bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–04–26
fifty-six papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. The immunometabolic role of pyruvate dehydrogenase kinase/pyruvate dehydrogenase axis in cardiovascular disease and beyond.
  2. Itaconate modifications: Mechanisms and applications.
  3. Protocol for metabolic profiling of antigen-specific CD8+ T cells using spectral flow cytometry.
  4. Palmitic Acid Promotes Antiviral Innate Immunity via ZDHHC20-Mediated CMPK2 Palmitoylation.
  5. Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8+ T cell-mediated cancer immunotherapy.
  6. Interaction networks of macrophage glycolysis and inflammation in sepsis: mechanisms and therapeutic potential.
  7. Metabolic licensing at the dendritic cell-NK cells immune synapse in viral asthma exacerbations.
  8. Nanoparticle-mediated metabolic reprogramming for immune modulation in inflammatory diseases.
  9. Macrophage MERTK restrains GRAMD1A-driven mitochondrial oxysterol trafficking to limit colitis.
  10. Adhesive polyethylene glycol hydrogels with metformin enabling in-situ drug delivery reprogramming immuno-metabolism for tissue repair in diabetic foot ulcers.
  11. Metabolic reprogramming of human macrophages drives the formation of hybrid M1/M2 pro-regenerative extracellular vesicles.
  12. LUCAT1/PTBP1/HIF-1α feedback loop promotes T cell over-differentiation and Th1/Th2-skewed immune imbalance in sepsis via glucose metabolism.
  13. Local Immunometabolic Intervention With Alanyl-Glutamine Resolves Peritoneal Dialysis-Induced Immune Cell Dysfunction.
  14. Nicotinamide metabolism is essential for Hepatitis C Virus replication and the production of infectious Lipo-Viro-Particles.
  15. PIM1 kinase-regulated cellular metabolism sustains differentiation and function of effector CD8+ T cells during chronic viral infection.
  16. Dietary EGCG reshapes metabolic-epigenetic interplay to induce transgenerational host defense.
  17. The role of macrophage metabolic reprogramming in efferocytosis: A dual-edged sword in atherosclerosis and tumor progression.
  18. Microbial metabolite Enterobactin impairs mitochondrial respiration and alleviates colitis.
  19. Metabolic Reprogramming and Signalling Networks in Microglial Activation: Implications for Neurodegeneration.
  20. Omega-3 modulates macrophage immunometabolic profile without changing Pseudomonas aeruginosa proliferation.
  21. A novel photosensitizer-based photodynamic therapy reprograms the Kynurenine-AhR axis to boost antitumor immunity in breast cancer.
  22. Glucose metabolic reprogramming in systemic lupus erythematosus and lupus nephritis: theoretical foundations and therapeutic implications.
  23. Polysaccharide-engineered mitochondria reprogram macrophages to resolve diabetic wound inflammation and promote repair.
  24. SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis.
  25. Ketogenic diet exacerbates DSS-induced colitis through a β-hydroxybutyrate-Thomasclavelia spiroformis-γδ17 T cell axis in mice.
  26. Salmonella-derived haem inhibits macrophage phagocytosis and promotes infection in mice.
  27. B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.
  28. Multifunctional Role of Mitochondrial Fatty Acid Oxidation in Cancer Immunotherapy and Aging.
  29. Immunometabolic remodeling: new perspectives and strategies for liver transplantation.
  30. Decoupling lactylation-associated metabolic remodelling in Asthma: Integrated multi-omics and machine learning identify RCC2 as a potential therapeutic target.
  31. Nano-granulated zoledronate sensitizes innate immune metabolism to enhance vaccine-induced and antitumor immunity.
  32. Lactate Activates TGF-β/SNAIL Signaling to Drive M2 Macrophage Polarization and CD8+ T Cell Exhaustion in Breast Cancer.
  33. Macrophage metabolic reprogramming by vanadium released from glucose-responsive bio-gel accelerates diabetic wound repair.
  34. MOF-based arginine nanocarriers for coordinated immunometabolic and antitumor modulation in triple negative breast cancer.
  35. Phagocytosis of Primary Human Macrophages is Elevated by Ex Vivo Supplementation with n-3 PUFA.
  36. Insights into neutrophil dysfunction in inherited metabolic disorders.
  37. Inhibition of calpain-mediated HMGB1 alleviates cardiac inflammation and dysfunction induced by ultra-processed foods.
  38. AXL prevents amyloid-β-induced microglial ferroptosis by sustaining SLC2A3-mediated mitochondrial respiration.
  39. Qinggan Jianpi formula attenuates atherosclerosis by suppressing macrophage lactate transport to activate repair genes via H3K18 lactylation.
  40. TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis.
  41. Proteasome-haem-BACH2 axis fuels T cell exhaustion.
  42. TREM2 sustains glucose metabolic homeostasis to drive antibacterial defense during sepsis.
  43. Bridging exercise biology and immunometabolism: A novel irisin pathway toward next-generation metabolic and neurodegenerative therapies.
  44. Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance.
  45. Host adenosine deaminase reprograms purinergic immunoregulation in Leishmania braziliensis infection.
  46. Lipid metabolic reprogramming regulates macrophage senescence in the tumor microenvironment.
  47. Vitamin D Mitigates Klebsiella pneumoniae-Induced Pneumonia by Regulating Macrophage Polarization Through miR-223/ACSL3 Axis-Mediated Lipid Metabolism Reprogramming.
  48. Redox index and capacity analysis (RICA) reveals NAD biology changes in T cell responses in vitro and ex vivo.
  49. Spermidine biosynthesis by hypervirulent Francisella tularensis promotes fitness and salvages adenine.
  50. The role of trained immunity in chronic non-communicable inflammatory diseases.
  51. Role of dual specificity phosphatase 1 in influencing inflammatory pathways in macrophages modulated by Borrelia burgdorferi lipoproteins.
  52. Creatine uptake promotes dendritic cell activation and enhances antitumor immunity.
  53. Metabolites in the tumor microenvironment: Key drivers of immune cell fate and function as therapeutic targets in cancer.
  54. Spatiotemporally reprogrammed L-arginine metabolic nanoregulator potentiates immunotherapy.
  55. Cells' survival pattern of kidney macrophages and epithelial cells in lupus nephritis is influenced by glycolysis.
  56. Monocyte Preprogramming by Tobacco Carcinogens and Fructose Intake Accelerates Lung Cancer Progression via Metabolic and Epigenetic Pathways.
  1. Cardiovasc Res. 2026 Apr 23. pii: cvag088. [Epub ahead of print]
    The immunometabolic role of pyruvate dehydrogenase kinase/pyruvate dehydrogenase axis in cardiovascular disease and beyond.
    Andrietta Grentzmann, Daniel F J Ketelhuth.
      The pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) axis plays a pivotal role in regulating cellular energy metabolism, controlling the flux between the tricarboxylic acid cycle and oxidative phosphorylation. Traditionally viewed through a metabolic lens, this axis is now emerging as a crucial regulator of immune cell function, placing it at the intersection of metabolism and immunity and underscoring its central role in immunometabolism. In this review, we highlight the multifaceted roles of the PDK/PDH axis in orchestrating metabolic reprogramming and immune cell plasticity, highlighting its broader significance across several pathological conditions. Thus, we emphasise the role of this axis in cardiometabolic disease, where its regulation has been shown to highly impact immune and vascular cell functions and to modulate disease progression. Given the promising results from clinical studies beyond the cardiovascular field and from preclinical models of cardiovascular disease, we discuss insights from metabolic reprogramming that may guide therapeutic strategies targeting the immunometabolic dysfunction driving vascular inflammation and its deleterious consequences.
    Keywords:  PDK; cardiovascular disease; immunometabolism; inflammation
    DOI:  https://doi.org/10.1093/cvr/cvag088
  2. J Intensive Med. 2026 Apr;6(2): 114-127
    Itaconate modifications: Mechanisms and applications.
    Yingyi Yang, Rui Kang, Huiting Zhou, Daolin Tang.
      Itaconate is a mitochondrial metabolite generated from the tricarboxylic acid cycle intermediate cis-aconitate by the enzyme aconitate decarboxylase 1 (ACOD1). Beyond its metabolic role, itaconate has emerged as a critical regulator of immune and inflammatory signaling. Together with its electrophilic derivatives (e.g., 4-octyl itaconate, dimethyl itaconate), it modulates diverse cellular processes through covalent post-translational modifications. These include S-itaconation, a cysteine-directed Michael addition primarily mediated by electrophilic derivatives, and K-itaconation, a lysine-targeted, reversible acylation involving an itaconyl-CoA intermediate derived from itaconate. Such modifications influence multiple immune regulators - including Kelch-like ECH-associated protein 1 (KEAP1), stimulator of interferon response cGAMP interactor 1 (STING1), NLR family pyrin domain containing 3 (NLRP3), glutathione peroxidase 4 (GPX4), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) - thereby modulating inflammation, oxidative stress, and cell death pathways such as pyroptosis and ferroptosis. Preclinical studies demonstrate that itaconate derivatives confer therapeutic benefits in sepsis, colitis, neurodegeneration, autoimmunity, and cancer. By contrast, endogenous itaconate exhibits context-dependent effects, acting as either a pro-resolving or immunostimulatory metabolite. This review integrates current insights into itaconate biosynthesis, molecular targets, post-translational modifications, detection technologies, and translational potential, underscoring its emerging role as a master regulator of immunometabolic reprogramming and inflammatory control.
    Keywords:  ACOD1; Disease pathogenesis; Inflammation; Itaconate; Itaconation
    DOI:  https://doi.org/10.1016/j.jointm.2025.10.002
  3. STAR Protoc. 2026 Apr 22. pii: S2666-1667(26)00170-X. [Epub ahead of print]7(2): 104517
    Protocol for metabolic profiling of antigen-specific CD8+ T cells using spectral flow cytometry.
    J Fréderique de Graaf, Nils Mülling, Ramon Arens.
      CD8+ T cells rely on tightly regulated metabolic remodeling to support effector function. Here, we present a protocol for single-cell metabolic profiling of rare antigen-specific CD8+ T cells in unstimulated and antigen-stimulated conditions using spectral flow cytometry. The workflow enables detailed assessment of key metabolic pathways, including glycolysis, fatty acid oxidation, amino acid metabolism, the pentose phosphate pathway, and mitochondrial oxidative phosphorylation. For complete details on the use and execution of this protocol, please refer to Mülling et al.1.
    Keywords:  Cell Biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2026.104517
  4. Adv Sci (Weinh). 2026 Apr 21. e75209
    Palmitic Acid Promotes Antiviral Innate Immunity via ZDHHC20-Mediated CMPK2 Palmitoylation.
    Yujia Wang, Zenghui Cui, Yunkai Zhang, Zhiqing Li, Xuetao Cao.
      While immunometabolic crosstalk is critical for antiviral defence, the regulation of this process, particularly through post-translational modifications, remains incompletely understood. How specific metabolites and associated modifications orchestrate antiviral immunity remains unclear. By screening a metabolic chemical library, we identify palmitic acid (PA) as an activator of antiviral immunity in macrophages. PA induces UMP-CMP kinase 2 (CMPK2) palmitoylation, maintaining its mitochondrial localization. CMPK2 is vital for the production of 3'-deoxy-3',4',-didehydrocytidine triphosphate (ddhCTP) and the stabilization of mitochondrial antiviral signaling protein (MAVS), both of which are crucial for defence against RNA viruses. Cmpk2 deficiency impairs IFN-I production and increases viral replication. Furthermore, the palmitoyl transferase ZDHHC20 catalyzes CMPK2 palmitoylation at cysteines 137 and 153, which are depalmitoylated by the thioesterase PPT1. PPT1 deficiency restores CMPK2 palmitoylation and antiviral immunity. Both a palm oil-rich diet and the in vivo administration of the PPT1 inhibitor DC661 increase IFN-I production. Therefore, the PA-ZDHHC20-CMPK2-PPT1 axis enhances the antiviral response, indicating that targeting PPT1 has the potential to treat RNA virus infections.
    Keywords:  CMPK2; IFN‐I; immunometabolism; innate immune response; palmitoylation
    DOI:  https://doi.org/10.1002/advs.75209
  5. Biomaterials. 2026 Apr 15. pii: S0142-9612(26)00244-9. [Epub ahead of print]333 124220
    Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8+ T cell-mediated cancer immunotherapy.
    Yang Liu, Xu Zhou, Weilin Li, Bing Feng, Jingshan Sun, Ruzhen Li, Huixia Ma, Lanpeng Li, Feng Zhou, Jianxun Ding, Xuesi Chen.
      Immunotherapy efficacy is constrained by immunosuppressive features of the tumor microenvironment (TME) beyond canonical molecular checkpoints, including emerging extracellular ionic regulatory mechanisms that remain poorly characterized. Here, we identify potassium ion (K+) as a metabolically coupled ionic immune checkpoint that suppresses CD8+ T cell antitumor immunity. Using a murine melanoma model with an elevated-K+ microenvironment, we demonstrate that excess extracellular K+ profoundly impairs CD8+ T cell proliferation, activation, and effector function while promoting functional exhaustion without reducing T cell abundance. Mechanistically, K+-mediated immunosuppression is accompanied by restricted glucose uptake, suppressed glycolytic flux, and impaired mitochondrial fitness, establishing metabolic insufficiency as a key basis for ionic checkpoint-driven T cell dysfunction. To therapeutically target this extracellular and non-molecular suppressive mechanism, we develop a localized K+-depleting strategy by encapsulating the clinically approved potassium-binding agent sodium zirconium cyclosilicate (ZS-9) within a thermosensitive poly (lactide-co-glycolide)-polyethylene glycol-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel, forming a peritumoral K+-scavenging depot. This biomaterial platform efficiently remodels the ionic TME, restores CD8+ T cell metabolic fitness and effector function, alleviates T cell exhaustion, and significantly enhances the antitumor efficacy of adoptive cell therapy (ACT). Collectively, this work establishes extracellular ionic modulation as a metabolically grounded immune checkpoint mechanism and highlights biomaterials-based ionic remodeling as a translatable strategy to augment cancer immunotherapy.
    Keywords:  Adoptive cell therapy; Immunomodulatory biomaterials; Ionic immune checkpoint; K(+)-scavenging hydrogel; T cell metabolism
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124220
  6. Front Immunol. 2026 ;17 1783409
    Interaction networks of macrophage glycolysis and inflammation in sepsis: mechanisms and therapeutic potential.
    Peiyao Luo, Hao Liu, Ting Zhang, Wenfang He.
      Sepsis is a severe threat to human health with high mortality rates, but so far its pathogenesis is unclear and lacks effective therapeutic drugs. Macrophages function as one of the most important innate immune cells and play an integral role in the sepsis inflammatory process. Recently, studies have shown that its immune function is associated with the Warburg effect. The Warburg effect refers to the preferential metabolism of glucose to lactate by cells through aerobic glycolysis even with abundant oxygen. It has shown that increasing aerobic glycolysis promotes M1 polarization of macrophages to facilitate inflammation, whereas decreasing aerobic glycolysis can lead to M2 polarization and alleviated inflammation. Interestingly, it was demonstrated that not only does glycolysis affect inflammation, but inflammation in sepsis in turn affects glycolysis. Currently, there is no comprehensive review regarding this issue. Therefore, our review focuses on the mechanisms of the interaction between inflammation and macrophage glycolysis in sepsis. We will address both how inflammatory molecules affect the process of glycolysis in septic macrophages and how glycolytic enzymes and related metabolites contribute to inflammation. We also discuss the potential in targeting glycolysis for the treatment of sepsis. We hope to bring a new perspective to clinical practice.
    Keywords:  inflammation molecules; macrophages; metabolism; sepsis; the Warburg effect
    DOI:  https://doi.org/10.3389/fimmu.2026.1783409
  7. Front Immunol. 2026 ;17 1798209
    Metabolic licensing at the dendritic cell-NK cells immune synapse in viral asthma exacerbations.
    Yan-Jiao Chen, Gabriel Shimizu Bassi, Yong-Qing Yang.
      Asthma exacerbations are predominantly triggered by respiratory viral infections, yet current therapies largely fail to restore effective antiviral immunity. Emerging data indicate that this failure is tightly coupled to dysregulated immunometabolism within the asthmatic lung. This review advances the concept of a dendritic cell-natural killer (DC-NK) metabolic checkpoint, whereby the metabolic state of DCs, regulated by autophagy and AMPK/mTOR signaling, licenses NK cells for antiviral effector function. In type 2-high, type 2-low, and obesity-related asthma endotypes, chronic hypoxia, HIF-1α stabilization, ORMDL3-ceramide signaling, and systemic metabolic stress converge to induce highly glycolytic, Th2/Th17-polarizing DCs in a lactate-rich, acidic microenvironment. We propose that these DCs modulate NK cell metabolism through three interlinked axes: (i) cytokine-mediated metabolic licensing (IL-12, IL-15, IL-18), (ii) exosome-mediated delivery of activating versus metabolically suppressive cargo, and (iii) intense perisynaptic nutrient competition that depletes local glucose while lactate accumulation and acidosis further inhibit NK cell function. The result is a "double metabolic hit" that renders lung-resident NK cells metabolically exhausted, IFN-γ-deficient, and unable to clear virally infected targets despite preserved cytotoxic machinery. Although many mechanistic insights derive from murine and in vitro models, converging human metabolomic, genetic, and functional data support this framework and define clear research gaps. If validated in human studies, targeting the DC-NK cell metabolic checkpoint with agents that restore autophagic plasticity, rebalance AMPK/mTOR signaling, or normalize airway nutrient and pH landscapes may represent a promising strategy to prevent viral-triggered asthma exacerbations.
    Keywords:  asthma; autophagy; dendritic cells; immunometabolism; natural killer cells; viral infection
    DOI:  https://doi.org/10.3389/fimmu.2026.1798209
  8. Nanoscale. 2026 Apr 22.
    Nanoparticle-mediated metabolic reprogramming for immune modulation in inflammatory diseases.
    Hailing Wang, Ahequeli Gemingnuer, Yan Liu, Yinan Wang, Xin Meng.
      Dysregulated immune cell metabolism including abnormal glycolysis, mitochondrial dysfunction, and excessive reactive oxygen species (ROS) generation contributes to the pathogenesis of various inflammatory diseases. Recent advances in immunometabolism have highlighted the critical role of metabolic reprogramming in shaping immune responses during chronic inflammation. However, a lack of selectivity for specific immune cells or tissues often leads to off-target effects. Nanoparticle-based therapeutic strategies have emerged as a promising platform for modulating immune cell metabolism with improved precision, enhanced bioavailability, and reduced systemic toxicity. Despite progress in this field, there has been no comprehensive review in recent years that systematically summarizes the use of engineered nanocarriers for immunometabolic regulation in inflammatory diseases. This review provides a systematic overview of nanoparticle-mediated metabolic reprogramming for the treatment of inflammatory diseases. These nanoparticles not only serve as delivery vehicles for metabolic modulators but also actively participate in immune regulation through their physicochemical properties and surface functionalities. Furthermore, this review analyzes early-stage clinical studies and the patent landscape, indicating encouraging efficacy and safety profiles for nanoparticle-based metabolic therapies. Collectively, nanoparticle-mediated immunometabolic reprogramming offers a transformative approach for precision intervention in inflammatory diseases.
    DOI:  https://doi.org/10.1039/d5nr04062k
  9. Redox Biol. 2026 Apr 20. pii: S2213-2317(26)00172-2. [Epub ahead of print]93 104174
    Macrophage MERTK restrains GRAMD1A-driven mitochondrial oxysterol trafficking to limit colitis.
    Juanhan Liu, Peizhao Liu, Yangguang Li, Tao Zheng, Cunxia Wu, Wenbin Gong, Ze Li, Guiwen Qu, Xuanheng Li, Yiyu Yang, Qianwen Li, Fansen Lin, Jinyao Liu, Zexing Lin, Yun Zhao, Jianan Ren, Xiuwen Wu.
      Impaired macrophage efferocytosis drives chronic inflammation, yet the underlying immunometabolic mechanisms remain poorly defined. In this study, we identify that impaired macrophage efferocytosis triggers excessive mitochondrial oxysterol accumulation, which drives mitochondrial ROS-associated inflammation in Crohn's disease (CD). We report an inverse correlation between CD activity and the abundance of MERTK+ macrophages. Mechanistically, MERTK loss enhances cholesterol biosynthesis in the endoplasmic reticulum (ER) and stabilizes the cholesterol transporter GRAMD1A. This promotes excessive cholesterol trafficking from the ER to mitochondria. Within mitochondria, this cholesterol is metabolized into specific oxysterols that, unlike other mevalonate pathway metabolites, directly impair the electron transport chain. This impairment triggers a burst of mitochondrial reactive oxygen species (ROS). Collectively, our findings define a pathogenic axis linking defective efferocytosis, dysregulated cholesterol metabolism, and oxysterol-induced mitochondrial damage.
    Keywords:  Crohn's disease; MERTK; Mitochondrial oxidative phosphorylation; Oxysterols; ROS
    DOI:  https://doi.org/10.1016/j.redox.2026.104174
  10. Acta Biomater. 2026 Apr 21. pii: S1742-7061(26)00252-7. [Epub ahead of print]
    Adhesive polyethylene glycol hydrogels with metformin enabling in-situ drug delivery reprogramming immuno-metabolism for tissue repair in diabetic foot ulcers.
    Xuehui Chen, Zhenyu Zou, Pengfei Wei, Xueying Zhang, Yunhuan Li, Wei Jing, Bo Zhao, Yuchen Liu, Yiqian Huang, Xiaowei Wu.
      Diabetic foot ulcer (DFU) is characterized by persistent inflammation, metabolic dysfunction, and impaired angiogenesis, leading to refractory chronic wounds. Here, we report an adhesive, metformin-loaded (1.0 mM) polyethylene glycol (PEG) based hydrogel (i.e., PEG/Met), constructed from equal volume of PEG-SG (20 wt.%) and PEG-NH2 (20 wt.%), to regulate macrophage polarization and metabolism in DFU. Density functional theory (DFT) calculations and infrared spectrum confirmed its crosslinking, yielding a homogeneous PEG network with strong tissue adhesion (31.4 ± 8.6 kPa) and sustained drug release till seven days (total release: 86.8 ± 0.6%). In a rat DFU model, the PEG/Met significantly accelerated wound closure (wound recovery: 91.9 ± 3.4%, which was 1.96-fold to the control), collagen deposition, M2-like macrophage infiltration, and neovascularization. Under lipopolysaccharides (LPS) or Staphylococcal protein A (SpA) induced pro-inflammatory stimulation, the PEG/Met suppressed glycolytic flux, reduced glucose uptake and consumption, yet increased adenosine triphosphate (ATP) production and restored oxygen consumption, indicating a shift from glycolysis toward oxidative phosphorylation (OXPHOS). Likewise, the PEG/Met restored mitochondrial membrane potential, reduced reactive oxygen species (ROS) accumulation, increased Egln3 expression, and decreased Hif-1α and IL-1β levels, thereby alleviating Hif-1α-driven inflammatory signaling. Pharmacologic inhibition of OXPHOS with rotenone reversed PEG/Met-induced M2 polarization and reactivated pro-inflammatory gene expression, confirming the intact mitochondrial respiration for its immunoregulatory effects. This PEG/Met hydrogel functioned as both an adhesive, drug-delivery platform and immune-metabolic modulator, effectively reprogramming macrophage phenotype and mitochondrial metabolism, which held substantial promise as a localized therapy for DFU and other chronic wounds. STATEMENT OF SIGNIFICANCE: Diabetic foot ulcer (DFU) is a leading cause of limb loss worldwide, as traditional dressings only passively cover wounds without resolving chronic inflammation caused by metabolic and immune disorders. Here, we fabricated a polyethylene glycol (PEG) based adhesive hydrogel for local metformin delivery (PEG/Met), which achieved strong tissue adhesion, biodegradability, and sustained drug release. The hydrogel reprogramed macrophage metabolism from glycolysis to oxidative phosphorylation, thereby improving mitochondrial function, decreasing mitochondrial reactive oxygen species, enhancing Egln3-mediated Hif-1α ubiquitination, and alleviating IL-1β-mediated inflammation. This constructed a pro-angiogenic microenvironment to accelerate DFU healing in vivo. By linking the clinically approved metformin, the adhesive hydrogel platforms offered a translational strategy for treating DFU and other chronic wounds.
    Keywords:  Diabetic foot ulcer; PEG hydrogel; immunometabolism; macrophage polarization; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.actbio.2026.04.033
  11. Biomaterials. 2026 Apr 15. pii: S0142-9612(26)00240-1. [Epub ahead of print]333 124216
    Metabolic reprogramming of human macrophages drives the formation of hybrid M1/M2 pro-regenerative extracellular vesicles.
    Cansu Gorgun, Paula Klavina, Carolina S Martins, Cloe Payet, Brenton L Cavanagh, Marianne Pultar, Matthias Hackl, Annie M Curtis, David A Hoey.
      The coordinated activity of macrophages is essential for bone repair, with pro-inflammatory M1 macrophages driving early responses and anti-inflammatory M2 macrophages supporting later tissue remodeling. While both phenotypes are required, prolonged persistence of either subtype can impair healing, underscoring the correct transition between the two states. Macrophage polarization is closely linked to cellular metabolism, and human macrophages display distinct metabolic profiles. Macrophage-derived extracellular vesicles (EVs) carry bioactive cargo and reflect parental polarization, influencing recipient cell function. This raises critical questions about how metabolic regulation influences human macrophage function, their EVs and their effect on angiogenesis and osteogenesis. This study investigates EVs derived from polarized primary human macrophages and from macrophages exposed to DASA-58, a small molecule which activates the metabolic enzyme pyruvate kinase M2 (PKM2). Alterations in macrophage metabolism modify the molecular cargo of their EVs, including microRNAs (miRNAs), to modulate regenerative activity. These findings demonstrate that human macrophage-derived EVs exert metabolically dependent effects on angiogenesis and osteogenesis, and that metabolic modulation enables the generation of EVs with hybrid pro-regenerative properties intermediate between M1 and M2. This establishes metabolic reprogramming within human macrophages using small molecules as a strategy to engineer novel phenotypes and EVs for bone repair.
    Keywords:  Angiogenesis; Extracellular vesicles; Human macrophages; Osteogenesis; Reprogramming; miRNA
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124216
  12. Cytokine. 2026 Apr 21. pii: S1043-4666(26)00052-9. [Epub ahead of print]203 157157
    LUCAT1/PTBP1/HIF-1α feedback loop promotes T cell over-differentiation and Th1/Th2-skewed immune imbalance in sepsis via glucose metabolism.
    Weiyin Gao, Hong Zhang, Jun Fan, Lidong Wu, Wenting Liu.
       BACKGROUND: Sepsis, a life-threatening clinical syndrome linked to Th1/Th2-skewed immune imbalance, involves glucose metabolism reprogramming. Because women remain under-represented in many sepsis studies and sex-specific host responses may influence disease trajectories, this study aims to delineate the mechanism of lncRNA LUCAT1 in Th1/Th2-skewed immune imbalance during sepsis in women via glucose metabolism reprogramming.
    METHOD: Peripheral blood from female patients with post-traumatic sepsis was examined for LUCAT1, PTBP1, and HIF1A expression. Flow cytometry quantified CD4+/CD8+ and Th1/Th2 ratios. Starbase analysis predicted regulatory relationships among LUCAT1, PTBP1, and HIF1A. These predictions were validated through dual luciferase reporter gene assays, ChIP, RIP, and actinomycin D assay. Primary human CD4+ T cells were cultured and activated with anti-CD3/CD28 (αCD3/CD28), treated with 2-DG (glycolysis inhibitor), and assayed for inflammatory factors (IL-1β, IL-6 and TNF-α), glycolytic genes (GLUT1, HK2, LDHA), glycolytic indexes (glucose uptake, lactate generation, ATP, ECAR and OCR) and Th1/Th2 differentiation.
    RESULT: Post-traumatic sepsis patients display elevated LUCAT1, PTBP1, and HIF1-A in peripheral blood lymphocytes alongside decreased CD4+/CD8+ and elevated Th1/Th2. HIF-1α promoted LUCAT1 transcription. LUCAT1, acting as a scaffold, may facilitate PTBP1's regulation on HIF1A mRNA stability. Silencing LUCAT1 inhibited and overexpressing LUCAT1 increased inflammatory mediator secretions, glycolysis, Th1/Th2 ratio in αCD3/CD28-induced Primary human CD4+ T cells. 2-DG partially reversed the effects of LUCAT1 overexpression, whereas HIF1A overexpression countered (rescued) the effects of LUCAT1 silencing.
    CONCLUSION: LUCAT1/PTBP1/HIF-1α positive feedback loop drives excessive T cell differentiation and Th1/Th2-skewed immune imbalance in sepsis via glucose metabolic reprogramming, which may contribute to disease progression.
    Keywords:  Glucose metabolism reprogramming; Lung cancer-related transcript 1; Polypyrimidine tract binding protein 1; Sepsis; Th1/Th2-skewed immune imbalance
    DOI:  https://doi.org/10.1016/j.cyto.2026.157157
  13. Kidney Int Rep. 2026 May;11(5): 106342
    Local Immunometabolic Intervention With Alanyl-Glutamine Resolves Peritoneal Dialysis-Induced Immune Cell Dysfunction.
    Rebecca Herzog, Lisa Daniel-Fischer, Fabian Eibensteiner, Isabel J Sobieszek, Markus Unterwurzacher, Juan Manuel Sacnun, Phoebe K T Uhl, Elisabeth Lang, Anja Wagner, Franz König, Seth L Alper, Luke C Davies, Christoph Aufricht, Andreas Vychytil, Klaus Kratochwill.
       Introduction: Peritoneal dialysis (PD) is the most prevalent home-based dialysis therapy. However, chronic exposure to metabolically imbalanced high-glucose PD fluids is associated with infectious complications and morphological changes that limit PD duration and patient survival. Here, we analyzed interactions among peritoneal cell immune function, inflammation, and glucose metabolism in a prospective cohort study of patients on PD.
    Methods: In 117 patients (mean follow-up: 2.15 years), samples from peritoneal equilibration tests (PETs) were assessed for interleukin (IL)-6 levels as a measure of peritoneal inflammation, and ex vivo toll-like receptor (TLR)-stimulated cytokine release as a measure of immune cell function. In addition, proteomic profiling and targeted metabolomics (1000 metabolites) were performed on peritoneal effluents. Coincubation experiments using patient effluents from a single-center randomized controlled trial (RCT) (n = 20 patients) and immune cells from healthy donors were also conducted to assess effluent-induced immune modulation. Samples from a multicenter RCT (n = 37 patients) were used as a validation cohort.
    Results: Peritoneal inflammation correlated negatively with peritoneal cell immune function and positively with increased risk of subsequent peritonitis (hazard ratio: 3.8). Patients with higher peritoneal inflammation had an altered peritoneal metabolomic profile, with significant perturbation of glucose and amino acid metabolism. Immunometabolic intervention with alanyl-glutamine (AlaGln) supplementation of PD fluid restored immune cell function specifically in patients with high peritoneal inflammation, highlighting the potential to prevent subsequent infections.
    Conclusion: These results provide the first direct, longitudinal evidence linking immunometabolism with peritoneal glucose exposure, local inflammation, as well as impaired peritoneal cell function and infection in a human PD cohort. Metabolic intervention designed to restore adequate peritoneal cell immune function represents a novel therapeutic approach with promise for improved clinical outcomes in chronic PD.
    Keywords:  amino acid metabolism; glucose metabolism; glutamine; immune paralysis; peritoneal inflammation; peritonitis
    DOI:  https://doi.org/10.1016/j.ekir.2026.106342
  14. PLoS Pathog. 2026 Apr 22. 22(4): e1014165
    Nicotinamide metabolism is essential for Hepatitis C Virus replication and the production of infectious Lipo-Viro-Particles.
    Johan Toesca, Marion Castell, Clémence Jacquemin, Alexandre Lalande, Eva Ogire, Julien Burlaud-Gaillard, Philippe Roingeard, Christophe Ramière, Cyrille Mathieu, Laure Perrin-Cocon, Vincent Lotteau, Pierre-Olivier Vidalain, Olivier Diaz.
       BACKGROUND & AIMS: Hepatitis C virus (HCV) has the unique characteristic of forming lipo-viro-particles (LVPs), which are lipid-rich virions containing both the viral components and host apolipoproteins such as ApoB and E. This unique composition gives to LVPs a low buoyant density, facilitates their entry into the hepatocyte, and is a hallmark of highly-infectious HCV particles. Although recent studies have shown that inhibiting NAD biosynthesis can both disrupt central carbon metabolism and thereby interfere with the replication of hepatotropic viruses such as dengue virus (DENV) and hepatitis B virus (HBV), the impact of nicotinamide biosynthesis inhibition on HCV replication and LVP formation has not yet been explored.
    METHODS: We therefore investigated the dependance of HCV on NAD(H) biosynthesis in Huh7 cells by using the antimetabolite 6-Aminonicotinamide (6-AN) or by specifically inhibiting NAMPT, a key enzyme in the nicotinamide salvage pathway. The impact on cellular metabolism was assessed by LC-MS/MS to quantify metabolites, by confocal microscopy to analyze lipid droplets and by ELISA for ApoB/E secretion. Glycolytic activity and mitochondrial respiration were evaluated by real-time measurement of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively. Consequences on viral replication were analyzed using both a subgenomic replicon (strain JFH1) and the full-length infectious virus (strain Jc1). The effect of 6-AN on the formation of double-membrane vesicles (DMVs) where the virus replicates was determined transmission electron microscopy. Finally, the secretion and specific infectivity of virions were analyzed by RT-qPCR and titration technics, either before or after separation by density-gradient centrifugation to focus on LVPs.
    RESULTS: Pharmacological inhibition of NAD(H) biosynthesis in Huh7 cells impaired HCV replication, the formation of DMVs and the production of infectious LVPs. Mechanistically, 6-AN drastically inhibited glycolysis but increased oxidative phosphorylation as compensatory mechanism. This metabolic reprogramming was associated with decreased intracellular levels of triglycerides, smaller lipid droplets and reduced secretion of Apo B and E, which altogether could explain the impact of 6-AN on HCV replication and the production of LVPs.
    CONCLUSIONS: Inhibiting NAD(H) biosynthesis disrupts central carbon metabolism, reduces intracellular triglycerides and blocks ApoB ⁺ -lipoprotein secretion-a pathway essential for HCV replication and LVP production. These results reveal, for the first time, that HCV life cycle is critically dependent on NAD(H) metabolism, reinforcing the interest of this pathway as a potential therapeutic target against hepatotropic viruses.
    DOI:  https://doi.org/10.1371/journal.ppat.1014165
  15. J Immunol. 2026 Apr 15. pii: vkag062. [Epub ahead of print]215(4):
    PIM1 kinase-regulated cellular metabolism sustains differentiation and function of effector CD8+ T cells during chronic viral infection.
    Ashley K Brown, Hongshen Niu, Jian Shen, Yuqi Zhang, Pedro A S Vaz de Castro, Moujtaba Y Kasmani, Siying Lin, Paytsar Topchyan, Nikita L Mani, Peter J Volberding, Samuel E Weinberg, Weiguo Cui.
      CD8+ T-cell differentiation during chronic viral infection is supported by metabolic reprogramming to meet distinct bioenergetic demands. Early effector CD8+ T-cell differentiation and function are supported by the PI3K-Akt-mTOR pathway, while the differentiation of late exhausted CD8+ T cells remains incompletely understood. We first characterized the metabolic heterogeneity of the progenitor, effector, and exhausted CD8+ T-cell subsets in chronic infection by utilizing the Compass algorithm, which provides metabolic state predictions based on single-cell RNA sequencing data and flux-based analysis. Our analysis revealed metabolic programs distinct to each subset of virus-specific CD8+ T cells. In addition, it is known that the differentiation of progenitor to effector CD8+ T cells depends on IL-21-producing CD4+ T cells. We found that PIM1 kinase, a known regulator of cellular energy metabolism that functions downstream of IL-21 signaling, displays high gene expression in the effector CD8 T-cell subset. Using the lymphocytic choriomeningitis virus clone 13 model of chronic viral infection, we showed that CD8+ T cell-specific deletion of PIM1 kinase impairs the differentiation and cytolytic function of late effector CD8+ T cells. Furthermore, deficiency in PIM1 kinase reduced oxidative and glycolytic metabolism, potentially contributing to the diminished effector differentiation and function. Overall, these data reveal not only the metabolic heterogeneity of exhausted CD8+ T cells, but also how metabolic regulation through the IL-21-PIM1 axis impacts CD8+ T-cell differentiation.
    Keywords:  CD8 T cells; PIM kinase; metabolism; viral infection
    DOI:  https://doi.org/10.1093/jimmun/vkag062
  16. J Adv Res. 2026 Apr 18. pii: S2090-1232(26)00332-2. [Epub ahead of print]
    Dietary EGCG reshapes metabolic-epigenetic interplay to induce transgenerational host defense.
    Wenqi Huang, Shiye Lin, Xuanyu Zheng, Mohamed A Farag, Thomas Efferth, Jesus Simal-Gandara, Zimiao Chen, Jianbo Xiao, Hui Cao.
       INTRODUCTION: Parental diet is a key determinant of offspring health and immune function, in part through epigenetic regulation. Metabolic and epigenetic networks integrate nutrient sensing with chromatin dynamics to maintain cellular and organismal homeostasis. However, the mechanism by which specific dietary bioactive compounds reshape metabolic-epigenetic networks to drive transgenerational adaptive responses remains poorly understood.
    OBJECTIVES: Here, we investigate whether and how epigallocatechin-3-gallate (EGCG), a well-characterized dietary bioactive compound, modulates heritable host defense through metabolic-epigenetic crosstalk.
    METHODS: To address both physiological relevance and mechanistic insight, we employed mouse and Drosophila melanogaster models. Parental animals were administered EGCG, and offspring were subsequently assessed for immune function upon infection with Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus. By integrating transcriptomics, metabolite analysis, and isotopic tracing, we analyzed metabolism-related pathways and constructed a dynamic network linking metabolic changes to epigenetic modifications in Drosophila.
    RESULTS: In mice, EGCG administration led to a decrease in Escherichia coli burden across multiple tissues in paternal and male offspring in a sex-specific manner, accompanied by metabolic and pro-inflammatory factor changes. In Drosophila melanogaster, early-life EGCG exposure increased survival upon Pseudomonas aeruginosa or Staphylococcus aureus infection and persisted for two subsequent generations. Mechanistically, EGCG reduced intestinal amino acids, thereby moderately inducing activation of activating transcription factor 4 (ATF4), which in turn enhanced maternal glycolysis and immune adaptation. Tyrosine supplementation abolished the enhanced host defense and metabolic changes. Furthermore, ATF4-induced activation of glycolysis promoted ovarian lactate production, serving as a substrate for increased global H3K27 acetylation in the offspring.
    CONCLUSION: Together, these findings suggest that dietary bioactive compounds modulate metabolic and gene regulatory processes, with functional evidence supporting a role for amino acid metabolism and lactate in linking metabolic remodeling to enhanced resistance to infection in the offspring. This work provides mechanistic insight into how diet can shape heritable immune function through metabolic-epigenetic interplay.
    Keywords:  Epigenetics; Flavonoids; Histone acetylation; Host defense; Metabolic reprogramming; Phytotherapy; Transgenerational inheritance
    DOI:  https://doi.org/10.1016/j.jare.2026.04.028
  17. Mol Immunol. 2026 Apr 17. pii: S0161-5890(26)00069-6. [Epub ahead of print]194 63-72
    The role of macrophage metabolic reprogramming in efferocytosis: A dual-edged sword in atherosclerosis and tumor progression.
    Qiaoling Chen, Changyu Liu, Qianhe Wang, Xiaolu Zhang, Yujia Zheng, Maojuan Guo, Jie Wang.
      Macrophage efferocytosis-the process by which macrophages recognize, engulf, and degrade apoptotic cells (ACs)-is essential for maintaining tissue homeostasis and resolving inflammation. Dysregulation of efferocytosis has been implicated in the progression of various diseases, including atherosclerosis (AS) and cancer. In AS, effective efferocytosis reduces inflammation, stabilizes plaques, and slows disease progression. Conversely, in the tumor microenvironment (TME), efferocytosis contributes to immune suppression, supporting cancer cell survival, proliferation, and metastasis. Impaired efferocytosis leads to the accumulation of secondary necrotic ACs, which exacerbate inflammation. Interestingly, in tumors, this process can paradoxically induce pro-inflammatory, anti-tumor immune responses. Therefore, understanding the regulatory mechanisms controlling efferocytosis is critical for the development of targeted therapies for inflammatory diseases and cancer. Recent findings highlight macrophage metabolic reprogramming as a key modulator of efferocytosis. Metabolic pathways, including glycolysis, amino acid metabolism, and fatty acid oxidation (FAO), provide the energy and biosynthetic intermediates necessary for macrophages to execute efferocytosis efficiently. These pathways influence all stages of efferocytosis-recognition, engulfment, and degradation of ACs-while shaping macrophage function and inflammatory responses. Moreover, metabolic adaptations in macrophages exhibit context-specific roles in atherosclerotic plaques and the TME, underscoring the complex and disease-specific effects of efferocytosis in pathological conditions. This review synthesizes current knowledge on the molecular mechanisms underlying efferocytosis and its regulation through macrophage metabolic reprogramming. It discusses how metabolic shifts impact efferocytosis and explores their broader implications in AS and cancer. Understanding the intricate interplay between macrophage metabolism and efferocytosis presents new opportunities for therapeutic intervention, with the potential to transform the clinical management of inflammatory and neoplastic diseases.
    Keywords:  Atherosclerosis; Efferocytosis; Inflammatory; Macrophage; Metabolic Reprogramming; Tumor
    DOI:  https://doi.org/10.1016/j.molimm.2026.04.006
  18. Gut Microbes. 2026 Dec 31. 18(1): 2662638
    Microbial metabolite Enterobactin impairs mitochondrial respiration and alleviates colitis.
    Vinita Kushwaha, Beng San Yeoh, Piu Saha, Benoit Chassaing, Bina Joe, Andrew T Gewirtz, Matam Vijay-Kumar.
       BACKGROUND AND AIMS: Host-microbe interactions critically shape cellular metabolism and immune responses. The bacterial siderophore enterobactin (Ent) is known for pilfering iron from the host, but recent evidence suggests that it may also deliver iron to host mitochondria. Its impact on mitochondrial respiration, however, remains poorly understood. Here, we assess the interplay among Ent, iron, and lipocalin-2 (Lcn2, which sequesters Ent) on mitochondrial function. We also examine the effects of the 2, 3-dihydroxybenzoic acid (2, 3-DHBA), the monomeric derivative of Ent, and the mammalian siderophore 2, 5-DHBA in a murine model of colitis.
    METHODS: Murine bone marrow-derived macrophages (BMDMs) and the human model intestinal epithelial cells (IEC) were treated with Ent, with or without iron or rec-Lcn2, and mitochondrial respiration was assessed via Seahorse XFe96 analyzer. For in vivo study, mice were treated with dextran sulfate sodium (DSS) to induce colitis and administered with 2, 3-DHBA or 2, 5-DHBA.
    RESULTS: Iron-free Ent impaired mitochondrial oxidative phosphorylation in BMDMs and IEC, as evidenced by reduced ATP production and elevated reactive oxygen species. These effects of Ent were mitigated by iron saturation or upon co-administered with rec-Lcn2. Intriguingly, administration of 2, 3-DHBA, but not 2, 5-DHBA, to mice with DSS-induced colitis attenuated inflammation, increased expression of tight junction proteins, preserved epithelial architecture, and promoted mucosal repair. 2, 3-DHBA treatment also enhanced mitochondrial biogenesis, dynamics, and redox balance.
    CONCLUSIONS: Ent in its 2, 3-DHBA form confers mucosal protection, despite its inhibitory effects on mitochondrial respiration. These findings suggest that modulating mitochondrial activity, thus reducing cellular metabolism, may be beneficial during colitis and position 2, 3-DHBA as a promising microbiota-derived metabolite for therapeutic intervention in inflammatory bowel disease.
    Keywords:  Iron chelation; Lipocalin-2; mammalian siderophore; oxidative phosphorylation
    DOI:  https://doi.org/10.1080/19490976.2026.2662638
  19. Ageing Res Rev. 2026 Apr 22. pii: S1568-1637(26)00130-3. [Epub ahead of print] 103138
    Metabolic Reprogramming and Signalling Networks in Microglial Activation: Implications for Neurodegeneration.
    Mohsine-Ali El-Hamri, Oualid Abboussi.
      Microglia, the brain's innate immune cells, undergo a complex activation process characterized by metabolic reprogramming and inflammatory signalling that transcends the classical M1/M2 polarization framework. Recent advances in single-cell technologies have unveiled remarkable microglial heterogeneity, including the emergence of disease-associated microglia (DAM), which play critical roles in neurodegeneration. This study synthesizes recent findings from single-cell transcriptomics, spatial proteomics, and metabolomics to provide an integrated perspective on microglial activation. We focus on the interplay between key metabolic pathways, including glycolysis, the pentose phosphate pathway, and oxidative phosphorylation, as well as inflammatory signalling networks such as NF-κB, HIF-1α, and JAK/STAT, across diverse neurodegenerative conditions. Our synthesis reveals that microglial activation is driven by coordinated metabolic and inflammatory reprogramming, forming self-reinforcing cycles that sustain neuroinflammation. Disease-associated microglia display unique transcriptional profiles distinct from traditional polarization states, with notable regional and sex-specific variations in activation patterns. Crucially, crosstalk between the HIF-1α and NF-κB pathways modulated by metabolic sensors like CARKL underpins persistent inflammatory responses. Additionally, researchers have identified novel neuroprotective mechanisms, including mitochondrial transfer from microglia to neurons via tunnelling nanotubes. Importantly, chronic neuroinflammation in neurodegenerative diseases appears to arise not from persistent microglial activation per se, but from failures in inflammatory resolution. Viewing microglial activation as an integrated metabolic-inflammatory network highlights new therapeutic avenues. While metabolic inhibitors hold conceptual promise, their clinical infeasibility necessitates a paradigm shift toward TREM2 immunomodulators and resolution agonists with established human safety profiles. Strategies targeting metabolic reprogramming, enhancing resolution pathways, and promoting beneficial microglial-neuronal interactions hold promise for treating neurodegenerative disorders. Furthermore, identifying biomarkers of microglial activation states may enable the development of personalized therapeutic approaches.
    Keywords:  Disease-Associated Microglia (DAM); Metabolic Reprogramming; Microglia; Neurodegeneration; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.arr.2026.103138
  20. Life Sci. 2026 Apr 20. pii: S0024-3205(26)00223-7. [Epub ahead of print] 124414
    Omega-3 modulates macrophage immunometabolic profile without changing Pseudomonas aeruginosa proliferation.
    Priscila Vilela Sousa, Evandro Neves Silva, Leonardo Pereira de Araújo, Ana Clara Moreira, Fernanda Silva Carneiro, Yasmin Vieira Braida, Tatiana Teixeira de Miranda, Caio Tavares Fagundes, Lirlândia Pires de Sousa, Leonardo Augusto de Almeida, Patrícia Paiva Corsetti.
      The increasing and often indiscriminate use of medications challenges populations with limited access to effective treatments. Natural compounds such as omega-3 fatty acids (FA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert immunomodulatory effects by incorporating into macrophage membranes and modulating cytokine production and metabolism. This study evaluated the effects of omega-3 FA on inflammatory responses, metabolic reprogramming, and signaling pathways in bone marrow-derived macrophages (BMDMs) infected with Pseudomonas aeruginosa. BMDMs from C57BL/6 mice were pretreated for 3 h with 26 mg DHA and 36 mg EPA, then stimulated with P. aeruginosa (PA14), heat-killed bacteria (HKPA), or lipopolysaccharide (LPS). Omega-3 FA pretreatment reduced pro-inflammatory mediators, including TNF-α, IL-1β, nitric oxide, and NLRP3 expression in macrophages stimulated with PA14, HKPA and LPS, while IL-10 secretion was also reduced under these stimuli. However, omega-3 FA increased IL-10 production under basal conditions. Gene expression analysis revealed upregulation of M2-associated markers (ARG1 and CD206), without changes in the M1 marker iNOS. Metabolic and transcriptional analyses demonstrated downregulation of glycolysis-related genes and upregulation of genes associated with mitochondrial function and lipid metabolism. Omega-3 FA did not alter P. aeruginosa proliferation but increased bacteria phagocytosis. Molecular docking suggested that omega-3 FA interact with key inflammatory targets, including GPR120 and PPARγ. Consistently, pharmacological antagonism of PPARγ reversed the omega-3 FA suppressive effects on TNF-α and IL-1β production and NLRP3 expression. These results indicate that omega-3 FA modulates macrophage immune responses and metabolism during P. aeruginosa infection, promoting an anti-inflammatory, metabolically adapted phenotype without impairing bacterial clearance.
    Keywords:  DHA; EPA; Fatty acids; Immunometabolic regulation; PA14
    DOI:  https://doi.org/10.1016/j.lfs.2026.124414
  21. Redox Biol. 2026 Apr 15. pii: S2213-2317(26)00169-2. [Epub ahead of print]93 104171
    A novel photosensitizer-based photodynamic therapy reprograms the Kynurenine-AhR axis to boost antitumor immunity in breast cancer.
    Yuetong Liu, Ge Hong, Tianjun Liu, Hong Liu.
      Photodynamic therapy (PDT) has emerged as a promising local treatment for breast cancer, with emerging evidence highlighting its potential to modulate the immune response. However, its effects on tumor microenvironment (TME) metabolism remain poorly understood. In this study, we introduce a novel photosensitizer, DTP, which efficiently generates reactive oxygen species and induces apoptosis in breast cancer cells in vitro. In vivo, DTP preferentially accumulates in tumors, significantly inhibiting tumor growth and reducing Ki-67 expression upon 650 nm irradiation. Untargeted metabolomics revealed significant alterations in the tryptophan metabolism pathway following DTP-PDT. Further targeted metabolomic analysis identified a specific reduction in kynurenine (Kyn), an immunosuppressive metabolite, within the tumor. Mechanistically, DTP-PDT reduced indoleamine 2,3-dioxygenase 1 (IDO1)-dependent Kyn production, diminished AhR nuclear localization and decreased AhR transcriptional activity in tumor-infiltrating T cells. This metabolic reprogramming alleviated the immunosuppressive TME, as evidenced by increased infiltration of CD8+ T cells and a reduction in regulatory T cells. Notably, exogenous Kyn partially restored the Kyn-AhR axis and attenuated the immune remodeling induced by DTP-PDT. Building on these immune-activating effects, we combined DTP-PDT with PD-L1 blockade, which significantly suppressed pulmonary metastasis and enhanced central memory T-cell generation, resulting in durable systemic antitumor immunity.
    Keywords:  Breast cancer; Indoleamine 2,3-dioxygenase 1; Kynurenine-AhR axis; PD-L1 blockade; Photodynamic therapy; Tumor immunometabolism
    DOI:  https://doi.org/10.1016/j.redox.2026.104171
  22. Front Immunol. 2026 ;17 1799232
    Glucose metabolic reprogramming in systemic lupus erythematosus and lupus nephritis: theoretical foundations and therapeutic implications.
    Hongyong Su, Le Zhang, Qiaofei Zhang, Lijing Liu, Liping Zhai, Xiaocui Chen, Chen Yang, Ning An, Hua-Feng Liu.
      Lupus nephritis (LN) represents the most severe and frequent complication of systemic lupus erythematosus (SLE), yet its treatment remains a significant unmet clinical need. Recent advances in immunometabolism have revealed that glucose metabolic reprogramming-including shifts in glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle-plays a central role in driving pathogenic immune cell activation in SLE. However, a critical gap persists in understanding how these metabolic alterations specifically operate within the renal microenvironment to promote immune cell infiltration and intrinsic kidney cell injury in LN. This review synthesizes current evidence on the molecular mechanisms linking glucose metabolism to immune dysfunction in innate immune cells including monocytes/macrophages, neutrophils and DCs and adaptive immune cells including T cells, B cells and renal resident cells. We further discuss therapeutic strategies targeting metabolic pathways, including repurposed drugs (metformin, hydroxychloroquine, rapamycin), preclinical small molecules (PKM2, PFKFB3, LDHA, GLUT1 inhibitors), and combination therapies with biologics. Safety considerations, particularly the sensitivity of regulatory T cells (Tregs) to glycolysis inhibition, underscore the need for dose optimization. Finally, we highlight future directions, including real-time metabolic imaging, personalized glycolysis scoring, and spatiotemporal metabolic epigenetic models, which hold promise for advancing precision medicine in LN.
    Keywords:  glucose; glycolysis; immune cells; metabolic reprogramming; systemic lupus erythematosus
    DOI:  https://doi.org/10.3389/fimmu.2026.1799232
  23. Bioact Mater. 2026 Sep;63 484-505
    Polysaccharide-engineered mitochondria reprogram macrophages to resolve diabetic wound inflammation and promote repair.
    Chenyan Yu, Qian Feng, Yuheng Liao, Meijun Tan, Yanzhi Zhao, Lang Chen, Wenqian Zhang, Chuanlu Lin, Ruiyin Zeng, Fawwaz Al-Smadi, Haochen Wang, Longyu Du, Xin Zhang, Ying Hu, Guodong Liu, Zhiyong Hou, Hang Xue, Guohui Liu.
      Chronic diabetic wounds are characterized by persistent inflammation, defective resolution and impaired tissue regeneration, in which macrophage dysfunction and mitochondrial damage play central roles. Here, we developed a macrophage-targeted engineered mitochondrial transplantation system by coating adipose-derived stem cell (ADSC) mitochondria with triphenylphosphonium-modified konjac glucomannan (Mito-TPP-KGM). This design preserves mitochondrial membrane potential and ATP production while reducing ROS generation, and provides a mannose-rich corona for lectin receptor-related uptake. In RAW264.7 macrophages exposed to high glucose plus H2O2 or LPS, Mito-TPP-KGM is efficiently internalized, restores mitochondrial homeostasis, rebalances glycolysis and oxidative phosphorylation, and shifts inflammatory profiles toward a less inflammatory and more reparative phenotype. Engineered mitochondria also restore efferocytosis of apoptotic neutrophil-like cells and enhance the pro-angiogenic capacity of macrophage-conditioned media, thereby improving endothelial tube formation, migration and proliferation. Blocking experiments with mannan and anti-CD206/anti-DC-SIGN antibodies, together with species-specific mtDNA quantification, indicate that mannose-type lectin receptors contribute to the uptake and immunomodulatory effects of Mito-TPP-KGM. In a db/db mouse full-thickness wound model, local delivery of Mito-TPP-KGM promotes wound repair, improves histological healing, reduces oxidative damage, enhances angiogenesis, and modulates wound macrophage phenotype, leading to accelerated wound closure; these therapeutic benefits are partially attenuated by local CD206 blockade. Collectively, these findings demonstrate that polysaccharide-engineered mitochondria can reprogram diabetic wound macrophages via targeted mitochondrial transplantation, offering a promising immunometabolic strategy for chronic wound therapy.
    Keywords:  Diabetic wound healing; Engineered mitochondria; Immunometabolism; Macrophage polarization; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.04.009
  24. Cell Rep. 2026 Apr 21. pii: S2211-1247(26)00372-4. [Epub ahead of print]45(5): 117294
    SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis.
    Guomei Su, Jiangyun Peng, Jingyun Quan, Zhihang Feng, Yu Zhong, Zhilin Xiong, Jiewen Huang, Zhao Zhao, Yingying Lv, Wenhong Hou, Lianxiang Luo, Xiao Li, Yiming Shao, Jielin Duan, Xiao Gao, Tianwen Lai.
      Neutrophilic asthma is a steroid-resistant condition linked to immunometabolic dysregulation. While the NAD+-dependent deacetylase Sirtuin 6 (SIRT6) regulates immune responses, its role in neutrophilic asthma remains unknown. Utilizing multiple human samples and neutrophilic asthma murine model, we identify macrophage SIRT6 as a key regulator that governs airway neutrophil infiltration in severe asthma. Myeloid-specific Sirt6 deletion attenuates allergen-induced airway neutrophil infiltration by suppressing lactate dehydrogenase A (LDHA)-mediated lactate production and neutrophil-recruiting chemokines secretion. Mechanistically, SIRT6 directly interacts with LDHA and deacetylates LDHA at lysine 261 (K261) via SIRT6-N-terminal domain. Lactate accumulation promotes histone H4 lysine 12 (H4K12) lactylation, up-regulating Cxcl1 and Cxcl2 transcription to drive airway neutrophil infiltration. Importantly, we screen flavonoid astragalin as a specific SIRT6 inhibitor that attenuates airway neutrophil infiltration in severe asthmatic mice. Collectively, our findings reveal a critical role of the SIRT6-mediated metabolic reprogramming in neutrophilic asthma and establish SIRT6 as a promising therapeutic target.
    Keywords:  CP: immunology; CP: metabolism; LDHA; SIRT6; lactylation; neutrophilic asthma
    DOI:  https://doi.org/10.1016/j.celrep.2026.117294
  25. Nat Commun. 2026 Apr 23.
    Ketogenic diet exacerbates DSS-induced colitis through a β-hydroxybutyrate-Thomasclavelia spiroformis-γδ17 T cell axis in mice.
    Yameng Liu, Xuan Wu, Li Chen, Shan Wang, Jingyi Xu, Weifeng Wang, Xueting Yao, Wei Xie, Xianchun Zhong, Shuai Li, Yueying Li, Lin Han, Cen Xie, Lei Chen, Frank J Gonzalez, Weiwei Liu.
      Ketogenic diet (KD) is widely recognized for its immunomodulatory and metabolic benefits, but the impact on inflammatory bowel disease remains controversial. Here, we demonstrate that KD maintains homeostasis under physiological conditions but exacerbates colitis by triggering a ketogenesis-microbe-immune cascade upon mucosal injury. Mechanistically, KD elevates luminal β-hydroxybutyrate (β-HB), promoting the expansion of Thomasclavelia spiroformis (T. spiroformis). In turn, T. spiroformis activates colonic γδ17 T cells via cell wall components, ultimately driving IL-17A-mediated iinflammation. Adoptive transfer of γδ17 T cells into Tcrd-/- mice confirmed their pathogenicity. Ketogenesis or IL-17A blockades abolish KD-exacerbated colitis, whereas β-HB supplementation or ketogenesis activation recapitulated disease exacerbation. Clinically, T. spiroformis abundance correlates with fecal β-HB and serum IL-17A in ulcerative colitis (UC) patients, but not Crohn's disease, supporting a UC-specific β-HB-T. spiroformis-γδ17 T cell axis. Thus, we identify a diet-induced immunometabolic circuit linking ketogenesis to colitis, highlighting ketone metabolism and IL-17A signaling as potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-026-72044-0
  26. Nat Microbiol. 2026 Apr 20.
    Salmonella-derived haem inhibits macrophage phagocytosis and promotes infection in mice.
    Zuoqiang Wang, Huang Tang, Wanqiu Huang, Chengyue Wang, Yana Chen, Jingchen Yu, Tao Zhou, Bingjie Wen, Jinjing Ni, Danni Wang, Jing Tao, Siqi Zhu, Lin Lyu, Lei Chen, Jun Li, Qihong Kuang, Daojin Yu, Jianping Liu, Lifeng Pan, Mei Zhang, Yue Xu, Guo-Ping Zhao, Jie Lu, Yu-Feng Yao.
      Bacterial pathogens such as Salmonella enterica serovar Typhimurium can resist phagocytosis by macrophages. Here we explored the role of bacterial haem biosynthesis in phagocytosis resistance. Using transposon sequencing (Tn-seq) during Salmonella infection of macrophages, we identify a methyltransferase, SirM, that indirectly inhibits phagocytosis of bacteria. Mechanistically, sirM is activated upon interaction with macrophages and methylates HemL, a key enzyme in haem biosynthesis, resulting in upregulation of haem synthesis by Salmonella. Salmonella-derived haem inhibits Cdc42 activation in a Toll-like receptor 4 (TLR4)-dependent manner to inhibit phagocytosis. Moreover, sirM promotes macrophage death by increasing haem synthesis. Experiments in mouse models show that sirM is required for virulence and confers a competitive advantage over intestinal commensal bacteria during infection. We also found that sirM is distributed among enteric pathogens. Collectively, our findings show that bacterial haem promotes evasion of phagocyte responses and pathogenesis to confer an advantage in the host.
    DOI:  https://doi.org/10.1038/s41564-026-02341-3
  27. Cell. 2026 Apr 17. pii: S0092-8674(26)00340-5. [Epub ahead of print]
    B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.
    Youxiang Mao, Ziyan Xia, Xu Pan, Wenjun Xia, Peng Jiang.
      B cells are an essential component of humoral immunity, and B cell depletion therapies have clinically succeeded in eliminating cancerous B cells and treating autoimmune diseases. Here, we report an immune-independent function of B cells that spatially and metabolically drives exercise capacity. During exercise, B cell deficiency reduces transforming growth factor (TGF)-β1 production, which alters hepatic glutamate metabolism and decreases blood and muscle glutamate. Mechanistically, B cell-derived TGF-β1 transcriptionally upregulates hepatic glutaminase 2 (GLS2) and solute carrier family 7 member 5 (SLC7A5) expression, increasing glutamine catabolism and thus glutamate production in the liver. The resulting increase in glutamate fosters skeletal muscle calcium oscillations, calmodulin-dependent protein kinase (CaMK) kinase activity, and mitochondrial biogenesis, thereby improving exercise performance. Thus, we identify a metabolite-driven liver-muscle connection that regulates exercise capacity, linking B cell function to skeletal muscle calcium signaling via alteration of hepatic glutamate metabolism.
    Keywords:  B cells; TGF-β1; exercise capacity; hepatic glutamate metabolism; immune-independent regulation; immunoexercise; skeletal muscle function; transforming growth factor
    DOI:  https://doi.org/10.1016/j.cell.2026.03.039
  28. Cancer Sci. 2026 Apr 20.
    Multifunctional Role of Mitochondrial Fatty Acid Oxidation in Cancer Immunotherapy and Aging.
    Koji Kitaoka, Shuhei Hirose, Yu Wang, Tomonori Yaguchi, Kenji Chamoto.
      Recent studies have demonstrated the intricate relationship between tumor immunity, aging, and inflammation. Mitochondrial activity is one of the major connection hubs of this physiological interplay. Fatty acid oxidation (FAO) is a center of the mitochondrial metabolic pathway and plays a pivotal role in maintaining cellular homeostasis. Dysfunction in mitochondrial FAO leads to an accumulation of reactive oxygen species (ROS), contributing to oxidative stress and chronic inflammation. This persistent inflammatory stress not only accelerates aging but also impairs immune surveillance, facilitating tumor progression. Modulation of mitochondrial FAO reprograms the metabolism of tumor-infiltrating lymphocytes and macrophages, thereby impacting anti-tumor immunity. Understanding these interconnected pathways offers potential therapeutic avenues to enhance cancer immunotherapy and mitigate inflammation.
    Keywords:  T cell exhaustion; T cell senescence; glycolysis; mitochondrial morphology; oxidative stress
    DOI:  https://doi.org/10.1111/cas.70388
  29. Front Immunol. 2026 ;17 1776694
    Immunometabolic remodeling: new perspectives and strategies for liver transplantation.
    Longbo Wang, Xiyang Sheng, Gengyuan Shi, Yongzhao Li, Dongdong Wang, Wei Wang, Chen Mi, Siyang Wang, Yongyue Du, Hanteng Yang.
      Liver transplantation (LT) has become the optimal therapeutic strategy for end-stage liver disease. Beyond chronic conditions, acute liver failure (ALF) and the emerging field of transplant oncology have also become critical indications for LT. It is important to note that the systemic and local immunometabolic states in these specific pathologies may differ significantly from those in traditional end-stage liver disease, presenting unique challenges for immune management. With advancements in surgical techniques and perioperative management, the long-term survival rates of patients have significantly improved. However, extended patient survival and an expanding donor pool have unmasked long-term complications such as post-transplant metabolic syndrome (PTMS). Furthermore, the patient's systemic metabolic state influences both the metabolism of immune cells and the utilization of immunosuppressants, posing severe challenges to patient management. Studies indicate that following liver transplantation, distinct immune cells undergo dynamic adaptive changes in energy metabolism, which directly determine the outcomes of rejection, ischemia-reperfusion injury (IRI), and immune tolerance. This review systematically elucidates the mechanisms of immune cell metabolic remodeling. Furthermore, it explores the translational prospects of targeting immunometabolic pathways to optimize immunosuppressive regimens, mitigating IRI, and establish non-invasive biomarkers for immune monitoring, ultimately providing new insights for improving the long-term outcomes of liver transplant recipients.
    Keywords:  immune tolerance; immunometabolism; ischemia-reperfusion injury; liver transplantation; metabolic remodeling; post-transplant metabolic syndrome
    DOI:  https://doi.org/10.3389/fimmu.2026.1776694
  30. Comput Methods Programs Biomed. 2026 Apr 15. pii: S0169-2607(26)00136-7. [Epub ahead of print]281 109371
    Decoupling lactylation-associated metabolic remodelling in Asthma: Integrated multi-omics and machine learning identify RCC2 as a potential therapeutic target.
    Yubin Feng, Shuqing Zhou, Jiayao Xu, Lianxiang Luo.
       BACKGROUND: Aerobic glycolysis promotes lactate accumulation and histone lactylation (Kla), yet the cell-type-specific distribution of this axis and its link to metabolically stratified intercellular signalling in asthma remain poorly defined. We aimed to map lactate/Kla-associated metabolic states across airway lineages and develop an interpretable Lactate Metabolic Biomarker Diagnosis (LMBD) framework.
    METHODS: By integrating bulk transcriptomes (training: GSE63142; validation: GSE43696) and scRNA-seq (GSE193816), we quantified lactate metabolic activity via four gene sets and 114 metabolic pathways. We identified metabolic subtypes using consensus clustering and trained a Gaussian-mixture-model-guided logistic regression classifier with external validation. Mechanistic insights were inferred through CellChat and Monocle2, followed by functional validation of RCC2 in house dust mite (HDM)-stimulated 16HBE cells using siRNA knockdown, lactate quantification, Pan-Kla immunofluorescence, and untargeted LC-MS metabolomics.
    RESULTS: Asthma exhibited a macrophage-predominant high-lactate state. We identified a disease-associated macrophage module (Epi1) and two metabolic subtypes, in which the high-lactate group (MBC2) displayed stronger inflammatory transcriptional programs. The LMBD classifier consistently outperformed single-pathway models in the external validation cohort (AUC = 0.799), with RCC2 emerging as the top-ranked feature. Trajectory analysis linked RCC2 to terminal epithelial remodelling. Functional assays demonstrated that RCC2 knockdown significantly reduced intracellular lactate levels, suppressed the expression of glycolysis-associated proteins, and attenuated Pan-Kla signals. Metabolomics further revealed coordinated shifts in redox balance and glycerophospholipid metabolism following RCC2 depletion.
    CONCLUSION: This integrative study delineates lactate/Kla-associated metabolic remodelling in asthma. The LMBD framework offers a robust transcriptomic proxy for metabolic and inflammatory patient stratification, and RCC2 emerges as a candidate regulatory hub linking glycolysis to epigenetic remodelling, thus warranting further investigation in vivo and in clinical cohorts.
    Keywords:  Asthma; Lactylation; RCC2
    DOI:  https://doi.org/10.1016/j.cmpb.2026.109371
  31. Cell Rep Med. 2026 Apr 22. pii: S2666-3791(26)00182-5. [Epub ahead of print] 102765
    Nano-granulated zoledronate sensitizes innate immune metabolism to enhance vaccine-induced and antitumor immunity.
    Meifang Chen, Xiaojia Jiao, Zhicheng Yan, Yueheng Wang, Jing Zhang, Qinghua Wu, Minghui Li, Shumin Fan, Yuan Wang, Wenbing Dai, Hua Zhang, Xueqing Wang, Qiang Zhang, Bing He.
      Metabolic reprogramming targeting the mevalonate pathway represents an emerging innate immune activation target. However, its regulatory mechanisms remain incompletely elucidated. Here, we target the mevalonate pathway and construct a nano-granulated zoledronate (Nano-ZD) modulator. Following subcutaneous injection, Nano-ZD preferentially accumulates in draining lymph nodes rather than in bone tissues, enabling targeted delivery to innate immune cells. Nano-ZD functions as an immune-metabolic adjuvant, sensitizing and amplifying immune responses. By integrating Nano-ZD with the TLR4 agonist monophosphoryl lipid A (MPLA), MPLA-loaded Nano-ZD (Nano-ZDM) elicits robust humoral and antitumor cellular immunity. Mechanistically, Nano-ZD not only inhibits the isoprenylation of RhoA GTPases but also reduces coenzyme Q (CoQ) biosynthesis. CoQ deficiency disrupts oxidative phosphorylation (OXPHOS) and pyrimidine metabolism, causes mitochondrial ROS accumulation, induces mitochondrial antiviral protein (MAVS) oligomerization, and activates the pyrin inflammasome. This mevalonate-CoQ-OXPHOS/pyrimidine metabolism axis serves as a promising target for screening additional immune-metabolic adjuvants, and nanofabrication offers a paradigm for the lymph-targeted in vivo delivery of such adjuvants.
    Keywords:  bisphosphonate; innate immunity; metabolic regulation; nano-adjuvants; the mevalonate pathway
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102765
  32. FASEB J. 2026 Apr 30. 40(8): e71753
    Lactate Activates TGF-β/SNAIL Signaling to Drive M2 Macrophage Polarization and CD8+ T Cell Exhaustion in Breast Cancer.
    Peiling Zhu, Zhisheng Tian, Ying Wang, Haiying Liao, Zehui Mi.
      This study demonstrates that lactate promotes M2-like macrophage polarization by activating the TGF-β/SNAIL signaling axis, thereby weakening CD8+ T cell-mediated antitumor immunity and promoting breast cancer progression. In vitro experiments using bone marrow-derived macrophages (BMDMs) and THP-1 cells treated with 25 mM lactate revealed a marked increase in M2 markers (CD206, Arg-1, IL-10) and a reduction in M1 markers (iNOS, TNF-α, IL-12), confirmed by Western blotting and flow cytometry. RNA-Seq analysis identified TGF-β/SNAIL pathway activation, with increased TGFBR1/2 expression, Smad2/3 phosphorylation, and PI3K/AKT pathway enrichment. Functional studies revealed that lactate-polarized M2 macrophages impaired CD8+ T cell cytotoxicity (reduced IFN-γ, GzmB, PRF1; elevated PD-1, Tim-3) and disrupted mitochondrial metabolism. In vivo validation using a breast cancer xenograft model showed that lactate treatment increased tumor growth and angiogenesis (VEGF/CD31+), while TGF-β inhibition (SB431542) reversed these effects. Mechanistically, lactate-induced TGF-β/SNAIL signaling promoted EMT in cancer cells and created an immunosuppressive TME. These findings establish lactate as a critical metabolic regulator that coordinates macrophage polarization and T cell exhaustion through the TGF-β/SNAIL axis, highlighting this pathway as a promising therapeutic target for breast cancer immunotherapy.
    Keywords:  CD8+ T Cells; M2 polarization; SNAIL; breast cancer; lactate; transforming growth factor‐beta
    DOI:  https://doi.org/10.1096/fj.202502538RR
  33. Signal Transduct Target Ther. 2026 Apr 23. pii: 148. [Epub ahead of print]11(1):
    Macrophage metabolic reprogramming by vanadium released from glucose-responsive bio-gel accelerates diabetic wound repair.
    Jiangfeng Li, Zheng Li, Lili Han, Na Xu, Jiezhi Jia, Ao Hu, Yu Chen, Chang Liu, Xiaorong Zhang, Wei Zhu, Yunlong Yu, Gaoxing Luo.
      Dysregulated glucose metabolism in diabetic wound macrophages impairs polarization toward the reparative M2 phenotype, leading to compromised innate immunity, chronic inflammation, and delayed wound healing. However, effective strategies to restore macrophage metabolic function remain limited. Here, inspired by vanadium's potential to modulate glucose metabolism and the immunomodulatory properties of bioactive glasses, we developed vanadium-doped mesoporous bioactive glass nanospheres (V-MBG) to regulate macrophage-mediated inflammation in diabetic wounds. V-MBG reprogrammed the metabolic environment, promoted M2 polarization, suppressed inflammation, and significantly enhanced wound healing in diabetic models. Mechanistically, V-MBG remodeled the glycolysis-dependent energy pathway in LPS-stimulated M1 macrophages by enhancing glucose-driven oxidative phosphorylation (OXPHOS). This metabolic shift was mediated by activation of the INSR-PI3K signaling axis, which increased glucose uptake and rescued tricarboxylic acid (TCA) cycle suppression. Furthermore, V-MBG-induced citrate/acetyl-CoA metabolism contributed to M2 polarization. To achieve responsive and sustained delivery, V-MBG was incorporated into glucose-sensitive GCP hydrogels, which further accelerated wound repair by enhancing M2 macrophage polarization and mitigating inflammation. Our findings demonstrate that V-MBG is a metabolically active nanomaterial capable of reprogramming macrophage energy metabolism to improve diabetic wound regeneration. This work offers new insight into immune-metabolic regulation via material design and establishes a promising vanadium-based strategy for clinical diabetic wound therapy.
    DOI:  https://doi.org/10.1038/s41392-026-02647-y
  34. Biomater Sci. 2026 Apr 24.
    MOF-based arginine nanocarriers for coordinated immunometabolic and antitumor modulation in triple negative breast cancer.
    Amir M Alsharabasy, Aibhe Boran, Roberto González-Gómez, Harry Revill, Abhay Pandit, Pau Farràs.
      L-Arginine (L-Arg) is a key immunometabolite and nitric oxide (˙NO) precursor with therapeutic potential in cancer and immunotherapy. However, its clinical application is hindered by poor bioavailability and uncontrolled dosing. Here, two distinct metal-organic frameworks (MOFs), NH2-MIL-125(Ti) and MOF-808(Zr), were engineered as nanocarriers for L-Arg to enable coordinated tumour-immune modulation in triple-negative breast cancer (TNBC). L-Arg loading and release were systematically characterized, followed by Seahorse metabolic flux, flow cytometry, live-cell imaging, and wound healing assays to evaluate biological effects in activated human T cells and inducible nitric oxide synthase (iNOS)-transduced MDA-MB-231 cells. Both MOFs demonstrated successful L-Arg encapsulation with distinct release kinetics. In activated CD4+ T cells, Arg-loaded MOFs induced profound metabolic reprogramming independent of detectable ˙NO production. MOF-808-Arg enhanced oxidative phosphorylation and preserved spare respiratory capacity, while NH2-MIL-125-Arg triggered hypermetabolism characterized by elevated proton leak and loss of respiratory reserve, mimicking high-dose L-Arg stress. In contrast, in iNOS-expressing MDA-MB-231 cells, both MOFs increased intracellular ˙NO levels, resulting in reduced viability and inhibited migration. These findings demonstrate that controlled arginine delivery exerts dual and context-dependent effects, coupling ˙NO-mediated tumour cytotoxicity with ˙NO-independent enhancement of T-cell metabolic fitness. Overall, this work establishes MOF-based nutrient delivery as a strategy that integrates redox-based gasotransmitter therapy with immunometabolic reprogramming, highlighting the importance of carrier-dependent release kinetics in shaping both tumour and immune cell responses in metabolically hostile cancers such as TNBC.
    DOI:  https://doi.org/10.1039/d6bm00195e
  35. Mol Nutr Food Res. 2026 Apr;70(8): e70475
    Phagocytosis of Primary Human Macrophages is Elevated by Ex Vivo Supplementation with n-3 PUFA.
    Rebecca Kirchhoff, Michel André Chromik, Nils Helge Schebb.
      Epidemiologic studies show that a high n-3 polyunsaturated fatty acid (PUFA) status is beneficial for health and inflammatory diseases. However, results of nutrition studies investigating the impact of n-3 PUFA intake on immune functions, such as phagocytosis are contradictory. In order to gain more insights into the role of n-3 PUFAs on phagocytosis, we investigated the modulation of phagocytosis by n-3 PUFAs and derived oxylipins in human macrophages. Using an established ex vivo supplementation strategy, primary human macrophages were supplemented with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The PUFA pattern of the cells was shifted from a low n-3 PUFA status towards a high n-3 PUFA status. This was accompanied by a shift in the oxylipin pattern, reduced pro-inflammatory prostaglandin levels, increased phagocytosis in the supplemented macrophages, and reduced inhibitory effect of PGE2 on phagocytosis. However, when tested alone, n-3 PUFA derived oxylipins did not impact phagocytosis. Under controlled conditions, an increased n-3 PUFA status of macrophages resulted in an elevation of phagocytosis. Less formation of prostaglandins could contribute to this effect, whereas n-3 PUFA derived oxylipins, particularly multihydroxy PUFAs, appear to have a limited impact on phagocytosis following n-3 PUFA supplementation.
    Keywords:  COX; DHA; EPA; arachidonic acid cascade; inflammation; lipid mediators; omega‐3 fatty acids; oxylipins; prostaglandins
    DOI:  https://doi.org/10.1002/mnfr.70475
  36. J Innate Immun. 2026 Apr 20. 1-41
    Insights into neutrophil dysfunction in inherited metabolic disorders.
    Anja Wolf, Giulia Montanelli, Déborah Mathis, Andrea Felser, Alexander Lämmle, Jean-Marc Nuoffer, Matthias Gautschi, Carole Bourquin, Darko Stojkov.
       BACKGROUND: Inherited metabolic disorders (IMDs) often manifest with defects in neutrophil development, function, or survival, resulting in recurrent severe infections and elevated morbidity. Although neutropenia and immunodeficiency are frequently underrecognized, they are central to the clinical course of several IMDs.
    SUMMARY: Advances in human genetics and immunometabolism have elucidated the multifaceted mechanisms linking metabolic abnormalities to impaired innate immunity. This review provides a comprehensive analysis of current understanding regarding the pathophysiology, clinical presentation, and management of IMDs with prominent neutrophil involvement, including glycogen storage disease type Ib (GSD-Ib), glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, glucose-6-phosphate dehydrogenase (G6PD) deficiency, glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1DS1), propionic acidemia (PA), methylmalonic acidemias (MMA), and Barth syndrome (BTHS). We discuss how impaired glucose metabolism, redox imbalance, and disrupted mitochondrial metabolism undermine neutrophil homeostasis and effector function, resulting in increased susceptibility to infections, failure to thrive, and, in some cases, life-threatening inflammatory complications. Emerging therapies, ranging from dietary metabolic or pharmacological interventions to experimental gene therapies, are reshaping clinical management of IMDs.
    KEY MESSAGE: Rare IMDs involving neutrophil dysfunction reveal essential links between metabolism, intracellular trafficking, and innate immunity. Molecular diagnosis is crucial for guiding targeted treatments, preventing infectious complications, and improve outcomes. Defining the precise immunometabolic disturbance in these diseases not only advances clinical care but also deepens our understanding of neutrophil biology in broader infectious and inflammatory contexts.
    DOI:  https://doi.org/10.1159/000552119
  37. JCI Insight. 2026 Apr 09. pii: e199622. [Epub ahead of print]
    Inhibition of calpain-mediated HMGB1 alleviates cardiac inflammation and dysfunction induced by ultra-processed foods.
    Claire Ross, Sanskruti Ravindra Gare, Nasser H Alatawi, Oveena Fonseka, Xinyi Chen, Jiayan Zhang, Yihua Han, Andrea Ruiz-Velasco, Riham Re Abouleisa, Yingjuan Liu, Xiangjun Zhao, Han Xiao, Bernard Keavney, Gareth J Howell, Tao Wang, Tamer Ma Mohamed, Elizabeth J Cartwright, Wei Liu.
      Increased consumption of ultra-processed foods (UPFs) is a risk factor for metabolic disorders-associated heart failure (HF). Here, we demonstrate that UPF-induced calpain-1 aggravated oxidative stress, thereby increasing high mobility group box 1 (HMGB1)-mediated myocardial inflammation, which contributes to cardiac dysfunction. After illustrating the dysregulated inflammatory pathways in human and murine hearts upon metabolic stress, we revealed an increase in calpain-1 alongside profound oxidative stress and inflammation in the failing myocardium. Mechanistically, in neonatal rat cardiomyocytes (NRCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), HMGB1 was upregulated by calpain-1 and reactive oxygen species (ROS) upon stress of saturated and trans fatty acids (FA). Consequently, HMGB1 promoted a pro-inflammatory response in macrophages. On the contrary, inhibition of calpain or ROS efficiently repressed HMGB1 in cardiomyocytes. Therapeutically, either recombinant adeno-associated virus 9 (AAV9) delivered inhibitor of calpain-1 or its pharmacological inhibitor attenuated ROS and HMGB1-induced inflammation in the myocardium and mitigated HF in both male and female mice fed with an ultra-processed diet (UPD). Collectively, we have demonstrated the effects of suppressing calpain-1 and oxidative stress on alleviating myocardial inflammation via blockage of HMGB1 and cardiac dysfunction. The results provide a promising therapeutic strategy for preventing or treating HF in metabolic disorders.
    Keywords:  Cardiology; Diabetes; Heart failure; Inflammation; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.199622
  38. Pharmacol Res. 2026 Apr 21. pii: S1043-6618(26)00118-0. [Epub ahead of print] 108203
    AXL prevents amyloid-β-induced microglial ferroptosis by sustaining SLC2A3-mediated mitochondrial respiration.
    Shuai Liu, Chunjie Yang, Ningjun Zhang, Lin Xiang, Fei Li, Lifengrong Qi, Xiaojun Xu.
      Dysregulated iron metabolism is a pivotal driver of Alzheimer's disease (AD). Excess iron promotes Aβ aggregation and tau hyperphosphorylation, thereby accelerating disease progression. Serving as the primary iron reservoir in the central nervous system, microglia are intrinsically susceptible to ferroptosis, thereby amplifying neurotoxicity to neighboring neurons. While plaque-associated receptors (e.g., TREM2, AXL, MERTK) govern microglial responses, their precise contribution to metabolic susceptibility to ferroptosis remains elusive. Here, we identify the receptor tyrosine kinase AXL as a critical metabolic safeguard against Aβ-induced ferroptosis in microglia. Mechanistically, our findings indicate that, under our experimental conditions, oAβ exposure is associated with downregulation of AXL in microglia, thereby impairing SLC2A3-dependent glucose uptake and mitochondrial ATP production, which ultimately increases ferroptotic vulnerability. Moreover, through an optimized surface plasmon resonance imaging (SPRi) screening approach, we identified the FDA-approved drug levothyroxine (L-T4) as a potent AXL agonist. L-T4 treatment restores microglial homeostasis, inhibits Aβ-induced ferroptosis, and ameliorates neuropathology in vivo. These findings establish AXL as a novel metabolic safeguard in microglia and highlight L-T4 as a promising therapeutic strategy for AD and other ferroptosis-related disorders via drug repurposing.
    Keywords:  AXL; Alzheimer’s disease; SLC2A3; ferroptosis; levothyroxine sodium; microglia
    DOI:  https://doi.org/10.1016/j.phrs.2026.108203
  39. Chin Med. 2026 Apr 24. pii: 121. [Epub ahead of print]21(1):
    Qinggan Jianpi formula attenuates atherosclerosis by suppressing macrophage lactate transport to activate repair genes via H3K18 lactylation.
    Xuefeng Zhuang, Rui Zhang, Jiatong Sun, Wenli Song, Jing Wang, Yvna Han, Jinji Wang, Hongzhu Chen, Zhijie Zhu, Weijia Liu, Lijing Li.
       BACKGROUND: Atherosclerosis (AS) is a complex vascular disease characterized by lipid accumulation, chronic inflammation, and immune dysregulation. Qinggan Jianpi Formula (QGJP), a traditional Chinese medicinal preparation, is widely used for treating lipid metabolism disorders. However, the mechanisms of action and active components remain unclear. These uncertainties restrict its clinical use and necessitate systematic research to clarify them. This study aims to investigate the therapeutic effects of QGJP on AS and to elucidate the role of suppressing macrophage M1 polarization in this process, mediated by the regulation of lactate transport and the promotion of histone lactylation.
    METHODS: In this study, first, major chemical components of QGJP were identified via UHPLC-HRMS. We employed a high-fat diet (HFD) fed ApoE⁻/⁻ C57BL/6 mice to establish an AS model, along with in vitro models of ox-LDL-induced lipid injury in HUVECs and ox-LDL-induced foam cell formation in THP-1, followed by QGJP treatment. We elucidated the therapeutic effects and underlying mechanisms of QGJP in AS through multiple approaches, including protecting endothelial cells and regulating macrophage polarization.
    RESULTS: QGJP significantly reduced blood lipids, modulated plaque lipid and collagen content, and alleviated aortic pathological damage in AS mice. Moreover, QGJP downregulated the expression of matrix metalloproteinases, adhesion molecules, and chemokines, enhanced endothelial migration capacity, and inhibited monocyte-endothelial adhesion. Further analysis of macrophage polarization phenotypes revealed that QGJP significantly modulated their polarization state. Mechanistically, QGJP suppressed the expression of key glycolytic enzymes while promoting that of FH. Consequently, it reversed the increase in glycolytic activity observed in macrophages during atherosclerosis. Furthermore, QGJP regulated lactate transport by suppressing MCT4 expression. This modulation orchestrated histone H3K18 lactylation, which in turn activated repair-related gene programs in macrophages. Through UHPLC-HRMS analysis, 47 bioactive constituents of QGJP were identified. Experimental validation confirmed that SAA, LA, and CAB effectively inhibited M1 macrophage polarization and activated the expression of proteins related to reparative genes.
    CONCLUSIONS: This study establishes the critical role of metabolic reprogramming and epigenetic regulation in AS progression. Our findings suggest that a mechanism whereby QGJP alleviates AS may involve the inhibition of the HIF-1α/MCT4 axis and lactate transport, which regulates histone H3K18 lactylation to promote a reparative macrophage phenotype.
    Keywords:  Atherosclerosis; H3K18la; Lactate; Macrophage; Metabolic reprogramming
    DOI:  https://doi.org/10.1186/s13020-026-01394-0
  40. JCI Insight. 2026 Apr 23. pii: e199449. [Epub ahead of print]
    TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis.
    Fei Li, Niv Vigder, David R Ziehr, Mari Kamiya, Hung N Nguyen, Diana E Ferreyra Faustino, Aseel H Khalil, Hilaire C Lam, Matthew L Steinhauser, Edy Y Kim, William M Oldham.
      Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by aberrant fibroblast-to-myofibroblast differentiation, which requires metabolic reprogramming. Here, we identify alanine as an essential metabolite for myofibroblast differentiation. Transforming growth factor-β1 (TGF-β) increases intracellular alanine levels through enhanced synthesis and import in both normal and IPF lung fibroblasts. Alanine synthesis is primarily mediated by glutamate-pyruvate transaminase 2 (GPT2), whose expression is regulated by the glutamine-glutamate-α-ketoglutarate axis. Inhibition of GPT2 depletes alanine and suppresses TGF-β-induced α-SMA and COL1A1 expression, which are rescued by exogenous alanine. We also identify solute carrier family 38 member 2 (SLC38A2) as a transporter for both alanine and glutamine, upregulated by TGF-β or alanine deprivation. SLC38A2 and GPT2 form a coordinated regulatory axis sustaining intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency impairs glycolytic flux and depletes tricarboxylic acid cycle intermediates, while alanine supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly under glutamine deprivation. Combined inhibition of alanine synthesis and uptake suppresses fibrogenic responses in fibroblasts and human precision-cut lung slices, highlighting dual metabolic targeting as a potential therapeutic strategy for fibrotic lung disease. .
    Keywords:  Amino acid metabolism; Cell biology; Fibrosis; Metabolism; Metabolomics; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.199449
  41. Trends Immunol. 2026 Apr 23. pii: S1471-4906(26)00095-5. [Epub ahead of print]
    Proteasome-haem-BACH2 axis fuels T cell exhaustion.
    Jiajia Wang, Ziyi Luo, Haitao Shen, Lianjun Zhang.
      It remains unclear how mitochondrial stress instructs the transcriptional programme of terminal T cell exhaustion. In a recent study, Xu et al. uncovered a proteasome-haem-BACH2 axis in which haem liberated from damaged mitochondrial haemoproteins acts as a molecular messenger that couples mitochondrial injury to terminal T cell exhaustion.
    Keywords:  BACH2; T cell exhaustion; mitochondrial stress; proteostasis; regulatory haem
    DOI:  https://doi.org/10.1016/j.it.2026.04.002
  42. iScience. 2026 Apr 17. 29(4): 115415
    TREM2 sustains glucose metabolic homeostasis to drive antibacterial defense during sepsis.
    ZeHua Wu, XueKe Wang, YiChao Ren, LiHua Shen, YiHang Pan, Yan Zhang, JiaQian Fan, Qiang Shu, Xiangming Fang, QiXing Chen.
      Metabolic disturbances, particularly glucose imbalances, are common in sepsis and are strongly associated with increased mortality. However, the mechanisms underlying glucose dyshomeostasis remain poorly understood. Here, we revealed the role of triggering receptor expressed on myeloid cells 2 (TREM2) in regulating glucose metabolism during sepsis. Macrophage-specific TREM2 deficiency significantly increased the level of abdominal IL-1β, which is predominantly released by pyroptotic peritoneal macrophages. IL-1β then acts on IL-1R1 receptors on pancreatic islet β-cells, promoting insulin release and inducing hypoglycemia. Transfusing TREM2-overexpressing macrophages and administering glucose solutions can restore glucose homeostasis and improve sepsis outcomes in mice. In summary, our study reveals a mechanism by which TREM2 orchestrates glucose metabolism during sepsis and highlights the potential of TREM2 as a therapeutic target for sepsis.
    Keywords:  immunology; microbiology; molecular physiology
    DOI:  https://doi.org/10.1016/j.isci.2026.115415
  43. Metabol Open. 2026 Jun;30 100466
    Bridging exercise biology and immunometabolism: A novel irisin pathway toward next-generation metabolic and neurodegenerative therapies.
    Maria Dalamaga.
      Recent work by Mu et al. identifying irisin as a modulator of adipose tissue IL-33 and regulatory T cells introduces a new paradigm in immunometabolic biology, shifting attention from thermogenesis alone toward immune-stromal crosstalk as a determinant of metabolic health. By inducing IL-33 production in adipose mesenchymal stromal cells, irisin preserves ST2+ regulatory T cells (Tregs) in visceral adipose tissue, thereby restraining inflammation, improving insulin sensitivity, and promoting metabolic homeostasis. This mechanism expands the concept of exercise-induced metabolic protection by highlighting adipose tissue immune niches as critical targets of myokine action. In parallel, emerging evidence from preclinical models indicates that irisin-driven IL-33 signaling in subcutaneous adipose tissue contributes to thermogenic activation through mechanisms distinct from Treg-mediated immune regulation, highlighting depot-specific effects of this pathway. Beyond adipose tissue, irisin has emerged as a pleiotropic mediator with reported roles in glucose homeostasis, cardiovascular protection, and neurobiology. Importantly, accumulating evidence indicates that irisin may also exert neuroprotective effects, including the induction of brain-derived neurotrophic factor (BDNF), amyloid-β (Aβ) clearance, and α-synuclein degradation, thereby linking metabolic and neurodegenerative pathways. Although the findings of Mu et al. derive from preclinical models, they provide a conceptual model for therapeutic strategies aimed at reproducing selected benefits of exercise in obesity, metabolic and neurodegenerative disorders. Notably, these effects appear to depend on sustained irisin exposure in preclinical systems, supporting a role for irisin as a regulator of long-term immunometabolic homeostasis. Collectively, these observations position the irisin/IL-33/Treg axis as a promising link between exercise, adipose tissue immunity, and systemic metabolic regulation, suggesting that targeting immunometabolic circuits, rather than energy balance alone, may open new avenues for future therapeutic intervention.
    Keywords:  Adipose tissue; Exercise mimetics; IL-33; Immunometabolism; Insulin resistance; Irisin; Neurodegenerative disorders; Obesity; Regulatory T cells
    DOI:  https://doi.org/10.1016/j.metop.2026.100466
  44. Cent Eur J Immunol. 2025 ;50(4): 341-352
    Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance.
    Xiaohan Jin, Jinglong Tao.
      Autoimmune diseases are severe disorders that affect populations worldwide. Their occurrence is considered to be multifactorial: genetic, hormonal and immunological factors all contribute to the development of autoimmune diseases. CD4 T cells differentiate into different subtypes, among which Th17 and Treg cells are the two most important in regulation of immune response balance. The Th17/Treg equilibrium is crucial in the pathogenesis of autoimmune diseases. Glutamate, an excitatory neurotransmitter in the nervous system, induces multiple effects. It activates normal T cells, enhancing cell adhesion, migration, secretion and gene expression. However, the effect of glutamate on T cell fate remains unclear. Here, we found that glutamate promotes Treg differentiation but suppresses Th17 differentiation. Further results showed that the rate-limiting enzyme of glutamate metabolism, glutaminase (GLS), is the key regulator for Treg cell generation. These findings suggest that GLS-mediated glutamate metabolism is critical for Treg cell differentiation, and may represent a potential therapeutic target for autoimmune disease.
    Keywords:  Th17; Treg; autoimmune; glutaminase; glutamine
    DOI:  https://doi.org/10.5114/ceji.2025.155429
  45. Cytokine. 2026 Apr 18. pii: S1043-4666(26)00050-5. [Epub ahead of print]203 157155
    Host adenosine deaminase reprograms purinergic immunoregulation in Leishmania braziliensis infection.
    Wesley Lima de Paula, Geovanna Medeiros de Oliveira, Fátima Ribeiro-Dias, Rodrigo Saar Gomes.
      Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by intense inflammation that contributes both to parasite control and tissue pathology. Purinergic signalling, particularly mediated by adenosine and its receptors, has been implicated in immune modulation during Leishmania infection, yet its functional relevance in L. braziliensis remains poorly defined. Here, we investigated the roles of adenosine A2A and A2B receptors and adenosine deaminase (ADA) in regulating immune responses during L. braziliensis infection. Transcriptomic analyses of human CL lesions revealed increased expression of ADORA2A, which paradoxically correlated positively with pro-inflammatory and microbicidal gene signatures. Despite modulating the receptor expression on L. braziliensis-infected macrophages as well, pharmacological inhibition of A2A or A2B receptors did not affect parasite burden, reactive oxygen species (ROS) production, or inflammatory cytokine release. Thus suggesting that adenosine receptor signalling is dispensable in this context. In contrast, ADA and ADA2 were markedly upregulated in CL lesions and infected macrophages and showed strong positive correlations with inflammatory mediators. Functional inhibition of ADA with pentostatin significantly increased intracellular parasite load and reduced ROS, TNF-α, and IL-1β production, demonstrating a critical role for ADA in sustaining macrophage microbicidal activity. These findings suggest that ADA activity is central to modulating adenosine-mediated immunosuppression in CL and may serve as both a biomarker of disease activity and a potential therapeutic target.
    Keywords:  Adenosine deaminase; Adenosine receptors; Cutaneous Leishmaniasis; Immune response; Leishmania braziliensis
    DOI:  https://doi.org/10.1016/j.cyto.2026.157155
  46. Cytokine Growth Factor Rev. 2026 Apr 19. pii: S1359-6101(26)00031-6. [Epub ahead of print]89 41-57
    Lipid metabolic reprogramming regulates macrophage senescence in the tumor microenvironment.
    Yixi Liu, Chenchi Li, Jiao Wang, Miaomiao Gao, Shulong Jiang.
      Immune checkpoint inhibitors (ICIs) have made significant progress in the treatment of many malignant tumors; however, their efficacy remains limited by the complex immune-suppressive characteristics of the tumor microenvironment (TME), with only a subset of patients experiencing durable remission. Identifying new targets for immune modulation has therefore become a major focus of current cancer research. In this context, tumor-associated macrophages (TAMs) have emerged as key regulators of tumor initiation, progression and immune modulation owing to their striking functional plasticity. TAMs exhibit considerable phenotypic plasticity, with metabolic reprogramming shaping their polarization towards anti-tumor M1-like or pro-tumor M2-like states. The alterations in lipid metabolism not only affect the phenotypic transformation of TAMs, but more importantly, they also drive macrophage senescence, leading to impaired immune surveillance, weakened anti-tumor immunity and ultimately immune escape. This process is marked by lipid accumulation, mitochondrial dysfunction, and activation of the senescence-associated secretory phenotype (SASP), collectively contributing to the establishment of an immunosuppressive TME. In this review, we summarize the key mechanisms by which lipid metabolic reprogramming in TAMs regulates macrophage senescence, with particular emphasis on the role of SASP in shaping the immunosuppressive microenvironment. We also discuss therapeutic strategies targeting TAM senescence and lipid metabolism, highlighting their potential synergy with ICIs and metabolic modulators. Collectively, targeting these TAM-related pathways may provide a promising strategy to overcome immune evasion and ICIs resistance.
    Keywords:  Immune checkpoint inhibitors; Lipid metabolism reprogramming; Senescence-associated secretory phenotype; Tumor immune microenvironment; Tumor-associated macrophages senescence
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.04.002
  47. J Gene Med. 2026 Apr;28(4): e70092
    Vitamin D Mitigates Klebsiella pneumoniae-Induced Pneumonia by Regulating Macrophage Polarization Through miR-223/ACSL3 Axis-Mediated Lipid Metabolism Reprogramming.
    Jiajia Hu, Yushen Lin, Wanrong Guo, Jingcong Zhang, Benquan Wu, Yanhong Wang.
       BACKGROUND: Pneumonia caused by Klebsiella pneumonia (Kp) poses a significant risk to global public health. Vitamin D may reduce Kp infection risk and improve prognosis through immunomodulation. This study aimed to validate the treatment effects of Vitamin D and explore its regulatory mechanism in Kp-pneumonia.
    METHODS: In this study, a murine model of Kp-induced pneumonia and the MH-S alveolar macrophage cell line were used. Experimental assays included RT-qPCR, Western blot, TUNEL assay, ELISA, flow cytometry, dual-luciferase reporter assay, and metabolic analyses (FAO activity, Seahorse XF Glycolysis Stress Test).
    RESULTS: The results showed that vitamin D administration mitigated Kp-induced lung injury in mice. Mechanically, vitamin D alleviated inflammation by inhibiting macrophage M1 polarization. Vitamin D exerted its effects by upregulating miR-223, which directly targeted and suppressed ACSL3 expression. In macrophages, miR-223 overexpression alleviated macrophage apoptosis and M1 polarization by downregulating ACSL3. Knockdown of ACSL3 induced a shift to M2 polarization by enhancing FAO and suppressing glycolysis. In vivo, miR-223 overexpression alleviated Kp-induced lung injury by downregulating ACSL3.
    CONCLUSION: In conclusion, vitamin D induces macrophage M2 polarization by upregulating miR-223, which inhibits ACSL3, leading to lipid metabolism reprogramming. This novel axis represents a potential therapeutic strategy for Kp-induced pneumonia.
    Keywords:   Klebsiella pneumonia ; ACSL3; lipid metabolism reprogramming; macrophage polarization; miR‐223; pneumonia; vitamin D
    DOI:  https://doi.org/10.1002/jgm.70092
  48. J Immunol. 2026 Apr 15. pii: vkag035. [Epub ahead of print]215(4):
    Redox index and capacity analysis (RICA) reveals NAD biology changes in T cell responses in vitro and ex vivo.
    Alicia M Bostwick-Galaviz, Edward J Usherwood.
      The importance of NAD metabolism in T cell differentiation and function has gained attention in recent years. However, technical limitations impede the specific interrogation of NAD dynamics in living immune cells. In this report, we present the redox index and capacity analysis (RICA) assay, a novel technique for measuring mitochondrial NAD content and redox balance. The RICA assay is a flow cytometry-based technique that uses NADH autofluorescence and mitochondrial inhibitors to assess NAD within specific phenotypic subsets of immune cells. We validated this technique using metabolic modulators and used it to examine murine CD8 T cell subsets in vitro and ex vivo. Consistent with previous findings, we observed that metabolically active, effector-like cells had a higher mitochondrial NADH:NAD+ ratio than quiescent cells. We discovered that cells with greater differentiation potential often possessed a larger pool of mitochondrial NAD than terminally differentiated cells in vitro and in a vaccinia viral immunization model. Mitochondrial NAD content fluctuated considerably in response to fuel availability and metabolic modulators, even within short treatment timeframes. Finally, tumor localization and differentiation status dramatically affected the mitochondrial NAD pool but not the NADH:NAD+ ratio of adoptively transferred CD8 T cells in a B16 melanoma model. This study establishes a tool for evaluating mitochondrial NAD biology in living immune cells at a greater level of detail than previously possible. It also highlights dynamic changes in mitochondrial NAD pool size as an important and novel element of CD8 T cell biology.
    Keywords:  NAD; T cells; cancer; techniques
    DOI:  https://doi.org/10.1093/jimmun/vkag035
  49. J Bacteriol. 2026 Apr 22. e0061625
    Spermidine biosynthesis by hypervirulent Francisella tularensis promotes fitness and salvages adenine.
    Yinshi Yue, Dhananjay Shinde, Robert Moore, Yangsheng Yu, Vinai Chittezham Thomas, Tomáš Helikar, Marilynn A Larson.
      Francisella tularensis is a highly infectious Tier 1 select agent that causes tularemia, a potentially fatal disease. F. tularensis subspecies tularensis (type A), including subtypes A.I and A.II, and subspecies holarctica (type B) differ considerably in pathogenicity, with A.I strains being recognized as some of the most virulent bacterial pathogens known. We previously revealed that only the A.I clade can synthesize spermidine de novo. In this study, we show that deletion of spermidine synthase speE (ΔspeE) in prototype A.I strain SCHU S4 reduced spermidine levels relative to wild-type SCHU S4, type B live vaccine strain (LVS), and LVS ΔspeE. In conventional spermidine-containing chemically defined medium (cCDM), SCHU S4 and SCHU S4 ΔspeE grew substantially faster than LVS and LVS ΔspeE; however, SCHU S4 ΔspeE grew slower than SCHU S4. In modified cCDM without spermidine, SCHU S4 ΔspeE grew in a biphasic manner, which was alleviated by methylthioadenosine, adenine, or adenosine supplementation. Conversely, spermidine addition caused diauxic growth by LVS and LVS ΔspeE and was inhibitory above 0.1 mM, while SCHU S4 replication was substantially and similarly promoted by spermidine or spermine supplementation, with 0.02 mM spermidine being sufficient for maximum growth enhancement. These previously unknown traits demonstrate that de novo spermidine synthesis by A.I strains salvages adenine and promotes fitness, while exogenous spermidine and spermine further increase the rapid replication rate of hypervirulent A.I SCHU S4. These F. tularensis A.I attributes are likely an adaptation to an intracellular environment that contributes to persistence, while outcompeting an effective immune response during an infection.IMPORTANCEFrancisella tularensis is one of the most pathogenic bacteria known due to a low infectious dose, expansive host range, and high rate of mortality. This zoonotic pathogen poses a serious risk to public health and, therefore, is considered a potential bioterrorism agent. Our study revealed that hypervirulent strains of F. tularensis endogenously produce spermidine, which promotes fitness and salvages adenine, while exogenous spermidine or spermine further enhances the rapid replication rate of this intracellular pathogen. A better understanding of the inherent traits that allow F. tularensis to persist and outcompete an effective immune response is needed and may provide insight into preventing lethal infections by other intracellular pathogens.
    Keywords:  adenine salvage; arginine and methionine metabolism; hypervirulent Francisella tularensis; methylthioadenosine; polyamine biosynthesis and acquisition; putrescine; spermidine; spermine; tularemia
    DOI:  https://doi.org/10.1128/jb.00616-25
  50. Innate Immun. 2026 Jan-Dec;32:32 17534259261446050
    The role of trained immunity in chronic non-communicable inflammatory diseases.
    Joseph Mucumbitsi, Jean Claude Hakizimana, Marie Gorette Kampire, Callixta Kaneza, Themistocles Bushobozi, Sophie Mukantwari, Jean Mfizi Ngaboyishema, Alex Butera, Abdullateef Isiaka Alagbonsi.
      BackgroundTrained immunity, a form of long-term functional reprogramming of innate immune cells through epigenetic and metabolic changes, traditionally confers protection against infections. However, inappropriate activation by endogenous sterile stimuli can drive persistent maladaptive inflammation in non-communicable diseases (NCDs).ObjectiveThis systematic review synthesizes primary evidence for trained immunity in atherosclerosis, type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and neurodegenerative disorders, focusing on endogenous inducers, cellular mediators, mechanisms, and translational implications.Data Sources and MethodsFollowing PRISMA guidelines, we included original studies demonstrating trained immunity induced by sterile endogenous signals in the targeted diseases. Narrative synthesis was performed due to heterogeneity precluding meta-analysis.ResultsTwelve primary studies met the inclusion criteria. In atherosclerosis (n = 8 studies), oxLDL, aldosterone, Western diet lipids, and post-myocardial infarction signals induced trained immunity in monocytes or macrophages and hematopoietic progenitors via H3K4me3 enrichment, mTOR/NLRP3 activation, and glycolytic/fatty acid shifts, leading to persistent cytokine hyperproduction (TNF-α, IL-6), foam cell formation, and transmissible plaque progression. In T2DM/hyperglycemia (n = 3), high glucose levels triggered MLL-mediated epigenetic reprogramming and glycolysis-dependent "metabolic memory," which skewed myelopoiesis and accelerated atherosclerosis despite normoglycemia. In CKD (n = 1), indoxyl sulfate induced AhR-dependent arachidonic acid pathway activation with metabolic rewiring, sustaining systemic inflammation. In neurodegeneration (n = 1), peripheral stimuli caused epigenetic reprogramming in microglia, yielding hyperresponsive or tolerized states modulating amyloid-β pathology. Convergent mechanisms (H3K4me3, glycolysis, mTOR/AhR/NLRP3) highlight trained immunity as a shared driver of chronic sterile inflammation.ConclusionsTrained immunity emerges as a unifying maladaptive mechanism perpetuating low-grade inflammation across these diseases, bridging transient endogenous insults to sustained pathology. Targeting reprogramming pathways, such as glycolysis or epigenetic inhibitors, offers promising therapeutic strategies. Expanded human studies are needed to address preclinical dominance and data gaps, particularly in CKD and neurodegeneration, where evidence is preliminary.
    Keywords:  Epigenetic reprogramming; innate immune memory; metabolic memory; sterile inflammation; trained immunity
    DOI:  https://doi.org/10.1177/17534259261446050
  51. Front Immunol. 2026 ;17 1766756
    Role of dual specificity phosphatase 1 in influencing inflammatory pathways in macrophages modulated by Borrelia burgdorferi lipoproteins.
    Venkatesh Kumaresan, Susanta Pahari, Chiung-Yu Hung, Brian P Hermann, Larry S Schlesinger, J Seshu.
      Borrelia burgdorferi (Bb), the spirochetal agent of Lyme disease, has a large array of lipoproteins that play a significant role in mediating host-pathogen interactions within ticks and vertebrates. While prior work has established that borrelial lipoproteins (BbLP) modulate immune signaling pathways, the broader transcriptional and proteomic programs induced by these molecules in macrophages are unclear. Here, we used integrated multi-omics approaches to characterize host signaling pathways activated specifically by purified borrelial lipoproteins in murine bone marrow derived macrophages (BMDMs). Single-cell RNA-Seq (scRNA-Seq) performed on BMDMs treated with various concentrations of borrelial lipoproteins revealed macrophage subsets within the BMDMs. Differential expression analysis showed that genes encoding various receptors, type I IFN-stimulated genes, signaling chemokines are upregulated while mitochondrial and ribosomal genes are downregulated in BMDMs in response to lipoproteins. Unbiased proteomics analysis of lysates of BMDMs treated with lipoproteins corroborated several of these findings. Notably, dual specificity phosphatase 1 (Dusp1) gene was upregulated during the early stages of BMDM exposure to BbLP. Pharmacological inhibition with benzylidene-3-cyclohexylamino-1-indanone hydrochloride (BCI), an inhibitor of both DUSP1 and 6 prior to exposure to BbLP, demonstrated that DUSP1 negatively regulates NLRP3-mediated pro-inflammatory signaling and positively regulates the expression of interferon-stimulated genes and those encoding Ccl5, Il1b, and Cd274. Using human monocytic reporter cell lines, we showed MyD88- and IKK-dependent pathways contribute to mitochondrial alterations upon stimulation with lipoproteins. Extracellular flux analysis using the Seahorse assay revealed decreased oxygen consumption rate (OCR) and increased extracellular acidification rate (ECAR), indicating time-dependent metabolic reprogramming and a shift toward a glycolytic, pro-inflammatory metabolic state in BMDMs following BbLP stimulation. Collectively, these findings define signaling networks, regulatory nodes and metabolic alterations induced by borrelial lipoproteins in macrophages and highlight DUSP1 as a key modulator of lipoprotein-driven innate immune responses. This work provides a mechanistic framework for understanding how borrelial lipoproteins shape macrophage signaling, independent of the broader complexity of infection with intact pathogen.
    Keywords:  Lyme disease; bone marrow-derived macrophages; dual-specificity phosphatases; lipoprotein; mitochondrial oxidative stress; scRNA-Seq
    DOI:  https://doi.org/10.3389/fimmu.2026.1766756
  52. iScience. 2026 Apr 17. 29(4): 115436
    Creatine uptake promotes dendritic cell activation and enhances antitumor immunity.
    Elliot Kang, James Elsten-Brown, Yu-Chen Wang, Ashley Lam, Elise Sanchez, Renee Wen, Tiffany Wang, Jennifer Chiang, Quentin Scarborough, Yan-Ruide Li, Yichen Zhu, Jie Huang, Matthew Williams, Sarah Eckl, Bo Li, Lili Yang.
      Dendritic cells (DCs) are central regulators of antitumor T cell immunity and are highly sensitive to metabolic cues. However, the therapeutic potential of targeting DC metabolism remains underexplored. Here, we report upregulation of the creatine transporter (CrT; Slc6a8) in intratumoral DCs, which facilitates the cellular uptake of creatine, an energy-storage metabolite. DCs from CrT knockout mice exhibited impaired activation and reduced ability to elicit antigen-specific CD8 T cell responses. Conversely, creatine supplementation enhanced mouse DC activation in vitro and in vivo, and suppressed tumor growth in a syngeneic melanoma model. Notably, creatine uptake similarly boosted the activation and immunostimulatory function of human monocyte-derived DCs. Mechanistically, CrT promotes DC activation by preserving intracellular ATP levels and enhancing energy-dependent inflammatory signaling pathways. Together, these findings uncover a previously unrecognized role for creatine metabolism in regulating DC function and support the use of creatine supplementation as a strategy to augment DC-based cancer immunotherapy.
    Keywords:  cancer; immunological methods; immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.115436
  53. Biochim Biophys Acta Rev Cancer. 2026 Apr 16. pii: S0304-419X(26)00062-4. [Epub ahead of print]1881(3): 189590
    Metabolites in the tumor microenvironment: Key drivers of immune cell fate and function as therapeutic targets in cancer.
    Xiao-Ping Zhao, Chu-Tian Mai, Yi-Lin Zhao, Xin-Yi Zhou, Nian-Hong Lai, Xiao-Jun Zhang, Xing-Xing Fan.
      Tumor cells employ multiple strategies to evade immune detection, largely facilitated by the immunosuppressive tumor microenvironment (iTME). This environment not only hinders therapeutic efficacy but also drives metabolic reprogramming of tumor cells, resulting in localized nutrient deprivation and the accumulation of immunomodulatory metabolites. Metabolites such as lactic acid and adenosine accumulate under hypoxic and poorly perfused conditions, directly altering immune cell function and promoting tumor immune escape. Consequently, these metabolites have emerged as promising therapeutic targets in cancer immunotherapy. In this review, we systematically examine how TME-derived metabolites influence diverse immune cell populations and summarize current clinical progress in targeting their production and signaling pathways for anticancer treatment.
    Keywords:  Cancer immunotherapy; Immune cells; Metabolites; Oncometabolites; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189590
  54. Bioact Mater. 2026 Sep;63 439-458
    Spatiotemporally reprogrammed L-arginine metabolic nanoregulator potentiates immunotherapy.
    Qian Cheng, Xiaolei Shi, Qushuhua Qin, Yuzhe Chen, Jiawei Wang, Lin Wang, Zheng Wang.
      L-arginine (L-Arg) deprivation in the tumor microenvironment (TME) drives effector T cell dysfunction and immunotherapy resistance. However, simply supplementing L-Arg can be counterproductive, as tumor cells and immunosuppressive myeloid cells act as dominant consumers, co-opting the nutrient to promote tumor progression. To break this detrimental cycle without fueling protumoral networks, we develop a near-infrared (NIR)-triggered nanoregulator (hPFL@Lipo) to simultaneously alleviate intratumoral L-Arg deficiency and redirect its metabolism to support antitumor immunity. This nanoregulator was constructed through coordination-driven self-assembly to co-load and stabilize L-Arg and Fe3+ within hollow Prussian blue (hPB) nanoparticles, followed by lipid membrane encapsulation for enhanced systemic stability. Under NIR irradiation, hPFL@Lipo releases Fe3+ and L-Arg while generating localized hyperthermia. Fe3+ repolarizes M2-like macrophages toward an M1 phenotype, thereby increasing the intratumoral M1-to-M2 ratio. The photothermal effect induces immunogenic tumor cell death, which promotes the infiltration of cytotoxic CD8+ T cells. Concurrently, the released L-Arg supplements the local pool, while thermal ablation reduces the overall cellular burden within the tumor, thereby alleviating arginine local depletion. Together, this strategy resolves the tumor-immune conflict over L-Arg by remodeling the intratumoral landscape of L-Arg consumers in favor of antitumor effector cells, thereby reprogramming the net metabolism of the tumor from a tumor-promoting to a tumor-suppressing state and achieving potent synergy with αPD-1 therapy.
    Keywords:  Immunotherapy resistance; L-arginine deprivation; Metabolic competition; Nanoregulator; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.04.015
  55. Lupus Sci Med. 2026 Apr 20. pii: e001933. [Epub ahead of print]13(1):
    Cells' survival pattern of kidney macrophages and epithelial cells in lupus nephritis is influenced by glycolysis.
    Soraya Jativa, Selene Torrico, Angeles Muñoz, Maria T Torres Salido, Georgina Hotter.
       OBJECTIVE: Macrophages and kidney cell pyroptosis/ferroptosis could play an important role in the pathogenesis of lupus nephritis (LN). We aim to determine if glycolysis influences cell death and sustained renal inflammation in these cells.
    METHODS: For this purpose, we evaluated glycolysis, glutathione peroxidase and Caspase 1 activities and gene expression levels related to glycolysis, pyroptosis, ferroptosis and fatty acid oxidation in: (1) cultured human tubular cells and monocytes treated with healthy human serum or human LN serum. (2) Epithelial cells and macrophages isolated from kidneys from an in vivo murine model of LN in mice subjected to intraperitoneal administration of pristane. (3) NRK-52E tubular cells and mice Raw 264.7 macrophages treated with ovalbumin immunocomplexes (OVA-IC) to mimic LN model in vitro.
    RESULTS: Our results indicate that treatment of human cells and human monocytes from serum of patients with LN provoked upregulated glycolysis and enhancement of pyroptosis and ferroptosis. In the in vivo mice pristane model, the isolated renal epithelial cells and macrophages from kidneys showed an increase in expression of glycolytic and pyroptotic/ferroptotic related genes, while fatty acid oxidation was downregulated. OVA-IC administration in NRK and RAW cells promotes glycolysis upregulation and enhances pyroptosis and ferroptosis. Pharmacological inhibition of glycolysis reduces pyroptosis/ferroptosis and kidney damage in vitro and in vivo.
    CONCLUSION: In LN, kidney macrophages and epithelial cells have an enhanced pyroptosis/ferroptosis influenced by glycolysis since 2-deoxy-D-glucose treatment reverts these effects.
    Keywords:  Autoimmune Diseases; Inflammation; Lupus Nephritis; Therapeutics
    DOI:  https://doi.org/10.1136/lupus-2025-001933
  56. Int J Biol Sci. 2026 ;22(7): 3788-3806
    Monocyte Preprogramming by Tobacco Carcinogens and Fructose Intake Accelerates Lung Cancer Progression via Metabolic and Epigenetic Pathways.
    Jee Hwan Ahn, Hye-Young Min, Jisung Kim, Xuan Wei, Namwon Kim, Ho-Young Lee.
      Although tobacco smoking is the leading cause of lung cancer (LC), excessive sugar intake has also emerged as a potential risk factor, yet its mechanistic contribution remains poorly defined. In this study, we investigated how high-fructose intake modulates the tobacco carcinogen-induced LC progression. Co-exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and benzo[a]pyrene (NNK and BaP; collectively referred to as NB) combined with a high-fructose diet markedly accelerated tumor progression in multiple mouse models, including KrasG12D/+-driven LC and LKB1-deficient (LKB1KO) lung tumors. NB-induced LC progression was suppressed by restricting glucose metabolism, indicating a metabolic dependency. Mechanistically, NB exposure stimulated transcriptional programs that promote monocyte/macrophage recruitment within the tumor microenvironment and enhanced fructose uptake through both transcriptional and post-transcriptional upregulation of fructose transporters, including glucose transporter 8 (GLUT8). This metabolic reprogramming increased acetylation of histones and signal transducer and activator of transcription 3 (STAT3), leading to transcriptional upregulation of genes governing macrophage differentiation and M2 polarization. Analysis of human LC samples revealed enrichment of pro-metastatic IL-10+ and VEGFA+ M2 macrophages, which correlated with poor clinical outcomes. Collectively, these findings demonstrate that NB-driven fructose metabolism induces epigenetic reprogramming of macrophages to promote LC progression and identify pro-metastatic M2 macrophages as potential prognostic biomarkers and therapeutic targets.
    Keywords:  cancer progression; fructose; metabolic reprogramming; non-small cell lung cancer; tobacco carcinogens
    DOI:  https://doi.org/10.7150/ijbs.125622
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