bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–12–28
38 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Glucose metabolism controls oxidative burst and lipid mediator production in neutrophils upon microbial challenge.
  2. Multi-omics approach to dissect the significance of lipid metabolism in helper T cell subset.
  3. Deciphering the antitumor immune effects of succinate.
  4. Flipping the Switch: MeCP2-Mediated Lactylation Rewires Microglial Metabolism and Inflammation via the HK2/mTOR Axis in Poststroke Neuroinflammation.
  5. Trained immunity attenuated acute lung injury by activating alveolar macrophages via AKT2-PDK1 axis-mediated metabolic reprogramming.
  6. Metabolic control of macrophages in coronavirus disease 2019.
  7. Metabolic Reprogramming of Adaptive Immunity Induced by Viral Infections.
  8. Activated T cells degrade extracellular proteins to enhance effector functions.
  9. Notopterol attenuates synovitis via α7nAChR-dependent metabolic reprogramming of macrophage polarisation.
  10. PI3K/Akt/mTOR signaling pathway mediates energy metabolic reprogramming and regulates mitochondrial homeostasis in host cells exposed to Toxoplasma gondii.
  11. Multidimensional plasticity of natural killer cells in tumours.
  12. Diet-derived microbial metabolites as regulators of immune function.
  13. CD155 reprograms glycolysis via the YAP/TEAD1-GLUT1 axis to promote lung adenocarcinoma progression and M2 macrophage polarization: a metabolic-immune target visualized by 18F-FDG PET/CT.
  14. Emerging roles for methionine metabolism in immune cell fate and function.
  15. Systematic screening of tryptophan metabolism identifies site- and microbial-specific signatures of tryptophan utilization in experimental colitis.
  16. Multi-omics dissection of SNP-mediated immunometabolic signatures in Alzheimer's disease reveals a novel individual predictive model.
  17. Macrophage Nrf1/NFE2L1-Foxo1 axis controls liver fibrosis by modulation of mitochondrial reprogramming.
  18. Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b + Leukocytes from Patients with Sepsis.
  19. Regulating Tumor Metabolic Reprogramming with Biomimetic Co-Delivery of Simvastatin and Kynureninase for Immunotherapy.
  20. Fatty Acid Composition of Isoenergetic Meals Drives Distinct Postprandial Immunometabolic Responses in Healthy Adults: A Randomised Crossover Pilot Study.
  21. Modulating CD8⁺ T cell immunity through exercise: mechanistic insights and implications for precision immunotherapy.
  22. Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity.
  23. AMPK agonism optimizes the in vivo activation and antileukemic efficacy of chimeric antigen receptor T cells.
  24. Lysophosphatidic acid regulates macrophage polarisation via LPAR1 by suppressing inflammatory responses and promoting M2-like characteristics.
  25. Palmitic acid reduces cytosolic potassium and induces IL-1β production in lipopolysaccharide-primed human macrophages.
  26. STING-IFN-CH25H lipid axis links innate immune activation to tau pathology.
  27. Immunometabolism and male reproductive function: linking inflammation, oxidative stress, and declining fertility.
  28. Exosomes loaded with metabolites: Roles in crosstalk between tumor cells and their microenvironment.
  29. Acid ceramidase regulates CD8+ T-cell exhaustion via type I interferon-mediated upregulation of PD-L1.
  30. Spatial microbiome-metabolic crosstalk drives CD8+ T-cell exhaustion through the butyrate-HDAC axis in colorectal cancer.
  31. Metabolomic signatures of electroconvulsive therapy in schizophrenia: Mitochondrial energy metabolism and inflammation as therapeutic targets.
  32. Temporal dynamics of IgG-mediated immunometabolic dysfunction: from acute obesity to chronic aging.
  33. Immune cell-derived cytokines synergistically interact to drive synovial fibroblast invasive function and metabolic capacity.
  34. An updated overview of lipid-regulated immunobiology in macrophages.
  35. PFKFB3 alleviates the advancement of Fusarium solani keratitis by attenuating macrophage inflammation.
  36. Indole-3-propionic acid exerts radio-protective effects by modulating Wnt1/STAT3 pathway to alleviate oxidative stress and neuroinflammation in microglia.
  37. SLC16A3 in lung adenocarcinoma regulates glycolysis and lactate release to facilitate M2 polarization of tumor-associated macrophages : Short Title: SLC16A3 reinforces macrophage M2 polarization through glycolysis.
  38. 2-Deoxy-D-glucose attenuates lipopolysaccharide-induced inflammation and restricts Zika, Chikungunya, and Mayaro virus replication in monocyte-derived macrophages.
  1. Microlife. 2025 ;6 uqaf040
    Glucose metabolism controls oxidative burst and lipid mediator production in neutrophils upon microbial challenge.
    Alexandra Freitag, Kerstin Günther, Miriam Campillo Prados, Sophia M Hochrein, Werner Schmitz, Katrin Sinning, Gunther Zischinsky, Bert Klebl, Knut Ohlsen, Joachim Morschhäuser, Oliver Werz, Paul M Jordan, Martin Vaeth.
      Neutrophils are frontline responders against bacterial and fungal pathogens, requiring rapid energy and biosynthetic precursors to mount effective antimicrobial responses. To meet these demands, they primarily rely on aerobic glycolysis, making glucose uptake essential. Murine and human neutrophils express the glucose transporters GLUT1 and GLUT3; however, their specific roles in neutrophil immunobiology have not yet been fully elucidated. Here, we show that neutrophilic immune responses to Candida albicans and Staphylococcus aureus critically depend on GLUT1/3-dependent glucose uptake and glycolysis. Combined deletion of GLUT1 and GLUT3 almost completely abolished glucose uptake and aerobic glycolysis in murine neutrophils, yet did not impair granulopoiesis, indicating that homeostatic neutrophil development is largely independent of extracellular glucose. By contrast, during microbial challenge, loss of GLUT1/3 severely compromised NADPH-dependent ROS production, oxidative burst, and cyclooxygenase-derived lipid mediator (LM) biosynthesis, demonstrating that glucose uptake via GLUT1/3 controls inflammatory effector functions of neutrophils. Moreover, genetic and pharmacologic inhibition of GLUT1/3-mediated glucose utilization reprograms neutrophil metabolism and LM biosynthesis toward an immunomodulatory phenotype. These findings identify a conserved nutrient-sensing metabolic checkpoint that governs neutrophil reprogramming and highlight novel opportunities for therapeutic immunomodulation.
    Keywords:  GLUT1; GLUT3; glycolysis; immunometabolism; neutrophils
    DOI:  https://doi.org/10.1093/femsml/uqaf040
  2. Front Immunol. 2025 ;16 1708616
    Multi-omics approach to dissect the significance of lipid metabolism in helper T cell subset.
    Toshio Kanno, Keiko Nakano, Yukie Iwao, Yusuke Endo.
      The immunometabolism has fundamentally reshaped our understanding of T cell biology. Recent advances have demonstrated that metabolic reprogramming is not merely a consequence of T cell activation but a central driver of lineage specification and effector function. For example, quiescent naïve T cells primarily rely on mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to meet baseline energy needs, whereas activation triggers a metabolic shift toward anabolic pathways dominated by aerobic glycolysis and de novo biosynthesis of macromolecules. Concurrently, the lipid metabolism confers extensive remodeling: activated T cells upregulate the pathways for de novo fatty acid synthesis and cholesterol biosynthesis, uptake, and storage to sustain membrane biogenesis and signal transduction. Conversely, fatty acid catabolism via β-oxidation is essential for the generation of memory T cells and the differentiation of regulatory T cells. This review reports recent advances by integrating experimental findings and methodological developments, highlighting how metabolic programs across distinct stages of T cell differentiation-with particular emphasis on the lipid metabolism-govern their specialized functions.
    Keywords:  Acc1; T cell; Th17 and Treg cells; acetyl-CoA carboxylase 1; lipid metabolism; memory T cell; multi-omics
    DOI:  https://doi.org/10.3389/fimmu.2025.1708616
  3. Trends Endocrinol Metab. 2025 Dec 22. pii: S1043-2760(25)00265-6. [Epub ahead of print]
    Deciphering the antitumor immune effects of succinate.
    Ziyan Xia, Zhaoyi Li, Peng Jiang.
      Through metabolic remodeling, tumor cells can modulate neighboring CD8+ T cell function via metabolites. A recent study by Ma et al., published in Immunity, reveals that tumor-cell-derived succinate exhibits an antitumor immune effect, promoting the survival and stemness of CD8+ T cells by enhancing mitochondrial fitness and inducing epigenetic reprogramming.
    Keywords:  CD8(+) T cell stemness; ICB therapy; epigenetic regulation; mitochondrial homeostasis; succinate
    DOI:  https://doi.org/10.1016/j.tem.2025.12.001
  4. Adv Sci (Weinh). 2025 Dec 22. e13400
    Flipping the Switch: MeCP2-Mediated Lactylation Rewires Microglial Metabolism and Inflammation via the HK2/mTOR Axis in Poststroke Neuroinflammation.
    Zengyu Zhang, Shanshan Huang, Yong Wang, Zhiwen Jiang, Zhuohang Liu, Chenran Wang, Rong Ji, Yiwen Yuan, Xueyu Mao, Kaicheng Yang, Huicong Niu, Yanqin Gao, Jing Zhao.
      Microglial metabolic/inflammatory reprogramming critically influences stroke outcomes, yet its mechanisms remain poorly understood. Lysine lactylation, an epigenetic modification in which lactate-derived lactyl groups modify lysine residues, regulates immune and neurological processes. Here, lysine lactylation is identified as a key link between ischemic metabolic stress and microglial dysfunction. Stroke-induced lactate accumulation drives microglial protein lactylation, which correlates with poor neurological outcomes. Proteomics identified that methyl-CpG binding protein 2 (MeCP2) is lactylated at lysine 210 (K210), enhancing its transcriptional activation of glycolytic/inflammatory genes, especially hexokinase 2 (HK2). HK2 overexpression mimics lactylation-induced pathology (mitochondrial dysfunction, glycolytic shift, inflammation), while knockdown reverses these effects. Lactylated MeCP2 impairs mitochondrial respiration, disrupts metabolic signaling (leading to dysregulated activation of the mammalian target of rapamycin (mTOR)/AMPK pathway), and sustains neuroinflammation. Genetic ablation of MeCP2-K210 lactylation (via K210R mutation), pharmacological inhibition of lactyltransferase p300, or HK2 inhibition with lonidamine restores mitochondrial function, attenuates neuroinflammation, and improves neurofunctional recovery. The findings establish MeCP2-K210 lactylation as a critical metabolic-epigenetic switch driving microglial activation via the HK2/mTOR axis, identifying a therapeutic target for postischemic neuroinflammation.
    Keywords:  MeCP2; ischemic stroke; lactylation; microglia; neuroinflammation
    DOI:  https://doi.org/10.1002/advs.202513400
  5. J Transl Med. 2025 Dec 23. 23(1): 1412
    Trained immunity attenuated acute lung injury by activating alveolar macrophages via AKT2-PDK1 axis-mediated metabolic reprogramming.
    Zhiheng Sun, Huiwen Meng, Xinru Wang, Xinya Guo, Wanyu He, Yanlin Zhou, Ze Wang, Zhensheng Li, Xingbin Li, Yuan Wang.
       BACKGROUND: Acute lung injury (ALI) is a life-threatening clinical syndrome typically triggered by sepsis or severe trauma lacking effective treatment options. Alveolar macrophages (AMs), representing the most abundant immune cell population in pulmonary tissue, exhibited functional abnormalities that were closely associated with ALI pathogenesis. Notably, elevated pulmonary lactate secretion served not only as a characteristic pathological feature of ALI but also participated in disease progression through modulation of AMs activity. Trained immunity was found to activate innate immune cells including macrophages, regulating metabolic adaptations that alleviated ALI, though the precise mechanisms remained unclear.
    METHODS: We used β-glucan and LPS to establish both in vivo and in vitro models of trained immunity and ALI, enabling investigation of trained immunity effects on AMs immunoregulatory functions.
    RESULTS: The results demonstrated that trained immunity effectively attenuated ALI severity by up-regulating glycolytic activity in AMs, thereby potentiating their immune responsiveness, and primarily enabled alveolar macrophages to sustain immune responses in high-lactate environments through the AKT2-PDK1 axis, an effect that was abolished by relevant inhibitors.
    CONCLUSIONS: We concluded that β-glucan induced trained immunity could enhance alveolar macrophage immune activity and improve lactate metabolic tolerance, offering a novel therapeutic approach for acute lung injury (ALI).
    Keywords:  AKT2; Acute lung injury; Alveolar macrophages; Lactate; Pyruvate dehydrogenase kinase 1; Trained immunity
    DOI:  https://doi.org/10.1186/s12967-025-06879-4
  6. Virulence. 2026 Dec;17(1): 2609397
    Metabolic control of macrophages in coronavirus disease 2019.
    Li An, Houxi Xu, Qiaoling Fan, MengJiang Lu, Dongdong Sun.
      In the context of COVID-19, macrophages are primarily responsible for sensing and responding to the virus, significantly influencing disease outcomes. They are involved in early pathogen recognition, immune activation, and tissue repair. Heterogeneity and phenotypic plasticity of macrophages are dynamically shaped by microenvironmental cues, including metabolites, hypoxia, and pathogen-derived signals. Notably, emerging evidence underscores that cellular metabolism, particularly in macrophages, dictates immune responses to viral infection. This metabolic-immune crosstalk critically determines COVID-19 severity, ranging from viral clearance to hyperinflammation or fibrosis. In this review, we systematically dissect how cell-intrinsic metabolic nodes and extrinsic factors modulate macrophage effector functions, while illustrating the complications associated with macrophage metabolic dysregulation in SARS-CoV-2 infection. These mechanistic insights provide a rational foundation for therapeutic strategies targeting macrophage metabolism to rebalance immune responses and mitigate COVID-19 complications.
    Keywords:  COVID-19; COVID-19 implications; SARS-CoV-2; macrophages; metabolism
    DOI:  https://doi.org/10.1080/21505594.2025.2609397
  7. Immunology. 2025 Dec 25.
    Metabolic Reprogramming of Adaptive Immunity Induced by Viral Infections.
    Guoshuai Tong, Jingwen Dai, Qianqian Liu, Xu Gao, Su Li, Hua-Ji Qiu.
      Metabolic reprogramming induced by viral infections plays a key role in shaping the efficacy and durability of the host's adaptive immune response. Notably, metabolic reprogramming not only directly governs the differentiation fates of functional subgroups, such as Th1, Th2, Th17, Treg and cytotoxic T cells, but also contributes to supportive immune responses and T-cell exhaustion mediated by metabolic disorders in the context of acute and chronic infections, respectively. Moreover, the metabolic reprogramming of B cells precisely regulates their germinal centre response, plasma cell differentiation and antibody production, thereby modulating the intensity and quality of humoral immunity. Beyond these direct effects, viruses indirectly impair the functionality of T and B cells by altering the metabolic status of innate immune cells such as dendritic cells and macrophages. This review summarises the recent advances of regulatory mechanisms regarding metabolic characteristics of T cells and B cells at various statuses, including rest, activation, differentiation and memory, and discusses immune intervention strategies targeting glycolysis, glutamine and lipid metabolism, and outlines future research directions and clinical translation potential of metabolic reprogramming. A comprehensive understanding of virus-mediated metabolic reprogramming will provide an important theoretical basis for the development of new antiviral therapies and immunotherapy strategies.
    Keywords:  adaptive immunity; immune regulation; immunotherapy; metabolic reprogramming; viral infections
    DOI:  https://doi.org/10.1111/imm.70089
  8. Cell Rep. 2025 Dec 24. pii: S2211-1247(25)01569-4. [Epub ahead of print]45(1): 116797
    Activated T cells degrade extracellular proteins to enhance effector functions.
    Yunxue Yin, Xiaorong Lin, Linlin Li, Shuo Kan, Wenrong Jiang, Yuchen Han, Lixin Wang, Shiwen Wang, Jun Jin.
      Proteins are the most abundant source of amino acids in body fluids. However, the potential contribution of extracellular protein catabolism to the regulation of T cell immunity remains poorly understood. In this study, we show that endocytosed extracellular proteins function as an amino acid source in activated T cells, maintaining mTORC1 activity and sustaining cytokine production following T cell activation. Genetic ablation of Tfe3 impairs the activation-induced upregulation of lysosomal genes and disrupts extracellular protein catabolism, resulting in attenuated mTORC1 signaling and compromised anti-viral and anti-tumor T cell responses. The TFE3-protein-mTORC1 signaling axis demonstrates clinical relevance. CD8+PD-1+ tumor-infiltrating T cells from older patients with lung cancer display reduced lysosomal degradation capacity and impaired cytokine secretion compared to their middle-aged counterparts. This functional defect is rescued by treatment with Vismodegib, a TFE3-inducing drug. Our findings reveal lysosome-mediated extracellular protein catabolism as an important metabolic pathway supporting T cell immunity.
    Keywords:  CP: immunology; CP: metabolism; activated T cells; amino acids; extracellular proteins; lysosomal proteolysis; mTORC1; protein degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116797
  9. Phytomedicine. 2025 Dec 09. pii: S0944-7113(25)01319-4. [Epub ahead of print]150 157684
    Notopterol attenuates synovitis via α7nAChR-dependent metabolic reprogramming of macrophage polarisation.
    Xiaomei Chen, Cheng Zhang, Yonghua Ye, Yixue Zhuang, Meixia Huang, Hongmin Yu, Zitong Qin, Ying Chen, Zhiyuan Hong, Hongyang Tu, Yingzheng Wang, Zhifu Wang, Yinghao Wang.
      Synovitis, a characteristic feature of inflammatory arthritis (IA), is often driven by an aberrant macrophage-mediated inflammatory response that promotes irreversible joint damage. The α7 nicotinic acetylcholine receptor (α7nAChR) is a key regulator of the cholinergic anti-inflammatory pathway. Despite its therapeutic potential, how α7nAChR coordinates macrophage metabolic reprogramming to resolve synovitis remains underexplored. This study aims to elucidate the therapeutic effects of Notopterol, a bioactive constituent derived from the rhizome of Notopterygium incisum Ting ex H.T. Chang, a traditional Chinese medicine known for its potent anti-inflammatory and antioxidant properties, in treating inflammatory arthritis and the molecular mechanisms by which α7nAChR modulates macrophage reprogramming in synovitis. An in vivo mouse model of IA was established through complete Freund's adjuvant (CFA)-induced, Notopterol administration significantly attenuated synovitis progression, reduced joint swelling, and enhanced mechanical pain thresholds as well as suppressed the production of pro-inflammatory cytokines (IL-1β, TNF-α, and IFN-γ) while promoting anti-inflammatory IL-4 secretion. Complementary in vitro models employing lipopolysaccharide (LPS)-stimulated macrophages demonstrated that Notopterol exerts anti-inflammatory effects, restores mitochondrial function while shifting energy metabolism towards oxidative phosphorylation, a transition mechanistically linked to M1/M2 polarisation. Mechanistically, Notopterol promotes a shift from glycolysis to oxidative phosphorylation in macrophages, restoring mitochondrial function and enhancing their polarizing capacity through α7nAChR activation, thus revealing this receptor's pivotal role in macrophage metabolic regulation. Furthermore, biophysical validation confirms the high-affinity binding of Notopterol to α7nAChR, supporting its therapeutic potential in anti-inflammatory treatment. These findings highlight the innovative prospect of targeting macrophage metabolic pathways as a novel strategy for treating inflammatory arthritis.
    Keywords:  Inflammatory arthritis; Macrophage polarisation; Metabolic reprogramming; Notopterol; α7 nicotinic acetylcholine receptor (α7nAChR)
    DOI:  https://doi.org/10.1016/j.phymed.2025.157684
  10. Microbiol Spectr. 2025 Dec 22. e0138525
    PI3K/Akt/mTOR signaling pathway mediates energy metabolic reprogramming and regulates mitochondrial homeostasis in host cells exposed to Toxoplasma gondii.
    Kangzhi Xu, Shifan Zhu, Jing Ma, Mingyue Zu, Jin Yang, Fan Xu, Linwei Dai, Dandan Liu, Yanhong Wang, Xinjun Zhang, Siyang Huang, Jinjun Xu, Zhiming Pan, Jianping Tao, Zhaofeng Hou.
      Toxoplasma gondii (T. gondii) relies on host cells for energy and nutrition. Our previous studies showed that T. gondii regulates host cell apoptosis via the mitochondrial pathway, highlighting the essential role of mitochondria in its parasitism. In this study, T. gondii infection was found to significantly affect mitochondrial morphology and dynamic homeostasis in porcine kidney-15 (PK-15) cells, characterized by aggregated, swollen, fragmented, and oval-shaped mitochondria with disappearing cristae, accompanied by increased fusion and decreased fission. Additionally, the energy metabolic reprogramming of PK-15 cells exposed to T. gondii was affirmed from the perspectives of glucose consumption; changes in NAD+/NADH, lactate, pyruvate, and ATP production; and expressions of proteins related to glycolysis and oxidative phosphorylation (OXPHOS). T. gondii-induced mitochondrial damage impaired the OXPHOS process; however, the glycolysis level was significantly increased. Mechanistically, we demonstrated that activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway played a critical role in energy metabolic reprogramming and mitochondrial damage induced by T. gondii, and this effect could be attenuated by LY294002 (a PI3K inhibitor), which significantly reduced intracellular proliferation of T. gondii through inhibiting PI3K/Akt/mTOR signaling pathway. These findings highlight the PI3K/Akt/mTOR pathway as a key mediator of T. gondii-induced cellular metabolic reprogramming and mitochondrial dysfunction; however, its potential as a therapeutic target remains to be validated in vivo.IMPORTANCEToxoplasma gondii, a globally distributed obligate intracellular protozoan parasite, poses severe health risks to immunocompromised individuals and pregnant women, causing miscarriage and fetal abnormalities. Current therapies suffer from high toxicity and limited targets, with unclear mechanisms underlying host-parasite interactions. This study reveals a novel parasitic strategy: T. gondii hijacks host mitochondrial dynamics and energy metabolism. Infection disrupts mitochondrial morphology and suppresses oxidative phosphorylation while activating the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway to drive metabolic reprogramming, enhancing glycolysis to meet energy demands. Critically, inhibiting PI3K/Akt/mTOR with LY294002 reduces intracellular parasite proliferation, validating this pathway as a therapeutic target. Conventional antiparasitic drugs targeting the parasite directly face resistance challenges. By focusing on host metabolic regulation via PI3K/Akt/mTOR, this work advances understanding of parasitism and proposes host-directed therapies to disrupt parasite proliferation by modulating the metabolic microenvironment, highlighting its therapeutic potential against toxoplasmosis.
    Keywords:  LY294002; PI3K/Akt/mTOR; Toxoplasma gondii; energy metabolic reprogramming; mitochondrial dynamics
    DOI:  https://doi.org/10.1128/spectrum.01385-25
  11. Cell Death Dis. 2025 Dec 22.
    Multidimensional plasticity of natural killer cells in tumours.
    Xinya Yang, Zhaoyang Song, Ligang Chen, Qingge Jia, Mingyang Li.
      Natural killer (NK) cells exhibit remarkable adaptability within the tumour microenvironment (TME), where dynamic shifts in phenotype, function and metabolism govern their dual roles in antitumour immunity and tumour immune evasion. In the TME, NK cells undergo receptor remodelling, which is characterised by upregulated inhibitory signals and suppressed activating receptors, leading to the formation of dysfunctional subsets, such as exhausted TIM-3⁺ NK cells or tissue-resident CD49a⁺ populations. Immunosuppressive factors within the TME drive a transition from cytotoxic activity to regulatory or senescent-like states, impairing tumour surveillance. Metabolic reprogramming further compromises NK cell effector functions, as nutrient deprivation and metabolic byproducts disrupt energy pathways and suppress immune responses. Therapeutic strategies targeting this plasticity include engineered natural killer (NK) cells with enhanced specificity, metabolic restoration approaches and microenvironment-modulating interventions. However, challenges persist because of TME heterogeneity and persistent dysfunctional states. Understanding these adaptive mechanisms provides a framework for developing NK cell-based therapies that leverage plasticity to counteract tumour resistance.
    DOI:  https://doi.org/10.1038/s41419-025-08361-x
  12. Curr Opin Immunol. 2025 Dec 22. pii: S0952-7915(25)00189-X. [Epub ahead of print]98 102713
    Diet-derived microbial metabolites as regulators of immune function.
    Francesco Siracusa, Andres Machicote, Samuel Huber, Nicola Gagliani.
      The intestinal microbiota transforms dietary components into bioactive metabolites that profoundly influence mucosal and systemic immunity. Short-chain fatty acids, secondary bile acids and tryptophan-derived indoles are among the most studied microbial metabolites shaping T, B and innate immune cell functions through a variety of mechanisms, including receptor signaling, epigenetic modification and metabolic reprogramming. Dietary habits strongly affect the composition of the intestinal microbiota and thus, the production and availability of these microbial metabolites, with consequences that range from protective immune regulation to detrimental inflammatory responses. Here, we review recent findings from mouse and human studies, highlighting how the microbiota-immunity axis can be modulated by diets and discuss implications for tissue homeostasis, infection and chronic inflammatory diseases. Understanding this complex interplay may guide the development of ad hoc dietary and microbial interventions to restore tolerance and improve therapeutic outcomes.
    DOI:  https://doi.org/10.1016/j.coi.2025.102713
  13. J Transl Med. 2025 Dec 22.
    CD155 reprograms glycolysis via the YAP/TEAD1-GLUT1 axis to promote lung adenocarcinoma progression and M2 macrophage polarization: a metabolic-immune target visualized by 18F-FDG PET/CT.
    Zhiming Cheng, Shu Wang, Shuoyan Xu, Yuxiang Wang, Yao Diao, Bulin Du, Xuena Li, Yaming Li.
       BACKGROUND: CD155, an emerging immune checkpoint, contributes to tumor immune evasion and progression, but its roles in metabolic reprogramming and tumor-associated macrophages (TAMs) polarization in lung adenocarcinoma (LUAD) remain uncharacterized. This study combines molecular biology, metabolic imaging, and clinical data to elucidate CD155's dual role in driving LUAD progression through glycolytic rewiring and immunosuppressive TAMs polarization.
    METHODS: Through immunohistochemistry (IHC) and 18F-FDG PET/CT imaging, we analyzed CD155 expression and its association with glycolysis in 80 LUAD patients. Functional assays and molecular studies revealed CD155-mediated regulation of tumor glycolysis and macrophage polarization via YAP/TEAD1-GLUT1 signaling. Xenograft models validated the in vivo findings, with 18F-FDG micro-PET imaging performing noninvasive metabolic profiling.
    RESULTS: CD155 was significantly overexpressed in LUAD tissues and positively correlated with advanced TNM stage, lymph node metastasis and elevated 18F-FDG uptake. Mechanistically, CD155 interacts with YAP, reducing YAP phosphorylation at Ser127 to promote its nuclear translocation and TEAD1 activation, thereby upregulating GLUT1 transcription. This signaling axis enhanced glycolysis, thereby fueling LUAD proliferation and migration. Notably, CD155-induced lactate production and extracellular acidification drove macrophage polarization toward the immunosuppressive M2 phenotype. In vivo, CD155 silencing suppressed tumor glucose metabolism and growth, whereas overexpression accelerated tumor progression, both dynamically monitored through 18F-FDG PET visualization.
    CONCLUSIONS: We identify a novel CD155/YAP/TEAD1/GLUT1 axis that reprograms LUAD metabolism and facilitates immunosuppressive tumor microenvironment formation. CD155 functions as a metabolic-immune hub in LUAD, and its targeting could simultaneously suppress tumor growth and restore antitumor immunity, offering dual therapeutic advantages. Clinically, 18F-FDG PET/CT represents a noninvasive biomarker for CD155-driven metabolic aggression, potentially guiding precision immunotherapy.
    Keywords:  CD155; Glycolysis; Lung adenocarcinoma; Macrophage polarization; TEAD1; YAP
    DOI:  https://doi.org/10.1186/s12967-025-07551-7
  14. Front Immunol. 2025 ;16 1701505
    Emerging roles for methionine metabolism in immune cell fate and function.
    Shaojuan Liu, Xiaotian Tang, Min Huang, Jianian Tang, Yiwen Yang.
      Metabolic reprogramming is a critical characteristic essential for the activation of immune cells. The altered amino acid metabolism, particularly changes in methionine metabolism, holds significant importance in directing the fate and function of diverse immune cells. Here we summarize the main transport system and metabolic pathway of methionine in immune cells, and the well-established and novel research findings of methionine metabolism-dependent modulation on major immune cell lineages and cancer cells are provided afterward. Unraveling the potential regulatory mechanism of methionine metabolism reprogramming in immune cells provides the new strategies for the therapy of autoimmune diseases and cancers.
    Keywords:  autoimmunity; cancer; immune cells; methionine metabolism; reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2025.1701505
  15. bioRxiv. 2025 Dec 18. pii: 2025.12.16.693850. [Epub ahead of print]
    Systematic screening of tryptophan metabolism identifies site- and microbial-specific signatures of tryptophan utilization in experimental colitis.
    Lina Welz, Abrar I Alsaadi, Danielle Mm Harris, Meiping Yu, Taous Mekdoud, Johanna Bornhäuser, Eva Springer, Clara Gilloteau, Anant A Pothakamury, Jaclyn D Smith, Brenita C Jenkins, Felix Sommer, Silvio Waschina, Philip Rosenstiel, Stefan Schreiber, Melanie R McReynolds, Konrad Aden.
       Background: Altered tryptophan (Trp) metabolism and disrupted nicotinamide adenine dinucleotide (NAD⁺) synthesis are hallmarks of IBD, yet how intestinal microbiota contribute to these metabolic shifts during intestinal inflammation remains poorly understood.
    Methods: We used targeted metabolomics to systematically profile Trp- and NAD⁺-related metabolites across multiple biological compartments - including tissues, luminal contents, stool, and serum - in mice treated with dextran sulfate sodium (DSS) alone or in combination with a broad-spectrum antibiotic (ABX) cocktail.
    Results: Microbial depletion significantly attenuated colitis and increased host Trp bioavailability, implicating the gut microbiota as a competitive Trp consumer. In DSS colitis, Trp degradation along the kynurenine pathway (KP) was exaggerated but blocked at the key KP enzyme quinolinate phosphoribosyltransferase (QPRT), resulting in mucosal NAD(H) depletion. ABX co-treatment normalized metabolite conversion along the KP and restored mucosal NAD(H) levels, revealing a dual role of the gut microbiota during colitis: while they compete with the host for Trp utilization, they simultaneously shape host KP regulation and NAD⁺ de novo synthesis, supporting host energy homeostasis.
    Conclusion: Our findings demonstrate that mucosal NAD⁺ de novo synthesis is a microbially regulated metabolic process that alleviates intestinal inflammation and may represent a novel therapeutic target in IBD through modulation of the gut microbiota or their metabolites.
    DOI:  https://doi.org/10.64898/2025.12.16.693850
  16. NPJ Digit Med. 2025 Dec 24.
    Multi-omics dissection of SNP-mediated immunometabolic signatures in Alzheimer's disease reveals a novel individual predictive model.
    Ji Wu, Xueyang Wang, Qing Tian, Chengliang Yin, Dandan Gao, Xiaoyang Ai, Xi Yang, Tingting Xiao, Yijia Gao, Fanggang He, Jianjuan Ke, Wenxin Yao, Xiaobo Feng, Dan He, Ling Yu, Jiewen Zhang, Ying Yu, Nanxiang Xiong, Lei-Lei Wang.
      While genome-wide association studies (GWAS) have implicated immune and metabolic pathways in Alzheimer's disease (AD), their specific cellular impacts remain unclear. To address this, we employed bidirectional two-sample Mendelian randomization to identify single nucleotide polymorphism (SNP)-mediated, AD-associated immunometabolic signatures, which revealed both positively and negatively correlated immune cell types and metabolic pathways. Integrated single-cell omics analysis further delineated distinct astrocyte subpopulations in patient brains: one enriched for Glutamate-glutamine uptake and metabolism was positively associated with AD, while another characterized by Amino acid metabolism and transport was negatively associated. In peripheral blood, mononuclear cells (PBMCs) primarily displayed AD-negative metabolic signatures accompanied by downregulated immune responses. Leveraging these findings, we developed and optimized a blood transcriptome-based AD prediction model on a gene set derived from blood immune cells that is negatively associated with AD, using multiple machine learning approaches. This model is applicable to both European and Asian populations, enables pre-symptomatic detection for familial AD, effectively discriminates AD from other neurodegenerative disorders, and is readily accessible for clinical implementation. Our study provides novel evidence underscoring the critical role of immunometabolism in AD and delivers a practical predictive tool suitable for large-scale, routine population screening.
    DOI:  https://doi.org/10.1038/s41746-025-02265-y
  17. Theranostics. 2026 ;16(5): 2269-2283
    Macrophage Nrf1/NFE2L1-Foxo1 axis controls liver fibrosis by modulation of mitochondrial reprogramming.
    Yuanbang Lin, Xiyun Bian, Yao Yao, Jingman Xu, Yingli Cao, Qiong Wu, Wen Ning, Lian Li, Mingwei Sheng, Fengmei Wang.
      Rationale: Nuclear factor erythroid 2-like 1 (Nrf1/NFE2L1) is a crucial redox-sensitive factor essential for mitochondrial homeostasis. However, its function in controlling macrophage-associated liver inflammation and fibrosis remains to be fully understood. Herein, this study was conducted to elucidate the roles of macrophage Nrf1 in regulating liver fibrosis. Methods: Expression levels were analyzed in human liver tissues collected from individuals diagnosed with or without liver fibrosis. High-fat diet feeding, carbon tetrachloride injection or bile duct ligation was performed respectively to established three mouse models of liver fibrosis. Myeloid-specific Nrf1-knockout (Nrf1M-KO ) mice were developed to investigate the role and underlying mechanisms of macrophage Nrf1 in vivo and in vitro. Results: Macrophage Nrf1 expression was markedly reduced in liver samples from both humans and mice with liver fibrosis. The deletion of myeloid Nrf1 remarkably accelerated liver inflammation and fibrosis. Macrophages from Nrf1M-KO mice exhibited enhanced M1 polarization and mitochondrial dysfunction. Mechanistically, Nrf1 directly binds to Foxo1 and inhibits its transcriptional activity. The target gene KLF16, regulated by the Nrf1-Foxo1 complex, is crucial for modulating mitochondrial function and immune response. Conclusions: Our study highlights the functional properties of macrophage Nrf1-Foxo1 axis in controlling mitochondrial reprogramming and liver fibrosis progression.
    Keywords:  inflammation; innate immunity; liver fibrosis; mitochondria
    DOI:  https://doi.org/10.7150/thno.112337
  18. bioRxiv. 2025 Dec 18. pii: 2025.12.16.694726. [Epub ahead of print]
    Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b + Leukocytes from Patients with Sepsis.
    Christine Rodhouse, Evan L Barrios, Leilani Zeumer-Spataro, Leandro Balzano-Nogueira, Ruoxuan Wu, Xuanxuan Yu, Guimei Tian, Jason O Brant, Marie-Pierre L Gauthier, Jing Chen, Miguel Hernandez-Rios, Valerie E Polcz, Whitman Wiggins, Angel M Charles, Marvin L Dirain, Ricardo Ungaro, Jaimar Rincon, Tyler Loftus, Feifei Xiao, Guoshuai Cai, Lyle L Moldawer, Robert Maile, Michael P Kladde, Philip A Efron, Clayton E Mathews.
       Introduction: Sepsis leads to expansion of myeloid-derived suppressor cells (MDSC) and their subtypes. These normally transitory MDSCs suppress T cell activation and alter T cell cytokine production while simultaneously promulgating systemic low-grade inflammation. Immune metabolism can shape cell responses, regulate immune suppression, and enhance effector activity. Although MDSC metabolism has been extensively studied in cancer, the metabolic phenotype of this heterogeneous population in sepsis remains unclear. Our goal was to assess metabolic flux in blood MDSCs during and after sepsis and to stratify these patients' clinical features and outcome with differences in metabolic flux that may guide treatment decisions.
    Methods: Peripheral blood mononuclear cells (PBMC) from healthy subjects and sepsis patients at 4 days, 2-3 weeks, and 6 months underwent CD66b + or CD3 + enrichment, followed by assessment of metabolic flux, flow cytometry, mRNA sequencing, and chromatin accessibility.
    Results: Mitochondrial basal oxygen consumption rates (OCR) and maximal oxygen consumption rates (SRC, spare respiratory capacity) were decreased in MDSC from septic patients at 4 days after infection and persisted for up to 6 months after sepsis onset. Sepsis was not associated with differences in glycolysis. In contrast, oxidative metabolism in CD3 + T cells was similar between sepsis patients and healthy subjects. Reduced MDSC oxidative metabolism was linked to adverse clinical outcomes. The decline in oxygen consumption from MDSCs in septic patients was also associated with significant reductions in MDSC mitochondrial content. Transcriptomic analysis of CD66b + cells isolated from PBMC of healthy participants and patients with sepsis at 4 days, 2-3 weeks, and 6 months revealed 19 differentially expressed genes and three long non-coding RNAs as potentially responsible for this decline in mitochondrial mass. Specifically, NR4A3 , NR4A2, and TAMLIN/NR4A1 expression, all critical for mitochondrial biogenesis, were persistently decreased with reduced chromatin accessibility indicative of gene silencing.
    Discussion: After sepsis, blood CD66b + cells present with reduced mitochondrial mass and oxidative metabolism that continue at least 6 months after sepsis. These changes in mitochondrial function result from a reduced content of these organelles. We have also identified gene silencing, reduced gene expression of key transcription factors that regulate mitochondrial biogenesis, as well as increased long non-coding RNA as potential drivers of this unique metabolic phenotype. These results highlight the potential benefit of targeting metabolism in sepsis to promote immune homeostasis and recovery.
    DOI:  https://doi.org/10.64898/2025.12.16.694726
  19. Adv Sci (Weinh). 2025 Dec 23. e08107
    Regulating Tumor Metabolic Reprogramming with Biomimetic Co-Delivery of Simvastatin and Kynureninase for Immunotherapy.
    Jiaxin Yin, Shengcai Yang, Zengguang Liu, Songchen Zhao, Siyu Sun, Ziling Liu, Quanshun Li.
      The metabolic reprogramming of immunosuppressive tumor microenvironment (ITME) greatly influences the anti-tumor immunity. Bioinformatic analysis demonstrates that indoleamine 2,3-dioxygenase 1 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (key enzymes of kynurenine (Kyn) and cholesterol metabolism, respectively), are overexpressed in human colon adenocarcinoma tissues. Herein, biomimetic and pH/ROS dual-responsive nanoparticles (PTSK@CRM) loaded with simvastatin and kynureninase (KYNase) are prepared to regulate Kyn and cholesterol metabolism, thereby enhancing the immunotherapeutic efficacy of PD-1 antibody (αPD-1). The monodisperse spherical PTSK@CRM is stable at pH 7.4, while it can release simvastatin and KYNase under low pH and high H2O2 concentration. PTSK@CRM achieves excellently homologous tumor targeting to CT26 cells and induces cell apoptosis more effectively than PTSK. Moreover, PTSK@CRM significantly reduces the contents of Kyn and cholesterol and decreases the activation of the Kyn-AhR pathway in tumor metabolism. In vivo experiments show that PTSK@CRM possesses a favorable tumor-targeting ability to effectively suppress tumor growth and increase the infiltration of immune cells, including CD8+ T cells, CD4+ T cells, M1-like macrophages, and mature dendritic cells. Further, PTSK@CRM reduces the infiltration of immunosuppressive cells, thereby reversing ITME to improve the therapeutic efficacy of αPD-1. Overall, this immune-metabolic therapeutic strategy provides a potential route for remodeling ITME to enhance tumor immunotherapy.
    Keywords:  immunotherapy; kynureninase; simvastatin; tumor metabolic reprogramming
    DOI:  https://doi.org/10.1002/advs.202508107
  20. J Nutr Biochem. 2025 Dec 24. pii: S0955-2863(25)00404-8. [Epub ahead of print] 110242
    Fatty Acid Composition of Isoenergetic Meals Drives Distinct Postprandial Immunometabolic Responses in Healthy Adults: A Randomised Crossover Pilot Study.
    Elvira Marquez-Paradas, Maria Torrecillas-Lopez, Alfredo Corell-Almuraza, Teresa Gonzalez-de la Rosa, Luna Barrera-Chamorro, Beatriz Bermudez, Carmen M Claro-Cala, Sergio Montserrat-de la Paz.
       BACKGROUND: The postprandial period represents a critical and dynamic phase during which dietary components can acutely influence metabolic and immune functions. While the chronic effects of dietary fat quality are well characterized, their immediate postprandial immunometabolic impact remains poorly understood.
    OBJECTIVE: To investigate the acute effects of energy-matched test meals enriched in saturated (SFA), monounsaturated (MUFA), or omega-3 long-chain polyunsaturated fatty acids (ω3-LCPUFA), compared to a fat-free control, on systemic metabolic and immune parameters in healthy adults.
    METHODS: In this randomized, crossover pilot study, ten healthy participants consumed four test meals separated by 2-week washouts. Blood samples were collected at fasting, 2-3 h (peak), and 5-6 h (late phase) postprandially. Biochemical and immunological biomarkers were assessed. Statistical analyses included two-way repeated-measures ANOVA, linear mixed models, and area under the curve (AUC/iAUC) calculations.
    RESULTS: MUFA- and ω3-LCPUFA-enriched meals induced significantly greater postprandial changes in glucose, triacylglycerides, LDL-C, and C-peptide compared to the SFA and fat-free meals, particularly at the late postprandial phase. These effects were confirmed by AUC and iAUC analyses. In contrast, although transient changes in immune cell counts and humoral markers were observed over time, no significant differences between fat types were detected in postprandial immune responses.
    CONCLUSION: In healthy adults, the fatty acid composition of energy-matched meals acutely modulates key metabolic pathways in a fat-type-specific manner, whereas systemic immune parameters remain largely unchanged. These preliminary findings suggest a functional dissociation between postprandial metabolic and immune response and underscore the need to more sensitive or compartment-specific immune readouts in future nutritional research.
    Keywords:  Postprandial metabolism; hyperlipidaemia; immunometabolism; monounsaturated fatty acids; olive oil; omega-3 fatty acids
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.110242
  21. Theranostics. 2026 ;16(5): 2539-2558
    Modulating CD8⁺ T cell immunity through exercise: mechanistic insights and implications for precision immunotherapy.
    Xinyuan Zhao, Xu Chen, Pei Lin, Yunfan Lin, Weiyao Feng, Meiyan Zou, Nina Li, Li Cui.
      CD8⁺ T lymphocytes are pivotal effectors of adaptive immunity, executing cytotoxic mechanisms essential for pathogen clearance, tumor surveillance and tissue protection. Their activity is shaped by antigenic stimulation, cytokine networks and the metabolic and structural architecture of the tissue microenvironment. Physical exercise has emerged as a potent, non-pharmacological modulator of CD8⁺ T cell biology, capable of influencing recruitment, activation, differentiation and functional persistence. Acute exercise mobilizes effector and memory subsets, enhances trafficking to peripheral tissues and transiently alters activation thresholds, while sustained training remodels subset composition, preserves mitochondrial competence and attenuates immunosenescence. These adaptations are orchestrated through integrated neuroendocrine, vascular and metabolic pathways that recalibrate chemokine gradients, nutrient availability and energetic support. However, the magnitude and direction of these effects are highly context-dependent, varying with host physiology, disease state and microenvironmental constraints. This Review integrates mechanistic and translational evidence across physiological and pathological settings-including cancer, infectious, neurological and metabolic diseases-to clarify when and how exercise can be leveraged to reinforce cytotoxic immunity. We highlight key methodological and biological challenges, and propose biomarker-guided, microenvironment-informed and adaptively titrated exercise interventions as a framework for advancing exercise from an adjunctive measure to a modulatory, precision immunotherapy.
    Keywords:  CD8⁺ T cells; T cell dynamics; immune metabolism; immunomodulation; physical exercise
    DOI:  https://doi.org/10.7150/thno.126053
  22. Cell. 2025 Dec 24. pii: S0092-8674(25)01369-8. [Epub ahead of print]
    Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity.
    Jian Gu, Yu Li, Qiuyang Chen, Ziyan Song, Qufei Qian, Yuan Liang, Tianning Huang, Lei Qiao, Xiangyu Li, Miao Yu, Mu Liu, Jinren Zhou, Qing Shao, Xiaozhang Xu, Robert Zeiser, Ling Lu.
      Mechanisms of adaptation of regulatory T cells (Tregs) to harsh tumor metabolic microenvironments for suppression of anti-tumor immunity remain largely unclear. Here, using spatial metabolomics and transcriptomics, we show that human hepatocellular carcinoma harbored metabolically heterogeneous subregions characterized by high glutaminolysis and ammonia contents, where Tregs were frequently present but CD8+ and CD4+ effector T cells die. We found Tregs used the urea cycle to detoxify ammonia by upregulating argininosuccinate lyase (ASL); meanwhile, ammonia was also converted to spermine by the FOXP3 transcription factor regulated spermine synthase (SMS). A direct interaction between spermine and PPARγ was verified by X-ray crystallography, leading to comprehensively modulating the transcription of multiple mitochondrial complex proteins to enhance oxidative phosphorylation and immunosuppression of Tregs. Clinically, anti-PD-1-treated dying tumor cells used transdeamination to release ammonia, which reinforced Treg function, leading to immunotherapeutic resistance. Targeting ammonia production to suppress Tregs presents a potential strategy for anti-tumor immunotherapy.
    Keywords:  Tregs; ammonia; cancer immunotherapy; glutaminolysis; metabolic adaptation; polyamine metabolism; urea cycle
    DOI:  https://doi.org/10.1016/j.cell.2025.11.034
  23. J Immunother Cancer. 2025 Dec 21. pii: e010312. [Epub ahead of print]13(12):
    AMPK agonism optimizes the in vivo activation and antileukemic efficacy of chimeric antigen receptor T cells.
    Erica Braverman, Mengtao Qin, Elisabet Ampudia-Mesias, Herbert Tres Schuler, Harrison Brown, Lukas Murdych, Ann Titus, Allison MacLean, Bhavya Kanagala, Christopher Wittmann, Archana Ramgopal, Felicia Kemp, Steven J Mullet, Aaron Yang, Amanda C Poholek, Stacy Gelhaus, Craig Byersdorfer.
       BACKGROUND: Chimeric antigen receptor (CAR) T cells have achieved remarkable clinical success. However, up to 50% of patients with CAR T-cell treated leukemia relapse and long-term survivor data indicate that CAR T cell persistence is key to enforcing extended, relapse-free survival. Unfortunately, ex vivo expansion protocols often drive metabolic and functional exhaustion, reducing in vivo efficacy. Preclinical models have demonstrated that redirecting metabolism can improve in vivo T-cell function. Here, we hypothesized that exposure to an agonist targeting AMP-activated protein kinase (AMPK) would create CAR T cells capable of increased in vivo function and enhanced leukemia clearance.
    METHODS: CAR T cells were generated from healthy human donor T cells via lentiviral transduction, followed by exposure to either Compound 991 or dimethyl sulfoxide (DMSO) for 96 hours. During and after agonist treatment, T cells were harvested for metabolic and functional assessments. To test in vivo efficacy, immunodeficient mice were injected with luciferase+NALM6 leukemia cells, and 1 week later with 991- versus DMSO-expanded CAR T cells. Leukemia burden and antileukemia efficacy were assessed via radiance imaging and overall survival.
    RESULTS: Compound 991 treatment activated AMPK without limiting cellular expansion, and increased both mitochondrial density and handling of reactive oxygen species. Mechanistically, 991 treatment mimicked nutrient starvation, with increased autophagy and generation of mitochondrially protective metabolites. Importantly, receipt of 991-exposed CAR Ts significantly improved in vivo leukemia clearance and prolonged recipient survival, likely as a result of elevated activation and increased CD4+T cell yields at early times post-injection.
    DISCUSSION: Ex vivo expansion is necessary to generate sufficient cell numbers for in vivo administration, but sustained activation and differentiation often negatively impact in vivo persistence and function. Here, we demonstrate that promoting AMPK activity during in vitro CAR T expansion metabolically reprograms cells without limiting T cell yield, increases early activation following in vivo transfer, and ultimately enhances anti-leukemia efficacy. Importantly, Compound 991 treatment achieves these results without further modifying the expansion media, changing the CAR T construct, or genetically altering the cells. Together, these data highlight AMPK agonism as a potent and readily translatable approach to improve the metabolic profile and in vivo efficacy of adoptively transferred T cells.
    Keywords:  Adoptive cell therapy - ACT; Immunotherapy; Leukemia; T cell
    DOI:  https://doi.org/10.1136/jitc-2024-010312
  24. Clin Exp Immunol. 2025 Dec 21. pii: uxaf083. [Epub ahead of print]
    Lysophosphatidic acid regulates macrophage polarisation via LPAR1 by suppressing inflammatory responses and promoting M2-like characteristics.
    Wataru Nagata, Kayoko Kodama, Keiichi Nakagawa, Toshiaki Ishizuka.
       INTRODUCTION: Lysophosphatidic acid (LPA) is a crucial bioactive lipid mediator involved in various physiological processes. However, its role in macrophage polarisation remains poorly understood. The aim of this study was to elucidate the modulatory effect of LPA on macrophage polarisation, particularly its ability to shift M1 macrophages toward an M2-like phenotype.
    METHODS: Using murine macrophage RAW264.7 cells, we confirmed the expression of LPA receptor 1 (LPAR1) through immunofluorescence staining.
    RESULTS: Treatment of resting M0 macrophages with LPA decreased inflammatory cytokines (IL-6, TNF-α) and increased TGF-β; similar effects were observed in LPS-stimulated cells and were reversed by the LPAR1 inhibitor AM095. Immunostaining demonstrated a notable shift from an M1- to M2-like phenotype, as evidenced by an increase in the arginase-1/CD68 ratio. Furthermore, LPA significantly decreased lactate production and increased ATP production in M1 macrophages. LPA promoted a shift toward oxidative phosphorylation in M1 macrophages, suggesting metabolic reprogramming toward an M2-like phenotype. Treatment with LPA significantly influenced macrophage polarisation, promoting a shift from a pro-inflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype.
    CONCLUSION: These results suggest that treatment with LPA may help ameliorate diseases characterised by aberrant macrophage polarisation. Our study provides insights for the development of potential therapeutic strategies for inflammatory and autoimmune diseases.
    Keywords:  autoimmune disease; inflammation; lysophosphatidic acid; macrophage; macrophage activation syndrome
    DOI:  https://doi.org/10.1093/cei/uxaf083
  25. J Nutr Sci. 2025 ;14 e84
    Palmitic acid reduces cytosolic potassium and induces IL-1β production in lipopolysaccharide-primed human macrophages.
    Jyue-Wei Chuang, Shao-Chun Lu.
      Saturated fatty acids, particularly palmitic acid (PA), promote inflammation and contribute to chronic diseases such as type 2 diabetes and cardiovascular disease. PA induces interleukin-1 beta (IL-1β) production in lipopolysaccharide (LPS)-primed macrophages via NLRP3 inflammasome activation; but the underlying mechanism remains unclear. This study investigates whether PA-induced IL-1β production involves cytosolic potassium (K+) depletion. In LPS-primed macrophages, treatment with PA conjugated to bovine serum albumin (PA-BSA) significantly reduced cytosolic K+ levels and increased IL-1β production 2.4-fold. Stearic acid-BSA produced similar effects, whereas BSA-bound oleic, linoleic and docosahexaenoic acids had minimal impact. Voltage-gated potassium (Kv) channel blockers, 4-aminopyridine and tetraethylammonium chloride, attenuated PA-BSA-induced K+ efflux and IL-1β production in LPS-primed macrophages, implicating Kv channels as key mediators. These findings reveal a novel inflammatory pathway in which PA-BSA promotes IL-1β production via Kv channel-dependent K+ efflux, highlighting a mechanistic link between saturated fatty acid exposure and inflammatory signalling.
    Keywords:  interleukin-1 beta (IL-1β); macrophages; palmitic acid; potassium efflux; saturated fatty acids
    DOI:  https://doi.org/10.1017/jns.2025.10053
  26. bioRxiv. 2025 Dec 18. pii: 2025.12.16.694702. [Epub ahead of print]
    STING-IFN-CH25H lipid axis links innate immune activation to tau pathology.
    Hao Chen, Li Fan, Man Ying Wong, Yohannes A Ambaw, Jingjie Zhu, Kendra Norman, Pearly Ye, Nessa Foxe, Daphne Zhu, Yuansong Wan, Mahalashmi Srinivasan, Sue-Ann Mok, Laura Beth J McIntire, Tobias C Walther, Robert V Farese, Li Gan, Wenjie Luo.
      Genetic risk for Alzheimer's disease is strongly enriched in pathways governing microglial activation and cholesterol metabolism, yet how these processes converge to drive neurodegeneration remains unclear. Here, we identify the oxysterol 25-hydroxycholesterol (25- HC) as a pathogenic lipid downstream of the cGAS-STING-IFN pathway. In models of tau pathology, interferon signaling induces Cholesterol 25-hydroxylase (CH25H) expression in microglia. Ch25h deletion in female P301S mice suppressed tau aggregation, preserved synapses, prevented brain atrophy, and rescued memory. Mechanistically, loss of CH25H disrupted STING trafficking, attenuated IFN activation, dampened self-perpetuating microglial inflammation. Strikingly, 25-HC directly accelerated tau propagation in human iPSC derived neurons. It also disrupted lysosomal and mitochondrial lipid composition, driving cholesteryl ester accumulation and promoting apoptosis under tau-induced stress. These findings define a STING-IFN-CH25H lipid axis that bridges innate immune activation to tau pathology and toxicity, offering a tractable therapeutic pathway for inflammation-driven neurodegenerative conditions.
    DOI:  https://doi.org/10.64898/2025.12.16.694702
  27. Front Immunol. 2025 ;16 1736492
    Immunometabolism and male reproductive function: linking inflammation, oxidative stress, and declining fertility.
    Jiedong Zhou, Shian Hu, Yong Ouyang, Yucheng Kong, Min Liu.
       Background: Male infertility accounts for approximately 50% of all infertility cases, and its pathogenesis is highly complex. Beyond traditional factors such as genetics, endocrine disorders, and infections, growing evidence indicates that dysregulation of immunometabolism plays a pivotal role in the onset and progression of male reproductive dysfunction.
    Objective: This review aims to systematically elucidate the role of immunometabolism in male reproductive health, focusing on the complex interplay among inflammation, oxidative stress, and metabolic imbalance. Additionally, it seeks to summarize potential therapeutic targets and outline future research directions.
    Methods: A narrative review was conducted in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) guidelines. Relevant studies published between January 2010 to March 2025 were retrieved from PubMed, Embase, and Web of Science using keywords such as "immunometabolism," "testis," "male infertility," and "oxidative stress."
    Results: Testicular immune homeostasis depends on the metabolic coordination among Sertoli cells, Leydig cells, and local immune cells. Aberrant immunometabolism disrupts the blood-testis barrier and endocrine balance by enhancing glycolysis, suppressing oxidative phosphorylation, and promoting the accumulation of reactive oxygen species (ROS), thereby impairing spermatogenesis and testosterone synthesis. Systemic metabolic inflammation induced by obesity, diabetes, and gut microbiota dysbiosis further exacerbates testicular dysfunction through the mTOR/HIF-1α signaling axis and the "gut-immune-gonadal axis." Pharmacological modulation of key immunometabolic regulators, including AMPK, SIRT1, and PPARγ, has been shown to improve sperm quality and hormone levels in experimental models.
    Conclusion: Immunometabolism serves as a crucial mechanistic bridge linking inflammation, oxidative stress, and the decline of male fertility. Future studies integrating multi-omics and spatial analysis technologies are expected to delineate immunometabolic phenotypes associated with male infertility, paving the way for precision diagnosis and personalized therapeutic interventions.
    Keywords:  gut microbiota; immunometabolism, testicular immunity; male infertility; metabolic signaling; oxidative stress
    DOI:  https://doi.org/10.3389/fimmu.2025.1736492
  28. Eur J Pharmacol. 2025 Dec 24. pii: S0014-2999(25)01264-6. [Epub ahead of print] 178510
    Exosomes loaded with metabolites: Roles in crosstalk between tumor cells and their microenvironment.
    Ping Ye, Mingjun Sun, Jia Wang, Xianzhao Bai, Zihan Li, Qiang Lin, Ran Liu.
      Exosomes, small endosome-derived vesicles, mediate intercellular crosstalk among cancer cells within the tumor microenvironment (TME), while metabolic reprogramming directly drives these phenotypic changes. Recently, the application of nanoparticle tracking analysis and mass spectrometry to exosome identification and metabolite detection has brought exosome-loaded metabolites in the TME into sharp research focus. In this study, we compared the exosomal metabolites derived from cancer versus normal cells, and elucidated how these differences modulate communication between tumor and stromal or immune cells. The differences in oncometabolites associated with tumors mainly include changes in fatty acids and amino acids. Tumor metabolic shifts reflected by exosomal amino-acids alterations center on glutamate metabolism and arginine biosynthesis. Tumor-associated alterations in exosomal fatty acids centered around the biosynthesis and metabolism of phosphatidylcholine and ceramide. Like nucleic acids and proteins, exosomal metabolites serve as non-invasive, efficient biomarkers for cancer detection.
    Keywords:  Exosomal metabolites; Intercellular communication; Precision therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178510
  29. Front Immunol. 2025 ;16 1638403
    Acid ceramidase regulates CD8+ T-cell exhaustion via type I interferon-mediated upregulation of PD-L1.
    Zhongwen Hu, Hossam Abdelrahman, Abdelrahman Elwy, Fei Kuang, Swati Dhiman, Shafaqat Ali, Marcel Marson, Lisa Holnsteiner, Thamer A Hamdan, Justa Friebus-Kardash, Elisa Wiebeck, Wiebke Hansen, Stefanie Scheu, Erich Gulbins, Philipp Alexander Lang, Karl Sebastian Lang, Judith Lang.
      Besides its robust antiviral activity, type I interferon (IFN-I) also exerts immunomodulatory effects and can even drive pathology during chronic viral infections. Mechanisms that regulate IFN-I induction during virus infection, thus strongly affecting the outcome of disease, remain to be defined. Here, using the lymphocytic choriomeningitis virus (LCMV) Docile strain, we identified acid ceramidase (aCDase, Asah1) as a critical lipid-metabolic regulator of endosomal, nucleic acid-driven IFN-I responses and disease outcome during chronic virus infection. aCDase is highly expressed in plasmacytoid dendritic cells (pDCs) and required for robust early IFN-I production. aCDase deficiency resulted in ceramide accumulation, blunting IFN-α/β induction, impairing IFN-I-dependent upregulation of programmed death-ligand 1 (PD-L1) on antigen-presenting cells and preventing the exhaustion of virus-specific CD8+ T cells, leading to severe immunopathology. This pathology is abrogated by CD8+ T-cell depletion or by adoptive transfer of IFN-I-induced PD-L1-expressing macrophages. Conversely, limiting ceramide production in acid sphingomyelinase (Asm)-deficient mice prevented ceramide accumulation, and pDCs showed accelerated IFN-I induction. Mechanistically, ceramide abundance regulated IFN-I production by altering endosomal signaling microdomains. Collectively, our findings reveal ceramide homeostasis as a key determinant of IFN-I-driven CD8+ T-cell exhaustion and immunopathology during chronic viral infection and highlight aCDase as a potential therapeutic target.
    Keywords:  LCMV Docile; T cell exhaustion; acid ceramidase (aCDase); ceramide; chronic infection; plasmacytoid dendritic cell; programmed death ligand 1 (PD-L1); type I interferon
    DOI:  https://doi.org/10.3389/fimmu.2025.1638403
  30. Front Microbiol. 2025 ;16 1704491
    Spatial microbiome-metabolic crosstalk drives CD8+ T-cell exhaustion through the butyrate-HDAC axis in colorectal cancer.
    Xiaoyang Chen, Yinxu Zhang, Guangyu Zhang, Dai Wang, Linhua Dou, Yuxi Wang, Zining Huang, Xiaomei Liu.
       Background: The spatial organization of intratumoral microbiota and its metabolic impact on immunotherapy response in colorectal cancer (CRC) is unclear, limiting targeted interventions.
    Methods: We integrated single-cell RNA-seq, spatial transcriptomics, and microbial multi-omics from a discovery cohort of 23 treatment-naïve CRC patients. Findings were validated in an independent validation cohort from The Cancer Genome Atlas (TCGA-CRC, n = 159).
    Results: Spatial depletion of Streptococcus and Acetivibrio in tumor niches disrupts butyrate-histone deacetylase (HDAC) signaling, leading to programmed cell death 1 (PDCD1) hyperacetylation and CD8+ T-cell exhaustion. The Colorectal Cancer Microbiome Score (CMS) may serve as a predictive biomarker for immunotherapy response and HDAC inhibitor-based combination therapy. We developed the CMS, a spatial biomarker that stratifies patients by microbial-metabolic dysfunction, predicting immunotherapy resistance (e.g., higher tumor immune dysfunction and exclusion (TIDE) scores; p < 0.01) and guiding combinatorial HDAC inhibition for CMS-defined subgroups. In silico fecal microbiota transplantation (FMT) validated CMS as an actionable target for microbiota modulation. Butyrate supplementation in vitro restored HDAC activity and reduced PD-1 expression on CD8+ T cells, validating the proposed mechanism.
    Conclusion: Our study unveils a spatially defined, microbiome-driven metabolic niche that epigenetically programs CD8+ T-cell exhaustion via the butyrate-HDAC axis, revealing a targetable mechanism to overcome immunotherapy resistance in CRC.
    Keywords:  CD8+ T-cell exhaustion; HDAC inhibition; butyrate metabolism; colorectal cancer; microbiome-metabolic-immune crosstalk; spatial microbiome
    DOI:  https://doi.org/10.3389/fmicb.2025.1704491
  31. Brain Behav Immun. 2025 Dec 20. pii: S0889-1591(25)00477-5. [Epub ahead of print] 106235
    Metabolomic signatures of electroconvulsive therapy in schizophrenia: Mitochondrial energy metabolism and inflammation as therapeutic targets.
    Yan Li, Guangfa Wang, Xinyu Fang, Yuru Ling, Chao Zhou, Jin Fang, Renliang Cai, Yunshan Hu, Chaoran Wu, Shaotong Zhang, Ayesha Zafar Iqbal, Yu Wang, Kuan-Pin Su, Xiangrong Zhang.
       BACKGROUND: Electroconvulsive therapy (ECT) demonstrates efficacy in treatment-resistant schizophrenia, yet the underlying metabolic mechanisms remain poorly understood. This study employed comprehensive metabolomics to elucidate the therapeutic mechanisms of ECT and identify predictive biomarkers.
    METHODS: We conducted untargeted metabolomics analyses (GC-MS/LC-MS) on plasma samples from 78 schizophrenia patients (pre- and post-ECT) and 76 healthy controls, followed by targeted metabolomics validation in an independent schizophrenia cohort (n = 66). Advanced bioinformatics, including WGCNA and SVM-RFE, identified treatment-responsive metabolites.
    RESULTS: Schizophrenia patients exhibited 542 differentially expressed metabolites compared to controls (420 downregulated, 122 upregulated), predominantly lipids involved in energy metabolism pathways. Post-ECT, 200 metabolites changed significantly (153 upregulated, 47 downregulated), primarily affecting glycolysis, ketone body metabolism, and inflammatory pathways. WGCNA revealed metabolites in the turquoise module (n = 1329) strongly correlated with symptom severity. SVM-RFE identified 10 baseline metabolites distinguishing ECT responders from non-responders (AUC = 0.724). Targeted validation confirmed 6 metabolites, with 4 showing consistent elevation in responders: N-phenylanthranilic acid, Hydroxy-alpha-sanshool and Linoelaidic acid, and Piperine. Crucially, only responders demonstrated significant post-ECT increases in Hydroxy-alpha-sanshool and Piperine, both TRPV1/TRPA1 channel agonists implicated in neuroprotection and inflammation modulation.
    CONCLUSIONS: This first comprehensive metabolomic investigation of ECT in schizophrenia reveals energy metabolism dysregulation as a core pathophysiological mechanism. ECT's therapeutic effects involve metabolic reprogramming and inflammation resolution, with Hydroxy-alpha-sanshool and Piperine emerging as potential predictive and therapeutic candidates. These findings advance precision psychiatry approaches and provide mechanistic insights for developing novel schizophrenia treatments targeting mitochondrial-inflammatory networks.
    Keywords:  Electroconvulsive therapy (ECT); Energy; Inflammation; Metabolomics; Schizophrenia
    DOI:  https://doi.org/10.1016/j.bbi.2025.106235
  32. Front Immunol. 2025 ;16 1661391
    Temporal dynamics of IgG-mediated immunometabolic dysfunction: from acute obesity to chronic aging.
    Sohyun Kim, Junghyun Kim, Hyung-Lae Lee, Man S Kim.
      Immunoglobulin G (IgG) is traditionally recognized as a circulating immune effector; however, recent discoveries have revealed that IgG accumulates in adipose tissue-up to 16-fold above plasma levels-and functions as a critical mediator of metabolic dysfunction in obesity and aging. This review summarizes evidence showing that adipocyte IgG accumulation occurs via neonatal Fc receptor (FcRn)-mediated uptake and directly competes with insulin for receptor binding through Fc-CH3 domain interactions. IgG initiates tissue-specific inflammatory responses. Functional outcomes depend on glycosylation patterns: sialylated IgG (e.g., control IgG) signals anti-inflammatory pathways via DC-SIGN and CD22, whereas hyposialylated IgG (e.g., disease-associated IgG) activates endothelial FcγRIIB receptors, impairs insulin transcytosis, and promotes vascular insulin resistance. This mechanism may help explain the limited success of conventional anti-inflammatory treatments for metabolic diseases. The timeline of IgG-mediated effects progresses through acute inflammation (weeks), subacute deposition and insulin interference (months), and chronic fibrosis (years). Notably, FcRn antagonists can reverse insulin resistance, while restoration of IgG sialylation using sialic acid precursors improves function without depleting antibodies. These findings suggest that IgG dysfunction occurs at the intersection of obesity, aging, and metabolic disease, offering new biomarkers and therapeutic targets. Glycosylation profiling enables the discrimination between insulin-sensitive and -resistant individuals with similar body mass indices, supporting precision medicine approaches. This paradigm shift, from cell-centric to antibody-mediated models, reframes our understanding of metabolic disease pathogenesis and offers novel treatment strategies.
    Keywords:  FcRn; IgG; adipose tissue inflammation; immunometabolism; insulin resistance; metabolic dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2025.1661391
  33. J Autoimmun. 2025 Dec 22. pii: S0896-8411(25)00164-7. [Epub ahead of print]158 103519
    Immune cell-derived cytokines synergistically interact to drive synovial fibroblast invasive function and metabolic capacity.
    Órla Tynan, Alyssa Gilmore, Aenea A I Brugman, Achilleas Floudas, Conor M Smith, Dumitru Anton, Siobhán Wade, Carl Orr, Douglas J Veale, Ursula Fearon.
      Rheumatoid Arthritis (RA) is a chronic autoimmune disease, defined by synovial inflammation and joint destruction. A significant proportion of patients still have sub-optimal/no response to current treatments, with recent synovial scRNA-seq studies highlighting the complexity of the inflamed joint. This study investigates synovial-scRNA-seq predicted IL-1β/TGF-β synergistic regulation of RA synovial-fibroblast (FLS) pathogenic function. Synovial bulk RNA-seq analysis demonstrated increased expression of IL-1β and TGF-β signalling components in healthy controls (HC) versus early RA versus established RA, with synovial scRNA-seq demonstrating enrichment in specific RA-FLS clusters. In RA-FLS, IL-1β/TGF-β synergistically increased baseline glycolysis, ECAR:OCR ratio, proton-efflux rate, %PER glycolysis, compensatory glycolysis, and glycolytic genes (GLUT-1, PKM2, PFKFB3). Synergistic dysregulation of mitochondrial function (biogenesis and DRP1 fission protein) and endoplasmic reticulum (ER) stress responses (ER size, stress genes, chaperone protein (PDI)) were also demonstrated. The altered metabolic profile was paralleled by synergistic induction of pro-inflammatory mediators/chemokines including IL-8, MCP-1, MMP-3, and CXCL5 in RA-FLS. IL-1β and non-canonical TGF-β signalling converge on TAK1 activation. Takinib (TAK1-inhibitor) significantly reduced glycolytic and pro-inflammatory responses of RA-FLS. Importantly, in RA ex vivo synovial explants (reflecting the inflamed joint), Takinib reduced spontaneous release of pro-inflammatory mediators and the process of synovial growth. In conclusion, IL-1β/TGF-β synergistically drive a pathogenic RA-FLS phenotype in RA, blockade of which reduces inflammatory and invasive mechanisms.
    Keywords:  Fibroblast-like synoviocyte (FLS); Interleukin (IL)-1β; Rheumatoid arthritis; Transforming growth factor (TGF)-β
    DOI:  https://doi.org/10.1016/j.jaut.2025.103519
  34. Acta Biochim Biophys Sin (Shanghai). 2025 Dec 24.
    An updated overview of lipid-regulated immunobiology in macrophages.
    Ziyang Huang, He Xu, Han Lin, Quan D Zhou.
      Macrophages are well known for their widespread distribution, diverse roles, and involvement in multiple pathophysiological contexts, thereby constructing an immunological front line. Meanwhile, constant efforts over the past few decades have unveiled diverse reprogramming patterns of lipid metabolism as crucial, response- and context-specific drivers of macrophage functions and fate. Here, we take a bird's-eye view of major fields across the research landscape of lipid-regulated macrophages; review the latest advances in understanding how alterations in several lipid subclasses, especially their fatty acyl composition and oxidative status, direct macrophage-mediated responses and pathology outcomes; and summarize representative insights that have deciphered the lipidome composition of macrophages or profiled specific lipid species under different scenarios. We hope that this review provides readers with a handy grip to learn and explore the field of lipid-regulated immunobiology, exemplified by but not limited to macrophages.
    Keywords:  LC-MS/MS; cancer; fatty acids; infection and inflammation; lipid metabolism; lipid nanoparticles; macrophage; oxidized phospholipids; oxylipins; sphingolipids
    DOI:  https://doi.org/10.3724/abbs.2025239
  35. Front Cell Infect Microbiol. 2025 ;15 1623027
    PFKFB3 alleviates the advancement of Fusarium solani keratitis by attenuating macrophage inflammation.
    Yani Zhang, Yanqing Zhang, Hanfeng Tang, Jianzhang Hu.
       Objective: To investigate the anti-inflammatory effect of glycolysis rate-limiting enzyme 6-phosphofructose-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) in fungal keratitis (FK) infected by Fusarium solani (F. solani).
    Methods: We identified the up-regulation of PFKFB3 in fungal keratitis via western blot, quantitative real-time polymerase chain reaction (RT-PCR), and immunofluorescence staining. Subsequently, elucidated the augmentation of glycolytic flux in cornea and bone marrow-derived macrophages (BMDM) following F. solani invasion by RT-PCR, cellular energy metabolism analyzer, and lactate content assay. After that, we reduced PFKFB3 expression utilizing small interfering RNA (siRNA) in vitro and adeno-associated virus (AAV) in vivo and also assessed the expression levels of inflammatory factors. The severity of corneal infection following PFKFB3 depletion was checked by slit-lamp microscopy, corneal OCT, and H&E staining. Ultimately, we assessed the phosphorylation status of the PI3K/AKT/NF-κB p65 signaling pathway following PFKFB3 suppression via western blot and immunofluorescence staining.
    Results: PFKFB3 was highly triggered in F. solani-infected corneas and BMDM compared to normal tissue. Besides, infection with F. solani promotes the increase of inflammatory mediators and glycolytic flux in the cornea and BMDM. Whereas inflammation in BMDM and the degree of fungal keratitis lesions worsen by suppressing PFKFB3 expression, which increased corneal ulcer infiltration, elevated clinical scores, enhanced corneal thickness, and upregulation of inflammatory signals could be demonstrated. Furthermore, we found that F. solani infection can activate the phosphorylation of PI3K/AKT/NF-κB p65 at low PFKFB3 expression levels.
    Conclusions: In F. solani-infected corneas and BMDM, the glycolysis rate-limiting enzyme PFKFB3 was markedly upregulated. After infection, moderate PFKFB3 activation effectively mitigates inflammation and the progression of fungal keratitis. Moreover, activated PFKFB3 may rely on the PI3K/AKT/NF-κB p65 signaling pathway to safeguard the cornea from further damage due to inflammation.
    Keywords:  BMDM; Fungal keratitis; PFKFB3; glycolysis; inflammation
    DOI:  https://doi.org/10.3389/fcimb.2025.1623027
  36. Mol Immunol. 2025 Dec 22. pii: S0161-5890(25)00294-9. [Epub ahead of print]189 192-205
    Indole-3-propionic acid exerts radio-protective effects by modulating Wnt1/STAT3 pathway to alleviate oxidative stress and neuroinflammation in microglia.
    Yue Si, Biying Zhang, Jingjing Wei, Mengyun Li, Yong Liu, Hongwei Ma.
      Radiation-induced delayed brain injury (RIBI) refers to structural and functional brain alterations that develop several months to years after exposure to ionizing radiation (IR). Microglia activation-mediated neuroinflammation, as well as oxidative stress, constitutes a key factor contributing to RIBI. Indole-3-propionic acid (IPA) is an indole metabolite specifically produced by the tryptophan metabolism of gut microbiota. It can cross the blood-brain barrier and modulate the central nervous system (CNS). In order to explore the protective mechanism of IPA on IR-induced cerebral function, we studied the effect of IPA on the activation of BV2 microglia in vitro. The experimental results show that IPA can suppress the oxidative stress and inflammation of microglia, which is represented as upregulating the expression of antioxidant genes (Hmox1, Ho-1, and Nqo1), and reducing the mRNA levels of pro-inflammatory factors (Tnf-α, Il-6, Inos, and Nox2). This protective effect may be related to the inhibition of Wnt1 expression and STAT3 phosphorylation (p-STAT3 Y705; p = 0.0008) in microglia. Additionally, it was found that IPA could alleviate the IR-induced neuroinflammation and synaptic damage of mice, as evidenced by reduced serum TNF-α and IL-6 levels and widened postsynaptic density (PSD) thickness (p = 0.0239). Collectively, this study provides novel insights into the potential application of IPA in the therapeutic intervention of radiation-induced brain injury.
    Keywords:  Indole-3-propionic acid; Ionizing radiation; Microglia activation; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.molimm.2025.12.011
  37. Cancer Immunol Immunother. 2025 Dec 23. 75(1): 25
    SLC16A3 in lung adenocarcinoma regulates glycolysis and lactate release to facilitate M2 polarization of tumor-associated macrophages : Short Title: SLC16A3 reinforces macrophage M2 polarization through glycolysis.
    Peirui Chen, Qiusha Qing, Hongxia Gao, Zheng Qin, Jing Lv.
       BACKGROUND: SLC16A3 is considered to affect the malignant progression of lung adenocarcinoma (LUAD), but its mechanism remains elusive. Lactate secretion can facilitate the M2 polarization of macrophages, which are essential components of the tumor immune microenvironment (TIME).
    METHODS: Based on the Cancer Genome Atlas (TCGA) database, differential expression analysis of SLC16A3 in LUAD was undertaken and the Pearson correlation analysis was on SLC16A3 and targets of M2 macrophages. Pathway enrichment analysis on SLC16A3 was achieved by utilizing the gene set enrichment analysis (GSEA). The expression of SLC16A3 in cells was examined by qPCR and Western blot (WB). The levels of glycolysis marker proteins in cells were tested by WB. The Glucose test kit, lactate test kit, Seahorse energy metabolism analyzer, and pHrodo™ Green AM intracellular indicator reagent kit were applied in assessing cellular glycolysis levels. CCK-8, scratch assay, Transwell assay, and flow cytometry were conducted to evaluate the malignant phenotype and apoptosis level of cancer cells. Flow cytometry and Enzyme-linked immunosorbent assay (ELISA) were utilized to assess the polarization of macrophages. Finally, a mouse model of allograft tumors was created, and the effects of SLC16A3 on glycolysis and M2 polarization of macrophages in vivo were evaluated by tracking tumor growth and detecting related protein distribution through Immunohistochemistry.
    RESULTS: SLC16A3 was greatly upregulated in LUAD. Knocking down SLC16A3 remarkably repressed the malignant phenotype of LUAD cells and reinforced apoptosis. The results derived from GSEA manifested that SLC16A3 had a higher enrichment in the glycolysis pathway. SLC16A3 positively modulated the extracellular and intracellular levels of lactate and glycolysis. Pearson correlation analysis uncovered a positive linkage between SLC16A3 and M2 macrophage markers. According to the rescue experiment, glycolysis inhibitors were observed to greatly reduce the enhancement in M2 polarization of macrophages caused by overexpression of SLC16A3. The final mouse experiment demonstrated that SLC16A3 boosted tumor growth in vivo and enhanced tumor glycolysis level and M2 macrophage infiltration in the TIME.
    CONCLUSION: SLC16A3 in LUAD modulates the glycolysis pathway to facilitate M2 polarization of macrophages.
    Keywords:  Glycolysis; Lung adenocarcinoma; M2 macrophages; SLC16A3; Tumor immune suppression
    DOI:  https://doi.org/10.1007/s00262-025-04264-0
  38. Antiviral Res. 2025 Dec 24. pii: S0166-3542(25)00264-5. [Epub ahead of print] 106338
    2-Deoxy-D-glucose attenuates lipopolysaccharide-induced inflammation and restricts Zika, Chikungunya, and Mayaro virus replication in monocyte-derived macrophages.
    Y S Tamayo-Molina, Yisel García-Marin, Silvio Urcuqui-Inchima.
      Re-emerging arthropod-borne viruses such as Mayaro (MAYV), Chikungunya (CHIKV), and Zika (ZIKV) pose a growing global health concern as Aedes mosquito populations expand. These arboviruses infect innate immune cells, particularly monocyte-derived macrophages (MDMs), which support viral replication and serve as reservoirs that facilitate dissemination. Because no effective antiviral treatments are available, strategies that modulate macrophage responses and restrict viral replication are urgently needed. Here, we evaluated the immunomodulatory and antiviral effects of 2-deoxy-D-glucose (2-DG) in human MDMs. First, we assessed how 2-DG shapes transcriptional responses to lipopolysaccharide (LPS), a canonical TLR4 agonist. Co-treatment with 2-DG and LPS induced genes linked to inflammatory, antiviral, and endoplasmic reticulum (ER) stress pathways. Notably, IL10 mRNA and IL-10 protein displayed an inverse relationship with metabolic stress yet correlated positively with inflammatory and antiviral gene expression, whereas GADD34 was positively associated with both inflammatory and ER stress responses, suggesting an integrative regulatory role. We next investigated whether 2-DG pretreatment limits replication of MAYV, CHIKV, and ZIKV in infected MDMs. Antiviral assays demonstrated that 2-DG reduced replication of all three arboviruses by approximately one log10. Additional analyses revealed distinct temporal sensitivities: MAYV and CHIKV showed early and late susceptibility, whereas ZIKV exhibited a distinct kinetic profile. Mechanistic experiments confirmed that 2-DG acts post-entry primarily and reverses the antiviral phenotype observed in LPS-primed MDMs. Collectively, these findings reveal crosstalk among inflammatory, antiviral, and ER stress pathways and demonstrate that 2-DG modulates LPS-driven inflammation while reducing replication of pathogenic arboviruses in human MDMs.
    Keywords:  2-deoxy-D-glucose; Antiviral; Arbovirus; ER stress; Inflammatory; Lipopolysaccharide
    DOI:  https://doi.org/10.1016/j.antiviral.2025.106338
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