-deficient mice with analyses of human IBD and control samples. Blood and mucosal T cells were assessed using multi-colour flow cytometry, cytokine profiling, and untargeted metabolomics. Single-cell sequencing data were analysed. The TIM3 ligand galectin-9 was used to study TIM3 function.
    RESULTS: TIM3 expression was higher on blood Th1 cells and mucosal Th17 cells in IBD patients compared to controls, with levels being particularly high in anti-TNF refractory patients. Mice lacking TIM3 showed exacerbated oxazolone colitis and increased effector T cell activation. Metabolome profiling and functional analyses revealed that TIM3 signaling functions as an immunometabolic regulator, suppressing adenosine deaminase and the purine degradation pathway to keep effector T cells in an exhausted PD1+ state. However, insufficient availability of the TIM3 ligand galectin-9 limited effective TIM3 signalling in chronic inflammation. Treatment with galectin-9 ameliorated experimental colitis via adenosine deaminase inhibition. Moreover, in IBD T cells, galectin-9 induced an immunometabolic switch associated with reduction of terminally exhausted Th17 cells.
    CONCLUSION: TIM3 plays a key role in the immunometabolism of effector T cells in colitis by suppressing adenosine deaminase and the purine degradation pathway. Targeting the immunometabolic functions of effector T cells via TIM3 activation emerges as a promising strategy for chronic intestinal inflammation.
    Keywords:  Immunometabolism; Inflammatory bowel disease (IBD); T cell exhaustion; TIM3/galectin-9 axis
    DOI:  https://doi.org/10.1053/j.gastro.2026.05.027
  16. Apoptosis. 2026 Jun 18. pii: 176. [Epub ahead of print]31(7):
    Retiring M1/M2: a view from the succinate receptor.
    Franco Grimolizzi.
      
    Keywords:  GPR91; Immunometabolism; M1/M2; Macrophage polarization; Macrophage-to-myofibroblast transition; SUCNR1; Succinate; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s10495-026-02382-3
  17. Curr Mol Med. 2026 Jun 10.
    Immunometabolic Reprogramming: A New Frontier in Cancer Immunotherapy.
    Saeed Mohammadi, Mahmoud Darweesh, Mina Rahmati, Moosa Al-Hamadani, Milad Ahmadaghdami, Ahmed Al-Harrasi.
      The interaction between cellular metabolism and immune function, termed immunometabolism, has been regarded as a crucial determinant of anti-tumor immunity and the efficacy of cancer immunotherapy. Understanding the metabolic dependencies and vulnerabilities of various immune cell subsets and cancer cells is enabling researchers to study novel therapeutic strategies. These strategies aim to reprogram the metabolic landscape of the TME to enhance stronger anti-tumor immune responses and overcome resistance to current immunotherapies. This review provides a comprehensive overview of the fundamental principles of immunometabolism, detailing the key metabolic pathways and regulators in immune and cancer cells. We explore the distinct metabolic profiles of various immune cell subsets and how they are altered during an anti-tumor response. Furthermore, we discuss the metabolic hallmarks of cancer cells, considering variations across different cancer types. Then, we discuss how current immunotherapies, such as checkpoint inhibitors and CAR-T cell therapy, impact and are influenced by cellular metabolism. Finally, we highlight promising therapeutic opportunities for targeting immunometabolism, including metabolic inhibitors, modulators, and combination strategies. This review aims to introduce immunometabolic reprogramming as a new frontier to enhance the efficacy of cancer immunotherapy and improve patient outcomes.
    Keywords:  CAR-T engineering; Immunometabolism; cancer heterogeneity; checkpoint blockade; metabolic reprogramming; precision oncology.; tumor microenvironment
    DOI:  https://doi.org/10.2174/0115665240435650260516221100
  18. ACS Chem Biol. 2026 Jun 13.
    Comparative Interactome Profiling of Itaconate and α-Ketoglutarate by the Peptide-Centric Local Stability Assay.
    Yunzhu Meng, Chenlin Zhang, Anqi Yu, Yuan Liu, Chu Wang.
      Itaconate (ITA) is an immunoregulatory metabolite that is significantly upregulated in macrophages during bacterial infection. It can mediate immune and metabolic responses through both covalent modifications and noncovalent interactions with key proteins. While covalent itaconation has been systematically mapped using chemical probes, the global landscape of noncovalent targets of itaconate remains poorly explored. Here, we applied the peptide-centric local stability assay (PELSA) to globally profile the interactome of ITA in macrophage lysates. PELSA successfully identified known ITA targets and assigned ITA-responsive regions that correspond to authentic binding pockets. Comparative profiling with a structurally similar metabolite, α-ketoglutarate (AKG), further revealed the functional crosstalk between the two ligands. We biochemically validated the cytosolic isocitrate dehydrogenase 1 (IDH1) as a target of ITA, in which noncovalent interaction played a critical functional role. This study provides a valuable resource and underscores the importance of metabolic crosstalk between ITA and AKG.
    DOI:  https://doi.org/10.1021/acschembio.6c00419
  19. Cell Mol Life Sci. 2026 Jun 13.
    RNF34 restrains endometriosis through SREBP1-dependent metabolic-immune crosstalk.
    Chenjing Yue, Zilong Li, Mengze Wang, Jie Zhang, Shiyu Du, Xiaofang Ge, Jiayu Liu, Chao Lu, Wushan Li, Zhenhai Yu.
      Endometriosis is a chronic inflammatory disease with cancer-like features, yet the mechanisms linking metabolic dysregulation to immune remodeling during lesion progression remain poorly understood. Here, we identify the ubiquitin E3 ligase RNF34 as a central suppressor of endometriosis that integrates cell-intrinsic metabolic control with macrophage-mediated immune regulation. Mechanistically, RNF34 directly interacts with SREBP1 and promotes its K48 and K63-linked ubiquitination and proteasomal degradation, thereby restraining lipogenic gene expression and fatty acid synthesis in endometrial stromal cells. Functionally, RNF34 suppresses stromal cell proliferation, clonogenic growth, migration, and invasion in an SREBP1-dependent manner. Loss of RNF34 stabilizes SREBP1, leading to excessive synthesis and extracellular release of monounsaturated fatty acids, particularly oleic acid. Oleic acid acts as a paracrine metabolic cue that drives macrophage polarization toward an immunosuppressive M2-like phenotype, which in turn reinforces endometriotic cell proliferation, migration, and resistance to apoptosis, establishing a feed-forward metabolic-immune circuit. In vivo, genetic ablation of RNF34 markedly accelerates endometriosis development, accompanied by increased accumulation of M2 macrophages within ectopic lesions, whereas pharmacological inhibition of SREBP1 or macrophage depletion using clodronate liposomes significantly suppresses lesion growth. Consistently, human endometriotic tissues exhibit reduced RNF34 expression that inversely correlates with SREBP1 abundance and M2 macrophage markers. Collectively, our findings define an RNF34-SREBP1-oleic acid axis that links lipid metabolism to immune remodeling in endometriosis, revealing a metabolically driven therapeutic vulnerability.
    Keywords:  Endometriosis; Lipid metabolism; Macrophage polarization; RNF34; SREBP1
    DOI:  https://doi.org/10.1007/s00018-026-06290-2
  20. iScience. 2026 Jun 19. 29(6): 116258
    3-Hydroxypropionic acid converts inflammatory macrophage glycolysis into mitochondrial oxidation through GAPDH carboxyethylation.
    Kefei Wu, Yankun Jia, Qi Lin, Fu Wang, Tianyue Liu, Mengjie Gao, Baodong Gao, Yumeng Zhu, Sifeng Xiong, Dong Sun, Ling Li, Huanyu Lu, Ping Zhu, Yue Zhai.
      Macrophages dynamically reprogram their metabolic states in response to environmental stimuli, thereby exerting distinct immune functions. In our preliminary study, a gut microbiota-derived metabolite, 3-hydroxypropionic acid (3-HPA), is increased in chronic inflammation and generates cysteine carboxyethylated neoantigens. However, the role of such metabolite-induced modification in regulating the function of macrophages remains obscure. Here, we show that 3-HPA alleviates inflammation in a mouse model of sepsis and inhibits the macrophage inflammatory response. Mechanistically, 3-HPA induces glyceraldehyde-3-phosphate dehydrogenase (GAPDH) carboxyethylation, which promotes GAPDH degradation via the ubiquitin-proteasome pathway, thereby suppressing its enzymatic activity and expression to inhibit glycolysis. Concomitantly, reduced GAPDH activity elevates the NAD+/NADH ratio, which enhances mitochondrial oxidation by upregulating arginine biosynthesis and the TCA cycle pathway. Overall, our research reveals the mechanism by which GAPDH carboxyethylation mediates metabolic reprogramming and regulates inflammation during inflammatory macrophage activation.
    Keywords:  cell biology; immunology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.116258
  21. J Pharmacol Sci. 2026 Aug;pii: S1347-8613(26)00027-7. [Epub ahead of print]161(4): 119-129
    Dendrobine alleviates lung injury in septic mice by inhibiting mitochondrial-endoplasmic reticulum crosstalk-mediated NLRP3 inflammasome activation.
    Shichao Zhang, Kaihang Luo, Xinyue Wei, Cheng Qing, Jianguo Zhang, Huazhang Wei, Yongan Yan, Yuting Yang, Zhenguo Zeng, Shuying Huang.
      Sepsis, a life-threatening disorder driven by a dysregulated host response to infection, is frequently accompanied by acute lung injury (ALI), worsening disease severity, and mortality. Excessive macrophage-mediated inflammation is central to its pathogenesis. Given emerging evidence that mitochondria-endoplasmic reticulum (ER) crosstalk drives inflammatory injury, we investigated whether modulating this interaction could mitigate sepsis-induced damage. Using LPS-stimulated THP-1 macrophages and a murine model of LPS-induced sepsis, we evaluated the anti-inflammatory and organ-protective effects of dendrobine, a bioactive alkaloid from Dendrobium nobile Lindl. Dendrobine suppressed glycolysis-induced mitochondria-ER crosstalk, thereby reducing macrophage-driven inflammation and tissue injury. In vivo, dendrobine lowered circulating interleukin (IL)-1β and IL-18 levels and alleviated ALI. Mechanistically, dendrobine decreased reactive oxygen species production and mitochondrial DNA (mtDNA) release, leading to downregulation of NLRP3 and cleaved caspase-1. These effects stemmed from inhibition of hypoxia-inducible factor-1α (HIF-1α) and hexokinase 2 (HK2)-mediated glycolysis, preventing HK2 dissociation from voltage-dependent anion channel 1 (VDAC1) and disrupting IP3R-GRP75-VDAC1 complex formation. Collectively, these findings demonstrate that dendrobine protects against sepsis-induced organ injury by targeting the IP3R-GRP75-VDAC1-HK2 axis in macrophages, highlighting its therapeutic potential for sepsis.
    Keywords:  Acute lung injury(ALI); Dendrobine; Hexokinase2(HK2); Mitochondria-associated endoplasmic reticulum membrane (MAMs); Sepsis
    DOI:  https://doi.org/10.1016/j.jphs.2026.05.007
  22. J Transl Med. 2026 Jun 19.
    Glycolytic reprogramming in cancer: tumour cell metabolism, immune modulation, and therapeutic opportunities.
    Lei Wang, Fangfang Liu, Yuxuan Wei, Qingzhu Jia, Bo Zhu, Qian Chu.
       BACKGROUND: Aberrant metabolism is a hallmark of tumours. Cancer cells develop metabolic patterns distinct from those of normal cells, characterized by the conversion of glucose into lactate under both aerobic and hypoxic conditions. The intermediates and end products generated in this process modulate the function and survival of immune cells within the tumour microenvironment (TME).
    METHODS: In this review, we summarize recent advances in the interplay between glycolysis and the immune microenvironment, potential therapeutic targets within the glycolytic pathway, and the clinical translation of glycolysis-related molecules.
    MAIN BODY: Through in-depth research into the glycolytic process, it has been found that the aberrant glycolytic metabolism of tumor cells not only supports their own proliferation but also reshapes the tumor microenvironment. This, in turn, forces immune cells to alter their metabolic profiles, ultimately resulting in an imbalanced anti-tumor immune response. To date, multiple small-molecule inhibitors targeting key molecules and nodes in the glycolytic pathway have been developed, some of which demonstrate promising anti-tumor efficacy in preclinical models.
    CONCLUSION: The review emphasizes the significance of glycolysis in shaping the immune response within the TME and underscores the therapeutic potential of targeting glycolytic pathways, with several inhibitors showing promise for future clinical translation.
    Keywords:  Glycolysis; Immune regulation; Lactate; Therapeutic targets; Tumour microenvironment
    DOI:  https://doi.org/10.1186/s12967-026-08418-1
  23. Front Cell Infect Microbiol. 2026 ;16 1870765
    Editorial: Immunometabolic circuits in host-pathogen interaction.
    Jaime David Acosta-España, Samuel Martins Gonçalves, Diana Santos-Ribeiro, Relber Aguiar Gonçales, Ricardo Silvestre, Rita Silva-Gomes.
      
    Keywords:  CRP; IgA; NK cell; bacteria; immunometabolism; iron; macrophages; virus
    DOI:  https://doi.org/10.3389/fcimb.2026.1870765
  24. Cell Death Dis. 2026 Jun 15.
    CD300e modulates metabolic programs in adipose tissue macrophages during obesity.
    Sara Coletta, Simone Pizzini, Stefania Vassallo, Elisabetta Trevellin, Annica Barizza, Sofia Giacometti, Gabriele Sales, Mattia Laffranchi, Silvano Sozzani, Marta Murgia, Agnese De Mario, Cristina Mammucari, Fabrizia Carli, Camilla Bean, Amalia Gastaldelli, Roberto Vettor, Marina de Bernard.
      Previous studies in monozygotic twins discordant for body mass index (BMI) revealed that individuals with obesity exhibit elevated expression of the immune receptor CD300e in white adipose tissue (WAT). Notably, CD300e levels decreased following weight loss, implicating its involvement in adipose tissue remodeling and metabolic regulation. To elucidate the functional role of CD300e, we employed a Cd300e knockout (Cd300e-/-) mouse model subjected to a high-fat diet (HFD). Our findings demonstrate that CD300e deficiency exacerbates obesity-associated metabolic dysfunction, including increased weight gain, adipocyte hypertrophy, hepatic steatosis, and impaired glucose and insulin sensitivity. Adipose tissue macrophages (ATMs) lacking CD300e displayed reduced lipid and glucose uptake, alongside diminished mitochondrial respiration-a phenotype consistent with a broader metabolic impairment, as evidenced by proteomic profiling. These metabolic deficits were genotype-dependent and persisted after 16 weeks of HFD. Concurrently, adipocytes from Cd300e-/- mice exhibited enhanced lipogenesis and attenuated lipolysis. Remarkably, the impaired metabolic fitness exhibited by Cd300e-/- mouse macrophages was recapitulated in human cells upon gene silencing. Collectively, these results establish CD300e as essential for ATM metabolic activation, positioning it as a key regulator of adipose tissue homeostasis and a critical mediator of obesity-induced metabolic dysfunction. Given its pivotal role, CD300e emerges as a promising therapeutic target for modulating adipose tissue function and improving metabolic health in obesity.
    DOI:  https://doi.org/10.1038/s41419-026-08974-w
  25. Cell Rep. 2026 Jun 18. pii: S2211-1247(26)00454-7. [Epub ahead of print]45(7): 117376
    Remodeling of the immune-metabolic landscape triggered by long-term high-altitude exposure.
    Jiaqi Wang, Yutong Dong, Ruoyi Xue, Yi Huang, Wubin Yang, Chen Zhang, Yangkai Zhang, Fengsheng Wang, Ran Yang, Jiangjun Wang, Meng Yu, Yixiao Xu, Manying Guo, Yanping Tian, Rui Jian, Junlei Zhang, Yan Ruan, Yan Hu.
      Immunometabolic remodeling drives adaptation to long-term high-altitude exposure (LTHAE), yet the underlying mechanisms remain elusive. By integrating single-cell transcriptomics and metabolomics from 46 lowlanders following a 90-day LTHAE, we identified a strategy of "innate activation and adaptive suppression." Neutrophils exhibited enhanced maturation and phagocytosis, whereas adaptive immunity was dampened, characterized by suppressed B cell function and T cell responsiveness. Metabolically, LTHAE induced systemic shifts in steroid and amino acid metabolism associated with immune remodeling. Furthermore, multi-omics integration indicated a conserved upregulation of the glycolysis-TCA-OXPHOS axis across immune lineages, a metabolic adaptation supported by enzymatic assays in hematopoietic tissues of a hypobaric hypoxia mouse model. Collectively, these findings provide integrated insights into immune-metabolic landscape remodeling and suggest a potential mutual regulatory relationship between immune and metabolic state following LTHAE, offering a molecular foundation for high-altitude adaptation research.
    Keywords:  CP: immunology; CP: metabolism; high-altitude exposure; hypoxia adaptation; immune dysregulation; metabolic reprogramming; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2026.117376
  26. Cell Cycle. 2026 Dec;25(1): 1-21
    FCGR2B drives immunosuppressive M2 polarization of tumor-associated macrophages via metabolic reprogramming of fatty acid oxidation.
    Zexu Han, Pei Rao, Fuzhou Wang, Yunying Xing, Xueling Guo, Chao Du, Yingze Wang.
      FCGR2B, the only inhibitory receptor in the Fcγ receptor family, plays a crucial role in both innate and adaptive immunity. In this study, we observed high FCGR2B expression in tumor-associated macrophages (TAMs) induced by B16 melanoma cells. Knockdown of Fcgr2b in these TAMs suppressed their M2 polarization, as evidenced by decreased expression of immunosuppressive factors, including Arg-1, IL-10, and Fizz1. Furthermore,Fcgr2b knockdown enhanced the phagocytic and antigen-presenting capacities of TAMs, promoted ROS production, and improved their ability to kill melanoma cells in vitro. Transcriptomic analysis revealed thatFcgr2b knockdown predominantly affected key metabolic and signaling pathways, including the JAK-STAT and PPAR-γ pathways. Using classic pharmacological inhibitors (2-DG and C75), we confirmed that FCGR2B interference remodels glycolipid metabolism in TAMs, which is characterized primarily by attenuated fatty acid metabolism, accompanied by increased glycolysis and intracellular free fatty acid accumulation. Moreover, FCGR2B interference downregulated the fatty acid oxidation key enzyme CPT1a by inhibiting the JAK/STAT6/PPAR-γ signaling axis, thereby reducing fatty acid oxidation. Concomitantly, it alleviated endoplasmic reticulum stress via the IRE1/XBP1 pathway, ultimately attenuating the tumor-promoting phenotype of TAMs. Our findings delineate a mechanism by which FCGR2B integrates metabolic and signaling pathways to regulate TAM function, providing a mechanistic basis for targeting FCGR2B in cancer immunotherapy.
    Keywords:  FCGR2B; M2 polarization; glycolipid metabolism; tumor-associated macrophages
    DOI:  https://doi.org/10.1080/15384101.2026.2684942
  27. Front Immunol. 2026 ;17 1850399
    Glycolytic reprogramming in ovarian cancer: mechanisms, immune crosstalk, and therapeutic implications.
    Jiao Fu, Yi Dai, Qiaoling Wang, Xiayu Qian.
      Ovarian cancer is characterized by extensive peritoneal dissemination, frequent recurrence, and chemoresistance. Glycolytic reprogramming has emerged as a central metabolic adaptation in ovarian cancer, but its significance extends beyond increased glucose consumption. In this review, we summarize how key glycolytic regulators, including GLUT1, HK2, PFKFB3, PDK1, and LDHA, are controlled by oncogenic, microenvironmental, and non-coding RNA-mediated pathways to reshape tumor metabolism. We emphasize that glycolysis supports ovarian cancer progression by promoting biosynthetic activity, redox balance, invasive dissemination, stem-like plasticity, and therapy resistance. Importantly, this review highlights glycolysis as an immunometabolic regulator of the ovarian tumor microenvironment. Lactate accumulation, macrophage reprogramming, IL-1β/NF-κB signaling, PD-L1 induction, and CD4+ T-cell metabolic remodeling collectively contribute to immune escape. Targeting glycolytic pathways may therefore provide therapeutic opportunities not only to suppress tumor growth but also to enhance chemotherapy and immunotherapy. However, metabolic heterogeneity, compensatory pathway activation, limited biomarkers, and insufficient clinical validation remain major challenges. A glycolysis-centered understanding of ovarian cancer may support biomarker-guided combination strategies and improve translational therapeutic design.
    Keywords:  chemoresistance; glycolysis; immune crosstalk; metabolic reprogramming; ovarian cancer
    DOI:  https://doi.org/10.3389/fimmu.2026.1850399
  28. Front Immunol. 2026 ;17 1746043
    The SIRT1/STAT3 axis as a central regulator of immune, inflammatory, and lipid metabolic dysregulation in rheumatoid arthritis: therapeutic implications.
    Chengzhi Cong, Yuan Wang, Jian Liu.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, joint destruction, and systemic comorbidities, particularly cardiovascular disease (CVD) associated with severe dyslipidemia. The bidirectional crosstalk between immune-inflammatory processes and lipid metabolic disturbances is increasingly recognized as a key driver of RA pathogenesis, yet the molecular mechanisms integrating these domains remain poorly understood. This review synthesizes current evidence to propose the Sirtuin 1 (SIRT1)/signal transducer and activator of transcription 3 (STAT3) axis as a central regulator of immune, inflammatory, and lipid metabolic dysregulation in RA. SIRT1, an NAD+-dependent deacetylase, functions as a metabolic sensor with anti-inflammatory and lipid-regulating properties, whereas STAT3 acts as a proinflammatory transcription factor driving Th17 differentiation, synovial hyperplasia, and metabolic reprogramming. SIRT1 directly deacetylates and inactivates STAT3, establishing an antagonistic yin-yang relationship. In RA, chronic inflammation and metabolic stress suppress SIRT1 and hyperactivate STAT3, creating a positive feedback loop that perpetuates immune imbalance and lipid dysfunction. We further discuss therapeutic strategies targeting this axis, including SIRT1 activators, STAT3 inhibitors, and dietary interventions such as n-3 polyunsaturated fatty acids, which hold promise for simultaneously mitigating inflammation and correcting metabolic abnormalities in RA. This integrated perspective challenges the traditional siloed approach and opens new avenues for immunometabolic therapy in RA.
    Keywords:  SIRT1/STAT3; immunometabolism; lipid dysregulation; rheumatoid arthritis; therapeutic target
    DOI:  https://doi.org/10.3389/fimmu.2026.1746043
  29. J Transl Med. 2026 Jun 19.
    Resveratrol derivative restores macrophage cholesterol homeostasis via stabilizing xanthine oxidoreductase in hepatocellular carcinoma.
    Guojun Liang, Lin Zeng, Xiaohui Huang, Qingqing Ma, Hongyu Wang, Yi Wang, Ting Liu, Xiaoxin Tu, Jianxin Peng, Huijie Huang, Wendao Liu, Peifeng Ke, Jun Yan, Min He.
       BACKGROUND: Tumor-associated macrophages (TAMs) are key determinants of the immunosuppressive microenvironment in hepatocellular carcinoma (HCC) and critically influence the efficacy of immunotherapy. However, how metabolic regulators shape TAM immunophenotypes and subsequent CD8⁺ T cell dysfunction in HCC remains incompletely understood.
    METHODS: Single-cell RNA sequencing data and primary tumor samples from patients with HCC were used to characterize xanthine oxidoreductase (XOR) expression on TAMs, and to clarify the underlying mechanisms mediating the effects of XOR⁺ monocytes/macrophages on CD8⁺ T cells. An in-house small-molecule library was screened to identify compounds capable of modulating XOR activity, followed by mechanistic and therapeutic validation in vivo.
    RESULTS: We identified a marked downregulation of XOR expression in TAMs within HCC tumors, which was significantly associated with poor clinical outcomes. Mechanistically, loss of XOR disrupted PPARγ signaling and cholesterol homeostasis in macrophages, driving their polarization toward an alternatively activated, immunosuppressive M2 phenotype. XOR-deficient TAMs exhibited an impaired capacity to support CD8⁺ T cell activation through enhancing PD-L1 expression, thereby facilitating tumor progression. Notably, a resveratrol derivative, Res616, directly bound to and stabilized the XOR protein, restoring cholesterol metabolic balance and reversing the immunosuppressive phenotype of TAMs. Therapeutically, targeting XOR with Res616 significantly enhanced intratumoral CD8⁺ T cell responses and synergized with anti-PD-L1 therapy to suppress tumor growth in murine HCC models.
    CONCLUSIONS: Our study identified XOR as a pivotal metabolic checkpoint governing TAM-mediated immunosuppression in HCC. Pharmacological stabilization of XOR to restore macrophage cholesterol homeostasis represented a previously unrecognized strategy to remodel the tumor immune microenvironment and improve the efficacy of immune checkpoint blockade.
    Keywords:  Cholesterol metabolism; Hepatocellular carcinoma; Immunotherapy; Resveratrol derivative; Tumor-associated macrophages; Xanthine oxidoreductase
    DOI:  https://doi.org/10.1186/s12967-026-08433-2
  30. Am J Physiol Endocrinol Metab. 2026 Jun 15.
    Glutamine metabolism shapes the phenotypic adaptation of uterine dendritic cells in response to early allogeneic pregnancy.
    Songchen Cai, Agnes Wieczorek, Christopher Urbschat, Maria Emilia Solano, Yong Zeng, Petra Clara Arck, Lianghui Diao, Kristin Thiele.
      The impact of metabolic reprogramming on immune cell functions is increasingly recognized. However, it remains largely unexplored in terms of immune cells adaptation during reproduction. Dendritic cells (DC) are crucial for establishing and maintaining pregnancy by orchestrating maternal immune adaptation essential for embryo implantation and decidualization. Here, we characterized the phenotypic and metabolic characteristics of DCs during early pregnancy in an allogeneic mouse model and in response to the specific deletion of hormonal receptors on DCs. Frequency of uterine CD11c+ DCs on gestational day (gd) 7.5 remained equal to that of non-pregnant mice. However, we observed a functional shift from cDC1 to cDC2 in pregnant mice. In parallel, a metabolic switch in uterine DCs was identified by upregulation of genes representing fatty acid synthesis (Fasn, Acaca), fatty acid oxidation (Cpt1a), and glutamine-related metabolic pathways (Got2). The cell-specific deletion of the glucocorticoid receptor in DCs reduced their MHCII expression, accompanied by a reduction in Got2 expression. Glutamine deprivation in vitro dramatically reduced the absolute number of cultured bone marrow cells and the frequency of cDC1s while simultaneously increasing the frequency of cDC2s. Collectively, these findings establish glutamine metabolism as a key driver of DC adaptation during early pregnancy, revealing novel metabolic-immunological crosstalk at the maternal-fetal interface.
    Keywords:  Allogeneic pregnancy; Dendritic cells; Glutamine; Immunometabolism; Pregnancy hormones
    DOI:  https://doi.org/10.1152/ajpendo.00520.2025
  31. J Immunol. 2026 Jun 07. pii: vkag146. [Epub ahead of print]215(6):
    Metabolic adaptations of inflammatory macrophages govern ferroptosis susceptibility via the GCH1-BH4-iNOS axis.
    Julia Sauer, Patricia P Ogger, Jasmina Dukic, Alina Nessensohn, Svenja Gabler, Ann-Katrin Schwenzer, Julia Kirstin Unsöld, Birgit Maria Cortès, Barbara Steigenberger, Nuria Fernandez Perez, Alexander Strasser, Rodrigo Dias Requiao, Ulrike Schleicher, Eva Griesser, Tom Bretschneider, Florian Gantner, Matthew James Thomas, Carolin Kirstin Watson, Karim Christian El Kasmi, Peter J Murray.
      In inflammatory tissue niches, macrophages encounter intense oxidative stress due to their own production of reactive oxygen and nitrogen species as part of antimicrobial defense. Our findings reveal that inflammatory macrophages deploy distinct, context-dependent redox-protective mechanisms to survive this self-inflicted stress, thereby avoiding ferroptotic cell death. Specifically, LPS-activated macrophages, M(LPS), rely on the GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway for ferroptosis resistance, whereas LPS + IFN-γ-activated macrophages, M(LPS-IFN-γ), depend primarily on nitric oxide produced by inducible nitric oxide synthase (iNOS)-with the BH4 pathway suppressing cell death in the absence of nitric oxide. These distinct adaptations highlight a novel GCH1-BH4-iNOS axis that governs macrophage ferroptosis susceptibility. In both the LPS or the LPS + IFN-γ-activated settings, the redox-protective phenotype is reversible: Removal of inflammatory stimuli abolishes the protection, indicating that this metabolic programming requires continuous stimulation and is not a permanently fixed state. These findings uncover redox metabolism-guided metabolic distinctions between inflammatory macrophages and reveal how they preserve viability over prolonged inflammatory activation. Ultimately, our findings establish the GCH1-BH4-iNOS axis as a central, targetable mechanism to manipulate macrophage ferroptosis resistance for therapeutic purposes.
    Keywords:  lipopolysaccharide; monocytes/macrophages; nitric oxide
    DOI:  https://doi.org/10.1093/jimmun/vkag146
  32. Front Immunol. 2026 ;17 1795042
    Mechanisms and therapeutic advances of gut metabolites in the regulation of neuroimmune inflammatory diseases.
    Xiaodan Shen, Caiji Zheng, Renyong Lin, Juan Wang, Zheng Chen.
      Gut-derived metabolites function as critical signaling intermediaries that translate environmental cues into central nervous system (CNS) responses, playing an indispensable role in the pathogenesis and trajectory of neuroimmune inflammatory disorders. Key metabolites, including short-chain fatty acids (SCFAs) and bile acids, either traverse the blood-brain barrier directly or orchestrate immune modulation peripherally, thereby fine-tuning the dynamic crosstalk between systemic immunity and neural homeostasis. SCFAs exert potent anti-inflammatory effects by promoting regulatory T-cell (Treg) differentiation through activation of G protein-coupled receptors (GPCRs) on immune cells and inhibition of histone deacetylases (HDACs). Within the CNS, they further confer neuroprotection by suppressing the pro-inflammatory activation of microglia and astrocytes. In contrast, bile acids display a context-dependent, "double-edged sword" effect: while certain subtypes activate the anti-inflammatory TGR5 receptor, neurotoxic metabolites (e.g., taurolithocholic acid) can accumulate and directly provoke pro-inflammatory polarization of microglia, thereby fueling neuroinflammation. Dysbiosis of the gut microbiota and consequent metabolite profile alterations are strongly implicated in neuroimmune inflammatory diseases-such as multiple sclerosis (MS), Alzheimer's disease (AD), and neuromyelitis optica spectrum disorders (NMOSD) -which are characterized by both a distinct metabolite imbalance and a pervasive pro-inflammatory immune milieu. Building on this framework, novel therapeutic strategies targeting the "gut-immune-brain axis" are evolving along two complementary avenues: (1) Immune-centric approaches that directly modulate neuroimmune pathways (e.g., by tempering microglial activation or expanding Treg populations); and (2) Microbiota-centric interventions that employ specific probiotics, prebiotics, or metabolite supplements to restore gut ecological balance, systemically recalibrate immunity, and mitigate neuroinflammation. Future research must prioritize elucidating the precise molecular dialogues between metabolites and immune cell subsets, conducting large-scale clinical validation, and advancing personalized, precision-medicine strategies. Such efforts will solidify a novel systemic perspective and strategic paradigm for preventing and treating neuroimmune inflammatory diseases.
    Keywords:  gut metabolites; gut-immune-brain axis; immunomodulation; neuroimmune inflammatory diseases; precision medicine
    DOI:  https://doi.org/10.3389/fimmu.2026.1795042
  33. Nat Commun. 2026 Jun 17.
    Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.
    Yuhan Zhou, Jing Li, Fangfang Liu, Yuan Gao, Songlin Yin, Liguo Yang, Xiaoxiao Li, Junhong Lin, Yan Li, Haotian Shang, Xiang Cheng, Tengfei Chao, Qian Chu, Fujia Lu, Weimin Wang.
      Therapeutic strategies targeting cancer metabolism are advancing rapidly. However, perturbing distinct nodes within the same metabolic pathway often yields divergent outcomes. Ferroptosis, a metabolic cell death driven by lipid peroxidation, has garnered attention for potentiating antitumor immunity. Here, we demonstrate that interruption of fatty acid oxidation (FAO) at hydroxyacyl-CoA dehydrogenase (HADHA) node promotes tumoral ferroptosis, whereas targeting upstream enzymes does not. HADHA inhibition causes accumulation of hydroxylated C18 (C18-OH) acylcarnitine to exacerbate mitochondrial lipid peroxidation. In vivo, HADHA ablation or acylcarnitine C18-OH supplementation suppresses tumor growth, enhances antitumor T-cell immunity, and potentiates PD-1 blockade therapy. Clinically, elevated plasma acylcarnitine C18-OH correlates with improved prognosis and immunotherapy response in lung cancer patients. Trimetazidine, an approved anti-ischemic drug and HADHA inhibitor, similarly delays tumor progression and augments immunotherapy. Together, our findings identify HADHA as a ferroptosis regulator and offer a clinically actionable strategy to enhance ferroptosis and immunotherapy through metabolic intervention.
    DOI:  https://doi.org/10.1038/s41467-026-74430-0
  34. Eur J Immunol. 2026 Jun;56(6): e70219
    Plasmacytoid Dendritic Cells Exhibit High Transferrin Receptor Expression Without Iron Accumulation.
    Carrie Corkish, Simon O'Shaughnessy, Claire Lin, Sophia Wugk, Sarah Kenny, Linda Sinclair, Suzanne Cloonan, David Finlay.
      Plasmacytoid dendritic cells (pDCs) are specialized antiviral sentinels defined by rapid type I interferon (IFN‑I) production, yet their proteomic organization and metabolic requirements remain incompletely understood. We established the steady‑state proteome of murine splenic pDCs directly ex vivo using deep, absolute quantitative mass spectrometry and compared it with conventional dendritic cell subsets and human pDCs. pDCs exhibited a highly conserved proteomic architecture across species, with selective divergence in central carbon metabolism, amino‑acid utilization, and nutrient transporter expression. Notably, pDCs expressed exceptionally high levels of the transferrin receptor (TFRC) in both mice and humans and displayed robust transferrin‑mediated iron uptake relative to other splenic immune populations. Despite this, pDCs did not demonstrate increased total cellular iron or enhanced ferritin‑based storage. Instead, proteome‑wide iron mapping revealed preferential allocation of iron to functional iron-sulfur and heme‑containing proteins, particularly within mitochondrial pathways. Detection of the iron exporter ferroportin indicated coordinated iron import and efflux, establishing sustained iron flux rather than net accumulation. Functional assays showed that iron availability does not constrain TLR9‑induced IFN‑I or TNF production. Together, these data define a conserved iron‑handling program in pDCs characterized by high TFRC expression, balanced iron flux, and targeted redistribution into essential protein systems.
    Keywords:  CD71; TFRC; dendritic cells; interferons; metabolism; nutrient transport; pDC; plasmacytoid; proteomics; transferrin receptor
    DOI:  https://doi.org/10.1002/eji.70219
  35. J Neuroinflammation. 2026 Jun 13. pii: 199. [Epub ahead of print]23(1):
    Neuroglial P2Y1 receptor signalling differentially contributes to inflammatory neurodegeneration.
    Charlotte Schubert, Ricardo Lopes Fonseca, Alexandros Hadjilaou, Vanessa Vieira, Karoline Degenhardt, Anna Lena Seemann, Alice Hakimy, Jana K Sonner, Peter Ludewig, Tim Magnus, Marion Schneider, Christa E Müller, Daniela Hirnet, Manuel A Friese.
      Extracellular adenosine triphosphate (ATP) and diphosphate (ADP) act as key signalling molecules in the central nervous system (CNS) and regulate neuroinflammatory responses through purinergic receptors. Although astrocytes and neurons undergo profound changes in signalling and metabolism during inflammation, the contribution of specific purinergic pathways to inflammation-induced neurodegeneration remains unclear. Here we show that the ADP/ATP-activated Gq-coupled receptor P2Y1 drives astrocyte-mediated neurotoxicity in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Using plasma membrane-targeted luciferase reporter mice, we demonstrate that extracellular ATP levels are increased during acute EAE. This was accompanied by elevated astrocytic P2ry1 expression, which is also observed in inflammatory MS lesions. In vivo, pharmacological inhibition or astrocyte-specific deletion of P2Y1 reduced disease severity, astrocytosis, and neuronal loss, whereas neuron-specific deletion exerted only modest effects. Mechanistically, astrocytic P2Y1 signalling promoted cytokine-induced ERK activation, inflammatory gene expression, and metabolic reprogramming in vitro. In contrast to supernatants from stimulated P2Y1-deficient astrocyte culture, supernatants derived from stimulated P2Y1-proficient astrocytes reduced neuronal viability, demonstrating neurotoxic effects mediated by astrocyte-derived factors. In contrast, neuronal P2Y1 signalling primarily contributed to oxidative stress and mitochondrial dysfunction. Together, these findings identify astrocytic P2Y1 as a key regulator of neuroinflammatory damage and a potential therapeutic target.
    Keywords:  Adenine nucleotides; EAE; Neuroinflammation; Neuron-glial crosstalk; Purine receptors
    DOI:  https://doi.org/10.1186/s12974-026-03904-1
  36. Cytotechnology. 2026 Aug;78(4): 137
    Pam3Csk4 regulates glycolysis in PMN-MDSCs and attenuates their immunosuppressive effect on T cells.
    Mengyue Dang, Qingchi He, Linqiang Deng, Yueting Li, Rong Li, Yiguo Chen.
      To investigate the effects of Pam3Csk4 treatment on glycolysis, proliferation-related features, and immunosuppressive functions of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), as well as the subsequent impact of PMN-MDSCs on T cell proliferation. Because MRSA infection is frequently associated with antibiotic resistance and host immunosuppression, this study aimed to explore Pam3Csk4 as a potential non-antibiotic immunomodulatory strategy. An immunosuppression mouse model was established via daily LPS injections. Bone marrow MDSCs were magnetically sorted, and PMN-MDSCs versus M-MDSCs were identified by flow cytometry. PMN-MDSCs derived from both in vitro induction and in vivo models were treated with Pam3Csk4. The expression of glycolytic markers (HK2/3, LDHA, PKM2) was analyzed using qPCR and Western blot. ARG1 levels were measured by ELISA, while proliferation-related proteins were detected via WB. Additionally, CD3+ T cells isolated from heat-inactivated MRSA-immunized mice were co-cultured with Pam3Csk4-pretreated PMN-MDSCs for 72 h to evaluate CD4+ and CD8+ T cell distribution. The LPS-induced model was used to generate an immunosuppressive MDSC-enriched condition, whereas heat-inactivated MRSA immunization was used to assess antigen-associated T-cell responses under controlled experimental conditions. LPS-treated mice showed an MDSC-enriched immunosuppressive condition characterized by increased MDSC-related myeloid populations in bone marrow. Pam3Csk4 treatment of PMN-MDSCs modulated the expression of glycolysis-related markers, including HK2/3, LDHA, and PKM2, in a time-dependent manner and significantly increased lactate production. Functionally, Pam3Csk4 treatment modestly reduced M-MDSC proportions and markedly decreased ARG1 levels in supernatants, while modulating proteins associated with PMN-MDSC proliferation/differentiation and immunosuppression. Notably, combined treatment with Pam3Csk4 and MRSA enhanced the expression of selected glycolysis-related markers in a time- and marker-dependent manner. In co-culture experiments, although heat-inactivated MRSA immunization increased splenic CD3+ T cells, Pam3Csk4 pretreatment significantly attenuated the inhibitory effect of PMN-MDSCs specifically on CD3+ CD4+ T cell proliferation and altered CD4+/CD8+ T-cell subset distribution. Pam3Csk4 treatment activates the glycolytic pathway in PMN-MDSCs and modulates proliferation/differentiation-related markers and immunosuppressive function, thereby weakening the ability of PMN-MDSCs to suppress CD3+ CD4+ T cell proliferation. These findings suggest that metabolic regulation of PMN-MDSCs by Pam3Csk4 may represent a potential immunomodulatory approach for improving host immune responses during MRSA-associated immunosuppression or immune dysregulation.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-026-01006-7.
    Keywords:  Glycolysis; PMN-MDSCs; Pam3Csk4; T cells
    DOI:  https://doi.org/10.1007/s10616-026-01006-7
  37. Curr Opin Hematol. 2026 Jun 22.
    Nutrition as a regulator of hematopoietic stem cell biology and transplantation.
    Sophia Shi, Ying Liang.
       PURPOSE OF REVIEW: Nutrition is increasingly recognized as a biologically active regulator of hematopoietic stem cell (HSC) function and transplant recovery. This review summarizes recent advances linking nutrient availability, metabolic signaling, and the gut-marrow axis to HSC maintenance and hematopoietic stem cell transplantation (HSCT) outcomes.
    RECENT FINDINGS: Recent work supports a model in which nutrient sensing, glucose, amino acid and lipid metabolism, mitochondrial redox control, and microbiome-derived metabolites collectively shape HSC quiescence, regenerative capacity, immune recovery, and susceptibility to transplant-related complications. Dietary states such as caloric restriction, fasting, obesity, and high-fat diet exposure alter HSC behavior through metabolic, inflammatory, and niche-mediated pathways. In HSCT, nutritional status before and after transplantation appears to interact with mucosal injury, microbial disruption, graft-versus-host disease (GVHD), infection, and overall outcomes, although causal evidence remains limited.
    SUMMARY: Nutrition should be viewed as more than a background component of supportive care in hematology. A better mechanistic understanding of how diet and metabolism influence HSC biology may help define biomarker-informed and clinically actionable nutritional strategies to improve transplant recovery.
    Keywords:  hematopoietic stem cell; hematopoietic stem cell transplantation; metabolism; microbiome; nutrition
    DOI:  https://doi.org/10.1097/MOH.0000000000000940
  38. Front Immunol. 2026 ;17 1871148
    Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.
    Zhenyuan Xu, Qingli Zhou, Jifei Miao.
      Intercellular mitochondrial transfer has emerged as a significant mode of communication within the tumor microenvironment (TME). We propose that this process operates as a stress-adaptive organelle economy, redistributing three biologically decisive assets (respiratory competence, redox tolerance, and stress history) among tumor, immune, and stromal cells according to local metabolic asymmetry. Cancer cells acquire healthy mitochondria from stromal and immune populations, thereby restoring oxidative phosphorylation, expanding metabolic plasticity, and driving chemoresistance. Tumor cells also engage in outward transfer that is recipient-selective. Damaged mitochondria may be exported to CD8+ T cells and fibroblasts, corrupting effector function and reprogramming the stroma, whereas functional mitochondria may be delivered to pro-tumor immune populations such as M2 tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells to sustain their immunosuppressive activity. Functional mitochondria therefore play a dual role in tumorigenesis. The consequences for antitumor immunity depend on donor identity, cargo quality, and recipient lineage rather than on transfer itself. The principal transport routes are tunneling nanotubes, extracellular vesicles, and cell fusion, but biological outcome is ultimately governed by a post-transfer fate checkpoint involving PINK1/Parkin-mediated mitophagy and USP30-facilitated retention. Therapeutically, the goal is not to block or enhance transfer globally but to achieve context-selective modulation within an inherently bidirectional system.
    Keywords:  cancer plasticity; extracellular vesicles; mitochondrial transfer; t cell exhaustion; tumor microenvironment; tunneling nanotubes
    DOI:  https://doi.org/10.3389/fimmu.2026.1871148
  39. Cell Rep. 2026 Jun 12. pii: S2211-1247(26)00622-4. [Epub ahead of print]45(6): 117544
    SARS-CoV-2 ORF3a blocks lysosomal cholesterol egress by disrupting VPS39-regulated NPC2 trafficking and BMP metabolism.
    Baley A Goodson, Valeria Montenegro Vazquez, Aliza Doyle, Oralia M Kolaczkowski, Rui Liu, Jingyue Jia, Morié Ishida, Chunyan Ye, Alison M Kell, Steven B Bradfute, Monica Rosas Lemus, Hu Wang, Xianlin Han, Jing Pu.
      Cholesterol homeostasis depends on lysosomes liberating cholesterol from degraded lipids. We show that SARS-CoV-2 blocks lysosomal cholesterol egress through the viral protein ORF3a. ORF3a binds the HOPS subunit VPS39 via the W193 and Y184 residues. Disrupting this interface restores cholesterol trafficking. Mechanistically, the ORF3a-VPS39 interaction exerts dual effects. First, it traps the retromer complex on endolysosomes, preventing endosome-to-Golgi recycling and mislocalizing the cholesterol transporter NPC2. Retromer deletion reproduced these defects, whereas the ORF3a W193A mutant restored retromer trafficking. Second, ORF3a-VPS39 interaction reduces bis(monoacylglycerol)phosphates (BMPs), lysosomal lipids required for cholesterol egress, by disrupting the transfer of their precursor, phosphatidylglycerols, from mitochondria. Lipidomics revealed increased mitochondrial and decreased lysosomal phosphatidylglycerol metabolites. Disturbing autophagy or mitochondrion-derived vesicles did not alter BMP levels, whereas ORF3a reduced mitochondrion-lysosome membrane contacts. These findings identify dual functions of VPS39-regulating retromer trafficking and BMP biosynthesis-and also reveal how ORF3a blocks lysosomal cholesterol egress.
    Keywords:  BMPs; CP: cell biology; CP: microbiology; HOPS; bis(monoacylglycero)phosphates; cellular cholesterol transport; lysosome-mitochondrion interactions; retromer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117544
  40. J Transl Med. 2026 Jun 13.
    The role of macrophage autophagy and mitochondrial metabolic reprogramming in the treatment of myocardial infarction.
    Gongchang Zhang, Fengjuan Hu, Yiping Deng, Daiping Li, Tingting Huang, Lixing Zhou, Yan Zhang, Xueling Deng, Chenying Fu, Birong Dong.
       BACKGROUND: Myocardial infarction (MI) is a life-threatening cardiovascular event, and preventing subsequent heart failure remains a major clinical challenge despite available treatments. The repair outcome critically depends on the cardiac immune microenvironment, where macrophages play a pivotal role. Their functional switch from pro-inflammatory to reparative phenotypes is driven by mitochondrial metabolic reprogramming, a process regulated by autophagy, particularly mitophagy. However, the integrated role of the macrophage autophagy-metabolism axis in post-MI repair is not fully systematized.
    MAIN BODY: This review comprehensively examines the interplay between macrophage autophagy and mitochondrial metabolic reprogramming. It details how mitophagy maintains mitochondrial fitness to suppress inflammation and fuel the oxidative metabolism essential for reparative macrophage function. The discussion extends to advanced regulatory mechanisms, including inter-organelle communication, mechanosensing, and intercellular mitochondrial transfer. Furthermore, the review evaluates emerging therapeutic strategies, such as precision nanomedicine and multi-target interventions, within complex clinical contexts like diabetic MI. Key challenges, including the spatiotemporal complexity of macrophage dynamics and translational bottlenecks, are also addressed.
    CONCLUSIONS: By synthesizing current insights, this review establishes a novel immunometabolic framework centered on the macrophage autophagy-metabolism axis. It highlights that targeting this axis holds significant therapeutic potential for optimizing cardiac repair. The review provides forward-looking perspectives, emphasizing the need for intelligent, spatiotemporally precise therapeutic platforms to advance the development of targeted therapies for MI.
    Keywords:  Autophagy; Cardiac repair; Immunometabolism; Macrophage; Mitochondrial metabolism; Myocardial infarction
    DOI:  https://doi.org/10.1186/s12967-026-08383-9
  41. Front Immunol. 2026 ;17 1844075
    T cell dysfunction and metabolic disruption in chronic hepatitis C virus infection.
    Bhavya Sajeet, Uma Ganapathi, Kiruthika Naganathan, Aarthi Parthasarathy, Pramod Darvin, Varun Sasidharan Nair.
      Hepatitis C virus (HCV) infection remains a major global health burden and a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Despite the availability of highly effective direct-acting antivirals, sustained immune dysfunction and long-term complications continue to challenge disease management. Chronic HCV infection is facilitated by multiple viral evasion mechanisms, including rapid sequence variation, disruption of innate antiviral signaling, and altered natural killer cell function. A key feature of disease progression is the dysfunction of virus-specific CD4+ and CD8+ T cells caused by prolonged antigen exposure. These cells gradually develop an exhausted phenotype marked by reduced proliferation, impaired cytokine production, and increased expression of inhibitory receptors such as PD-1, CTLA-4, TIM-3, and TIGIT. At the same time, intrahepatic accumulation of regulatory T cells further suppresses antiviral immune responses and promotes viral persistence. Recent studies also show that chronic HCV infection induces significant metabolic and mitochondrial dysfunction including oxidative stress, impaired bioenergetics, and altered glycolytic adaptation, all of which contribute to defective T cell responses and disease progression. Notably, some of these immune defects persist even after viral eradication because of stable transcriptional and epigenetic changes in exhausted T cells. This review summarizes current understanding of how T cell dysfunction, epigenetic programming, and metabolic disruption interact in chronic HCV infection. Understanding these interconnected mechanisms may guide the development of novel therapeutic strategies that combine antiviral, immunomodulatory, and metabolic interventions to achieve durable immune restoration and improved clinical outcomes.
    Keywords:  T cell exhaustion; epigenetic scarring; hepatitis C virus; mitochondrial dysfunction; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1844075
  42. Biochem Pharmacol. 2026 Jun 18. pii: S0006-2952(26)00519-8. [Epub ahead of print] 118180
    Anakinra prevents high glucose-mediated potentiation of IL-1β-induced NLRP3 inflammasome activation, small extracellular vesicle release and vascular inflammation.
    Inés Valencia, Xavier Vidal-Gómez, Álvaro San Hipólito-Luengo, Alicia Villacampa, Licia Shamoon, Ana Cuadrado-Gómez, Diego Berlanas-Vicente, Fernando de la Cuesta, Salvador Moncada, Jorge F Gomez-Cerezo, Carlos F Sánchez-Ferrer, M Carmen Martínez, Ramaroson Andriantsitohaina, Concepción Peiró.
      Cardiometabolic diseases, including diabetes mellitus, are complicated by vascular disease, a major driver of morbidity and mortality. Although hyperglycaemia contributes to vascular dysfunction, it does not fully explain the vascular complications observed in patients. Chronic low-grade inflammation and persistent release of pro-inflammatory cytokines as interleukin-1β (IL-1β) are increasingly recognized as central mediators of diabetic vasculopathy. However, the mechanisms by which elevated glucose amplifies inflammatory signalling and vascular dysfunction, and their pharmacological modulation, remain incompletely understood. We investigated the interplay between IL and 1β and high glucose in human aortic smooth muscle cells (HASMC) and its impact on NLRP3 inflammasome activation, cellular metabolism and small extracellular vesicles (sEV)-mediated intercellular communication. IL-1β induced NLRP3 inflammasome activation and a metabolic reprogramming characterized not only by a glycolytic shift, but also by activation of the pentose phosphate pathway and NADPH oxidase. IL-1β promoted the release of sEV enriched in inflammasome components, particularly caspase-1, which propagated inflammation and senescence in recipient vascular cells. High glucose alone had no effect but potentiated IL-1β-induced responses. Pharmacologically, blockade of IL-1R with anakinra prevented inflammasome activation, metabolic reprogramming and sEV release. Moreover, both anakinra and the NLRP3 inhibitor MCC950 impeded, at different levels, the potentiating effect of high glucose on IL-1β-driven responses, reinforcing the relevance of targeting the IL-1β-NLRP3 autoinflammatory axis. These findings reveal that high glucose potentiates IL-1β-driven vascular inflammation by altering bioenergetic flexibility and sEV signalling in human vascular cells, providing novel mechanistic insight into how IL-1β-targeted therapies may mitigate vascular complications in cardiometabolic disorders as diabetes.
    Keywords:  Diabetes mellitus; High glucose; Intercellular communication; Interleukin 1β; NLRP3 inflammasome; Small extracellular vesicles
    DOI:  https://doi.org/10.1016/j.bcp.2026.118180
  43. Front Immunol. 2026 ;17 1806015
    Immunometabolic and immune regulatory functions of capsaicin in cancer: mechanistic insights and emerging perspectives.
    Kun Xie, Zhihong Qi, Zhuo Chen, Rui Zhang, Liang Liu, Weini Li, Duoyao Cao, Daxing Xie, Jie Shen.
      Capsaicin, a natural bioactive alkaloid derived from chili peppers, has garnered increasing interest for its broad spectrum of pharmacological activities. Beyond its well-recognized analgesic, anti-inflammatory, and metabolic regulatory properties, accumulating evidence underscores its emerging roles in tumor suppression and immune modulation. Recent studies demonstrate that capsaicin profoundly influences the function and metabolism of diverse immune cell populations-including T cells, natural killer cells, macrophages, and dendritic cells-thereby enhancing antitumor immunity and immune surveillance. Building upon these findings, recent studies support combinatorial strategies that integrate capsaicin with conventional anticancer therapies to improve chemosensitivity and therapeutic efficacy. This review summarizes the latest advances in understanding how capsaicin regulates immunometabolism and remodels the tumor immune microenvironment, with an emphasis on the molecular mechanisms underlying its antitumor activity and potential implications for future therapeutic development.
    Keywords:  cancer therapy; capsaicin; immune cells; immune metabolism; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1806015
  44. Anal Chem. 2026 Jun 19.
    Cell-Resolved Mass Spectrometry Imaging Integrated with Isotope Tracing Elucidates Macrophage Polarization-Specific Metabolic Reprogramming.
    Min Li, Junjie Ge, Bangzhen Ma, Shiping Chen, Hongya Zhao, Mengxuan Li, Xiutong Zhang, Junwen Shi, Xiao Wang, Panpan Chen, Quanbo Wang, Chenglong Sun.
      Tumor-associated macrophages, pivotal regulators of antitumor immunity, exert dual functions through their tumoricidal M1 and tumor-promoting M2 phenotypes, which are closely linked to their metabolic states. While conventional mass spectrometry imaging (MSI) can characterize the metabolic features of macrophages, it fails to capture dynamic metabolic activity and real-time substrate utilization within individual cells. In this research, we present an integrated approach that couples cell-resolved matrix-assisted laser desorption/ionization (MALDI)-MSI with stable isotope tracing to visualize dynamic metabolic heterogeneity across individual macrophage phenotypes in situ. Using isotopically labeled fatty acids as metabolic tracers, we revealed that M1 macrophages exhibit significantly enhanced synthesis of phospholipids, including phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidic acid (PA), compared to M2 macrophages, highlighting a polarization-specific metabolic signature linked to their antitumor function. Moreover, we observed that coculture with tumor cells markedly downregulated the levels of newly labeled phospholipids in M1 macrophages. Critically, the pharmacological inhibition of cPLA2, a key enzyme in the phospholipid metabolic pathway, significantly impaired the antitumor efficacy of M1 macrophages. These findings collectively demonstrate the functional importance of phospholipid metabolism in sustaining macrophage-mediated antitumor immunity. We envision that this spatially resolved metabolic tracing strategy will open new avenues for investigating cell-resolved metabolic crosstalk in complex biological environments.
    DOI:  https://doi.org/10.1021/acs.analchem.6c02192
  45. J Immunol. 2026 Jun 07. pii: vkag120. [Epub ahead of print]215(6):
    Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.
    Paul L Lindau, Alex V Nesta, Caroline E Roe, Madelyn D Landis, Zaid Hatem, Allison E Sewell, Allison K Blount, Jackie E Bader, Reddy Anupama, W Kimryn Rathmell, Jonathan M Irish, Jeffrey C Rathmell, Kathryn E Beckermann.
      Checkpoint inhibitors have transformed cancer treatment, yet predicting responses remains challenging. Mitochondrial quality decreases in tumor infiltrating lymphocytes and correlates with impaired antitumor immunity in animal models. Mitochondrial membrane potential (MMP) increases with T cell activation and may also indicate cellular dysfunction. Here, we assessed the MMP of tumor-associated T cells as an indicator of cell phenotypes and immunotherapy responses in non-small cell lung carcinoma and clear cell renal cell carcinoma patients. Primary tumors were collected followed by analysis of peripheral blood mononuclear cells prior to and after 3 wk on treatment with immune checkpoint inhibitors (ICIs). Peripheral blood mononuclear T cells were analyzed for MMP using tetramethylrhodamine ethyl ester (TMRE) and sorted into high and low populations. TCRβ and single-cell RNA sequencing of primary tumors identified and characterized peripheral blood T cell clones associated with the tumor microenvironment. As anticipated, ICI therapy increased the frequency of effector T cells in patients who experienced clinical benefit. TMREhigh peripheral blood T cells with tumor-matching TCRβ sequences had elevated oxidative phosphorylation gene signatures. Gene signatures of stress and exhaustion, such as Tigit and Cmc1, were also elevated in the TMREhigh CD8 T cell populations, while gene expression patterns in TMRElow cells suggested mitochondrial fitness and cell longevity. Importantly, clinical benefit from ICIs was negatively correlated with the TMREhigh CD8 T cell gene expression signature. These findings highlight a T cell population characterized by elevated MMP that correlates with exhaustion-like transcriptional states and poor response to immunotherapy.
    Keywords:  T cells; checkpoint inhibitor; kidney cancer; lung cancer; metabolism; mitochondria
    DOI:  https://doi.org/10.1093/jimmun/vkag120
  46. J Exp Bot. 2026 Jun 19. pii: erag304. [Epub ahead of print]
    A viral protein promotes host L-asparaginase activity and weakens the asparagine-induced resistance pathway for the benefit of virus infection.
    Yong He, Xinyue Chen, Yuefei Guo, Yingqi Zhao, Siying Ye, Yanxiao Zhao, Lei Jiang, Xiaoyang Chen, Qiangqiang Zhu, Jing Chen.
      Amino acids are not only essential for plant nutrition but also serve as critical immune signaling molecules, particularly during pathogen invasion. Pathogens can manipulate amino acid metabolic pathways to counteract host immune defenses, yet the underlying mechanisms remain poorly understood. Here, we demonstrate that the Pepper mild mottle virus (PMMoV) 126 kDa protein interacts with host L-asparaginase (LA), identified as a negative regulator of antiviral defense. LA converts asparagine (Asn) to aspartic acid (Asp). Exogenous application of Asn markedly enhanced resistance to PMMoV, whereas Asp produced the opposite effect. Transcriptomic analysis revealed that Asn activates key antiviral immune pathways involving salicylic acid (SA), ethylene (Eth), and reactive oxygen species (ROS), while Asp suppresses them. Further experiments showed that the 126 kDa protein binds directly to the LA active region, enhancing its enzymatic activity and promoting Asn-to-Asp conversion, thereby weakening immune signaling. This process may also involve the VSR (viral suppressor of RNA silencing) function of the 126 kDa protein. Notably, LA also interacts with pathogenic proteins from other RNA viruses (e.g., CMV 2b, RSV NS3, TBSV P19) and facilitates Tomato bush stunt virus (TBSV) accumulation. This study elucidates how viruses exploit amino acid metabolism to promote infection and provides a novel strategy for environmentally friendly control of pepper viral diseases.
    Keywords:  L-asparaginase activity; PMMoV viral protein; ROS; SA; ethylene (Eth); virus infection
    DOI:  https://doi.org/10.1093/jxb/erag304
  47. Cell Death Dis. 2026 Jun 18.
    Labile iron starvation in embryonic Kupffer cells aggravates MASH via mitochondrial failure and macrophage dysfunction.
    Ke Wang, Garam An, Junho Park, Karina Cunha E Rocha, Zixuan Zeng, Houji Qin, Andrea Farrell, Alex Schlotthauer, Whasun Lim, Wei Ying.
      Metabolically-dysfunction-associated steatohepatitis (MASH) is characterised by embryonic Kupffer cell (emKC) loss and proinflammatory macrophage infiltration. While iron dysregulation is implicated in MASH, the role of labile iron (Fe2 + ) in mediating emKC survival and function remains unknown. In human and mouse MASLD/MASH livers, emKCs exhibit repressed iron metabolism, reduced labile iron pools, and mitochondrial dysfunction. KC-specific ferroportin knockout mice recapitulate these defects, accelerating Western diet-induced steatosis and fibrosis. Conversely, ferritin depletion restores emKC labile iron levels, mitigates mitochondrial damage, and attenuates disease severity. Fe2+ deficiency blunts Trem2 expression, whereas restoring Fe2+ homeostasis elevates emKC Trem2 abundance in MASH liver. Weight loss reverses hepatic iron dysfunction and restores emKC homeostasis. Our findings establish labile iron deficiency as a key driver of emKC loss and functional switch in MASH, linking iron metabolism to mitochondrial fitness and inflammation. Targeting emKC iron homeostasis could offer novel therapeutic strategies for MASLD/MASH.
    DOI:  https://doi.org/10.1038/s41419-026-08985-7
  48. Autoimmun Rev. 2026 Jun 19. pii: S1568-9972(26)00137-0. [Epub ahead of print] 104123
    The role of short-chain fatty acids as key mediators of gut microbiota - host crosstalk in athyroid diseases.
    Shuyan Shen, Juzhong Zhang, Xin Qi.
      The gut-thyroid axis has emerged as a pivotal area of research in endocrinology. Growing evidence suggests that gut microbiota (GM) dysbiosis is implicated in the pathogenesis of thyroid diseases. Short-chain fatty acids (SCFAs), key microbial metabolites, are proposed as critical mediators in this interplay, but a comprehensive synthesis of their roles is needed. This review provides an overview of the mechanisms and therapeutic potential of SCFAs in thyroid diseases. Patients with thyroid diseases commonly exhibit gut microbiota dysbiosis, characterized by reduced SCFA-producing bacteria and decreased systemic SCFA levels. Mechanistically, SCFAs regulate immune and metabolic homeostasis through G protein-coupled receptor signaling, histone deacetylase inhibition, mitochondrial metabolism, mTOR-S6K signaling, and intestinal barrier protection. Their deficiency may disrupt immune tolerance, promoting autoimmunity and tumor progression. However, current research remains largely correlative, with insufficient mechanistic evidence. SCFAs are central to gut-thyroid crosstalk. Targeting SCFA pathways through probiotics, prebiotics, or microbiota transplantation represents a promising therapeutic frontier. Future research must prioritize establishing causality using advanced models and validating these approaches in rigorous clinical trials to pave the way for personalized microbiome-based therapies for thyroid diseases.
    Keywords:  Graves' disease; Gut microbiota; Hashimoto's thyroiditis; Short-chain fatty acids; Thyroid diseases
    DOI:  https://doi.org/10.1016/j.autrev.2026.104123
  49. ACS Infect Dis. 2026 Jun 16.
    Enhanced Respiratory Electron Dissipation by Immunometabolites Promotes Mycobacterial Biofilm Longevity.
    Kaushik Poddar, Gunjan Tripathi, Snehal V Khairnar, Stuti Srivastav, Amitesh Anand.
      Mycobacterial species inhabit diverse ecological niches and frequently adopt a biofilm lifestyle, including within host environments, where this organization critically influences the persistence and pathophysiological outcomes. Here, using Mycobacterium smegmatis, we demonstrate that nitrate, a host-derived immunometabolite, markedly extends the biofilm lifespan. Mechanistically, nitrate sustains respiratory activity and suppresses the induction of the dormancy response. This effect is accompanied by the maintenance of intracellular redox balance, consistent with enhanced electron dissipation. Importantly, fumarate, a distinct host-relevant metabolite capable of facilitating electron dissipation, recapitulates this phenotype, indicating that the observed biofilm longevity is not limited to nitrate but instead is linked to the availability of alternative electron sinks. Together, our findings establish that the electron dissipation capacity is a key determinant of respiratory homeostasis and biofilm persistence in mycobacteria. We report a similar phenotype for M. abscessus, a nontuberculous opportunistic pathogen. These results highlight respiratory flexibility as a central adaptive axis through which mycobacteria exploit host metabolic cues to prolong survival.
    Keywords:  Biofilms; Dormancy response; Immunometabolites; Metabolism; Mycobacteria; Respiration
    DOI:  https://doi.org/10.1021/acsinfecdis.6c00483
  50. J Transl Med. 2026 Jun 13.
    ARF-like GTPase 8B orchestrates lipophagy and exocytosis to drive single-stranded RNA virus replication.
    Bonan Lv, Xingran Wang, Ying Zhou, Zihan Su, Yidan Sun, Li Zhou, Yang Lu, Zishu Pan, Xiao-Feng Tang, Chao Shen.
       BACKGROUND: Single-stranded RNA (ssRNA) viruses, including foot‑and‑mouth disease virus (FMDV), enterovirus 71 (EV71), and vesicular stomatitis virus (VSV), reprogram host lipid metabolism to facilitate replication. However, the mechanisms governing virus‑induced lipid droplet (LD) degradation remain poorly defined, which limits the development of host‑directed antiviral strategies.
    METHODS: We employed virological, biochemical, and imaging approaches to investigate the role of the lysosomal GTPase ARL8B in ssRNA virus infection. Lipid droplet dynamics, lipophagy, and lysosomal exocytosis were assessed using confocal microscopy and biochemical assays. Small‑molecule inhibitors targeting ARL8B were identified through virtual screening and validated in vitro for antiviral activity. The in vivo efficacy of selected inhibitors was evaluated in a murine EV71 infection model, with disease severity and survival as endpoints.
    RESULTS: ARL8B was identified as a central host factor that promotes replication of multiple ssRNA viruses by coordinating LD degradation with viral egress. Mechanistically, ARL8B drove lysosome‑dependent LD breakdown via selective lipophagy, releasing free fatty acids that fuel membrane remodeling within viral replication complexes. Concurrently, ARL8B facilitated viral exit through a noncanonical lysosomal-exosome pathway, enhancing progeny virus dissemination. Virtual screening yielded small‑molecule ARL8B inhibitors that potently suppressed ssRNA virus replication in vitro. In a murine EV71 infection model, these inhibitors provided robust protection and substantially reduced disease severity.
    CONCLUSIONS: Our findings establish ARL8B as a key host factor coupling lipid catabolism with viral export, and unveil a class of broad‑spectrum antiviral candidates targeting a lipid reprogramming node essential for multiple pathogenic RNA viruses. This study provides a mechanistic framework for developing host‑directed antiviral therapies against ssRNA viruses.
    Keywords:  ARL8B; Foot-and-mouth disease virus; LD degradation; Lysosomal–exosome pathways; Small-molecule inhibitors
    DOI:  https://doi.org/10.1186/s12967-026-08417-2
  51. Cell Rep. 2026 Jun 15. pii: S2211-1247(26)00634-0. [Epub ahead of print]45(6): 117556
    Microbial metabolites at the front line: Orchestrating gastrointestinal and systemic barrier immunity across the lifespan.
    Omry Koren, Maria Carmen Collado, Benoit Chassaing, Michael A Silverman, Liza Konnikova.
      Microbiota-derived metabolites are central mediators between commensal microbes and host immune system at mucosal barrier surfaces. Insights from mouse models have revealed precise molecular mechanisms by which numerous metabolites, including short-chain fatty acids, tryptophan catabolites and bile acid derivatives, regulate epithelial integrity, innate immune tone, and adaptive immunity and tolerance. Parallel studies in humans increasingly confirm these pathways and link metabolite dysregulation to diseases, such as inflammatory bowel disease, asthma, and atopic dermatitis. This review synthesizes current understanding of how microbial metabolites orchestrate gastrointestinal barrier immunity, while also integrating emerging insights into the gut-lung and gut-skin axes. Crucially, we examine these interactions through a developmental lens, highlighting how metabolite exposure during critical early-life "windows of opportunity" shapes long-term immune trajectories. We integrate evidence from experimental models and human data to highlight conserved mechanisms, species-specific divergences, and the therapeutic potential of targeting these metabolic pathways as strategies to promote barrier health and durable immune homeostasis.
    Keywords:  AHR ligands; CP: immunology; CP: microbiology; SCFA; barrier immunity; intestinal barrier; metabolites; mucosal immunity
    DOI:  https://doi.org/10.1016/j.celrep.2026.117556
  52. J Control Release. 2026 Jun 18. pii: S0168-3659(26)00514-6. [Epub ahead of print] 115111
    A TIGIT nanotrapping-guided STING-activatable immunometabolic strategy overcomes innate immune silence and T cell exhaustion in breast cancer.
    Shuai Guo, Xiaoke Wang, Huiwan Chen, Xiaopan Chen, Tianyu Li, Xueqin Shi, Baoyan Ou, Juntao Yuan, Zhilu Yang, Jun Zhou, Shaohui Deng, Yang Liu, Xing-Jie Liang, Caiwen Ou.
      Breast cancer exhibits a profoundly immunosuppressive tumor microenvironment (TME), where innate immune silence prevents antigen sensing and persistent T cell exhaustion limits effector responses, rendering most immunotherapies ineffective. Clinical profiling of 1093 The Cancer Genome Atlas (TCGA) cases identified a glucose-fueled glutathione (GSH)-glutathione peroxidase 4 (GPX4)-dihydrolipoamide S-acetyltransferase (DLAT) axis as a dominant metabolic shield that suppresses oxidative stress, and thereby enforces both stimulator of interferon genes (STING) silence and CD8+ T cell exclusion. To dismantle this barrier, we developed an immunometabolic nanotherapy, GOx/ES-CO-LDH@TIGIT-Nanotrap (TNT). In acidic tumors, proton-driven layered double hydroxide (LDH) disassembly releases glucose oxidase (GOx) and extremely small cuprous oxide (ES-CO). GOx depletes glucose and nicotinamide adenine dinucleotide phosphate (NADPH) to induce disulfidptosis, while ES-CO releases cuprous ions (Cu+) that trigger cuproptosis via binding to lipoylated mitochondrial proteins. Their mutual biochemical amplification produces a cycloacclerated disulfidptosis-cuproptosis cascade that collapses the GSH-GPX4-DLAT axis and restores STING activation. Meanwhile, the macrophage-derived T cell immunoreceptor with Ig and ITIM domains (TIGIT) Nanotrap sequesters CD155 to prevent T cell suppression. Together, this coordinated innate reactivation and adaptive rescue converts immune-cold tumors into STING-inflamed and T cell responsive lesions.
    Keywords:  Cuproptosis; Disulfidptosis; Innate immune silence; STING-activable immunometabolic nanotherapy; T cell exhaustion; TIGIT nanotrap
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115111
  53. Sci Rep. 2026 Jun 15.
    Mucosal-associated invariant T (MAIT) cells are reduced and dysfunctional in acute melioidosis.
    Fazle Rabbi Chowdhury, Martha Zewdie, Priyanka Abraham, Srija Moulik, Hadiza Adebowale, Jennifer Hill, Md Robed Amin, Lovely Barai, Md Rokibul Hasan, Ayako Kurioka, Patpong Rongkard, Direk Limmathurotsakul, Nicholas P J Day, Parinya Chamnan, Paul Klenerman, Chris B Willberg, Barbara Kronsteiner, Susanna J Dunachie.
      Burkholderia pseudomallei (BP), the causative agent of melioidosis, is a major cause of sepsis in Southeast Asia, especially in people with diabetes mellitus (DM). The role of Mucosal-associated invariant T (MAIT) cells; innate-like T cells important for antibacterial immunity; in melioidosis is unknown. We measured MAIT cell activation by BP in vitro using co-culture assays with THP-1 cells, and evaluated MAIT cell frequency, activation, and function ex vivo in an observational cohort (n = 120) of melioidosis patients and endemic controls with and without DM in Thailand. We show that BP induces IFN-γ secretion by MAIT cells in a cytokine dependent manner. In acute melioidosis, circulating MAIT cells, particularly the double-negative (DN) subset, were significantly reduced, and highly activated but dysfunctional, with reduced IFN-γ responses to BP and E. coli which were restored upon recovery. Among acute patients, non-survivors showed lower granzyme B and IFN-γ expression. Acute melioidosis patients with DM co-morbidity exhibited reduced DN MAIT cell frequency and responses to E. coli compared to non-DM patients. Overall, the frequency and function of MAIT cells is impaired during acute melioidosis, especially in patients with DM, indicating a key role for these cells in antibacterial defence and disease susceptibility.
    Keywords:  Diabetes; Melioidosis; Mucosal associated invariant T cells; Sepsis
    DOI:  https://doi.org/10.1038/s41598-026-57890-8
  54. Phytomedicine. 2026 Aug;pii: S0944-7113(26)00610-0. [Epub ahead of print]158 158378
    Ma-Xing-Shi-Gan decoction alleviates allergic asthma by modulating the gut microbiota-tryptophan metabolism-ILC2 axis.
    Mengmeng Lv, Chen Wang, Yanfei Hong, Fei Ye, Xiaoyu Cao, Zhixin Zheng, Enning Zhang, Jie Liu, Anqi Jia, Guiying Peng.
       BACKGROUND: Ma-Xing-Shi-Gan decoction (MXSG) shows clinical efficacy in asthma, yet how it shapes gut-lung immunity-particularly type 2 innate lymphoid responses-remains poorly defined.
    PURPOSE: To investigate whether MXSG mitigates asthma by restraining group 2 innate lymphoid cells (ILC2s) via a gut microbiota-tryptophan metabolic pathway, and to identify microbiota-dependent active compounds.
    METHODS: An asthma mouse model was used. ILC2 in the lung and intestinal lamina propria were assessed by flow cytometry. Rag1⁻/⁻ mice were used to assess T and B cell-independent effects. Untargeted fecal metabolomics and antibiotic-mediated microbiota depletion were conducted to evaluate metabolic and microbial contributions. Microbiota-dependent MXSG constituents were traced using anaerobic fecal fermentation coupled with LC-MS/MS profiling, followed by in vivo validation.
    RESULTS: MXSG significantly alleviated pulmonary inflammation, reduced bronchoalveolar lavage eosinophils and improved histopathology. It decreased ILC2s populations in lung and gut. These effects were preserved in Rag1⁻/⁻ mice but abolished with antibiotics pretreatment, indicating microbiota dependence. Metabolomics revealed that MXSG reprogrammed tryptophan metabolism, restoring tryptamine and rebalancing kynurenine, indole, and serotonin-related branches. Anaerobic fermentation and LC-MS/MS profiling identified microbiota-dependent flavonoids, and isorhamnetin partially reproduced the anti-inflammatory and ILC2-modulating effects in vivo.
    CONCLUSION: MXSG exerts its anti-asthmatic effects via the gut microbiota-tryptophan metabolism-ILC2 axis. These findings reveal a novel gut-lung mechanism centered on type 2 innate immunity and microbiota-derived indole metabolism.
    Keywords:  Asthma; Gut-lung axis; ILC2; Ma-Xing-Shi-Gan decoction; Tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.phymed.2026.158378
  55. Front Cell Infect Microbiol. 2026 ;16 1850127
    Amplified inflammatory and immune responses in viral-associated pulmonary aspergillosis.
    Xue Li, Guiying Xu, Jiancun Cao, Ruyu Yang, Shasha Fu, Zhonghua Qin, Lijia Xie, Hongxia Shao, Junping Wu, Huaiyong Chen.
       Background: Viral-associated pulmonary aspergillosis (VAPA) is a severe complication of viral pneumonia (VP) that is associated with pronounced inflammatory amplification, immune dysregulation, and increased mortality. However, systemic metabolic and immune response patterns accompanying VAPA remain incompletely understood.
    Methods: Plasma samples were obtained from 35 patients with viral pneumonia (VP group) and 20 with viral-associated pulmonary aspergillosis (VAPA group). An integrated multi-omics strategy combining data-independent acquisition (DIA)-based proteomics and untargeted metabolomics was used. In total, 1,930 proteins and 1,532 metabolites were identified. Differential analyses along with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to characterize host immune and metabolic alterations associated with viral-fungal coinfection.
    Results: Compared to patients with VP, those with VAPA showed more pronounced systemic inflammatory activity, immune dysregulation, hepatic and renal impairment, and coagulation abnormalities. Proteomic profiling revealed a higher abundance of proteins related to antioxidant responses, protein degradation pathways, and inflammatory and immune signaling in patients with VAPA. Metabolomic analyses indicated substantial alterations in lipid metabolism, increased oxidative stress-related metabolites, and dysregulation of hormone- and vitamin-associated metabolic pathways. Together, these proteomic and metabolomic patterns were associated with enhanced inflammatory burden, disrupted immune regulation, and greater disease severity.
    Conclusions: This study provides a systematic overview of immune and metabolic alterations in patients with VAPA. The observed multi-omics features offer insights into host responses associated with viral-fungal coinfection and provide potential theoretical support for early identification and targeted intervention of VAPA.
    Keywords:  aspergillus infection; immune dysregulation; metabolic reprogramming; oxidative stress; viral pneumonia
    DOI:  https://doi.org/10.3389/fcimb.2026.1850127
  56. iScience. 2026 Jun 19. 29(6): 116156
    Chronic hyperglycemia induces macrophage iron accumulation and promotes Mycobacterium tuberculosis virulence.
    Gaurav Kumar Chaubey, Rahul Dilawari, Radheshyam Modanwal, Sharmila Talukdar, Asmita Dhiman, Anil Patidar, Surbhi Chaudhary, Anurag Sindhu, Ajay Kumar, Chaaya Iyengar Raje, Manoj Raje.
      Tuberculosis-diabetes comorbidity represents significant global health challenges, though the underlying mechanisms remain poorly understood. Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, has a very high requirement of iron and its availability is a determining factor for successful establishment of infection. Host innate immune system and macrophages attempt to limit iron availability to restrict bacterial growth. We investigated the relationship between hyperglycemia and intracellular iron dynamics during infection using, THP-1-derived and primary macrophages from diabetic mice maintained under high-glucose conditions. Both showed increased intracellular iron along with higher expression of iron uptake receptors. Bacteria inside macrophages also contained more iron. Iron chelation significantly reduced M.tb burden in the lungs and spleen of infected diabetic mice. These findings suggest that hyperglycemia creates a "glucose legacy" that promotes iron accumulation, thereby increasing host susceptibility to M.tb infection, and reveals iron chelation as a promising adjunct therapeutic strategy.
    Keywords:  Immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.116156
  57. J Clin Invest. 2026 06 15. pii: e200316. [Epub ahead of print]136(12):
    Hyperglycemia aggravates vitiligo through succinate/SUCNR1-mediated T cell activation.
    Pan Kang, Yuqian Chang, Tingting Wang, Xiuli Yi, Yinghan Wang, Pengran Du, Jiaxi Chen, Baizhang Li, Shuli Li, Zhongjun Shao, Jianru Chen, Chunying Li.
      Vitiligo is an autoimmune skin disease characterized by depigmentation, mainly due to CD8+ T cell-mediated destruction of melanocytes. Hyperglycemia exacerbates autoimmune responses and is associated with vitiligo; however, the underlying immunometabolic mechanisms are poorly understood. Here, we demonstrated the correlation between hyperglycemia and vitiligo in a case-control study and demonstrated that hyperglycemia aggravated vitiligo based on a mouse model. Targeted metabolomics identified succinate as the potential metabolite mediating hyperglycemia-aggravated vitiligo. Mechanistically, succinate promotes the activation of CD8+ T cells through succinate receptor 1 (SUCNR1) and promotes keratinocytes to secrete CXCL9 and CXCL10 by enhancing the stability and nuclear translocation of hypoxia-inducible factor-1α, facilitating the skin-homing of CD8+ T cells. Thus, hyperglycemia aggravates vitiligo through succinate/SUCNR1 axis-regulated CD8+ T cell hyperactivation. Our study provides insights into the long-observed yet previously unclear mechanism by which hyperglycemia accelerates vitiligo progression and highlights SUCNR1 as a potential therapeutic target.
    Keywords:  Autoimmunity; Dermatology; Glucose metabolism; Immunology; Skin; T cells
    DOI:  https://doi.org/10.1172/JCI200316
  58. Cell Rep. 2026 Jun 15. pii: S2211-1247(26)00632-7. [Epub ahead of print]45(6): 117554
    Lonicera japonica polysaccharide restores mucosal integrity in ulcerative colitis by increasing microbiota-derived spermidine.
    Xinyu Bai, Xiuming Rao, Keke Tian, Chaoyu Wang, Hengyan Shen, Hong Li, Ping Liu.
      WLJP-025p, a homogeneous polysaccharide from Lonicera japonica Thunb., alleviates experimental ulcerative colitis in mice by reshaping the gut microbiota and restoring intestinal spermidine. Microbial fermentation, microbiota depletion, and microbiota transplantation support a microbiota-dependent mechanism. Microbiota-derived spermidine interacts with HADHA and partially reverses inflammatory HADHA-associated metabolic reprogramming, as shown by restored fatty acid oxidation (FAO), reduced lactate accumulation, improved basal respiration and etomoxir-sensitive oxygen consumption rate (OCR), and preserved epithelial integrity in Caco-2 cells and intestinal organoids. In vivo, WLJP-025p dose-dependently reduces colitis pathology and inflammation, partially reverses FAO-related metabolic disruption, and promotes epithelial maturation and barrier integrity. Serum biochemical and protein analyses further support reduced systemic inflammation and improved mucosal homeostasis. These findings define a microbiota-derived spermidine-HADHA axis that supports mucosal homeostasis in ulcerative colitis.
    Keywords:  CP: metabolism; CP: microbiology; Fatty acid oxidation; Gut microbiota; HADHA; Lonicera japonica polysaccharide; Mitochondrial metabolism; Spermidine; Ulcerative colitis; WLJP-025p
    DOI:  https://doi.org/10.1016/j.celrep.2026.117554
  59. Food Funct. 2026 Jun 15.
    Taurine supplementation at the crossroads of metabolism, inflammation and aging: mechanistic and nutritional perspectives.
    Benedikt Justus Beine, Melissa Castellano, Jarlei Fiamoncini, Karsten Hiller.
      Taurine is a non-proteinogenic β-amino acid that plays fundamental roles in cellular homeostasis. Although it is the most abundant free amino acid in many tissues, the full spectrum of its molecular functions has only recently begun to be elucidated. Taurine supplementation has shown promising outcomes in human studies, with emerging relevance in precision nutrition and the prevention of metabolic and age-related diseases. In this review, we summarize the current knowledge on taurine's molecular mechanisms, including its roles in antioxidant defense, anti-inflammatory signaling, calcium regulation, mitochondrial function, and lipid metabolism. We integrate mechanistic insights with evidence from clinical and nutritional studies examining taurine supplementation in the contexts of oxidative stress, inflammation, metabolic syndrome, and physical performance. Increasing data suggest that taurine can modulate key pathways linked to metabolism, inflammation, and healthy aging. Physiological synthesis and dietary intake appear sufficient to maintain basal health; however, human trials indicate that supplementation of 1-6 g day-1 may further promote metabolic resilience and mitochondrial function without adverse effects. Collectively, these findings position taurine as a promising dietary compound at the interface of metabolism, inflammation, and aging, highlighting its potential as a modulator of healthspan within precision nutrition strategies.
    DOI:  https://doi.org/10.1039/d6fo01808d
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