bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–07–19
sixty-four papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Glucose Metabolism in Immune Regulation: From Mechanisms to Therapeutic Opportunities.
  2. Itaconic acid alleviates acute hepatitis by reprogramming NK cell metabolism with mitochondrial dysfunction.
  3. Tuberculosis and Cellular Metabolism: Insights into the Crosstalk Between Macrophage Immunometabolism and Muscle Dysregulation.
  4. Metabolic Control of Immunity-Unveiling Neutrophil Mechanisms.
  5. Intercellular transfer of LncRNA NEAT1 drives post-infarction inflammation by blocking the macrophage IRG1-itaconate metabolic axis.
  6. Metabolomics of in vivo inflammation identifies soluble sialic acid as a conserved myeloid-cell metabolite.
  7. Metabolite-driven epigenetic modifications remodel immune cell functions in COPD: From Lactylation to Succinylation.
  8. Immuno-metabolic reprogramming in pulmonary fibrosis: Emerging therapeutic targets beyond inflammation.
  9. Tetherin enforces an immunometabolic checkpoint that coordinates glycolytic and interferon signaling in adipocytes.
  10. Lysophosphatidic acid promotes lipid metabolism through AMPK signaling to support Coxsackievirus infection.
  11. Itaconate Ameliorates Skin Fibrosis Through Inhibition of HIF-1α/LDHA-Driven Aerobic Glycolysis.
  12. A targetable micropeptide reprograms macrophages to suppress T cell anti-tumor immunity.
  13. ENO3-mediated glycolytic reprogramming participates in β-glucan-induced dendritic cells activation and anti-tumor responses.
  14. IL-7-glucose-Aiolos axis orchestrates pathogenic CD8+ T cell function in spondyloarthritis.
  15. Medium chain fatty acid sensing receptor GPR84 limits antitumor immunity mediated by CD4 T cells in mice.
  16. Macrophage Metabolic Reprogramming in Rheumatoid Arthritis: Pathogenic Mechanisms and Therapeutic Implications.
  17. Gut microbe-derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice.
  18. TRAF6 Lactylation in Glycolytic Macrophages Drives NF-κB Signaling and M1 Polarization During Orthodontic Tooth Movement.
  19. Macrophage-derived oxysterols organize T helper 2 cells to suppress type 1 inflammation during pulmonary fungal infection.
  20. Metabolic Reprogramming of Macrophages Plays a Dual Role in Periodontitis: From Pathogenesis to Therapy.
  21. The dual role of metabolic reprogramming in macrophage polarization in rheumatoid arthritis and coronary heart disease and the intervention strategy of traditional Chinese medicine.
  22. Classical swine fever virus hijacks triglyceride metabolism via the NS5B-PLIN5 axis to facilitate viral replication.
  23. Lactylation: a novel epigenetic bridge connecting metabolic reprogramming and immune dysregulation in sepsis-associated ARDS.
  24. Hepatitis C Virus Remodels Lipid Droplets to Promote Mitochondrial Fatty Acid Accumulation and Metabolic Activation.
  25. Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells.
  26. Butyrate epigenetically licenses sustained epithelial-T cell crosstalk for intestinal immune tolerance.
  27. β-Hydroxybutyrate precursor 1,3-butanediol modulates enteric pathogen susceptibility and Th17 responses via commensal bacteria.
  28. Augmenting CAR T cell functionality and metabolism through CD39 downtuning.
  29. Dendritic Cells as Immunometabolic Regulatory Nodes in Diabetes: Molecular Mechanisms and Therapeutic Reprogramming.
  30. Fusobacterium nucleatum-derived succinic acid aggravates colitis by triggering macrophage pro-inflammatory phenotypic transformation via SUCNR1/NF-κB axis.
  31. Targeting TKT-associated immunometabolic remodeling attenuates experimental lupus nephritis and NET-related inflammation.
  32. A metabolically reprogrammable nanoplatform potentiates photodynamic immunotherapy through glycolytic blockade.
  33. MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion.
  34. Adipose tissue macrophages in metabolic inflammation and disease: Insights from single-cell and multi-omics studies.
  35. Lactate-associated H3K18 lactylation is involved in IGF2BP2-mediated MARCKSL1 mRNA stabilization and inflammatory signaling in LPS-induced acute lung injury.
  36. Vitronectin metabolically programs profibrotic macrophages in 3D cultures and idiopathic pulmonary fibrosis.
  37. Cellular Glucose Transport and Inflammatory Blood Markers in Rheumatoid Arthritis Spectrum: An Immunometabolic Perspective.
  38. Dietary stearic acid aggravates acute graft-versus-host disease by promoting oxidative stress and pro-inflammatory macrophage polarization.
  39. Role of Fatty Acid Oxidation in Crohn's Disease and Ulcerative Colitis: Metabolomics Analysis and Experimental Evidence.
  40. Fueling bone loss: the immunometabolic reprogramming of the bone microenvironment in diabetic osteoporosis.
  41. Mitochondrial Immunometabolism in Sepsis: From Oxidative Stress and mtDAMP Signaling to Biomarker-Guided Therapy.
  42. Distinct macrophage and T cell programs shape pancreatic inflammation during metabolic stress and aging.
  43. Fatigue after COVID-19 infection is associated with peripheral immunometabolic alterations affecting neuroimmune responses in the hippocampus.
  44. The glycolysis-H4K12la-PKM2 positive feedback loop drives M2 polarization of macrophages in colorectal cancer.
  45. MGMT deficiency augments STING-mediated inflammatory responses accompanied by metabolic alterations in macrophages.
  46. Site-specific profiling of lysine itaconylation via a thiol-based probe.
  47. Ischemia-induced p300-dependent histone lactylation activates an AP-1-SPP1 program in microglia to exacerbate ischemic brain injury.
  48. Disrupting fumarylacetoacetate hydrolase by stratified nanoplatforms orchestrates metabolic-immune reprogramming and prevents post-ablation HCC relapse.
  49. Hypoxia-inducible Factors in Macrophage Polarization and Metabolic Reprogramming Under Stress: Implications for Inflammation and Tissue Repair.
  50. Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
  51. ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.
  52. Immunometabolic Stress and Immune Suppression in Clear-Cell Renal Cell Carcinoma: Perspectives in Therapeutic Strategy.
  53. Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma.
  54. Exercise-evoked immunometabolic niches coordinate context-dependent muscle metabolism.
  55. Integrated multi-omics and machine learning identify OGDHL as a key regulator of glioblastoma progression and antitumor immunity via glutamine metabolism and histone lactylation.
  56. PLX3397 Reshapes Hepatic Lipid Metabolism Independent of Microglial Depletion.
  57. Myeloid PKM2 deficiency alleviates allergic airway inflammation and promotes macrophage efferocytosis via SLC13A3.
  58. Baseline-dependent immunometabolic effects of low-volume plasma exchange on inflammation and iron homeostasis in metabolic syndrome.
  59. Sleep restriction reprograms systemic immunity through NK and T cell crosstalk.
  60. Purine and pyrimidine-based bacterial cyclic dinucleotides egress the phagosome and activate the innate immune sensor STING.
  61. From barrier to trigger: leveraging tumor hypoxia for precise control of CAR-T cell activity.
  62. Serum lipidome remodeling in viral pneumonia: from pathophysiology to therapeutics.
  63. IFN γ and IFN γ mimetics prevent IFN-I-mediated TB susceptibility by regulating iron metabolism and lipid peroxidation.
  64. Knockout of acod1 promotes liver regeneration after hepatectomy by promoting fatty acid mobilization.
  1. J Cell Biochem. 2026 Jul;127(7): e70111
    Glucose Metabolism in Immune Regulation: From Mechanisms to Therapeutic Opportunities.
    Takhellambam Malemnganba, Anurag Kumar Pandey, Sramona Kar, Vijay Kumar Prajapati.
      Immune cell activation and differentiation are tightly coupled to metabolic reprogramming, with glucose availability and intracellular glycolytic flux serving as central determinants of immune cell fate and function. While increased glucose uptake and aerobic glycolysis support rapid proliferation and effector programs, persistent glucose abundance or dysregulated glycolytic signaling can contribute to immune dysfunction, chronic inflammation, and impaired host defense. Conversely, controlled limitation of glucose availability-through altered systemic supply, tissue microenvironmental competition, or targeted modulation of glycolysis-can rebalance immune metabolism toward oxidative phosphorylation, fatty acid oxidation, and mitochondrial fitness. This review examines how glucose availability and glycolytic flux operate as metabolic checkpoints that integrate with nutrient-sensing pathways, including mTORC1, AMPK, and HIF-1α, to shape immune activation, effector differentiation, and memory formation. We discuss evidence across disease contexts, including hyperglycemia-associated immune dysfunction, viral infection, autoimmunity, and cancer, and summarize emerging strategies to therapeutically modulate glucose metabolism using dietary interventions and pharmacologic tools. By distinguishing dietary carbohydrate intake from systemic glucose availability and cell-intrinsic glycolytic control, this review provides a coherent framework for understanding when glucose modulation can enhance immunity and when it risks immune suppression or metabolic exhaustion.
    Keywords:  antiviral immunity; cancer immunotherapy; glucose availability; glycolytic flux; hyperglycemia; immunometabolism
    DOI:  https://doi.org/10.1002/jcb.70111
  2. Int Immunopharmacol. 2026 Jul 16. pii: S1567-5769(26)00982-3. [Epub ahead of print]186 117136
    Itaconic acid alleviates acute hepatitis by reprogramming NK cell metabolism with mitochondrial dysfunction.
    Ying Sun, Mingyue Duan, Xi Zhang, Xiaoguai Liu, Jun She, Yi Lv, Hong Lei.
       BACKGROUND: Immunometabolism provides critical insights into the pathogenesis and treatment of inflammatory diseases. Itaconic acid (ITA), a key immunomodulatory metabolite derived from the tricarboxylic acid cycle, has been extensively characterized in macrophages; however, its direct effects on NK cells and NK cell-mediated liver pathology remain poorly defined.
    METHODS: Using SCENITH and Seahorse analyses, we assessed ITA's impact on NK cell metabolism via multi-omics, and investigated its underlying mechanisms. The therapeutic potential was then evaluated in a mouse model of poly (I:C)-induced liver injury.
    RESULTS: We show that ITA reprograms NK cell metabolism to suppress their proliferation and killing capacity, simultaneously suppressing oxidative phosphorylation while inducing a compensatory glycolytic shift. Multi-omics integration revealed that this metabolic shift corresponds with the upregulation of glycolytic gene networks and significant mitochondrial impairment, mechanistically linked to the inhibition of succinate dehydrogenase (SDH) activity and the downregulation of the NRF1/TFAM mitochondrial biogenesis pathway. ITA also damages mitochondria and impairs autophagic activity, resulting in accumulation of dysfunctional mitochondria in NK cells. All these alterations lead to profound suppression of NK cell proliferation and cytotoxic function. Administration of ITA in mice with poly (I:C) -induced liver injury substantially attenuated hepatic damage and suppressed over-inflammation in the liver. This protective effect was associated with inhibited hepatic infiltration and function of both NK and T cells.
    CONCLUSION: Our findings extend the understanding of the immune regulation and metabolic reprogramming of ITA to NK cells, showing that ITA inhibits SDH activity to down-regulate mitochondrial biogenesis through NRF1/TFAM in NK cells with consequent limitation of cytotoxic function, suggesting the further therapeutic potential of ITA application in NK cells-mediated liver pathologies.
    Keywords:  Energy metabolism; Itaconic acid; Liver injury; NK cells; SCENITH
    DOI:  https://doi.org/10.1016/j.intimp.2026.117136
  3. Int J Mol Sci. 2026 Jul 06. pii: 6062. [Epub ahead of print]27(13):
    Tuberculosis and Cellular Metabolism: Insights into the Crosstalk Between Macrophage Immunometabolism and Muscle Dysregulation.
    Mohammed J A Haider, Halemah AlSaeed, Fatema Al-Rashed.
      Tuberculosis (TB) remains a leading cause of death from a single infectious agent, and its outcome is shaped not only by Mycobacterium tuberculosis (Mtb) itself, but also by the host's metabolic state. This review synthesises current understanding of how Mtb reprograms macrophage immunometabolism and how this reprogramming propagates to a systemic level, culminating in skeletal muscle dysregulation and TB-associated cachexia. We describe the molecular mechanisms by which Mtb subverts phagosomal maturation, the glycolytic (Warburg-like) switch governed by HIF-1α and accumulation of immunomodulatory tricarboxylic acid cycle intermediates, and the M1/M2 polarisation balance that dictates bacterial containment versus persistence. We then trace the cytokine- and metabolite-mediated circuits (TNF-α, IL-6, IL-1β, lactate, ketone bodies, free fatty acids) that link infected macrophages to ubiquitin-proteasome and autophagy-lysosome-driven muscle proteolysis, mitochondrial dysfunction and oxidative stress. Building on these mechanisms, we propose an immunometabolic and muscle-derived biomarker framework that, although still requiring clinical validation, may offer value for diagnosis, host-response stratification and treatment monitoring, and we discuss host-directed therapeutic strategies that target macrophage metabolism and muscle preservation. By integrating immunity, metabolism and systemic pathology at the molecular level, this work highlights translational opportunities relevant to the host immunity, diagnosis and treatment of tuberculosis.
    Keywords:  HIF-1α; Mycobacterium tuberculosis; Warburg effect; biomarkers; cachexia; host-directed therapy; macrophage immunometabolism; mitochondrial dysfunction; muscle wasting; tuberculosis
    DOI:  https://doi.org/10.3390/ijms27136062
  4. Adv Exp Med Biol. 2026 ;1501 575-600
    Metabolic Control of Immunity-Unveiling Neutrophil Mechanisms.
    Bruna F Correia, Daniela Grosa, M Guadalupe Cabral.
      Immune metabolism is a central determinant of neutrophil development, plasticity, and function. Once considered strictly glycolytic, neutrophils are now recognized as metabolically flexible cells that dynamically engage glycolysis, the pentose phosphate pathway (PPP), amino acid metabolism, and lipid oxidation to meet energetic and biosynthetic demands. Neutrophil metabolism is tightly regulated by nutrient-sensing and stress-response pathways, including mTOR, AMPK, and HIF-1α, which integrate environmental cues such as hypoxia and nutrient deprivation. In disease, metabolic rewiring underlies functional dysregulation, highlighting its role in chronic inflammatory disorders, metabolic syndromes, infection, and cancer. Therefore, targeting neutrophil metabolism offers therapeutic potential by restoring homeostasis, reducing inflammation, or enhancing antimicrobial and anti-tumor responses. Altogether, understanding neutrophil metabolic plasticity provides critical insights into immune regulation in health and disease, and offers promising avenues for novel therapies in chronic inflammation, metabolic disorders, infection, and cancer.
    Keywords:  Immunometabolism; Inflammation; Metabolic reprogramming; Neutrophil metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-3-032-12166-0_21
  5. Biochem Biophys Rep. 2026 Sep;47 102684
    Intercellular transfer of LncRNA NEAT1 drives post-infarction inflammation by blocking the macrophage IRG1-itaconate metabolic axis.
    Jiacheng Ge, Diankui Ge.
      Post-infarction inflammation and adverse remodeling remain major therapeutic challenges in ischemic heart disease. However, how specific intercellular communication drives macrophage metabolic maladaptation during this process remains unclear. This study aimed to elucidate the mechanisms by which damaged cardiomyocytes epigenetically reprogram macrophage immunometabolism post-myocardial infarction. Here, we identify a novel inter-organelle and inter-cellular signaling axis wherein hypoxic cardiomyocyte-derived exosomal NEAT1 acts as a pivotal epigenetic rheostat of macrophage immunometabolism. Using single-cell RNA sequencing and molecular tracing in a murine MI model, we demonstrate that exosomal NEAT1, rather than endogenous transcription, accumulates in infiltrating macrophages and interacts with nuclear Sox2. This interaction triggers IRG1 promoter hypermethylation, silencing the biosynthesis of the anti-inflammatory metabolite itaconate, thereby exacerbating pro-inflammatory polarization. To exploit this mechanism therapeutically, we employed an AAV9-mediated, cardiomyocyte-specific shNEAT1 delivery system to intercept this pathological exosomal transfer. This genetic intervention successfully restored macrophage itaconate homeostasis, suppressed the surge of pro-inflammatory cytokines (including MCP-1 and IL-1β), and significantly preserved cardiac contractility (LVEF/LVFS) 28 days post-MI. Our findings delineate the Hypoxic Cardiomyocyte-Exosomal NEAT1-Macrophage Sox2-IRG1 pathway as a critical driver of post-ischemic injury and establish AAV-mediated gene silencing of lncRNAs as a potent translational strategy for cardiac immunometabolic reprogramming.
    Keywords:  Exosomes; Immunometabolism; Macrophage; Myocardial infarction; lncRNA NEAT1
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102684
  6. bioRxiv. 2026 Jul 07. pii: 2026.07.06.736822. [Epub ahead of print]
    Metabolomics of in vivo inflammation identifies soluble sialic acid as a conserved myeloid-cell metabolite.
    Helen A Jordan, Joseph A Tandurella, Vineeth Vengayil, Tanay S Parnaik, Swechha Mainali Pokharel, Kathleen Mulka, Sara Cherry, E John Wherry, Caroline R Bartman.
      During an immune response, metabolism changes dramatically. Metabolites are oxidized to power immune cell functions, serve as building blocks for proliferation, and act as effectors to regulate pathogen or host cells. Though metabolic changes in cultured cells have been studied extensively, metabolism changes in vivo are less understood. Here, we measured metabolomic changes across six mouse tissues in three models of immune activation: CpG-DNA cytokine storm, lymphocytic choriomeningitis virus infection, and polyI:C viral mimetic injection; and carried out metabolomics in cultured macrophages activated with different stimuli. We found most metabolomic changes were exclusive to either inflamed tissues or cultured macrophages, although itaconate was strongly induced in both contexts. We then mechanistically dissected the role of the soluble sialic acid N-glycolylneuraminic acid, which is highly induced in inflamed tissues yet only modestly in cultured macrophages. This metabolite rises in tissues in different models of inflammation, and the analogous human metabolite, N-acetylneuraminic acid, is increased in human patients experiencing inflammation. We found that N-glycolylneuraminic acid is produced in CD11b+ myeloid cells by cleavage of protein-bound sialic acid. However, blocking its production did not affect CpG-DNA liver inflammation or LCMV infection in mice. Therefore, these experiments identify soluble sialic acid as a conserved biomarker of inflammation in mice and humans and highlight the differences in metabolism between in vitro and in vivo models of inflammation.
    DOI:  https://doi.org/10.64898/2026.07.06.736822
  7. Pathol Res Pract. 2026 Jul 09. pii: S0344-0338(26)00272-4. [Epub ahead of print]286 156619
    Metabolite-driven epigenetic modifications remodel immune cell functions in COPD: From Lactylation to Succinylation.
    Fubiao Yang, Xing Li, Zhuying Li.
      Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation, progressive immune dysfunction, and irreversible structural remodeling. Although cigarette smoke-induced oxidative stress has long been recognized as the predominant pathogenic driver, conventional inflammatory theories fail to fully account for the sustained inflammatory state that persists even after smoking cessation. Accumulating evidence indicates that COPD is governed by a metabolite-centered epigenetic regulatory network. Intracellular metabolic intermediates function not only as substrates for energy metabolism, but also as signaling molecules that directly modulate chromatin architecture and transcriptional programs. In this context, metabolic reprogramming emerges as a pivotal determinant of immune cell fate and inflammatory memory formation. This review systematically summarizes recent research advances in the "metabolite-redox-epigenetics" axis in COPD. We specifically discuss histone lactylation as a glycolysis-dependent inflammatory amplification mechanism and propose that histone succinylation represents a redox-sensitive epigenetic mechanism linked to mitochondrial dysfunction, bridging tricarboxylic acid (TCA) cycle dysregulation and persistent immune activation. We further integrate acetylation, crotonylation, β-hydroxybutyrylation, DNA methylation, and RNA m6A modification to construct a unified immunometabolic regulatory network. We propose that COPD is essentially a metabolically imprinted inflammatory memory disease, whose core mechanism resides in the chronic oxidative stress-triggered persistent remodeling of chromatin accessibility, which stably enforces pathogenic immune phenotypes. Targeting metabolite-driven epigenetic remodeling may offer novel therapeutic strategies to reverse chronic inflammatory memory and restore immune homeostasis. Recent evidence further suggests that cGAS-STING-mediated mitochondrial DNA sensing, inflammasome-dependent pyroptosis, gut-lung axis-derived metabolites, and AMPK/SIRT1/PGC-1α signaling may provide additional links between metabolic stress, epithelial injury, and immune dysfunction.
    Keywords:  Chronic obstructive pulmonary disease; Epigenetics; Immunometabolism; Lactylation; Succinylation
    DOI:  https://doi.org/10.1016/j.prp.2026.156619
  8. Int Immunopharmacol. 2026 Jul 13. pii: S1567-5769(26)00973-2. [Epub ahead of print]186 117127
    Immuno-metabolic reprogramming in pulmonary fibrosis: Emerging therapeutic targets beyond inflammation.
    Hemraj Singh, Anushka Purwar, Rajeev Taliyan.
      Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive extracellular matrix deposition, tissue remodeling, and irreversible loss of lung function. Although inflammation contributes to disease progression, increasing evidence indicates that immunometabolic reprogramming is a central driver of fibrotic persistence. Alterations in glycolysis, mitochondrial function, lipid metabolism, and redox homeostasis actively regulate immune responses, fibroblast activation, and epithelial cell dysfunction, thereby sustaining a profibrotic microenvironment. This review synthesizes current advances in understanding how metabolic pathways regulate immune and structural cell behavior during pulmonary fibrosis. Particular emphasis is placed on metabolic checkpoints, including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and nicotinamide adenine dinucleotide (NAD+)-dependent signaling, which integrate metabolic and inflammatory responses. We further discuss how mitochondrial dysfunction, hypoxia-inducible factor-1α (HIF-1α), reactive oxygen species (ROS), cellular senescence, and metabolic memory contribute to disease persistence. Emerging evidence supports metabolic crosstalk between immune cells and fibroblasts as a key mechanism driving fibrotic remodeling. Finally, we evaluate therapeutic strategies targeting immunometabolic pathways and discuss current translational challenges, including cellular heterogeneity, pathway redundancy, and limited clinical validation. Collectively, this review highlights immunometabolic regulation as a promising therapeutic framework and identifies opportunities for precision-based interventions in pulmonary fibrosis.
    Keywords:  AMPK; Fibroblast activation; Glycolysis; Immunometabolism; Metabolic memory; Metabolic reprogramming; Mitochondrial dysfunction; Pulmonary fibrosis; Therapeutic targeting; mTOR signaling
    DOI:  https://doi.org/10.1016/j.intimp.2026.117127
  9. bioRxiv. 2026 Jul 07. pii: 2026.07.06.735062. [Epub ahead of print]
    Tetherin enforces an immunometabolic checkpoint that coordinates glycolytic and interferon signaling in adipocytes.
    Chung Hwan Cho, YoungUk Jang, Aidan Warnock, Ramazan Yildiz, Jing Jhang, Kajal Davi, Niki F Brisnovali, Victoria Huhn, Peng Wang, Romina Bevaqua, Leigh Goedeke, Michael A Schotsaert, Mirela Berisa, Daniel Puleston, Prashant Rajbhandari.
      Coordination between innate immune signaling and glucose metabolism is fundamental to organismal homeostasis, yet despite decades of study linking immunity and metabolism, the mechanisms by which metabolic cells restrain antiviral innate signaling while preserving glycolytic competence during overnutrition remain poorly defined. Here we identify Tetherin (BST2) as a unique cell-intrinsic immunometabolic checkpoint that couples restraint of type I interferon (IFN-I) signaling to preservation of glycolytic capacity in adipocytes. Tetherin localizes to endoplasmic reticulum and organizes an interactome enriched for antiviral sensing regulators and glycolytic control nodes in adipocytes. Mechanistically, Tetherin directly engages the ubiquitin-dependent degradation machinery NDFIP1 and RNF128 to terminate IRF3 activation, thereby limiting pro-inflammatory, anti-glycolytic signaling and protecting adipocytes from metabolic dysfunction. In parallel, multiomics integration reveals that Tetherin also acts as a scaffold that binds and spatially organizes and activates PFKFB3 to increase glycolytic capacity and restrain MAVS-IRF3 innate immune signalling. In vivo, adipocyte-specific loss of Tetherin amplifies high sucrose diet and high-fat-diet-induced glucose intolerance and liver steatosis, whereas overexpression of human Tetherin in adipocyte suppresses obesity-driven interferon signaling, restores glycolytic pathway, and improves metabolic homeostasis. Orthogonal perturbations in cancer and insulinoma cells further confirm an immunometabolic role for Tetherin. Together, these findings define Tetherin as a dual node immunometabolic checkpoint that couples restraint of antiviral innate inflammatory signaling to maintenance of glycolytic competence, thereby safeguarding adipocyte metabolic homeostasis.
    DOI:  https://doi.org/10.64898/2026.07.06.735062
  10. J Virol. 2026 Jul 16. e0039526
    Lysophosphatidic acid promotes lipid metabolism through AMPK signaling to support Coxsackievirus infection.
    Natalie J LoMascolo, Caroline E Thomas, Madison L Lange, Bryan C Mounce.
      Lysophosphatidic acid (LPA) is a bioactive signaling lipid that regulates cellular processes, including growth, survival, differentiation, and metabolic homeostasis. LPA signals through its G-protein-coupled receptor, LPA receptor 1 (LPAR1), to modulate pathways controlling cellular signaling and metabolism. Viruses rely on cellular metabolism for efficient replication, and lipids function at nearly every stage in virus replication. Using Coxsackievirus B3 (CVB3) as a model, we performed global metabolomic analysis of infected Huh7 cells and identified lipid classes altered upon infection. Using small-molecule inhibitors targeting lipids, we identified LPA signaling as a key factor in CVB3 infection. Inhibiting LPA signaling with AM095 or via siRNA knockdown reduces CVB3 infection by over 100-fold. We find that LPA mediates CVB3 genome replication. Mechanistically, LPA signaling through LPAR1 facilitates cellular lipid synthesis by regulating AMPK and downstream enzymes, including fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1). In AM095-treated cells, lipid droplets are depleted, and cells exhibit a quiescent-like phenotype. Replenishing lipids fully rescues viral replication, indicating that LPA's proviral function is to facilitate lipid synthesis through AMPK signaling. These findings identify LPA-LPAR1 signaling as a regulator of host lipid metabolism that supports CVB3 replication, revealing a metabolic axis for antiviral intervention.IMPORTANCECellular metabolism supports virus infection by providing energy and the building blocks for virus replication. During viral infection, cellular metabolism changes drastically, and we find that lipids are among the most significantly changed metabolites during infection with Coxsackievirus B3, a picornavirus. We used metabolomics to characterize changes in metabolites in infected cells, and we followed up on these data with a drug screen with molecules targeting cellular lipid pathways. We identified lysophosphatidic acid (LPA) signaling as a major regulator of Coxsackievirus infection, supporting viral genome replication via lipid synthesis. This study underscores the importance of lipids in viral infection, uncovers new mechanisms by which LPA signals, and provides new insight into LPA's function in Coxsackievirus infection.
    Keywords:  AMPK; Coxsackievirus B3; lipids; lysophosphatidic acid; lysophosphatidic acid receptor 1
    DOI:  https://doi.org/10.1128/jvi.00395-26
  11. Antioxid Redox Signal. 2026 Jul 14. 15230864261467594
    Itaconate Ameliorates Skin Fibrosis Through Inhibition of HIF-1α/LDHA-Driven Aerobic Glycolysis.
    Linxiao Li, Xiaohui Miao, Yu Cheng, Yingying Zhuang, Wuyan Lu, Yishu Lu, Yu Jiang, Zihao Hu, Jinyi Deng, Fengting Niu, Guangpeng Liu, Lei Cui, Shuaijun Li, Jiefeng Huang.
       BACKGROUND: Skin fibrosis is a hallmark of scleroderma and other fibrotic skin disorders, yet effective therapies remain limited. Immune-derived metabolites have emerged as regulators of inflammation and tissue remodeling, but whether metabolic reprogramming within dermal fibroblasts contributes to skin fibrosis remains unclear.
    METHODS: Human fibrotic skin samples, a bleomycin-induced mouse model, and primary dermal fibroblasts were used to investigate the role of immune-responsive gene 1 (Irg1) and its metabolic product itaconate. Transcriptomic analyses, metabolic profiling, pharmacologic modulation, and genetic perturbation were employed to define downstream signaling mechanisms.
    KEY FINDINGS: Irg1 expression and endogenous itaconate levels were reduced in fibrotic human and murine skin. Restoration of itaconate significantly attenuated dermal thickening, collagen deposition, and fibroblast activation. Mechanistically, itaconate suppressed glycolytic reprogramming in activated fibroblasts, as evidenced by reduced glucose uptake, lactate production, and glycolytic enzyme expression. This metabolic effect was associated with inhibition of the Akt/GSK-3β pathway, destabilization of hypoxia-inducible factor 1α (HIF-1α), and subsequent downregulation of lactate dehydrogenase A (LDHA) transcription. Genetic or pharmacologic interference with HIF-1α or LDHA partially phenocopied itaconate's antifibrotic effects, supporting a functional link between itaconate signaling, fibroblast metabolism, and fibrotic progression.
    CONCLUSIONS: This study identifies loss of Irg1-itaconate signaling as a previously unrecognized driver of fibroblast metabolic reprogramming in skin fibrosis. By revealing a fibroblast-intrinsic, metabolism-centered mechanism linking immunometabolite deficiency to extracellular matrix overproduction, these findings extend itaconate's scope beyond immune regulation and highlight metabolic targeting of fibroblasts as a promising therapeutic strategy for fibrotic skin disease. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  glycolysis; itaconate; metabolic reprogramming; skin fibrosis
    DOI:  https://doi.org/10.1177/15230864261467594
  12. Nat Cancer. 2026 Jul 15.
    A targetable micropeptide reprograms macrophages to suppress T cell anti-tumor immunity.
      
    DOI:  https://doi.org/10.1038/s43018-026-01196-1
  13. Cell Mol Life Sci. 2026 Jul 16.
    ENO3-mediated glycolytic reprogramming participates in β-glucan-induced dendritic cells activation and anti-tumor responses.
    Jun Ding, Yongzhe Hao, Meng Yuan, Jie Pan, Yewen Xie, Xiao Sun, Yongling Ning, Chunjian Qi.
      Dendritic cells (DCs) are key initiators of antitumor immunity, yet the metabolic drivers governing their activation remain incompletely defined. Here, we show that the fungal immunomodulator β-glucan induces robust immune-metabolic reprogramming in bone marrow-derived DCs (BMDCs), characterized by coordinated increases in glycolysis and tricarboxylic acid cycle activity. This metabolic shift is essential for BMDCs activation, as inhibition of glycolysis or oxidative metabolism diminishes β-glucan-induced costimulatory molecule expression, proinflammatory cytokine production and T-cell priming. Multi-omics profiling identifies enolase 3 (ENO3) as a key glycolytic regulator selectively upregulated by β-glucan. ENO3 knockdown reduces glycolytic flux, decreases mitochondrial ATP and ROS production, and consequently impairs BMDCs maturation and CD8⁺ T-cell responses. In DC-specific ENO3-knockout mice, ENO3 deficiency significantly compromises the antitumor efficacy of β-glucan, which characterized by accelerated tumor growth, impaired DCs activation, reduced CD8⁺ T-cell infiltration, and an immunosuppressive tumor milieu. These findings reveal ENO3 as a critical metabolic regulator linking β-glucan sensing to DC-mediated antitumor immunity.
    Keywords:  Dectin-1 agonist; Glycolytic metabolism; Immune cells; Tumor microenvironment; β-enolase
    DOI:  https://doi.org/10.1007/s00018-026-06350-7
  14. Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2536238123
    IL-7-glucose-Aiolos axis orchestrates pathogenic CD8+ T cell function in spondyloarthritis.
    Mitsuhiro Akiyama, Waleed Alshehri, Mirei Koroyasu, Tomohiro Kaburaki, Keiko Yoshimoto, Koichi Saito, Kanako Shimanuki, Yuko Kaneko.
      CD8+ T cells are essential mediators of host defense, whereas their aberrant activation contributes to inflammatory diseases such as spondyloarthritis. The molecular mechanisms governing human CD8+ T cell effector programming remain incompletely understood. Here, we identify a metabolically distinct subset of human CD8+ T cells defined by high expression of CXCR3, IL-7R, and GLUT1 and low expression of the transcription factor Aiolos. IL-7-JAK-STAT signaling was associated with increased GLUT1 expression and glucose uptake, accompanied by reduced Aiolos expression in CD8+ T cells. Consistent with this, Aiolos functioned as a regulatory constraint on effector cytokine production under glucose-limited conditions, and its reduction was associated with enhanced cytokine production in metabolically active CD8+ T cells. Circulating CD8+ T cells from patients with spondyloarthritis exhibited elevated GLUT1 expression compared with rheumatoid arthritis and healthy controls, which correlated with disease activity. In addition, CXCR3+ IL-7R+ pSTAT5+ GLUT1+ Aioloslow CD8+ T cells were enriched in inflamed joints, where CXCL10 may contribute to their recruitment. Increased FDG uptake in inflamed sacroiliac joints further supports enhanced metabolic activity at sites of inflammation. JAK inhibitor therapy was associated with reduced GLUT1 expression and increased Aiolos expression in CD8+ T cells, accompanied by decreased effector cytokine production and clinical improvement in patients with spondyloarthritis. Together, these findings support a model in which cytokine signaling, metabolic state, and transcriptional regulation are functionally linked in human CD8+ T cells, and suggest that Aiolos may act as a regulatory node integrating these inputs in inflammatory diseases.
    Keywords:  Aiolos; CD8+ T cells; Interleukin-7; Janus kinase; glucose transporter
    DOI:  https://doi.org/10.1073/pnas.2536238123
  15. Immunohorizons. 2026 Jul 10. pii: vlag039. [Epub ahead of print]10(7):
    Medium chain fatty acid sensing receptor GPR84 limits antitumor immunity mediated by CD4 T cells in mice.
    Anamaria Morales-Alvarez, Timothy A Gilbertson, Hung Nguyen.
      CD4+ T cells play an important role in antitumor immunity due to their capacity to acquire highly functional effector states and cytotoxic-like programs in the tumor microenvironment. However, the mechanisms underlining this process remain largely undefined. Herein, we identify the medium chain fatty acid-sensing receptor GPR84 as a metabolic checkpoint that restricts the antitumor immunity mediated by CD4+ T cells. GPR84 upregulation was detected in tumor-infiltrating CD4+ T cells, and in the absence of GPR84, CD4+ T cells exhibited enhanced tumor control, associated with increase in their proliferation and survival, and with a reprogramming toward a more functionally competent state characterized by increased polyfunctional cytokine production and reduced expression of inhibitory receptors, without accumulation of regulatory T cells. In the tumor antigen-specific mouse model, GPR84 deficiency drastically improved the therapeutic efficacy of adoptively transferred CD4+ T cells. Mechanistically, without GPR84, CD4+ T cells, by upregulating mTORC1 signaling activity, metabolically enhance both glycolysis and mitochondrial activities, thereby gearing toward tumor-killing cytotoxic phenotypes. Importantly, pharmacologic inhibition of GPR84 drastically improves the effectiveness of both PD-1 blockade therapy and adoptive cell transfer. Together, these findings validate GPR84 as a key regulator of CD4+ T-cell metabolic fitness and establish the extracellular lipid sensing pathway as a targetable axis for improving the efficacy and responsiveness of cancer immunotherapies.
    Keywords:  GPR84; cancer immunotherapy; cytotoxic CD4+ T cells; immunometabolism; medium chain fatty acids
    DOI:  https://doi.org/10.1093/immhor/vlag039
  16. Cells. 2026 Jun 26. pii: 1166. [Epub ahead of print]15(13):
    Macrophage Metabolic Reprogramming in Rheumatoid Arthritis: Pathogenic Mechanisms and Therapeutic Implications.
    Longping Chen, Siyuan Leng, Xin Liu, Junlan Zhang, Fang Zhao, Zeyu Hu, Xiong Cai, Ye Lin.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovitis, progressive cartilage destruction and bone erosion. Recent advances in single-cell and spatial omics, together with immunometabolic studies, have revealed marked state heterogeneity among synovial macrophages in RA. Their metabolic reprogramming appears to sustain pathogenic cellular states, drive aberrant intercellular communication and impair the resolution of inflammation. Rather than acting as an independent initiating factor, it more likely operates as a downstream amplifier of disease. In this review, we outline the principal functional states and metabolic features of synovial macrophages in health and RA. We focus on how the rewiring of glucose, lipid and amino acid metabolism links inflammatory transcription, tissue remodelling and bone destruction. These connections are mediated by metabolic enzymes, metabolic intermediates, redox regulation and epigenetic modifications. We further summarise the immunometabolic effects of currently available antirheumatic drugs. We also appraise the preclinical evidence and translational limitations of metabolic pathway inhibitors, natural products and nanodelivery systems. It should be noted that most existing evidence still relies on in vitro polarisation systems and rodent models. Validation of metabolic flux, cell-state specificity and causal relationships in human synovium remains limited. As a narrative review focused on recent studies of synovial macrophage metabolism in health and inflammation, this work aims to delineate how metabolic reprogramming shapes the phenotypic heterogeneity and pathogenic functions of macrophages in RA. It also seeks to appraise the potential value and current boundaries of evidence for therapeutically targeting macrophage metabolism.
    Keywords:  immunometabolism; macrophages; metabolic reprogramming; rheumatoid arthritis; synovial microenvironment
    DOI:  https://doi.org/10.3390/cells15131166
  17. J Clin Invest. 2026 Jul 15. pii: e202262. [Epub ahead of print]136(14):
    Gut microbe-derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice.
    Fang R Zhao, Maksim Kleverov, Emma S Winkler, Russell B Williams, Hana Janova, Lindsay Droit, Leran Wang, Ting-Ting Li, Leah Heath, Ana Jung, Matthias Mack, Megan T Baldridge, Thaddeus S Stappenbeck, Larissa B Thackray, Chyi-Song Hsieh, Scott A Handley, Chun-Jun Guo, Michael A Fischbach, Maxim N Artyomov, Michael S Diamond.
      Oral antibiotics can predispose to joint inflammation, but this phenomenon remains poorly understood. Here, we leverage mouse models of alphavirus-induced arthritis to investigate the roles of gut commensals, metabolites, and host immune mechanisms in promoting musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya (CHIKV) or Mayaro virus infections. This phenotype was associated with loss of short-chain fatty acids (SCFAs), greater intestinal permeability, and activation of gut-associated immune cells and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4+ T cells, and proinflammatory cytokines. Administration of exogenous SCFAs or colonization of mice with bacterial species that generate SCFAs mitigated CHIKV-induced joint inflammation. scRNA-seq revealed that gut-derived SCFAs ameliorate the inflammatory phenotype of synovial CD4+ T cells, infiltrating monocytes, and resident osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.
    Keywords:  Adaptive immunity; Immunology; Infectious disease; Innate immunity; Microbiology
    DOI:  https://doi.org/10.1172/JCI202262
  18. Adv Sci (Weinh). 2026 Jul 14. e76518
    TRAF6 Lactylation in Glycolytic Macrophages Drives NF-κB Signaling and M1 Polarization During Orthodontic Tooth Movement.
    Xinyi He, Guodong Zhao, Yun Hu, Wenya Bai, Hao Tan, Shuai Yuan, Sihan Yang, Ye Zhu, Xiaohui Xu, Leilei Zheng.
      Protein lactylation is an emerging lactate-derived modification, coupling metabolic reprogramming to inflammatory regulation while modulating cellular responses to the microenvironment. However, the role of macrophage lactylation in orthodontic tooth movement (OTM) remains unclear. Transcriptomic and metabolomic profiling of compressed macrophages identified glycolytic reprogramming as the core regulatory axis, with elevated lactate levels validated in macrophages, mice, and human saliva. Exogenous lactate promoted M1 polarization and NF-κB signaling activation in compressed macrophages, identifying lactate dehydrogenase A (LDHA) as a critical regulatory node. Myeloid-specific Ldha deficiency inhibited OTM and attenuated sterile inflammation, confirming the critical link between lactate metabolism and OTM progression. Mechanistically, we utilized lactylation proteomics and identified that lactate induces specific lactylation of TRAF6 at lysine residues 171, 180, and 388 (K171, K180, K388). Molecular dynamics simulations and site-directed mutagenesis revealed that K171/K180 lactylation enhances TRAF6 K63-linked ubiquitination, thereby driving NF-κB signaling activation. Consistently, mutation of K171 and K180 diminished TRAF6 K63-linked ubiquitination and suppressed NF-κB activation. Collectively, our findings demonstrate that sustained compressive force reprograms macrophage metabolism toward glycolysis and drives lactylation of TRAF6 at K171/K180, which serves as a core regulatory node that amplifies NF-κB signaling, thereby facilitating OTM-associated sterile inflammation and alveolar bone remodeling.
    Keywords:  bone remodeling; inflammation; lactate dehydrogenases; metabolic reprogramming; molecular dynamics simulations; posttranslational modifications
    DOI:  https://doi.org/10.1002/advs.76518
  19. Sci Immunol. 2026 Jul 17. 11(121): eaee0990
    Macrophage-derived oxysterols organize T helper 2 cells to suppress type 1 inflammation during pulmonary fungal infection.
    Yufan Zheng, Hannah E Dobson, Makheni Jean Pierre, Lillian B LeBlanc, Chinaemerem U Onyishi, Dominic P Golec, Nathan Carrillo, Anshu Deewan, Claudia A Rivera, Eduard Ansaldo, Pamela L Schwartzberg, Eric V Dang.
      Effective pulmonary immunity requires the precise spatial organization of immune cells, yet the mechanisms guiding their intratissue positioning during inflammation remain unclear. Here, we identify a cholesterol-derived chemotactic axis that spatially organizes T helper 2 (TH2) cells during fungal-induced pulmonary type 2 inflammation. Inflammation-expanded macrophages expressing cholesterol-25-hydroxylase (CH25H) produced 25-hydroxycholesterol, which was converted into the oxysterol 7α,25-dihydroxycholesterol to attract GPR183-expressing TH2 cells into infectious lesions. This TH2 cell positioning suppressed interferon-γ responsiveness in inflammatory Ly6C+ macrophages, promoting fungal persistence. Disruption of this axis via TH2-specific GPR183 deletion restored type 1 macrophage activation and enhanced fungal clearance. Our findings reveal a macrophage-driven, metabolite-based mechanism of immunosuppressive cell positioning in inflamed lung tissue.
    DOI:  https://doi.org/10.1126/sciimmunol.aee0990
  20. FASEB J. 2026 Jul 31. 40(14): e72141
    Metabolic Reprogramming of Macrophages Plays a Dual Role in Periodontitis: From Pathogenesis to Therapy.
    Tao Chen, Hongyu Ming, Junning He, Feng Zhou, Dongyang Wang, Fuwei Bai, Tongfeng Fang, Yi Man, Yingying Wu.
      The pathogenesis of periodontitis is closely intertwined with a complex immune and inflammatory cascade initiated by a dysbiotic dental biofilm. As key regulators of both innate and adaptive immunity, macrophages play a central role in the development and progression of periodontitis. Recent advances in immunometabolism have underscored the significance of metabolic reprogramming in shaping macrophage immune responses and influencing inflammation progression. In this review, we discuss the metabolic reprogramming of macrophages in glucose, lipid, and amino acid metabolism during periodontitis, as well as its intercellular consequences within the periodontal microenvironment. Moreover, we discuss how periodontal inflammatory microenvironmental factors drive this metabolic reprogramming, establishing a bidirectional, self-perpetuating vicious cycle. Finally, we highlight the therapeutic potential of targeting macrophage metabolism and emphasize the dual role of metabolic reprogramming as both a driver of periodontitis progression and a potentially reversible process that can be therapeutically redirected.
    Keywords:  immunometabolism; macrophage; metabolic reprogramming; pathogenesis; periodontitis; therapy
    DOI:  https://doi.org/10.1096/fj.202600558RRR
  21. Front Cardiovasc Med. 2026 ;13 1874530
    The dual role of metabolic reprogramming in macrophage polarization in rheumatoid arthritis and coronary heart disease and the intervention strategy of traditional Chinese medicine.
    Haichun Zheng, Xiuyue Li, Jing Ru, Zhuoran Meng, Weibing Liu, Tao Jia, Shan Zhang, Qianwen Deng, Wenyi Huang, Renjie Dong, Qianrong Li.
      Macrophage polarization has become increasingly acknowledged as a process that is governed by metabolism which will have significant impacts on long-term inflammatory and cardiovascular diseases. Through the atherosclerotic component of coronary pathology, both rheumatoid arthritis and coronary heart disease result in macrophages undergoing dramatic metabolic changes that ultimately determine how they functionally behave in terms of their inflammatory characteristics. While pro-inflammatory M1 macrophages exhibit a preference for aerobic glycolysis, anti-inflammatory/tissue repair M2 macrophages are more heavily reliant upon oxidative phosphorylation/fatty acid oxidation. The balance between these two types of metabolism is typically disrupted towards the glycolysis dominant type in both rheumatoid arthritis and atherosclerosis; thus contributing to increased inflammation, sustained inflammatory amplification, and exacerbated tissue damage. Metabolic regulators involved in modulating the glycolytic metabolism of macrophages include Pim2 kinase (in rheumatoid arthritis), phosphoglycerate kinase 1, pyruvate dehydrogenase E1 alpha 1 (in rheumatoid arthritis), and granulocyte-macrophage colony stimulating factor (in rheumatoid arthritis). Furthermore, in coronary heart disease, activation of the PI3K/AKT pathway increases the programming of glycolytic metabolism in macrophages and increases plaque inflammation/lesion instability while the oxidative metabolism associated with M2 macrophages results in resolution/plaque stability. Given this context, there is an increasing amount of evidence demonstrating that certain compounds found within traditional Chinese medicines, including berberine, ginsenoside Rb1 and formulae targeted at the HIF-1α/PDK1 axis can be used to re-balance macrophage metabolism to induce a shift away from inflammatory dominance. This review focuses on the dual roles of macrophage metabolic re-programming in rheumatoid arthritis and coronary heart disease, compare common/disease specific signaling components such as HIF-1α, AMPK, and mTORC1 and evaluate the therapeutic potential of traditional Chinese medicine for restoring immunometabolic homeostasis.
    Keywords:  Macrophage polarization; Rheumatoid arthritis; Traditional Chinese Medicine; atherosclerosis; coronary heart disease; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fcvm.2026.1874530
  22. Vet Microbiol. 2026 Jul 13. pii: S0378-1135(26)00275-0. [Epub ahead of print]320 111138
    Classical swine fever virus hijacks triglyceride metabolism via the NS5B-PLIN5 axis to facilitate viral replication.
    Xiao-Wen Li, Liang-Chun Liu, Fei-Fan Zhao, Yan-Hong Yong, Xiang-Hong Ju.
      Classical swine fever virus (CSFV) represents a critical pathogen that causes substantial economic losses to the swine industry and heavily relies on host lipid metabolic reprogramming during infection. However, the detailed regulatory mechanisms governing CSFV-induced lipid metabolic remodeling remain poorly understanding. In this study, we systematically investigated how CSFV reprograms lipid metabolism to facilitate viral replication. Our results demonstrated that CSFV infection significantly promotes the accumulation of triglycerides (TG), phosphatidylethanolamine (PE), and phosphatidylglycerol (PG), with pathway enrichment analysis revealing pronounced activation of cholesterol metabolism and autophagy pathways. Administration of autophagy inhibitor chloroquine resulted in prominent alterations in TG metabolites, with integrative analyses demonstrating that TG constituted 56.36% of the shared differential metabolites, underscoring the pivotal role of TG metabolism in CSFV infection. Notable, the lipid droplet-associated protein Perilipin 5 (PLIN5) was significantly upregulated following CSFV infection, and the viral nonstructural protein NS5B was found to directly interact with PLIN5 and promote its expression. Functional assays revealed that CSFV RNA localizes to lipid droplets, and overexpression of PLIN5 significantly enhanced viral replication. Collectively, this study uncovers a mechanism by which CSFV hijacks TG metabolism through the NS5B-PLIN5 axis and exploits lipid droplets as platforms for viral replication.
    Keywords:  Classical swine fever virus; Perilipin 5; Triglycerides Metabolism
    DOI:  https://doi.org/10.1016/j.vetmic.2026.111138
  23. Front Immunol. 2026 ;17 1879961
    Lactylation: a novel epigenetic bridge connecting metabolic reprogramming and immune dysregulation in sepsis-associated ARDS.
    Linxiao Wang, Lin Liu, Yanjun Wang, Fang Wang, Xi Gao, Yinghui Li.
      Sepsis-associated acute respiratory distress syndrome (ARDS) is driven by metabolic reprogramming and immune dysregulation, but the molecular link between them remains unclear. Lactylation, a lactate-derived post-translational modification, couples metabolic state to transcriptional and functional outcomes in immune and parenchymal cells as an epigenetic reader of glycolytic flux. Recent evidence demonstrates that lactylation regulates macrophage polarization, neutrophil extracellular trap formation, myeloid derived suppressor cell function, and T cell differentiation, while also controlling ferroptosis, autophagy, and endothelial injury in the septic lung. Clinical studies have identified histone H3K18 lactylation as a potential biomarker for sepsis severity and prognosis. This review establishes lactylation as a novel epigenetic bridge connecting metabolic reprogramming and immune dysregulation in sepsis associated ARDS and highlights therapeutic opportunities targeting this modification.
    Keywords:  acute respiratory distress syndrome; epigenetics; histone lactylation; immune dysregulation; lactylation; metabolic reprogramming; post translational modification; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1879961
  24. bioRxiv. 2026 Jul 10. pii: 2026.07.09.737644. [Epub ahead of print]
    Hepatitis C Virus Remodels Lipid Droplets to Promote Mitochondrial Fatty Acid Accumulation and Metabolic Activation.
    Imaan Muhammad, Kaci Craft, Shaokai Pei, Kaia Conte, Junyan Li, Shaolei Teng, Ruth Cruz-Cosme, Shaomin Yang, Yanjin Zhang, Qiyi Tang.
      Hepatitis C virus (HCV) depends on host lipid metabolism and lipid droplets (LDs) for genome replication, assembly, and particle production, yet how LD structure and lipid utilization change over the course of infection remains incompletely understood. Here, we investigated the temporal remodeling of LD-associated metabolic pathways during HCV JFH-1 infection of human hepatoma Huh7 cells. HCV infection transiently increased LD fluorescence intensity at 24 hours post-infection (hpi), followed by normalization or relative loss of LD signal at later time points. Concomitantly, LDs became progressively clustered and enlargement during late infection, despite reduced protein levels of the canonical LD fusion proteins CIDEA, CIDEB, and CIDEC, suggesting that HCV-induced LD enlargement occurs through CIDE-independent mechanisms. Transcriptomic, RT-qPCR, and immunoblot analyses revealed time-dependent regulation of genes and proteins involved in LD structure, triglyceride synthesis, lipolysis, lipid uptake, and mitochondrial fatty acid utilization. Subcellular fractionation demonstrated preferential accumulation of fatty acids in mitochondrial fractions at 24-72 hpi. This redistribution was accompanied by increased oxygen consumption rate, elevated extracellular acidification, and progressive reactive oxygen species accumulation, indicating infection-associated metabolic activation and oxidative stress. Pharmacological inhibition of DGAT1-dependent LD biogenesis, LIPA-dependent lysosomal lipid hydrolysis, LIPE/HSL-dependent lipolysis, or CPT1-dependent mitochondrial fatty acid transport markedly reduced mitochondrial fatty acid accumulation and suppressed HCV-induced respiratory activity. Inhibition of LIPA or LIPE/HSL reduced both HCV RNA and core protein levels, whereas inhibition of CPT1 or DGAT1 had more pronounced effects on core protein than on viral RNA. Together, these findings support a model in which HCV dynamically remodels LDs, mobilizes LD-associated fatty acids, and redirects them toward mitochondria to support infection-associated metabolism and downstream stages of the viral life cycle. Lipid hydrolysis and mitochondrial fatty acid trafficking therefore represent potential host-directed targets for limiting HCV infection.
    SIGNIFIGANCE: Hepatitis C virus depends on host lipid metabolism for replication, assembly, and production of infectious particles, but how it uses lipid droplets over time remains incompletely understood. This study shows that hepatitis C virus dynamically remodels lipid droplets, causing an early increase in lipid storage followed by droplet enlargement and mobilization of fatty acids during later infection. The released fatty acids preferentially accumulate in mitochondria, where they are associated with increased cellular respiration and oxidative stress. Blocking lipid droplet formation, lipid breakdown, or fatty acid transport to mitochondria reduced this metabolic response and decreased viral RNA or core protein accumulation. Inhibition of lysosomal acid lipase and hormone-sensitive lipase suppressed both viral RNA and protein levels. These findings identify lipid droplet breakdown and mitochondrial fatty acid trafficking as important host processes used by hepatitis C virus and as potential targets for host-directed antiviral intervention.
    DOI:  https://doi.org/10.64898/2026.07.09.737644
  25. Mol Biol Rep. 2026 Jul 17. pii: 1192. [Epub ahead of print]53(1):
    Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells.
    Francisco Alejandro Lagunas-Rangel.
      Metabolic competition within the tumor microenvironment shapes the availability of nutrients and metabolites that regulate both tumor progression and antitumor immunity. Among the molecules linking metabolism to gene regulation, the NAD + -dependent enzyme SIRT7 has emerged as an important regulator of ribosome biogenesis, genome stability, chromatin organization, and metabolic adaptation. Although SIRT7 is frequently associated with tumor progression, emerging evidence indicates that it also supports the metabolic fitness and effector functions of immune cells, suggesting that its biological consequences are highly cell type-dependent. However, the mechanisms underlying these apparently opposing functions remain poorly understood. A conceptual framework is presented in which differences in intracellular NAD + availability contribute to asymmetric SIRT7 activity in tumor and immune cells within the tumor microenvironment. Many tumor types preserve intracellular NAD + through metabolic rewiring, whereas infiltrating immune cells frequently experience sustained metabolic stress and progressive NAD + depletion owing to nutrient competition. Although direct evidence demonstrating that physiological fluctuations in intracellular NAD + regulate SIRT7 activity in vivo remains limited, biochemical studies indicate that SIRT7 displays a relatively high apparent Michaelis constant (Km) for NAD + compared with other mammalian sirtuins, providing a biochemical rationale for increased sensitivity to changes in intracellular NAD + availability. Current evidence from SIRT7 biology, cancer metabolism, and immunometabolism is integrated to evaluate this conceptual framework, identify key limitations in the available data, and highlight experimental questions that should be addressed to determine whether differential NAD + availability represents a fundamental mechanism underlying the context-dependent functions of SIRT7.
    Keywords:  Immune dysfunction; PD-L1; Sirtuin; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11033-026-12400-x
  26. Nat Commun. 2026 Jul 15.
    Butyrate epigenetically licenses sustained epithelial-T cell crosstalk for intestinal immune tolerance.
    Tianming Yu, Wenjing Yang, Anthony J Bilotta, Suxia Yao, Jeong-Heon Lee, Qihong Zhao, Jia Zhou, Tamas Ordog, Parambir S Dulai, Yingzi Cong.
      Intestinal epithelial cells (IEC) are the primary cell type in direct contact with stimuli from the luminal microbiota, playing a critical role in host-microbe interactions. However, how IECs communicate with underlying immune cells to maintain homeostasis remains poorly understood. In addition, the mechanisms by which IECs sense microbiota-derived stimuli to initiate this crosstalk are not yet fully understood. Here, we demonstrate that oral administration of the gut microbiota metabolite butyrate induces sustained IL-10 production in CD4⁺ T cells, conferring long-lasting protection against intestinal inflammation even after treatment withdrawal. This persistent immunoregulatory effect is also observed in germ-free mice, indicating the establishment of a butyrate-conditioned intestinal environment. By metabolomic profiling, we identify N1-acetylspermidine as a metabolite contributing to the IL-10-inducing activity of butyrate-treated IEC-conditioned medium. Mechanistically, butyrate induces sustained transcriptional and epigenetic activation of the acetylpolyamine biosynthetic enzyme Sat1 in IECs, which catalyzes the acetylation of spermidine to generate N1-acetylspermidine, and this activation persists after butyrate withdrawal. Together, our findings reveal a mechanism by which butyrate sensing establishes persistent crosstalk between IECs and T cells, thereby maintaining intestinal immune tolerance through epigenetic regulation and reprogramming of epithelial metabolism.
    DOI:  https://doi.org/10.1038/s41467-026-75600-w
  27. mSystems. 2026 Jul 16. e0032426
    β-Hydroxybutyrate precursor 1,3-butanediol modulates enteric pathogen susceptibility and Th17 responses via commensal bacteria.
    Wenxuan Dong, Chi Yan, Bethany Korwin-Mihavics, Kate Stack, Gillian Hughes, Aidan Schmidt, Kevin J Schwartz, Gustavo Caballero-Flores, Margaret Alexander.
      T helper 17 (Th17) cells are a critical T lymphocyte subset involved in mucosal immunity and host defense against enteric pathogens. Although ketogenic diets (KD) and the major ketone body β-hydroxybutyrate (BHB) reshape gut microbiota and suppress Th17 responses under defined diet conditions, it remains unclear whether elevation of BHB alone, independent of dietary macronutrient composition and systemic metabolic shifts, is sufficient to remodel Th17-inducing commensals and alter host susceptibility to enteric infection. Here, we used 1,3-butanediol (BD), a precursor metabolized to BHB independently of KD, to elevate systemic BHB levels in mice. BD treatment significantly reduced the frequency of ileal Th17 cells, as assessed by flow cytometry for Th17 markers IL-17A and RORγt. 16S rRNA gene sequencing revealed that BD altered gut microbial community structure, as indicated by beta-diversity analysis based on Bray-Curtis dissimilarity, and reduced Shannon diversity and evenness. Linear discriminant analysis effect size identified segmented filamentous bacteria (SFB) as significantly decreased in the ileum following BD treatment, and SFB abundance positively correlated with Th17 markers. Microbiota transplantation demonstrated that BD-shaped microbiota was sufficient to suppress Th17 responses in recipient mice, accompanied by reduced SFB abundance. In a Citrobacter rodentium infection model, BD treatment was associated with increased pathogen burden, and fecal C. rodentium levels were negatively correlated with SFB abundance. Together, these results support a model in which BD treatment, accompanied by elevated circulating BHB, reshapes the commensal microbiota, including reducing SFB levels, and is associated with dampened Th17 responses as well as increased susceptibility to enteric infection.IMPORTANCEDiet is a key determinant of gut microbial composition and mucosal immune function, yet the microbial mechanisms linking diet-mediated metabolic changes to immune regulation remain incompletely understood. T helper 17 (Th17) cells play central roles in both protective mucosal immunity and inflammatory pathology, making them a critical target of immunometabolic regulation. In this study, we show that 1,3-butanediol (BD) treatment, which leads to elevated circulating β-hydroxybutyrate (BHB) independently of diet, is associated with suppression of intestinal Th17 responses, remodeling of the gut microbiota, and reduced levels of segmented filamentous bacteria (SFB). We further demonstrate that BHB-associated microbiota changes are linked to increased susceptibility to enteric infection. This work provides a mechanistic framework illustrating how metabolic state can influence host immunity through selective effects on commensal microbes. These findings inform future studies of microbiota-mediated immune regulation.
    Keywords:  Citrobacter rodentium infection; T helper (Th) 17 cells; microbiota; microbiota immune interactions; segmented filamentous bacteria; β-hydroxybutyrate
    DOI:  https://doi.org/10.1128/msystems.00324-26
  28. Mol Ther Oncol. 2026 Sep 17. 34(3): 201277
    Augmenting CAR T cell functionality and metabolism through CD39 downtuning.
    Dennis Christoph Harrer, Jeremy Baldwin, Markus Barden, Hong Pan, Bence Gergely, Árpád Szöőr, György Vereb, Wolfgang Herr, Hinrich Abken.
      The CD39/CD73 axis is a potent intrinsic repressor of T cell functionality. CAR T cell activation triggers the increase of CD39; its downregulation reduced extracellular ATP degradation and enhanced the functional capacities in CD39low CAR T cells compared with conventional CAR T cells with respect to an increase in granzyme/perforin and degranulation upon repetitive CAR stimulation. CD39low CAR T cells, moreover, displayed superior mitochondrial function and enhanced glycolytic activities. Consequently, CD39low CAR T cells outperformed conventional CAR T cells in controlling CEA+ gastric carcinoma in xeno-transplanted NSG mice. The CD39 effect is unique, since downtuning CD38, also involved in the regulation of exhaustion, did not provide benefits under stimulatory "stress conditions". Activation-induced upregulation of CD39/CD73 contributes to a negative feedback loop for CAR T cells; downregulated CD39 levels augmented T cell anti-tumor activities by reducing AMP and adenosine-mediated repression. In the broader context, CD39 downregulation is unlikely to be sufficient as a standalone intervention in all settings but may be particularly valuable as part of combination strategies with complementary approaches targeting additional metabolic or immune checkpoint pathways to further enhance CAR T cell persistence and anti-tumor activity.
    Keywords:  CAR T cell; CD39; adenosine; adoptive T cell therapy; exhaustion; metabolism
    DOI:  https://doi.org/10.1016/j.omton.2026.201277
  29. Int J Mol Sci. 2026 Jul 06. pii: 6057. [Epub ahead of print]27(13):
    Dendritic Cells as Immunometabolic Regulatory Nodes in Diabetes: Molecular Mechanisms and Therapeutic Reprogramming.
    Fangfang Jin, Weidong Wu, Xuan Yang, Xiang Fan, Xiaosen Zhao, Wei Liu, Xinrong Fan.
      Diabetes mellitus comprises a group of heterogeneous metabolic disorders characterized by persistent hyperglycemia, progressive β-cell dysfunction, and multi-organ complications. Although type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have distinct pathogenic origins, both involve immune dysregulation, tissue stress, release of danger signals, and chronic inflammation. Dendritic cells (DCs), as antigen-presenting cells, integrate innate immune sensing, antigen presentation, cytokine production, T-cell regulation, and peripheral immune tolerance, placing them at a critical interface between autoimmunity and metabolic inflammation. In T1DM, DCs contribute to β-cell autoantigen presentation, tolerance breakdown, autoreactive T-cell activation, and insulitis amplification. In T2DM, DCs may contribute to adipose tissue inflammation, hepatic immunometabolic crosstalk, β-cell stress, vascular inflammation, and immune remodeling associated with diabetes-related complications. Here, we review the disease-specific roles of DC subsets in T1DM and T2DM and discuss shared molecular mechanisms, including pattern-recognition receptor signaling, metabolic reprogramming, inflammasome activation, cytokine networks, and the shift from immune tolerance to inflammation. We also evaluate therapeutic DC reprogramming strategies and their potential implications for targeted immunometabolic intervention in diabetes.
    Keywords:  dendritic cells; immunometabolism; metabolic inflammation; type 1 diabetes mellitus; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/ijms27136057
  30. Gut Microbes. 2026 Dec 31. 18(1): 2702183
    Fusobacterium nucleatum-derived succinic acid aggravates colitis by triggering macrophage pro-inflammatory phenotypic transformation via SUCNR1/NF-κB axis.
    Suqi Zeng, Shanshan Jiang, Jianxuan Sun, Yan Chen, Meiqi Qiu, Jiao Li, Qingzhi Lan, Yu Pu, Zongbiao Tan, Xingzhou Guo, Haodong He, Shuo Wang, Luyun Zhang, Yafei Liu, Jiaming Hu, Ruxue Wang, Fei Liao, Jixiang Zhang, Weiguo Dong.
      Fusobacterium nucleatum (F. nucleatum) has been increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD), yet the mechanisms underlying its effects remain incompletely defined. In this study, we integrated human fecal and mucosal samples, comparative metabolomics, multiple experimental colitis models, bacterial genetic manipulation, macrophage functional assays, and host signaling analyses to identify a macrophage-centered mechanism through which F. nucleatum exacerbates colitis. We show that F. nucleatum colonization increases intestinal and systemic levels of its metabolite succinic acid, upregulates the expression of its cognate receptor SUCNR1 on intestinal macrophages, activates NF-κB signaling, and promotes pro-inflammatory macrophage activation. This macrophage inflammatory response is associated with epithelial barrier disruption, increased epithelial apoptosis, and aggravated mucosal and systemic inflammation. A fumarate reductase-deficient (frdA-KO) F. nucleatum strain with impaired succinic acid production showed a markedly reduced capacity to activate macrophage NF-κB signaling, induce macrophage inflammatory activation, and aggravate colitis, whereas exogenous succinic acid restored these effects in the frdA-KO setting. Moreover, siSUCNR1 and pharmacological NF-κB inhibition substantially attenuated succinic acid-induced macrophage inflammatory activation, supporting the involvement of a SUCNR1-NF-κB signaling cascade. Collectively, these findings demonstrate that F. nucleatum exacerbates colitis by producing succinic acid and engaging SUCNR1-NF-κB-dependent inflammatory activation of macrophages, highlighting the F. nucleatum-succinic acid-SUCNR1-NF-κB axis as a potential therapeutic target in IBD.
    Keywords:  Fusobacterium nucleatum; Inflammatory bowel disease; NF-κB; SUCNR1; macrophage; succinic acid
    DOI:  https://doi.org/10.1080/19490976.2026.2702183
  31. Front Cell Dev Biol. 2026 ;14 1835407
    Targeting TKT-associated immunometabolic remodeling attenuates experimental lupus nephritis and NET-related inflammation.
    Litong Zhu, Taoyan Lin, Lai Yee Cheong, An Ying Christy Chui, Tak Mao Chan, Desmond Y H Yap.
      Lactic acid metabolism and neutrophil extracellular traps (NETs) are critical immune regulators, yet their specific crosstalk in systemic lupus erythematosus (SLE) and lupus nephritis (LN) pathogenesis remains poorly understood. Here, by integrating bulk and single-cell RNA sequencing (scRNA-seq) analyses, we identified TKT and ITGAM as pivotal upregulated genes in SLE, demonstrating robust diagnostic value (AUC >0.7) supported by reliable nomogram models. Additional analysis of a human LN renal biopsy dataset (GSE32591) showed increased ITGAM and TKT in LN glomerular samples, supporting their renal relevance. Regulatory network analyses suggested potential molecular interactions involving these genes with specific microRNAs (e.g., hsa-miR-142-5p-ITGAM and hsa-miR-1-3p-TKT), while scRNA-seq analysis suggested cell-type-associated expression patterns, with donor-level analysis showing higher TKT expression in monocytes from SLE patients. To translate these computational insights into biological relevance, we conducted rigorous in vivo validations. In an apoptotic cell-induced LN mouse model, we confirmed renal injury, increased ITGAM and TKT protein expression, and enrichment of TKT in CD14+ monocyte-lineage cells. Crucially, targeted pharmacological inhibition of TKT using oxythiamine significantly mitigated disease progression in LN mice. Oxythiamine treatment not only restored renal function and attenuated tissue fibrosis but also reprogrammed aberrant lipid metabolism and cellular proliferation. Oxythiamine treatment was further associated with reduced ITGAM expression and lower renal Cit-H3 levels, consistent with an attenuation of NET-associated inflammatory activity. Together, our integrated multi-omics and in vivo data indicate that TKT is closely linked to immunometabolic remodeling in experimental lupus nephritis, accompanied by alterations in lactate accumulation, ITGAM expression, and NET-associated inflammatory activity. These findings support TKT-associated metabolic remodeling as a potential therapeutic avenue that warrants further mechanistic investigation in LN.
    Keywords:  immunometabolism; lupus nephritis; neutrophil extracellular traps (NET); systemic lupus erythematosus; transketolase (TKT)
    DOI:  https://doi.org/10.3389/fcell.2026.1835407
  32. Biomaterials. 2026 Jul 09. pii: S0142-9612(26)00463-1. [Epub ahead of print]336 124439
    A metabolically reprogrammable nanoplatform potentiates photodynamic immunotherapy through glycolytic blockade.
    Jingtian Zhang, Zhaoyun Liu, Yajing Jiang, Cuixiao Cao, Hui Liu, Hao Wang, Kai Ding, Jia Song, Deping Wang, Jiming Cao, Wenbo Wu, Dan Ding, Rong Fu, Xin Zhou.
      Tumor glycolysis supports malignant progression and promotes an immunosuppressive microenvironment, but glycolysis blockade alone often gives limited therapeutic benefit because tumor cells can adapt metabolically and metabolic inhibition does not necessarily elicit antitumor immunity. Here, we report a metabolically reprogrammable nanoplatform, TCP@PRL3 nanoparticles (TCP@PRL3 NPs), integrating an aggregation induced emission photosensitizer with a phosphatase of regenerating liver 3 (PRL3) inhibitor for combined photodynamic and immunometabolic therapy. Upon irradiation, TCP@PRL3 NPs generated reactive oxygen species (ROS) to induce immunogenic cell death (ICD), while PRL3 inhibition suppressed glycolysis, reduced lactate production, and alleviated tumor acidification. In multiple myeloma (MM) cells, TCP@PRL3 NPs decreased adenosine triphosphate (ATP) and lactate levels, downregulated pyruvate kinase M2 (PKM2), and inhibited extracellular acidification and oxygen consumption. These metabolic changes promoted dendritic cell maturation, reduced senescent T cell populations, expanded activated CD27+CD28+ T cells, and increased secretion of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 2 (IL-2). In a humanized MM model, TCP@PRL3 NPs markedly inhibited tumor growth, and combination with daratumumab further improved efficacy without evident systemic toxicity. The platform also suppressed CT26 and 4T1 tumors by enhancing dendritic cell activation, CD8+ T cell responses, and intratumoral metabolic remodeling. These findings identify TCP@PRL3 NPs as a promising immunometabolic nanoplatform for metabolically active tumors.
    Keywords:  Antitumor immunity; Energy metabolism; Metabolic reprogramming; Multiple myeloma; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124439
  33. Immunity. 2026 Jul 13. pii: S1074-7613(26)00263-3. [Epub ahead of print]
    MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion.
    Tanmana Mitra, Jahan Rahman, Madeline Hwee, Yan-Ting Chen, Ruben Jose Jesus Faustino Ramos, Hui Liu, Travis Hartman, Justin Cross, Miguel de Jesus, Morgan Huse, Valerie Longo, Pat Zanzonico, Santosha A Vardhana.
      Loss of mitochondrial function promotes CD8+ T cell dysfunction during persistent antigen encounter. Here, we examined the pathways whereby chronic antigen stimulation leads to metabolic dysfunction. Chronic T cell receptor (TCR) engagement increased ATP demand, leading to mitochondrial NADH accumulation, accumulation of reactive oxygen species, and subsequent mitochondrial dysfunction. Among TCR-dependent proximal signaling components, inhibiting the kinase MEK uniquely reduced nutrient uptake and mitochondrial NADH accumulation while restoring proliferation. Accordingly, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II C-terminal domain phosphorylation, reducing transcription rates at loci encoding effector- and terminal-exhaustion-associated genes while maintaining transcription of genes associated with T cell memory. Thus, MEK-dependent metabolic demand is a driver of T cell exhaustion, providing insight into how MEK inhibition enhances immunotherapy efficacy.
    Keywords:  NADH; RNA polymerase II; T cell exhaustion; bioenergetics; metabolism; mitochondria; nascent transcription; redox balance; terminal exhaustion; translation
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.012
  34. Cytokine. 2026 Jul 14. pii: S1043-4666(26)00087-6. [Epub ahead of print]205 157192
    Adipose tissue macrophages in metabolic inflammation and disease: Insights from single-cell and multi-omics studies.
    Qining Huang, Jingwen Tang, Xiaozheng Shu, Zhaoliang Su, Yu Tian.
      Adipose tissue macrophages (ATMs) have emerged as central regulators at the interface of immunity and metabolism. Accumulating evidence indicates that ATMs play multifaceted roles in the initiation and progression of obesity-associated metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease. This review synthesizes current knowledge on ATM functional diversity, with a particular focus on microenvironment-driven polarization, metabolic reprogramming, intercellular communication, and cross-organ immune regulation. We highlight how lipid overload, inflammatory mediators, and oxidative stress cooperatively shape ATM fate and function, endowing these cells with dual capacities to preserve tissue homeostasis or to propagate chronic metabolic inflammation. From a translational perspective, ATMs represent attractive biomarkers and therapeutic targets. Emerging strategies-including small-molecule modulators, natural compounds, and macrophage-targeted delivery systems such as miRNA-loaded nanoparticles-have demonstrated promise in reprogramming ATM phenotypes and alleviating metabolic dysfunction. Moreover, recent advances in single-cell omics, spatial transcriptomics, and fate-mapping technologies are redefining our understanding of ATM heterogeneity and temporal dynamics in human adipose tissue, thereby enabling precision immunometabolic interventions. A deeper elucidation of the immunometabolic mechanisms governing ATMs will provide both a conceptual framework and therapeutic foundation for the precision treatment of metabolic diseases.
    Keywords:  Adipose tissue macrophages; Lipid-associated macrophages; Macrophage activation states; Macrophage heterogeneity; Metabolic diseases; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.cyto.2026.157192
  35. Mol Immunol. 2026 Jul 17. pii: S0161-5890(26)00162-8. [Epub ahead of print]197 46-60
    Lactate-associated H3K18 lactylation is involved in IGF2BP2-mediated MARCKSL1 mRNA stabilization and inflammatory signaling in LPS-induced acute lung injury.
    Yangdi Peng, Junyao Zhang, Yang Yang, Yangjing Lin, Piaopiao Cai, Peiliang Wu.
      N6-methyladenosine (m6A) RNA modification regulates pulmonary inflammation, yet the precise function of the m6A reader IGF2BP2 in acute lung injury (ALI) remains elusive. Here, we reveal that IGF2BP2 and global m6A levels are significantly upregulated in lipopolysaccharide (LPS)-induced ALI. Prophylactic genetic silencing or pharmacological inhibition of IGF2BP2 robustly mitigated pulmonary hyperinflammation, epithelial apoptosis, and pathological tissue damage. Mechanistically, transcriptome profiling identified MARCKSL1 as a direct downstream target. We demonstrate that IGF2BP2 binds and post-transcriptionally stabilizes MARCKSL1 mRNA in a partially METTL3/m6A-dependent manner. Elevated MARCKSL1 subsequently drives NF-κB p65 nuclear translocation and activation, fueling the inflammatory cascade. Strikingly, we trace this IGF2BP2 dysregulation upstream to inflammatory metabolic reprogramming: elevated alveolar glycolysis drives lactate accumulation, which triggers EP300-mediated histone lactylation (H3K18la) at the IGF2BP2 promoter to activate its transcription. Pharmacological manipulation of glycolysis confirmed this metabolic-epigenetic coupling. Collectively, our findings decipher a novel H3K18la/IGF2BP2/MARCKSL1 signaling cascade that integrates metabolic reprogramming with m6A epitranscriptomics in ALI, highlighting IGF2BP2 as a promising target for preventive intervention in airway epithelial inflammation.
    Keywords:  Acute lung injury; H3K18 lactylation; IGF2BP2; MARCKSL1
    DOI:  https://doi.org/10.1016/j.molimm.2026.07.001
  36. Sci Adv. 2026 Jul 17. 12(29): eaec8501
    Vitronectin metabolically programs profibrotic macrophages in 3D cultures and idiopathic pulmonary fibrosis.
    Sean W Cutter, Gang Liu, Eleanor Saunders, Bailey Cardwell, Vinzenz Hofferek, Thomas Soerianto, Kaitlyn Ritchie, Erin N S McGowan, Tien K Nguyen, Ivan K H Poon, Malcolm J McConville, Benjamin J Marsland, Glen P Westall, Mark D Hulett, Nicholas P Reynolds, Mark D Wright, Philip M Hansbro, Katrina J Binger.
      Macrophages are key drivers of inflammatory and fibrotic diseases, and their activation is shaped by interactions in their tissue microenvironment. However, dissecting the processes that drive immunopathology has proved challenging, as traditional two-dimensional (2D) culture methods fail to capture the complex molecular environment that macrophages inhabit in vivo. To address this, we generated a 3D in vitro model to better mimic the in vivo biophysical microenvironment. We show that the extracellular matrix protein vitronectin promotes a previously unknown profibrotic macrophage phenotype in 3D that is characterized by increased expression of the nicotinamide adenine dinucleotide (NAD+) ectoenzyme CD38, elevated glycolysis and mitochondrial metabolism, and synthesis of the immunomodulatory metabolite itaconate. This is validated in vivo where patients with idiopathic pulmonary fibrosis have elevated vitronectin and MRC1+CD38+ macrophages, while vitronectin-deficient mice were protected from an experimental model of lung injury and fibrosis. Thus, we uncover a previously unidentified link between the composition of tissue niches and macrophage profibrotic function via altered metabolic reprogramming.
    DOI:  https://doi.org/10.1126/sciadv.aec8501
  37. Cureus. 2026 Jun;18(6): e110719
    Cellular Glucose Transport and Inflammatory Blood Markers in Rheumatoid Arthritis Spectrum: An Immunometabolic Perspective.
    Diptimayee Upadhyay, Subhashree Ray, Bandana Thakur, Rajesh Kumar Bhola, Chetan Kumar Kellellu.
       BACKGROUND: Rheumatoid arthritis (RA) is increasingly recognized as an immunometabolic disorder. This study evaluated whether glucose-handling markers, including glucose transporter 1 (GLUT1) and hexokinase 2 (HK2), and circulating inflammatory markers differed between RA cases and healthy controls and whether these markers were associated with DAS28-based disease activity in an exploratory secondary analysis.
    METHODS: A retrospective secondary analysis was conducted using data from 160 participants, comprising 80 cases and 80 controls. Variables included demographic characteristics, fasting glucose, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), serum amyloid A (SAA), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), Disease Activity Score in 28 joints (DAS28), GLUT1, and HK2. Nonparametric tests were used for group comparisons, and Spearman's correlation was used to assess within-case associations.
    RESULTS: Cases demonstrated significantly higher GLUT1 and HK2 levels than controls (both p < 0.001), along with elevated ESR, interleukin-6, SAA, NLR, and PLR. HK2 was significantly higher in high-activity than moderate-activity cases (p = 0.037), whereas GLUT1 was not. Within-case correlations were weak and nonsignificant.
    CONCLUSION: These findings support a measurable immunometabolic signature in RA. HK2 may show exploratory association with DAS28-based activity categories; however, prospective validation is required before clinical application.
    Keywords:  autoimmune synovial disease; glut1; hk2; immunometabolism; rheumatoid arthritis
    DOI:  https://doi.org/10.7759/cureus.110719
  38. Int Immunopharmacol. 2026 Jul 11. pii: S1567-5769(26)00970-7. [Epub ahead of print]186 117124
    Dietary stearic acid aggravates acute graft-versus-host disease by promoting oxidative stress and pro-inflammatory macrophage polarization.
    Yue Du, Hui Feng, Yi Liu, Runyu Yang, Ruimin Liu, Fan Niu, Pengcheng He, Bingyu Yang.
      Acute graft-versus-host disease (aGVHD) remains a major life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although immune activation and tissue inflammation are central to aGVHD pathogenesis, how dietary fatty acid exposure shapes inflammatory responses after transplantation remains insufficiently defined. Building on our previous finding that a high stearic acid diet (HSAD) alters the gut microbiota and aggravates aGVHD, we hypothesized that stearic acid (SA), a major saturated fatty acid, further exacerbates aGVHD by inducing oxidative stress and promoting pro-inflammatory macrophage polarization. Using a murine aGVHD model, we found that HSAD significantly increased serum SA levels and aggravated disease severity. Mechanistically, HSAD enhanced reactive oxygen species (ROS) production in splenocytes and disrupted glutathione redox homeostasis, indicating increased systemic oxidative stress. SA promoted M1-like macrophage polarization both in vivo and in vitro, without directly altering Th1 or Th17 differentiation. Pharmacological ROS scavenging with N-acetylcysteine (NAC) attenuated SA-induced ROS accumulation and M1 polarization. Additionally, SA activated mTOR signaling and promoted NLRP3 inflammasome activation in macrophages, as evidenced by increased NLRP3 expression, caspase-1 cleavage, and IL-1β maturation, which were attenuated by rapamycin. Collectively, these findings identify dietary SA as a modifiable factor that aggravates aGVHD by linking lipid metabolic stress to oxidative injury and M1 macrophage polarization. This work provides a rationale for targeting SA intake or its downstream signaling pathways as a strategy to mitigate aGVHD severity.
    Keywords:  Acute graft-versus-host disease; Macrophage polarization; Oxidative stress; Stearic acid
    DOI:  https://doi.org/10.1016/j.intimp.2026.117124
  39. Cell Biochem Funct. 2026 Jul;44(7): e70246
    Role of Fatty Acid Oxidation in Crohn's Disease and Ulcerative Colitis: Metabolomics Analysis and Experimental Evidence.
    Fang Yan, Shimin Wu, Wenqiang Yuan, Qian Yang, Jie Yang, Dejun Cui.
      The metabolic determinants that distinguish Crohn's disease (CD) from ulcerative colitis (UC) and their roles in driving immune dysregulation remain elusive. We aimed to identify systemic metabolic signatures of inflammatory bowel disease (IBD) and elucidate the mechanistic link between metabolite availability and regulatory T cell (Treg) homeostasis. We performed untargeted LC-MS-based metabolomics on plasma from patients with CD (n = 17), UC (n = 13), and healthy controls (n = 15). Pathway enrichment and topology analysis were used to identify perturbed biological processes. The functional role of identified metabolites was validated using primary murine naive CD4+ T cell differentiation assays, Seahorse XF metabolic flux analysis, and siRNA-mediated knockdown. The therapeutic relevance was assessed in a DSS-induced murine model of colitis. Metabolomic profiling identified 175 significant differential metabolites, revealing a profound systemic depletion of fatty acids and a specific deficit in the fatty acid oxidation (FAO) pathway in CD patients. Palmitic acid and butyrate emerged as robust diagnostic biomarkers (AUC = 0.877-0.975). In vitro, butyrate dose-dependently promoted iTreg differentiation by increasing the oxygen consumption rate and maximal respiratory capacity. This effect was dependent on carnitine palmitoyltransferase 1A (CPT1A), as pharmacological or genetic inhibition of CPT1A-mediated FAO abolished butyrate's pro-differentiation capacity. In vivo, the ability of butyrate to attenuate colitis and promote colonic iTreg accumulation was significantly reversed by the CPT1 inhibitor etomoxir. CPT1A-mediated fatty acid oxidation is a critical metabolic pivot through which butyrate signals to maintain immune tolerance. The systemic loss of FAO intermediates in CD patients directly contributes to impaired iTreg development, identifying the butyrate-CPT1A axis as a potential target for precision metabolic intervention.
    Keywords:  CPT1A; butyrate; fatty acid oxidation; inflammatory bowel disease; metabolomics analysis
    DOI:  https://doi.org/10.1002/cbf.70246
  40. Front Immunol. 2026 ;17 1850044
    Fueling bone loss: the immunometabolic reprogramming of the bone microenvironment in diabetic osteoporosis.
    Yunfang Wang, Jinwen Han, Zheng Wang, Gai Zhang, Ruilan Niu, Yaqing Wei, Kang Yi, Jinxing Quan.
      Diabetic osteoporosis (DOP) is a serious skeletal complication of type 2 diabetes mellitus (T2DM), characterized by deteriorated bone microarchitecture and elevated fracture risk independent of reduced bone mineral density. Emerging evidence indicates that immunometabolic reprogramming of bone marrow immune cells serves as a core driver of DOP pathogenesis. This review focuses on macrophages and CD4+ Th17/Treg cells, the pivotal immune subsets mediating skeletal immune-metabolic homeostasis. We systematically elaborate how hyperglycemia triggers glycolytic predominance, HIF-1α stabilization, and succinate-SUCNR1 axis activation in macrophages, alongside mTORC1-HIF-1α-dependent Th17/Treg imbalance. Bidirectional immunometabolic crosstalk between these immune cells disrupts the RANKL/OPG and Wnt/β-catenin signaling pathways, thereby disturbing bone formation and resorption. Furthermore, we summarize current immunometabolic-targeted modulators for DOP, stratifying their preclinical and clinical evidence, skeletal benefits, and safety limitations. We also highlight existing clinical diagnostic defects and translational bottlenecks in DOP research. Finally, we prospect emerging research directions including spatial immunometabolic profiling, gut-immune-bone axis regulation, and artificial intelligence-assisted precision intervention, aiming to provide mechanistic insights and novel translational strategies for DOP targeted therapy.
    Keywords:  Th17/Treg balance; bone microenvironment; bone remodeling; diabetic osteoporosis; immunometabolism; macrophage; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1850044
  41. Int J Mol Sci. 2026 Jun 30. pii: 5918. [Epub ahead of print]27(13):
    Mitochondrial Immunometabolism in Sepsis: From Oxidative Stress and mtDAMP Signaling to Biomarker-Guided Therapy.
    Minsoo Kim, Phyu Phyu Khin, Hyeran Jung, Chang Woo Chae, Byeong Hwa Jeon, Cuk-Seong Kim.
      Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine.
    Keywords:  biomarkers; immunometabolism; mitochondria; mitochondria-targeted therapy; mitochondrial DNA; mitophagy; organ dysfunction; oxidative stress; sepsis
    DOI:  https://doi.org/10.3390/ijms27135918
  42. bioRxiv. 2026 Jul 09. pii: 2026.07.08.737054. [Epub ahead of print]
    Distinct macrophage and T cell programs shape pancreatic inflammation during metabolic stress and aging.
    Somesh Sai, Ibrahim Omar, Matthias Barone, Kerstin Mühle, Maria Schneider, Fenfen Liu, Sharanya Sriram, Juliette Claire Johnson, Tizia Thoma, Thomas Conrad, Tatiana Borodina, Birgit Sawitzki, Maike Sander, Han Zhu.
      Type 2 diabetes is linked to systemic inflammation driven by metabolic stress and aging. Although pancreatic inflammation associated with these factors is well documented, the dynamics of immune cell populations and their molecular changes remain poorly understood. We characterized immune cell alterations in the pancreas and pancreatic islets during Western diet (WD) feeding and aging using imaging mass cytometry (IMC) and single-cell RNA sequencing (scRNA-seq). Spatial and transcriptional analyses were performed to define immune cell subtype composition, activation states, and inferred cell-cell communication programs under metabolic and age-related stress conditions. Our analyses identified expansion of an F4/80 low macrophage subtype and activated effector-like CD8 + T cells throughout the pancreas during WD feeding and aging. Within pancreatic islets, single-cell RNA sequencing identified a type I interferon-responsive macrophage population with low F4/80 expression that expanded during overnutrition. Notably, the type I interferon responses elicited by these stressors diverged: aging was associated with a more canonical type I interferon response, whereas overnutrition induced a broader response that included STAT3-associated transcriptional programs. We further provide evidence for enhanced cytokine-mediated communication between macrophages and a CD8 + cytotoxic T-cell population under overnutrition and aging. These findings show that metabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms, involving expansion of F4/80 low macrophages, activation of divergent type I interferon programs, and enhanced macrophage-CD8 + T-cell communication. Together, these findings suggest that distinct therapeutic approaches may be required to preserve islet function in type 2 diabetes driven by metabolic stress versus aging.
    Article Highlights: Metabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms.Spatial and single-cell analyses identified conserved remodeling of pancreatic macrophage populations accompanied by activation of cytotoxic T-cell responses during metabolic stress and aging.In pancreatic islets, macrophages exhibited distinct type I interferon-associated transcriptional programs, with aging showing a more canonical interferon response and metabolic stress eliciting a broader inflammatory program that included STAT3-associated transcriptional signatures.These findings provide a framework for understanding how metabolic stress and aging differentially shape pancreatic inflammation.
    DOI:  https://doi.org/10.64898/2026.07.08.737054
  43. Transl Psychiatry. 2026 Jul 15.
    Fatigue after COVID-19 infection is associated with peripheral immunometabolic alterations affecting neuroimmune responses in the hippocampus.
    Nicole Mariani, Daniel Martins, Federico Imbeni, Madeline Kirkpatrick, Nuriza Tukiran, Silvia Alboni, Carmine Pariante, Alessandra Borsini.
      Fatigue is a common and disabling symptom reported following SARS-CoV-2 infection, yet the underlying biological mechanisms remain poorly understood. In this study, we investigated whether fatigue severity in individuals previously infected with SARS-CoV-2 is associated with immune and metabolic alterations in serum and whether these peripheral changes can influence hippocampal cell function in vitro. Serum cytokines, kynurenine pathway, and tryptophan-derived and monoamine-related metabolites were measured in a total of 38 individuals with past COVID-19 infection. Human hippocampal progenitor cells were exposed to 1% patient serum during proliferation and differentiation, with readouts including cytokine release, metabolite production, and markers of neurogenesis (doublecortin, DCX) and astrocytic reactivity (glial fibrillary acidic protein, GFAP; aquaporin-4, AQP4). Results show that fatigue severity correlates with lower serum levels of interleukin-8 (IL-8) and with lower levels of metabolites of the kynurenine pathway and tryptophan-derived and monoamine-related metabolites, including kynurenine (KYN) and quinolinic acid (QUIN), and 5-hydroxyindoleacetic acid (5HIAA). Exposure of hippocampal cells to serum from individuals with higher fatigue was associated with increased endogenous production of interleukin-13 (IL-13) and the kynurenine metabolite anthranilic acid (ANA) in the cell supernatant, as well as with increased neurogenesis (increased DCX expression) and enhanced astrocytic reactivity (increased GFAP expression). Notably, serum IL-8 level was inversely correlated with both cellular outcomes. Likewise, serum 5-HIAA levels were negatively correlated with IL-13 release, with mediation analysis indicating that 5-HIAA significantly mediated the association between fatigue severity and IL-13 production (71% explained). Overall, our results suggest that fatigue after COVID-19 infection is associated with neuroimmune and metabolic changes in hippocampal cells, involving peripheral serotonin metabolism (5-HIAA) and cytokine signalling (IL-13).
    DOI:  https://doi.org/10.1038/s41398-026-04250-9
  44. Clin Epigenetics. 2026 Jul 13.
    The glycolysis-H4K12la-PKM2 positive feedback loop drives M2 polarization of macrophages in colorectal cancer.
    Zhuo Zhang, Qiaoling Peng, Shaohu Wang, Quan Xun, Xingming Chen, Mingliang Zhou, Jianguan Luo, Lishun Yang, Chunming Tang, Yiqing Luo, Junlin Liu.
       BACKGROUND: Despite the dominance of M2-polarized tumor-associated macrophages in colorectal cancer (CRC), the metabolic-epigenetic mechanisms by which CRC cells sustain this immunosuppressive phenotype remain elusive. We hypothesize that a glycolysis-driven positive feedback loop, involving PKM2-mediated lactate production and subsequent H4K12 lactylation (H4K12la) at the PKM2 promoter, enables CRC cells to metabolically reprogram macrophages toward M2 polarization. This study aims to characterize this regulatory circuit and determine its potential as a therapeutic target to enhance immunotherapy efficacy.
    METHODS: We used qRT-PCR, Western blot, and metabolic flux analysis (ECAR, lactate production, 2-NBDG uptake) to assess the glycolysis-H4K12la-PKM2 axis in CRC cells following genetic manipulation (PKM2 overexpression/knockdown) and pharmacological inhibition (2-DG). Chromatin immunoprecipitation (ChIP-qPCR) quantified H4K12la enrichment at the PKM2 promoter. The functional impact on macrophage polarization was evaluated using THP-1-derived and primary human macrophage co-culture systems (flow cytometry for CD163), complemented by an in vivo xenograft model.
    RESULTS: PKM2 was highly expressed in CRC cells and sustained aerobic glycolysis, leading to elevated intracellular lactate and H4K12la levels. Mechanistically, H4K12la accumulated at the PKM2 promoter, forming a positive feedback loop that amplified glycolytic flux. Disruption of this loop-via PKM2 knockdown or glycolytic inhibition-suppressed M2 macrophage polarization in vitro. In vivo, combined PKM2 knockdown and 2-DG treatment synergistically inhibited tumor growth, reduced M2 macrophage infiltration, and diminished H4K12la levels.
    CONCLUSION: Our findings identify a glycolysis-H4K12la-PKM2 positive feedback loop in CRC cells that drives M2 macrophage polarization. Interrupting this circuit offers a promising strategy to reconfigure the tumor immune landscape and improve immunotherapeutic outcomes.
    Keywords:  Colorectal cancer; Glycolysis; H4K12la; M2 polarization; PKM2
    DOI:  https://doi.org/10.1186/s13148-026-02200-2
  45. Sci Rep. 2026 Jul 15.
    MGMT deficiency augments STING-mediated inflammatory responses accompanied by metabolic alterations in macrophages.
    Pornrat Kongkavitoon, Atsadang Boonmee, Thitiporn Pattarakankul, Benjawan Wongprom, Salisa Benjaskulluecha, Thadaphong Sukdee, Chanat Aonbangkhen, Benchaphorn Limcharoen, Takashi Kobayashi, Tanapat Palaga.
      The cGAS-STING pathway senses cytosolic DNA derived from both pathogens and host cells and plays a central role in innate immune responses. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes alkylation-induced DNA lesions and modulates macrophage inflammatory responses. Here, we investigated the role of MGMT in macrophage responses to STING activation. Bone marrow-derived macrophages (BMMs) from Lyz2ΔMgmt mice produced higher levels of IL6, TNFα, and IFNβ following stimulation with the STING agonist DMXAA, accompanied by increased phosphorylation of TBK1 and IRF3. Lyz2ΔMgmt BMMs also exhibited increased expression of CD86, CD40, and CD120a (TNFRI), but reduced MHC class II expression. Metabolic flux analysis revealed enhanced mitochondrial oxidative respiration, increased ATP production, and greater maximal respiratory capacity, whereas glycolytic capacity remained unchanged. In addition, DMXAA-stimulated Lyz2ΔMgmt BMMs displayed increased γH2AX levels and reduced activation of the energy sensor AMPK and autophagy. Transcriptomic analysis further identified enrichment of pathways associated with cellular respiration. Collectively, these findings indicate that MGMT deficiency is associated with enhanced STING-induced inflammatory responses, altered cellular metabolism, and increased DNA damage in macrophages.
    Keywords:  Inflammation; MGMT; Macrophages; Oxidative phosphorylation; STING
    DOI:  https://doi.org/10.1038/s41598-026-62431-4
  46. Bioorg Med Chem Lett. 2026 Jul 11. pii: S0960-894X(26)00198-8. [Epub ahead of print]140 130731
    Site-specific profiling of lysine itaconylation via a thiol-based probe.
    Xia-Ping Fu, Ziming Tang, Chu Wang.
      Lysine itaconylation is a novel post-translational modification (PTM) that was recently discovered in macrophage proteomes mediated by the immunoregulatory metabolite, itaconate. However, comprehensive and high-accuracy analytical methods are currently lacking for the global identification of itaconylation sites in proteomes, which limits the study of their biological functions. Here, we developed a thiol-based bioorthogonal probe, BMAyne, to site-specifically profile itaconylation in macrophage proteomes by a chemoproteomic strategy. Notably, 31 endogenous itaconylation sites on 29 proteins were identified in lipopolysaccharide (LPS)-stimulated macrophages using BMAyne, which complemented the results obtained previously by the promiscuous antibody enrichment. Our effort provides a unique chemical tool to enrich endogenous lysine itaconylation and establishes a rich database for guiding subsequent functional studies of this unique lysine PTM.
    Keywords:  Bioorthogonal probe; Chemoproteomics; Itaconate; Lysine itaconylation; Post-translational modification
    DOI:  https://doi.org/10.1016/j.bmcl.2026.130731
  47. Int J Biol Macromol. 2026 Jul 15. pii: S0141-8130(26)03519-1. [Epub ahead of print] 153574
    Ischemia-induced p300-dependent histone lactylation activates an AP-1-SPP1 program in microglia to exacerbate ischemic brain injury.
    Meng Zhang, Huiyuan Zhang, Weidong Liu, Jiheng Hao, Liyong Zhang, Zhe Peng.
      Cerebral ischemia causes profound metabolic disruption, but how ischemia-associated metabolites reshape microglial chromatin and inflammatory function remains unclear. Here we identify histone lactylation as an epigenetic mechanism linking ischemic metabolic stress to pathogenic microglial activation. In transient middle cerebral artery occlusion mice and oxygen-glucose deprivation/reperfusion models, ischemic stress robustly increased H3K18la and H4K12la in microglia. CUT&Tag profiling showed widespread remodeling of both lactylation landscapes, with gained peaks preferentially associated with inflammatory, chemotactic, migratory and efferocytic programs. Integration with microglial RNA sequencing identified a concordantly activated gene network enriched for TNF, NF-κB, IL-17 and cytoskeletal regulatory pathways, with Spp1 emerging as a prominent effector linked to ischemia-induced lactylation. Motif enrichment and locus-level analyses implicated AP-1-associated regulatory elements, and ChIP-qPCR confirmed increased H3K18la and H4K12la at Fos and Spp1 regulatory regions after ischemia-like stress. Mechanistically, p300 depletion or inhibition reduced H3K18la/H4K12la accumulation, impaired AP-1-associated promoter engagement, and suppressed Fos, Spp1 and chemokine induction. Non-lactylatable H3K18R and H4K12R mutants attenuated Fos-Spp1 transcription and microglial migration, supporting cooperative regulation by these two marks. Functionally, microglia-specific Spp1 deletion reduced inflammatory microglial activation, neuronal apoptosis and long-term neurological deficits after ischemic injury. Pharmacological inhibition of p300 or AP-1, and SPP1 neutralization, similarly limited neuroinflammation and improved sensorimotor and cognitive recovery. Together, our findings define a lactate-p300-AP-1-SPP1 axis that couples ischemic metabolism to microglial chromatin remodeling and post-stroke neuroinflammatory injury.
    Keywords:  AP-1; Histone lactylation; Ischemic stroke; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153574
  48. Nat Commun. 2026 Jul 14.
    Disrupting fumarylacetoacetate hydrolase by stratified nanoplatforms orchestrates metabolic-immune reprogramming and prevents post-ablation HCC relapse.
    Zhiwen Hong, Xiaolong Liu, Rouhan A, Zengzhen Chen, Qianjiang Wu, Jixian Fu, Xue Guan, Can Wang, Xinghua Wang, Shan Jiang, Bolong Li, Zhaobo Wang, Lei Zhang, Xianwei Meng, Yali Cui, Tengchuang Ma.
      Hepatocellular carcinoma (HCC) recurrence following microwave ablation poses a pressing clinical challenge, driven by metabolically adapted residual cells that establish an immunosuppressive tumour microenvironment. Our study identifies the post-ablation upregulation of fumarylacetoacetate hydrolase (FAH) as a crucial "metabolic checkpoint" promoting relapse. Elevated FAH expression results in increased fumarate levels within residual HCC cells, supporting tumour cell survival by enhancing energy metabolism while concurrently impairing CD8+ T cell function. Mechanistically, fumarate binds to and stabilises heat shock protein 70 (HSP70), establishing a thermal ablation induced FAH-fumarate-HSP70 axis that drives immunosuppression. To counteract this pivotal axis, we engineered a gallium-based functionalized nanoplatform. This system incorporates a lactate oxidase shell that responds to the lactate-rich tumour microenvironment, enabling the site-specific co-release of Ga3+, FAH-silencing plasmids and the glycolysis inhibitor 2-deoxy-D-glucose. Our nanoplatforms disrupt the FAH-fumarate-HSP70 axis to eradicate residual HCC, activate CD8+ T cells, and restore immunity, targeting recurrence dysregulation while integrating metabolic blockade with immunomodulation to prevent post-ablation relapse with clinical translation potential.
    DOI:  https://doi.org/10.1038/s41467-026-75422-w
  49. Antiinflamm Antiallergy Agents Med Chem. 2026 Jul 07.
    Hypoxia-inducible Factors in Macrophage Polarization and Metabolic Reprogramming Under Stress: Implications for Inflammation and Tissue Repair.
    Shawna Yadav, Kaliyamurthi Venkatachalam, Ambika Binesh.
      Hypoxia-inducible Factors (HIFs) are the transcriptional regulators of the cellular response to low oxygen tension and metabolic changes. The transition of macrophages and their adaptability to environmental stressors, such as hypoxia and nutrient deprivation, serve as the central regulators of immune responses. This review covers the role of Hypoxia-Inducible Factors (HIFs), chiefly HIF-1α and HIF-2α, in stress-mediated macrophage polarization and metabolic reprogramming. HIF-1α drives glycolytic activity and inflammatory gene expression, resulting in the development of an M1 - like pro-inflammatory activation state, while HIF-2α enables alternatively activated (M2- like) macrophages to support tissue remodeling, angiogenesis, and resolution of inflammation through oxidative metabolism and tissue repair. The two proteins HIF-1α and HIF-2α maintain a balance that controls whether macrophages develop inflammatory diseases or repair damaged tissues; therefore, this balance serves as a potential target for medical treatments. The balance between HIF-1α and HIF-2α determines how macrophages respond to inflammation versus tissue repair, representing a new area for potential treatment development. Additional modulation of these responses is achieved through interaction with the NF-κB, mTOR, and STAT3 signaling pathways. Any metabolic changes downstream of the HIFs can alter the functional outcome of macrophages in diseases such as obesity, cancer, atherosclerosis, and chronic inflammation. Inflammation resolution and angiogenesis, probably facilitated via HIFs, follow efficient wound healing and tissue regeneration. With the refinement in emerging technologies and future therapeutic opportunities in molecular technologies such as CRISPR and single-cell multi-omics, it has become possible to unravel the finely regulated, context-dependent roles of HIFs, thus opening exciting vistas for immune therapeutics.
    Keywords:  HIF-1α; HIF-2α; PHD inhibitors; hypoxic signaling; immunometabolism; macrophage plasticity
    DOI:  https://doi.org/10.2174/0118715230462552260701063409
  50. Nat Metab. 2026 Jul 14.
    Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
    Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A Ryback, Carl D Novina, Karine Auclair, Haopeng Xiao, Evanna L Mills.
      Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3-14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance.
    DOI:  https://doi.org/10.1038/s42255-026-01572-2
  51. J Mol Endocrinol. 2026 Jul 15. pii: JME-25-0203. [Epub ahead of print]
    ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.
    Dandan Chen, Yuxin Jia, Xiaohong Duan, Jianhua Huang, Xiaohong Deng.
      Mitochondrial dysfunction driven by chronic hyperglycemia is a hallmark of diabetes, yet how this metabolic stress communicates pathological signals beyond individual cells remains poorly understood. In this study, we identified a novel mechanism linking chronic hyperglycemia to systemic metabolic impairment through ROS-mediated extracellular release of structurally intact mitochondria and mitochondrial DNA (mtDNA). In HepG2 cells exposed to high glucose (HG), extracellular release of structurally intact mitochondria was visualized by co-staining of mitochondria and the plasma membrane, together with electron microscopy. Mitochondria-enriched fractions isolated from culture supernatants were further quantified using flow cytometry and qPCR. Cell-free mtDNA (cf-mtDNA) was visualized with co-staining of mitochondria and double- stranded DNA, isolated through differential centrifugation and ultrafiltration, and quantified by qPCR. We demonstrate that HG stimulates the release of exosome-enclosed mtDNA as well as fragmented cf-mtDNA. Concurrently, HG induces mitochondrial dysfunction and markedly increases mitochondrial ROS (mtROS). Treatment with MitoTEMPO, a mitochondria-targeted ROS scavenger, significantly reduced HG-induced extracellular release of mitochondria and mtDNA, supporting the ROS dependence of this process. In diabetic mice, we detected elevated circulating mtDNA copy number and pronounced mitochondrial dysfunction in liver and muscle, including reduced ATP production, mitochondrial swelling, cristae disruption, and elevated MDA levels. Resting metabolic rate was markedly decreased, indicating impaired systemic respiratory metabolism. Serum analyses revealed increased 8-OHdG, pyruvic acid, GDF-15, and FGF-21, along with reduced FT3, reflecting severe oxidative stress and mtDNA damage. These findings uncover a novel mechanism in which hyperglycemia-induced ROS drive mitochondrial extrusion, potentially linking metabolic stress to systemic metabolic deterioration.
    Keywords:  Diabetes mellitus; ROS; mitochondrial release; resting metabolic rate
    DOI:  https://doi.org/10.1530/JME-25-0203
  52. Int J Mol Sci. 2026 Jul 04. pii: 6021. [Epub ahead of print]27(13):
    Immunometabolic Stress and Immune Suppression in Clear-Cell Renal Cell Carcinoma: Perspectives in Therapeutic Strategy.
    Tuong-Vi Nguyen, Tien Hsu.
      Solid tumors frequently experience hypoxia during tumor progression, resulting in profound metabolic alterations. This phenomenon is particularly pronounced in clear-cell renal cell carcinoma (ccRCC) because of loss of the von Hippel-Lindau (VHL) tumor suppressor gene and constitutive activation of hypoxia-inducible factor (HIF) signaling. ccRCC is the most common subtype of kidney cancer, and durable therapeutic responses remain limited despite advances in immune checkpoint inhibition. Owing to its strong pseudohypoxic phenotype and extensive metabolic rewiring, ccRCC is widely regarded as a metabolic disease. These alterations generate a unique immune landscape characterized by abundant immune-cell infiltration together with profound T-cell dysfunction and exhaustion. This paradoxical "immune-hot yet immunosuppressed" phenotype is largely driven by hypoxia-associated immunometabolic reprogramming within tumor cells and the tumor microenvironment (TME). Several metabolic pathways are critically involved in this process, including lactate acidosis, arginine (Arg) depletion, tryptophan (Trp) depletion, kynurenine (Kyn)-mediated T-cell exhaustion, and adenosine-driven immune suppression. This review summarizes the current understanding of hypoxia-driven immunometabolic interactions in ccRCC and discusses how targeting these pathways may improve future therapeutic strategies against this aggressive malignancy.
    Keywords:  clear-cell renal cell carcinoma; hypoxia; immune suppression; immunometabolism; kynurenine pathway; metabolic reprogramming
    DOI:  https://doi.org/10.3390/ijms27136021
  53. Nat Commun. 2026 Jul 13.
    Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma.
    E Perpiñán, N Sompairac, D Marin Correa, E Ramon-Gil, Rch Man, D Camell-Raventos, R Savoldelli, M Fleming, L Bellersheim, C X Santos, M Elgosbi, J J Lozano, M Maddaloni, C Schmidl, E Kodela, M Piqué-Gili, A H de Sande, R Pinyol, S Higginbotham, Q Peng, E Landman, J Torres-Yaguana, V Sharma, C Zhang, A Kurt, X Liao, T Dowe, M Habarwaa, Z Liu, Y Zen, R Miquel, D Sarker, S Kordasti, T Tree, A M Shah, G O Fruhwirth, A T Dinkova-Kostova, E L Pearce, J Leslie, J M Llovet, A Sánchez-Fueyo, N Safinia.
      Excessive recruitment and/or activation of regulatory T cells (Treg) into the tumour microenvironment (TME) hamper anti-cancer immunity. Targeting Tregs is therefore a promising strategy to reverse the immunosuppressive features of the TME. Here, we investigate how the development of hepatocellular carcinoma (HCC) impacts the molecular programmes of tissue-resident Tregs. Tregs residing in non-tumoral liver are metabolically inert and prone to apoptosis. Conversely, HCC-infiltrating Tregs activate the nuclear factor erythroid 2-related factor-2 (Nrf2) pathway in response to the lactate-rich TME, which couples redox homeostasis with mitochondrial function and promotes Treg metabolic activity, survival, and suppressive function. Nrf2 loss of function, through either Treg-specific Nfe2l2 ablation or systemic pharmacological inhibition, prevents intra-tumoral Treg accumulation and suppresses cancer growth. Furthermore, patients with advanced HCCs enriched in Tregs with high Nrf2 activation exhibit shorter progression-free survival following atezolizumab/bevacizumab treatment. We propose Nrf2 as a target to disrupt Treg metabolic adaptation within the TME, tipping the balance between effector and regulatory immune cells and reducing cancer progression.
    DOI:  https://doi.org/10.1038/s41467-026-73485-3
  54. Trends Endocrinol Metab. 2026 Jul 18. pii: S1043-2760(26)00169-4. [Epub ahead of print]
    Exercise-evoked immunometabolic niches coordinate context-dependent muscle metabolism.
    Makoto Kanzaki.
      Exercise improves metabolic health; yet paradoxically, many exercise-responsive myokines and immune mediators are also implicated in chronic inflammation and metabolic dysfunction. In this opinion article, we propose that these immune responses are organized within spatially defined immunometabolic niches. Endothelial-associated neutrophils act as early coordinating cells that integrate muscle-derived and vascular signals, initiate local immune remodeling, and are associated with neutrophil extracellular trap formation. Metabolic outcomes arise from coordinated intercellular interactions rather than individual mediators, even in the absence of overt muscle injury. We further suggest that postexercise insulin sensitization emerges as a spatially regulated property of these niches. This perspective provides a conceptual framework in which inflammatory signals, including interleukin-1, exert context-dependent beneficial effects on metabolism and muscle function.
    Keywords:  GLUT4 translocation; NETs; exercise–inflammation paradox; immunometabolic niche; insulin sensitivity; neutrophils
    DOI:  https://doi.org/10.1016/j.tem.2026.06.008
  55. Int J Neurosci. 2026 Jul 15. 1-22
    Integrated multi-omics and machine learning identify OGDHL as a key regulator of glioblastoma progression and antitumor immunity via glutamine metabolism and histone lactylation.
    Xindong Shi, Xiao Hu, Ziyan Shi, Fang Chen.
       BACKGROUND: Glioblastoma (GBM) has an extremely poor prognosis, and its malignant progression is closely associated with glutamine metabolic reprogramming and immune evasion; however, the key regulatory networks remain unclear.
    METHODS: This study integrated bioinformatics data and identified key proteins through weighted gene co-expression network analysis (WGCNA), screening for differentially expressed proteins (DEPs), and machine learning algorithms. The functions and molecular mechanisms were validated using in vitro cell experiments and in vivo mouse models.
    RESULTS: Oxoglutarate dehydrogenase L (OGDHL) was identified as the key protein in GBM it was down-regulated in both GBM and low-grade glioma (LGG) tissues and was correlated with immune cell infiltration. OGDHL overexpression inhibited GBM cell proliferation and reduced glutamate, α-ketoglutarate (α-KG), and lactate production and programmed death-ligand 1 (PD-L1) expression, while promoting apoptosis. OGDHL overexpression enhanced CD8+ T cell-mediated cytotoxicity and interferon-γ (IFN-γ) secretion. Mechanistically, OGDHL overexpression suppressed histone H3 lysine 18 lactylation (H3K18la) enrichment, reduced luciferase activity, and inhibited PD-L1 expression in GBM cells, effects that were rescued by exogenous lactate supplementation. In vivo, OGDHL up-regulation inhibited tumor growth, reduced glutamate and lactate production, and decreased Ki-67- and PD-L1-positive cells, while increasing OGDHL-positive cells.
    CONCLUSION: OGDHL exerts a tumor-suppressive function in GBM by regulating glutamine metabolism and histone lactylation-mediated PD-L1 expression, representing a potential new target for immunometabolic therapy.
    Keywords:  Glioblastoma; Glutamine metabolism; Histone lactylation; Immune escape; Oxoglutarate dehydrogenase L; Programmed death-ligand 1
    DOI:  https://doi.org/10.1080/00207454.2026.2705220
  56. Neurosci Bull. 2026 Jul 13.
    PLX3397 Reshapes Hepatic Lipid Metabolism Independent of Microglial Depletion.
    Jiahui Lyu, Wang Cheng, Chun-Yue Li, Jiayan Wang, Xiaorong Zhang, Huifang Lou, Yalin Hu, Zhihua Gao, Shumin Duan, Kelei Cao.
      Colony-stimulating factor 1 receptor (CSF1R) inhibitors, such as PLX5622 and PLX3397 (pexidartinib), are widely used for in vivo microglial depletion and for investigating microglial functions and therapeutic potential. Although CSF1R inhibitor-based studies have uncovered important roles for microglia in processes, such as anesthesia, addiction, and obesity, whether the resulting phenotypes reflect microglial depletion alone remains increasingly debated. Our previous work has shown that PLX5622 activates hepatic constitutive androstane receptor (CAR)-dependent xenobiotic metabolism, altering the metabolism of anesthetics and addictive drugs, and amplifying apparent microglial phenotypes. Whether other CSF1R inhibitors, particularly the FDA-approved PLX3397, exert systemic metabolic effects that may influence the interpretation of brain phenotypes remains unknown. Here, we demonstrate that PLX3397 exerts hepatic metabolic effects that are mechanistically distinct from those induced by PLX5622. Although PLX3397 only weakly affects xenobiotic metabolism, it markedly enhances endogenous hepatic lipid metabolism, inducing a fasting-like state characterized by increased lipid utilization and ketogenesis despite the absence of nutrient deprivation. By uncovering previously unrecognized peripheral effects of PLX3397, our findings identify brain-periphery interactions as a potential source of confounding in studies of microglial function. These results suggest that systemic metabolic effects should be carefully considered when interpreting neural or behavioral phenotypes in pharmacological microglia depletion paradigms.
    Keywords:  Lipid metabolism; Microglial depletion; PLX3397·PLX5622; Xenobiotic metabolism
    DOI:  https://doi.org/10.1007/s12264-026-01668-5
  57. Inflamm Res. 2026 Jul 15. pii: 176. [Epub ahead of print]75(1):
    Myeloid PKM2 deficiency alleviates allergic airway inflammation and promotes macrophage efferocytosis via SLC13A3.
    Lingli Chen, Yile Liu, Yating Chen, Yue Zhang, Lei Yu, Yantong Zhu, Wang Peng, Maolan Wu, Xiangrong Zheng.
       BACKGROUND: Allergic asthma is characterized by chronic airway inflammation that fails to resolve efficiently. Defective efferocytosis and metabolic reprogramming of macrophages are crucial factors in allergic diseases. While PKM2 is known to participate in phagocytosis and metabolism, its specific role in modulating asthma remains unclear.
    OBJECTIVE: To delineate the underlying mechanisms of PKM2 in allergic asthma.
    METHODS: We generated myeloid cell-specific LysMcrePKM2fl/fl mice, with littermate PKM2fl/fl mice serving as controls, and challenged them with ovalbumin (OVA) extract to induce allergic airway inflammation. In vivo, we assessed airway hyperresponsiveness, pulmonary inflammation, Th2 cytokine levels, apoptosis, and efferocytosis-related receptor expression. Primary bone marrow-derived macrophages(BMDMs) were isolated for in vitro evaluation of efferocytic activity under distinct polarization conditions. To investigate underlying mechanisms, we performed RNA-seq to identify PKM2 downstream targets, followed by lentiviral-mediated overexpression of the candidate molecule SLC13A3 in THP-1 cells, with validation through molecular docking, immunoprecipitation, and functional assays.
    RESULTS: We found that PKM2 is upregulated in macrophages during asthma. Myeloid cell-specific PKM2 deficiency mitigated OVA-induced Th2 inflammation and eosinophilic apoptosis while reducing airway hyperresponsiveness (AHR). Mechanistically, PKM2-expressing macrophages exhibited decreased SLC13A3 transcription, which drove activation of the PI3K-AKT and redistributed STAT6/1 ratio to impair efferocytosis. This impairment disturbed the M2/M1 balance. In vitro experiments confirmed that SLC13A3 overexpression enhanced efferocytic capacity and promoted a shift toward M2/M1 balance. Conversely, PKM2 overexpression in macrophages impaired efferocytosis and exacerbated chronic airway inflammation.
    CONCLUSION: Our study reveals a novel role for myeloid cell-specific PKM2 and SLC13A3 in asthma, linking efferocytosis to immune metabolism during allergic inflammation.
    Keywords:  Allergic inflammation; Efferocytosis; Macrophage polarization; PKM2; SLC13A3
    DOI:  https://doi.org/10.1007/s00011-026-02329-z
  58. Transfus Apher Sci. 2026 Jul 14. pii: S1473-0502(26)00124-2. [Epub ahead of print]65(4): 104492
    Baseline-dependent immunometabolic effects of low-volume plasma exchange on inflammation and iron homeostasis in metabolic syndrome.
    Vjeroslava Slavić, Danijela Ranđelović, Gordana Rajović, Tanja Antunović, Nevena Terzić Stanić, Jelena Boljević.
       BACKGROUND: Metabolic syndrome (MetS) is characterized by chronic low-grade inflammation, metabolic endotoxemia, and dysregulation of iron and vitamin D homeostasis. Lipopolysaccharide (LPS) and LPS-binding protein (LBP) play key roles in linking metabolic and immune pathways.
    OBJECTIVE: To evaluate the effects of low-volume plasma exchange (LVPE) on inflammatory markers, iron metabolism, and vitamin D status in adults with MetS, and to determine whether these effects depend on baseline biomarker levels.
    METHODS: In this prospective interventional study, 48 adults with MetS underwent four LVPE sessions using a nanomembrane-based system. Anthropometric and biochemical parameters were assessed before and after treatment. Baseline-stratified analyses were performed to evaluate individualized responses.
    RESULTS: LVPE significantly reduced C-reactive protein and increased transferrin levels, while vitamin D levels decreased. No significant changes were observed in IL-6, ferritin, serum iron, or LBP in the overall cohort. Baseline-stratified analyses revealed bidirectional, homeostatic effects, with normalization of both elevated and reduced biomarker levels. Reductions in inflammatory markers, particularly CRP, hsCRP, and LBP, were more pronounced in participants with higher baseline values, while individuals with low baseline levels remained largely unchanged.
    CONCLUSION: LVPE acts as a baseline-dependent immunometabolic modulator in MetS, selectively reducing inflammation and normalizing iron-related parameters while preserving physiological stability. These findings support its potential as a personalized adjunctive therapy in cardiometabolic risk management.
    Keywords:  Inflammation; Iron metabolism; Lipopolysaccharide-binding protein; Low-volume plasma exchange; Vitamin D
    DOI:  https://doi.org/10.1016/j.transci.2026.104492
  59. NPJ Syst Biol Appl. 2026 Jul 14.
    Sleep restriction reprograms systemic immunity through NK and T cell crosstalk.
    Zhengyang Qiu, Jichen Jin, Pengqi Zhang, Chen Li, Yongmei Xi.
      Insufficient sleep is a recognized risk factor for inflammatory diseases, yet how sleep loss functionally perturbs immune regulation remains unclear. Here, we apply a multi-omics framework combining two-sample Mendelian randomization, sleep-restriction intervention microarray, and PBMC single-cell profiling to dissect immune consequences of sleep loss. Mendelian randomization associated genetically proxied sleeplessness/insomnia symptoms with alterations in 162 plasma proteins and increased risk across 94 clinical diagnosis traits. Gene expression microarray after sleep restriction confirmed immune activation and stress-response programs. Single-cell RNA sequencing revealed PBMC remodeling with increased NK/NKT cells and decreased γδ T cells and dendritic cells, alongside pro-inflammatory pathway activity. Ligand-receptor analysis identified altered intercellular communication patterns, characterized by increasing signals to NK cells and enhancing NK-T cell-associated interfaces. These findings nominate dysregulated NK cell-T cell crosstalk as a putative mechanism underlying sleep-related inflammation and provide prioritized targets for future validation.
    DOI:  https://doi.org/10.1038/s41540-026-00787-z
  60. Immunity. 2026 Jul 17. pii: S1074-7613(26)00274-8. [Epub ahead of print]
    Purine and pyrimidine-based bacterial cyclic dinucleotides egress the phagosome and activate the innate immune sensor STING.
    Stephanie A Ragland, Katherine E Lindblad, Yao Li, Joon H Choi, Daniel Okin, Joshua Q Mao, Desmond Richmond-Buccola, Daniela R Coronado, Madison R Brown, Scott B Snapper, Philip J Kranzusch, Jonathan C Kagan.
      Toll-like receptors (TLRs) are considered general sensors of bacterial encounters. Here, we examined whether other pattern recognition receptors are commonly activated during bacterial infection. TLR-independent interferon (IFN) responses were induced in macrophages in response to diverse bacterial encounters. Of the cytoplasmic receptor families examined, the cyclic dinucleotide (CDN) sensor STING was required for IFN responses to evolutionarily diverse bacteria. Various bacterial CDNs were present in murine tissues; these activated stimulator of interferon genes (STING) after bacteriolysis in phagolysosomes in a manner requiring two CDN transporters. Importantly, bacterial CDNs were increased in colonic biopsies from patients with inflammatory bowel disease. Systemic delivery of dead, CDN-laden bacteria promoted anti-tumor immunity in mice. Detection of diverse CDNs, including pyrimidine-based CDNs, was an evolutionarily conserved feature of STING, with distinct binding modes for purine- and pyrimidine-based CDNs. Thus, a phagocytosis-CDN-STING connection places cytoplasmic sensing as a common outcome of host-bacteria interactions that set the immune tone of a tissue, with implications for host defense.
    Keywords:  2′3′-cUMP-AMP; LRRC8A; STING; bacteria; cGAS; cyclic dinucleotides; interferon; macrophage; phagosome; toll-like receptor
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.023
  61. Mol Biol Rep. 2026 Jul 15. pii: 1163. [Epub ahead of print]53(1):
    From barrier to trigger: leveraging tumor hypoxia for precise control of CAR-T cell activity.
    Parisa Pedram Rad, Ali Reyhani, Mohammadreza Dashti.
      CAR-T cell therapy has revolutionized the treatment of hematologic malignancies, yet its translation to solid tumors remains a formidable challenge. A central determinant of this limitation is the hypoxic tumor microenvironment, which imposes profound immunosuppressive pressure on infiltrating CAR-T cells, impairing their persistence, effector function, and metabolic fitness. Rather than viewing hypoxia purely as an obstacle, emerging engineering paradigms are reframing it as a tumor-selective switch one that can be harnessed to spatially confine CAR-T cell activation, enhance metabolic fitness, and reduce off-tumor toxicity. This review critically examines how hypoxia subverts CAR-T cell immunity, and how next-generation hypoxia-responsive constructs, metabolic reprogramming strategies, and armored cytokine-secreting designs are beginning to turn this hostile microenvironment into a therapeutic advantage. We further discuss unresolved clinical challenges and the translational outlook for hypoxia-adapted CAR-T cells in solid tumor immunotherapy.
    Keywords:  CAR-T cell therapy; HIF-1α; Hypoxia; Immunotherapy; Metabolic reprogramming; Solid tumors; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11033-026-12321-9
  62. Front Immunol. 2026 ;17 1836315
    Serum lipidome remodeling in viral pneumonia: from pathophysiology to therapeutics.
    Yige Wang, Qiang Xiao.
      Viral pneumonia remains a preeminent global health threat, frequently culminating in acute respiratory distress syndrome (ARDS) and systemic organ failure. While traditional paradigms have centered on protein-based inflammatory cascades, this review synthesizes a vast body of emerging evidence to redefine viral pneumonia as a profound systemic metabolic crisis, specifically characterized by the radical remodeling of the host lipidome. Based on a meta-synthesis of clinical and mechanistic data, we delineate a consistent "metabolic crash" during severe infection, where a precipitous decline in serum low-density lipoprotein (LDL)-cholesterol and the functional conversion of high-density lipoprotein (HDL) from a protective "immunometabolic shield" into a pro-inflammatory vehicle serve as decisive prognostic indicators. We further dissect the molecular mechanisms of this reprogramming, detailing how respiratory viruses hijack the host SREBP-SCAP axis to repurpose lipid droplets for viral assembly, while simultaneously triggering ferroptotic cell death through the exhaustion of the GPX4-lipid-peroxidase defense system. By integrating the "gut-lipid-lung axis" and the role of systemic metainflammation, we illustrate how the host's baseline metabolic architecture dictates the threshold for lethal alveolar-capillary barrier failure. Finally, we evaluate the therapeutic potential of restoring lipid homeostasis through specialized pro-resolving mediators (SPMs) and metabolic stabilizers. We conclude that transitioning toward a lipid-centric precision medicine model, supported by AI-driven metabolic endotyping, is essential for advancing host-directed therapies in the management of severe respiratory viral infections.
    Keywords:  ARDS; HDL dysfunction; Host-directed therapy; SREBP pathway; ferroptosis; immunometabolism; lipidomics; viral pneumonia
    DOI:  https://doi.org/10.3389/fimmu.2026.1836315
  63. bioRxiv. 2026 Jul 07. pii: 2026.07.01.735930. [Epub ahead of print]
    IFN γ and IFN γ mimetics prevent IFN-I-mediated TB susceptibility by regulating iron metabolism and lipid peroxidation.
    Prasanna Babu Araveti, Shivraj M Yabaji, Muhammad Zainul Arifin, Suruchi Lata, Yuriy O Alekseyev, Alexander A Gimelbrant, William R Bishai, Vadim Zhernovkov, Oleksii S Rukhlenko, Boris N Kholodenko, Igor Kramnik.
      Type I interferons (IFN-I) and IFNγ exert divergent effects during tuberculosis, but the mechanisms that determine whether macrophage activation promotes host defense or inflammatory pathology remain incompletely understood. Here, we dissect the interplay between IFN-I and IFNγ in macrophage activation using genetically susceptible B6.Sst1S macrophages. We show that, during tumor necrosis factor (TNF) stimulation, susceptible macrophages enter a persistent pathological activation state (pPAS) characterized by sustained lipid peroxidation and super-induction of IFN-I responses. This pathological state is maintained by autocrine IFN-I signaling. In contrast, IFNγ priming prevents pPAS development by enhancing macrophage resilience to oxidative stress, in part through regulation of iron metabolism and induction of ferritin expression. Computational c ell s tate t ransition a ssessment and r egulation (cSTAR) analysis identified pathways and small molecules predicted to promote the transition of susceptible macrophages toward an IFNγ-induced, Mtb-resistant state. Consistent with these predictions, the CDK4/6 inhibitor trilaciclib reduced lipid peroxidation by regulating iron metabolism, whereas retinoic acid signaling enhanced GPX4 expression and lipid biosynthesis programs. Combined CDK4/6 inhibition and retinoic acid receptor activation efficiently prevented the pathological activation state. Together, these findings delineate a mechanism of IFN-I/IFNγ crosstalk during macrophage activation and identify pharmacologic strategies to prevent IFN-I-dominant, lipid peroxidation-driven macrophage pathology.
    DOI:  https://doi.org/10.64898/2026.07.01.735930
  64. Biochem Biophys Res Commun. 2026 Jul 14. pii: S0006-291X(26)01053-3. [Epub ahead of print]830 154289
    Knockout of acod1 promotes liver regeneration after hepatectomy by promoting fatty acid mobilization.
    Duo Zhang, Jing Kuai, Yanzhi Jiang, Shubin Zhang, Pei Chen, Huihong Wang, Xi Liu, Xiangyue Guo, Zhongyi Jiang, Pusen Wang, Chunguang Wang, Dong Zhao, Weitao Que, Lin Zhong.
      The regenerative capacity of the liver critically determines recovery outcomes following partial liver transplantation or hepatectomy. While cytokines, immune responses, and metabolic dynamics modulate hepatic regeneration, the role of aconitate decarboxylase 1 (Acod1)-a key enzyme catalyzing itaconate biosynthesis-remains underexplored. This study elucidates the regulatory function of Acod1 in liver regeneration and its underlying mechanisms. Male wild-type (WT) and Acod1-knockout (Acod1-/-) mice underwent 70% or 90% partial hepatectomy (PHx), with interventions including 4-octyl itaconate (4OI) and citraconate administration. Postoperative assessments at 0, 3, 6, 12, 24, 36 and 48 h included liver-to-body weight ratios, serum ALT/AST levels, histopathology, proliferation markers (Ki67, PCNA), cell cycle gene expression, and survival analysis. RNA seq and metabolic profiling were performed to explore mechanistic pathways. Our results demonstrated that Acod1 expression peaked at 36 h post-hepatectomy. In 90% lethal PHx model, Acod1-/- mice showed significantly improved survival versus WT controls. Following 70% PHx, Acod1-/- mice exhibited enhanced liver regeneration at 36 h, with significantly lower serum transaminase levels compared to WT controls. Exogenous 4-OI administration abrogated this pro-regenerative phenotype in Acod1-/- mice, whereas CITRA treatment in WT mice produced a similar pro-regenerative pattern, improving both regeneration-associated readouts and survival. Mechanistically, RNA-seq revealed upregulated ketone body metabolism genes in Acod1-/- mice, concomitant with elevated hepatic β-hydroxybutyrate and reduced intrahepatic lipids versus WT controls. This study demonstrates that Acod1 deficiency enhances post-hepatectomy liver regeneration by suppressing itaconate production, thereby promoting fatty acid mobilization. These findings support Acod1-associated metabolic regulation as a potential therapeutic target for optimizing liver regeneration and postoperative recovery.
    Keywords:  Fatty acid mobilization; Itaconate; Liver regeneration; Metabolic reprogramming; Partial hepatectomy; acod1
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154289
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