bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–07–05
38 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Glucose metabolic reprogramming: mechanisms and therapeutic implications in neuroinflammation.
  2. Single nucleotide variant in coenzyme Q6 reprograms macrophage metabolic remodeling in response to inflammatory signals.
  3. Immunometabolic reprogramming of Mycobacterium tuberculosis-responsive memory CD4+ T cell subsets is linked to long-term protective immunity.
  4. Yeast β-glucan supplementation supports immunometabolic anti-tumor responses and reverses obesity-induced dysfunction via trained hematopoiesis.
  5. Vitamin D supports activated CD4+ T-cell proliferation through enhanced glutaminolysis.
  6. Reactive species as regulators of immune cell metabolism, tolerance, and autoimmunity.
  7. The Impact of Cardiorespiratory Fitness on Cytotoxic T Cell Metabolism and Function.
  8. Myeloid HIF-1α Couples Glycolytic Energy Supply with NCF2-Dependent Oxidative Killing to Protect Against Klebsiella pneumoniae Pneumonia.
  9. α7 nicotinic acetylcholine receptor regulates decidual macrophage polarization through TLR4/NF-κB/HIF-1α-mediated glycolytic reprogramming in preeclampsia.
  10. GLUT1-driven glycolytic reprogramming in microglia promotes neuroinflammation and cognitive deficits in sepsis-associated encephalopathy.
  11. Fatty acid metabolism and lipid channeling in macrophages: mechanisms of inflammation, resolution, and lipotoxicity.
  12. Iron Regulates CD4 T Cell Quiescence by Controlling TGF-β Production.
  13. Paederoside alleviates rheumatoid arthritis by targeting SMAD4 to suppress histone lactylation through inhibiting lactate transport in senescent macrophages.
  14. Natural product FZJDXJ enhances CD8+ T-cell glycolysis to relieve exhaustion and augment antitumor immunity in HBV+ hepatocellular carcinoma.
  15. Cajaninstilbene acid in macrophage immunometabolism and angiogenesis: Mechanisms and therapeutic potential.
  16. IRG1/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa Alkylation in Subarachnoid Hemorrhage.
  17. Serotonin Degradation and Lipid Metabolism Regulate Human Tc2 Cell Effector Functions.
  18. Metabolic reprogramming of myeloid cells in cancer: from lactate-NAMPT axis to AI-guided therapeutics.
  19. Interplay between ischemia-reperfusion and metabolic reprogramming.
  20. Obesity-driven metabolic reprogramming and immune dysfunction in renal cancer.
  21. Targeting the cancer metabolism-immunity interface: update and perspectives.
  22. Bioengineered miR-148a-3p suppresses glycolysis and amino acid homeostasis in hepatocellular carcinoma cells by regulating multiple solute carrier transporters.
  23. The interplay between the microbiome and immune cells in metabolic homeostasis and disease.
  24. Neural-tumor crosstalk in driving tumor metabolic reprogramming.
  25. FABP4 as an immunometabolic hub in preeclampsia: from maternal-fetal interface to systemic inflammation.
  26. Epidermal Dominance of Metabolically Constrained Immune Niches Underpins Immune Activation Signatures and Clinical Severity in Psoriatic Disease.
  27. Multiomics reveals fatty acid metabolism and immune remodeling in retinal artery occlusion.
  28. Immunometabolism in Cardiovascular Disease: Linking Metabolic Reprogramming to Inflammation, Atherothrombosis, and Clinical Outcomes.
  29. Monocyte abundance and glycolytic reprogramming associate with motivational impairment in depression.
  30. Sodium Selenite Preconditioning Reprograms Mesenchymal Stem Cell Behavior Under Inflammatory Stress to Enhance Anti-Inflammatory Macrophage Responses.
  31. HIF-1α in CD4+ T cells drives gout pathogenesis via metabolic reprogramming and Th17 differentiation.
  32. Histidine metabolic reprogramming drives oxidative stress induced mtDNA release to promote necroptosis and airway inflammation in severe asthma.
  33. Mitochondrial STING Governs Glycolytic Reprogramming in Diabetic Cardiomyopathy.
  34. 4-Octyl itaconate ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by suppressing necroptosis in alveolar macrophages via Nrf2 activation.
  35. Lipocalin-2 Restores Mitochondrial and Antioxidant Adaptation in a Strain-Specific Manner During LPS Induced Sepsis.
  36. Imipramine inhibits feline infectious peritonitis virus infection by targeting host cholesterol metabolism via NPC1.
  37. Gut microbiota in type 2 diabetes mellitus: mechanistic links between dysbiosis, insulin resistance, and chronic low-grade inflammation.
  38. Targeting macrophage ferritin heavy chain mitigates ferroptosis and lung injury in experimental acute respiratory distress syndrome.
  1. Front Immunol. 2026 ;17 1737175
    Glucose metabolic reprogramming: mechanisms and therapeutic implications in neuroinflammation.
    Lan Zhang, Xinyue Yang, Xiaolin Ai.
      Microglia play dual and context-dependent roles in the central nervous system, contributing both to the maintenance of brain homeostasis and the propagation of neuroinflammatory responses. Under pathological conditions, microglia undergo profound glycolytic reprogramming, characterized by a shift from oxidative phosphorylation to enhanced aerobic glycolysis. This review focuses on the glucose-glycolysis-lactate metabolic axis and its pivotal role in microglial immunometabolism. We elucidated how key glycolytic enzymes (e.g., HK2, PKM2) and metabolites (e.g., lactate, pyruvate, ATP) regulate microglial function through both metabolic and non-metabolic mechanisms. Furthermore, therapeutic strategies that target this glycolytic shift to alleviate neuroinflammation were discussed. A deeper understanding of microglial glycolytic reprogramming may provide critical insights for developing novel therapies for neurodegenerative diseases.
    Keywords:  glycolysis; metabolic reprogramming; microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1737175
  2. Res Sq. 2026 Jun 22. pii: rs.3.rs-9986029. [Epub ahead of print]
    Single nucleotide variant in coenzyme Q6 reprograms macrophage metabolic remodeling in response to inflammatory signals.
    Xue Lin, Elizabeth M Todd, Edgar P Anaya, Sharon Celeste Morley.
      Macrophage metabolic remodeling sustains inflammatory responses to pathogens. At homeostasis, macrophages rely on oxidative phosphorylation (OXPHOS), but during inflammation, OXPHOS is downregulated and aerobic glycolysis increases. Increased flux through the tricarboxylic acid (TCA) cycle increases the availability of substrates, such as succinate, that promote pro-inflammatory transcription. While metabolic remodeling has been extensively characterized, the mechanisms governing the shift from OXPHOS to glycolysis remain unclear. We recently identified a single nucleotide variant (SNV) in a mitochondrial protein, coenzyme Q6 (COQ6), that accelerates OXPHOS downregulation during infection with the Gram-positive organism Streptococcus pneumoniae . Because the SNV converts an aspartate residue (D) to tyrosine (Y), we denote the variant as COQ6 DY . Here, we now systematically compare the inflammatory responses of macrophages expressing Coq6 DY or Coq6 WT after stimulation with the S. pneumoniae -derived pneumolysin (PLY), or with lipopolysaccaharide (LPS; a toxin derived from Gram-negative bacteria). We found that Coq6 DY reprograms macrophage mitochondrial metabolism by changing the balance between OXPHOS and glycolytic activity and relative TCA metabolite concentrations at homeostasis. Furthermore, responses to PLY varied by host genotype and by concentration of available glucose, whereas responses to LPS were less dependent upon genotype. We therefore identify a non-canonical function of COQ6 in governing mitochondrial metabolism.
    DOI:  https://doi.org/10.21203/rs.3.rs-9986029/v1
  3. Front Tuberc. 2026 ;pii: 1783887. [Epub ahead of print]4
    Immunometabolic reprogramming of Mycobacterium tuberculosis-responsive memory CD4+ T cell subsets is linked to long-term protective immunity.
    Vaishnavi Kaipilyawar, Samantha Leong, Arianne Lovey, Lorenzzo L Stringari, Reynaldo Dietze, Jerrold J Ellner, Rodrigo Ribeiro-Rodrigues, Padmini Salgame.
       Introduction: Memory CD4+ T cells are central to long-term immunity in tuberculosis (TB), yet their functional roles that define their protective capacity remain unclear. Understanding the immune mechanisms that prevent clinical progression from latent TB infection (LTBI) to active TB disease is critical for the development of next-generation vaccines and biomarkers.
    Methods: We characterized the transcriptomic, metabolic, and functional programs of Mycobacterium tuberculosis (Mtb) antigen-stimulated peripheral CD4+ T stem cell (T-SCM), central (T-CM), transitional (T-TM), and effector (T-EM) memory subsets from individuals with remote LTBI. We utilized a multi-platform validation strategy that integrated RNA-sequencing data with protein-level metabolic profiling using "Met-Flow" cytometry and functional growth restriction assays to link memory CD4+ T cell differentiation states to immunometabolism and antimycobacterial function. Finally, we evaluated the immunometabolic profiles of memory CD4+ T cell subsets in an independent, longitudinal cohort of Mtb-exposed progressors and non-progressors from Brazil (GSE112104).
    Results: We identified a differentiation gradient associated with distinct immunometabolic states. T-SCM and T-CM subsets exhibited elevated mitochondrial activity and oxidative metabolism (fatty acid oxidation), supporting their proliferative capacity. In contrast, T-TM and T-EM subsets underwent glycolytic reprogramming and engaged the pentose phosphate pathway, which fueled enhanced cytokine production and Mtb growth restriction. Importantly, we observed that non-progressors exhibit fatty acid oxidation-driven, stem/central memory-like signatures, while progressors and active TB cases display elevated exhaustion markers, glycolytic reprogramming and pro-inflammatory profiles aligned with disease progression.
    Conclusion: Collectively, findings from our proof-of-concept study suggest metabolic state as a key axis connecting Mtb antigen-induced memory T cell differentiation, restimulation-induced transcriptional programming, and durability of immune control. The findings provide the basis for future longitudinal studies to examine the dynamic metabolic and functional modulation in Mtb antigen-specific memory T cell subsets from contained infection to disease progression.
    Keywords:  central memory (T) CM; effector memory (T) EM; immunometabolism; latent TB (LTBI); memory CD4+ T cell subsets; stem cell memory (T) SCM; transitional memory (T) TM; tuberculosis
    DOI:  https://doi.org/10.3389/ftubr.2026.1783887
  4. Cell Rep. 2026 Jul 03. pii: S2211-1247(26)00726-6. [Epub ahead of print]45(7): 117648
    Yeast β-glucan supplementation supports immunometabolic anti-tumor responses and reverses obesity-induced dysfunction via trained hematopoiesis.
    Anna E Ledwith, Hannah Prendeville, Cian Jh Horneck Johnston, Stephen P Cunningham, John P McGrath, Carrie Corkish, Aaron M Walsh, Fatma Koc, Hugo Charles-Messance, Vasile Mihai Sularea, Caitlín Ní Chasaide, Heike C Hawerkamp, David K Finlay, Lydia Lynch, Kingston H G Mills, Catherine Stanton, Helen M Roche, Frederick J Sheedy.
      Obesity is associated with profound immune dysregulation, driving chronic inflammation while compromising host defense against tumors. While trained immunity can enhance innate effector functions, it has thus far required parenteral administration of microbial ligands. Here, we show that incorporating a yeast-derived β-glucan supplement in mouse diets induces trained immunity via reprogramming of hematopoietic stem and progenitor cells. This dietary intervention leads to sustained production of metabolically enhanced monocytes and macrophages that rescue anti-tumor immunity in high-fat diet-induced obese mice, and corrects immune dysfunction sustained after weight loss. Our work reveals that yeast β-glucans act as functional "immuno-nutrients," which remodel innate immunity and identifies the mucosal/bone-marrow axis as a target for dietary manipulations to restore immune resilience without impacting metabolism.
    Keywords:  CP: immunology; beta-glucan; dietary supplementation; hematopoiesis; immunometabolism; innate immunity; macrophage; monocyte; obesity; trained immunity; tumor immunity
    DOI:  https://doi.org/10.1016/j.celrep.2026.117648
  5. Front Immunol. 2026 ;17 1791098
    Vitamin D supports activated CD4+ T-cell proliferation through enhanced glutaminolysis.
    Agustín A Vera, Mauricio Hernandez, Ricardo A Cartes, Faryd Llerena, Solange E Cisterna, Romina A Quiroga, Sergio A Sanhueza, Camila P Muñoz-Grez, Francisco Vergara, Daniel Moena, Pablo A Alarcón, Rafael Burgos, Coralia I Rivas, Elena Uribe, Rafael J Argüello, Cristopher Almarza, Felix A Urra, Francisco Tapia-Belmonte, Luciano Ferrada, Liliana I Lamperti, Estefanía Nova-Lamperti.
       Background: Vitamin D (VitD) is an important immunometabolic regulator of T cell function. Its active form, 1,25-dihydroxyvitamin D3, signals through the VitD receptor (VDR), which is highly expressed in activated CD4+ T cells. Although VDR signaling suppresses glycolysis by reducing glucose uptake and glycolytic enzyme expression, early T cell expansion is preserved, suggesting the involvement of alternative metabolic pathways. Since glutaminolysis is essential for T cell activation and proliferation, we investigated whether VitD modulates glutamine metabolism during early CD4+ T cell activation.
    Methods: Human CD4+ T cells were stimulated with αCD3/CD28 for four days in the presence or absence of VitD, and analyzed using complementary metabolic, proteomic, and functional approaches.
    Results: VitD-treated cultures exhibited increased cell numbers despite reduced glucose uptake and lactate production, indicating proliferation partially independent of classical glycolytic metabolism. Proteomic analysis revealed increased expression of glutaminase, glutamate dehydrogenase, and CD38, together with enrichment of Selenium Metabolism and Selenoproteins and Nicotinate and Nicotinamide Metabolism, suggesting enhanced glutaminolysis and NAD+ remodeling. Consistently, tritiated and ¹³C-glutamine tracing demonstrated increased glutamine uptake and incorporation into glutamate, α-ketoglutarate, glucose, and inositol-related metabolites, supporting a glutaminolysis-dependent anabolic program rather than oxidative phosphorylation. Pharmacological inhibition of VDR (MeTC7, 1 nM), glutamine uptake (GPNA, 250 µM), or glutaminase activity (BPTES and compound 968, 5 µM) significantly reduced T cell expansion, highlighting glutamine metabolism as essential for the VitD-mediated cell expansion. Interestingly, prolonged cultures showed that VitD ultimately restricted proliferation at day 7; however, supplementation with glutamine and VitD restored cell expansion, suggesting that VitD promotes a metabolically restrained but adaptive proliferative state.
    Discussion: Overall, our findings identify glutaminolysis as a central metabolic pathway supporting VitD-induced CD4+ T cell expansion independently of canonical glycolytic and OXPHOS-associated programs, while promoting metabolic resilience and inflammatory restraint.
    Keywords:  T cell proliferation; T cell regulation; glutaminolysis; immunometabolism; vitamin D
    DOI:  https://doi.org/10.3389/fimmu.2026.1791098
  6. Cell Metab. 2026 Jun 29. pii: S1550-4131(26)00228-7. [Epub ahead of print]
    Reactive species as regulators of immune cell metabolism, tolerance, and autoimmunity.
    Takumi Kobayashi, Dirk Brenner.
      Reactive oxygen and nitrogen species (ROS and RNS) connect metabolism to immunity through dynamic spatially restricted chemical events. They regulate receptor signaling cascades, set kinase-phosphatase thresholds, and coordinate mitochondrial activity. Antioxidant systems keep this "signaling window" open by recycling oxidized targets using NADPH supplied by the pentose phosphate pathway, auxiliary enzymes, and 1-carbon metabolism. When generation and removal fall out of balance, hydroxyl radical and peroxynitrite accumulation causes oxidative stress and inflammatory signaling. The oxidized macromolecules perturb innate sensors and exacerbate inflammation, driving autoimmune diseases. Here, we review how reactive species shape immunometabolic regulation and autoimmunity. We first explain the chemical and metabolic foundations of reactive species generation in innate and adaptive immune responses. We then describe how redox imbalance breaks tolerance in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Finally, we outline targeted strategies that alleviate redox imbalance in autoimmune pathologies.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.002
  7. Med Sci Sports Exerc. 2026 Jun 30.
    The Impact of Cardiorespiratory Fitness on Cytotoxic T Cell Metabolism and Function.
    Justin C Crane, Charles F Hodgman, Rebekah M Maddux, Heather L Caslin, Mitzie Laughlin, Stacey L Gorniak, Emily C LaVoy.
       PURPOSE: Cardiorespiratory fitness (CRF) is associated with enhanced leukocyte metabolism. Whether CRF impacts the metabolism of specific leukocytes such as cytotoxic T cells (Tc) is unknown. As Tc metabolism and function, including interferon (IFN)-γ production, are linked, metabolic changes associated with higher CRF could impact Tc function. Therefore, this study aimed to determine whether CRF predicted Tc metabolism and function.
    METHODS: Forty-three adults (16 women) underwent a maximal oxygen consumption (VO2peak) test, had body fat percentage (BF%) measured, and donated resting blood. Tc mitochondrial mass, mitochondrial membrane potential, fatty acid and amino acid oxidation (FAO and AAO) capacity, glycolytic capacity, and IFN-γ expression were assessed via flow cytometry. Linear regression assessed CRF and BF% as predictors of metabolism and function. Analyses were conducted within total Tc and in Tc subsets.
    RESULTS: CRF predicted FAO and AAO capacity of Tc (ꞵ= 0.362; p= 0.017) and Tc subsets, and glycolytic capacity of Tc (ꞵ= 0.495; p< 0.001), central memory Tc (ꞵ= 0.304; p= 0.047), and effector memory re-expressing CD45RA (EMRA) Tc subsets (ꞵ= 0.451; p= 0.003). CRF also predicted IFN-γ expression by Tc (ꞵ= 0.384; p= 0.011), naïve Tc (ꞵ= 0.358; p= 0.020), and EMRA Tc subsets (ꞵ= 0.349; p= 0.022). Inclusion of BF% in models partially abrogated these relationships. CRF remained a significant predictor of Tc and EMRA Tc glycolytic capacity, and Tc function.
    CONCLUSIONS: CRF predicts Tc metabolism and function in healthy adults, where greater CRF associates with greater Tc FAO and AAO capacity, glycolytic capacity, and function. However, these relationships are in part attenuated by BF%, and Tc subsets exhibit differences in the degree to which they relate to CRF and BF%.
    Keywords:  AEROBIC CAPACITY; CD8+ T LYMPHOCYTES; IMMUNOMETABOLISM; MITOCHONDRIAL FUNCTION; SCENITH
    DOI:  https://doi.org/10.1249/MSS.0000000000004063
  8. Free Radic Biol Med. 2026 Jul 01. pii: S0891-5849(26)00913-5. [Epub ahead of print]
    Myeloid HIF-1α Couples Glycolytic Energy Supply with NCF2-Dependent Oxidative Killing to Protect Against Klebsiella pneumoniae Pneumonia.
    Yaqin Guo, Bao Meng, Rongqin Zhu, Si Dong, Shu Zhang, Jin Wang, Yasheng Li, Yi Yang, Yanyan Liu, Liang Yu, Jiabin Li.
       BACKGROUND: Hypervirulent Klebsiella pneumoniae (hvKp) induces severe pneumonia and sepsis. HIF-1α coordinates metabolic and immune responses in myeloid cells, but its role in hvKp-mediated pulmonary defense remains undefined.
    METHODS: Monocyte HIF-1α expression was assessed in patients with Klebsiella pneumoniae (K. pneumoniae) pneumonia. Myeloid-specific Hif-1α knockout mice and BMDMs were used to examine survival, bacterial burden, and macrophage function. RNA-seq, Seahorse flux analysis, and confocal microscopy were employed to investigate the regulatory effects of HIF-1α on phagocytosis and ROS production. The Hif-1α-NCF2-ROS signaling pathway was substantiated through the application of small interfering RNA (siRNA), JASPAR prediction tools, dual-luciferase reporter assays, chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), metabolic inhibitors, and dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α.
    RESULTS: Clinical data showed a negative correlation between monocyte HIF-1α levels and serum CRP, procalcitonin, ICU stay duration, and SOFA scores. In vivo, myeloid Hif-1α knockout mice demonstrated heightened susceptibility to hvKp, with markedly reduced survival and widespread bacterial dissemination. Mechanistically, Hif-1α-deficient macrophages displayed impaired phagocytosis, phagolysosomal maturation, and glycolytic reprogramming in response to infection. RNA-seq identified NCF2, encoding p67-phox, as a critical HIF-1α-dependent component of the NADPH oxidase complex. JASPAR prediction, dual-luciferase reporter assays, and ChIP-qPCR further demonstrated that NCF2 is directly transcriptionally regulated by HIF-1α. HIF-1α deficiency impaired both glycolytic ATP production and NCF2-mediated ROS generation, thereby compromising macrophage antibacterial activity. Inhibition of glycolysis or silencing NCF2 abolished HIF-1α-dependent defense, whereas pharmacological stabilization of HIF-1α using DMOG significantly enhanced host resistance.
    CONCLUSION: HIF-1α serves as a pivotal regulator of host defense in experimental hvKp pneumonia and is clinically associated with disease severity in K. pneumoniae pneumonia, linking glycolytic metabolism to the NCF2-ROS bactericidal pathway. These findings highlight the potential of targeting immunometabolic pathways to improve host defense against severe K. pneumoniae infections.
    Keywords:  Glycolysis; HIF-1α; Macrophage; NCF2; hvKp pneumonia
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.058
  9. Placenta. 2026 Jul 01. pii: S0143-4004(26)00312-7. [Epub ahead of print]182 217-228
    α7 nicotinic acetylcholine receptor regulates decidual macrophage polarization through TLR4/NF-κB/HIF-1α-mediated glycolytic reprogramming in preeclampsia.
    Hanbo Liu, Yuguo Deng, Lingyan Chen, Yuhong Long, Ying Gao, Jinying Yang.
       INTRODUCTION: Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by excessive inflammation at the maternal-fetal interface. The α7 nicotinic acetylcholine receptor (α7nAChR), a key mediator of the cholinergic anti-inflammatory pathway, is downregulated in decidual macrophages of PE patients, but the downstream mechanisms linking α7nAChR deficiency to macrophage inflammatory activation remain unclear. This study investigated whether α7nAChR deficiency promotes decidual macrophage M1 polarization through TLR4/NF-κB/HIF-1α-mediated glycolytic reprogramming.
    METHODS: Decidual tissues from PE patients and gestational age-matched healthy controls were analyzed by immunofluorescence, Western blot, qRT-PCR, Seahorse metabolic analysis, and ELISA. siRNA-mediated α7nAChR knockdown in THP-1-derived macrophages followed by LPS/IFN-γ stimulation was used to establish causality. Pharmacological inhibitors targeting TLR4, NF-κB, HIF-1α, or glycolysis were employed for pathway validation. Trophoblast function was assessed using macrophage-trophoblast co-culture systems.
    RESULTS: α7nAChR expression was significantly reduced in PE decidual macrophages and negatively correlated with TLR4, phosphorylated NF-κB, and HIF-1α levels. PE decidual macrophages exhibited enhanced M1 polarization, increased glycolytic enzyme expression, elevated extracellular acidification rate and pro-inflammatory cytokine secretion, with suppressed oxidative phosphorylation. In vitro, α7nAChR knockdown amplified LPS/IFN-γ-induced TLR4/NF-κB/HIF-1α signaling, glycolytic metabolism, and M1 polarization. These effects were attenuated by all four pathway inhibitors, confirming the hierarchical signaling cascade. Functionally, α7nAChR-deficient inflammatory macrophages induced trophoblast apoptosis and impaired invasion, both rescued by pathway inhibition.
    DISCUSSION: α7nAChR deficiency amplifies inflammatory stimuli-induced decidual macrophage M1 polarization through TLR4/NF-κB/HIF-1α-dependent glycolytic reprogramming, linking cholinergic anti-inflammatory pathway dysfunction to immunometabolic dysregulation at the maternal-fetal interface in PE. Targeting macrophage metabolic reprogramming may represent a potential therapeutic strategy for PE.
    Keywords:  Decidual macrophages; Glycolytic reprogramming; Preeclampsia; TLR4/NF-κB/HIF-1α; α7nAChR
    DOI:  https://doi.org/10.1016/j.placenta.2026.06.023
  10. Brain Res Bull. 2026 Jun 29. pii: S0361-9230(26)00314-X. [Epub ahead of print]243 112027
    GLUT1-driven glycolytic reprogramming in microglia promotes neuroinflammation and cognitive deficits in sepsis-associated encephalopathy.
    Hui Guo, Hongling Li, Hu Han, Yubo Wei, Shuaikang Liu, Keke Han, Hexin Zhai, Shimin Dong.
       BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe neurological complication driven by microglial neuroinflammation. Proinflammatory microglial activation requires glycolytic reprogramming, but whether GLUT1 governs this process in SAE remains unclear.
    METHODS: In vitro, LPS-stimulated BV2 microglia were transfected with siRNA targeting GLUT1 or GLUT3. Glucose uptake (2-NBDG), glycolytic flux (ECAR, lactate), mitochondrial respiration (OCR), glycolytic enzyme expression (HK2, PFKFB3, PKM2, LDHA), and inflammatory cytokine release were assessed. In vivo, SAE was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Hippocampal GLUT1 knockdown was achieved via stereotactic lentivirus injection. Cognitive function, neuronal damage, neuroinflammation, cerebral lactate/ATP levels, and glycolytic protein expression were evaluated.
    RESULTS: LPS significantly upregulated GLUT1, but not GLUT3, in BV2 cells. GLUT1 knockdown markedly suppressed LPS-enhanced glucose uptake, ECAR, lactate production, and expression of HK2, PFKFB3, PKM2, and LDHA, while restoring OCR and reducing TNF-α, IL-1β, and IL-6 secretion. GLUT3 knockdown showed no such effects. In SAE mice, hippocampal GLUT1 expression was increased. Hippocampal GLUT1 knockdown ameliorated cognitive deficits, attenuated hippocampal neuronal loss and Nissl body damage, reduced cerebral inflammatory cytokines and lactate, restored ATP content, and abrogated CLP-induced upregulation of glycolytic enzymes.
    CONCLUSIONS: GLUT1 is a critical metabolic checkpoint driving microglial glycolytic reprogramming and proinflammatory activation in SAE. Targeted GLUT1 knockdown in microglia alleviates neuroinflammation and cognitive impairment in experimental SAE models. These findings provide a proof-of-concept that metabolic checkpoint targeting may counteract microglial pro-inflammatory activation.
    Keywords:  GLUT1; Glycolysis; Microglia; Neuroinflammation; Sepsis-associated encephalopathy
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.112027
  11. Front Immunol. 2026 ;17 1839069
    Fatty acid metabolism and lipid channeling in macrophages: mechanisms of inflammation, resolution, and lipotoxicity.
    Temitayo T Bamgbose, Oluwakemi O Igiehon, Javier Nion-Fieira, Cora R Palmer, Andrii Andriichuk, Matthew D Woolard.
      Macrophages integrate metabolic signals with immune activation, and their ability to handle fatty acids is central to preventing lipotoxicity and to sustaining effector functions. In cardiometabolic settings such as obesity, metabolic dysfunction-associated steatotic liver disease, and atherosclerosis, chronic exposure to excess free fatty acids and toxic lipid species, such as ceramides, disrupts organelle integrity, impairs efferocytosis, and skews macrophages toward pro-inflammatory phenotypes. This review examines how macrophages channel fatty acids into β-oxidation, glycerolipid synthesis and storage, sphingolipid production, and polyunsaturated fatty acid-derived lipid mediator biosynthesis to shape the balance among metabolic adaptation, inflammatory activation, resolution, and lipid-induced dysfunction. We also highlight lipin-1 as a regulatory node at a key branchpoint in macrophage lipid metabolism. By linking glycerolipid synthesis, lipid storage, mitochondrial metabolism, and inflammatory signaling, lipin-1 illustrates how lipid routing can influence macrophage function in cardiometabolic disease.
    Keywords:  fatty acid metabolism; inflammation resolution; lipid channeling; lipotoxicity; macrophages
    DOI:  https://doi.org/10.3389/fimmu.2026.1839069
  12. bioRxiv. 2026 Jun 23. pii: 2026.06.18.733147. [Epub ahead of print]
    Iron Regulates CD4 T Cell Quiescence by Controlling TGF-β Production.
    Amber L Siglin, Zelong Han, Afia Nkansah, WanJun Chen, Cheong-Hee Chang.
      Transforming growth factor-β (TGF-β) regulates CD4 T cell quiescence, activation, and regulatory T cell differentiation, but its role in T cell iron metabolism is poorly defined. Here, we investigated whether TGF-β regulates iron homeostasis and how iron overload alters TGF-β responsiveness. During T cell activation, TGF-β enhanced survival but markedly reduced proliferation. These effects were accompanied by decreased CD71 expression and cytosolic iron availability, as well as increased mitochondrial iron accumulation. Genetic deletion of TGFβR1 reversed these changes, demonstrating that TGF-β regulates CD4 T cell iron homeostasis through TGFβR1-dependent signaling. Iron-overloaded CD4 T cells lacking the heme exporter FLVCR1 exhibit hypersensitivity to TGF-β, increased TGF-β secretion, and sustained TGFβR1 expression upon activation. Pharmacologic inhibition of TGFβR1restored proliferation, CD71 expression, and iron levels in FLVCR1-deficient cells. Although TGF-β selectively induced total and mitochondrial ROS levels in FLVCR1-deficient cells, antioxidant treatment or Nox2 inhibition did not rescue this phenotype, suggesting that ROS is associated with, but not sufficient to explain, TGF-β hypersensitivity. Acute FeSO 4 -induced iron overload partially recapitulated the phenotype of FLVCR1-deficient cells, although TGFβR1 expression and TGF-β production differed. Finally, regulatory T cells generated in vitro in the presence of TGF-β displayed reduced iron acquisition, and excess iron impaired FoxP3 induction. Together, this work identifies TGF-β as a context-dependent regulator of CD4 T cell iron homeostasis.
    DOI:  https://doi.org/10.64898/2026.06.18.733147
  13. Phytomedicine. 2026 Jun 29. pii: S0944-7113(26)00756-7. [Epub ahead of print]159 158523
    Paederoside alleviates rheumatoid arthritis by targeting SMAD4 to suppress histone lactylation through inhibiting lactate transport in senescent macrophages.
    Jiayao Chen, Jing Zhang, Yingjie Ma, Bocen Chen, Shaoqin Jian, Tong Chen, Wenguang Wang, Man Xiao.
       BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovial inflammation and progressive joint destruction. Senescent macrophages are key drivers of RA pathogenesis through metabolic reprogramming, leading to intracellular lactate accumulation and histone lactylation, which promotes the expression of pro-inflammatory cytokines and synovial hyperplasia. Paederoside, an iridoid glycoside from Paederia scandens, has demonstrated anti-inflammatory effects, but its precise molecular targets in RA remain unclear.
    PURPOSE: This study aimed to elucidate the mechanism by which paederoside alleviates RA by targeting the SMAD4-MCT1 axis to suppress lactate transport and histone lactylation in senescent macrophages.
    METHODS: A senescent RAW264.7 macrophage model was established using bleomycin (BLM). The effects of paederoside on macrophage polarisation, lactate metabolism, and histone lactylation were assessed using ELISA, qRT-PCR, Western blot, and immunofluorescence. Molecular docking, cellular thermal shift assay (CETSA), and dual-luciferase reporter assays were employed to validate the interaction between paederoside and SMAD4. A collagen-induced arthritis (CIA) mouse model was used to evaluate the therapeutic efficacy of paederoside in vivo.
    RESULTS: Paederoside significantly reduced BLM-induced lactate accumulation and H3K14 lactylation (H3K14la) in senescent macrophages by inhibiting monocarboxylate transporter 1 (MCT1) expression. Mechanistically, paederoside directly binds to SMAD4 at Arg100, blocking its nuclear translocation and transcriptional activation of Mct1. This led to decreased lactate influx, reduced H3K14la levels at the promoters of pro-inflammatory genes, including chemokines (Ccl7, Cxcl1) and matrix metalloproteinase Mmp1, and a shift from pro-inflammatory M1 to anti-inflammatory M2 macrophage polarisation. Consequently, paederoside suppressed the proliferation and invasion of synovial fibroblasts. In the CIA model, paederoside attenuated joint swelling, bone erosion, and synovial inflammation comparably to methotrexate.
    CONCLUSION: Paederoside alleviates RA by targeting SMAD4 to inhibit MCT1-mediated lactate transport, thereby suppressing histone lactylation and pro-inflammatory macrophage polarisation. These findings highlight the SMAD4-MCT1 axis as a promising metabolic-epigenetic target for RA therapy and support paederoside as a lead compound for the precision treatment of elderly RA patients.
    Keywords:  Cellular senescence; Glycolysis; Histone lactylation; MCT1; Paederoside; Rheumatoid arthritis (RA); SMAD4
    DOI:  https://doi.org/10.1016/j.phymed.2026.158523
  14. Front Nutr. 2026 ;13 1829200
    Natural product FZJDXJ enhances CD8+ T-cell glycolysis to relieve exhaustion and augment antitumor immunity in HBV+ hepatocellular carcinoma.
    Fengna Yan, Yuqing Xie, Ke Shi, Lihua Yu, Qun Zhang, Zhiyun Yang, Xianbo Wang.
       Objective: To investigate whether Fuzheng Jiedu Xiaoji Formula (FZJDXJ) reverses immunosuppression in HBV? hepatocellular carcinoma (HCC) by reprogramming CD8? T-cell glycolysis and enhance antitumor immunity.
    Methods: A translational study was conducted with 80 HBV? HCC patients, Hepa1-6 tumor-bearing mouse models and in vitro CD8? T-cell assays. Flow cytometry, GC/LC-MS metabolomics, Western blot and functional experiments were used to detect CD8? T-cell immunophenotype, glycolytic metabolism and antitumor activity. A 1-year overall survival (OS) prediction framework was constructed and validated.
    Results: FZJDXJ increased peripheral CD8? T-cell frequency, downregulated exhaustion markers (PD-1/CTLA-4/TIM-3) and upregulated glycolysis-related metabolites in patients, with metabolites correlating with CD8? T-cell function. In mice, FZJDXJ suppressed tumor growth, enhanced tumor-infiltrating CD8? T-cell cytotoxicity and glycolytic flux (GLUT1/HK2/PFKFB3/PKM2 upregulation). In vitro, FZJDXJ-containing serum dose-dependently promoted CD8? T-cell glucose uptake and glycolytic molecule expression. The OS prediction framework had high discriminatory power (AUC=0.946). No severe safety signals were observed.
    Conclusion: FZJDXJ alleviates CD8? T-cell exhaustion by enhancing glycolysis to strengthen antitumor immunity in HBV? HCC. Immunometabolism is a promising target for herbal interventions, and glycolysis-immune features may serve as prognostic stratifiers. Prospective trials and ICI combination studies are warranted.
    Keywords:  CD8+ T cell immunosuppression; Fuzheng Jiedu Xiaoji Formula; glycolysis metabolomic; hepatocellular carcinoma; immune response modulation
    DOI:  https://doi.org/10.3389/fnut.2026.1829200
  15. Pharmacol Res. 2026 Jun 29. pii: S1043-6618(26)00238-0. [Epub ahead of print]231 108323
    Cajaninstilbene acid in macrophage immunometabolism and angiogenesis: Mechanisms and therapeutic potential.
    Jiamei Liao, Xue Zhao, Yang Zhang, Qiaoqiao Ji, Xueping Wu, Jian Lin.
      Macrophage immunometabolism is an important regulator of inflammatory resolution and angiogenic responses. Aberrant macrophage polarization, accompanied by metabolic disturbances such as enhanced glycolysis and mitochondrial dysfunction, has been implicated in impaired angiogenesis in chronic inflammatory conditions. Cajaninstilbene acid (CSA), a natural stilbene derived from Cajanus cajan, exhibits anti-inflammatory, antioxidant, and metabolic regulatory activities. In non-diabetic inflammatory settings, including liver injury, ischemia-reperfusion injury, and inflammatory bowel disease, CSA promotes macrophage functional reprogramming and activates AMPK/Nrf2 signaling. Notably, these effects may facilitate a shift from glycolysis-associated inflammatory states toward oxidative phosphorylation-supported reparative macrophage states. VEGF, PDGF-BB, and SDF-1 are established mediators of macrophage-associated angiogenic responses. Their involvement in CSA-related regulation has yet to be examined. Several limitations warrant consideration. Direct experimental validation in disease-relevant contexts exhibiting sustained metabolic stress (e.g., diabetic wounds or chronic ischemia) has not yet been conducted. In addition, causal relationships between metabolic remodeling and macrophage phenotypic transition remain incompletely defined. The proposed involvement of CSA in exosomal miRNA regulation also awaits experimental confirmation. Throughout the article, experimentally supported findings are distinguished from mechanistic interpretation, with unresolved questions highlighted as priorities for future research. CSA may represent a potential modulator of immunometabolic dysfunction, although systematic validation in pathophysiologically relevant disease models is still required.
    Keywords:  Angiogenesis; Cajaninstilbene acid; Chronic inflammation; Immunometabolic reprogramming; Macrophage polarization; Natural product
    DOI:  https://doi.org/10.1016/j.phrs.2026.108323
  16. Aging Dis. 2026 Jun 23.
    IRG1/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa Alkylation in Subarachnoid Hemorrhage.
    Zeyu Zhang, Yanlin Chen, Weizhen Gao, Fengchen Zhang, Yichao Jin, Jie Li, Jiaqi Wang, Tao Lv, Feng Jia, Xiaohua Zhang.
      Aging is a potent risk factor for poor prognosis in subarachnoid hemorrhage (SAH), yet the molecular mechanisms underlying the age-related exacerbation of early brain injury remain incompletely understood. This study investigates the immunometabolic regulation of the microglial senescence-like transition following SAH, focusing on the immune-responsive gene 1 (IRG1)/itaconate axis. We observed that the endogenous upregulation of IRG1 and itaconate is a protective response to hemorrhagic stress that is significantly blunted in aged mice. Microglia-specific IRG1 deficiency exacerbated SAH-induced brain injury, characterized by an accelerated senescence-like transition and the secretion of senescence-associated secretory phenotype (SASP) factors. Mechanistically, we demonstrate that IRG1 deficiency leads to excessive mitochondrial fission and dysfunction via the hyperactivity of Dynamin-related protein 1 (Drp1). Using click chemistry-based proteomics and site-directed mutagenesis, we identified that itaconate exerts its neuroprotective effects by directly alkylating the small GTPase RhoA at the cysteine 107 (C107) residue. This specific post-translational modification inhibits RhoA-GTP binding and downstream ROCK1 activation, thereby suppressing Drp1-mediated mitochondrial fragmentation. Importantly, treatment with the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) rescued mitochondrial dynamics and attenuated microglial senescence and neurological deficits, whereas the RhoA-C107S mutation abolished these protective effects. Collectively, our findings unveil a novel metabolic-mitochondrial checkpoint involving the IRG1/itaconate-RhoA-Drp1 axis. Restoring this pathway represents a promising therapeutic strategy to combat the age-related exacerbation of neuroinflammation and improve outcomes in SAH patients.
    DOI:  https://doi.org/10.14336/AD.2025.1527
  17. Allergy. 2026 Jul 01.
    Serotonin Degradation and Lipid Metabolism Regulate Human Tc2 Cell Effector Functions.
    Sabrina de Souza Ferreira, Lisa Holla, Sophia Björkander, Marie Kaarup Bek, Lorenz Wirth, Patrick A Shearer, Jesper Säfholm, Erik Sachs, Mamdoh Al-Ameri, Kasra Vali, Sandra Ekström, Erik Melén, Jenny Mjösberg, Christopher Andrew Tibbitt.
       BACKGROUND: Cytotoxic type 2 T cells (Tc2) are increasingly recognized as contributors to type 2 inflammation, including asthma, yet the metabolic programs that support their function remain poorly defined. We aimed to define the metabolic requirements of Tc2 cells, identify pathways that regulate their effector function, and assess whether serotonin-modifying therapies are associated with altered Tc2 responses and allergic sensitization in humans.
    METHODS: Tc2 cells from human peripheral blood and lung tissue were analyzed using Seahorse metabolic assays, Mitotracker staining, flow cytometry, and RNA sequencing. Effector functions were evaluated following inhibition of glycolysis, fatty acid metabolism, and monoamine oxidase A (MAOA) inhibition. In parallel, anti-depressant prescription data were analyzed in the population-based BAMSE cohort to assess associations with allergic sensitization. Peripheral blood mononuclear cells from individuals prescribed selective serotonin reuptake inhibitors (SSRIs) and matched controls were stimulated ex vivo to assess cytokine production.
    RESULTS: Tc2 cells exhibited a distinct metabolic profile characterized by increased mitochondrial respiration, glycolytic activity, and elevated expression of GLUT1 and CD36. Type 2 cytokine production (IL-4, IL-5, IL-13) was enhanced by alarmins and significantly reduced following inhibition of glycolysis, fatty acid metabolism, or PPARγ activity. RNA sequencing identified high MAOA expression in Tc2 cells, and pharmacological inhibition of MAOA selectively reduced type 2 cytokine production without affecting IFN-γ. In the BAMSE cohort, dispensing of prescribed anti-depressive drugs was associated with reduced IgE sensitization. Consistent with these findings, individuals prescribed SSRIs exhibited reduced IL-5+ and IL-13+ expressing Tc2 cells and increased IFN-γ-producing Tc2 cells following ex vivo stimulation.
    CONCLUSION: Tc2 cells rely on coordinated lipid metabolism and serotonin catabolism to sustain type 2 cytokine production. Serotonin-modifying therapies were associated with reduced allergic sensitization and altered Tc2 function in humans, consistent with a link between serotonin signaling and type 2 immunity.
    Keywords:  Tc2 cells; lipid metabolism; metabolic reprogramming; serotonin signaling; type 2 immunity
    DOI:  https://doi.org/10.1111/all.70399
  18. Exp Mol Med. 2026 Jul 01.
    Metabolic reprogramming of myeloid cells in cancer: from lactate-NAMPT axis to AI-guided therapeutics.
    In-Gu Lee, Keehoon Jung.
      Myeloid cells-including macrophages, monocytes, neutrophils and dendritic cells-are metabolically plastic sentinels that shape the tumor microenvironment. Among the myriad metabolites in cancer, lactate and nicotinamide adenine dinucleotide (NAD⁺) stand out as central coordinators of myeloid cell fate. Lactate accumulation, driven by tumor glycolysis, profoundly reprograms myeloid metabolism through receptor-mediated signaling, monocarboxylate transport and histone lactylation, establishing immunosuppressive and pro-angiogenic phenotypes. Parallel to this, the nicotinamide phosphoribosyltransferase (NAMPT)-dependent NAD⁺ salvage pathway sustains redox homeostasis and epigenetic regulation in myeloid cells, controlling sirtuin-mediated deacetylation and transcriptional rewiring. Emerging evidence suggests a lactate-NAMPT feedback circuit that couples extracellular lactate availability with intracellular NAD⁺ turnover to maintain immunoregulatory states within tumors. In this Review, we integrate current knowledge on lactate metabolism and NAMPT signaling in tumor-associated myeloid cells, highlighting their convergence on metabolic and epigenetic checkpoints. We further discuss how artificial intelligence (AI)-through single-cell multi-omics integration, spatial metabolomic inference and graph-based modeling-can decode complex immunometabolic networks and accelerate drug discovery targeting these pathways. Finally, we outline therapeutic strategies combining lactate-targeting agents, NAMPT inhibitors and immunotherapies, emphasizing the promise of AI-guided precision immunometabolism. Understanding and modeling the lactate-NAMPT axis may unlock new avenues to reprogram myeloid immunity and overcome resistance in cancer therapy.
    DOI:  https://doi.org/10.1038/s12276-026-01759-3
  19. Apoptosis. 2026 Jul 01. pii: 182. [Epub ahead of print]31(7):
    Interplay between ischemia-reperfusion and metabolic reprogramming.
    Lei Duan, Hui Ao, Lizhou Song, Haoling Zhang, Yan Liao, Wangzheqi Zhang.
      A common pathological process associated with acute organ injury, which is closely connected to metabolic reprogramming, is ischemia-reperfusion injury (IRI). Ischemia leads to decreased oxygen and substrate availability, with rapid activation of energy-sensing pathways, increased dependence on glycolysis, and predisposition of mitochondria to later oxidative injury. Reperfusion involves the rapid restoration of blood supply, with oxidative stress, inflammatory responses and remodeling of metabolic networks. Here, we summarize current evidence for the bidirectional interaction between IRI and metabolic reprogramming by organizing conceptual topics around glucose metabolism, lipid remodeling, amino acid metabolism and tricarboxylic acid cycle (TCA)-centered substrate convergence. Here, we focus on metabolic events according to the ischemic and reperfusion stages, from the early to the delayed phase, including succinate accumulation, reactive oxygen species (ROS) generation via reverse electron transport, mitochondrial quality control, immunometabolic remodeling, as well as apoptosis, ferroptosis, pyroptosis and post-translational modifications. In addition, recent advances in metabolic biomarkers, experimental models and novel therapeutic strategies are highlighted. Recent evidence suggests that metabolic reprogramming is not simply a passive response to IRI, but an active regulatory process that controls the initiation and amplification of injury, as well as its resolution. A metabolomic framework within a time-staged and cell death-centered context may inform more clinically useful biomarkers and intervention windows for IRI.
    Keywords:  Biomarkers; Immunometabolism; Ischemia–reperfusion injury; Metabolic reprogramming; Mitochondrial homeostasis; Oxidative stress
    DOI:  https://doi.org/10.1007/s10495-026-02392-1
  20. Front Immunol. 2026 ;17 1866875
    Obesity-driven metabolic reprogramming and immune dysfunction in renal cancer.
    Henry N Ogbonna, Lyse A Norian.
      Renal cell carcinoma (RCC), specifically clear cell renal cell carcinoma (ccRCC), is a metabolic tumor wherein the physiological state of the host is central to tumor development, progression, and therapeutic resistance. Obesity has emerged as one of the major risk factors associated with RCC; however, its impact on RCC is more complex than simply the accumulation of excess body fat. Obesity transforms the renal tumor microenvironment through metabolic rewiring and alterations in inflammation, vasculature, and anti-tumor immunity. The expansion of adipose tissue in obesity alters the renal microenvironment through the production of fatty acids, adipokines, and cytokines in a manner that not only supports tumor growth but also promotes immunosuppression. Increased levels of leptin, resistin, IL-1β, IL-6, IL-8, and VEGF - together with decreased levels of adiponectin and omentin-1 - promote angiogenesis, stromal remodeling, recruitment of myeloid cells, and evasion of immune checkpoint inhibition. These obesity-driven factors interact with the intrinsic metabolism of ccRCC cells, including lipid accumulation, glycolysis, hypoxic signaling, and metabolic plasticity. Furthermore, obesity reshapes the immune environment through recruitment of MDSCs, polarization of TAMs, dysfunction of DCs, neutrophil-mediated immunosuppression, T cell exhaustion, and increased abundance of regulatory T cells, reinforcing an immunosuppressive state. These effects of obesity in RCC are particularly relevant in the context of the obesity paradox, wherein obesity has been associated with improved treatment outcomes, which are not uniformly observed across RCC cohorts. These differences may reflect the limitations of body mass index as a biological indicator of obesity, together with variations in systemic inflammation, body composition, and treatment context. Here, we summarize current knowledge on obesity-driven immunometabolic rewiring in RCC and outline key priorities for the field, including obesity-relevant preclinical models, biomarkers of visceral adiposity and systemic inflammation, and clinical trials targeting immunometabolism.
    Keywords:  adipokines; clear cell renal cell carcinoma; immune checkpoint inhibitors; immunometabolism; lipid metabolism; myeloid cells; obesity; obesity paradox
    DOI:  https://doi.org/10.3389/fimmu.2026.1866875
  21. Exp Hematol Oncol. 2026 Jul 02.
    Targeting the cancer metabolism-immunity interface: update and perspectives.
    Emma Di Carlo.
      Metabolic crosstalk between cancer cells and immune cells is now recognized as a major determinant of immune escape and resistance to anticancer treatments. Cancer cells profoundly reshape the metabolic landscape of the tumor microenvironment, driving nutrient competition, hypoxia, and the accumulation of immunosuppressive oncometabolites that collectively blunt antitumor immunity. Effector T cells, NK cells, and dendritic cells are exposed to nutrient deprivation and suppressive metabolites, including lactate, adenosine, and kynurenine, resulting in impaired T cell proliferation and cytotoxic function and expansion of metabolically adapted regulatory T cells and myeloid-derived suppressor cells. Cancer-associated fibroblasts further reinforce this metabolic reprogramming through extracellular matrix remodeling, secretion of immunosuppressive metabolites, and nutrient recycling that supports tumor growth. Abnormal tumor vasculature sustains metabolic stress by causing uneven perfusion, hypoxia, and acidosis, thereby limiting immune cell infiltration, and promoting immune exhaustion. In addition, diet- and microbiome-driven metabolic cues dynamically shape cancer-immunity interactions and therapeutic responses. Targeting key metabolic checkpoints, including glycolysis, adenosine signaling, tryptophan metabolism, fatty acid oxidation, and lactate production, has emerged as a promising strategy to restore antitumor immunity. Nevertheless, metabolic heterogeneity, context-dependent immune responses, and safety concerns pose persistent challenges to its successful implementation. Recent advances in biomarker development, patient stratification, and rational combination strategies underpin the clinical translation of metabolic-immune vulnerabilities in cancer therapy. Integrating metabolic interventions with immune checkpoint blockade or adoptive cell therapies has demonstrated synergistic effects in preclinical and early clinical studies, enhancing T cell persistence and cytotoxic function within metabolically hostile tumor microenvironments. This review addresses these issues and delineates the mechanistic basis of the dynamic interplay between cancer metabolism and immune regulation. It discusses how anti-cancer therapies affect metabolic and immune pathways and highlights next-generation, metabolically targeted therapies that leverage newly uncovered, tumor-specific rewiring of glycolysis, mitochondrial function, and nutrient uptake. Special emphasis is given to the development of first-in-class inhibitors targeting glutaminase, lipid biosynthesis, one-carbon pathways, and redox homeostasis, which, when paired with immunotherapy or conventional treatments, offer unprecedented opportunities to overcome metabolic barriers, abrogate resistance, and achieve durable immune control of cancer.
    Keywords:  Cancer-associated fibroblasts; Diet and cancer; Immune cell metabolism; Immunotherapy; Microbiome and cancer; Oncometabolites; Therapy resistance; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-026-00776-2
  22. Liver Res. 2026 Jun;10(2): 166-176
    Bioengineered miR-148a-3p suppresses glycolysis and amino acid homeostasis in hepatocellular carcinoma cells by regulating multiple solute carrier transporters.
    Su Guan, Xin Li, Yimei Wang, Mei-Juan Tu, Ai-Ming Yu.
       Background and aims: Hepatocellular carcinoma (HCC) cells are metabolically reprogrammed for excessive uptake and metabolism of many nutrients. The tumor suppressive microRNA-148a-3p (miR-148a-3p) is downregulated in HCC, whereas its function in regulating HCC cell metabolism remains obscure. Herein we aimed to delineate the role of miR-148a-3p in HCC cell metabolism by using novel bioengineered miR-148a-3p (BioRNALeu/miR-148a-3p) agent produced in vivo.
    Methods: BioRNALeu/miR-148a-3p was designed by using human leucyl transfer RNA fused hsa-pre-miR-34a carrier, overexpressed in Escherichia coli (E. coli), and purified to high homogeneity. After transfection into HCC cells, the released miR-148a-3p levels were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell proliferation was determined by CellTiter-Glo assays. Targets were validated by dual-luciferase reporter assays, immunoblotting, and immunofluorescence confocal imaging. Glycolysis capacity was evaluated by Seahorse XF assays, and glucose, lactate, and amino acid levels were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods.
    Results: BioRNALeu/miR-148a-3p was efficiently processed into target miR-148a-3p in HCC cells to effectively inhibit cell proliferation in a dose- and time-dependent manner. Mechanistically, miR-148a-3p suppressed the protein levels of glucose transporter GLUT1/SLC2A1 and L-type amino acid transporter LAT1/SLC7A5 via acting on their 3'-untranslated regions, as well as amino acid transporter ASCT2/SLC1A5. These, in turn, led to a reduction of glucose uptake, lactate production, and glycolytic flux in HCC cells, and alteration of intracellular amino acid metabolome including glutamine, leucine, phenylalanine, tyrosine, and methionine.
    Conclusions: Reintroduction of miR-148a-3p into HCC cells modulates glucose and amino acid metabolism via regulating multiple SLC transporters, thereby suppressing HCC cell viability. These findings highlight the role of miR-148a-3p in HCC cell metabolism and potential of bioengineered miRNA molecules for functional studies and therapeutic development.
    Keywords:  Amino acids; Cell metabolism; Glucose; Hepatocellular carcinoma (HCC); MicroRNA-148a-3p (miR-148a-3p)
    DOI:  https://doi.org/10.1016/j.livres.2026.04.001
  23. Cell Metab. 2026 Jun 29. pii: S1550-4131(26)00230-5. [Epub ahead of print]
    The interplay between the microbiome and immune cells in metabolic homeostasis and disease.
    Hagit Shapiro, Birgit Jickeli, Idan Niv, Ben Ernan, Eran Elinav.
      Microbiome-derived metabolites, including short-chain fatty acids, bile acids, indoles, and lipopolysaccharides, among other bioactives, modulate mammalian immune cells through a variety of molecular processes, including epigenetic remodeling, mitochondrial metabolic reprogramming, and regulation of mTOR and AMPK signaling pathways. These diverse signals shape inflammatory programs that influence metabolic outcomes in a context-dependent manner, which may sustain metabolic health or drive chronic inflammation impacting obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular diseases. Here, we review these metabolite-driven immune-metabolic influences and highlight innovative directions in their exploration, including integration of spatial and single-cell multi-omics to deconvolute microbiome-derived signaling networks within metabolic tissues. We further outline emerging microbiome-based therapeutic strategies targeting immune pathways in cardiometabolic disease, ranging from personalized nutrition, precision probiotics, and microbial consortium transplantation to metabolite-based postbiotics. Collectively, advancing our understanding of host immune-microbiome-metabolic interactions may support the development of targeted interventions for the prevention and treatment of cardiometabolic diseases.
    Keywords:  immune system; metabolism; metabolites; microbiome; microbiota; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.004
  24. Biochim Biophys Acta Rev Cancer. 2026 Jun 28. pii: S0304-419X(26)00116-2. [Epub ahead of print]1881(4): 189644
    Neural-tumor crosstalk in driving tumor metabolic reprogramming.
    Xia Xiao, Congcong Zhang, Jiahao Chen, Jiayi Zhang, Hanyu Li, Weiming Yu, Xianlei Cai.
      Neural-tumor interactions have emerged as critical drivers of metabolic reprogramming in cancer. This review systematically examines how neural signaling reshapes tumor metabolism through a conceptual framework that classifies neural-tumor crosstalk into three principal modes: direct physical contacts, paracrine signaling, and indirect mediation via immune and glial cells. Key neurotransmitters (norepinephrine, acetylcholine, glutamate) and neurotrophic factors (NGF, BDNF) engage specific receptors on tumor cells, activating downstream signaling cascades that regulate glycolysis, lipid synthesis, and amino acid metabolism. Central to this axis is lactate, which not only fuels tumor growth but also drives histone lactylation, an epigenetic modification that links metabolic flux to sustained transcriptional reprogramming. Beyond the lactate-centered model, emerging mechanisms-including mitochondrial transfer via tunneling nanotubes, extracellular vesicle-mediated metabolic hijacking, and direct nutrient supply by neurons-reveal the remarkable diversity of neural-driven metabolic regulation. The neuro-immune-metabolic circuit adds another layer of complexity, whereby neural signals reprogram immune cell metabolism to create an immunosuppressive microenvironment. This review further evaluates therapeutic strategies targeting the neural-metabolic axis, from repurposed β-blockers to Trk inhibitors and metabolic interventions. By integrating these multifaceted interactions into a unified framework, we highlight future research directions and therapeutic opportunities that may yield novel treatments targeting the neural-metabolic interface in cancer.
    Keywords:  Lactate; Metabolic reprogramming; Neural-tumor crosstalk; Neuro-immune-metabolic circuit; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189644
  25. Front Immunol. 2026 ;17 1856187
    FABP4 as an immunometabolic hub in preeclampsia: from maternal-fetal interface to systemic inflammation.
    Hui Sun, Fei Gu, Lipei Wu, Xin Chen, Shihai Xuan.
      Preeclampsia (PE) is a multisystem vascular disease that occurs specifically during pregnancy, and the understanding of its pathogenesis is gradually shifting from the traditional "placental ischemia-endothelial injury" model to immunometabolic disorders. In this article, we propose a conceptual framework positioning fatty acid binding protein 4 (FABP4) as an immunometabolic hub in the pathogenesis of PE. Clinical studies suggest that FABP4 is significantly elevated in preeclamptic placentas and maternal circulation; epigenetic derepression via miR-148a/152-mediated DNMT1 downregulation contributes to this placental upregulation. Leveraging its primary identity as an intracellular lipid chaperone, we hypothesized a spatiotemporal cascade linking local immune imbalance to systemic vascular injury. Intracellularly, drawing upon highly conserved lipotoxic pathways established in non-pregnancy models, we extrapolate that FABP4 participates in the regulation of the immune microenvironment at the maternal-fetal interface by modulating macrophage polarization toward the M1-type and activating the NLRP3 inflammasome axis; a recent study in an EVT-derived cell line (HTR-8/SVneo) demonstrated that pharmacological inhibition or siRNA knockdown of FABP4 impairs mitochondrial membrane potential, reduces ATP synthesis, and increases oxidative stress, resulting in proliferative arrest. These findings position FABP4 as a viability factor for trophoblast-like cells under metabolic stress, though direct validation in primary EVTs is still required. Extracellularly, upon entering maternal circulation, FABP4 may trigger systemic inflammatory cascade responses and induce endothelial dysfunction. While single-cell transcriptomic studies have revealed significant reprogramming of lipid metabolism-related gene expression in PE placental immune cells, direct single-cell quantification of FABP4 across specific placental subpopulations remains to be performed. Consequently, by integrating macroscopic clinical data with these microscopic intercellular networks, we frame the FABP4-driven axis as a plausible mechanistic convergence, highlighting its promise as a critical translational target for immunometabolic intervention.
    Keywords:  FABP4; endothelial dysfunction; immunometabolism; macrophage polarization; maternal-fetal interface; preeclampsia
    DOI:  https://doi.org/10.3389/fimmu.2026.1856187
  26. Immunology. 2026 Jul 01.
    Epidermal Dominance of Metabolically Constrained Immune Niches Underpins Immune Activation Signatures and Clinical Severity in Psoriatic Disease.
    Caio Santos Bonilha.
      Psoriatic disease is characterised by persistent immune activation that is closely linked to tissue context and clinical severity. How immune metabolism is organised within inflamed skin and across systemic immune compartments remains incompletely elucidated. Here, spatial transcriptomics and CITE-seq datasets were analysed to characterise immune metabolic niche organisation across skin and circulation. Two metabolic constraint axes capturing oxygen redox and nutrient limitation were used to define metabolically constrained and permissive immune niches within leukocyte-rich tissue regions and circulating immune lineages. Psoriatic lesions exhibited a pronounced shift towards metabolically constrained immune niches that distinguished psoriasis from atopic dermatitis. This imbalance showed strong spatial organisation, with dominance within the epidermis and close alignment with immune activation programmes. Epidermal metabolic organisation scaled with clinical severity and was accompanied by increased immune activation in severely affected tissue, while dermal organisation remained comparatively stable. Extending these observations to circulation, immune metabolic states were further skewed towards constraint in psoriatic patients with joint involvement, consistent with higher systemic inflammatory burden, with prominent effects observed in CD4 T cells. Together, these findings identify immune metabolic niche organisation as a spatially and systemically structured feature of psoriatic disease that links tissue architecture, immune activation and clinical severity.
    Keywords:  adaptive immunity; immune microenvironment; psoriasis; skin inflammation; spatial transcriptomics
    DOI:  https://doi.org/10.1111/imm.70164
  27. iScience. 2026 Jul 17. 29(7): 116445
    Multiomics reveals fatty acid metabolism and immune remodeling in retinal artery occlusion.
    Jiaqing Feng, Duan Chen, Chuansen Wang, Runlang Zhu, Longfei Chen, Liang Hu, Ting Chen, Ying Li, Xuan Xiao.
      Retinal artery occlusion (RAO), an acute ocular ischemic stroke, is critically linked to cardiovascular and metabolic dysfunction. To elucidate the interplay between lipid metabolism and immune regulation in RAO, we performed an integrated analysis using serum metabolomics, PBMC transcriptomics, and machine learning in 66 patients with RAO and 66 cataract controls. We identified systemic disruptions in fatty acid metabolism, notably elevated levels of long-chain fatty acids (C22:5n-3, C22:2n-6, C22:1n-9), as distinguishing features of RAO. Upon stratifying patients by lipid status, C20:2n-6 emerged as the top biomarker distinguishing dyslipidemic RAO from non-dyslipidemic cases. Multiomics analysis correlated this accumulation with specific immune pathways, particularly Treg modulation. In Treg-like MT-2 cells, C20:2n-6 promoted Treg proliferation and induced the secretion of the anti-inflammatory cytokine IL-10, independent of TGF-β. These findings highlight C20:2n-6 as a candidate biomarker and implicate the C20:2n-6-Treg-IL-10 axis as a therapeutic target for restoring immune homeostasis in dyslipidemia-associated RAO.
    Keywords:  biological sciences
    DOI:  https://doi.org/10.1016/j.isci.2026.116445
  28. Cardiol Rev. 2026 Jul 08.
    Immunometabolism in Cardiovascular Disease: Linking Metabolic Reprogramming to Inflammation, Atherothrombosis, and Clinical Outcomes.
    Saneha Rani, Syeda Aimen Gillani, Rimsha Naseer, Mahroo Khalid, Areena Fatima, Muhammad Bilal Akram, Asaad Dilshad.
      Cardiovascular disease remains the leading global cause of death, and a major part of its residual risk is now understood to be inflammatory rather than purely lipid-driven. Immunometabolism provides the missing link between metabolic stress and immune activation: excess lipids, hyperglycemia, and tissue hypoxia reprogram immune and vascular cells toward glycolysis, altered glutamine use, mitochondrial dysfunction, and durable epigenetic memory. In atherosclerosis, this metabolic shift fuels endothelial dysfunction, macrophage foam-cell formation, cytokine release, defective efferocytosis, and plaque instability. The concept extends beyond the plaque itself through trained immunity, in which monocytes and bone marrow progenitors retain a pro-inflammatory memory that can persist after the original trigger has passed. This helps explain why myocardial infarction, diabetes, and hyperlipidemia can leave a long inflammatory imprint on the vasculature. Immunometabolism also contributes to thromboinflammation, where activated platelets, neutrophils, and extracellular traps reinforce clot formation and amplify arterial injury. In heart failure, postischemic remodeling and chronic congestion are accompanied by immune-cell and cardiomyocyte metabolic remodeling that sustains inflammation, fibrosis, and adverse ventricular remodeling. Clinical trials targeting inflammation, especially canakinumab and low-dose colchicine, have shown that suppressing inflammatory pathways can reduce cardiovascular events, supporting the translational value of this biology. A clearer understanding of immunometabolic circuits may enable better risk stratification, biomarker-guided therapy, and new treatments that simultaneously stabilize plaques, reduce thrombosis, and improve postinfarction healing.
    Keywords:  atherosclerosis; cardiovascular outcomes; heart failure; immunometabolism; thromboinflammation; trained immunity
    DOI:  https://doi.org/10.1097/CRD.0000000000001391
  29. Brain Behav Immun. 2026 Jun 28. pii: S0889-1591(26)00630-6. [Epub ahead of print]138 106882
    Monocyte abundance and glycolytic reprogramming associate with motivational impairment in depression.
    Mandakh Bekhbat, Genevieve Craig, Evanthia C Wommack, Clara Coblenz, Noah Choe, Nora Balidemaj, Paula-Dene C Nesbeth, David R Goldsmith, Michael T Treadway, Ebrahim Haroon, Jessica A Cooper, Jessica A Alvarez, Andrew H Miller, Jennifer C Felger.
      Inflammation and altered glucose metabolism are implicated in motivational anhedonia, a core feature of major depression (MD) that is sensitive to energy homeostasis. We previously reported preliminary evidence that MD with elevated inflammation is characterized by greater monocyte abundance and monocyte transcriptional signatures consistent with increased glycolysis - a cellular metabolic state reflecting heightened energetic cost to sustain pro-inflammatory functions. However, whether monocyte abundance and cellular bioenergetics directly relate to motivational impairment in MD remains unclear. We first examined monocyte cell counts in relation to self-reported motivation in a larger cohort of 178 medically stable, medication-free adults with MD (Study 1). These analyses were complemented by assessments of glycolytic and mitochondrial metabolism in intact monocytes using Seahorse XF assays in a smaller cohort of similarly enrolled patients with MD (Study 2, n = 40). In Study 1, circulating monocyte percentage was associated with greater self-reported reduced motivation (β = 0.17, SE = 0.08, p = 0.035). In Study 2, bioenergetic assays in isolated monocytes revealed that elevated inflammation (CRP ≥ 3 mg/L) was associated with increased glycolysis (β = 0.97, SE = 0.33, p = 0.005) and greater glycolytic shift (β = 0.92, SE = 0.34, p = 0.011), consistent with a hypermetabolic monocyte phenotype. Greater glycolytic shift predicted lower effort-based motivation as objectively measured by the effort expenditure for rewards task (EEfRT; β = -0.58, SE = 0.24, p = 0.021). Mediation analysis showed that glycolytic shift mediated the association between CRP and low effort-based motivation (ACME = -0.15, 95% CI [-0.37, -0.01], p = 0.032), suggesting that inflammatory burden may relate to reduced reward motivation through its association with monocyte metabolic programming. Exploratory analyses in Study 2 indicated that glycolytic shift was also related to greater monocyte abundance (β = 0.37, SE = 0.17, p = 0.042). Furthermore, replicating the findings of Study 1, higher monocyte percentage was associated with lower effort-based motivation in Study 2 (β = 0.46, SE = 0.22, p = 0.041). Together, these findings suggest that monocyte abundance and immunometabolism may represent a link between peripheral inflammation and its impact on motivational impairment in depression.
    Keywords:  Depression; Glycolysis; Immunometabolism; Inflammation; Monocyte; Motivation
    DOI:  https://doi.org/10.1016/j.bbi.2026.106882
  30. Biol Trace Elem Res. 2026 Jul 03.
    Sodium Selenite Preconditioning Reprograms Mesenchymal Stem Cell Behavior Under Inflammatory Stress to Enhance Anti-Inflammatory Macrophage Responses.
    Iolanda Silva Rafael Pizzolato-Cezar, Edson Naoto Makiyama, Luis Ricardo Pizzolato-Cezar, Kalil Auzier Martins Costa, Carlos Eduardo da Silva Gonçalves, Sumara de Freitas, Renata Chaves Albuquerque, Ricardo Ambrósio Fock.
      Inflammation critically influences mesenchymal stem cell (MSC) behavior, affecting their survival, plasticity, and immunomodulatory functions. MSC preconditioning has emerged as a promising strategy to enhance their therapeutic potential before clinical application. Among the factors capable of modulating MSC responses, selenium has gained attention due to its role in regulating inflammatory signaling. In this study, we investigated whether high-dose sodium selenite (Na2SeO3) preconditioning modulates MSC behavior under inflammatory stimulation and how these changes affect macrophage responses through paracrine mechanisms. MSCs were preconditioned with Na2SeO3 in the presence or absence of lipopolysaccharide (LPS). Cellular metabolism, apoptosis, cell-cycle progression, migration, intracellular signaling, reactive oxygen species (ROS) production, and soluble mediator release were evaluated. Macrophage responses were assessed using conditioned medium from treated MSCs. Na2SeO3 alone did not significantly affect MSC metabolic viability. However, under inflammatory conditions, Na2SeO3 enhanced apoptotic signaling and promoted cell-cycle accumulation in S/G2/M phases. In addition, Na2SeO3 preconditioning reduced intracellular ROS levels, attenuated NFκB and JNK activation, and altered the MSC secretory profile, increasing nitric oxide, transforming growth factor-β, and prostaglandin E2 production while decreasing IL-6 levels. Importantly, conditioned medium from preconditioned MSCs reprogrammed macrophage responses, reducing TNF-α and IL-1β production while increasing IL-1 receptor antagonist levels. These findings demonstrate that high-dose Na2SeO3 reprograms MSCs under inflammatory stress, enhancing their anti-inflammatory paracrine activity and capacity to modulate macrophage inflammatory responses. These results identify selenium as a key regulator of MSC-mediated immunomodulation and support sodium selenite preconditioning as a strategy to optimize MSC-based therapies for inflammatory diseases.
    Keywords:  Immunomodulation; Inflammation; Macrophages; Mesenchymal Stem Cells; Selenium
    DOI:  https://doi.org/10.1007/s12011-026-05192-5
  31. J Pharm Anal. 2026 Jun;16(6): 101494
    HIF-1α in CD4+ T cells drives gout pathogenesis via metabolic reprogramming and Th17 differentiation.
    Siyue Song, Jiatao Li, Fusen Chen, Kaiyue Shi, Yu Lou, Anyi Xu, Yun Zhang, Chengping Wen, Tiejuan Shao.
      Hypoxia-inducible factor 1-alpha (HIF-1α), a central regulator of immunometabolic reprogramming, has been associated with multiple inflammatory conditions. However, its function in CD4+ T cell-mediated glycolytic dysregulation during gout pathogenesis remains unclear. Herein, we demonstrated that HIF-1α expression was elevated in CD4+ T cells derived from patients with gout and urate oxidase (Uox)-knockout (KO) mice. Both pharmacological inhibition (PX-478) and CD4+ T cell-specific genetic ablation of HIF-1α alleviated gout symptoms, including reduced serum uric acid levels, diminished T helper 17 (Th17) cell polarization, and mitigated renal injury. RNA sequencing (RNA-seq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that HIF-1α disruption impaired Th17 differentiation, which was further validated using flow cytometry. Seahorse metabolic profiling and 2-deoxy-D-glucose (2-DG) treatment confirmed that HIF-1α promotes gout pathogenesis by driving glycolysis-dependent Th17 expansion and interleukin-17 (IL-17) production. Importantly, the natural compound dioscin was found to directly bind HIF-1α, suppress its expression, and reverse the disease phenotypes in vitro and in vivo. Conversely, HIF-1α activation using 1,1-dimethylethyl ester 6-[2,5-dihydro-5-oxo-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl]-3-pyridinecarboxylic acid (IOX4) exacerbated gout features, which were effectively counteracted by dioscin. Collectively, these findings identify CD4+ T cell-derived HIF-1α as a key glycolytic regulator in gout and highlight dioscin as a promising candidate for HIF-1α-targeted therapeutic intervention.
    Keywords:  CD4+ T cells; Dioscin; Glycolysis; Gout; HIF-1α
    DOI:  https://doi.org/10.1016/j.jpha.2025.101494
  32. Redox Biol. 2026 Jun 27. pii: S2213-2317(26)00279-X. [Epub ahead of print]95 104280
    Histidine metabolic reprogramming drives oxidative stress induced mtDNA release to promote necroptosis and airway inflammation in severe asthma.
    Ying Chen, Junwen Huang, Zhaoqian Gong, Yuemao Li, Yaoxin Chen, Keke Fan, Bang Zhu, Yanyan Ma, Dapeng Hu, Shuyu Huang, Jie Yang, Xiaoqian Peng, Wenqu Zhao, Haijin Zhao.
      Metabolic dysregulation is increasingly recognized as a critical contributor to asthma pathogenesis. Emerging clinical and metabolomic evidence has implicated histidine metabolism in asthma; however, whether histidine metabolic reprogramming contributes to severe asthma pathogenesis and the underlying mechanisms remain unclear. Here, we integrated clinical cohort analyses, multi-omics profiling, primary human airway epithelial cell experiments, and both toluene diisocyanate (TDI)- and house dust mite/lipopolysaccharide (HDM/LPS)-induced severe asthma murine models to systematically delineate this relationship. Histidine levels were markedly elevated in induced sputum from asthma patients and were strongly associated with disease severity, airflow limitation, and inflammatory indices. Integrated metabolomic and transcriptomic analyses revealed a pathogenic reprogramming of histidine metabolism, characterized by enhanced histamine biosynthesis and depletion of the cytoprotective carnosine, thereby amplifying airway inflammatory responses. Pharmacological blockade of histidine metabolism significantly alleviated airway hyperresponsiveness, inflammation, and structural remodeling in both TDI- and HDM/LPS-induced severe asthma models. Mechanistically, histidine metabolic dysregulation drives oxidative stress mediated mitochondrial dysfunction, leading to mtDNA release and subsequent activation of mt-ND6/FPR2 signaling, ultimately triggering necroptotic epithelial cell death. Collectively, these findings define a histidine-driven oxidative stress-mtDNA-necroptosis axis as a central mechanism of airway inflammation in severe asthma, offering new therapeutic opportunities through metabolic targeting.
    Keywords:  Airway inflammation; Asthma; Histidine metabolism; Necroptosis; Oxidative stress; mtDNA
    DOI:  https://doi.org/10.1016/j.redox.2026.104280
  33. Circ Res. 2026 Jul 02.
    Mitochondrial STING Governs Glycolytic Reprogramming in Diabetic Cardiomyopathy.
    Shiwu Zhang, Dechao Zhao, Mengyi Wang, Xiaorong Shen, Fan Yang, Zhen Tian, Haining Du, Fanghao Lu, Xueya Zhang, Heyu Chen, Jiaxin Kang, Mingjie Dong, Denis V Abramochkin, Huitao Fan, Jinwei Tian, Bo Yu, Shuijie Li, Weihua Zhang.
       BACKGROUND: Diabetic cardiomyopathy, a severe complication of diabetes, is marked by mitochondrial dysfunction, metabolic inflammation, and progressive cardiac impairment. Although STING (stimulator of interferon genes) is well recognized as a central mediator of innate immunity, its noncanonical role in metabolic regulation and mitochondrial dynamics in the diabetic heart remains largely unexplored.
    METHODS: To elucidate the role of STING in diabetic cardiac remodeling, we used single-cell RNA sequencing, echocardiography, and transmission electron microscopy in both genetic (db/db) and chemically induced (high-fat diet [HFD] plus streptozotocin, HFD/streptozotocin) diabetic mouse models. STING knockout mice and primary neonatal mouse cardiomyocytes were used for mechanistic investigations and functional validation. Mitochondrial respiration and glycolytic flux were assessed using Seahorse extracellular flux analysis. Posttranslational modifications of STING, including S-palmitoylation and S-sulfhydration, were evaluated via acyl-biotin exchange and biotin-switch assays, respectively. ENO1 (enolase 1) enzymatic activity was measured in vitro to assess glycolytic reprogramming. Furthermore, 13C-glucose tracing-based targeted metabolomics was performed to quantify cardiac metabolic flux in db/db mice. Glycolytic metabolites, including lactate and pyruvate, were quantified in cardiac tissues and cultured cardiomyocytes to assess glycolytic activity.
    RESULTS: Exposure to high-palmitate conditions induced mitochondrial DNA leakage, thereby activating the cGAS-STING signaling pathway in cardiomyocytes. Mechanistically, STING underwent aberrant translocation to mitochondria, where it interacted with the outer membrane protein TOM (translocase of outer mitochondrial membrane) 40 to impair mitochondrial protein import and disrupt mitochondrial homeostasis. In addition, mitochondrial STING functioned as a scaffold to recruit and activate the glycolytic enzyme ENO1, thereby enhancing its enzymatic activity, accelerating glycolytic flux, and promoting lactate accumulation in diabetic cardiac tissues. Notably, diabetes-associated depletion of endogenous hydrogen sulfide reduced S-sulfhydration of STING at Cys88/91, facilitating its S-palmitoylation and mitochondrial localization. Genetic ablation of STING or pharmacological restoration of hydrogen sulfide levels with GYY4137 effectively rescued mitochondrial dysfunction, decreased lactate overproduction, and preserved cardiac contractile performance in diabetic mice.
    CONCLUSIONS: These findings identify STING as a spatial immunometabolic modulator that bridges mitochondrial dysfunction with metabolic imbalance in diabetic cardiomyopathy. Enhancing STING S-sulfhydration or targeting its palmitoylation through hydrogen sulfide-based interventions represents a promising therapeutic strategy for the treatment of diabetic cardiomyopathy.
    Keywords:  diabetic cardiomyopathies; inflammation; metabolism; mitochon dria; streptozotocin
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327867
  34. Sci Rep. 2026 Jul 02.
    4-Octyl itaconate ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by suppressing necroptosis in alveolar macrophages via Nrf2 activation.
    Zhe Wang, Xiaofeng Li, Tingting Zhang, Ping Huang, Xichen Pang, Xiaoli Zeng, Xiaoju Liu.
      Cigarette smoke (CS)-induced necroptosis of alveolar macrophages (AMs) is critical in chronic obstructive pulmonary disease (COPD) pathogenesis. The itaconate derivative 4-octyl itaconate (4-OI) is a macrophage immunomodulator; however, its effects on AMs in COPD remain unclear. In this study, a COPD mouse model was established via CS exposure, and a murine alveolar macrophage (MH-S) cell model was generated via cigarette smoke extract (CSE) stimulation to investigate the protective effects of 4-OI and elucidate the underlying mechanisms. In vivo, CS exposure induced lung dysfunction, airway inflammation, and emphysema, which were significantly ameliorated by 4-OI administration. Furthermore, CS exposure upregulated the necroptosis-related proteins RIPK1, RIPK3, MLKL, and p-MLKL in lung tissue and triggered the excessive extracellular release of HMGB1, all of which were suppressed by 4-OI. In vitro, 4-OI inhibited CSE-induced necroptosis and the release of cytokines from AMs. Mechanistically, Nrf2 pathway-mediated antioxidant defenses were impaired in the lungs of COPD model mice and in CSE-stimulated AMs, and 4-OI partially restored antioxidant protein activity. Critically, pharmacological inhibition with ML385 or shRNA-mediated genetic knockdown of Nrf2 reversed the protective effects of 4-OI against CSE-induced necroptosis in AMs. In conclusion, 4-OI ameliorates CS-induced COPD by alleviating necroptosis in AMs, which depends on Nrf2 antioxidant pathway activation.
    Keywords:  4-Octyl itaconate; Airway inflammation; Alveolar macrophages; Chronic obstructive pulmonary disease; Necroptosis
    DOI:  https://doi.org/10.1038/s41598-026-59351-8
  35. J Cell Physiol. 2026 Jun;241(6): e70205
    Lipocalin-2 Restores Mitochondrial and Antioxidant Adaptation in a Strain-Specific Manner During LPS Induced Sepsis.
    Vinita Kushwaha, Mrunmayee R Kandalgaonkar, Sukhvinder Singh, Piu Saha, Ashok Kumar, Beng San Yeoh, Matam Vijay-Kumar.
      Sepsis induces profound metabolic and mitochondrial dysfunction, contributing to multiple organ injury and mortality. Lipocalin-2 (Lcn2), an acute-phase protein, regulates iron homeostasis and oxidative stress, but its impact on mitochondrial resilience remains poorly understood. Here, we investigated the role of Lcn2 in modulating mitochondrial function and hepatic stress responses in C57BL/6 J (BL6) and BALB/c mice in LPS-induced endotoxemia. Lcn2-deficient (Lcn2KO) mice exhibited reduced basal respiration, maximal respiration, and spare respiratory capacity, indicating impaired mitochondrial oxidative phosphorylation. Administration of recombinant Lcn2 (rLcn2) restored mitochondrial respiration in both mouse strains under basal conditions; however, during LPS challenge, only BL6 mice partially preserved mitochondrial function, whereas BALB/c mice remained compromised. To explore underlying mechanisms, we assessed hepatic gene expression by qRT-PCR. LPS induced Acyl-CoA synthetase long-chain family member 4 (ACSL4) and suppressed lysophosphatidylcholine acyltransferase 3 (LPCAT3), markers associated with lipid remodeling, as well as altered antioxidant genes glutathione peroxidase 4 (GPX4) and superoxide dismutase 2 (SOD2) in both strains. rLcn2 treatment in BL6 mice normalized ACSL4 and LPCAT3 expression and enhanced antioxidant gene transcription, whereas BALB/c mice showed minimal recovery. In BL6 mice, Lcn2 supports oxidative phosphorylation while simultaneously modulating lipid metabolism and antioxidant defenses, highlighting its integrated role in cellular adaptation to endotoxemia. Our results reveal that differential Lcn2 responsiveness contributes to inter-strain variation in susceptibility to sepsis-induced mitochondrial dysfunction and identify Lcn2 as a potential therapeutic target for enhancing metabolic resilience during sepsis.
    Keywords:  Siderocalin; innate immunity; oxidative phosphorylation; redox balance; systemic inflammation
    DOI:  https://doi.org/10.1002/jcp.70205
  36. Antimicrob Agents Chemother. 2026 Jun 23. e0186625
    Imipramine inhibits feline infectious peritonitis virus infection by targeting host cholesterol metabolism via NPC1.
    Rui Jing, Yao Yao, Yuhan Li, Shuo Zheng, Hongxuan Li, Li Kang, Li Gao, Pinghuang Liu.
      Feline infectious peritonitis (FIP), a fatal disease caused by FIP virus (FIPV), currently lacks effective vaccines and treatments. Imipramine, a tricyclic antidepressant with known broad-spectrum antiviral properties, was investigated for its efficacy against FIPV. Our in vitro studies demonstrated that imipramine inhibits FIPV infection in a dose-dependent manner, with a high selectivity index (SI = 291) and maximal effect when administered during co-treatment. Time-of-addition assays revealed that imipramine acts at multiple stages, interfering with both viral entry and replication. Mechanistically, we found that imipramine targets the host protein Niemann-Pick C1 (NPC1), disrupting cholesterol metabolism to block viral entry. It also independently suppresses FIPV-induced pro-inflammatory cytokine production without relying on type I interferon signaling. Notably, in an in vivo model, imipramine treatment reduced viral loads and alleviated clinical signs in FIPV-infected cats. These findings collectively identify imipramine as a promising, host-targeted therapeutic candidate for FIP.
    Keywords:  FIPV; NPC1; cholesterol metabolism; imipramine
    DOI:  https://doi.org/10.1128/aac.01866-25
  37. Front Endocrinol (Lausanne). 2026 ;17 1856667
    Gut microbiota in type 2 diabetes mellitus: mechanistic links between dysbiosis, insulin resistance, and chronic low-grade inflammation.
    Yi Chen, Danru Jin, Xue Han, Xiaoting Liu, Yisi Liu, Li Wang.
      It is becoming more well acknowledged that type 2 diabetes mellitus (T2DM) is a metabolic and inflammatory condition linked to microbiota that involves interrelated disruptions in intestinal integrity, immune control, and insulin signalling. Butyrate-producing bacteria, such as Faecalibacterium prausnitzii and Roseburia spp., are reduced in gut dysbiosis in type 2 diabetes, whereas opportunistic Gram-negative pathobionts that cause endotoxemia and mucosal inflammation proliferate. Increased intestinal permeability makes it easier for lipopolysaccharide (LPS) to translocate and activate the TLR4/MyD88/IKKβ/NF-κB pathway. This increases the production of TNF-α, IL-6, MCP-1, and IL-1β, which disrupt insulin signalling by serine phosphorylation of IRS-1 and subsequent inhibition of PI3K/Akt/GLUT4 function. Concurrently, JNK and NLRP3 inflammasome pathway activation increases oxidative stress, caspase-1 activation, and inflammatory β-cell damage. Simultaneously, decreased microbial-derived short-chain fatty acid synthesis impairs GPR41/GPR43- and HDAC-mediated signalling, which in turn affects AMPK activation, mitochondrial function, and enteroendocrine release of GLP-1 and PYY. FXR-FGF19 and TGR5-cAMP signalling are further disrupted by altered bile acid biotransformation, which encourages hepatic gluconeogenesis, fat buildup, and insulin resistance. Moreover, dysregulated branched-chain amino acid metabolism and overactivation of the mTOR/S6K1 pathway lead to chronic low-grade inflammation and metabolic rigidity. When taken as a whole, these interrelated microbiota-host signalling pathways are significant mechanistic contributors to the pathophysiology of type 2 diabetes and new treatment targets.
    Keywords:  bile acid signalling; branched-chain amino acid; gut dysbiosis; insulin resistance; microbial metabolites; short-chain fatty acids; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3389/fendo.2026.1856667
  38. Nat Commun. 2026 Jun 27.
    Targeting macrophage ferritin heavy chain mitigates ferroptosis and lung injury in experimental acute respiratory distress syndrome.
    William Z Zhang, Kihwan Kim, Divya Bhatia, Lynne Faherty, Will Simmons, Eleni Kallinos, Sebastian E Carrasco, Katherine L Hoffman, Sean Houghton, Chia-Lang Hsu, Leora Haber, Cem Meydan, Christopher E Mason, Ananda S Mirchandani, Sarah R Walmsley, Parag Goyal, Kuei-Pin Chung, Karla V Ballman, David Redmond, Joseph D Mancias, Augustine M K Choi, Edward J Schenck, Maria Plataki, Suzanne M Cloonan.
      Ferritin, composed of heavy chain (FTH1) and light chain (FTL) subunits, is a key intracellular iron storage protein, but the origin and biological role of extracellular ferritin (ex-ferritin) remain poorly understood. Elevated serum ex-ferritin is associated with worse outcomes in acute respiratory distress syndrome (ARDS). Here, we show that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AM) of individuals with ARDS, findings we replicate in a murine hyperoxia-induced acute lung injury model. Myeloid-specific FTH1 (Fth1ΔLysM) deletion attenuates lung injury, and is associated with reduced macrophage ferroptosis, altered airway inflammatory responses, lower extracellular iron and compensatory secretion of FTL-ex-ferritin. While pharmacologic ferroptosis inhibition prior to hyperoxia had no effect, transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid conferred protection from lung injury. These findings identify macrophage ferritin metabolism and ex-ferritin secretion as critical regulators of lung injury, offering new insights into the pathobiology of ARDS.
    DOI:  https://doi.org/10.1038/s41467-026-74828-w
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