bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–01–11
47 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Immunometabolism of T cells and macrophages: Human translational perspectives.
  2. Lipoic Acid Ameliorates Lipopolysaccharide-Induced Inflammation via Inhibition of Glycolysis in RAW264.7 Macrophages.
  3. Macrophage glycine transporter supports IL-1β production by modulating the AKT1/mTOR/NLRP3 pathway.
  4. Porcine epidemic diarrhea virus promotes viral replication via ROS/HIF-1α-mediated glycolysis.
  5. Metabolic hijackers: how viral proteins redefine host cell landscapes.
  6. Multi-omics and perturbation screens as discovery tools in immunometabolism.
  7. Zika Virus Reprograms Microglial Mitochondrial Metabolism to Support Immune Activation and Viral Replication: Omega-3 DHA Counteracts Neuroinflammation and Viral Persistence.
  8. Mitochondrial Transplantation Restores Immune Cell Metabolism in Sepsis: A Metabolomics Study.
  9. From "metabolic storm" to "immune paralysis": the dynamic evolution of macrophages and metabolism reprogramming in ARDS.
  10. ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors.
  11. Effects of lipopolysaccharide on energy metabolism and immune cell activation in different microglia model systems.
  12. Mitochondrial and lipid metabolism rewiring during HEV infection.
  13. Biodegradable microparticles promote anti-inflammatory innate immune memory though a size- and mTOR dependent process.
  14. Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism.
  15. Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment.
  16. CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction.
  17. Active aldehydes drive metabolic exhaustion in CD8+ T cells.
  18. Viral reprogramming of glial metabolism as a driver of neuroinflammation.
  19. Microglia Mitochondrial Metabolism in Neurological Diseases.
  20. Metformin Attenuates ox-LDL-Induced Macrophage Senescence and Inflammation via NR4A1-Mediated Mitophagy Regulation.
  21. Porcine epidemic diarrhea virus manipulates IMPDH-dependent nucleotide biosynthesis to facilitate replication.
  22. Nutritional intervention alleviates T cell exhaustion and empowers anti-tumor immunity.
  23. Interleukin-7R and chemokine receptor type 7 differentially regulate metabolism in CD4+ and CD8+ T cells.
  24. Chronic Kidney Disease Induces Distinct Alterations of Macrophage Lipid Metabolism in a Mouse Model of Atherosclerosis.
  25. How do immunometabolites shape bacterial infections?
  26. Alterations in NK Cell Function and Glucose Metabolism Characteristics in Patients With Progressive Hepatocellular Carcinoma.
  27. Glucose Metabolism and Innate Immune Responses in Influenza Virus Infection: Mechanistic Insights and Clinical Perspectives.
  28. Microbiota-derived D-amino acids in intestinal homeostasis and inflammatory bowel disease.
  29. Endogenous HIV-1 Tat Promotes Cell Proliferation, Migration, and Phagocytosis in Stably Infected Macrophages by Accumulating Lactate and Activating the Autophagy/MAPK Pathway.
  30. PFKFB3-involved glycolytic metabolism supports sepsis-induced neutrophil extracellular trap formation.
  31. H-ferritin engineered nanoplatform reprograms metabolism and immunity for glioblastoma immunotherapy.
  32. Metabolic Reprogramming of T Cells by Dual UCP2 and IL-17 Blockade Enhances Immunity Against Pancreatic Cancer.
  33. The metabolism-immune axis in colorectal cancer: remodeling the tumor microenvironment through metabolite signaling.
  34. Differential modulation of gestational immunity by fatty acids: tissue-specific immune remodeling and clinical implications.
  35. Anti-alcoholism drug disulfiram inhibits PANoptosis by blocking mitochondrial permeabilization in macrophages.
  36. Treadmill exercise alleviates Alzheimer's disease pathologies in APP/PS1 mice through modulation of microglial glucose metabolic reprogramming.
  37. Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1.
  38. METTL3 abrogation promotes glioma progression through regulating the ISG15-FASN axis-mediated lipid metabolism in macrophages.
  39. Albumin orchestrates a natural host defence mechanism against mucormycosis.
  40. Analysis of the impact of SARS-CoV-2 infection on immune function and metabolic changes in college students.
  41. Dual itaconate delivery systems modulate macrophage Acod1-Hif-1α-glycolysis axis for immunotherapy of bioprosthetic heart valve calcification.
  42. Lactylation: the metabolic-immune hub in autoimmune diseases.
  43. A metabolic perspective on microglia in Alzheimer's disease.
  44. Chronic macrophage activation derails muscle repair by disrupting mannose-receptor-linked plasticity revealed by endogenous irg1/acod1 tracking.
  45. Primary Human Reactive Microglia Display Mitochondrial Dysfunction and Metabolic Imbalance Upon Lipopolysaccharide Exposure.
  46. Hormone-sensitive lipase drives pro-resolving macrophage polarization and enhances efferocytosis.
  47. Inhibition of PFKFB3 in Macrophages Has a Dual Effect on Tumor-Regulating Lipid Metabolism.
  1. Immunobiology. 2025 Dec 27. pii: S0171-2985(25)00285-2. [Epub ahead of print]231(1): 153151
    Immunometabolism of T cells and macrophages: Human translational perspectives.
    Borros Arneth.
       BACKGROUND: Immunometabolism explores how immune-cell function depends on cellular energy metabolism. Recent insights demonstrate that nutrient utilization dictates activation, polarization, and tolerance.
    AIMS: To systematically review human studies on T-cell and macrophage metabolism, identify converging pathways, and outline translational implications for inflammation, autoimmunity, and cancer.
    METHODS: Following PRISMA 2020 guidelines, PubMed was searched (2015-2025) using predefined MeSH terms ("immunometabolism", "T lymphocytes", "macrophages", "metabolic reprogramming"). Of 999 records, 67 met inclusion criteria (human data, peer-reviewed, quantitative endpoints). Bias was assessed with ROBIS.
    RESULTS: Effector T cells and M1 macrophages favor glycolysis for rapid ATP and pro-inflammatory signaling, whereas memory T cells and M2 macrophages rely on oxidative phosphorylation and fatty-acid oxidation for sustained energy and tolerance. mTORC1/AMPK signaling, glutaminolysis, and the kynurenine pathway integrate metabolic and immune cues. Metabolic dysregulation in obesity or tumor microenvironments skews these pathways, driving chronic inflammation or immune escape.
    CONCLUSIONS: Human immunometabolism is defined by dynamic substrate switching. Targeting glycolysis, FAO, or tryptophan metabolism offers therapeutic leverage in cancer and autoimmune disease. Future directions include single-cell and spatial metabolomics and integrative metabolic-immune modeling.
    Keywords:  Immunometabolism; Inflammation; Macrophages; Metabolic reprogramming; PRISMA review; T cells
    DOI:  https://doi.org/10.1016/j.imbio.2025.153151
  2. Immun Inflamm Dis. 2026 Jan;14(1): e70313
    Lipoic Acid Ameliorates Lipopolysaccharide-Induced Inflammation via Inhibition of Glycolysis in RAW264.7 Macrophages.
    Liduo Yue, Kai Wang, Rongyuan Wang, Linbei Lu, Lihong Fan.
       BACKGROUND: Sustained pulmonary inflammation contributes significantly to lung carcinogenesis. Macrophages play a pivotal role in perpetuating inflammatory responses, undergoing a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis upon activation. The interplay between metabolic reprogramming and macrophage polarization remains poorly defined. The objective of this study is to examines the anti-inflammatory mechanism of lipoic acid (LA), focusing on its ability to modulate immunometabolism in activated macrophages.
    METHODS: We utilized lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and a murine acute lung injury (ALI) model to evaluate the anti-inflammatory effects of LA. Inflammatory cytokine expression was assessed by qPCR, ELISA, and Western blot. Metabolic profiling was performed using Seahorse XF technology to measure oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), evaluating glycolytic and oxidative metabolic functions.
    RESULTS: This study systematically elucidates the molecular mechanism by which LA modulates macrophage inflammatory responses through targeting the HIF1α/glycolysis axis. The main findings are as follows: (1) In LPS-induced RAW264.7 macrophages, LA treatment significantly inhibited the expression of M1 macrophage markers (iNOS, CD86) and the secretion of proinflammatory cytokines (IL-1β, IL-6, etc.). (2) LA effectively reduced the expression of GSDMD, the key executor of pyroptosis, demonstrating its inhibitory effect on macrophage pyroptosis. (3) Metabolic analysis revealed that LA reversed LPS-induced metabolic reprogramming by decreasing the ECAR and increasing the OCR, thereby suppressing glycolysis. (4) Mechanistic studies showed that siRNA-mediated knockdown of HIF1α replicated both the anti-inflammatory and metabolic regulatory effects of LA, confirming HIF1α as the key target in this pathway. (5) In an ALI mouse model, LA treatment significantly reduced HIF1α expression in lung tissues and effectively alleviated inflammatory responses, further validating the proposed mechanism.
    CONCLUSION: LA exerts potent anti-inflammatory effects by targeting HIF1α-mediated metabolic reprogramming in macrophages. Our results highlight the therapeutic potential of targeting immunometabolic pathways in inflammatory lung diseases, providing new insights into the mechanism by which LA ameliorates pulmonary inflammation.
    Keywords:  HIF1α; anti‐inflammation; lipoic acid; macrophage
    DOI:  https://doi.org/10.1002/iid3.70313
  3. Cell Rep. 2026 Jan 03. pii: S2211-1247(25)01455-X. [Epub ahead of print]45(1): 116683
    Macrophage glycine transporter supports IL-1β production by modulating the AKT1/mTOR/NLRP3 pathway.
    Yan Guo, Xiaoyan Wu, Xinmei Zhang, Qilin Hu, Zhending Gan, Shijie Liu, Xuehua Mei, Xiu Zeng, Wenkai Ren.
      Increasing investigations indicate that neurotransmitters shape immune cell function; however, current results about glycine (Gly) in inflammatory macrophage responses are conflicting. Here, we found that Gly transporters support interleukin-1β (IL-1β) production in inflammatory macrophages, while Gly receptors inhibit it. Inflammatory macrophages have higher expression of Gly transporter 1 (GlyT1; also known as SLC6A9). Notably, SLC6A9 inhibition leads to extracellular accumulation of Gly and limits IL-1β production in inflammatory macrophages. Mechanically, extracellular Gly suppresses phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT1)/mammalian target of rapamycin (mTOR) signaling through the Gly receptor alpha-4 (Glrα4), thereby inhibiting activation of the NOD-like receptor 3 (NLRP3) inflammasome and IL-1β production. Furthermore, Gly supplementation or myeloid-specific SLC6A9 depletion alleviates the lipopolysaccharide (LPS)-induced inflammatory response in vivo. Collectively, our findings reveal a previously uncharacterized mechanism for the Gly-ergic system in regulating inflammatory macrophage function, providing a potential alleviating target for macrophage-associated diseases.
    Keywords:  CP: immunology; CP: metabolism; IL-1β; PI3K; SLC6A9; glycine; mTOR; macrophages
    DOI:  https://doi.org/10.1016/j.celrep.2025.116683
  4. Redox Biol. 2026 Jan 05. pii: S2213-2317(26)00006-6. [Epub ahead of print]89 104008
    Porcine epidemic diarrhea virus promotes viral replication via ROS/HIF-1α-mediated glycolysis.
    Yafang Xu, Jinqiu Zhang, Chengwei Yin, Laizhen Liu, Zhenglei Wang, Shaodong Fu, Rong Fan, Yanyan Zhao, Jinfeng Miao.
      Porcine epidemic diarrhea virus (PEDV), a highly pathogenic coronavirus, causes recurrent outbreaks of severe enteric disease, posing a significant threat to the global swine industry. The persistent challenge highlights the urgent need for a deeper understanding of host-virus interactions to improve prevention and control strategies. Here, we demonstrated that PEDV infection reprogrammed host metabolism toward aerobic glycolysis, a metabolic shift that not only facilitated viral replication but also established an immunosuppressive microenvironment. PEDV infection activated the hypoxia-inducible factor-1α (HIF-1α) pathway and induced mitochondrial dysfunction, leading to the accumulation of mitochondrial reactive oxygen species (mROS), which in turn stabilized HIF-1α, creating a positive feedback loop that amplified glycolytic gene expression and lactate production. We confirmed that glycolysis was essential for PEDV replication, and that elevated glucose levels enhanced replication efficiency. Furthermore, PEDV-induced glycolysis and lactate accumulation inhibited the generation of interferons (IFNs), thereby facilitating immune evasion. Collectively, our findings revealed a metabolic-immune axis exploited by PEDV to optimize viral replication and subvert host defenses. This study not only provides novel insights into the metabolic adaptations underlying PEDV pathogenesis but also highlights host metabolic pathways as potential therapeutic targets to combat PEDV and other related coronaviruses.
    Keywords:  Glycolysis; HIF-1α; Metabolism; Mitochondria; Porcine epidemic diarrhea virus; ROS
    DOI:  https://doi.org/10.1016/j.redox.2026.104008
  5. J Virol. 2026 Jan 09. e0055625
    Metabolic hijackers: how viral proteins redefine host cell landscapes.
    Adam Hafner, Rebekah L Mokry, John G Purdy, Christiane E Wobus.
      Viruses are metabolic engineers of host cells. As obligate intracellular pathogens, they rely on host cell metabolism for efficient viral replication. The manipulation of host metabolic processes is a strategy shared among diverse virus families to secure the necessary resources for replicating new genomes, building more virus particles, and supporting cell growth and proliferation. Key metabolic pathways targeted by viruses for disruption and manipulation are glycolysis, glutaminolysis, and lipid metabolism. However, the mechanisms behind virus-induced metabolic reprogramming and the viral proteins mediating it remain poorly understood. This review explores how specific viral proteins reshape the metabolic milieu of host cells during viral infections. We also highlight common themes and outline gaps in knowledge to stimulate further investigations into how viral proteins manipulate host metabolism. Such mechanistic insights will deepen our understanding of virus-host interactions and may reveal novel therapeutic targets.
    Keywords:  RNA and DNA virus proteins; cellular metabolism; glutaminolysis; glycolysis; lipid metabolism
    DOI:  https://doi.org/10.1128/jvi.00556-25
  6. PLoS Biol. 2026 Jan;24(1): e3003570
    Multi-omics and perturbation screens as discovery tools in immunometabolism.
    Nicole M Chapman, Hongbo Chi.
      Metabolic rewiring of immune cells has broad impacts on immune responses and disease outcomes. Systems biology approaches, such as multi-omics profiling and perturbation screening, could uncover new actionable targets and therapeutic avenues to explore.
    DOI:  https://doi.org/10.1371/journal.pbio.3003570
  7. Mol Neurobiol. 2026 Jan 04. 63(1): 341
    Zika Virus Reprograms Microglial Mitochondrial Metabolism to Support Immune Activation and Viral Replication: Omega-3 DHA Counteracts Neuroinflammation and Viral Persistence.
    Heloísa Antoniella Braz-de-Melo, Fernanda Gomes Lago, Rafael Corrêa, Igor de Oliveira Santos, Paula Maria Quaglio Bellozi, Raquel das Neves Almeida, Wagner Fontes, Mariana S Castro, Aline Maria Araújo Martins, Raphaela Menezes de Oliveira, Nadia Martins Serpa Rossi, Gabriel Pasquarelli-do-Nascimento, Ana Luiza Gouvea, Paulo Sousa Prado, Andreza Fabro de Bem, Sônia Nair Báo, Bergmann Morais Ribeiro, Stevens Kastrup Rehen, Thomas Christopher Rhys Williams, Gary P Kobinger, Kelly Grace Magalhães.
      Microglial cells exhibit crucial metabolic adaptations to maintain neural homeostasis. However, their dysregulated activation during infections can lead to neurotoxicity and contribute to the development of neuroinflammatory disorders. Understanding the physiological and metabolic changes of microglia during immune activation is crucial for identifying protective targets against neuroinflammation. This study investigates how the Zika virus (ZIKV) alters microglia metabolism during inflammation, highlighting cellular adaptations that sustain oxidative metabolism linked to cell survival during cellular activation and viral replication. After identifying an enriched abundance of proteins related to oxidative phosphorylation and cellular component organization in the global proteomics of mouse brains following ZIKV exposure, we investigated the relevance of these pathways during in vitro infection of human microglia. ZIKV infection led to cytoskeleton remodeling via β-tubulin reallocation, which characterized an ameboid-like phenotype. Despite the indication of a shift toward increased glycolytic activity due to decreased intracellular glucose, which suggests its consumption, and the accumulation of tricarboxylic acid cycle (TCA) intermediates, ZIKV-infected microglia exhibit enhanced respiratory capacity and an abundance of smaller-sized mitochondria in the perinuclear region. The accumulation of citrate, succinate, and malate, while maintaining mitochondrial function, suggests an important metabolic adaptation that supports biosynthetic pathways and sustains cell viability under stress. Decreased intracellular glutamate abundance supports mitochondrial oxidative metabolism. Pre-treatment with the anti-inflammatory docosahexaenoic acid (DHA) mitigates ZIKV-induced metabolic alterations by reducing pro-inflammatory markers, downregulating viral entry receptors, and lowering microglial activation and viral load. This study reveals that while ZIKV induces cell death in neuronal-like cells, the mitochondrial adaptation observed in microglial infection could be a key to maintaining cell survival throughout neuroinflammation. Our findings elucidate a novel cellular adaptation during ZIKV infection involving β-tubulin reorganization and metabolic dynamics, reflecting microglial flexibility and resistance during neuroinflammation, and demonstrating the therapeutic potential of DHA in mitigating ZIKV-induced pathology.
    Keywords:  Immunometabolism; Metabolic adaptation; Mitochondrial dynamics; Neuroinflammation; Zika virus
    DOI:  https://doi.org/10.1007/s12035-025-05418-y
  8. Int J Mol Sci. 2025 Dec 28. pii: 332. [Epub ahead of print]27(1):
    Mitochondrial Transplantation Restores Immune Cell Metabolism in Sepsis: A Metabolomics Study.
    Tae Nyoung Chung, Se Rin Choi, Su-Hyun Kim, Choong Hwan Lee, Kyuseok Kim.
      Sepsis induces severe immune and metabolic dysfunction driven by mitochondrial failure. Mitochondrial transplantation (MT) has emerged as a promising strategy to restore mitochondrial bioenergetics, but its metabolic impact on immune cells remains unclear. Here, we used gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics to evaluate metabolic alterations in peripheral blood mononuclear cells (PBMCs) and splenocytes from a rat polymicrobial sepsis model treated with MT. Principal component and partial least-squares discriminant analyses revealed distinct clustering between sham, sepsis, and MT groups. Sepsis markedly suppressed metabolites related to amino acid, carbohydrate, and lipid metabolism, including aspartic acid, glutamic acid, AMP, and myo-inositol, reflecting mitochondrial metabolic paralysis. MT partially restored these metabolites toward sham levels, reactivating tricarboxylic acid (TCA) cycle, nucleotide, and lipid pathways. Pathway analysis confirmed that exogenous mitochondria reversed sepsis-induced metabolic suppression and promoted bioenergetic recovery in immune cells. These findings provide direct metabolomic evidence that MT reprograms immune metabolism and restores oxidative and biosynthetic function during sepsis, supporting its potential as a mitochondrial-based metabolic therapy.
    Keywords:  energy metabolism; gas chromatography–mass spectrometry; immune cells; metabolomics; mitochondrial dysfunction; mitochondrial transplantation; oxidative phosphorylation; peripheral blood mononuclear cells; sepsis; splenocytes
    DOI:  https://doi.org/10.3390/ijms27010332
  9. Front Immunol. 2025 ;16 1738713
    From "metabolic storm" to "immune paralysis": the dynamic evolution of macrophages and metabolism reprogramming in ARDS.
    Jia Tang, Mi Yan, Mengchun Li, Zhangxue Hu, Kun Zhou.
      Sepsis is characterized by high mortality and a complicated pathological mechanism. Macrophages play a crucial role in the initiation and progression of sepsis-associated acute respiratory distress syndrome (ARDS). Macrophage functional states and polarization phenotype have been significantly influenced by metabolic programming. This review delineates the metabolic reprogramming of macrophages from the initial 'metabolic storm' to subsequent 'immune paralysis' in sepsis-associated ARDS. It focuses on the interplay between macrophage polarization (classical activated macrophages (M1) and alternative activated macrophages (M2) phenotypes) and key metabolic pathways, including glycolysis and oxidative phosphorylation (OXPHOS). Furthermore, it explains the molecular mechanism underlying the metabolic pattern's influence on macrophage and lung tissue damage. The final section of this review focuses on the therapeutic implications of bone marrow mesenchymal stem cells (BMMSCs) and myeloid-derived suppressor cells (MDSCs), which alter macrophage metabolic reprogramming. Based on the latest progress, this article aims to provide a comprehensive theoretical framework and cli Based on recent advances, nical guidance for immunometabolic therapy in sepsis-associated ARDS.
    Keywords:  ARDS; BMMSCs; exosomes; glycolysis; immune paralysis; macrophage polarization; metabolic reprogramming; metabolic storm
    DOI:  https://doi.org/10.3389/fimmu.2025.1738713
  10. Cancers (Basel). 2025 Dec 22. pii: 34. [Epub ahead of print]18(1):
    ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors.
    Alex Wade Song, Xiaotong Song.
      CAR T cell therapy, while highly effective for hematological malignancies, continues to face significant hurdles in the treatment of solid tumors. Key challenges include severe nutrient deprivation and the presence of immunosuppressive metabolites such as adenosine in the tumor microenvironment, which limit CAR T cell persistence and antitumor activity. This review focuses on current progress and future directions for ADA1-based metabolic reprogramming as a targeted approach to enhance CAR T cell function. We discuss recent advances, particularly the engineering of CAR T cells to express ADA1, which facilitates the local conversion of immunosuppressive adenosine into inosine, thereby supporting T cell metabolism and improving therapeutic outcomes. Preclinical studies, including our own, demonstrate that ADA1-expressing CAR T cells exhibit reduced exhaustion, greater metabolic flexibility, and enhanced antitumor efficacy in solid tumor models. The selective clearance of adenosine and supplementation of inosine directly address the metabolic barriers within the tumor microenvironment and provide an effective strategy to bolster CAR T cell responses. Integration of ADA1-driven metabolic refueling with future innovations in CAR design holds promise for overcoming key obstacles in solid tumor immunotherapy. We conclude by highlighting the potential of ADA1-based strategies and offering our perspective on their translation toward clinical application.
    Keywords:  CAR T cells; adenosine; adenosine deaminase; inosine; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18010034
  11. Brain Behav Immun. 2026 Jan 04. pii: S0889-1591(26)00003-6. [Epub ahead of print]133 106255
    Effects of lipopolysaccharide on energy metabolism and immune cell activation in different microglia model systems.
    Susanne Michels, Johanna Eichberg, Fahd Alhamdan, Micha Engeser, Rafael Leite Dantas, Felix Sr Picard, Mona Mathews-Ajendra, Oliver Brüstle, Martin K-H Schäfer, Judith Alferink, Holger Garn, Markus Wöhr, Carsten Culmsee.
      Microglia, the brain's resident immune cells, constantly monitor their environment for signs of tissue damage or pathogens. Upon activation by stimuli like lipopolysaccharide (LPS), microglia undergo metabolic changes and release pro-inflammatory mediators. However, variations between human and rodent microglia, as well as differences between in vitro and in vivo conditions, likely influence microglial cellular functions and their responses to stimulation. In the present study, we compared several rodent and human model systems, including cell lines, primary cultures, induced pluripotent stem cell (iPSC)-derived cultures, and acutely isolated microglia, and revealed striking differences in LPS-induced metabolic changes and nitric oxide (NO) production. Using the murine microglial cell line BV-2, we demonstrated that NO was critical for restricting metabolism to glycolysis by blocking oxidative phosphorylation. In contrast, human iPSC-derived microglia and acutely isolated microglia from intraperitoneally injected rats maintained mitochondrial respiration upon LPS activation and did not show significant NO production and inducible nitric oxide synthase (iNOS) expression, respectively. Furthermore, we found that NO was not required for the increase in glycolysis rate or the release of pro-inflammatory cytokines upon LPS stimulation. Our results suggest that glycolysis is essential for microglial activation and cytokine production irrespective of NO production. However, the specific metabolic pathways involved may differ between species and experimental conditions. Understanding these differences is crucial for developing effective therapeutic strategies targeting microglial dysfunction in neurological diseases.
    Keywords:  Energy metabolism; Glycolysis; Inducible nitric oxide synthase (iNOS); Lipopolysaccharide (LPS); Microglia; Mitochondrial respiration; Pro-inflammatory cytokines
    DOI:  https://doi.org/10.1016/j.bbi.2026.106255
  12. Cell Mol Life Sci. 2026 Jan 08.
    Mitochondrial and lipid metabolism rewiring during HEV infection.
    Quentin Glaziou, Qian Chen, Jordi Gouilly, Ming Wu, Marie Duhamel, Michel Salzet, Jacques Izopet, Reem Al Daccak, Hicham El Costa, Nabila Jabrane-Ferrat.
      Hepatitis E virus (HEV), a leading cause of acute and chronic viral hepatitis, poses a persistent global health challenge. A deeper mechanistic understanding of virus-host interactions is critical for identifying therapeutic targets to mitigate HEV-associated disease. In this study, we employ a systems biology framework to comprehensively map metabolic and bioenergetic alterations induced by HEV genotypes 1 and 3 in HepG2/C3a-MAVS-KD cells, a robust model of HEV infection, enabling reliable assessment of virus- and host-driven cellular changes. Our analyses reveal extensive remodelling of host metabolism, including reprogramming of the tricarboxylic acid (TCA) cycle, mitochondrial oxidative phosphorylation (OXPHOS), fatty acid metabolism, and β-oxidation-pathways that collectively sustain the energetic and biosynthetic demands of viral infection. HEV infection also reshapes the cellular lipidome, increasing levels of long-chain neutral lipids and lipid droplet abundance, alongside elevated levels of pro-inflammatory oxylipins. Functional metabolic assays demonstrate a reliance on lipid-fuelled OXPHOS rather than glycolysis for efficient HEV infection. These findings uncover critical host metabolic dependencies exploited by HEV and offer a conceptual framework for targeting metabolic hubs as a therapeutic strategy against HEV infection. Author Summary: Viruses are obligate intracellular pathogens that reprogramme host cellular machinery to their advantage. Yet, the extent to which Hepatitis E virus (HEV) infection orchestrates metabolic reprogramming, and the implications of these changes for viral fitness, remain poorly defined. By integrating large-scale proteomics with lipid metabolic profiling, we delineate molecular strategies through which HEV subverts host lipid metabolism and mitochondrial function. Our findings provide mechanistic insight into how HEV infection modulates host metabolic pathways to its advantage, highlighting potential targets for therapeutic intervention.
    Keywords:  Hepatitis e virus infection; Host cell metabolism; Lipids; Mitochondria
    DOI:  https://doi.org/10.1007/s00018-025-05994-1
  13. J Leukoc Biol. 2026 Jan 10. pii: qiag005. [Epub ahead of print]
    Biodegradable microparticles promote anti-inflammatory innate immune memory though a size- and mTOR dependent process.
    Roisin I Lynch, Aoife L Gorman, Sean McCluskey, Cian J H Horneck-Johnston, Kate Roche, Frederick J Sheedy, Natalia Muñoz-Wolf, Ed C Lavelle.
      Emerging evidence demonstrates that innate immune cells can maintain a non-specific memory, not only in response to microbe-associated ligands such as β-glucan, but also synthetic biomaterials and nano- and microparticles. This creates an opportunity to leverage biomaterials which can establish favourable innate immune responses and memory for therapeutic applications. In this study, we identify particle size as a critical physical determinant influencing both acute macrophage activation and long-term innate immune memory. Specifically, biodegradable poly(lactic-co-glycolic acid) particles in the 1-2 µm size range promoted an anti-inflammatory phenotype and enhanced oxidative phosphorylation in bone marrow-derived macrophages, through a process dependent on mTOR signalling. In contrast to the well documented pro-inflammatory innate immune training seen with microbial stimuli such as β-glucans, exposure of macrophages to 1-2um poly(lactic-co-glycolic acid) particles promoted a durable anti-inflammatory reprogramming, marked by elevated IL-10 and IL-1 receptor antagonist secretion upon secondary stimulation, and metabolic re-wiring. Moreover, bone marrow from mice injected with PLGA particles in this size range, were reprogrammed to upregulate IL-1Ra and IL-10 secretion upon a re-stimulation, which persisted up to one week post-injection. These findings uncover how the physicochemical properties of polymeric nanoparticles differentially modulate innate immune cells and regulate the induction of innate training.
    Keywords:  PLGA particles; anti-inflammatory; innate-training; mTOR; macrophage
    DOI:  https://doi.org/10.1093/jleuko/qiag005
  14. bioRxiv. 2026 Jan 02. pii: 2025.12.31.697156. [Epub ahead of print]
    Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism.
    Daniel D Carroll, Kamacay Cira, Jack Archer, Jason Shapiro, Ue-Yu Pen, David Tieri, Lucia Leonor, Neda D Roofchayee, Samantha S Yee, Marc Wahab, Igor J Koralnik, John C Alverdy, Arjun S Raman, Lavanya Visvabharathy.
      Infection rates involving bacterial and viral pathogens have increased precipitously after the COVID-19 pandemic. While it has been speculated that higher infection rates resulted from increased hospitalizations throughout the pandemic or greater use of antibiotics, precisely why rates remain high today has remained unexplained. Mitochondrial dysfunction is known to occur post-COVID and may disrupt immune responses. Within T cells, SARS-CoV-2 infection is linked to low mitochondrial membrane potential, increased mitochondrial apoptosis, and decreased mitochondrial respiration, which together impact cellular activation and function beyond the acute phase of illness. Here, we demonstrate that decreased mitochondrial function in antigen-specific T cells post-COVID may contribute to higher infection susceptibility by metabolically immobilizing T cell memory responses. Using donor-matched peripheral blood samples from 31 COVID-naïve individuals who subsequently contracted COVID-19, we tracked how influenza A (IAV), Staphylococcus aureus (SA), and Varicella-zoster virus (VZV) T cell responses were impacted by COVID-19 infection. We found that gene expression linked to T cell activation decreased but mitochondrial redox pathways increased in CD4 memory T cells post-COVID. However, mitochondrial flux and reactive oxygen species production were limited in a plurality of post-COVID memory T cells after stimulation with IAV, SA, and VZV. Furthermore, we found a disordered relationship between memory T cell mobilization of glycolysis, fatty acid metabolism, and oxidative phosphorylation pathways post-COVID which resulted in diminished use of catabolic pathways including glycolysis and fatty acid oxidation in antigen-specific T cells. Modulation of mitochondrial function with metformin and ubiquinol partially rescued the post-COVID decline in T cell catabolism. Collectively, these findings indicate that COVID-19 infection may have lasting effects on inhibiting T cell memory responses to commonly encountered community-acquired pathogens which can be corrected with commonly available medications. This has significant implications for the clinical care of immunologically vulnerable populations in the post-pandemic era.
    DOI:  https://doi.org/10.64898/2025.12.31.697156
  15. Nat Immunol. 2026 Jan 07.
    Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment.
    Yasuharu Haku, Koji Kitaoka, Koki Ichimaru, Tomoko Hirano, Jun Wang, Kazuhiro Sonomura, Asuka Maruo, Shuhei Hirose, Yu Wang, Katsuhiro Ito, Tomohiro Kozuki, Keiko Yurimoto, Mai Kiyono, Hidetaka Kosako, Toshi Menju, Hiroshi Date, Takashi Kobayashi, Koichi Omori, Tomonori Yaguchi, Tasuku Honjo, Kenji Chamoto.
      Glycolysis and mitochondrial fatty acid oxidation (FAO) regulate CD8+ T cell differentiation, but how this metabolic balance regulates T cell exhaustion is unclear. PD-1 signaling inhibits glycolysis and enhances FAO. Here, we show that CD8+ T cells in tumors adhere to glycolysis with attenuated FAO despite high PD-1 expression. Active aldehydes, final products of lipid peroxidation, accumulate in CD8+ T cells in proportion to their level of exhaustion, defined by mitochondrial mass and potential. Aldehydes promote glycolysis and inhibit FAO in T cells. Mice deficient in an FAO enzyme in T cells generate more acrolein, a representative aldehyde, enhancing T cell exhaustion and attenuating antitumor immunity. Acrolein is generated partly from mitochondria and damages mitochondrial architecture. Inhibitors of lipid peroxidation or aldehydes enhanced PD-1-blockade by rectifying metabolic imbalance. Therefore, active aldehydes resulting from FAO impairment can cause a vicious cycle of metabolic imbalance that leads to T cell exhaustion.
    DOI:  https://doi.org/10.1038/s41590-025-02370-w
  16. Cancer Lett. 2026 Jan 02. pii: S0304-3835(26)00003-0. [Epub ahead of print]639 218240
    CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction.
    Lingling Si, Di Wei, Jinghao Pan, Renato B Baleeiro, Louisa S Chard Dunmall, Yaohe Wang.
      Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a transformative advancement in cancer immunotherapy, but remains limited by multiple challenges. The exhaustion of T cells represents a critical obstacle limiting the success of immunotherapeutic interventions. Targeting mitochondrial metabolism offers a promising approach to mitigate exhaustion and enhance CAR-T persistence. Mechanistically, mitochondrial dysfunction within the tumor microenvironment disrupts energy metabolism, reactive oxygen species (ROS) homeostasis, and cell survival, impairing CAR-T function. Here, we review the current challenges facing the clinical application of CAR-T therapy in cancers and summarize mitochondrial-centered approaches to overcome some of these obstacles by optimizing mitochondrial metabolic pathways. We emphasize the essential role of mitochondrial metabolism in augmenting therapeutic efficacy and persistence of CAR-T cells. Future breakthroughs will depend on robust clinical evidence and precise metabolic modulation to enhance CAR-T therapies.
    Keywords:  CAR-T therapy; Combination therapy; Metabolic reprogramming; Mitochondrial metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2026.218240
  17. Nat Immunol. 2026 Jan 08.
    Active aldehydes drive metabolic exhaustion in CD8+ T cells.
      
    DOI:  https://doi.org/10.1038/s41590-025-02413-2
  18. Front Immunol. 2025 ;16 1686774
    Viral reprogramming of glial metabolism as a driver of neuroinflammation.
    Tamara Rodrigues, Gabriel Salles Beltrão, Heloísa Girardi, Aguinaldo R Pinto.
      Considerable attention has been recently devoted to the involvement of immune cells in the central nervous system (CNS) during infections with neurotropic viruses, such as SARS-CoV-2, HIV-1, and ZIKV. These viruses are capable of infecting astrocytes and microglia, the main glial cells in the CNS, responsible for regulating neuronal activity. Here, we discuss how viral infections lead to metabolic reprogramming toward aerobic glycolysis in these cells, enhancing pro-inflammatory pathways, such as inflammasome activation, resulting in the secretion of inflammatory cytokines that favor the development of neuroinflammation. In this mini review, we discuss the pivotal interplay between metabolism and immunity towards viral pathogenesis in the CNS, pointing out the relevance of therapeutic strategies targeting both metabolic and immunological pathways to enhance antiviral and neuroprotective responses.
    Keywords:  CNS; glial cells; inflammasome; metabolic reprogramming; neuroinflammation; neurotropic viruses
    DOI:  https://doi.org/10.3389/fimmu.2025.1686774
  19. Mol Neurobiol. 2026 Jan 03. 63(1): 337
    Microglia Mitochondrial Metabolism in Neurological Diseases.
    Jin Wang, Yikun Gao, Qing Chen, Xiaoxing Xiong, Sen Miao, Xuemei Chen, Youjia Tang, Lijuan Gu.
      Microglia, the resident immune cells of the central nervous system (CNS), play critical roles in maintaining brain homeostasis and responding to neurological insults. Recent advances have fundamentally reshaped our understanding of how microglial mitochondrial metabolism influences neuroinflammation and disease progression. Single-cell transcriptomics has revealed unexpected metabolic heterogeneity, identifying distinct phenotypes such as disease-associated microglia (DAM) and lipid-laden microglia (LLM) that represent not merely activated states but terminal endpoints of metabolic paralysis. These discoveries converge on a unified pathogenic mechanism: mitochondrial quality control failure leads to mitochondrial DNA release, which activates the cGAS-STING pathway to create an "epigenetic lock" that drives sustained neuroinflammation. Interestingly, we highlight that the loss of metabolic flexibility-rather than glycolysis per se-is the true driver of pathology, explaining why the same metabolic shift can be protective during acute injury but pathological when sustained chronically. We critically examine conflicting evidence across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke, including the puzzling dual roles of glycolysis, controversies surrounding the experimental autoimmune encephalomyelitis (EAE) model in multiple sclerosis research, and the paradoxical worsening of stroke outcomes following microglial depletion. By synthesizing these mechanistic insights with lessons from failed clinical trials, we identify critical translational gaps-including the lack of longitudinal human data and validated biomarkers-and propose a precision medicine framework focused on restoring mitochondrial dynamics and metabolic flexibility in neurological diseases.
    Keywords:   Metabolic reprogramming; Mitochondrial metabolism; Neuroinflammation; Microglia
    DOI:  https://doi.org/10.1007/s12035-025-05640-8
  20. Basic Clin Pharmacol Toxicol. 2026 Feb;138(2): e70188
    Metformin Attenuates ox-LDL-Induced Macrophage Senescence and Inflammation via NR4A1-Mediated Mitophagy Regulation.
    Luling Li, Xiuting Huang, Pei Li.
      Metformin alleviates oxidized low-density lipoprotein (ox-LDL)-induced macrophage senescence, a key process in atherosclerosis. Our in vitro findings demonstrate that metformin suppresses ox-LDL-induced overexpression of the nuclear receptor NR4A1 in macrophages. This inhibition subsequently reduces excessive mitophagy, improves mitochondrial membrane potential and decreases reactive oxygen species (ROS) production. The amelioration of this mitochondrial dysfunction directly attenuated cellular senescence markers and reduced the secretion of inflammatory cytokines. Furthermore, we identified Caveolin-1 as a critical regulator of metformin's protective effects. Overexpression of Caveolin-1 was shown to reverse metformin-mediated improvements in mitochondrial function. These results establish that metformin mitigates macrophage senescence by targeting the NR4A1-mitophagy pathway, with Caveolin-1 serving as an essential modulator. This NR4A1-mitophagy axis represents a promising therapeutic target, positioning metformin as a potential candidate for slowing atherosclerosis progression by preserving mitochondrial health in macrophages.
    Keywords:  atherosclerosis; inflammation; macrophage senescence; metformin; ox‐LDL
    DOI:  https://doi.org/10.1111/bcpt.70188
  21. J Virol. 2026 Jan 09. e0173625
    Porcine epidemic diarrhea virus manipulates IMPDH-dependent nucleotide biosynthesis to facilitate replication.
    Shuting Zhou, Houde Zhao, Junrui Zhu, Yanjun Zhou, Zhibiao Yang, Zhe Wang.
      Porcine epidemic diarrhea virus (PEDV) causes acute intestinal disease in pigs and remains a major threat to the global swine industry due to its high morbidity and mortality in neonatal piglets. To investigate host metabolic alterations upon PEDV infection, we performed untargeted metabolomic profiling in LLC-PK1 and Vero E6 cells. Pathway enrichment analysis revealed significant changes in nucleotide metabolism, cofactor biosynthesis, amino acid biosynthesis, and purine metabolism. Notably, PEDV infection led to divergent regulation of purine metabolism in the two cell types-upregulation in Vero E6 cells and downregulation in LLC-PK1 cells at 18 h post-infection. We further identified inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide biosynthesis, as a critical host factor for PEDV replication. Both genetic knockdown of IMPDH2 and pharmacological inhibition using merimepodib (VX-497, MMPD) significantly reduced viral RNA levels and impaired replication. These treatments also suppressed host nucleotide biosynthetic activity. Together, our findings demonstrate that PEDV hijacks the IMPDH-dependent guanosine biosynthesis pathway to support its replication and identify IMPDH as a promising host-directed antiviral target against PEDV.
    IMPORTANCE: PEDV poses a major global threat to swine health. This study uncovers a key mechanism of pathogenesis: PEDV exploits host nucleotide metabolism, inducing significant reprogramming with emphasis on purine biosynthesis. Comparative infection of porcine (LLC-PK1) and primate (Vero E6) cells revealed cell-specific metabolic adaptations. Crucially, we identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for guanosine biosynthesis, as an essential host dependency factor for PEDV replication. Inhibiting IMPDH genetically or pharmacologically significantly reduced viral titers, validating it as a critical vulnerability. These findings reveal a novel mechanism by which PEDV hijacks host metabolism and establishes IMPDH as a promising host-directed therapeutic target for combating this economically devastating virus.
    Keywords:  IMPDH; merimepodib; nucleotide biosynthesis; porcine epidemic diarrhea virus (PEDV)
    DOI:  https://doi.org/10.1128/jvi.01736-25
  22. Front Immunol. 2025 ;16 1689317
    Nutritional intervention alleviates T cell exhaustion and empowers anti-tumor immunity.
    Yuqi Xu, Wenhui Yuan, Ke Li, Peng Li.
      T cells are central mediators of adaptive immunity, playing a pivotal role in eliminating pathogens and tumor cells. In the context of chronic infections and cancer, however, persistent antigenic stimulation drives T cells into a state of exhaustion characterized by diminished effector function, sustained expression of inhibitory receptors, and profound metabolic reprogramming. Emerging evidence indicates that T cell exhaustion is not irreversible and can be alleviated through immune checkpoint blockade, such as targeting PD-1. Moreover, increasing attention has been directed toward the role of intracellular metabolic pathways in shaping T cell fate and function. Strategies aimed at enhancing nutrient availability and metabolic fitness offer an additional avenue to restore T cell activity. This review highlights recent advances in reversing T cell exhaustion through immune checkpoint inhibitors and nutritional interventions, providing novel insights into the precision and personalization of cancer immunotherapy.
    Keywords:  antitumor immunity; exhausted T cells; immune checkpoint inhibitors; immunotherapy; nutrients
    DOI:  https://doi.org/10.3389/fimmu.2025.1689317
  23. Immunohorizons. 2026 Jan 06. pii: vlaf071. [Epub ahead of print]10(1):
    Interleukin-7R and chemokine receptor type 7 differentially regulate metabolism in CD4+ and CD8+ T cells.
    Kimberly A Morrissey, Miriam Valenzuela-Cardenas, Rebekah Gridley, Maria Gabaldon-Parish, Anthony Languit, Judy L Cannon.
      Naïve T cells are highly metabolically active, maintaining homeostatic function as well as continuously moving and surveying lymph nodes for dendritic cells (DCs) presenting cognate antigen. T-cell metabolism is thought to change throughout development: Naïve T cells have been found to predominantly utilize catabolism for naïve T-cell homeostasis while T-cell activation leads effector T cells to become glycolytic. There is still relatively less known about how individual and combinations of molecular signals drive specific metabolic programs in naïve T cells. Naïve T cells primarily depend on IL-7 signaling to IL-7R for homeostasis and are driven by the chemokine receptor CCR7 responding to CCL21 for rapid motility in lymph nodes, leading to T-cell surveillance. We identify specific roles for IL-7R and CCR7 in driving differential metabolic programs in naïve CD8+ and CD4+ T cells. We find that while IL-7 treatment increases glycolysis in both naïve CD4+ and CD8+ T cells, CCL21 treatment does not affect glycolysis. Instead, CCR7 signaling decreases respiratory capacity and mitochondrial intensity and area. While IL-7 treatment does not impact overall oxidative phosphorylation, IL-7 also alters mitochondrial dynamics. Interestingly, a combination of IL-7R and CCR7 signaling using IL-7 with CCL21 differentially affects CD4+ versus CD8+ T-cell metabolism. Our results demonstrate that multiple molecular signals can differentially regulate naïve CD4+ and CD8+ T-cell metabolism, leading to changes in both glycolysis and oxidative phosphorylation in naïve T cells.
    Keywords:  CCR7; IL-7; chemokines; immunometabolism
    DOI:  https://doi.org/10.1093/immhor/vlaf071
  24. J Lipid Res. 2026 Jan 02. pii: S0022-2275(26)00001-5. [Epub ahead of print] 100975
    Chronic Kidney Disease Induces Distinct Alterations of Macrophage Lipid Metabolism in a Mouse Model of Atherosclerosis.
    Keith Saum, Xinyi Liu, Thekkelnaycke Rajendiran, Lixia Zeng, Pradeep Kayampilly, Jaeman Byun, Farsad Afshinnia, Subramaniam Pennathur.
      Chronic kidney disease (CKD) is associated with altered lipid metabolism and chronic inflammation, which both contribute to an accelerated risk of atherosclerotic cardiovascular disease (ASCVD). Macrophage polarization towards a pro-inflammatory phenotype plays a key role in ASCVD development and is mediated by a rewiring of macrophage immunometabolism. While prior studies have investigated associations between the systemic lipidome and CKD-accelerated CVD, the impact of CKD on macrophage lipid metabolism remains unknown. In this study, we profiled the macrophage lipidome in mice with and without CKD induced by 5/6 nephrectomy. After 16 weeks of a high-fat diet, thioglycollate-elicited peritoneal macrophages (PMΦ) were collected and subjected to lipidomics by LC-MS/MS. Quantification of 481 distinct lipids across 19 lipid classes identified an increased abundance of saturated C16-C24 free fatty acids, phosphatidylglycerols, phosphatidylethanolamines, modified ceramides, and polyunsaturated ether lipids in PMΦ from CKD mice compared to controls. PMΦ from CKD mice also exhibited decreased abundance of unsaturated free fatty acids, triglycerides and phosphatidylcholines. Long-chain-to-intermediate-chain acylcarnitine ratio, a metric of β-oxidation efficiency, was reduced in CKD PMΦ, without altering macrophage de novo lipogenesis suggesting a shunting of exogenous lipids towards complex lipid synthesis. Pathway enrichment analysis identified long-chain acyl-CoA synthetase 1 (ACSL1) as a potential upstream mediator of these observed changes in macrophage lipid metabolism. Expression of ACSL1 and inflammatory cytokines was increased in CKD PMΦ or following treatment with palmitate or uremic serum in RAW 264.7 macrophages. These effects were blunted by the knockdown of ACSL1 in RAW264.7 cells. Partitioning of fatty acids towards complex lipid synthesis by ACSL1 may be a mechanism underlying chronic inflammation in advancing CKD.
    Keywords:  Lipidomics; glycerophospholipid; inflammation; kidney disease; macrophages
    DOI:  https://doi.org/10.1016/j.jlr.2026.100975
  25. PLoS Biol. 2026 Jan;24(1): e3003585
    How do immunometabolites shape bacterial infections?
    Griffin Gowdy, Alice Prince.
      Metabolites generated by host and pathogen have a major impact on the severity and outcomes of infection. The metabolic response to infection shapes the nature and intensity of the immune response, both in bloodstream infections and, especially, in the pathogenesis of pneumonia. Some metabolites are closely linked to pro-inflammatory responses, whereas others act as immunomodulators in mitigating damage to the host, a common consequence of inflammation. Immunometabolites are also major factors in driving bacterial adaptation to the host, enabling pathogens acquired from environmental sources to modify their gene expression to optimize for persistent infection. In this era of diminishing antimicrobial efficacy, an appreciation of the immunometabolic responses to bacterial infection may provide novel targets for therapy.
    DOI:  https://doi.org/10.1371/journal.pbio.3003585
  26. Immunology. 2026 Jan 07.
    Alterations in NK Cell Function and Glucose Metabolism Characteristics in Patients With Progressive Hepatocellular Carcinoma.
    Lihua Yu, Yuyong Jiang, Xiaoli Liu, Fengna Yan, Huiwen Yan, Yuqing Xie, Wanxin Shi, Zimeng Shang, Juan Du, Zhiyun Yang.
      Natural killer (NK) cell immunosuppression represents a critical factor in patients with progressive hepatocellular carcinoma (HCC), yet its underlying characteristics at the single-cell level remain poorly defined. This study investigates the functional and metabolic alterations in NK cells associated with progressive HCC. We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood samples from six treatment-naïve HCC patients, categorised into progressive and stable disease groups based on a 3-year follow-up. This was complemented by multicolor flow cytometry of peripheral blood, alongside multicolor fluorescence analyses of paired tumour and adjacent tissues. Our analyses revealed a significant reduction in NK cell proportion and a marked downregulation of immune-related genes in patients with progressive HCC. scRNA-seq further identified a distinct NK cell characterised by high expression of HAVCR2 (TIM3). Compared to TIM3-NK cells, TIM3+NK cells exhibited an exhausted phenotype, evidenced by upregulated CD39 and TIGIT, impaired functional capacity (reduced CD107a and IFN-γ) and downregulated key glycolytic enzymes (HK2, ATP5a). Clinically, high TIM3 expression correlated with shorter progression-free survival and an increased risk of tumour progression. Collectively, our findings delineate a state of NK cell immunosuppression and metabolic impairment in progressive HCC, potentially driven by glycolytic reprogramming and establish TIM3 as a critical marker and potential therapeutic target.
    Keywords:  NK cell; glucose metabolism; hepatocellular carcinoma; progressive tumour; single‐cell RNA sequencing
    DOI:  https://doi.org/10.1111/imm.70095
  27. Cells. 2025 Dec 26. pii: 47. [Epub ahead of print]15(1):
    Glucose Metabolism and Innate Immune Responses in Influenza Virus Infection: Mechanistic Insights and Clinical Perspectives.
    Kareem Awad, Nancy N Shahin, Tarek K Motawi, Maha Abdelhadi, Reham F Barghash, Ahmed M Awad, Laura Kakkola, Ilkka Julkunen.
      This review article discusses glucose metabolic alterations affecting immune cell responses to influenza virus infection. It highlights possible relationships between essential metabolic targets and influenza replication dynamics in immune cells. Thus, kinases as essential regulators of glucose metabolism as well as critical immune mediators during this infection such as interferons, tumor necrosis factor-alpha and transforming growth factor beta have been illustrated. Mechanistic highlights are provided for both the Warburg effect, where glycolysis shifts to lactate production during influenza infection, and the PFK1/PFKFB3 enzyme complex as the rate-determining regulator of glycolysis whose activity increases during the course of influenza infection. The mechanisms of mammalian target of rapamycin (mTOR) signaling as a promotor of glycolysis and a regulator of inflammatory cytokine production are discussed across various immune cell types during infection. We conclude that modulation of the metabolic changes associated with immune responses plays an important role in disease progression, and that targeting metabolic checkpoints or kinases may offer promising avenues for future immunotherapy approaches for the treatment of influenza virus infection. We also emphasize the need for further research to develop a comprehensive biological model that clarifies host outcomes and the complex nature of immune-metabolic regulation and crosstalk.
    Keywords:  glucose metabolism; host-pathogen interactions; immune-metabolism; influenza; kinases; therapeutic targets
    DOI:  https://doi.org/10.3390/cells15010047
  28. Inflamm Regen. 2026 Jan 06.
    Microbiota-derived D-amino acids in intestinal homeostasis and inflammatory bowel disease.
    Kentaro Miyamoto, Tomohisa Sujino.
      Inflammatory bowel disease (IBD) encompasses chronic, relapsing inflammatory disorders of the gastrointestinal tract, which are driven by intricate interactions between the host immune system and intestinal microbiota. Recent studies have revealed that microbiota-derived D-amino acids (D-AAs), once considered biologically inert, play critical roles in maintaining mucosal homeostasis and modulating immune responses. These metabolites, which are increasingly classified as postbiotics, directly influence epithelial barrier integrity, immune cell activity, and microbial ecology. In this review, we summarize the current insights into the biosynthesis, bacterial functions, and immunological implications of D-AAs in the gut, with a particular focus on their involvement in IBD pathogenesis. Specific D-AAs, such as D-alanine, contribute to bacterial cell wall integrity and quorum sensing and interact with host immune cells, alter microbial communities, and regulate mucosal barrier function. Evidence from both human studies and murine models highlights how disrupted D-AAs' metabolism through dysbiosis or impaired host sensing via enzymes such as D-amino acid oxidase (DAO) exacerbates inflammation. Finally, we discuss the translational potential of D-AAs as non-invasive biomarkers and therapeutic targets in IBD, emphasizing the need for integrative multi-omics approaches that connect microbial metabolism with host immune regulation and disease outcomes.
    Keywords:  D-amino acids; IBD; Microbiome
    DOI:  https://doi.org/10.1186/s41232-025-00403-3
  29. J Med Virol. 2026 Jan;98(1): e70788
    Endogenous HIV-1 Tat Promotes Cell Proliferation, Migration, and Phagocytosis in Stably Infected Macrophages by Accumulating Lactate and Activating the Autophagy/MAPK Pathway.
    Yang Wei-Ling, Xiao Na, Liu Lin, Zou Yu-Ting, Cao Zi-Yi, Jiang Yan, Zeng Yi.
      HIV-1 infection remains difficult to treat due to the virus's ability to persist in host cells such as memory CD4+ T cells and peripheral macrophages. Tat, an HIV-1 regulatory protein, also modulates transcription in host cells. However, the mechanisms by which Tat stably affects macrophage functions, critical host cells for HIV-1, remain unclear. This study demonstrates that Tat promotes macrophage proliferation, migration, and phagocytosis. In-depth analysis reveals that HIV-1 Tat enhances lactate accumulation, induces reactive oxygen species (ROS), and activates the MAPK pathway in macrophages. Additionally, lactate induces autophagy activation, leading to increased levels of Arg1 and TGF-β, which drive phagocytosis and migration, respectively. By examining the activity of macrophages stably infected with Tat, this study provides new insights into Tat's latent influence on macrophage function, offering theoretical support for understanding HIV-1 infection mechanisms.
    Keywords:  HIV‐1 Tat; autophagy/MAPK pathway; lactate; macrophages; phenotypes
    DOI:  https://doi.org/10.1002/jmv.70788
  30. Int Immunopharmacol. 2026 Jan 08. pii: S1567-5769(26)00022-6. [Epub ahead of print]171 116179
    PFKFB3-involved glycolytic metabolism supports sepsis-induced neutrophil extracellular trap formation.
    Jiangtao Yin, Caixia Wu, Wutao Wang, Min Xiao, Jingwen Peng, Chao Liu, Guoying Liu, Dadong Liu.
      Uncontrolled formation of neutrophil extracellular traps (NETs) is one of the main mechanisms leading to death in septic patients. PFKFB3, a notable enzyme of glycolysis metabolism, is involved in the inflammatory activation of granulocytes. Our previous studies demonstrated that PFKFB3-involved glycolytic metabolism supports CXCR4hi neutrophil inflammatory activation, which is a key mechanism for the inflammatory injury of the lungs induced by sepsis. However, the specific mechanism by which PFKFB3 supports NET formation in sepsis remains unclear. Here, we found that high expression of neutrophil PFKFB3 is essential for sepsis-induced NET formation. Further mechanistic studies revealed that PFKFB3 promoted sepsis-related NET formation via glycolytic reprogramming and peptidylarginine deiminase 4 (PAD4)-dependent chromatin decondensation. However, inhibiting glycolytic metabolism supported by PFKFB3 can significantly reduce PAD4-dependent NET formation and alleviate sepsis-related lung inflammatory damage. In summary, our results revealed that PFKFB3-supported glycolytic metabolism promotes sepsis-induced NET formation via PAD4-mediated chromatin decondensation. Targeting PFKFB3-supported glycolysis represents a potential strategy to alleviate sepsis-induced hyperinflammation and tissue damage.
    Keywords:  Glycolysis; NET; Neutrophil; PAD4; PFKFB3; Sepsis
    DOI:  https://doi.org/10.1016/j.intimp.2026.116179
  31. J Control Release. 2026 Jan 06. pii: S0168-3659(26)00014-3. [Epub ahead of print] 114613
    H-ferritin engineered nanoplatform reprograms metabolism and immunity for glioblastoma immunotherapy.
    Jing Zuo, Yichun Huang, Hailong Tian, Siyuan Qin, Yonghao Yan, Han Yan, Yining Jiang, Lei Li, Shiqi Wang, Yongfeng Jia, Yuan Zhao, Canhua Huang.
      Disrupting mitochondrial metabolism and reactivating antitumor immunity offers a compelling strategy to enhance therapeutic outcomes in glioblastoma (GBM). Here, we report a mitochondria-targeting nanoplatform that integrates GBM-selective delivery, metabolic disruption, and immune activation for synergistic GBM therapy. The nanoplatform co-encapsulates L820-a conjugate of lonidamine (LND) and IR820 with mitochondrial affinity-and the immunomodulator TP5 into a ZIF-8 framework, which is coated with H-ferritin (HFn) for TfR1-mediated blood-brain barrier (BBB) penetration and GBM targeting. After endocytosis and GBM-specific, acid-triggered degradation, L820 accumulates in mitochondria and causes profound mitochondrial dysfunction, including membrane potential collapse, ATP depletion, and AMPK activation. Concurrently, Zn2+ released from ZIF-8 suppresses GLUT1 and HIF-1α, impairing glycolysis and reducing CD47 expression. These dual metabolic stresses induce mitochondrial DNA (mtDNA) release and activate the cGAS-STING pathway, promoting type I interferon production and immunogenic cell death. TP5 enhances T cell activation while suppressing Tregs, further remodeling the GBM immune microenvironment. This mitochondria-focused strategy achieves potent metabolic interference and immune reprogramming for effective GBM treatment.
    Keywords:  Glioblastoma; Immunogenic cell death; Metabolic disruption; Mitochondria-targeting nanoplatform; cGAS-STING pathway
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114613
  32. Adv Sci (Weinh). 2026 Jan 04. e13020
    Metabolic Reprogramming of T Cells by Dual UCP2 and IL-17 Blockade Enhances Immunity Against Pancreatic Cancer.
    Chuan-Teng Liu, Chun-Chieh Yeh, Tsai-Chen Wu, Chia-Hsin Lin, Yi-Ting Kuo, Yoichiro Iwakura, Yuan-Ji Day, Charles Drake, Vedran Radojcic, Ying-Chyi Song, Heng-Hsiung Wu, Hung-Rong Yen.
      Pancreatic ductal adenocarcinoma (PDAC) remains resistant to immunotherapy due to its immunosuppressive tumor microenvironment (TME) and impaired metabolic fitness of effector T cells. Here, we show that targeting UCP2 reprograms T-cell metabolism, and that dual blockade with IL-17 further enhance antitumor responses in PDAC. Pharmacologic UCP2 inhibition with genipin increases IFN-γ production by CD8⁺ T cells through IL-12R/STAT4/mTOR signaling and enhanced mitochondrial oxidative phosphorylation, promoting a T-bet-driven cytotoxic program. However, UCP2 inhibition alone does not suppress tumor growth. Accordingly, combination with IL-17 depletion synergistically augments Tc1/Th1 responses, reduces myeloid-derived suppressor cells (MDSCs), and improves survival across multiple PDAC models, including genetically engineered and orthotopic systems. CD8⁺ T-cell depletion abrogates these effects. Moreover, UCP2 inhibition enhances IFN-γ production in patient-derived PBMCs and tumor-infiltrating lymphocytes. These findings identify UCP2 as a metabolic checkpoint in cytotoxic T cells and support dual UCP2/IL-17 blockade as a promising immunotherapeutic strategy for PDAC.
    Keywords:  cytotoxic T cell; immunotherapy; interleukin‐17; pancreatic cancer; uncoupling protein 2
    DOI:  https://doi.org/10.1002/advs.202513020
  33. Front Immunol. 2025 ;16 1735873
    The metabolism-immune axis in colorectal cancer: remodeling the tumor microenvironment through metabolite signaling.
    Shaofan Hu, Hui Heng, Fang Yang, Meng Wang, Guoxiang Liu, Yuancai Xiang, Hongming Miao.
      Metabolic reprogramming is a defining hallmark of tumors, and plays a pivotal role in sustaining malignant growth by rewiring core bioenergetic and biosynthetic pathways. Beyond supporting tumor cell proliferation, survival, and metastasis, it profoundly shapes the tumor microenvironment through nutrient competition, accumulation of immunosuppressive metabolites, and modulation of immune cell function, thereby facilitating immune evasion and therapy resistance. This review comprehensively elaborates on metabolic reprogramming in colorectal cancer, covering key alterations in glucose metabolism (Warburg effect), tricarboxylic acid cycle remodeling, lipid biosynthesis/oxidation, cholesterol metabolism, and amino acid (glutamine, methionine, tryptophan, arginine) metabolism. It further dissects how these metabolic shifts impact the tumor microenvironment in colorectal cancer, including their effects on effector immune cells (CD8+ T cells, NK cells), immunosuppressive populations (Tregs, MDSCs, M2-TAMs), and antigen-presenting cells. Additionally, this review highlights the role of the gut microbiota and their metabolites (e.g., SCFAs, secondary bile acids and indoles) in remodeling the immune microenvironment via metabolic crosstalk. Overall, this work provides a comprehensive understanding of CRC metabolic reprogramming and its microenvironmental impacts, offering critical insights to guide the development of novel metabolism-targeted therapeutic strategies for CRC.
    Keywords:  colorectal cancer (CRC); gut microbiota; immune evasion; metabolic reprogramming; metabolism-targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1735873
  34. Clin Sci (Lond). 2026 Jan 09. pii: CS20257900. [Epub ahead of print]140(1):
    Differential modulation of gestational immunity by fatty acids: tissue-specific immune remodeling and clinical implications.
    Jiajia Chen, Lingyu Chang, Xianyang Hu, Jiani Guo, Yang Yan, Dajin Li, Jinlong Qin, Meirong Du, Weijie Zhao.
      Pregnancy necessitates dynamic maternal metabolic adaptations where fatty acids (FAs) serve dual roles as energy substrates and immunomodulators. However, the effects of specific FAs on gestational immunity and pregnancy outcomes remain elusive. In the present study, we administered saturated palmitic acid (PA), monounsaturated oleic acid (OA), polyunsaturated arachidonic acid (AA), or vehicle solutions daily to pregnant mice (gestational day 0.5 [GD0.5]-7.5) and performed comprehensive immune profiling at GD13.5. Mendelian randomization (MR) analysis was employed to evaluate translational relevance in human pregnancies. AA increased embryo resorption rates and decreased both embryonic and placental weights, aligning with MR evidence linking elevated maternal circulating AA to miscarriage risk. Decidual AA exposure amplified pro-inflammatory macrophages (CD11c+), cytotoxic natural killer (NK) cells (NKp46+, IFN-γ+), and cytotoxic T lymphocytes (CTLs, TNF-α+), contrasting OA-driven expansion of M2-like macrophages (CD206+) and pregnancy-protective NK cells (B220+CD11c+). Systemically, AA polarized Th1/CTL dominance (IFN-γ+CD8+) and Ly-6Chigh monocyte retention, whereas OA enhanced Th2 responses and Ly-6Clow monocyte maturation. Paradoxically, AA up-regulated ULN tolerogenic dendritic cells (DCs) and IL-10 expressing regulatory B cells, suggesting tissue-specific lipid sensing. PA activated splenic IFN-γ+ NKs but spared decidual/ULN tolerance. In summary, distinct FAs differentially program gestational immunity in a tissue-specific manner: OA enforces systemic tolerance, while AA drives localized inflammation despite compensatory ULN immunosuppression. These findings advocate personalized FA interventions to optimize pregnancy outcomes.
    Keywords:  arachidonic acid; maternal–fetal tolerance; miscarriage; oleic acid; palmitic acid
    DOI:  https://doi.org/10.1042/CS20257900
  35. Front Immunol. 2025 ;16 1726408
    Anti-alcoholism drug disulfiram inhibits PANoptosis by blocking mitochondrial permeabilization in macrophages.
    Ya-Ping Li, Xin-Jian Niu, Ge Zhang, On-Kei Chan, Nuo Sun, Bo Hu, Zi-Jian Shi, Dong-Yun Ouyang, Xian-Hui He, Qing-Bing Zha.
       Introduction: PANoptosis is a form of inflammatory cell death that exhibits simultaneous activation of pyroptosis, apoptosis and necroptosis signaling. Disulfiram is a clinically used anti-alcoholism drug and can inhibit NLRP3 inflammasome activation and pyroptosis. However, it is unknown whether and how disulfiram interferes with PANoptosis and related inflammatory diseases.
    Methods: PANoptosis was induced in murine macrophages and related protein levels were assayed by immunoblotting. The effects of disulfiram on PANoptosis were assessed both in macrophages in vitro and in a mouse model of hemophagocytic lymphohistiocytosis (HLH) in vivo.
    Results: Mitochondrial permeabilization preceded lytic cell death upon PANoptosis and binding of GSDMD-NT, GSDME-NT and p-MLKL to mitochondria was linked to mitochondrial dysfunction, which was depending on cardiolipin synthesis in mitochondria. Intriguingly, disulfiram not only prevented mitochondrial permeabilization but also suppressed PANoptotic signaling activation in macrophages. Mechanistically, disulfiram prevented the binding of GSDMD-NT, GSDME-NT and p-MLKL from mitochondria to attenuate its permeabilization, release of its components and generation of reactive oxygen species. Furthermore, the assembly of PANoptosome was effectively blocked by disulfiram. In a mouse model of HLH, intraperitoneal administration of disulfiram substantially decreased systemic inflammation and mitigated liver, lung and kidney injury, which were accompanied by reduced activation of PANoptosis signaling in these organs.
    Conclusion: A previously unappreciated action of disulfiram to inhibit PANoptosis both in vitro and in vivo was discovered, thus repurposing this anti-alcoholism drug for the treatment of PANoptosis-related inflammatory diseases.
    Keywords:  PANoptosis; disulfiram; hemophagocytic lymphohistiocytosis; macrophages; mitochondrial permeabilization
    DOI:  https://doi.org/10.3389/fimmu.2025.1726408
  36. Front Aging Neurosci. 2025 ;17 1734837
    Treadmill exercise alleviates Alzheimer's disease pathologies in APP/PS1 mice through modulation of microglial glucose metabolic reprogramming.
    Fei Liang, Feng Sun, Cuijun Guo, Huacong Zhong.
       Objective: Our preliminary studies have demonstrated that exercise counteracts Alzheimer's disease (AD) by mitigating microglia-mediated neuroinflammation and enhancing microglial Aβ clearance. However, the underlying mechanism remains unclear. Given the crucial role of glucose metabolic reprogramming in regulating microglial functions, this study investigated the effects of treadmill exercise on microglial glucose metabolism and associated AD pathologies.
    Materials and methods: Three-month-old male APP/PS1 transgenic mice were randomly assigned to a sedentary group (AD-SED) or an exercise group (AD-EXE). Age- and sex-matched C57BL/6 mice served as the wild-type control group (WT-SED). The AD-EXE group underwent a 3-month treadmill exercise intervention. Following the intervention, we assessed spatial learning and memory using the Morris water maze test, measured neuroinflammation and Aβ levels via Western blot and ELISA, and analyzed microglial glucose metabolism using LC-MS/MS targeted metabolomics and Seahorse assays.
    Results: APP/PS1 mice exhibited longer escape latencies during place navigation trial and fewer platform crossings during the spatial probe trial; these deficits were partially reversed by treadmill exercise. Furthermore, the exercise intervention significantly reduced hippocampal Aβ levels and suppressed neuroinflammation. Notably, microglia from 6-month-old APP/PS1 mice showed significant impairments in both glycolysis and oxidative phosphorylation (OXPHOS), with a metabolic profile primarily reliant on glycolysis. Treadmill exercise enhanced both glycolysis and OXPHOS, and shifted the metabolic phenotype from glycolytic-dominant toward oxidative phosphorylation, and restored metabolic homeostasis.
    Conclusion: Treadmill exercise promotes microglial glucose metabolic remodeling, which attenuates neuroinflammation and Aβ pathology, and restores spatial learning and memory deficits in APP/PS1 mice.
    Keywords:  Alzheimer’s disease; glycolysis; microglia; oxidative phosphorylation; treadmill exercise
    DOI:  https://doi.org/10.3389/fnagi.2025.1734837
  37. bioRxiv. 2026 Jan 01. pii: 2025.12.31.697202. [Epub ahead of print]
    Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1.
    Nicholas L Arp, Uzziah S Urquiza, Marcel Morgenstern, Jonathan H Schrope, James A Votava, Steven V John, Jack J Stevens, Anna Huttenlocher, Joshua J Coon, Jing Fan.
      Nitric oxide (NO•) is an important signaling molecule in many biological processes, including immune response. During response to classical activation stimuli lipopolysaccharide (LPS) and interferon-γ (IFNγ), macrophages generate NO• via inducible nitric oxide synthase (iNOS). To comprehensively define the effects of NO•, we applied a multi-omic strategy integrating proteomics and transcriptomics to profile murine macrophages across conditions with or without LPS/IFNγ-activation, with or without iNOS expression or exogenous NO• donor treatment. The results revealed NO• has broad, yet selected and controlled, regulatory effects, playing a key role in coordinating the systematic remodeling during macrophage classical activation. Among the proteins that are most suppressed in a NO•-dependent manner, electron transport chain (ETC) is the most enriched. NO• drives complex-specific remodeling of ETC, causing selected downregulation of complex I, II, and IV, through a different combination of transcriptional and post-transcriptional mechanisms for each complex. Functionally, we found NO• is required, but not sufficient, for the strong suppression of cellular respiration upon macrophage activation. Among the most consistently upregulated proteins are many enzymes involved in redox defense. AKR1A1 was identified as a top hit. We found Akr1a1 induction requires both NO• and LPS/IFNγ stimulation. The S-nitroso-CoA reductase activity of AKR1A1 mitigates NO•-driven inhibition of pyruvate dehydrogenase complex by limiting the inhibitory modifications targeting its lipoyl cofactor. Knocking out Akr1a1 causes accelerated remodeling of TCA cycle, dysregulated immunoregulatory metabolite level, and altered functional gene expression and cytokine production at later stage of immune response. Thus, the NO•-dependent upregulation of AKR1A1 forms a negative regulatory loop to fine-tune NO•-mediated metabolic and functional remodeling during immune response. Together, this work provided a systems-level map of NO•-dependent regulation, revealed the crosstalk between NO• and immune signaling, and demonstrated mechanisms providing redox adaptation and precise control of NO•'s effects.
    DOI:  https://doi.org/10.64898/2025.12.31.697202
  38. Nat Commun. 2026 Jan 08.
    METTL3 abrogation promotes glioma progression through regulating the ISG15-FASN axis-mediated lipid metabolism in macrophages.
    Huilong Yin, Xiaoyi Yu, Chenglong Hu, Yuhang Yang, Mengke Wang, Yating Xing, Baile Zuo, Chenxing Zhang, Weilong Yang, Yitong Li, Zhuoya Yin, Lijun Zhao, Haijun Ma, Yu Chen, Chaowei Wang, Zhuan Ju, Bowen Liu, Mingming Song, Xiaoqing Chai, Fudi Wang, Angang Yang, Rui Zhang.
      Tumor-associated macrophages (TAMs) constitute a pivotal cellular component within the intricate tumor microenvironment (TME). However, the relationship between the N6-methyladenosine (m6A) and metabolic pattern of TAMs remains poorly understood. Here we show that the m6A methyltransferase METTL3 is conspicuously downregulated in monocyte-derived macrophages from glioblastoma (GBM) patients. Conditional knockout of Mettl3 in myeloid cells augments lipid metabolism and accelerates glioma progression. Furthermore, we found that METTL3 deficiency facilitates fatty acid synthase (FASN) expression, while compromising CD8+ T cell response. Mechanistically, ISG15 is highly expressed in METTL3-deficient macrophages. ISG15 interacts with FASN and regulates FASN ISGylation and its stability through impeding FASN ubiquitination. Notably, the suppression of ISG15 in METTL3-deficient macrophages reverses the enhanced FASN expression and restores CD8+ T cell functionality. Furthermore, we demonstrate that FASN knockout or FASN inhibitor treatment in myeloid cells abrogates the exaggerated tumor progression triggered by METTL3 knockout. Collectively, this study highlights the pivotal role of m6A in regulating macrophage metabolism and identifies potential targets in controlling GBM progression.
    DOI:  https://doi.org/10.1038/s41467-025-68079-4
  39. Nature. 2026 Jan 07.
    Albumin orchestrates a natural host defence mechanism against mucormycosis.
    Antonis Pikoulas, Ioannis Morianos, Vassilis Nidris, Rania Hamdy, Evangelia Intze, Ángeles López-López, Maria Moran-Garrido, Valliappan Muthu, Maria Halabalaki, Varvara Papaioanou, Maria Papadovasilaki, Irene Kyrmizi, Yiyou Gu, Sandra Camunas-Alberca, Robina Aerts, Toine Mercier, Yuri Vanbiervliet, Sung-Yeon Cho, Amy Spallone, Ying Jiang, Dimitrios Samonakis, Efstathios Kastritis, Carlos Lax, Maria Tzardi, Aristides Eliopoulos, Konstantina Georgila, Agostinho Carvalho, Oliver Kurzai, Shivaprakash Mandya Rudramurthy, Caroline Elie, Fanny Lanternier, Kyriakos Petratos, Victoriano Garre, Elias Drakos, Johan Maertens, Vincent M Bruno, Dimitrios P Kontoyiannis, Coral Barbas, Sameh S M Soliman, Ashraf S Ibrahim, Georgios Chamilos.
      Mucormycosis is an emerging, life-threatening human infection caused by Mucorales fungi1-3. Metabolic disorders uniquely predispose an ever-expanding group of patients to mucormycosis through poorly understood mechanisms1,2,4,5, suggesting that uncharacterized host metabolic effectors may confer protective immunity against this infection. Here we uncover a master regulatory role of albumin in host defence against Mucorales through the modulation of fungal pathogenicity. Our initial studies identified severe hypoalb uminaemia as a prominent metabolic abnormality and an independent biomarker of poor mucormycosis outcome across three distinct cohorts of patients with mucormycosis. Notably, purified albumin selectively inhibits Mucorales growth among a range of pathogens, and albumin-deficient mice display susceptibility specifically to mucormycosis. The antifungal activity of albumin is mediated by the release of bound free fatty acids (FFAs). Albumin prevents FFA oxidation, which otherwise abolishes their antifungal properties, and sera from patients with mucormycosis display high levels of oxidized FFAs. Physiologically, albumin-bound FFAs suppress the expression of key virulence factors by inhibiting protein synthesis, the reby rendering Mucorales avirulent in vivo. Overall, we identify a host defence mechanism that directs the pathogen to suppress its pathogenicity program in response to unfavourable metabolic cues regulated by albumin. These findings have major implications for the pathogenesis and management of mucormycosis.
    DOI:  https://doi.org/10.1038/s41586-025-09882-3
  40. Clin Invest Med. 2025 Dec;48(4): 3-9
    Analysis of the impact of SARS-CoV-2 infection on immune function and metabolic changes in college students.
    Fengzhi Li, Yijin Zan, Yukun Cao, Fan Liu, Bingxin Si, Qingling Zhang, LeLa Lin, Jing Guo, Dong Wang, Xianrong Xu.
       BACKGROUND: The long-term immune and metabolic effects of COVID-19 in vaccinated populations remain incompletely characterized. This study aimed to analyze dynamic changes in lymphocyte subpopulations (T, B, and Natural Killer [NK] cells [TBNK]) and key metabolic indicators among college students post-Omicron infection with prior vaccination.
    METHODS: A prospective observational cohort of 71 male students infected with the Omicron variant of COVID-19 (Beijing, China; March-April 2022) and 18 uninfected controls was followed for 2 years. TBNK subsets and metabolic parameters (uric acid, lipid profiles, β2-microglobulin) were analyzed at 3, 6, 12, and 24 months post-infection.
    RESULTS: Immunologically, total lymphocytes were elevated at 3 months when compared with controls (P = 0.0063). Total T cells declined at 6 and 12 months but rebounded by 24 months (P < 0.0001). NK cells increased until 12 months, then declined (P < 0.0001). B cells decreased persistently (P < 0.05). Metabolically, uric acid and lipid parameters (total cholesterol, LDL-C, lipoprotein [a]) showed significant fluctuations, with notable increases at 1 year post-infection (P < 0.05). β2-microglobulin levels decreased significantly over time (P < 0.0001).
    CONCLUSION: Omicron infection induces immune and metabolic disturbances lasting at least 1 year, with gradual but incomplete recovery by 2 years. The interplay between immune dysregulation and metabolic alterations may contribute to the long-term health effects of COVID-19. Monitoring both lymphocyte and metabolic dynamics may guide the long-term management of post-COVID-19 sequelae.
    Keywords:  COVID-19; College students; Immune function; Metabolic changes; Omicron variant; TBNK lymphocyte subsets
    DOI:  https://doi.org/10.3138/CIM-2025-0009
  41. Bioact Mater. 2026 Apr;58 388-407
    Dual itaconate delivery systems modulate macrophage Acod1-Hif-1α-glycolysis axis for immunotherapy of bioprosthetic heart valve calcification.
    Shuyu Wen, Junwei Zhang, Ying Zhou, Jinchi Zhang, Chao Zhang, Chunli Wang, Yixuan Wang, Zongtao Liu, Yin Xu, Bohao Jian, Hong Cao, Shijie Wang, Xing Liu, Yunlong Wu, Jiawei Shi, Fei Li, Kang Xu, Weihua Qiao, Nianguo Dong.
      Calcification remains a major barrier to the long-term durability of bioprosthetic heart valves (BHVs), yet effective therapeutic strategies are still lacking. Emerging evidence suggests that targeting the immune response holds strong promise for mitigating BHV calcification, although the precise mechanisms remain elusive. Here, we integrated single-cell RNA sequencing, spatial transcriptomics, and multiple experimental models to elucidate the immunological mechanisms of BHV calcification and to develop targeted immunomodulatory strategies for anti-calcification therapy. The first spatiotemporal cell atlas of BHV calcification highlights macrophages as key immune drivers, confirmed by various immunodeficient mouse models. Notably, we identified a novel pro-calcification macrophage subset characterized by low Acod1 expression and reduced itaconate production. In macrophage-specific Acod1 knockout models, increased apoptosis, oxidative stress, and extracellular matrix disruption via the HIF-1α-glycolysis pathway accelerated calcification, which was reversed by itaconate supplementation. Guided by these findings, we designed two biomaterial-based therapeutic strategies: a BHV surface functionalized with itaconate via layer-by-layer assembly for localized, sustained release; and tetrazine-functionalized nanoparticles encapsulating itaconate, selectively delivered to trans-cyclooctene-modified BHVs through a bioorthogonal click reaction. Both platforms exhibited favorable biocompatibility and effectively attenuated BHV calcification in vivo, demonstrating strong translational potential. Together, our findings underscore the immune-metabolic axis underlying BHV calcification and pave the way for advanced immune-modulating treatments in BHV management.
    Keywords:  Acod1/itaconate axis; Bioprosthetic heart valve calcification; Glycolysis; Immunotherapy; Macrophage; Targeted delivery
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.11.040
  42. Front Immunol. 2025 ;16 1651923
    Lactylation: the metabolic-immune hub in autoimmune diseases.
    Qingqing Xia, Dantong Sun, Ke Wan, Chengcheng Liu, Han Shu, Miao Wang, Tongsheng Zhou, Ying Chen, Xue Yang, Xiao-Feng Li, Biao Song, Facai Wang.
      In recent years, lactate modification, as an emerging post-translational modification mechanism, has attracted increasing attention for its role in the regulation of the immune system. Autoimmune diseases are a category of complex disorders characterized by abnormal attacks of the immune system on self-tissues. The limitations of traditional treatments have made the search for new therapeutic targets a hot topic in research. Lactate modification plays a significant role in the development and progression of autoimmune diseases. It can modulate the activation and function of T cells, B cells, macrophages, and dendritic cells, thereby influencing inflammatory and autoimmune responses. In diseases such as experimental autoimmune uveitis (EAU), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), lactate modification is closely related to disease progression and can exert its effects by regulating key signaling pathways and cytokine networks. Research on lactate modification as a therapeutic target has also made certain progress, providing new ideas for the treatment of autoimmune diseases. However, there are still many challenges to be faced, such as the development of specific inhibitors, the evaluation of potential side effects, and the feasibility of clinical application. The important regulatory role of lactate modification in autoimmune diseases offers a new target for treatment. Future research needs to further explore its specific mechanisms in the immune system, optimize therapeutic strategies, and assess its clinical application prospects, in order to bring breakthrough progress to the treatment of autoimmune diseases.
    Keywords:  autoimmune diseases; immune cells; immunometabolism; lactate modification; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2025.1651923
  43. Neural Regen Res. 2026 Jan 02.
    A metabolic perspective on microglia in Alzheimer's disease.
    Moris Sangineto, Gaetano Serviddio.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01035
  44. Nat Commun. 2026 Jan 07.
    Chronic macrophage activation derails muscle repair by disrupting mannose-receptor-linked plasticity revealed by endogenous irg1/acod1 tracking.
    Caroline G Spencer, Matthew Hamilton, Ethan Bedsole, Yingshan N Wei, Alison M Rojas, Andrew Burciu, John Zhu, Keith Z Sabin, Celia E Shiau.
      Macrophages are central drivers of chronic inflammation, yet how a sustained inflammatory state alters their function remains unclear. Using GFP knock-in zebrafish targeting irg1/acod1 that marks macrophage activation, we track the dynamic transitions of macrophage states during acute muscle injury under homeostatic and chronically inflamed conditions, induced by genetic mutation of nlrc3l. In the chronic inflammation model, muscle repair is impaired and expression of the mannose receptor mrc1b/cd206 is severely downregulated in a myd88-dependent manner. Two reparative macrophage subtypes, defined by their cellular behavior and single-cell transcriptomics profile, clustering and muscle-encasing, are lost. A chronic infection model recapitulates these defects, underscoring the link to macrophage mrc1b repression. Depleting either mrc1b or macrophages impairs muscle repair. Reinstating normal macrophage states by restoring macrophage nlrc3l expression or ablating myd88-mediated inflammatory pathways rescues muscle repair in nlrc3l mutants. Contrary to conventional discrete states, we identify hybrid M1/M2 macrophage states post-injury. While transient during normal injury response, a pro-inflammatory hybrid state persists during chronic activation, which restricts macrophage heterogeneity, represses mrc1b, and inhibits intracellular cathepsin K accumulation, a hallmark of reparative subtypes. Thus, our study provides mechanistic insight into the dynamics of macrophage activation during muscle injury and repair, and how these processes are modulated under chronic inflammation.
    DOI:  https://doi.org/10.1038/s41467-025-68204-3
  45. Neurochem Res. 2026 Jan 07. 51(1): 34
    Primary Human Reactive Microglia Display Mitochondrial Dysfunction and Metabolic Imbalance Upon Lipopolysaccharide Exposure.
    Gabriel Fontes, Lívia de Sá Hayashide, Daniel Fernandes Messor, Mariana Marques, Vitor Emanuel Leocadio, Pedro Amorim, Alan Silva Minho, Elaine Paiva-Pereira, Luiz Eduardo Baggio Savio, Patricia Dias Fernandes, Rafael Serafim Pinto, Luan Pereira Diniz.
      Microglial activation is a central component of neuroinflammation and contributes to the progression of neurodegenerative diseases. However, most of our current understanding is derived from rodent models, which do not fully recapitulate human-specific responses. In this study, we employed a human primary microglial model isolated from astrocyte-enriched cultures to investigate the cellular and metabolic alterations induced by inflammatory stimulation with lipopolysaccharide (LPS). The isolated human microglia were characterized by strong expression of canonical markers, including IBA-1, CD68, CD45, F4/80, and TMEM119. Upon LPS exposure, cells displayed a robust reactive phenotype with increased expression of activation markers and NF-κB. Functional validation showed preserved phagocytic activity, confirming the immunocompetent status of the cells. Importantly, this is the first study to demonstrate that human primary reactive microglia exhibit mitochondrial dysfunction in response to inflammatory stimuli. LPS treatment led to a significant reduction in mitochondrial mass (TOMM20), increase in mitochondria fragmentation. We observed that LPS increases the phosphorylation of DRP1, indicating enhanced mitochondrial fission and reduction in mitochondrial membrane potential (TMRE), accompanied by increased production of mitochondrial superoxide (MitoSOX), elevated levels of hydrogen peroxide and nitric oxide. This effect was temporally associated with a decrease in intracellular ATP levels, followed by an increase in extracellular lactate production, suggesting a compensatory glycolytic shift in response to mitochondrial bioenergetic failure. Together, these findings highlight a previously uncharacterized vulnerability of human microglia to inflammatory mitochondrial stress and establish a robust and physiologically relevant platform for studying human-specific mechanisms of microglial activation and bioenergetic failure in neurodegenerative conditions.
    Keywords:  Human microglia; Lipopolysaccharide; Metabolic reprogramming; Mitochondrial dysfunction; Neuroinflammation; Primary cell culture
    DOI:  https://doi.org/10.1007/s11064-025-04647-w
  46. Cell Commun Signal. 2026 Jan 03.
    Hormone-sensitive lipase drives pro-resolving macrophage polarization and enhances efferocytosis.
    Haruki Watanabe, Brianna Palacio, Moses Lee, Hei Sook Sul, Junhwan Kim, Betty Diamond, Myoungsun Son.
      
    Keywords:  Efferocytosis; HSL; Lipid droplet; Lipolysis; Macrophages
    DOI:  https://doi.org/10.1186/s12964-025-02631-z
  47. Int J Mol Sci. 2025 Dec 24. pii: 217. [Epub ahead of print]27(1):
    Inhibition of PFKFB3 in Macrophages Has a Dual Effect on Tumor-Regulating Lipid Metabolism.
    Elena Shmakova, Tatiana Sudarskikh, Kseniia Shalygina, Vitaliy Chagovets, Natalia Starodubtseva, Alisa Tokareva, Anastasia Novoselova, Vladimir Frankevich, Anna Tarasova, Dmitry Kostromitsky, Alexey Dobrodeev, Sergey Afanas'ev, Irina Larionova, Julia Kzhyshkowska.
      Colorectal cancer is the third most common cancer worldwide, making lymph node recovery critical for treatment decisions and prognosis. Within the colorectal tumor microenvironment, the metabolic programming of tumor-associated macrophages (TAMs) can drive both pro- and anti-tumor responses, yet the specific glycolytic pathways governing their pro-metastatic conversion present promising therapeutic targets. This study investigated the role of glycolysis activating enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in mediating TAMs metabolic polarization, and its potential as a therapeutic target. PFKFB3 expression was found to be predominant in TAMs in CRC tumor samples. Lipidomic analysis performed by HPLC-MS/MS revealed that PFKFB3 inhibition altered glycerophospholipid metabolism (p = 6.13 × 10-10), and shifted TAMs toward sphingolipid-mediated immunosuppressive metabolism. PFKFB3 activity was associated with a specific reduction in asparagine availability, potentially pointing to a targeted reprogramming of amino acid metabolism supporting distinct TAM functions under conditions of intra-tumoral metabolic stress. These findings highlight PFKFB3 as an essential regulator of TAMs pro-tumoral metabolism in CRC, particularly in colon cancer.
    Keywords:  PFKFB3; amino acid metabolism; colorectal cancer; lipid metabolism; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/ijms27010217
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