bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–12–21
fifty papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Hyperinflammation by Human Macrophages Induced by SARS-CoV-2 Anti-Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism.
  2. Effector biology and immunometabolic (re)programming: microbial strategies for compatibility.
  3. HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8+ T cell glutamine metabolism via KIR3DL3 interaction.
  4. Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells.
  5. Lactate and Lactylation in Immune Cell Function and Autoimmune Diseases: Mechanisms and Therapeutic Potential.
  6. The Diverse Roles of Lipid Metabolism Reprogramming in Shaping the Tumor Immune Microenvironment.
  7. Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
  8. Persistent glycolysis defines pathological foreign body-associated inflammation to polymeric implants.
  9. From metabolic alterations to chronic inflammation: mechanisms and immunoregulation of metabolic reprogramming in COPD.
  10. Metabolic hijacking styles: a review of how viral life cycles dictate glucose metabolism reprogramming.
  11. Galectin-1 induces macrophage immunometabolic reprogramming, modulates T cell immunity and attenuates atherosclerotic plaque formation.
  12. Reprogramming of the kynurenine pathway impairs NAD+ homeostasis and mediates doxorubicin-induced cardiotoxicity in mice.
  13. Bcl-2 protein Noxa is required for metabolic reprogramming to glutamine dependence and for apoptosis in stimulated human CD8 + T cells.
  14. VNUT-mediated ATP release suppresses T helper 1 (TH1) cell differentiation via the P2X7R-JNK-FOXO3a-Eomes signaling cascade.
  15. Macrophages: their role in immunity and their relationship with fatty acids in health and disease.
  16. The Role of Mitochondrial Regulation in Macrophage Polarization: Implications for the Pathogenesis of Rheumatoid Arthritis.
  17. DANCR promotes septic cardiomyopathy by enhancing macrophage glycolytic reprogramming via the IGF2BP2/HK2 axis.
  18. FIP200 regulates plasma B cell differentiation via mitochondrial and heme homeostasis.
  19. Efferocytosis-induced metabolic shift in bone macrophages drives lactate production and modulates inflammation and osteoclastogenesis.
  20. SLC7A5 regulates B cell metabolism and plasma cell differentiation independent of leucine transport.
  21. Neutrophil Irg1/itaconate axis protects against experimental colitis by suppressing local inflammation and maintaining hematopoietic homeostasis.
  22. A genome-wide CRISPR screen identifies GRA38 as a key regulator of lipid homeostasis during Toxoplasma gondii adaptation to lipid-rich conditions.
  23. Metabolic reprogramming by pseudorabies virus: nucleotide metabolism as a central vulnerability for viral replication and pathogenesis.
  24. Spike protein-induced VSIR-ISX signaling disrupts metabolic homeostasis and promotes COVID-19-related immune dysfunction.
  25. Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
  26. The Role of Interferon-Mediated Suppression of Monocyte Immunothrombosis in Infection Susceptibility in SLE.
  27. An intermediate-crystalline phase manganese nanoadjuvant potently activates cGAS-STING signaling and antitumor immunity via immunometabolism normalization.
  28. Melatonin alleviates atherosclerosis by inhibiting pro-inflammatory differentiation of macrophages via regulating Sirt3-Drp1 mediated mitochondrial fission.
  29. PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction.
  30. Maternal milk-derived lipids dictate neonatal macrophage phenotype and function.
  31. A metabolism-chromatin axis promotes differential ribosomal RNA transcription in the human malaria parasite.
  32. Mitochondrial pyruvate metabolism in club cells drives airway inflammation.
  33. Rapamycin preserves cardiac function in autoimmune myocarditis by reprogramming Cxcl9+ macrophages via the mTORC1-C/EBPβ-OSM axis.
  34. Immunometabolic profiling of T cells in response to prolonged moderate intensity cycling in humans.
  35. Chemotherapy-driven intestinal dysbiosis and indole-3-propionic acid rewire myelopoiesis to promote a metastasis-refractory state.
  36. Metabolic Adaptation in Colorectal Cancer Microenvironment: Focus on Cancer-Associated Fibroblasts (CAFs) and Tumor-Associated Macrophages (TAMs).
  37. Exercise-induced histone lactylation in monocyte-derived macrophages restores cardiac immune homeostasis and function in sepsis-induced cardiomyopathy.
  38. Spatial transcriptomics uncovers lipid metabolic dysregulation driving immune-stroma crosstalk in Sjögren's Disease.
  39. Immunometabolic insights into the foreign body response.
  40. Celastrol inhibits intrahepatic cholangiocarcinogenesis through dual suppression of glycolysis and tumor-associated macrophages.
  41. The Neuroprotective Effect of 4-Octyl Itaconate on Acute Period of Experimental Autoimmune Neuritis.
  42. Lipopolysaccharide-induced histone lactylation mediates m6A RNA modification causing mitochondrial dysfunction and pulmonary fibroblasts activation to exacerbate sepsis-associated pulmonary fibrosis.
  43. Long-Term High-Protein Diet Intake Accelerates Adipocyte Senescence Through Macrophage CD38-Mediated NAD+ Depletion.
  44. MTHFR allele and one-carbon metabolic profile predict severity of COVID-19.
  45. Intestinal γδ T17-IL-17A signaling disrupts hippocampal mitophagy in stress-induced depression and is restored by arketamine.
  46. Exploring the gut microbiome in systemic lupus erythematosus: metagenomic and metabolomic insights into a new pro-inflammatory bacteria Clostridium scindens.
  47. Branched chain amino acids prime metabolic inflammation.
  48. Metabolic collusion driving immune evasion in cholangiocarcinoma: unmasking the dual control of the immuno-metabolic microenvironment.
  49. Gut microbiota promotes immune tolerance at the maternal-fetal interface.
  50. IL-36γ signalling promotes a proinflammatory macrophage state that is associated with reduced lipid uptake.
  1. Eur J Immunol. 2025 Dec;55(12): e70087
    Hyperinflammation by Human Macrophages Induced by SARS-CoV-2 Anti-Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism.
    Amsterdam UMC COVID‐19 Biobank
      Severe COVID-19 is an immunological disorder characterized by excessive immune activation following infection with SARS-CoV-2, which typically occurs around the time of seroconversion. Anti-spike IgG of critically ill COVID-19 patients induces excessive inflammation by activation of Fc gamma receptors (FcγRs) on human alveolar macrophages, leading to tissue damage, pulmonary edema, and coagulopathy. While metabolic reprogramming of immune cells is critical for the induction of inflammatory responses, still little is known about the metabolic pathways that are involved in COVID-19-specific hyperinflammation. In this study, we identified that anti-spike IgG immune complexes (ICs) induce rapid metabolic reprogramming of alveolar macrophages, which is essential for the induction of inflammation. Through functional inhibition, we identified that glycolysis, fatty acid synthesis, and pentose phosphate pathway (PPP) activation are critical for anti-spike IgG-induced hyperinflammation. Remarkably, while excessive proinflammatory cytokine production by macrophages is critically dependent on simultaneous stimulation with viral stimuli and anti-spike IgG complexes, we show that the required metabolic reprogramming is specifically driven by anti-spike IgG complexes. These findings provide new insights into the metabolic pathways driving hyperinflammation by macrophages in the context of severe COVID-19. Targeting of these pathways may reveal new possibilities to counteract pathological inflammatory responses in severe COVID-19 and related diseases.
    Keywords:  COVID‐19; antibodies; immunometabolism; macrophage
    DOI:  https://doi.org/10.1002/eji.70087
  2. Mol Plant. 2025 Dec 17. pii: S1674-2052(25)00446-0. [Epub ahead of print]
    Effector biology and immunometabolic (re)programming: microbial strategies for compatibility.
    Alga Zuccaro.
      Root immunometabolism: balancing defense and accommodation Plant health depends on balanced immune defense and microbial accommodation. As constant contact zones, roots must exclude pathogens while fostering beneficial symbionts. Classical, leaf-based immunity models fail to capture the spatial and metabolic complexity of roots, which contain functionally distinct zones and cell types with diverse immune sensitivities and responses (Tsai et al., 2023). Unlike broad immune responses in leaves, root defense is often confined to a few neighboring cells where cellular damage signals coincide with microbial cues. This localized activation likely prevents excessive immunity that could disrupt root development or beneficial colonization (Tsai et al., 2023), shaping microbiome assembly by determining which taxa persist in specific root niches. Beyond immunity, metabolic cues also influence niche formation, collectively defining the physicochemical landscape that selects specific microbial consortia (Loo et al., 2024). Microbial effector proteins from both pathogens and mutualists act individually or cooperatively to reprogram host immune and metabolic pathways, modulating compatibility and plant health. This integrated regulation, known as immunometabolism, is well established in animals, where defined metabolic pathways govern immune cell fate and function. In plants, immunometabolic control is emerging as a conceptual frontier, with host transporters, receptors, and microbial effectors increasingly recognized as key modulators along the mutualism-pathogenesis continuum. Central to this molecular dialogue are extracellular and intracellular signaling metabolites, or infochemicals, produced by both plants and microbes. These small molecules coordinate immune-metabolic states and shape community composition, with purine-derived signals and iron-mediated redox exchanges representing conserved regulatory axes across plant and animal systems (Dangol et al., 2019; Dunken et al., 2024). Together, these cross-kingdom principles offer conceptual and practical leverage for predictive microbiome engineering. Because this opinion piece spans immunity, metabolism, and microbial ecology, INFOBOX 1 defines key terms to establish a shared conceptual framework.
    DOI:  https://doi.org/10.1016/j.molp.2025.12.016
  3. Cancer Lett. 2025 Dec 12. pii: S0304-3835(25)00791-8. [Epub ahead of print]639 218219
    HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8+ T cell glutamine metabolism via KIR3DL3 interaction.
    Fei Wu, Jiannan Shen, Zhiting Zhao, Yan Chen, Binhui Ren, Ming Li, Rong Yin, Yanyan Zhang, Shaorong Yu.
      Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and EGFR-mutant tumors show limited response to current immunotherapy. The immunosuppressive tumor microenvironment, particularly metabolic constraints on effector T cells, is increasingly recognized as a major barrier to effective anti-tumor responses. HHLA2, a B7 family member frequently elevated in EGFR-mutant NSCLC, has an incompletely defined role in immune escape. In this study, we demonstrate that tumor-derived HHLA2 engages the inhibitory receptor KIR3DL3 on CD8+ T cells, driving T cell exhaustion through metabolic reprogramming of amino acid utilization. HHLA2-KIR3DL3 signaling suppresses glutamine utilization through ERK/MAPK-dependent repression of SLC1A5, SLC38A2, and ADHFE1, key glutamine transporters and metabolic enzymes, thereby inducing metabolic insufficiency and dysfunctional cytokine production in CD8+ T cells, including reduced IFN-γ, TNF-α, and increased IL-10. Disruption of this axis-via HHLA2 deletion or antibody blockade-restored T cell metabolism and effector function, leading to attenuated tumor progression in humanized mouse models. Notably, HHLA2/KIR3DL3 inhibition synergized with EGFR tyrosine kinase inhibitors to enhance anti-tumor immunity and suppress tumor progression. Together, these findings identify HHLA2-KIR3DL3 as a key immunosuppressive pathway in EGFR-mutant NSCLC and may provide a rationale for therapeutic targeting to improve clinical outcomes.
    Keywords:  CD8(+) T cell exhaustion; EGFR-Mutant lung cancer; ERK/MAPK signaling pathway; Glutamine metabolism; HHLA2
    DOI:  https://doi.org/10.1016/j.canlet.2025.218219
  4. J Clin Invest. 2025 Dec 15. pii: e194134. [Epub ahead of print]135(24):
    Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells.
    Keisuke Seike, Shih-Chun A Chu, Yuichi Sumii, Takashi Ikeda, Meng-Chih Wu, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Pavan Reddy.
      Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A-deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate these differences. SDHA deficiency induced metabolic changes and remodeled gene expression exclusively in activated T cells. In CD4+ T cells, SDHA loss dampened both oxidative phosphorylation (OXPHOS) and glycolysis, impaired cytokine production, proliferation, and reduced CD4+ T cell-mediated graft-versus-host disease after allogeneic stem cell transplantation (SCT). In contrast, SDHA deficiency in CD8+ T cells reduced OXPHOS but paradoxically upregulated glycolysis and demonstrated enhanced cytotoxic functions in vitro and in vivo. This metabolic reprogramming endowed SDHA-KO CD8+ T cells with superior in vivo antitumor efficacy after immune checkpoint inhibitor therapy and allogeneic SCT. These findings reveal MC II as a bifurcation point for metabolic and functional specialization in CD4+ and CD8+ T cells.
    Keywords:  Bone marrow transplantation; Hematology; Immunology; Metabolism; Mitochondria; T cells
    DOI:  https://doi.org/10.1172/JCI194134
  5. Immunology. 2025 Dec 16.
    Lactate and Lactylation in Immune Cell Function and Autoimmune Diseases: Mechanisms and Therapeutic Potential.
    Yiying Yang, Ying Zhang, Ke Liu, Huali Zhang, Xiaoxia Zuo, Muyao Guo.
      Lactate metabolism plays a crucial role in immune cell function, particularly during inflammation or metabolic stress. Under these conditions, immune cells often undergo a metabolic shift towards glycolysis, resulting in increased lactate production. This reprogramming not only provides energy but also influences cellular signalling pathways that regulate gene expression and immune responses. A key outcome of elevated lactate levels is lactylation, a novel post-translational modification where lactate molecules are covalently attached to proteins, typically at lysine residues. Lactylation regulates protein activity and function, impacting transcription factors, enzymes and other proteins involved in immune cell activation, differentiation and inflammation. The process of lactylation is controlled by specific enzymes known as 'writers', 'erasers' and 'readers', which add, remove and recognise lactate modifications on proteins. Lactylation plays a significant role in immune cell function, influencing cytokine production, immune cell proliferation and the regulation of inflammation. Abnormal lactylation can contribute to the pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), by enhancing immune cell activation and promoting chronic inflammation. Elevated lactate levels in these diseases exacerbate immune responses, leading to tissue damage and autoantibody production. Targeting lactate metabolism or modulating lactylation presents a promising therapeutic strategy for autoimmune diseases. By regulating the enzymes involved in lactylation or controlling lactate accumulation, it may be possible to modulate immune responses, reduce inflammation and alleviate disease symptoms. Although current evidence largely derives from pre-clinical models and cell-based studies, emerging findings suggest that targeting lactate metabolism or modulating lactylation represents a promising therapeutic approach for autoimmune diseases. Future clinical studies are warranted to validate the translational potential of lactylation-related pathways and to develop safe and effective therapeutic strategies.
    Keywords:  PTMs; autoimmune diseases; glycolysis; immune cells; lactate; lactylation
    DOI:  https://doi.org/10.1111/imm.70075
  6. Cancer Res. 2025 Dec 15.
    The Diverse Roles of Lipid Metabolism Reprogramming in Shaping the Tumor Immune Microenvironment.
    Jiin Lee, Jacinth Wing-Sum Cheu, Carmen Chak-Lui Wong.
      Lipid metabolism reprogramming modulates the tumor microenvironment (TME) and alters the function of immune cells, including tumor-infiltrating lymphocytes (TILs). While lipids can enhance general T cell activity, high lipid content in the TME may restrain the anti-tumor function of effector T cells and augment immunosuppression by regulatory T cells. In addition, lipid metabolism reprogramming greatly influences the crosstalk between TILs and other immune cells in the TME, including dendritic cells, macrophages, and myeloid-derived suppressor cells. By discussing potential therapeutic strategies to target lipid metabolism in TILs, along with combination approaches with chemo-immunotherapy, nanomedicine, and adoptive cell transfer therapy, we aim to lay the groundwork for advancing effective treatments for cancer patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2568
  7. Nat Cell Biol. 2025 Dec 19.
    Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
    Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.
      T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
    DOI:  https://doi.org/10.1038/s41556-025-01835-2
  8. Sci Adv. 2025 Dec 19. 11(51): eadx6368
    Persistent glycolysis defines pathological foreign body-associated inflammation to polymeric implants.
    Christian Rempe, Neal Callaghan, Lauren Fong-Hollohan, Sarah Nersesian, Zachary Froom, Kyle Medd, Ibrahim Ahmed, Tobias Karakach, Jeanette E Boudreau, Michael Bezuhly, Locke Davenport Huyer.
      The clinical deployment of nondegradable polymeric medical devices is hindered by unresolving inflammation that drives localized fibrosis. This inflammatory niche is distinct; phagocytic macrophages remain persistently activated by biomolecular signals adsorbed to the implant surface, exhibiting profibrotic behavior. Increasingly, alterations to metabolic regulation offers insight into chronically inflamed macrophage function, which remains unexplored in peri-implant inflammation. Here, ex vivo profiling of metabolic dependence and capacity in peri-implant tissues revealed persistent glycolytic reliance by macrophages up to 6 weeks postimplantation. Expression of glucose transporter 1 (GLUT1) increased temporally and with proximity to the implant interface in glycolytically dependent cells, paired with increased capacity for biosynthetic pathways. Glycolytic dependence was notable in multinucleated macrophages, hallmark to the phagocytic behavior of implant pathology. Transcriptomic assessment correlated the up-regulation of pathological wound healing to cells where the capacity for glucose import was highest, highlighting glycolysis as the definitive metabolic system in persistent peri-implant inflammation.
    DOI:  https://doi.org/10.1126/sciadv.adx6368
  9. Front Immunol. 2025 ;16 1698832
    From metabolic alterations to chronic inflammation: mechanisms and immunoregulation of metabolic reprogramming in COPD.
    Siyu Zeng, Yanqiu Zhang, Shiran Li, Zhimin Li, Pengfei Li, Jingxian Xie, Jiao Zhang, Liling Xie, Yong Yang.
      Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease characterized by high prevalence, mortality, and disease burden. Current understanding of COPD pathogenesis primarily focuses on airway inflammation, immune dysfunction, oxidative stress, and protease-antiprotease imbalance. Notably, recent studies have increasingly highlighted the role of metabolic reprogramming in COPD. Metabolic reprogramming refers to cellular adaptation through metabolic pathway alterations in response to environmental stress, enabling physiological or pathological state transitions. This review systematically summarizes COPD pathogenesis, with particular focus on metabolic reprogramming features (glucose, lipid, and amino acid metabolism) in immune cells from COPD experimental models. Furthermore, we analyze the interactions between these metabolic alterations and chronic inflammatory responses, providing new insights into COPD pathogenesis.
    Keywords:  Chronic Obstructive Pulmonary Disease; airway remodeling; immunometabolism; inflammation; metabolic reprogramming; oxidative stress
    DOI:  https://doi.org/10.3389/fimmu.2025.1698832
  10. Front Microbiol. 2025 ;16 1690133
    Metabolic hijacking styles: a review of how viral life cycles dictate glucose metabolism reprogramming.
    Ziyi Bie, Yixing Tan, Chun Ye, Ke Wei.
      Viral infection profoundly reprograms host glucose metabolism to support replication. This review proposes a "Sprint vs. Marathon" framework to explain how viral life cycles shape distinct metabolic hijacking styles. Acute RNA viruses employ a rapid, high-intensity "Sprint" strategy, aggressively activating glycolysis through pathways such as PI3K/Akt and HIF-1α. In contrast, chronic and latent viruses adopt a sustained "Marathon" strategy, subtly modulating glycolytic enzymes, glucose transporters, and survival pathways including NF-κB and mTOR. Understanding these divergent metabolic programs provides new insight into viral pathogenesis and highlights opportunities for developing host-directed antiviral therapies.
    Keywords:  glucose metabolism; glycolytic enzymes; host–virus interaction; metabolic reprogramming; viral infection
    DOI:  https://doi.org/10.3389/fmicb.2025.1690133
  11. Atherosclerosis. 2025 Dec 04. pii: S0021-9150(25)01506-0. [Epub ahead of print]413 120608
    Galectin-1 induces macrophage immunometabolic reprogramming, modulates T cell immunity and attenuates atherosclerotic plaque formation.
    Ya Li, Julian Leberzammer, Xavier Blanchet, Rundan Duan, Michael Lacy, Vasiliki Triantafyllidou, Veit Eckardt, Eva Briem, Anna Simone Jung, Rui Su, Joel Guerra, Yvonne Jansen, Michael Hristov, Wolfgang Enard, Jürgen Bernhagen, Christian Weber, Dorothee Atzler, Alexander Bartelt, Yvonne Döring, Donato Santovito, Herbert Kaltner, Anna-Kristin Ludwig, Philipp von Hundelshausen.
       BACKGROUND AND AIMS: Atherosclerosis is a chronic immunometabolic disease driven by lipid accumulation and immune cell infiltration. Macrophages and T cells play key roles throughout plaque development. Galectin-1 (Gal-1), a glycan-binding protein, modulates immune functions in these cells and has been reported to attenuate atherosclerosis, though its mechanisms remain incompletely understood. Here, we investigated the effects of Gal-1 on macrophages and T cells during plaque formation.
    METHODS: Effects of Gal-1 on atherosclerosis, macrophages and T cells during lesion formation were studied in Apoe-/- mice treated with recombinant Gal-1. Complementary mouse peritoneal foam cell and in vitro macrophage and T cell culture experiments were performed to study T cell differentiation, macrophage function, polarization and energy metabolism. The impact of Gal-1 on human macrophages was further evaluated in endarterectomy specimens.
    RESULTS: Gal-1 treatment reduced lesion size and increased circulating IL-10 levels, inversely correlating with plaque burden. Unexpectedly, IL-10 neutralization also mitigated atherosclerosis, indicating that its action is at least partially IL-10-independent. In plaques, Gal-1 promoted anti-inflammatory macrophage phenotypes, mirrored by a quiescent metabolic and anti-inflammatory profile in foamy macrophages ex vivo. The use of the Gal-1E71Q variant revealed that these effects were only partly dependent on glycan binding. Beyond IL-10, Gal-1 reshaped cytokine profiles by increasing IL-17, IL-22, and IL-23, consistent with a macrophage-driven regulatory Th17 response, alongside higher frequencies of IL-10-producing and regulatory T cells.
    CONCLUSION: Gal-1 protects against atherosclerosis associated with reprogramming macrophages and tuning T cell immunity through glycan-dependent and -independent pathways.
    Keywords:  Cytokine; Foam cell; Glycan; Glycolysis; Macrophage polarization; OXPHOS; Treg
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2025.120608
  12. Redox Biol. 2025 Dec 06. pii: S2213-2317(25)00470-7. [Epub ahead of print]89 103957
    Reprogramming of the kynurenine pathway impairs NAD+ homeostasis and mediates doxorubicin-induced cardiotoxicity in mice.
    Danlei Li, Yang Zhang, Yuanyuan Kuang, Zhong Lin, Ping Wang, Jianjun Jiang, Wenhu Pi, Qilin Ma.
      Imbalance of Nicotinamide adenine dinucleotide (NAD+) homeostasis is a key contributor to various cardiac pathologies, including doxorubicin (DOX)-induced cardiomyopathy (DIC). The kynurenine pathway (KP), initiated by indoleamine 2,3-dioxygenase 1 (IDO1), serves as the primary route for de novo NAD + biosynthesis. While this pathway regulates critical biological processes such as cellular metabolism, inflammatory responses, oxidative stress, and aging, its specific role in DIC remains poorly understood. Here, we reveal a protective function of the KP in DIC by facilitating NAD+ synthesis. Genetic ablation of IDO1 exacerbates DOX-induced cardiac injury and structural damage in mice. In cardiomyocytes, DOX treatment upregulates α-amino-β-carboxy-muconate-semialdehyde decarboxylase (ACMSD) while downregulating quinolinate phosphoribosyl-transferase (QPRT), thereby reducing levels of the intermediate metabolite quinolinic acid (QA) and NAD+ levels. These effects can be pharmacologically reversed by TES-1025, an ACMSD inhibitor that enhances QPRT activity and potentiates the cardioprotective effects of the KP pathway against DIC. Mechanistically, we show that DOX modulates the STING/interferon γ/5'-AMP-activated protein kinase (p-AMPK) signaling axis to elevate ACMSD and suppress QPRT. Our findings establish a novel therapeutic potential that targets the metabolic switch ACMSD to QPRT, restoring NAD+ redox homeostasis and conferring protection against DIC in murine models.
    Keywords:  ACMSD; Cardiotoxicity; DOX; Kynurenine pathway; NAD(+); ROS
    DOI:  https://doi.org/10.1016/j.redox.2025.103957
  13. bioRxiv. 2025 Dec 10. pii: 2025.12.08.692849. [Epub ahead of print]
    Bcl-2 protein Noxa is required for metabolic reprogramming to glutamine dependence and for apoptosis in stimulated human CD8 + T cells.
    Tingyuan Yang, Himani Sharma, Jenna M Benson, William J Valente, Rebecca LaRue, Beau Webber, Branden Moriarity, Christopher A Pennell, Stephen C Jameson, Ameeta Kelekar.
      Naïve or memory T cells reprogram their metabolism upon antigenic stimulation. They increase their glucose uptake, relying on aerobic glycolysis for generating biomass while switching to glutamine to fuel energy production. Here we have identified a requirement for human Bcl-2 family, Noxa, in the metabolic switch to glutamine dependence in activated CD8 + T cells, that is independent of its canonical role in apoptosis at the end of the immune response. Using an in vitro co-stimulation model, we demonstrate that Noxa is induced in CD8 + T cells and remains elevated during the proliferative and differentiation phases of the response and through the onset of apoptosis. Noxa protein induction requires glutamine, is mediated via mTOR, and is independent of glutaminolysis. Glutamine, in turn, requires Noxa to facilitate its conversion to glutamate. CD8 + T cells lacking Noxa showed reduced levels of intracellular glutamate but no impairment of mitochondrial or effector function, and decreased dependence on glutamine for both respiration and growth during the proliferative phase. NOXA knockout CD8⁺ T cells also displayed significantly higher viability in the apoptotic phase of the immune response. CD8 + T cells from a human NOXA gene-replacement mouse responded normally to in vitro stimulation and in vivo acute infection. However, human Noxa-expressing murine CD8 + T cells displayed a distinctly proliferative gene signature in their transcriptome following activation, supporting an early growth-promoting role for this BH3-only protein. Our studies suggest that knocking out NOXA in human CD8 + T cells to increase their lifespan as well as their ability to survive and function in glutamine-poor microenvironments could be a promising immunotherapeutic strategy.
    DOI:  https://doi.org/10.64898/2025.12.08.692849
  14. Sci Adv. 2025 Dec 19. 11(51): eadz7600
    VNUT-mediated ATP release suppresses T helper 1 (TH1) cell differentiation via the P2X7R-JNK-FOXO3a-Eomes signaling cascade.
    Bolong Wu, Linlin Sheng, Ziyi Feng, Xiaohu Wang, Ligong Chen.
      Extracellular ATP (eATP), a well-recognized danger signal and immune activator, is implicated in the activation, differentiation, and function of T cells, directly or indirectly. Yet, how T cells release ATP themselves and its effects remain poorly investigated. Here, we found vesicular nucleotide transporter (VNUT), critical for vesicular ATP storage/release, is highly expressed in TH1 cells and selectively restricts their differentiation and effector functions. Mechanistically, VNUT facilitates lysosomal ATP import and its extracellular release upon T cell receptor engagement. This eATP then activates the purinergic receptor P2X7R and downstream SRC kinase, triggering a signaling cascade involving heightened Ca2+ influx and hyperphosphorylation of JNK and FOXO3a, which ultimately impairs Eomes-directed IFN-γ production in TH1 cells. Genetic/pharmacological of VNUT inhibition significantly potentiates TH1 effector functions against Listeria infection and transplanted tumors. These findings identify VNUT as a critical checkpoint in limiting TH1 immunity, coupling vesicular ATP transport to transcriptional control via the P2X7R-JNK-FOXO3a-Eomes axis, offering a target for treating infection and cancer.
    DOI:  https://doi.org/10.1126/sciadv.adz7600
  15. Front Immunol. 2025 ;16 1694892
    Macrophages: their role in immunity and their relationship with fatty acids in health and disease.
    Mayte Rueda-Munguía, Luis Alberto Luévano-Martínez, Gerardo García-Rivas, Elena Cristina Castillo, Omar Lozano.
      The intricate interplay between macrophage biology and lipid metabolism has emerged as a critical determinant of metabolic homeostasis, disease progression and pathogenesis. This comprehensive review explores the molecular mechanisms through which fatty acids activate macrophage function, emphasizing their selective engagement of pattern recognition receptors such as Toll-like receptors (TLRs), CD36, and GPR120. Notably, saturated fatty acids (SFAs) like lauric acid (C12:0) and palmitic acid (C16:0) activate TLR2 and TLR4 signaling pathways. Palmitic acid triggers mitochondrial dysfunction and lysosomal destabilization, leading to NLRP3 inflammasome activation and chronic low-grade inflammation. In contrast, ω-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid, help resolve inflammation through GPR120-mediated signaling and the production of specialized pro-resolving mediators (SPMs) like resolvins, protectins, and maresins. This review establishes a paradigm for understanding the complex relationship between dietary lipids, innate immunity, and metabolic health, with broad implications for immunometabolic interventions.
    Keywords:  fatty acids; immunometabolism; inflammation; macrophages; metabolic diseases
    DOI:  https://doi.org/10.3389/fimmu.2025.1694892
  16. J Inflamm Res. 2025 ;18 17163-17183
    The Role of Mitochondrial Regulation in Macrophage Polarization: Implications for the Pathogenesis of Rheumatoid Arthritis.
    Pingshun Li, Gang Wang, Zhihui Peng, Lihuan Zhang, Fang Yang, Yong Wei, Meihan Pan, Haohao Zang, Mengru Zhou.
      Rheumatoid arthritis (RA) is an autoimmune arthropathy closely associated with chronic inflammation, whose pathogenesis involves macrophages, particularly M1 macrophage-induced inflammatory responses. Mitochondria, as key organelles governing macrophage metabolism and function, regulate M1/M2 macrophage polarization through multiple pathways and signaling molecules, thereby inducing immune and inflammatory responses that contribute to RA development. Therefore, this paper delves into the intricate mechanisms by which mitochondria regulate macrophage-specific polarization. These pathways encompass metabolic processes, signaling molecules, mitochondrial dynamics, mitochondrial-associated molecules, mitochondrial autophagy, ion homeostasis, and mitochondrial translocation. The study underscores the pivotal role of mitochondria in macrophage-specific polarization and highlights the potential for basic research to intervene in RA by modulating Mitochondrial metabolism, mitochondrial dynamics, mitochondrial autophagy, and mitochondrial translocation to promote M1-to-M2 macrophage conversion and suppress RA inflammatory responses. This holds significant implications for repairing RA-induced bone destruction and advancing clinical treatment.
    Keywords:  M1/M2 polarization; inflammatory response; macrophages; pathogenesis; rheumatoid arthritis
    DOI:  https://doi.org/10.2147/JIR.S560635
  17. Front Cell Dev Biol. 2025 ;13 1628915
    DANCR promotes septic cardiomyopathy by enhancing macrophage glycolytic reprogramming via the IGF2BP2/HK2 axis.
    Chunhui Ma, Shaoyu Liu, Yu Zhao, Hong Liu, Xuguang Zhang.
       Background: Metabolic reprogramming of macrophages shapes their phenotypic plasticity and contributes to the progression of septic cardiomyopathy. This study investigated the role of DANCR in modulating of macrophage glycolysis, thereby elucidating its mechanism for augmenting septic cardiomyopathy.
    Method: THP-1-derived macrophages were stimulated with LPS and subjected to DANCR knockdown or HK2 overexpression. Inflammatory cytokine levels, M1 polarization, and glycolytic activity were evaluated. Conditioned media from treated macrophages were used to treat cardiomyocytes. Mechanistic analyses, including bioinformatics, RNA immunoprecipitation (RIP), and RNA stability assays, were performed to identify downstream targets of DANCR.
    Result: DANCR silencing attenuated M1 polarization and activity in macrophages, improved cardiomyocyte viability and reducing apoptosis. Mechanistically, DANCR upregulated HK2 expression by enhancing IGF2BP2-mediated mRNA stabilization. HK2 overexpression reversed the protective effects of DANCR knockdown, whereas pharmacologic inhibition of glycolysis counteracted the effects of HK2 overexpression, confirming the involvement of the DANCR/IGF2BP2/HK2 axis.
    Conclusion: DANCR promotes septic cardiomyopathy by enhancing macrophage glycolytic reprogramming via the IGF2BP2/HK2 axis. Targeting this pathway may provide a novel therapeutic strategy.
    Keywords:  DANCR; HK2; IGF2BP2; glycolysis; macrophage M1 polarization; septic cardiomyopathy
    DOI:  https://doi.org/10.3389/fcell.2025.1628915
  18. J Exp Med. 2026 Mar 02. pii: e20250535. [Epub ahead of print]223(3):
    FIP200 regulates plasma B cell differentiation via mitochondrial and heme homeostasis.
    Liling Xu, Maria Bottermann, Paula M Villavicencio, John Warner, Stephanie R Weldon, Zhenfei Xie, Andrew Filby, Xiaotie Liu, Ian G Ganley, Alison E Ringel, Usha Nair, Facundo D Batista.
      Little is known about the role of autophagy in the human humoral immune system. Here, we found that in B cells, genetic ablation of FIP200, a mammalian metabolic sensor that regulates autophagy in response to a range of stimuli, led to diminished humoral immune responses in mice. FIP200-deficient B cells displayed decreased differentiation into plasma cells, as well as mitochondrial dysfunction, alterations in heme biosynthesis, and significant cell death. Notably, the addition of heme was sufficient to rescue plasma cell differentiation of FIP200-deficient B cells. Thus, FIP200 determines B cell fates by controlling mitophagy and metabolic reprogramming.
    DOI:  https://doi.org/10.1084/jem.20250535
  19. Front Immunol. 2025 ;16 1650465
    Efferocytosis-induced metabolic shift in bone macrophages drives lactate production and modulates inflammation and osteoclastogenesis.
    Rahasudha Kannan, Nicholas J Carruthers, Amy J Koh, Gabriel G Kleer, Kotoba Nakamura, Stephen C J Parker, Laurie K McCauley, Hernan Roca.
      During the critical process of homeostatic efferocytosis, macrophages clear apoptotic cells and subsequently transition to reparative functions that promote the resolution of inflammation and support tissue repair. Their inherent plasticity enables rapid changes in macrophage activity suited to specific microenvironments. However, the heterogeneity in their cell states also presents challenges in characterizing subsets of macrophages and analyzing their specific contributions post-efferocytosis. In this study, single-cell RNA sequencing data from bone-marrow derived macrophages engulfing apoptotic osteoblasts (OB) was used to characterize macrophage subpopulations enriched during efferocytosis. Clustering analysis revealed two subpopulations (c3 and c9) that were unique to efferocytic macrophages. These distinct subpopulations displayed a transcriptional profile characterized by enhanced glycolytic energy metabolism, along with an anti-inflammatory gene signature. Notably, HIF-1 signaling, glycolysis/gluconeogenesis, and carbon metabolism were among the top five most significantly enriched pathways in c3 and c9 macrophages. qRT-PCR analysis revealed that macrophages engulfing apoptotic OBs exhibited increased expression of key glycolytic enzymes and solute carriers, including Slc2a1, Pdk1, Ldha, and Slc16a3. Metabolomics analysis revealed a significant increase in intracellular lactate, phosphoenolpyruvic acid, glycerol-3-phosphate, 2-/3-glycerophosphate, and fructose-6-phosphate, indicative of enhanced glycolysis. In addition, efferocytic macrophages showed increased extracellular lactate production compared to control macrophages, as confirmed by lactate ELISA. The effects of lactate (0-20mM) on osteoblast mineralization, osteoclast differentiation and function, and macrophage-derived inflammatory factors were evaluated through various in vitro experiments. While no effect was seen in osteoblast mineralization, high lactate concentrations significantly reduced the number of multinucleated osteoclasts and their resorptive activity. Interestingly, extracellular lactate also significantly upregulated M2-like macrophage markers (Arg1, Il1rn, Klf4). These results support the concept that macrophage efferocytosis of apoptotic osteoblasts alters macrophage energy metabolism, which in turn plays a distinct and pivotal role in modulating the bone microenvironment.
    Keywords:  efferocytosis; energy metabolism; glycolysis; inflammation; lactate; macrophage; osteoimmunology
    DOI:  https://doi.org/10.3389/fimmu.2025.1650465
  20. J Immunol. 2025 Dec 13. pii: vkaf328. [Epub ahead of print]
    SLC7A5 regulates B cell metabolism and plasma cell differentiation independent of leucine transport.
    Anthony Y Tao, Ke Hu, Lucile Noyer, Li Zhong, Wenyi Li, Liwei Wang, Stefan Feske.
      B cells play critical roles in humoral immunity to infection, vaccination, and autoimmunity. The differentiation of B cells into antibody-producing plasma cells (PCs) has been extensively studied, but the role of metabolic transporters that mediate nutrient uptake during PC differentiation is not well-understood. Here, we characterized the dependence of B cells and PC differentiation on the neutral amino acid transporter SLC7A5. We demonstrate that SLC7A5 promotes B cell functions including proliferation and PC differentiation in vitro and in vivo after immunization with T dependent and independent antigens. Deletion of SLC7A5 in B cells suppressed the function of mTORC1 and enforced mTORC1 activity rescued PC differentiation. The role of SLC7A5 in B cells appears to be unrelated to leucine uptake because B cells were insensitive to extracellular leucine depletion. Defects in SLC7A5-deficient B cells could, however, be rescued by extracellular methionine supplementation, suggesting a role for methionine in SLC7A5-dependent B cell function and PC differentiation. Our study provides evidence for a leucine-independent role of SLC7A5 in B cell function and PC differentiation.
    Keywords:  SLC7A5; leucine; mTORC1; metabolism; plasma cells
    DOI:  https://doi.org/10.1093/jimmun/vkaf328
  21. Mol Biomed. 2025 Dec 19. 6(1): 143
    Neutrophil Irg1/itaconate axis protects against experimental colitis by suppressing local inflammation and maintaining hematopoietic homeostasis.
    Na Zhao, Guojian Wang, Shuang Long, Yin Chen, Jining Gao, Xiaofan Lv, Xinze Ran, Yi Jia, Tao Wang.
      Inflammatory bowel disease (IBD) is a chronic, relapsing disorder characterized by excessive inflammation and often associated with extraintestinal symptoms. Current treatments remain unsatisfactory. Although immune response gene 1 (Irg1) and its product itaconate show promise in alleviating experimental colitis, the underlying mechanisms are unclear. Here, we describe an endogenous, homeostatic pattern that controls both local and systemic inflammatory responses in experimental murine colitis. Our study identifies neutrophils in inflamed colon as the primary Irg1 source. Irg1 deficiency worsens disease severity, as shown by greater weight loss, higher disease activity index, shorter colon length, more severe tissue damage, and more neutrophil infiltration. Depleting neutrophils with Ly6G antibody worsened symptoms in wild-type mice but improved them in knockout mice, highlighting the key role of the Irg1/itaconate axis in neutrophil-mediated protection. Blood analysis showed that Irg1 deficiency increased inflammatory cells and worsened anemia. Bone marrow analysis revealed fewer granulocyte-monocyte progenitors (GMP) and more megakaryocyte-erythroid progenitors (MEP), suggesting a compensatory mechanism. We also found that Irg1 deficiency increased reverse migrated (rM-ed) neutrophils in blood and bone marrow. Exogenous itaconate (4-octyl itaconate, 4-OI) treatment significantly reduced colon inflammation, lowered rM-ed neutrophil levels, and restored hematopoietic homeostasis. RNA sequencing showed that 4-OI mainly acted by blocking NF-κB signaling, inhibiting endocytosis-related genes, and suppressing rM-ed neutrophils-related genes expression. In conclusion, the neutrophil-derived Irg1/itaconate axis plays a key role in mucosal repair and may help maintain hematopoietic balance by regulating rM-ed neutrophils, which suggest that exogenous itaconate derivatives like 4-OI may be effective treatments for IBD.
    Keywords:   Irg1 ; Experimental colitis; Hematopoietic homeostasis; Inflammatory bowel disease; Itaconate; Neutrophil
    DOI:  https://doi.org/10.1186/s43556-025-00390-4
  22. Nat Commun. 2025 Dec 17. 16(1): 11177
    A genome-wide CRISPR screen identifies GRA38 as a key regulator of lipid homeostasis during Toxoplasma gondii adaptation to lipid-rich conditions.
    Mebratu A Bitew, Tatiana C Paredes-Santos, Parag Maru, Shruthi Krishnamurthy, Yifan Wang, Lamba O Sangaré, Samuel Duley, Yoshiki Yamaryo-Botté, Cyrille Y Botté, Jeroen P J Saeij.
      Intracellular parasites like Toxoplasma gondii scavenge host nutrients, particularly lipids, to support their growth and survival. Although Toxoplasma is known to adjust its metabolism based on nutrient availability, the mechanisms that mediate lipid sensing and metabolic adaptation remain poorly understood. Here, we perform a genome-wide CRISPR screen under lipid-rich (10% Fetal Bovine Serum (FBS)) and lipid-limited (1% FBS) conditions to identify genes critical for lipid-responsive fitness. We identify the Toxoplasma protein GRA38 as a lipid-dependent regulator of parasite fitness. GRA38 exhibits phosphatidic acid (PA) phosphatase (PAP) activity in vitro, which is significantly reduced by mutation of its conserved DxDxT/V catalytic motif. Disruption of GRA38 leads to the accumulation of PA species and widespread alterations in lipid composition, consistent with impaired PAP activity. These lipid imbalances correlate with reduced parasite virulence in mice. Our findings identify GRA38 as a metabolic regulator important for maintaining lipid homeostasis and pathogenesis in Toxoplasma gondii.
    DOI:  https://doi.org/10.1038/s41467-025-66137-5
  23. Front Microbiol. 2025 ;16 1683365
    Metabolic reprogramming by pseudorabies virus: nucleotide metabolism as a central vulnerability for viral replication and pathogenesis.
    Xiaoyong Chen, Qingsen Wang, Xi Chen.
      Pseudorabies virus (PRV), a neurotropic alphaherpesvirus, causes severe neurological and reproductive disorders in swine, posing substantial threats to the global swine industry and emerging as a zoonotic concern. Viral metabolic reprogramming is a conserved strategy to support replication, yet the metabolic landscape of PRV infection remains incompletely defined. Here, we employed ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics combined with multivariate statistical analysis to systematically profile metabolic changes in PRV-infected porcine kidney PK-15 cells. Unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed a striking separation of metabolic phenotypes between PRV-infected (48 hpi) and control (0 hpi) cells, with the first principal component accounting for >73% of total variance, confirming significant metabolic reprogramming upon infection. We identified 1,634 and 925 differential metabolites in ESI+ and ESI- modes, respectively, with hierarchical cluster analysis revealing distinct signatures: amino acids and heterocyclic compounds were predominantly upregulated, while glycerophospholipids (GPs) were markedly downregulated. KEGG pathway enrichment analysis highlighted key perturbed networks underlying PRV pathogenesis: glycerophospholipid metabolism was targeted to modulate membrane dynamics for viral egress and dampen innate immune signaling; aminoacyl-tRNA and nucleotide sugar metabolism were enhanced to support viral protein synthesis and glycosylation. Notably, nucleotide metabolism was profoundly upregulated, with increased levels of adenosine, guanosine, adenine, and xanthosine. Transcriptomic validation (GSE8676 dataset) and qRT-PCR confirmed time-dependent upregulation of critical purine biosynthesis genes, including IMPDH, GMPS, ADSS2, GART, and ATIC, peaking at 48 hpi. These findings demonstrate that PRV orchestrates multifaceted metabolic takeover, with nucleotide metabolism emerging as a key vulnerability. Targeting this pathway may offer novel strategies to disrupt PRV replication, providing insights into viral-host metabolic crosstalk and antiviral development.
    Keywords:  LC–MS; PK-15 cells; metabolites; nucleotide metabolism; pseudorabies virus
    DOI:  https://doi.org/10.3389/fmicb.2025.1683365
  24. Cell Biol Toxicol. 2025 Dec 19. 42(1): 2
    Spike protein-induced VSIR-ISX signaling disrupts metabolic homeostasis and promotes COVID-19-related immune dysfunction.
    Li-Ting Wang, Shen-Nien Wang, Shyh-Shin Chiou, Chee-Yin Chai, Shih-Hsien Hsu.
      COVID-19 has caused millions of deaths worldwide since 2019. Vaccination has reduced both transmission and disease severity. However, emerging viral variants have weakened vaccine effectiveness, highlighting the need for new antiviral therapies. This study examines how the SARS-CoV-2-Spike protein (SARS-2-S) induces the VSIR-ISX signaling pathway, leading to metabolic disturbances that may worsen disease progression. Using RNA sequencing, we found that SARS-2-S expression in pulmonary cells activates genes involved in tryptophan and arachidonic acid (AA) metabolism, altering bioactive mediators like kynurenine and prostanoids, which are crucial for inflammation and immune responses. Mechanistically, the ACE2-MYD88 pathway, activated by SARS-2-S, enhances the VSIR-ISX axis through NF-κB signaling, driving these metabolic disruptions. Chromatin immunoprecipitation and genome sequencing revealed that ISX, activated via VSIR-MAPK signaling, upregulates enzymes involved in AA metabolism by binding directly to their gene promoters. Notably, disrupting the VSIR-ISX axis using shRNA interference or NF-κB inhibitors effectively mitigated these metabolic disturbances. Our findings suggest that the VSIR-ISX pathway could be a promising therapeutic target for treating COVID-19 by addressing virus-induced metabolic disruptions.
    Keywords:  AA metabolic pathway; ACE2; COVID-19; ISX; NF-kappaB
    DOI:  https://doi.org/10.1007/s10565-025-10119-2
  25. Cell Rep. 2025 Dec 17. pii: S2211-1247(25)01507-4. [Epub ahead of print]45(1): 116735
    Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
    Meng Zhang, Xiashiyao Zhang, Yandan Chen, Mengmeng Li, Qingwei Ding, Liang Zheng, Junke Zheng, Jun Wan, Bin Guo.
      Mitochondrial proteostasis is essential for hematopoietic stem cell (HSC) maintenance, yet how proteolytic regulation coordinates with metabolic pathways remains unclear. Here, we identify Afg3l2 as a key regulator of cobalamin metabolism and amino acid homeostasis in HSCs through its mediation of Mmadhc degradation. Loss of Afg3l2 leads to Mmadhc accumulation, driving excessive mitochondrial cobalamin import and its conversion to adenosylcobalamin. Elevated adenosylcobalamin levels hyperactivate methylmalonyl-CoA mutase, diverting branched-chain amino acid catabolism toward excessive succinyl-CoA production. This overstimulates the tricarboxylic acid cycle and creates a compensatory dependency on anaplerotic amino acid replenishment. Consequently, Afg3l2-deficient HSCs exhibit increased oxidative stress due to mitochondrial hyperactivation and reactive oxygen species accumulation, ultimately impairing their maintenance and engraftment capacity. Remarkably, Mmadhc overexpression phenocopies these defects, whereas Mmadhc knockdown partially restores HSC function in Afg3l2-deficient models. Our work defines a proteostatic-metabolic circuit in which Afg3l2-mediated Mmadhc degradation regulates cobalamin flux to maintain amino acid and energy balance in HSCs.
    Keywords:  CP: Metabolism; CP: Stem cell research; TCA cycle; amino acid metabolism; cobalamin metabolism; hematopoietic stem cell; mitochondrial protease
    DOI:  https://doi.org/10.1016/j.celrep.2025.116735
  26. Clin Exp Immunol. 2025 Dec 20. pii: uxaf085. [Epub ahead of print]
    The Role of Interferon-Mediated Suppression of Monocyte Immunothrombosis in Infection Susceptibility in SLE.
    Faye K Murphy, Anjali S Yennemadi, Natasha Jordan, Gina Leisching.
      Patients with Systemic Lupus Erythematosus (SLE) exhibit significant susceptibility to severe bacterial infections, a leading cause of mortality. A key host defence mechanism is immunothrombosis, wherein activated monocytes rapidly upregulate Tissue Factor (TF) to initiate localized fibrin deposition that traps and contains pathogens. Effective immunothrombosis is therefore critical for preventing microbial dissemination. This process appears deficient in SLE, a disease defined by a systemic prothrombotic state yet poor infection outcomes. A recently discovered molecular interaction suggests that TF directly binds to the interferon-α receptor (IFNAR1), acting as a rheostat to suppress interferon signalling. We hypothesize that in SLE, this regulatory axis is disrupted. The dominant, sustained interferon-stimulated gene (ISG) signatures in monocytes limit their capacity for TF upregulation in response to bacterial challenge, thereby impairing immunothrombosis and compromising bacterial containment. Supporting this, SLE patients with secondary antiphospholipid syndrome (APS) who have lower interferon signatures display markedly elevated TF levels and a different thrombotic profile, demonstrating the inverse relationship in a clinical subset. Furthermore, TF induction in monocytes is glycolysis-dependent, and SLE monocytes are known to have profound metabolic alterations. The chronic interferon state may thus impose a metabolic constraint that further limits the bioenergetic capacity for a robust TF response. Therefore, the confluence of interferon-driven suppression and metabolic dysfunction in SLE monocytes provides a compelling explanation for the failure of immunothrombosis, directly linking a core disease feature to infection susceptibility.
    Keywords:  Immunothrombosis; Infection Susceptibility; Monocytes; Systemic Lupus Erythematosus; Tissue Factor; Type I Interferon
    DOI:  https://doi.org/10.1093/cei/uxaf085
  27. Biomaterials. 2025 Dec 11. pii: S0142-9612(25)00821-X. [Epub ahead of print]328 123901
    An intermediate-crystalline phase manganese nanoadjuvant potently activates cGAS-STING signaling and antitumor immunity via immunometabolism normalization.
    Jie Zou, Guilin Meng, Yiming Huang, Jiangyan Huo, Hang Yuan, Huihui Ma, Zhi You, Xiaoli Yan, Bing Shen, Min Zhang, Yannan Yang.
      Manganese (Mn2+) serves as an inorganic activator of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, its activation efficiency remains lower than conventional organic STING agonists, hindering widespread applications in immune modulation and therapy. Herein, we report an intermediate-crystalline phase manganese layered double hydroxide/oxide (Mn-LDH/O150) nanocomposite, featuring both LDH and LDO structural phases, as a potent cGAS-STING activator. Surprisingly, Mn-LDH/O150 induced a type-I interferon level significantly higher than pure Mn-LDH or LDO phase nanocomposites, and comparable to organic STING agonists (cGAMP/diABZI). Mechanistically, conventional Mn nanocomposite impairs energy metabolism in dendritic cells and significantly reduces mitochondrial ATP production. In contrast, Mn-LDH/O150 modulates mitochondrial metabolism by normalizing the electron transport chain (ETC) process, which is termed "immunometabolism normalization", thereby promoting ATP production that in turn facilitates cGAMP synthesis and STING activation. In mice models, Mn-LDH/O150 acts as a potent immune adjuvant in inducing antibodies production and T cell responses. Using a model antigen (ovalbumin) and melanoma neoantigens, we further demonstrate the excellent activity of Mn-LDH/O150-based vaccine in inducing antitumor immunity to prevent tumor progression and metastasis. Our discoveries highlight the crucial involvement of energy metabolism in modulating STING activation, and present a simple yet translational material engineering approach for boosting metalloimmunotherapy.
    Keywords:  Energy metabolism; Immunometabolism normalization; Intermediate-crystalline phase; Manganese; cGAS-STING signaling
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123901
  28. Int Immunopharmacol. 2025 Dec 12. pii: S1567-5769(25)02008-9. [Epub ahead of print]169 116019
    Melatonin alleviates atherosclerosis by inhibiting pro-inflammatory differentiation of macrophages via regulating Sirt3-Drp1 mediated mitochondrial fission.
    Run Dai, Min-Ming Zheng, Ya-Ni Shi, Ming-Hao Luo, Yu Wang, Hua-Wei Wang, Dan-Qing Yu, Qing-Wei Chen, Ling Lin, Jing-Wei Zhou, Ze-da-Zhong Su.
       BACKGROUND: Pro-inflammatory macrophage function is linked to an increase in mitochondrial fission. Melatonin has a positive impact on atherosclerosis and has a significant effect on the control of mitochondrial fission and fusion. Nevertheless, it is still unclear how melatonin contributes to slowing the advancement of atherosclerosis.
    METHODS: The ApoE-/- mice were fed a 16-week high-fat diet (HFD). 16 weeks were spent on melatonin therapy. After using 3-TYP to suppress Sirt3 function, we were able to measure the vascular tissue's biochemical, inflammatory, and mitochondrial fission characteristics as well as the shape of atherosclerotic plaque. RAW264.7 cells were stimulated by oxidized low-density lipoprotein (oxLDL), pretreated with or without 3-TYP or Melatonin.
    RESULTS: The study found that melatonin treatment decreased the area of atherosclerotic plaque, decreased lipid deposition, suppressed inflammatory cytokine levels, inhibited macrophage pro-inflammatory differentiation, inhibited mitochondrial fragmentation, increased the level of Sirt3, and decreased Drp1 expression in atherosclerosis (AS) mice. However, Sirt3 inhibition abolished the protective affects of melatonin in AS mice. Melatonin therapy upregulated Sirt3 expression in RAW264.7 cells subjected to ox-LDL, blocked Drp1-mediated mitochondrial fission, and reduced inflammatory cytokine levels. On the other hand, melatonin's inhibitory effects on Drp1 expression and mitochondrial fission were lessened by Sirt3 inhibition. Additionally, DRP1 siRNA knockdown inhibited mitochondrial fission and pro-inflammatory differentiation of macrophages induced by ox-LDL.
    CONCLUSION: Melatonin inhibits the growth of atherosclerosis and the pro-inflammatory differentiation of macrophages by blocking the Sirt3-Drp1 pathway, which prevents mitochondria from fission. Melatonin's suppression of mitochondrial fission may be a viable strategy for postponing cardiovascular problems in atherosclerosis patients.
    Keywords:  Atherosclerosis; Inflammation; Macrophage; Melatonin; Mitochondrial fission; Sirt3-Drp1 pathway
    DOI:  https://doi.org/10.1016/j.intimp.2025.116019
  29. Gut. 2025 Dec 17. pii: gutjnl-2024-334562. [Epub ahead of print]
    PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction.
    Kang Wu, Luo Li, Yi Liu, Kai Wang, Jianghong Zheng, Huijun Liang, Fengli Xu, Renming Liu, Chang Chen, Luyi Huang, Haijun Deng, Xiaojian Han, Shi Chen, Zhirong Zhang, Xinyu Liu, Qiang He, Xiaosong Li, Aishun Jin, Ailong Huang, Ni Tang.
       BACKGROUND: Metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) has been reported to be less responsive to immune checkpoint inhibitors, which may be associated with metabolic reprogramming of tumour cells and abnormal tumour microenvironment.
    OBJECTIVE: Here, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumour microenvironment.
    DESIGN: Hepatocyte-specific phosphatase and tensin homologue (Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametrical flow cytometry were performed to analyse the immune landscape alterations. Untargeted metabolomics was conducted to elucidate the hepatic metabolism dysregulation.
    RESULTS: PCK1 is downregulated in tumour tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumour-infiltrating CD8+ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8+ T cells and activate the p38 mitogen-activated protein kinase pathway by directly interacting with the BTB and CNC homology 1 transcription factor, ultimately leading to CD8+ T cells dysfunction. Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD-1 treatment increases the antitumour capability of CD8+ T cells and suppresses MASH-HCC development.
    CONCLUSION: This study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8+ T cell dysfunction via 12-HETE-p38 signalling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD-1 immunotherapy in MASH-HCC.
    Keywords:  CARCINOGEN METABOLISM; FATTY LIVER; HEPATOCELLULAR CARCINOMA
    DOI:  https://doi.org/10.1136/gutjnl-2024-334562
  30. iScience. 2025 Dec 19. 28(12): 114058
    Maternal milk-derived lipids dictate neonatal macrophage phenotype and function.
    Lunhua Liu, Jiyeon Yang, Jiro Sakai, Ranadhir Dey, Isabelle Coppens, Hira L Nakhasi, Mustafa Akkoyunlu.
      Unique properties of neonatal macrophages play an important role in tissue regeneration and susceptibility to infections. We discovered that exposure to neonatal mouse serum is sufficient to convert adult mouse macrophages into the neonatal phenotype. Macrophages incubated with neonatal serum accumulated lipid droplets due to the high lipid content in neonatal serum. We hypothesized that maternal milk derived lipids may be responsible for the immunomodulatory properties of neonatal serum. Supporting this hypothesis, sera from cow milk-fed adult mice converted adult macrophages into a neonatal macrophage phenotype. These macrophage phenotypic changes increased adult mouse susceptibility to cutaneous Leishmania major challenge, with skin macrophages manifesting an M2-like phenotype and CD4+ T cells mounting diminished Th1 responses. These results highlight the importance of maternal milk-derived serum lipids in the emergence of M2-like phenotype of neonatal macrophages and may have therapeutic implications by formulating a diet with tailored lipid content depending on host's immunobiological needs.
    Keywords:  Cell; Immunity; Lipid
    DOI:  https://doi.org/10.1016/j.isci.2025.114058
  31. Nat Commun. 2025 Dec 19.
    A metabolism-chromatin axis promotes differential ribosomal RNA transcription in the human malaria parasite.
    Justine E Couble, Tiziano Vignolini, Grégory Doré, Selina Mussgnug, Bérangère Lombard, Michael Richard, Damarys Loew, Michael Büttner, Rafael Dueñas-Sánchez, Gernot Poschet, Jessica M Bryant, Sebastian Baumgarten.
      The transmission of the most virulent human malaria parasite, Plasmodium falciparum, relies on its survival in the contrasting environments of the human host and mosquito vector. One of the most fascinating adaptations to this lifestyle is the specific silencing of individual rDNA genes in the human host that are de-repressed following host-to-vector transmission. In this study, we define the epigenetic signatures of rRNA transcription and find that rDNA silencing relies on aerobic glycolysis, the sole energy-generating pathway in the human host. We show that disruption of NAD+ regeneration during lactate fermentation promotes rDNA de-repression and identify the sirtuin histone deacetylase Sir2a as the mediator between fluctuating NAD+ levels and a functional transcriptional outcome. Hence, rDNA activation appears to be coupled to the metabolic state of the parasite as it transitions from aerobic glycolysis to mitochondrial respiration during host-to-vector transmission.
    DOI:  https://doi.org/10.1038/s41467-025-67522-w
  32. Stem Cell Reports. 2025 Dec 18. pii: S2213-6711(25)00346-7. [Epub ahead of print] 102742
    Mitochondrial pyruvate metabolism in club cells drives airway inflammation.
    Jianhai Wang, Chunnan Du, De Hao, Qian Wu, Biyu Gui, Yu Li, Kuan Li, Xue Li, Qiuyang Zhang, Li Li, Huaiyong Chen.
      Asthma is a chronic inflammatory airway disease characterized by defective epithelial repair, resulting from metabolic dysregulation in facultative progenitor cells. Here, we investigate how pyruvate metabolism in airway club cells controls epithelial differentiation and allergic airway inflammation. Single-cell transcriptomics revealed elevated glycolytic activity in club and goblet cells from patients with asthma. In an ovalbumin (OVA)-induced asthma model, conditional deletion of Mpc2-but not Ldha-in club cells impaired club-to-goblet cell differentiation, reduced CLCA3 and Foxa3 expression, and attenuated eosinophilic inflammation and Il-13 expression. Mpc2 loss increased Cxcl17 expression in club cells, promoting Cxcl17-Cxcr4 signaling with alveolar macrophages that suppressed CCL17-mediated type 2 inflammation. Neutralizing CCL17 phenocopied the Mpc2 knockout by reducing airway inflammation and goblet cell differentiation. These findings reveal a metabolic-immune crosstalk underlying asthma pathogenesis and identify mitochondrial pyruvate metabolism as a therapeutic target to limit epithelial remodeling and type 2 inflammation.
    Keywords:  airway epithelium; allergic airway inflammation; club cells; mitochondrial pyruvate metabolism; pyruvate
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102742
  33. Redox Biol. 2025 Dec 13. pii: S2213-2317(25)00483-5. [Epub ahead of print]89 103970
    Rapamycin preserves cardiac function in autoimmune myocarditis by reprogramming Cxcl9+ macrophages via the mTORC1-C/EBPβ-OSM axis.
    Yan Zhuang, Yongcui Yan, Zheng Wen, Xiaoquan Rao, Jiangang Jiang, Huihui Li, Dao Wen Wang.
       BACKGROUND: Myocarditis is an inflammatory disease of the myocardium that can progress to chronic inflammatory cardiomyopathy and heart failure. Aberrant activation and metabolic reprogramming of macrophages drive myocardial inflammation and injury, yet effective targeted therapies remain limited.
    METHODS: Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice by α-myosin heavy chain immunization. Rapamycin was administered during the inflammatory phase. Cardiac function and injury were evaluated by echocardiography, Millar catheterization, histology, qPCR, and ELISA. Single-cell RNA sequencing (scRNA-seq) of cardiac CD45+ cells, coupled with pseudotime trajectory, SCENIC regulon, and NicheNet analyses, was performed to delineate macrophage heterogeneity, lineage dynamics, and macrophage-cardiomyocyte communication. Functional validation included Seahorse metabolic assays and Cebpb-overexpressing bone marrow-derived macrophage (BMDM)-cardiomyocyte co-culture experiments, along with in vivo OSM-neutralizing antibody (OSM-nAb) intervention.
    RESULTS: Rapamycin preserved cardiac function and alleviated myocardial inflammation and fibrosis in EAM mice, accompanied by reduced cytokine release and cardiac injury markers. scRNA-seq revealed that rapamycin reprogrammed cardiac monocyte-macrophages by inhibiting mTOR signaling, restoring mitochondrial metabolism, and suppressing inflammatory, glycolytic, and senescence pathways. It specifically targeted pathogenic Cxcl9+ macrophages by disrupting the mTORC1-C/EBPβ axis and limiting their differentiation from Plac8+ monocytes. Rapamycin further protected cardiomyocytes by blocking C/EBPβ-dependent OSM-mediated macrophage-cardiomyocyte crosstalk. Therapeutic OSM neutralization in vivo similarly mitigated myocardial inflammation and fibrosis while preserving ventricular contractility.
    CONCLUSION: Rapamycin preserves cardiac function in autoimmune myocarditis by reprogramming Cxcl9+ macrophages via the mTORC1-C/EBPβ-OSM axis. Targeting OSM provides mechanistic validation and highlights a translational therapeutic strategy for myocarditis and chronic inflammatory cardiomyopathy.
    Keywords:  Cxcl9(+) macrophages; Inflammatory cardiomyopathy; Myocarditis; Rapamycin; mTOR
    DOI:  https://doi.org/10.1016/j.redox.2025.103970
  34. Exerc Immunol Rev. 2025 ;31 19-35
    Immunometabolic profiling of T cells in response to prolonged moderate intensity cycling in humans.
    Fendi Pradana, Jonathan P Barlow, Jack Shayler, Sarah K Dimeloe, Nancy Gudgeon, Tim Podlogar, Gareth A Wallis, Alex J Wadley.
       Background: Emerging data indicates that enrichment of peripheral blood with T lymphocytes during exercise and their associated changes in function are underpinned by modulation of cellular bioenergetics. However, there is a dearth of literature examining these responses using metabolic thresholds to prescribe exercise intensity or providing single cell resolution on immunometabolic outcome measures.
    Objectives: The current study was designed to examine the metabolic phenotypes and real-time bioenergetic responses to activation of enriched naïve helper (CD4+) and cytotoxic (CD8+) T cells and peripheral blood mononuclear cells (PBMCs) in response to prolonged cycling.
    Methods: Tenaerobically trained males and females (mean ± SD: age 21±1 years; maximal oxygen consumption: 53.9 ± 9.8 ml · kg-1 · min-1) undertook a 2-hour bout of continuous cycling at a power output eliciting 95% lactate threshold-1. Blood samples were collected at rest, immediately (post), and 2 hours after cycling cessation (recovery). Using injection sequences of cell respiration modulators and a CD3/CD28 activator, bioenergetic profiles of PBMCs and enriched naïve CD4+ and CD8+ T cells were determined using extracellular flux analysis. Mitochondrial membrane potential (ΔΨm) was examined using flow cytometry.
    Results: Despite cycling evoking significant fluctuations in peripheral blood T cell numbers, there were no changes in absolute or relative measures of mitochondrial respiration, glycolytic flux and ATP synthesis rate post and recovery vs rest. Contribution of mitochondrial respiration to ATP production was greater than glycolysis in naïve T cells across all timepoints, but not PBMCs in recovery. This was despite absolute and relative changes in ΔΨm of memory T cells being greater in recovery vs. rest. Bioenergetic responses to ex vivo T cell activation were not different between cell types or timepoints.
    Conclusion: These data indicate that the metabolic phenotypes of naïve T cells and PBMCs were largely unaltered within 2 hours of prolonged moderate intensity cycling.
  35. Nat Commun. 2025 Dec 15.
    Chemotherapy-driven intestinal dysbiosis and indole-3-propionic acid rewire myelopoiesis to promote a metastasis-refractory state.
    Ludivine Bersier, L Francisco Lorenzo-Martin, Yi-Hsuan Chiang, Stephan Durot, Aleksander Czauderna, Tural Yarahmadov, Tania Wyss Lozano, Irena Roci, Jaeryung Kim, Nicola Zamboni, Nicola Vannini, Caroline Pot, Tinh-Hai Collet, Deborah Stroka, Jeremiah Bernier-Latmani, Matthias P Lutolf, Simone Becattini, Thibaud Koessler, Tatiana V Petrova.
      The contribution of chemotherapy-induced tissue injury to individual susceptibility to metastasis remains largely unexplored. We report that chemotherapy indirectly prevents colorectal cancer (CRC) liver metastases by inducing a lasting systemic "chemomemory". Chemotherapy-induced intestinal mucositis alters nutrient availability, promoting the expansion of tryptophan-metabolizing bacteria and production of the microbial metabolite indole-3-propionic acid (IPA). IPA reprograms bone marrow myelopoiesis by redirecting common myeloid progenitor fate toward the macrophage lineage, limiting generation of immunosuppressive Ly6ChighCCR2+ monocytes. This shift enhances CD4 + T cell antitumor function by promoting Th1 differentiation and spatially reorganizing CD8+ and CD4 + T cell interactions within the metastatic microenvironment. In a subset of CRC patients, circulating IPA levels increase after chemotherapy and inversely correlate with monocyte abundance, while high monocyte levels were associated with reduced survival. Our findings reveal that chemotherapy-induced intestinal injury normalizes pathological myelopoiesis through a microbiota-derived metabolite and identify IPA as a potential adjuvant to counteract monocyte-driven immunosuppression and metastasis.
    DOI:  https://doi.org/10.1038/s41467-025-67169-7
  36. Exp Cell Res. 2025 Dec 15. pii: S0014-4827(25)00467-7. [Epub ahead of print] 114867
    Metabolic Adaptation in Colorectal Cancer Microenvironment: Focus on Cancer-Associated Fibroblasts (CAFs) and Tumor-Associated Macrophages (TAMs).
    Chou-Yi Hsu, Amr Ali Mohamed Abdelgawwad El-Sehrawy, Mirza R Baig, Zahraa Khudhair, Saidmurodkhon Murtazaev, Pareshkumar N Patel, Subbulakshmi Ganesan, Vimal Arora, Sandeep Kumar Shukla, Priya Priyadarshini Nayak.
      Metabolic reprogramming within the tumor microenvironment (TME) is a critical driver of colorectal cancer (CRC) progression, influencing tumor growth, immune evasion, and metastatic dissemination. Cancer-associated fibroblasts (CAFs) undergo adaptive shifts toward aerobic glycolysis, a process often termed the "reverse Warburg effect," producing high levels of lactate and pyruvate that are shuttled to adjacent CRC cells to fuel oxidative phosphorylation and anabolic biosynthesis. CAFs additionally secrete cytokines and growth factors, including TGF-β, IL-6, and VEGF, which integrate metabolic and signaling networks to stimulate epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic potential. Similarly, tumor-associated macrophages (TAMs) exhibit remarkable metabolic plasticity that correlates with their functional heterogeneity. Beyond the classical M1/M2 dichotomy, TAM subsets display differential reliance on oxidative phosphorylation, fatty acid oxidation, or glycolysis depending on local oxygen and nutrient availability. M2-like TAMs, for example, preferentially use oxidative phosphorylation and fatty acid metabolism to sustain survival in hypoxic niches while secreting immunosuppressive metabolites such as arginase, polyamines, and lactate, which inhibit cytotoxic T-cell function. Crosstalk between CAFs and TAMs amplifies these metabolic adaptations: CAF-derived lactate promotes M2 polarization, while TAMs enhance glycolysis and biosynthetic activity in tumor cells. This study aims to systematically investigate the metabolic reprogramming of CAFs and TAMs within the CRC tumor microenvironment. Specifically, we seek to characterize the metabolic adaptations and heterogeneity of these stromal populations, elucidate their reciprocal interactions with tumor cells, and identify potential metabolic vulnerabilities that can be therapeutically targeted to disrupt tumor growth, immune evasion, and metastatic progression.
    Keywords:  CAF; Colorectal cancer; Immune cell; TAM; TME
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114867
  37. Nat Commun. 2025 Dec 15.
    Exercise-induced histone lactylation in monocyte-derived macrophages restores cardiac immune homeostasis and function in sepsis-induced cardiomyopathy.
    Shuo Sun, Chaojie Lai, Chengchen Huang, Xinrong Ren, Tingyu Zhang, Juan Zou, Yiping Tong, Qingyan Zhou, Jiangting Lu, Zhida Shen, Wentao Chen, Ruilin Wang, Nikola Rabrenovic, Xingwu Wang, Boxuan Ma, Junbin Qian, Guosheng Fu, Min Shang.
      An active lifestyle protects against cardiovascular diseases, yet its mechanisms in modulating the cardiac immune environment and preserving cardiac function remain unclear. Here, we identify a subpopulation of monocyte-derived cardiac macrophages, termed iNOS+Arg1+ macrophages, which simultaneously express pro-inflammatory and pro-reparative genes in exercised male mice. Inhibiting either pro-inflammatory iNOS or pro-reparative Arg1 in these macrophages counters the exercise-induced cardiac function preservation. Mechanistically, exercise enhances glycolysis in monocytes, increasing lactate production and driving histone lactylation at H3K18, mediated by p300 as the relevant lactyltransferase and counterbalanced by HDAC2 as deacetylase. H3K18la accelerates the transition of cardiac macrophages to a pro-reparative state, restoring immune homeostasis and preserving cardiac function. Notably, human monocytes from physically active individuals exhibit elevated levels of Pan-Kla and H3K18la compared to those from sedentary individuals. Importantly, adoptive transfer of highly histone-lactylated monocytes restores cardiac function in sepsis-induced cardiomyopathy, which might translate into a promising therapeutic strategy for cardiomyopathy.
    DOI:  https://doi.org/10.1038/s41467-025-67443-8
  38. EBioMedicine. 2025 Dec 17. pii: S2352-3964(25)00524-9. [Epub ahead of print]123 106074
    Spatial transcriptomics uncovers lipid metabolic dysregulation driving immune-stroma crosstalk in Sjögren's Disease.
    Shasha Li, Yan Liu, Haoshan Zhang, Simin Xu, Xiuzhen Wen, Yanhua Tang, Nana Zhang, David A Fox, Yanming Chen, Yunfeng Pan, Chenyang Lu.
       BACKGROUND: Sjögren's Disease (SjD) is a systemic autoimmune disorder characterised by exocrine gland dysfunction and immune infiltration. However, the spatial cellular architecture and metabolic-immune crosstalk underlying glandular pathology in SjD remain unclear.
    METHODS: We performed spatial transcriptomics on SjD salivary glands (SGs) and conducted integrative analyses with single-cell RNA sequencing to delineate disease-specific transcriptomic alterations, followed by validation in an independent cohort. Key findings were verified via immunofluorescence, immunohistochemistry, and function assays on cells.
    FINDINGS: Spatial clustering revealed distinct perturbations in SjD. We identified a pathogenic CCL2high fibroblast-ACKR1high endothelial cell axis that co-localised in lymphoid foci and correlated with immune infiltration and disease activity. Chemokine-receptor axes were associated with immune infiltration, with endothelial ACKR1 facilitating inflammatory niche organisation. Compartmentalised immune-stroma niches exhibited upregulated phospholipid, glycerophospholipid and phosphatidylinositol metabolism in lymphoid foci, correlating with B/T-cell activation and interferon responses. Key metabolic regulators (PIK3CD, PIK3CG, PIKFYVE, and PLCG2) were elevated in SjD, associated with CD45+ cell abundance in SGs, and exhibited diagnostic potential. Conversely, epithelial cells showed suppressed glycerolipid metabolism and decreased MGLL expression, linked to enhanced antigen presentation. Inhibiting monoacylglycerol lipase (encoded by MGLL) upregulates MHC in A253 cells, while interferon-γ suppresses MGLL expression.
    INTERPRETATION: Our study elucidates spatially organised metabolic-immune networks in SjD, implicating lipid metabolism in immune activation and epithelial metabolic reprogramming in secretory dysfunction, nominating promising therapeutic targets.
    FUNDING: National Natural Science Foundation of China (82104484,32301084), Joint funding from schools (colleges) and enterprises in Guangzhou (2025A03J3203, 2024A03J0987), Natural Science Foundation of Guangdong Province (2023A1515012790), Guangdong Provincial Enterprise Joint Fund (2022A1515220003), and Sun Yat-sen University (P02523).
    Keywords:  Lymphoid foci; Metabolism; Salivary gland; Sjögren's disease; Spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.ebiom.2025.106074
  39. Sci Adv. 2025 Dec 19. 11(51): eaed8370
    Immunometabolic insights into the foreign body response.
    Srinidhi Venkatesan, Dauda L Mshelia, Chima V Maduka.
      Differences in energy use by immune cells cause long-lasting inflammation, with higher glucose uptake strongly linked to the formation of scar tissue around implanted materials.
    DOI:  https://doi.org/10.1126/sciadv.aed8370
  40. Int Immunopharmacol. 2025 Dec 16. pii: S1567-5769(25)02014-4. [Epub ahead of print]169 116025
    Celastrol inhibits intrahepatic cholangiocarcinogenesis through dual suppression of glycolysis and tumor-associated macrophages.
    Yimeng Yang, Hui Rao, Yanyan Li, Rubin Cao, Zhenpeng Qiu, Guohua Zheng, Qi Wang, Chen Cheng, Junjie Hu.
      Intrahepatic cholangiocarcinoma (ICC) cells preferentially utilize aerobic glycolysis to support their uncontrolled proliferation. This metabolic reprogramming leads to lactate accumulation in the tumor microenvironment, which promotes the polarization of tumor-associated macrophages (TAMs) toward a pro-tumor phenotype, thereby facilitating immune escape and malignant progression. Although celastrol exhibits inhibitory effects on ICC, its underlying mechanism of action remains unclear. This study aims to elucidate whether celastrol suppresses ICC progression by targeting glycolysis and its subsequent impact on TAM polarization. The anti-tumor effect of celastrol and its influence on TAM polarization were systematically investigated using in vitro co-culture models and in vivo animal experiments. We demonstrated that celastrol significantly inhibits ICC progression and restrains the pro-tumor polarization of TAMs. Mechanistically, celastrol suppressed glycolysis in ICC cells and reduced lactate accumulation and further influenced TAMs polarization and ICC proliferation. In conclusion, our findings demonstrate that celastrol suppresses ICC progression by dually targeting glycolysis in tumor cells and lactate-mediated TAM polarization, highlighting its potential as a multi-faceted therapeutic agent against ICC.
    Keywords:  Celastrol; Glycolysis; Intrahepatic cholangiocarcinoma; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.intimp.2025.116025
  41. Inflammation. 2025 Dec 17. 49(1): 5
    The Neuroprotective Effect of 4-Octyl Itaconate on Acute Period of Experimental Autoimmune Neuritis.
    Lin-Jie Zhang, Ning Zhao, Jia Li, Hui Zhai, Jie Wu, Li Yang.
      
    Keywords:  4-Octyl itaconate; Experimental autoimmune neuritis; Guillain-Barré syndrome; Macrophages; NLRP3 inflammasome
    DOI:  https://doi.org/10.1007/s10753-025-02370-w
  42. Respir Res. 2025 Dec 16. 26(1): 347
    Lipopolysaccharide-induced histone lactylation mediates m6A RNA modification causing mitochondrial dysfunction and pulmonary fibroblasts activation to exacerbate sepsis-associated pulmonary fibrosis.
    Ri Tang, Shaojie Qin, Qiaoyi Xu, Wenyu Lin, Shuyi Zhang, Yawen Peng, Jinhua Feng, Shunpeng Xing, Yuan Gao, Shuya Mei, Zhengyu He.
      
    Keywords:  Lactylation; Lipopolysaccharide; Methyltransferase-like 3; N-6-methyladenosine; Pulmonary fibrosis; Sepsis
    DOI:  https://doi.org/10.1186/s12931-025-03422-3
  43. Mol Metab. 2025 Dec 13. pii: S2212-8778(25)00213-3. [Epub ahead of print] 102306
    Long-Term High-Protein Diet Intake Accelerates Adipocyte Senescence Through Macrophage CD38-Mediated NAD+ Depletion.
    Xiaohan Yang, Lun Hua, Dengfeng Gao, Yanni Wu, Yi Yang, Xianyang Jin, Xuemei Jiang, Chao Jin, Bin Feng, Lianqiang Che, Shengyu Xu, Yan Lin, Long Jin, Yong Zhuo, Mingzhou Li, De Wu.
      High-protein (HP) diets are widely adopted in Western societies for body-weight management; yet, they exacerbate senescence-associated metabolic deterioration, posing an unresolved pathophysiological conundrum. Here, we demonstrate that long-term HP intake mediates adipocyte-specific NAD+ depletion and mitochondrial dysfunction in white adipose tissue (WAT). Single-nucleus transcriptomic analyses revealed adipocyte-restricted senescence signatures in HP-fed mice. Mechanistically, HP intake triggers macrophage-specific upregulation of CD38 (a key NAD+ hydrolase), which depletes adipocyte NAD+ pools and thereby accelerates cellular senescence. Restoration of NAD+ levels, either via supplementation with NAD+ precursor or pharmacological inhibition of CD38 activity, alleviated the senescence-associated metabolic sequelae induced by HP diets. Our findings establish macrophage-adipocyte NAD+ crosstalk as a central axis linking dietary protein excess to WAT aging, providing actionable targets for the prevention and treatment of age-related metabolic disorders.
    Keywords:  Adipocyte senescence; CD38; High protein diet; Nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.1016/j.molmet.2025.102306
  44. Proc Natl Acad Sci U S A. 2025 Dec 23. 122(51): e2509118122
    MTHFR allele and one-carbon metabolic profile predict severity of COVID-19.
    IMPACC Network
      While the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are thousands of new hospitalizations and hundreds of deaths per week in the United States, many of whom develop long COVID. Early identification of individuals at high risk of severe COVID-19 is key for monitoring and supporting respiratory status and improving outcomes. Therefore, precision tools for early detection of patients at high risk of severe disease can reduce morbidity and mortality. Here, we report an untargeted, longitudinal plasma metabolomics study of COVID-19 patients. One-carbon metabolism, a pathway previously shown as critical for viral propagation and disease progression, and a potential target for COVID-19 treatment, scored strongly as differentially abundant in patients with severe COVID-19. Targeted metabolite profiling revealed that one arm of the one-carbon metabolism pathway, the methionine cycle, is a major driver of the metabolic profile associated with disease severity. Further, genomic data from the profiled patients revealed a genetic contributor to methionine metabolism and identified the C677T allele of the MTHFR gene as a preexisting contributor to disease trajectory-patients that show aberrant one-carbon metabolite levels and that are homozygous for the MTHFR C677T, have higher incidence of severe COVID. Our results raise the possibility that MTHFR variant status may inform precision COVID-19 treatment strategies.
    Keywords:  MTHFR; genetic predisposition; long COVID; plasma metabolic signature; severe COVID risk factors
    DOI:  https://doi.org/10.1073/pnas.2509118122
  45. J Neuroinflammation. 2025 Dec 18.
    Intestinal γδ T17-IL-17A signaling disrupts hippocampal mitophagy in stress-induced depression and is restored by arketamine.
    Mengqi Han, Bing Xie, Yuan Yu, Dan Xu, Yuan Shi, Meng Xu, Yuming Wu, Yujing Zhang, Xiaoyue Wen, Xin Wang, Zifan Zhen, Xinyu Zhang, Xueqiang Sun, Yin Yuan, You Shang, Shiying Yuan, Kenji Hashimoto, Jiancheng Zhang.
      Chronic stress precipitates depression, yet how gut-immune-brain interactions translate stress into mood pathology remains unclear. We tested the hypothesis that stress-primed small intestinal γδ T cells drive hippocampal mitochondrial dysfunction and depression-like behavior via interleukin-17A (IL-1A). In mice exposed to chronic restraint stress (CRS), we combined behavioral assays (open-field, sucrose-preference, tail-suspension, forced-swim), 16S rRNA profiling, fecal microbiota transplantation, Kaede photoconversion, conditional CD8α deletion in γδ T cells, hippocampal IL-17A overexpression, rapamycin treatment, and administration of the antidepressant arketamine. CRS increased gut and brain permeability, induced gut-microbiota dysbiosis, and promoted migration of small intestinal CD8α⁺ γδ T17 cells to the meninges and brain; γδ T cells were the predominant IL-17A source in the brain. Kaede tracing confirmed an intestinal origin, and CRS-associated microbiota alone transferred γδ T cell trafficking and depression-like behavior to recipients. In the hippocampus, CRS elevated IL-17A and impaired PINK1/Parkin-mediated mitophagy (decreased PINK1, Parkin, Beclin-1, and LC3B-II/I; increased p62), reduced ATP, and produced mitochondrial and synaptic ultrastructural deficits. IL-17A overexpression further worsened mitophagy and behavior, whereas rapamycin restored both. Conditional deletion of CD8α in γδ T cells reduced brain γδ T17 infiltration, lowered hippocampal IL-17A, rescued mitophagy and synapses, and improved behavior. Arketamine normalized dysbiosis and barrier markers, curtailed γδ T cell trafficking, decreased hippocampal IL-17A, restored mitophagy, and alleviated depression-like behavior in both sexes. These findings delineate a stress-responsive microbiota-γδ T cell-IL-17A pathway that compromises hippocampal mitophagy and identify arketamine as a candidate modulator of this axis, nominating mitophagy and γδ T cell trafficking as translational targets.
    Keywords:  Chronic restraint stress; Depression; Gut-brain axis; Ketamine; Mitophagy; γδT cells
    DOI:  https://doi.org/10.1186/s12974-025-03656-4
  46. Clin Rheumatol. 2025 Dec 17.
    Exploring the gut microbiome in systemic lupus erythematosus: metagenomic and metabolomic insights into a new pro-inflammatory bacteria Clostridium scindens.
    Hongli Wang, Miaomiao Zhang, Bi Hua, Juan He, Yuting Yang, Wenqi Wu, Yiling Zhang, Fuqin Wei, Yueming Cai, Qingwen Wang.
       OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with unclear pathogenesis. Emerging evidence indicates that the gut microbiome may play a critical role in immune regulation. This study aimed to investigate gut microbiome and metabolome alterations in SLE patients, with a focus on the pro-inflammatory bacterium Clostridium scindens (C. scindens), and explore its potential contribution to disease pathogenesis.
    METHOD: We performed metagenomic sequencing to analyze gut microbial composition in SLE patients and healthy controls, alongside untargeted metabolomic profiling of peripheral blood to assess systemic metabolic changes. We examined species diversity, taxonomic differences at both phylum and species levels, and metabolic alterations. Statistical analyses identified significant associations and potential diagnostic markers.
    RESULTS: SLE patients did not show a consistent reduction in species diversity, but exhibited significant microbial compositional differences compared to healthy controls. These patterns suggest potential diagnostic utility. Metabolomic analysis revealed systemic metabolic disturbances linked to gut dysbiosis. Ruminococcus gnavus was associated with altered amino acid, lactose, and sphingolipid metabolism, potentially affecting host immunity. Notably, C. scindens appeared to contribute to immune dysregulation via bile acid metabolism.
    CONCLUSIONS: This study reveals distinct microbial and metabolic profiles in SLE, identifying C. scindens as a potential driver of immune imbalance. The findings suggest that targeting the gut microbiome could offer novel strategies for diagnosis and therapeutic intervention in SLE. Key Points • Gut microbial composition is significantly altered in SLE patients compared to healthy controls. • Metabolomic profiling reveals systemic disturbances linked to gut dysbiosis. • Clostridium scindens is associated with bile acid metabolism and immune dysregulation in SLE. • The gut microbiome may serve as a potential target for diagnosis and treatment in SLE.
    Keywords:   Clostridium scindens ; Gut microbiome; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1007/s10067-025-07865-3
  47. Mol Metab. 2025 Dec 15. pii: S2212-8778(25)00215-7. [Epub ahead of print] 102308
    Branched chain amino acids prime metabolic inflammation.
    Nandini K Doshi, Tristan Pesaresi, Trishya Pagadala, William Dion, Yang Zhang, Natalie L David, Tânia Amorim, Wenjia Wang, Naveen G V Kumar, Bokai Zhu, Silvia Liu, Parth Patwari, Pouneh K Fazeli, Matthew L Steinhauser.
      Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used in vitro myeloid/macrophage culture and in vivo murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102308
  48. Front Immunol. 2025 ;16 1697056
    Metabolic collusion driving immune evasion in cholangiocarcinoma: unmasking the dual control of the immuno-metabolic microenvironment.
    Jingnan Xue, Longhao Zhang, Kai Zhang, Yu Wu, Kai Zhou, Xin Lu.
      Cholangiocarcinoma represents an aggressive malignancy with poor prognosis, particularly for intrahepatic Cholangiocarcinoma. Despite recent advancements in chemotherapy and immune checkpoint blockade therapies, survival outcomes remain suboptimal. A key obstacle in treating Cholangiocarcinoma is its immune exclusion and resistance to Cholangiocarcinoma, which is influenced by metabolic reprogramming within the tumor microenvironment. This review explores the dual control of metabolism and immunity in Cholangiocarcinoma, highlighting the intricate interplay between metabolic pathways (e.g., glycolysis, lactate accumulation, fatty acid oxidation) and immune evasion mechanisms. We examine how bile acid signaling, hypoxia, and stromal interactions shape Cholangiocarcinoma's immune landscape, facilitating tumor progression and immune resistance. Moreover, we discuss emerging therapeutic strategies that target metabolic vulnerabilities to "convert" immune-excluded Cholangiocarcinoma into a more immunologically responsive state. These strategies include metabolic inhibitors targeting lactate, amino acid catabolism, and fatty acid metabolism, as well as approaches to modulate bile acid signaling. We propose that combining metabolic reprogramming with immune checkpoint blockade therapies holds significant promise in enhancing immune responses and improving therapeutic outcomes for Cholangiocarcinoma patients. This review provides a comprehensive framework for future research and clinical trials, aiming to bridge the gap between metabolic insights and immunotherapy in Cholangiocarcinoma treatment.
    Keywords:  bile acids; cholangiocarcinoma; combination immunotherapy; immune evasion; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1697056
  49. Cell. 2025 Dec 17. pii: S0092-8674(25)01318-2. [Epub ahead of print]
    Gut microbiota promotes immune tolerance at the maternal-fetal interface.
    Julia A Brown, Mohammed Amir, Shui Yu, Daniel S H Wong, Jinghua Gu, Uthra Balaji, Christopher N Parkhurst, Seunghee Hong, Lucy R Hart, Hannah C Carrow, Mamadou A Bah, Aparna Ananthanarayanan, Katherine Z Sanidad, Mengze Lyu, Anisa Siddikova, Marina Lima Silva Santos, Inna Serganova, Gretchen E Diehl, Josef Anrather, Naohiro Inohara, Gregory F Sonnenberg, Virginia Pascual, Melody Y Zeng.
      Immune tolerance at the maternal-fetal interface (MFI) is required for fetal development. Excessive maternal interferon-gamma (IFN-γ) and interleukin-17 (IL-17) are linked to pregnancy complications, but the regulation of maternal IFN-γ and IL-17 at the MFI is poorly understood. Here, we demonstrate a gut-placenta immune axis in pregnant mice in which the absence or perturbation of gut microbiota dysregulates maternal IFN-γ and IL-17 responses at the MFI, resulting in fetal resorption. Microbiota-dependent tryptophan derivatives suppress IFN-γ+ and IL-17+ T cells at the MFI by priming myeloid-derived suppressor cells (MDSCs) and gut-derived RORγt+ regulatory T cells (Tregs), respectively. The tryptophan derivative indole-3-carbinol, or tryptophan-metabolizing Lactobacillus murinus, rebalances the T cell response at the MFI and reduces fetal resorption in germ-free mice. Furthermore, MDSCs, RORγt+ Tregs, and microbiota-dependent tryptophan derivatives are dysregulated at the MFI in human recurrent miscarriage cases. Together, our findings identify microbiota-dependent immune tolerance mechanisms that promote fetal development.
    Keywords:  MDSCs; T cells; Tregs; aryl hydrocarbon receptor; gut microbiota; gut-placenta axis; maternal-fetal immune tolerance; metabolites; tryptophan
    DOI:  https://doi.org/10.1016/j.cell.2025.11.022
  50. Cytokine. 2025 Dec 15. pii: S1043-4666(25)00238-8. [Epub ahead of print]198 157091
    IL-36γ signalling promotes a proinflammatory macrophage state that is associated with reduced lipid uptake.
    Jillian Yong Xin Sieh, Gabriel Osborn, Sophia N Karagiannis, Francesca Capon.
      Macrophages exhibit remarkable functional plasticity, adopting immune activating or immune suppressive states in response to environmental cues. While these phenotypic shifts are essential to immune homeostasis, the mechanisms whereby they are regulated in humans are poorly understood. Here, we investigated the role of interleukin (IL)-36γ, a barrier cytokine that is strongly induced in response to infection. We show that IL-36γ signalling modifies the anti-inflammatory phenotype of human alternatively activated (M2a) macrophages, by decreasing the expression the CD163 M2 marker. This change was accompanied by the upregulation of M1 surface markers (CD40, CD80) and M1 cytokines (e.g. TNFα, CXCL8). IL-36γ treatment of M2a macrophages also reduced the expression of TREM2 and CD36, two lipid-binding receptors that sustain the energy requirements of the M2 state. Accordingly, we also observed a decrease in the uptake of CD36 and TREM2 ligands (oxidized low-density lipoproteins). These findings indicate that IL-36γ shifts the immune and metabolic profile of M2a macrophages towards an M1-like state.
    Keywords:  Human macrophage; IL-36; Lipid receptor; M1 polarization; M2 states; Phenotype shift
    DOI:  https://doi.org/10.1016/j.cyto.2025.157091
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒21 at 21:50.