bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–03–01
47 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells.
  2. IRG1-itaconate axis in immunometabolism: mechanistic roles and therapeutic potential in inflammatory diseases.
  3. Metabolic control of neuroinflammation: focus on itaconate and its derivatives in CNS disorders.
  4. Glutathione is critical for NK cell-mediated immunity.
  5. De novo purine synthesis reprograms the macrophage inflammatory response and the immune response in sepsis.
  6. IFN-driven lipid synthesis shutdown in CD4⁺ T cells during acute SIV infection and persistent OXPHOS with ART initiation.
  7. Immunometabolites and cancer: the role of 2-hydroxyglutarate, succinate, fumarate and itaconate in tumour development and anti-tumour immunity.
  8. Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
  9. The immunometabolic topography of cellular organization and bacterial control in tuberculosis granulomas.
  10. Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors.
  11. CD38 expression by neonatal human naïve CD4+ T cells shapes their distinct metabolic and tolerogenic properties.
  12. Microbial tryptophan metabolism activates host lysosomal activity to facilitate lipid breakdown.
  13. Macrophage Metabolic Reprogramming-Related Osteoimmunity in Osteoporosis.
  14. Mitochondrial Quality Control in Macrophages during Cardiovascular Disease.
  15. A Druggable G Protein Checkpoint in Cholesterol Efflux.
  16. Pentagalloyl glucose Suppresses MSU Crystal-Induced Gout Inflammation and Arachidonic Acid Production In Vitro and In Vivo.
  17. IL-33-Driven Macrophage Reprogramming as a Potential Immunometabolic Strategy for Herpes Simplex Keratitis.
  18. ATF2-LPCAT1-mediated PKM2 acetylation links cholesterol stress to macrophage metabolic reprogramming and functional remodeling.
  19. Restoring Lysosomes in Adipose Tissue Macrophages Mitigates Obesity-Induced Inflammation and Insulin Resistance.
  20. Proline-Mediated Inhibition of ATPIF1-mTOR Signaling Alleviates Radiation-Induced Macrophage Polarization and Colon Inflammation.
  21. Harnessing nanomedicine and immunometabolism to treat allergic disease.
  22. Metabolic reprogramming and intracellular ATP homeostasis in immunity.
  23. CCL2 drives macrophage M2 polarization via CH25H-mediated metabolic reprogramming to ameliorate post-myocardial infarction remodeling.
  24. Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
  25. mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.
  26. The human plasma amino acids balance favours HIV replication in primary CD4 T lymphocytes.
  27. NEAT1 drives SARS-CoV-2 N protein-induced inflammation, metabolic reprogramming, and mitochondria-ER stress crosstalk.
  28. Chromium(VI) Modulates Macrophage Polarization and Metabolic Reprogramming to Impair Immune Function.
  29. Metabolic masqueraders of paediatric and adult rheumatic diseases.
  30. Restricting Itaconate Suppresses ZFTA-RELA Ependymoma Growth.
  31. Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition.
  32. ISG15 orchestrates dynamic crosstalk between mitochondrial fat oxidation and type 1 interferon in myeloid cells.
  33. Lactylation-YTHDF1 Axis Promotes DNAH5-dependent Ciliary Defense in Pseudomonas aeruginosa Infection.
  34. Hypoxia-inducible factors link inflammation and lipid metabolism in atherosclerotic macrophages.
  35. Targeting immunometabolic pathways with AZD1656 alleviates inflammation and metabolic dysfunction in type 2 diabetic cardiomyopathy.
  36. Complex I preserves mitochondrial polarization during infection of human macrophages by secretion-competent bacteria.
  37. Metabolic checkpoints in the regulation of Th17 cells: implications for uveitis pathogenesis and therapy.
  38. Context-specific regulatory genetic variation in MTOR dampens neutrophil-T cell crosstalk in pneumonia-associated sepsis.
  39. Shifting metabolism alters rRNA expression in malaria parasites.
  40. Microbial-derived 3-phenylpropionic acid orchestrates immune-progenitor cell crosstalk to promote beige adipogenesis and energy expenditure.
  41. Lactate regulation in high-altitude hypoxic adaptation attenuates LPS-Induced acute lung injury: links to glucose metabolism and anti-inflammatory therapeutic potential.
  42. Sustained monocyte activation by persistent challenges with either oxLDL or free cholesterol and underlying mechanisms.
  43. Altered cholesterol immunometabolism activates the macrophage NLRP3-inflammasome in lung fibrosis.
  44. Interplay between cholesterol, Bis(monoacylglycerol)phosphate, and parasitophorous vacuole dynamics in Leishmania infantum infection of macrophages.
  45. Dysregulated Copper Metabolism-Induced Cuproptosis Contributes to Mitochondrial Dysfunction and Macrophage Inflammatory Response in Acute Lung Injury.
  46. The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
  47. Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation.
  1. Cell Chem Biol. 2026 Feb 25. pii: S2451-9456(26)00033-4. [Epub ahead of print]
    Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells.
    Jianfeng Pang, Zengge Wang, Cuixia Yang, Lin Huang, Yiran Qiu, Hui Wang, Keling Huang, Xiaoxue Li, Zifeng Yang, Hudan Pan, Liang Liu, Xuemei Tong, Bin Li, Mingjun Zhang, Lin Zhong, Zhigang Li, Feng Wang.
      Metabolic reprogramming is pivotal for modulating antitumor immunity of T cell. Here, we identify a distinct CD8+ T cell state, designated as pentose phosphate pathway (PPP)-enhanced effector T cell (Tpeec), which is induced by NQO1-mediated redox cycling. We demonstrate that lawsone (Law) serves as a specific NQO1 substrate. The Law-NQO1 axis elevates mitochondrial ROS through NADPH consumption, activating the AKT-FOXO1 signaling cascade to drive effector differentiation. Importantly, this redox-dependent process amplifies PPP activity, redistributing glucose flux to not only enhance mitochondrial fitness but also promote ribose-5-phosphate (R5P) accumulation, endowing Tpeecs with superior proliferative capacity and stemness. Consequently, Tpeecs exhibit robust antitumor efficacy, as validated both in vitro and in vivo. Our findings uncover a critical metabolic axis linking redox cycling to PPP-driven stemness in CD8+ T cells, thereby reconciling their effector function with long-term persistence. This discovery positions NQO1-bioactivatable agents as promising therapeutic tools for optimizing T cell immunotherapy.
    Keywords:  CD8(+) T cell; NQO1; antitumor immunity; glucose metabolism; lawsone; metabolic reprogramming; mitochondrial ROS; pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.chembiol.2026.02.001
  2. Front Immunol. 2026 ;17 1767601
    IRG1-itaconate axis in immunometabolism: mechanistic roles and therapeutic potential in inflammatory diseases.
    Yang Liu, Pengyu Zhang, Weijie Kong, Jinghui Li, Haoqiang Yang, Hengqi Bai, Gexu Fan, Xinfang Cao, Yanjun Li.
      Cells can produce various metabolites, and both immune cells and the immune microenvironment are profoundly influenced by these metabolites. By reshaping the metabolic state of immune cells via metabolites, the host immune response can be effectively regulated, further impacting their behavior in inflammation. Itaconate, as a bypass metabolite of the tricarboxylic acid (TCA) cycle, has long been regarded as a small molecule involved in energy metabolism. However, recent studies reveal its production depends on immune response gene 1 (IRG1), which encodes aconitate decarboxylase. Under the stimulation of inflammation, the expression of IRG1 is significantly upregulated, leading to the rapid accumulation of itaconate within immune cells (especially macrophages), thus making it a key link between metabolism and immune response. Evidence indicates that macrophages are the cell type extensively synthesizing itaconate during M1 polarization driven by potent inflammatory signals (e.g., LPS stimulation). Concurrently, itaconate participates in regulating immune tolerance to cancer therapy via the transmembrane transporter SLC13A3. Under different pathological contexts the IRG1- itaconate axis exhibits distinct dynamic regulatory characteristics: During acute inflammation, itaconate limits excessive release of pro-inflammatory factors and reduces tissue damage by inhibiting succinate dehydrogenase (SDH), activating the Keap1-Nrf2 antioxidant pathway, blocking the ATF3/IκBζ-dependent pro-inflammatory program, and regulating the TET2-mediated epigenetic network. In chronic inflammation or certain tumor microenvironments, however, it may indirectly promote immunosuppression by inhibiting antigen presentation and weakening T cell cytotoxic effects. This bidirectional and environment-dependent nature makes it a key entry point for understanding the maintenance of immune homeostasis, inflammatory regulation and disease progression. This review systematically examines the production mechanisms, biochemical properties, central signaling pathways, and cross-cell effects of Itaconate as an immunomodulatory metabolite. It emphasizes its dual role in regulating inflammatory responses through multiple signaling axes and its contrasting behaviors in different disease contexts. By elucidating its molecular mechanisms, this study aims to provide novel theoretical foundations and potential therapeutic strategies for precision interventions in inflammatory diseases, while outlining future research directions and the clinical translation potential of itaconate-based approaches.
    Keywords:  ACOD1/itaconate axis; Keap1-Nrf2; SDH; TET2; immunometabolism; inflammation; macrophage activation; therapeutic targeting
    DOI:  https://doi.org/10.3389/fimmu.2026.1767601
  3. Front Immunol. 2026 ;17 1726379
    Metabolic control of neuroinflammation: focus on itaconate and its derivatives in CNS disorders.
    Ying Wang, Shihui Liu, Weijie Zhu, Pengyu Hao, Jiacan Xu, Diqi Mai, Ran Chen, Haojie Han, Xuechen Bian, Bodong Wang.
      The activation of microglia, which are the resident immune cells of the central nervous system (CNS), underpins the pathogenesis of neuroinflammatory and neurodegenerative diseases. Metabolic reprogramming has recently been recognized as a critical mechanism that regulates microglial activation because distinct activation phenotypes are tightly coupled to specific metabolic profiles that shape their functional and inflammatory responses. Accumulating evidence indicates that microglia produce itaconate through the tricarboxylic acid cycle, and itaconate and its derivatives play key antioxidant and anti-inflammatory roles. Mechanistically, itaconate has a major impact on the metabolic processes and functional state of microglia by blocking the NF-κB signaling route, activating the Nrf2 signaling pathway, and inhibiting succinate dehydrogenase synthesis as well as NLRP3 inflammatory vesicle activation. Collectively, these actions confer significant protection against CNS disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, and cerebral hemorrhage. Furthermore, structurally optimized itaconate derivatives exhibit enhanced pharmacokinetics and bioactivity. This review highlights the pivotal role of itaconate and its derivatives in microglial regulation, explores their therapeutic potential in neurological diseases, and outlines future research directions, with the aim of providing a theoretical foundation for novel metabolic interventions.
    Keywords:  central nervous system diseases; itaconate; metabolic control; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1726379
  4. Cell Rep. 2026 Feb 23. pii: S2211-1247(26)00064-1. [Epub ahead of print]45(3): 116986
    Glutathione is critical for NK cell-mediated immunity.
    Luana Guerra, Melanie Grusdat, Takumi Kobayashi, Joseph Longworth, Henry Kurniawan, Davide G Franchina, Georgios Theodorakis, Carole Binsfeld, Charlène Verschueren, Lynn Bonetti, Anouk Ewen, Leticia Soriano-Baguet, Sarah Alhamouieh, Sophie Farinelle, Catherine Dostert, Ying Chen, Vasilis Vasiliou, Eric Vivier, Philipp A Lang, Dirk Brenner.
      Natural killer (NK) cells are essential for immune protection against tumors and viruses. Disease environments impose oxidative stress and impair immune cell functions. Glutathione (GSH) is a major cellular antioxidant and is critical for the immune response, but how it modulates NK cell function remains largely unknown. Using a mouse model with a specific deletion of the catalytic subunit of glutamate-cysteine ligase (Gclc) in NK cells, we demonstrate that GSH supports interleukin-15 (IL-15)-driven activation of NK cells. Gclc deficiency causes an intracellular accumulation of reactive oxygen species (ROS), which impairs the metabolism of NK cells. This is accompanied by defective proliferation and cytokine production concurrent with subverted mTOR and STAT5 activation. During acute lymphocytic choriomeningitis virus (LCMV) infection, Gclc-deficient NK cells are unable to suppress the antiviral T cell response. Remarkably, Gclc deficiency impairs NK cell-mediated protection against tumor lung metastases. Our findings highlight an essential role of GSH in maintaining NK cell functionality.
    Keywords:  CP: immunology; CP: metabolism; IL-15; LCMV; NK cells; cancer; cytotoxic T cells; glutathione; immunometabolism; mTOR; metastasis; redox metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.116986
  5. Res Sq. 2026 Feb 19. pii: rs.3.rs-8887742. [Epub ahead of print]
    De novo purine synthesis reprograms the macrophage inflammatory response and the immune response in sepsis.
    György Haskó, Luyu Liu, Zoltán H Németh, Gebhard Wagener, Ugur Akcan, Muhammed Arif, Pál Pacher, Taha Kelestemur.
      Sepsis is characterized by profound immunometabolic dysregulation, yet the role of purine precursor synthesis in immune reprogramming remains poorly defined. Intracellular purine nucleotides, such as ATP, are generated by de novo synthesis, which assembles purinosomes to build inosine monophosphate (IMP) from small precursors, or by the salvage pathway, which recycles purine bases such as hypoxanthine. Here, we investigated how these pathways regulate macrophage activation and host responses in sepsis. Silencing the de novo purine enzyme glycinamide ribonucleotide transformylase (GART) in LPS-stimulated macrophages induced marked transcriptomic remodeling, suppressing anti-inflammatory mediators, including IL-10 and TIMP-1, while increasing TNF-α. These effects were reversed by hypoxanthine supplementation, indicating rescue through salvage. Similar findings were observed with silencing of phosphoribosyl pyrophosphate amidotransferase (PPAT) or pharmacological GART inhibition with azaserine or lometrexol, which also reduced intracellular ATP levels in a hypoxanthine-reversible manner. In contrast, inhibition of salvage enzymes (HPRT, APRT) did not alter IL-10 expression. De novo purine synthesis blockade increased Adora2a expression and decreased Adora3 expression without affecting MAPK signaling. Macrophages formed purinosomes under purine-depleted conditions, which disassembled in the presence of exogenous hypoxanthine. In vivo, azaserine treatment in cecal ligation and puncture-induced sepsis reduced IL-10, increased TNF-α, and elevated bacterial burden. LPS-treated macrophages and PBMCs from septic patients showed reduced GART and PPAT expression. These findings identify de novo purine synthesis as a metabolic checkpoint that sustains anti-inflammatory macrophage programming and host defense, highlighting purine metabolism as a potential translational target in sepsis.
    DOI:  https://doi.org/10.21203/rs.3.rs-8887742/v1
  6. bioRxiv. 2026 Feb 13. pii: 2026.02.12.705596. [Epub ahead of print]
    IFN-driven lipid synthesis shutdown in CD4⁺ T cells during acute SIV infection and persistent OXPHOS with ART initiation.
    Jinhee Kim, Anoop Ambikan, Jakob Harrison-Gleason, Kayla L Yerlioglu, Iva Filipovic, Romaila Abdelraouf, Catarina Ananias-Saez, Erin B Taylor, Mariluz Arainga, Deepanwita Bose, Francois J Villinger, Ujjwal Neogi, Elena Martinelli.
      Cellular metabolism regulates HIV/SIV replication and reservoir establishment, yet how infection and antiretroviral therapy initiation (ARTi) shape the metabolism of CD4⁺ Tcells-main HIV target- in vivo remains poorly defined. Using the SIVmac239 macaque model, we integrated single-cell metabolic profiling (MIST), transcriptomics, lipidomics, genome-scale metabolic modeling, and functional assays to characterize their metabolic remodeling. At peak viremia, CD4⁺ T cells exhibited a marked shutdown of de novo fatty-acid (FA) synthesis, reflected by acetyl-CoA carboxylase-1 (ACC1) downregulation, inhibition of lipid-anabolic reactions, and depletion of membrane phospholipids. This metabolic state was driven by strong type I interferon (IFN-I) responses, and IFN-I exposure was sufficient to suppress ACC1 in vitro . Pharmacologic inhibition of FA synthesis independently enhanced Tcell activation and reduced HIV replication, indicating direct antiviral and immunomodulatory effects. Following ARTi, most metabolic pathways were broadly suppressed, whereas mitochondrial oxidative phosphorylation (OXPHOS) remained elevated. Together, these findings identify IFN-driven FA synthesis shutdown and persistent OXPHOS as defining metabolic features of early HIV/SIV infection and treatment initiation, highlighting these pathways as potential targets to limit viral replication and reservoir formation.
    DOI:  https://doi.org/10.64898/2026.02.12.705596
  7. Immunol Lett. 2026 Feb 20. pii: S0165-2478(26)00026-X. [Epub ahead of print]279 107153
    Immunometabolites and cancer: the role of 2-hydroxyglutarate, succinate, fumarate and itaconate in tumour development and anti-tumour immunity.
    Thomas Pfefer, Anna Hanga Bessenyei, Luke A O'Neill.
      The field of immunometabolism has expanded substantially in recent years, with specific metabolic change becoming a key feature that defines the phenotype of immune cells. In cancer however, metabolic change has been investigated for much longer, and the exploration of oncometabolites as immunometabolites is increasingly being explored. 2-hydroxyglutarate was one of the first oncometabolites to be implicated in tumourigenesis but it also has immunomodulatory effects, with the D enantiomer suppressing anti-tumour immunity via various processes including inhibition of CD8+T cells. Fumarate also acts as an oncometabolite, affecting DNA methylation and DNA repair, but again also having immunomodulatory effects via inhibition of T and B cells, whilst also promoting Type I interferon production in macrophages. Succinate can act as an oncometabolite but also in immunomodulation. It has been shown to have pro-tumour effects, acting via HIF-1α and epigenetic modification and regulating tumour-associated macrophages (TAMs). Succinate can also promote T cell exhaustion whilst expanding cancer-associated fibroblasts. Finally, itaconate has been shown to have pro-tumour effects, by either supporting tumour cell survival or by suppressing anti-tumour immunity. TAMs and myeloid-derived suppressor cells are a source of itaconate, which can inhibit CD8+T cell responses and suppress tumour antigen presentation by dendritic cells. Emerging evidence indicates that the targeting of these metabolites holds promise for limiting tumour growth but in addition boosting anti-tumour immunity.
    Keywords:  2-hydroxyglutarate; Cancer; Fumarate; Itaconate; Oncometabolites; Succinate
    DOI:  https://doi.org/10.1016/j.imlet.2026.107153
  8. bioRxiv. 2026 Feb 17. pii: 2026.02.15.706043. [Epub ahead of print]
    Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
    Shikha Yadav, Sheela Nagarkoti, Varadarajan Sudhahar, Kamarajan Rajagopal, Archita Das, Stephanie Kelley Spears, Tohru Fukai, Masuko Ushio-Fukai.
      Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein DRP1 promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated "redox-dead" DRP1-C631A knock-in mutant ( Drp1 C/A ) BM exhibited markedly reduced limb perfusion recovery and CD31⁺ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G⁺ neutrophil accumulation, pro-inflammatory F4/80⁺CD80⁺ M1 macrophages and reduced anti-inflammatory F4/80⁺CD206⁺ M2 macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia-serum starvation (HSS) rapidly induced cytosolic ROS production and DRP1-CysOH formation in wild type macrophages. In contrast, Drp1 C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD.
    DOI:  https://doi.org/10.64898/2026.02.15.706043
  9. Nat Immunol. 2026 Feb 23.
    The immunometabolic topography of cellular organization and bacterial control in tuberculosis granulomas.
    Erin F McCaffrey, Alea C Delmastro, Isobel Fitzhugh, Jolene S Ranek, Sarah Douglas, Joshua M Peters, Christine Camacho Fullaway, Marc Bosse, Candace C Liu, Craig Gillen, Noah F Greenwald, Sarah Anzick, Craig Martens, Seth Winfree, Yunhao Bai, Cameron Sowers, Mako Goldston, Alex Kong, Potchara Boonrat, Carolyn L Bigbee, Roopa Venugopalan, Pauline Maiello, Edwin Klein, Mark A Rodgers, Charles A Scanga, Philana Ling Lin, Sean C Bendall, Denise E Kirschner, Sarah M Fortune, Bryan D Bryson, J Russell Butler, Joshua T Mattila, JoAnne L Flynn, Michael Angelo.
      Despite being heavily infiltrated by immune cells, tuberculosis (TB) granulomas often subvert the host response to Mycobacterium tuberculosis (Mtb) infection and support bacterial persistence. Human TB granulomas are enriched for immunosuppressive factors typically associated with tumor-immune evasion, raising the possibility that they promote tolerance to infection. Here we identify candidate drivers for establishing this tolerogenic niche and show that the magnitude of this response correlates with bacterial persistence. We conducted a multimodal spatial analysis of 52 granulomas from 16 nonhuman primates infected with low-dose Mtb for 9-12 weeks. Each granuloma's bacterial burden was quantified individually, enabling us to assess how granuloma spatial structure and function relate to infection control. We found that a universal feature of TB granulomas is partitioning of the myeloid core into two distinct metabolic environments, one of which is hypoxic. This hypoxic environment is associated with pathological immune cell states, dysfunctional cellular organization of the granuloma, and a near-complete blockade of lymphocyte infiltration that would be required for a successful host response. The extent of these hypoxia-associated features correlates with higher bacterial burden. We conclude that hypoxia correlates with immune cell state and organization within granulomas and might subvert immunity to TB.
    DOI:  https://doi.org/10.1038/s41590-026-02431-8
  10. Cell Rep. 2026 Feb 25. pii: S2211-1247(26)00113-0. [Epub ahead of print]45(3): 117035
    Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors.
    Yi Wang, Chao Huang, Guoxin Cai, Massimo Andreatta, Armand Kurum, Yang Zhao, Bing Feng, Min Gao, Santiago J Carmona, Zhan Zhou, Cheng Sun, Yugang Guo, Li Tang.
      Natural killer (NK) cells, a type of potent cytotoxic lymphocyte, are particularly promising for the treatment of cancers that lose or downregulate major histocompatibility complex class I (MHC class I) expression to evade T cell-mediated immunotherapy. However, the hostile and immunosuppressive tumor microenvironment (TME) greatly hinders the function of tumor-infiltrating NK cells, thus limiting the therapeutic efficacy. Here, we show a fusion protein of interleukin 21 (IL-21-Fc) that safely and effectively reprograms NK cell metabolism and restores their effector function in vivo. IL-21-Fc synergizes with IL-15 superagonist (IL-15SA) or adoptive NK cell transfer to eradicate MHC class I-deficient tumors and confer durable protection across multiple murine models. Mechanistically, we uncover that IL-21-Fc enhances NK cell effector function by upregulating glycolysis in a lactate dehydrogenase A (LDHA)-dependent manner. This study reveals LDHA-dependent metabolic reprogramming as a key axis for NK cell rejuvenation and positions IL-21-Fc as a promising, clinically translatable strategy to overcome TME-mediated suppression in solid tumors.
    Keywords:  CP: cancer; CP: metabolism; LDHA; MHC class I-deficient tumor; NK cell exhaustion; NK cell therapy; cancer immunotherapy; glycolysis; immunometabolism; interleukin 21
    DOI:  https://doi.org/10.1016/j.celrep.2026.117035
  11. J Clin Invest. 2026 Feb 26. pii: e200062. [Epub ahead of print]
    CD38 expression by neonatal human naïve CD4+ T cells shapes their distinct metabolic and tolerogenic properties.
    Laura R Dwyer, Andrea M DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E Rogers, Scott P Oltman, Laura L Jelliffe-Pawlowski, Theo van den Broek, Femke van Wijk, Susan V Lynch, Rachel L Rutishauser, Allon Wagner, Alexis J Combes, Tiffany C Scharschmidt.
      Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naïve CD4+ T cells into regulatory T cells (Tregs). Here, we demonstrated heightened capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4+ T cells and showed that this is linked to their unique metabolic profile and elevated expression of the NADase, CD38. Early-life naïve CD4+ T cells demonstrated a metabolic preference for glycolysis, which directly facilitated their differentiation trajectory. We revealed an age-dependent gradient in CD38 levels on naïve CD4+ T cells and showed that high CD38 expression contributes to both the glycolytic state and tolerogenic potential of neonatal CD4+ T cells, effects that were mediated at least in part via the NAD-dependent deacetylase SIRT1. Thus, the early-life window for peripheral tolerance in humans is critically enabled by the immunometabolic state of the naïve CD4+ compartment.
    Keywords:  Development; Immunology; Metabolism; T cell development; Tolerance; Tregs
    DOI:  https://doi.org/10.1172/JCI200062
  12. PLoS Biol. 2026 Feb 26. 24(2): e3003685
    Microbial tryptophan metabolism activates host lysosomal activity to facilitate lipid breakdown.
    Kenan Zhang, Zihan Luo, Yan Chen, Yan Li, Lang Wang, Yanan Liu, Ruizhi Yang, Qian Li, Jiahao Zhao, Bin Qi, Zhao Shan.
      Lysosomes are central to lipid metabolism, yet how gut microbiota-derived metabolites regulate lysosomal function to influence host lipid homeostasis remains unknown. Here, we identify a mechanism in which bacterial tryptophan metabolism activates lysosomal activity to promote lipid breakdown in Caenorhabditis elegans, and show that the bacterial tryptophan metabolite indole recapitulates these effects in mammalian hepatocytes. By developing a lysosomal-responsive lipid reporter in C. elegans to screen for bacterial metabolic states that modulate host lipid storage, we discover that Escherichia coli tryptophan catabolism via tryptophanase TnaA induces lysosomal lipid chaperone LBP-8, driving lipid mobilization. Moreover, tryptophan metabolite indole enhanced lysosomal acidification and degradation capacity, while genetic disruption of lysosomal regulators reversed these effects. Strikingly, bacterial tryptophan metabolism further promoted mitochondrial β-oxidation through lysosomal lipase activity. This pathway was conserved in mammalian hepatocytes, where E. coli-derived tryptophan metabolite indole enhances lysosomal function and reduce lipid accumulation. Our work uncovers microbiota-regulated lysosomal activation as a critical axis in lipid homeostasis, highlighting its potential as a therapeutic target for metabolic disorders linked to lysosomal dysfunction.
    DOI:  https://doi.org/10.1371/journal.pbio.3003685
  13. Calcif Tissue Int. 2026 Feb 24. pii: 35. [Epub ahead of print]117(1):
    Macrophage Metabolic Reprogramming-Related Osteoimmunity in Osteoporosis.
    Kejia Zhou, Zhenpeng Wang, Mei Zhang.
      Osteoporosis is a disease characterized by increased bone turnover and decreased bone mass, closely associated with suppressed osteogenesis, enhanced osteoclastogenesis, and immune-metabolic dysregulation. Studies in osteoimmunology have shown that immune dysregulation can disrupt bone homeostasis through multiple signaling pathways and metabolic interactions between immune cells and bone cells. Macrophages, as key players in osteoimmunity, dynamically alter their metabolism in specific environments, integrating environmental signals to exhibit context-specific functions. Among the primary metabolic phenotypes, classically activated macrophages (M1) mainly promote bone resorption, while alternatively activated macrophages (M2) primarily facilitate osteogenesis. These effects are mainly achieved through inflammatory pathways, macrophage-driven osteoclastogenesis, and efferocytosis. Dysregulation of macrophage metabolic reprogramming in osteoimmunity can lead to diseases such as osteoporosis. The link between metabolic reprogramming and epigenetic modifications is a research hotspot in immune-metabolic diseases, and targeting macrophage metabolic reprogramming has shown potential therapeutic benefits for osteoporosis. This review discusses the impact of macrophage metabolic reprogramming-related osteoimmune pathways on osteoporosis.
    Keywords:  Macrophages; Metabolic reprogramming; Osteoimmunity; Osteoporosis
    DOI:  https://doi.org/10.1007/s00223-026-01477-y
  14. Can J Cardiol. 2026 Feb 23. pii: S0828-282X(26)00152-2. [Epub ahead of print]
    Mitochondrial Quality Control in Macrophages during Cardiovascular Disease.
    Ryan C Falconer, Emily A Day.
      Macrophages are key cells of the innate immune system. Within the cardiovascular system, macrophages exhibit marked phenotypic plasticity, enabling them to sense local cues and regulate vascular inflammation, myocardial injury, and tissue remodeling. Mitochondria serve as multifunctional organelles in macrophages, integrating cellular metabolism with the production of immunogenic signals that shape inflammatory responses. In cardiovascular disease (CVD), mitochondrial dysfunction in macrophages drives maladaptive inflammatory responses that when unresolved, lead to chronic inflammation and tissue injury underlying adverse cardiovascular outcomes. To preserve mitochondrial integrity under diverse conditions, cells engage an interconnected network of mitochondrial quality control (MQC) mechanisms, namely mitochondrial biogenesis, maintenance of mitochondrial DNA (mtDNA), remodelling by fission and fusion, mitophagy, and the mitochondrial unfolded protein response. This review examines how these MQC systems govern macrophage polarization, inflammatory signalling, and survival in CVD, focusing on atherosclerosis, myocardial infarction, and heart failure. We discuss evidence demonstrating that the dysregulation of these mechanisms in macrophages, contributes to cardiovascular impairment, with particular emphasis on how dysregulated mitochondrial dynamics, heightened mitochondrial oxidative stress, and mtDNA release converge to amplify inflammation in CVD. We further highlight clinical evidence suggesting that current therapies, such as statins, SGLT2 inhibitors, and GLP-1 receptor agonists enhance macrophage MQC to alleviate stress, improve metabolic function, and dampen inflammation, which may contribute to their cardiovascular benefit. By examining the role of MQC in macrophages within the cardiovascular system, this review establishes the mechanisms governing mitochondrial homeostasis and dysfunction as a critical immunometabolic axis and potential therapeutic avenue underlying cardiovascular disease.
    Keywords:  Immunometabolism; Macrophages; Mitochondria; Mitochondrial Quality Control; cGAS-STING
    DOI:  https://doi.org/10.1016/j.cjca.2026.02.034
  15. bioRxiv. 2026 Feb 17. pii: 2026.02.15.705962. [Epub ahead of print]
    A Druggable G Protein Checkpoint in Cholesterol Efflux.
    Gajanan D Katkar, Mahitha Shree Anandachar, Celia R Espinoza, Megan Estanol, Caroline Biggs, Michelle Nacayama, Shu-Tsing-Hsu, Ellie Tam, Raktim Mukharjee, Ella McLaren, Stephanie Aviles, Vanessa Castillo, Madhubanti Mullick, Jerry Yang, Benedikt Kaufmann, Saptarshi Sinha, Pradipta Ghosh.
      Immunometabolic diseases such as obesity, fatty liver, and atherosclerosis arise when lipid-associated macrophages (LAMs) fail to clear excess lipids. Reverse cholesterol transport (RCT), the body's sole macrophage-to-feces lipid-clearance pathway, remains therapeutically inaccessible. By integrating systems modeling with human plaque transcriptomes, we identify LAM subpopulations that drive plaque progression and nominate GIV ( CCDC88A ) as a molecular brake on RCT. Myeloid-specific GIV deletion reduces aortic plaque burden, mobilizes hepatic and adipose lipids, and restores systemic RCT. Mechanistically, GIV traps the efflux transporter ABCA1 in endomembranes and activates Gαi●βγ to suppress cAMP/PKA-CREB signaling, silencing ABCA1 activity. Genetic or pharmacologic disruption of this checkpoint releases ABCA1 to the membrane, reactivating efflux and reprogramming LAMs toward an anti-atherogenic state. In murine and human plaque-in-a-dish models, targeting the GIV●Gαi-cAMP checkpoint restored efflux where statins and β-blockers failed, reducing modeled plaque-progression risk by ∼98%. Findings establish RCT-restoration as a druggable, macrophage-intrinsic therapeutic paradigm for immunometabolic disease.
    GRAPHIC ABSTRACT:
    eTOC blurb: Lipid-associated macrophages drive immunometabolic disease. Katkar et al. show that disabling a GIV-dependent G-protein brake restores cholesterol efflux, reverses plaque lipid accumulation, and establishes reverse cholesterol transport as a druggable therapeutic axis.
    Highlights: Statins slow but rarely reverse plaque burden, leaving residual risk driven by LAM dysfunctionGIV (CCDC88A) non-canonically modulates Gαi to suppress macrophage cholesterol effluxGIV loss or inhibition restores ABCA1 activity via transcriptional and post-translational controlBlocking the GIV●Gαi checkpoint defats LAMs, regresses plaques, and relieves systemic lipid overloadIdentifies a druggable node that redefines RCT restoration as a therapeutic paradigm in immunometabolic disease.
    DOI:  https://doi.org/10.64898/2026.02.15.705962
  16. Res Sq. 2026 Feb 19. pii: rs.3.rs-8904164. [Epub ahead of print]
    Pentagalloyl glucose Suppresses MSU Crystal-Induced Gout Inflammation and Arachidonic Acid Production In Vitro and In Vivo.
    Sadiq Umar, Yu Lu, Sugasini Dhavamani, Poorna Cr Yalagala, Matez S Wietecha, Sriram Ravindran.
      Background Gout is an acute inflammatory arthritis triggered by monosodium urate (MSU) crystal deposition and activation of innate immune responses. In addition to inflammasome signaling, emerging evidence suggests that metabolic reprogramming of arachidonic acid (AA) pathways amplifies inflammatory responses during gout flares. However, the contribution of upstream fatty acid desaturation processes that regulate endogenous AA availability remains poorly defined. 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (PGG) is a naturally occurring polyphenol with reported anti-inflammatory activity, but its effects on MSU-induced fatty acid metabolism and gouty inflammation have not been well established. Methods Publicly available bulk and single-cell transcriptomic datasets from human and mouse gout studies were analyzed to assess dysregulation of AA-associated pathways. MSU-induced inflammatory responses were examined in mouse bone marrow-derived macrophages and in a murine MSU-induced gout model. Macrophages were treated with PGG prior to MSU stimulation, and inflammatory cytokine production, phagocytosis, and expression of fatty acid desaturases were assessed. Lipidomic analysis of macrophages and plasma was performed using gas chromatography-mass spectrometry (GC-MS) to quantify arachidonic acid and related fatty acids. In vivo disease severity, cytokine expression, and anti-inflammatory markers were evaluated following PGG treatment. Results Analysis of public datasets revealed consistent dysregulation of arachidonic acid-associated inflammatory pathways during gout flares. In macrophages, MSU stimulation increased expression of fatty acid desaturases FADS1 and FADS2 and promoted accumulation of arachidonic acid, concomitant with robust production of pro-inflammatory cytokines. PGG treatment significantly suppressed MSU-induced FADS1, FADS2 and arachidonic acid levels, and attenuated pro-inflammatory cytokine production. PGG also markedly impaired macrophage phagocytosis of MSU crystals. In vivo, PGG treatment significantly reduced clinical disease severity in an MSU-induced gout model, suppressed fatty acid desaturation and arachidonic acid accumulation in plasma, decreased pro-inflammatory cytokine expression, and enhanced anti-inflammatory markers. Conclusion These findings identify fatty acid desaturation as an important metabolic contributor to gouty inflammation and demonstrate that PGG suppresses MSU-induced inflammation by limiting endogenous arachidonic acid availability, reducing inflammatory amplification, and impairing MSU crystal phagocytosis. Targeting upstream fatty acid metabolism represents a potential therapeutic strategy for modulating acute gout flares beyond conventional anti-inflammatory approaches.
    DOI:  https://doi.org/10.21203/rs.3.rs-8904164/v1
  17. Pharmaceuticals (Basel). 2026 Feb 08. pii: 285. [Epub ahead of print]19(2):
    IL-33-Driven Macrophage Reprogramming as a Potential Immunometabolic Strategy for Herpes Simplex Keratitis.
    Yun He, Yaoyao Liu, Junwen Ouyang, Chenchen Wang, Junpeng Liu, Changyu Wu, Qian Tan, Jiaxuan Jiang, Kai Hu.
      Background: Herpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1), is a major cause of infectious blindness. Macrophages are key antiviral effector cells, yet the metabolic mechanisms driving their protective responses remain poorly defined. This study aimed to determine whether interleukin-33 (IL-33) modulates macrophage metabolism and function to enhance antiviral protection in HSK. Methods: Bone marrow-derived macrophages (BMDMs) were stimulated with IL-33, followed by phenotypic and functional characterization using qRT-PCR, flow cytometry, and immunofluorescence. Integrated transcriptomic and non-targeted LC-MS metabolomic profiling was performed to uncover regulatory pathways. For in vivo validation, differently treated BMDMs were adoptively transferred subconjunctivally into a mouse HSK model. Clinical scoring, fluorescein staining, TCID50 quantification of tear samples, and corneal viral gene detection were used to evaluate disease severity and viral burden. Results: IL-33 stimulation increased CD169 and MHC-II expression, expanded the CD169+ macrophage subset, and suppressed HSV-1 replication in vitro. Multi-omics integration identified 616 differentially expressed genes and 417 differentially expressed metabolites, revealing substantial remodeling of lipid and amino acid metabolism and suggesting a critical IL-33-lipoprotein lipase (LPL)-palmitoylcarnitine (L-PC) metabolic axis. In vivo, prophylactic adoptive transfer of IL-33-treated BMDMs significantly reduced corneal opacity, epithelial injury, tear viral titers, and virogene expression. LPL inhibition eliminated these benefits, whereas L-PC supplementation partially restored antiviral and clinical improvements. Conclusions: IL-33 reprograms macrophages toward a CD169+ antiviral phenotype through an LPL-dependent metabolic pathway, establishing an LPL-L-PC axis essential for enhanced antiviral function and protection against HSK. These findings highlight metabolic tuning of macrophages as a potential preventive immunomodulatory approach for HSV-1-induced ocular disease.
    Keywords:  antiviral immunity; herpes simplex keratitis; interleukin-33; macrophage; metabolic reprogramming
    DOI:  https://doi.org/10.3390/ph19020285
  18. Biochem Biophys Res Commun. 2026 Feb 10. pii: S0006-291X(26)00198-1. [Epub ahead of print]809 153434
    ATF2-LPCAT1-mediated PKM2 acetylation links cholesterol stress to macrophage metabolic reprogramming and functional remodeling.
    Huiling Cao, Shujun Ma, Miaomiao Tian, Han Ding, Yinuo Yang, Xi Zhao, Can Zhang, Ping Lv, Xinru Wang, Zeyang Cao, Hongjun Bian, Zhen Yu, Jianni Qi.
      Pyruvate kinase M2 (PKM2) regulates cellular metabolism under stress. However, mechanisms involving PKM2 modification in cholesterol-loaded macrophages remain unclear. In this study, we first characterized the impact of cholesterol loading on macrophage functional and metabolic alterations. Although cholesterol loading did not alter PKM2 expression, it regulated PKM2 function by promoting its acetylation. Specifically, PKM2 acetylation at lysine 433 (K433) exacerbated cholesterol-induced metabolic disorders and inflammation, whereas K433 mutations ameliorated these effects. Mechanistically, cholesterol activated the p38 mitogen-activated protein kinase (MAPK) pathway, inducing activating transcription factor 2 (ATF2) and upregulating lysophosphatidylcholine acyltransferase 1 (LPCAT1) to promote PKM2 acetylation. Collectively, PKM2 acetylation mediates cholesterol-induced metabolic and functional reprogramming in macrophages, highlighting the novel p38-ATF2-LPCAT1-PKM2 axis in immune stress signaling.
    Keywords:  ATF2; Cholesterol; LPCAT1; Macrophage; PKM2 acetylation
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153434
  19. Int J Mol Sci. 2026 Feb 12. pii: 1755. [Epub ahead of print]27(4):
    Restoring Lysosomes in Adipose Tissue Macrophages Mitigates Obesity-Induced Inflammation and Insulin Resistance.
    Jiyeon Chang, Ellen Budiono, Shindy Soedono, Xaviera Riani Yasasilka, SungWan Chun, Kae Won Cho.
      Adipose tissue macrophages (ATMs) are key mediators of obesity-induced inflammation and insulin resistance. However, the contribution of lysosomal dysfunction to ATM inflammatory activation remains poorly defined. Here, we characterized lysosomal structural and functional alterations in ATMs during obesity and examined whether pharmacological restoration of lysosomal function using 2-hydroxypropyl-β-cyclodextrin (HPβCD) ameliorates metabolic inflammation. In diet-induced obese C57BL/6J male mice, adipose tissue exhibited increased lysosomal abundance, accompanied by reduced cathepsin L+V expression, modestly increased lysosomal acid lipase levels, and decreased expression of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Despite expanded lysosomal content, ATMs displayed impaired lysosomal acidification, indicating functional lysosomal dysfunction. Intraperitoneal administration of HPβCD for two weeks significantly improved glucose tolerance and insulin sensitivity without affecting body weight. Flow cytometric analysis revealed reduced pro-inflammatory M1 ATMs and CD8+ T lymphocytes in visceral adipose tissue, whereas immune cell populations in subcutaneous adipose tissue, blood, and spleen remained unchanged. In vitro, HPβCD suppressed pro-inflammatory gene expression in both classically and metabolically activated macrophages and attenuated inflammatory responses induced by lysosomal stressors, including bafilomycin A1 and chloroquine, while restoring TFEB expression. Collectively, these findings demonstrate that obesity is associated with lysosomal dysfunction in ATMs and that restoration of lysosomal function alleviates adipose tissue inflammation and metabolic dysfunction, highlighting lysosomal regulation in ATMs as a potential therapeutic target for obesity-associated metabolic diseases.
    Keywords:  adipose tissue macrophage; cyclodextrin; inflammation; lysosome; obesity
    DOI:  https://doi.org/10.3390/ijms27041755
  20. Inflammation. 2026 Feb 25.
    Proline-Mediated Inhibition of ATPIF1-mTOR Signaling Alleviates Radiation-Induced Macrophage Polarization and Colon Inflammation.
    Lei Chang, Le Zhou, Shan Jiang, Kai Wei, Jie Li, Junhong Zhao, Kavita Shah, Xinzhou Deng, Renhuang Sun, Xiaoyu Zuo, Zhenzhen Wang, Liting Ding, Zhiguo Luo, Lihua Duan, Yutao Yan.
      Radiation therapy often triggers inflammatory complications such as radiation colitis, which is driven by persistent M1 macrophage polarization. While metabolic reprogramming is pivotal in macrophage activation, the role of amino acid metabolism-particularly proline-in regulating radiation-induced inflammation remains unexplored. In this study, bone marrow-derived macrophages (BMDMs) and RAW264.7 cells exposed to 4 Gy radiation exhibited robust M1 polarization (increasing from 13.5% in controls to 23.7% in F4/80+CD86+ cells), elevated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6; 3- to 6-fold increase), and mitochondrial dysfunction ( 30% decrease in ATP levels, 60% reduction in oxygen consumption rate [OCR], and 2-fold increase in mitochondrial ROS). Proline supplementation reversed these effects, suppressing M1 polarization by 50%, restoring ATP levels by 1.6-fold, and normalizing oxidative phosphorylation. Mechanistically, radiation upregulated ATPIF1 (1.8-fold increase) and phosphorylated mTOR (p-mTOR; 3.2-fold increase), while proline abolished these changes (ATPIF1 decreased by 30%, p-mTOR reduced by 50%). RNA-seq and metabolomics linked proline to ATP metabolism and amino acid homeostasis. ATPIF1 knockdown abolished radiation-induced pro-inflammatory effects and eliminated proline's protective efficacy, confirming the ATPIF1-mTOR axis as the central regulatory mechanism. In a rat radiation colitis model, proline mitigated colon shortening, reduced histopathological damage, and decreased M1 macrophage infiltration. Collectively, our findings establish the ATPIF1-mTOR axis as a critical mediator of radiation-induced M1 macrophage polarization, which is effectively countered by proline supplementation.
    Keywords:  ATPIF1; MTOR; Macrophage; Proline; Radiation colitis
    DOI:  https://doi.org/10.1007/s10753-025-02404-3
  21. Nanomedicine (Lond). 2026 Feb 23. 1-10
    Harnessing nanomedicine and immunometabolism to treat allergic disease.
    Shruti Dharmaraj, Kathryn S Robinett, Achsah D Keegan, Ryan M Pearson.
      Allergic diseases affect an estimated 260 million people worldwide and develop due to dysregulated immune responses against harmless environmental antigens caused by a breakdown in immune tolerance mechanisms. Current standard-of-care treatments manage disease symptoms through nonspecific mechanisms impairing normal immune function, often leaving patients struggling with symptom management. Allergen-specific immunotherapies can modify the immune response by inducing tolerance, leading to long-term reduction or elimination of allergy symptoms. Recent advances in nanomedicine have opened new avenues of research to induce antigen-specific tolerance through the delivery of allergens alongside immunomodulators under controlled contexts. In this Special Report, we examine how nanomedicine and immunometabolism can be harnessed to develop next-generation therapies for allergic diseases. We first summarize current FDA-approved treatments and their limitations. We then discuss immunometabolic pathways that shape allergic inflammation and represent actionable therapeutic targets. Next, we review nanoparticle-based approaches designed to induce antigen-specific tolerance and highlight cutting-edge strategies that use metabolite-derived polymers for controlled immunomodulation. Finally, we offer a perspective on how integrating immunometabolism with nanomedicine may enable transformative therapies for allergic diseases and other inflammatory conditions. [PubMed and Google Scholar databases were searched for relevant articles published from May 2003 to January 2026].
    Keywords:  Allergic disease; immunology; metabolism; nanomedicine; tolerance
    DOI:  https://doi.org/10.1080/17435889.2026.2634276
  22. Pharmacol Ther. 2026 Feb 24. pii: S0163-7258(26)00038-0. [Epub ahead of print] 109011
    Metabolic reprogramming and intracellular ATP homeostasis in immunity.
    Luca Antonioli, Giulia Valdiserra, Pál Pacher, Simon C Robson, György Haskó.
      The purine molecule ATP plays a crucial role in essential cellular functions, including energy transfer and extracellular signaling. It also serves as a precursor for the structural components of nucleic acids, including DNA and RNA, as well as for cyclic AMP and various cofactors. ATP is continuously degraded in cells and in extracellular space, leading to the sequential formation of ADP, AMP, adenosine, inosine, and hypoxanthine. ATP degradation is counterbalanced by the coordinated action of de novo biosynthetic pathways and salvage mechanisms, which generate inosine-5'-monophosphate (IMP), a precursor of AMP, which is subsequently converted into ATP. The synthesis and overall metabolism of ATP is closely linked to immune cell function, and dysregulation of these metabolic pathways can lead to immunodeficiency or worsen inflammatory diseases. Several approved drugs targeting ATP metabolism, including methotrexate, azathioprine, and allopurinol, are widely used to modulate immune system activity in the treatment of cancer, autoimmune diseases, and in gout. Here, we highlight the role of intracellular ATP homeostasis in coordinating bioenergetics and metabolism of immune cells. We also discuss inherited and acquired disorders that result in compromised ATP metabolism and impact immunity, as well as reviewing novel therapeutic approaches to target purinergic pathways in immunodeficiency and inflammatory diseases.
    Keywords:  ATP metabolism; Immune cell function; Immunodeficiency; Purinergic signaling; Therapeutic approaches
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109011
  23. Cell Signal. 2026 Feb 24. pii: S0898-6568(26)00094-X. [Epub ahead of print] 112444
    CCL2 drives macrophage M2 polarization via CH25H-mediated metabolic reprogramming to ameliorate post-myocardial infarction remodeling.
    Chenxi Yang, Yang Lyu, Zengru Wang, Xiang Wei, Rifeng Gao, Su Zou, Yizhe Bian, Rui Shen, Junwen Gong, Yiqing Yang, Yingjia Xu.
      Myocardial infarction (MI) triggers intense inflammation that drives adverse ventricular remodeling and heart failure. The chemokine CCL2 is upregulated post-MI, but its specific role in cardiac repair remains controversial. This study investigated the therapeutic potential and mechanism of CCL2 in post-MI remodeling. MI was induced in mice, which were then treated with recombinant CCL2 (rCCL2). rCCL2 significantly improved cardiac function, reduced infarct size and fibrosis, and attenuated cardiomyocyte apoptosis. Flow cytometry revealed that CCL2 skewed the cardiac immune response toward an anti-inflammatory state, promoting M2 macrophage polarization and increasing regulatory T cells. In bone marrow-derived macrophages (BMDMs), RNA-seq identified cholesterol 25-hydroxylase (CH25H) as a key downstream effector. Mechanistically, CCL2 binding to CCR2 upregulated CH25H, which inhibited mTORC1 and activated AMPK, leading to STAT6 phosphorylation. This cascade enhanced oxidative phosphorylation and mitochondrial mass, driving M2 polarization. Critically, pharmacological inhibition of either CCR2 or AMPK abolished these benefits. We conclude that CCL2 confers cardioprotection by promoting reparative macrophage polarization via a novel CCR2-CH25H-mTOR-AMPK signaling axis, identifying this pathway as a promising therapeutic target for improving post-MI outcomes.
    Keywords:  CCL2; CH25H; Macrophage polarization; Myocardial infarction; Ventricular remodeling
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112444
  24. bioRxiv. 2026 Feb 20. pii: 2026.02.19.706884. [Epub ahead of print]
    Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
    Yongqing Liu, Minghua Fan, Yingzhi Ye, Henry Yi Cheng, Shuying Sun, Zhaozhu Qiu.
      Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of Cmpk2 , a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cGAS-STING and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease amyloid-β burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a promising therapeutic target for AD.
    DOI:  https://doi.org/10.64898/2026.02.19.706884
  25. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2522313123
    mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.
    Jie Jiang, Meiling Zuo, Kehan Zhao, Zhihao Ling, Zhida Wu, Dongfang Xue, Shouyong Mo, Yuanhui Liu, Yongjun Chen, Jie Wang, Bin Lu, Chuanzhou Li, Yaqi Duan, He He, Zhiyin Song.
      Epilepsy is increasingly recognized as a disorder involving metabolic dysregulation beyond neural hyperexcitability, yet the underlying metabolic mechanisms remain poorly defined. Here, we identify a mitochondrion-immunity-metabolism axis that drives spontaneous chronic epilepsy. Brain-specific deletion of Mic19 impairs mitochondrial cristae structure and mitochondrial integrity in neurons, leading to activation of the Z-mitochondrial DNA (mtDNA)-ZBP1-RIPK3-mixed lineage kinase domain-like protein (MLKL) axis and p-MLKL-mediated pore formation on the mitochondrial membrane. This process results in cytosolic and extracellular leakage of mtDNA, which is subsequently taken up by microglia and triggers cyclic GMP-AMP synthase (cGAS)-STING-dependent inflammatory signaling. The resulting neuroinflammation promotes sustained activation of astrocytes. Critically, reactive astrocytes undergo profound metabolic reprogramming, marked by upregulated glycolysis and enhanced L-serine biosynthesis. Astrocyte-derived L-serine is subsequently transferred to neurons and converted into D-serine, a key NMDA receptor coagonist that enhances neuronal excitability. This metabolic shift in astrocytes exacerbates excitotoxicity and sustains epileptic activity. Importantly, pharmacologic inhibition of STING with H-151 treatment markedly suppresses seizures, reinforcing the therapeutic potential of targeting immunometabolic crosstalk in epilepsy. Our findings reveal that mtDNA-mediated cGAS-STING activation and D-serine act as important drivers of epilepsy initiation, offering mechanistic insights into neuron-microglia-astrocyte crosstalk and highlighting immunometabolic modulation as a promising therapeutic strategy for epilepsy.
    Keywords:  cGAS–STING; epilepsy; mitochondrial DNA; neuroinflammation; serine
    DOI:  https://doi.org/10.1073/pnas.2522313123
  26. bioRxiv. 2026 Feb 14. pii: 2024.12.10.627699. [Epub ahead of print]
    The human plasma amino acids balance favours HIV replication in primary CD4 T lymphocytes.
    Lise Chauveau, Annemarie Fortuin, Arnaud Lecante, Nina Lager-Lachaud, Angéline Tellier, Shravya Honne, Aude Boulay, Fabien P Blanchet, Baek Kim, Floriant Bellvert, Laurence Briant, Jean-Luc Battini.
      Cellular metabolism supports all viral replication steps and the metabolic state of infected cells is therefore a key factor influencing viral infections. Human Immunodeficiency virus (HIV) remains latent in resting CD4 T lymphocytes but actively replicates in activated CD4 T cells due to enhanced energy metabolism. Here, using the recently developed Human Plasma-Like Medium (HPLM) that mimics physiological plasma concentration of metabolites, we investigated how this near-physiologic environment modulates HIV-1 infection in primary CD4 T cells. Compared to the conventional culture medium (RPMI), HPLM enhanced HIV-1 infection in CD4 T cells despite similar levels of cell activation, proliferation and expression of viral receptor. In contrast with previous studies in RPMI, HPLM increased infection while decreasing energy metabolism and affecting other non-energetic metabolic pathways. Adjusting levels of several metabolites in RPMI and HPLM, we uncovered that the amino acids balance rather than the energy metabolism favoured HIV-1 replication in this system. Overall, our study used near-physiological conditions to better define metabolic dependencies of viral infections and highlights previously overlooked non-energetic metabolism pathways important for HIV-1 infection.
    DOI:  https://doi.org/10.1101/2024.12.10.627699
  27. Sci Rep. 2026 Feb 25.
    NEAT1 drives SARS-CoV-2 N protein-induced inflammation, metabolic reprogramming, and mitochondria-ER stress crosstalk.
    Cheng Qing, Huaigang Chen, Shuying Huang, Jianguo Zhang, Chaoqi Zhou, Shichao Zhang, Kaihang Luo, Cheng Wang, Zhiguo Hu, Yuting Yang, Jia Zhou, Zhenguo Zeng.
      SARS-CoV-2 remains a global health concern. Although its nucleocapsid (N) protein supports viral replication and evades host immunity, its role in host metabolic reprogramming and organelle homeostasis is not fully understood. This study aims to elucidate whether the N protein modulates glycolysis and mitochondrial-ER stress crosstalk via the long non-coding RNA NEAT1. We established human bronchial epithelial (HBE) cells stably expressing the N protein. Inflammatory and glycolytic gene expression was analyzed by qRT-PCR and Western blot. ROS levels were measured by flow cytometry, while mitochondrial membrane potential, Ca²⁺ overload, and mitochondria-ER contact sites (MAMs) were assessed by confocal microscopy. NEAT1 knockdown and HK2-VDAC1 interaction studies were performed to explore underlying mechanisms. The N protein induced inflammatory responses, enhanced LPS sensitivity, and triggered mitochondrial dysfunction, ER stress, and MAM formation. It promoted glycolytic reprogramming by upregulating key enzymes (GLUT1, HK2, PKM2). NEAT1 was essential for these effects-N protein increased NEAT1 expression, and NEAT1 knockdown attenuated inflammation, glycolysis, and mitochondrial damage. Mechanistically, NEAT1 silencing restored HK2-VDAC1 association and suppressed VDAC1 oligomerization. The SARS-CoV-2 N protein exacerbates inflammation through a NEAT1-dependent mechanism that drives glycolytic reprogramming and disrupts mitochondrial-ER homeostasis.
    Keywords:  COVID-19 inflammation; Glycolytic reprogramming; Long non-coding RNA NEAT1; Mitochondria-ER stress crosstalk; SARS-CoV-2 nucleocapsid protein
    DOI:  https://doi.org/10.1038/s41598-026-40957-x
  28. Toxics. 2026 Feb 08. pii: 160. [Epub ahead of print]14(2):
    Chromium(VI) Modulates Macrophage Polarization and Metabolic Reprogramming to Impair Immune Function.
    Cheng Li, Ruihang Zhang, Yuhan Zhang, Hongxi Yu, Yu Zheng, Yifei Du, Shiyi Hong, Lihua Hu, Chaoyang Wang, Guang Jia, Guiping Hu.
      Hexavalent chromium (Cr(VI)) is a recognized environmental and occupational hazard with significant implications for immune function. However, the cell-intrinsic mechanisms by which Cr(VI) coordinately reshapes macrophage polarization together with immunometabolic and mitochondrial alterations remain incompletely characterized. This study investigated how Cr(VI) exposure influences macrophage morphology, polarization, energy metabolism, and mitochondrial integrity using an in vitro model. Macrophages exposed to Cr(VI) exhibited morphological changes, including pseudopod growth and fusiform shapes, alongside a shift toward M1-type polarization. Key M1 associated biomarkers, including TNF-α, CD36, and CD80, increased 24 h after Cr(VI) exposure, whereas the M2 associated VEGFb decreased. Cr(VI) exposure also impaired energy metabolism, reducing ATP production and shifting metabolism towards glycolysis, despite increased glucose uptake. Mitochondrial damage, membrane potential collapse, and elevated oxidative stress further highlighted the immunotoxic effects of Cr(VI). Cr(VI) exposure may drive a metabolic shift in macrophages toward less efficient energy production pathways, such as glycolysis. These findings provide critical insights into Cr(VI)-induced macrophage dysfunction and emphasize the environmental risks associated with Cr(VI) pollution, underscoring the need for further mechanistic research and mitigation strategies to safeguard public health.
    Keywords:  hexavalent chromium; immunotoxicity; macrophage; metabolic disruption
    DOI:  https://doi.org/10.3390/toxics14020160
  29. Nat Rev Rheumatol. 2026 Feb 25.
    Metabolic masqueraders of paediatric and adult rheumatic diseases.
    Steven H Lang, Cher Sha, Chelsi M Rose, V Reid Sutton, Tiphanie P Vogel, Lindsay C Burrage.
      Inborn errors of metabolism comprise a clinically diverse group of conditions that arise from the decreased activity of an enzyme or metabolite transporter and subsequent blockade in a metabolic pathway. These disorders are typically considered in the differential diagnosis of critically ill neonates or young children presenting with hypoglycaemia, metabolic acidosis or hyperammonaemia. However, beyond these classic presentations, a broader group of inborn errors of metabolism can manifest more subtly, with progressive articular and multi-systemic involvement that mimics or overlaps with typical features of rheumatological disease. Consequently, these conditions might be misdiagnosed for years as rheumatological diseases, including juvenile idiopathic arthritis, systemic sclerosis, idiopathic inflammatory myopathies and systemic lupus erythematosus. Moreover, these disorders provide unique opportunities to understand the complex interplay between metabolism and immune function. With the growing availability of disease-modifying therapies for inborn errors of metabolism, rheumatologists must be able to recognize these disorders, particularly in patients with atypical features or treatment-refractory disease.
    DOI:  https://doi.org/10.1038/s41584-026-01352-y
  30. Cancer Discov. 2026 Feb 20. OF1
    Restricting Itaconate Suppresses ZFTA-RELA Ependymoma Growth.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-025
  31. Cell. 2026 Feb 24. pii: S0092-8674(26)00102-9. [Epub ahead of print]
    Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition.
    Matthew L Miller, Timothy J Thauland, Smriti Sameer Nagarajan, Wenqi Ellen Zuo, Miguel A Moreno Lastre, Manish J Butte.
      Solid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is the building block of cellulose, contains a β-1,4-glycosidic bond that animals (or their tumors) cannot hydrolyze, but fungi and microbes have evolved enzymes to catabolize cellobiose into useful glucose. We equipped mouse T cells and human chimeric antigen receptor (CAR)-T cells with two proteins derived from fungi that enable import and hydrolysis of cellobiose, and we demonstrated that cellobiose supplementation during glucose withdrawal restores key anti-tumor T-cell functions: viability, proliferation, cytokine production, and cytotoxic killing. Engineered T cells offered cellobiose suppress tumor growth and prolong survival. Offering exclusive access to a natural disaccharide augments cancer immunotherapies. This approach could be used to answer questions about glucose metabolism across many cell types, biological processes, and diseases.
    Keywords:  CAR-T cell; T cells; cellobiose; glucose; immunotherapy; metabolism; tumors
    DOI:  https://doi.org/10.1016/j.cell.2026.01.015
  32. bioRxiv. 2026 Jan 21. pii: 2026.01.19.700051. [Epub ahead of print]
    ISG15 orchestrates dynamic crosstalk between mitochondrial fat oxidation and type 1 interferon in myeloid cells.
    Anand Kumar Gupta, Jing Wu, Pijush Das, Rahul Sharma, Sonali Das, Kim Han, Rachael J Klein, Rebecca D Huffstutler, Christian Combs, Warren J Leonard, Claudia Kemper, Erin E West, Michael N Sack.
      In contrast to Krebs cycle intermediates, the role of mitochondrial fatty acid oxidation (FAO) in immunometabolism remains incompletely characterized. Studying primary bone marrow-derived macrophages (BMDMs), we show that IFN-β and STING activation augments FAO and associated enzymes carnitine palmitoyltransferase 1a (CPT1a) and acetyl-CoA acetyltransferase 1 (ACAT1). Depleting BMDM Cpt1a reduces FAO and dampens type 1 interferon (IFN) signaling due to decreased histone H3-K9/K14 acetylation, supporting the prior finding of an epigenetic role of FAO in sustaining type 1 IFN. Interestingly, FAO induction by IFN was dynamic as a heightened IFN response suppressed FAO, suggesting a concurrent negative-feedback mechanism. This FAO blunting correlated with increased expression of interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier known to modulate metabolic proteins through ISGylation. This immune-metabolic signature was similarly operational in mice infected with lymphocytic choriomenigitis virus (LCMV) with temporal discordance between ISG15 levels and FAO. The role of ISG15 in this negative feedback was shown with increased FAO and type 1 IFN response in Isg15 knockout BMDMs. Parallely, endogenous co-immunoprecipitation showed interactions between ISG15 and CPT1a/ACAT1. This ISG15-FAO regulatory interaction was also evident in systemic lupus erythematosus (SLE)-associated interferonopathy and in primary monocytes from SLE individuals that exhibited increased ISG15 levels and reduced FAO rates. Collectively, these findings support a model in which type 1 IFN initially enhances FAO to amplify interferon production, but excessive IFN-signaling induces ISG15-mediated inhibition of FAO, a putative feedback loop that restrains inflammation and preserves immune homeostasis. Together these data identify a novel biphasic FAO-dependent immunometabolic regulatory program.
    Graphical Summary:
    Highlights: Type 1 IFN rewires myeloid cell metabolism towards FAO.FAO epigenetically fuels Type 1 1IFN response.Effect of IFN on FAO is dynamic: inducing FAO at low concentrations while suppressing it during a heightened IFN response.Enhanced Type 1 IFN response produces ISG15 which ISGylates key enzymes of FAO altering their stabilityISG15 negatively regulates FAO to control Type 1 IFN homeostasis in a negative feedback loop.
    DOI:  https://doi.org/10.64898/2026.01.19.700051
  33. Am J Respir Cell Mol Biol. 2026 Jan 23. pii: aanaf010. [Epub ahead of print]
    Lactylation-YTHDF1 Axis Promotes DNAH5-dependent Ciliary Defense in Pseudomonas aeruginosa Infection.
    Jing Wang, Xiang Shen, Yanan Li, Zhenwei Xia, Tong Yin, Jing Qiao, Yangyang Deng, Runying He, Yu Guo, Yuxuan Zhang, Guoliang Zhang, Jieming Qu.
      Pseudomonas aeruginosa infection poses a significant clinical challenge in respiratory diseases by subverting host defense mechanisms. While inflammatory responses in airway epithelial cells (AECs) during infection have been extensively studied, the interplay between epitranscriptomic regulation and metabolic reprogramming remains poorly understood. Here, we identify a lactylation-m6A axis that orchestrates ciliary function and antibacterial defense through dual-layer metabolic-epigenetic coordination. Using integrated in vivo and in vitro models, we demonstrate that P. aeruginosa infection depletes host lactic acid through direct consumption via lactate dehydrogenase and virulence factor-mediated glycolytic suppression. This metabolic perturbation reduces histone H3K18 lactyaltion, dimishing m6A methylation by directly downregulating YTHDF1; m6A-seq analysis reveals preferential hypomethylation of dynein axonemal heavy chain 5 (DNAH5) mRNA, a critical regulator of ciliary motility. Mechanistically, YTHDF1 recognizes m6A-modified DNAH5 transcripts to stabilize translation. The lactylation-YTHDF1-DNAH5 axis proves essential for maintaining ciliary beat frequency and mucociliary clearance capacity. This metabolic-epitranscriptomic circuitry significantly impacts host defense, as evidenced by increased bacterial burden in conditional YTHDF1 knockout mice. Our findings extend the paradigm of lactylation-mediated gene regulation to airway pathophysiology, revealing a novel mechanism where microbial-induced metabolic perturbations reprogram RNA modification landscapes to disable ciliary defenses. This study establishes a conceptual framework for understanding how opportunistic pathogens exploit host metabolic-epigenetic networks to establish persistent infections, suggesting therapeutic potential for targeting the lactate-YTHDF1 axis in P. aeruginosa-associated pulmonary disorders.
    Keywords:   Pseudomonas Aeruginosa ; Ciliary Beating; Lactylation; YTHDF1; m6A Modification
    DOI:  https://doi.org/10.1093/ajrcmb/aanaf010
  34. Front Cardiovasc Med. 2026 ;13 1765661
    Hypoxia-inducible factors link inflammation and lipid metabolism in atherosclerotic macrophages.
    Kyu Seong Park, Yu Jin Ko, Jae-Hoon Choi.
      Atherosclerosis is a chronic inflammatory disease driven by a complex interplay between immune cells, inflammation, metabolic dysfunction, and hypoxia. Among immune cells, macrophages interact bidirectionally with these factors, undergoing phenotypic and functional changes in response to the microenvironment, which contribute to both the progression and resolution of atherosclerosis. Recent studies have elucidated these dynamic interactions among these factors; however, research remains focused on individual aspects, and a more integrated understanding has yet to be fully established. Therefore, this review aimed to emphasize the importance of complex interactions among hypoxia, inflammation, and lipid metabolism, suggesting that the crosstalk among these response pathways operates actively and dynamically rather than following a simple cause-and-effect pathway. Further, this review highlights recent advances in understanding the inflammatory functions of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in macrophages under hypoxic stress. In addition, we explore the systemic implications of HIF signaling in lipid-regulating organs such as the liver, intestine, and adipose tissue, emphasizing the emerging paradigm that HIF-2α acts as a metabolic switch coordinating lipid accumulation and inflammation. Finally, we summarize therapeutic approaches targeting HIFs, including HIF stabilizers and HIF-2α-selective antagonists. Collectively, this review offers a comprehensive multi-organ perspective on the immune-metabolic roles of HIFs in atherosclerosis, providing valuable insights into future therapeutic interventions.
    Keywords:  agonist/antagonist; atherosclerosis; hypoxia-inducible factor; inflammation; lipid metabolism; macrophage
    DOI:  https://doi.org/10.3389/fcvm.2026.1765661
  35. Nat Cardiovasc Res. 2026 Feb;5(2): 138-154
    Targeting immunometabolic pathways with AZD1656 alleviates inflammation and metabolic dysfunction in type 2 diabetic cardiomyopathy.
    Stephanie Anderson, Anja Karlstaedt, Megan Young, Loucia Karatzia, Fenn Cullen, Jianmin Chen, Caroline E O'Riordan, Michael R Barnes, Zorana Štaka, Lauren J Albee, Conor Garrod-Ketchley, Sanushi Dambure, Hiran A Prag, Filip Cvetko, Jack J J J Miller, Christoph Thiemermann, Andrew J M Lewis, Michael P Murphy, David M Smith, Sian M Henson, Damian J Tyler, Dunja Aksentijevic.
      Type 2 diabetes (T2D) precipitates diabetic cardiomyopathy (dbCM), a condition characterized by chronic inflammation, metabolic dysregulation and impaired cardiac performance. Here we show that the glucokinase activator AZD1656, originally developed for glycemic control but later identified to have immunomodulatory effects, reverses cardiac dysfunction and metabolic remodeling in dbCM. In obese, hyperglycemic db/db mice with diastolic dysfunction, 6 weeks of AZD1656 treatment improved myocardial performance, reduced infarct size and enhanced post-ischaemic recovery. Integrated metabolic, functional and histological analyses revealed restoration of mitochondrial metabolism and attenuation of fibrosis. Mechanistically, AZD1656 remodeled the cardiac immune landscape by promoting infiltration of regulatory T cells. These findings demonstrate a link between cardiac inflammation and metabolic remodeling in dbCM and highlight that modulation of immune cells and metabolism can protect the diabetic heart. Targeting immunometabolic pathways may therefore offer a therapeutic strategy to alleviate cardiac dysfunction and reduce infarct vulnerability in T2D.
    DOI:  https://doi.org/10.1038/s44161-025-00769-0
  36. Infect Immun. 2026 Feb 27. e0049525
    Complex I preserves mitochondrial polarization during infection of human macrophages by secretion-competent bacteria.
    Francisco-Javier Garcia-Rodriguez, Paula Martinez-Oca, Carmen Buchrieser, Pedro Escoll.
      Intracellular bacteria remodel host bioenergetics and modulate mitochondrial membrane potential (Δψm). However, how individual electron transport chain (ETC) components sustain Δψm during infection of primary human macrophages remains unclear. Here, we combined extracellular flux analysis with single-cell live imaging to understand how the ETC functions in human monocyte-derived macrophages during infection with Legionella pneumophila (Lp) or Salmonella enterica serovar Typhimurium (S.Tm). At 5 h post-infection, the Lp type IV secretion system (T4SS) and the S.Tm SPI-1 T3SS were required for the early drop of the oxygen consumption rate. Despite reduced respiration, the Δψm was preserved in all infection conditions, and pathogen-specific strategies to maintain the Δψm were revealed. While Lp infection modulates the FOF1-ATPase to function in the reverse mode (hydrolase), with the adenine-nucleotide translocator remaining in forward mode, S.Tm does not reverse the FOF1-ATPase during infection. Systematic inhibition of ETC complexes established that Complex I is uniquely required to maintain the Δψm during infection with virulent bacteria, but not with secretion-deficient mutant strains. Complex II is required in all infection conditions, but its inhibition had a minimal effect in non-infected cells, indicating infection-driven participation of this complex in the electron flow in the ETC, coupled with the preservation of the Δψm. Complexes III and IV were essential in infected and non-infected cells. Together, our results identify a Complex I-driven maintenance of the Δψm, establishing Complex I as a bioenergetic checkpoint that distinguishes virulent from secretion-deficient intracellular bacteria. Furthermore, we reveal that divergent strategies are employed by Lp and S.Tm to preserve mitochondrial polarization of macrophages early during infection.
    Keywords:  Legionella pneumophila; Salmonella Typhimurium; electron transport chain; macrophages; mitochondria; virulence
    DOI:  https://doi.org/10.1128/iai.00495-25
  37. Front Immunol. 2026 ;17 1690141
    Metabolic checkpoints in the regulation of Th17 cells: implications for uveitis pathogenesis and therapy.
    YongFei Ma, QiuJin Zhang, ZhiXiang Ding.
      The disruption of the balance between helper T cells (Th17) and regulatory T cells (Tregs) is associated with various autoimmune diseases. Th17 cells contribute to inflammation, whereas Tregs play a crucial role in suppressing autoimmunity. Th17 cells are central to the pathogenesis of autoimmune diseases, with specific metabolic pathways, enzymes, signaling pathways, and transcription factors acting as key checkpoints that influence T cell differentiation and immune responses. This review aims to summarize recent advances in understanding the role of Th17 cells and the Th17/Treg immune balance in the pathogenesis of uveitis, focusing on the impact of metabolic reprogramming on the activation, differentiation, and effector functions of T cells. Understanding the regulators of key metabolic checkpoints offers promising prospects for the treatment of autoimmune diseases, including Th17-mediated uveitis.
    Keywords:  Th17; Tregs; metabolic checkpoint; metabolic reprogramming; uveitis
    DOI:  https://doi.org/10.3389/fimmu.2026.1690141
  38. Nat Commun. 2026 Feb 25.
    Context-specific regulatory genetic variation in MTOR dampens neutrophil-T cell crosstalk in pneumonia-associated sepsis.
    Ping Zhang, Patrick MacLean, Alicia Jia, Callum R O'Neill, Alice Allcock, Ethan Prince, Bora Ozcan, Roman M Doll, Imogen Dyne, Kiki Cano-Gamez, Hanyu Qin, Chloe Wainwright, Giuseppe Scozzafava, Andrew C Brown, James O J Davies, Amanda Y Chong, Alexander J Mentzer, Katie L Burnham, Emma E Davenport, Julian C Knight.
      Sepsis is a heterogeneous clinical syndrome with a high mortality, requiring personalised stratification strategies. Here, we characterise genetic variation that modulates MTOR, a critical regulator of metabolism and immune responses in sepsis. The effects are context specific, involving a regulatory element that affects MTOR expression in activated T cells with opposite effect in neutrophils. We show that the G-allele of the lead variant, rs4845987, which is associated with decreased risk of type 2 diabetes, reduces MTOR expression in T cells and improves survival in sepsis due to pneumonia, with effects specific to sepsis endotype. Using ex vivo models, we demonstrate that activated T cells promote immunosuppressive neutrophils through released cytokines, a process dampened by hypoxia and the mTOR inhibitor rapamycin. Our work demonstrates an epigenetic mechanism fine-tuning MTOR transcription and T cell activity via the variant-containing regulatory element, which further exhibits an allelic effect upon vitamin C treatment. These findings reveal how genetic variation interacts with disease state to modulate immune cell-cell communication, providing a framework for stratified therapy in sepsis.
    DOI:  https://doi.org/10.1038/s41467-026-69919-7
  39. Trends Parasitol. 2026 Feb 24. pii: S1471-4922(26)00035-8. [Epub ahead of print]
    Shifting metabolism alters rRNA expression in malaria parasites.
    Evi Hadjimichael, Kirk W Deitsch.
      Malaria parasites display the unique property of expressing distinct ribosomal RNAs at different points in their transmission cycle. Couble et al. determined that derepression of the mosquito-specific rDNA loci is initiated by altered NAD+/nicotinamide (NAM) ratios, resulting from the metabolic shift that parasites undergo as they transition into the mosquito stages.
    Keywords:  Silent Information Regulator 2 (Sir2); glycolysis; histone deacetylase; oxidative phosphorylation; ribosomal RNA
    DOI:  https://doi.org/10.1016/j.pt.2026.01.014
  40. Cell Metab. 2026 Feb 24. pii: S1550-4131(26)00019-7. [Epub ahead of print]
    Microbial-derived 3-phenylpropionic acid orchestrates immune-progenitor cell crosstalk to promote beige adipogenesis and energy expenditure.
    Defu Li, Bo Xia, Ruoci Hu, Zhao Zhang, Cong Xu, Hanjian Zhou, Xiao Li, Yonglin Hua, Shusong Wu, Ke Zhang, Yuwei Jiang, Jiangwei Wu, Yexian Yuan.
      Cold exposure induces beige adipogenesis in white adipose tissue, enhancing thermogenesis and energy expenditure. While gut microbiota-derived metabolites influence host metabolism, their role in thermogenic adaptation remains poorly defined. Here, we identify P. copri as a key microbial mediator of cold-induced adipose remodeling. Cold exposure expands P. copri in the colon, which produces 3-phenylpropionic acid (3-PPA), a metabolite that promotes beige adipocyte formation and increases energy expenditure. Mechanistically, 3-PPA signals through free fatty acid receptor 1 in M2-like macrophages, inducing chemokine C-X-C motif chemokine 13 (CXCL13) secretion, which recruits T follicular helper cells to facilitate beige adipogenesis. Lineage-tracing analyses show that adipocyte progenitor cells generate new beige adipocytes in response to 3-PPA. Moreover, 3-PPA supplementation counteracts high-fat diet-induced obesity in mice and promotes thermogenesis in mouse, pig, and human adipose progenitor cells. These findings define a microbiota-immune-adipose progenitor axis regulating cold adaptation and highlight microbial metabolites as potential metabolic therapies.
    Keywords:  3-PPA; CXCL13; FFAR1; M2-like macrophages; Prevotella copri; UCP1; adipocyte progenitor cells; beige adipogenesis; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.017
  41. Crit Care. 2026 Feb 23. pii: 94. [Epub ahead of print]30(1):
    Lactate regulation in high-altitude hypoxic adaptation attenuates LPS-Induced acute lung injury: links to glucose metabolism and anti-inflammatory therapeutic potential.
    Wantian Zhang, Ruixuan Wang, Yu Zhang, Qian Lei, Si Zeng.
      
    DOI:  https://doi.org/10.1186/s13054-026-05905-1
  42. Immunohorizons. 2026 Feb 12. pii: vlag005. [Epub ahead of print]10(2):
    Sustained monocyte activation by persistent challenges with either oxLDL or free cholesterol and underlying mechanisms.
    Yajun Wu, Shuo Geng, Grace Atkinson, Blake Caldwell, Jing Wang, Liwu Li.
      Chronic low-grade inflammation is a hallmark of atherosclerosis and cardiovascular diseases, with monocytes playing a central role in sustaining this pathological state. In this study, we demonstrate that prolonged exposure to oxidized low-density lipoprotein (oxLDL) or cholesterol reprograms murine bone marrow-derived monocytes into a persistent pro-inflammatory phenotype. This is characterized by elevated surface markers (CD49d, CD74, CD38, CD86), enhanced endothelial and T cell interactions, and sustained activation of the Src-SYK-mTORC1-STAT3/5 signaling axis. Notably, the inflammatory state persisted even after stimulus withdrawal, suggesting the establishment of an immune memory-like phenotype. Mechanistically, we defined the membrane clustering of Src is responsible for the generation of intra-cellular stress signaling and sustained monocyte activation, which can be alleviated by the administration of fumagillin, a selective inhibitor of protein myristoylation and Src membrane clustering. Our findings uncover mechanistic insights into the generation of sustained monocyte low-grade inflammatory memory and pinpoint potential therapeutic strategies in erasing low-grade inflammation related to chronic diseases.
    Keywords:  low-grade inflammation; memory; monocyte; resolution
    DOI:  https://doi.org/10.1093/immhor/vlag005
  43. Am J Respir Cell Mol Biol. 2026 Feb 21. pii: aanag029. [Epub ahead of print]
    Altered cholesterol immunometabolism activates the macrophage NLRP3-inflammasome in lung fibrosis.
    Mariza Vaso, Matija Dukic, Peter Pennitz, Artür Manukyan, Scott Collum, Wanchang Lin, Catherine L Winder, Warwick B Dunn, Jonas C Schupp, Peter Braubach, Malgorzata Wygrecka, Dewei Ren, Erik E Suarez, Howard J Huang, Rahat Hussain, Bela Patel, Harry Karmouty-Quintana, Altuna Akalin, Markus Landthaler, Geraldine Nouailles, Matthias Ochs, Elena Lopez-Rodriguez, Sonia Giambelluca.
      Previous research has highlighted dysregulation in lipid metabolism during lung fibrosis. However, the impact of cholesterol immunometabolism during lung fibrosis progression remains unclear but has been related to the NLRP3-inflammasome activation in cardiovascular diseases. The main objective of this work was to investigate the link between altered cholesterol metabolism and NLRP3 inflammasome activation in fibrotic lungs. Different pulmonary fibrosis patient cohorts (from 2 centers and a publicly available dataset) and a murine model of lung fibrosis (aged SP-C-/-) were included. Expression of cholesterol metabolism proteins and cholesterol content were determined in lungs from patients and bronchoalveolar lavage fluid (BALF) cells of aging SP-C-/- mice. Metabolomic and lipidomic analyses were conducted in BALF and BALF cells of SP-C-/- versus wild-type (WT) mice. NLRP3 inflammasome components were assessed by immunoblotting, ELISA, and immunofluorescence. Lung samples from fibrosis patients showed higher cholesterol content, altered cholesterol metabolism and higher IL-18 levels, compared to controls. Moreover, key genes related to inflammasome activation and cholesterol metabolism were differentially expressed in alveolar macrophages from IPF patients. Accordingly, BALF cells of SP-C-/- mice showed alteration of their cholesterol metabolism and inflammasome activation with age and fibrosis development. Lipidomic analysis pointed at cholesterol esters as potential activating agent. The molecular mechanism linking cholesterol esters to NLRP3 inflammasome and fibrosis markers was confirmed in vitro in a human macrophage model. In conclusion, altered cholesterol esterification activates the NLRP3 inflammasome in AM during pulmonary fibrosis in a murine model and fibrosis patients.
    Keywords:  IL-18; alveolar macrophages; cholesterol ester; cholesterol immunometabolism; inflammasome activation; pulmonary fibrosis
    DOI:  https://doi.org/10.1093/ajrcmb/aanag029
  44. Biochimie. 2026 Feb 24. pii: S0300-9084(26)00053-2. [Epub ahead of print]245 8-17
    Interplay between cholesterol, Bis(monoacylglycerol)phosphate, and parasitophorous vacuole dynamics in Leishmania infantum infection of macrophages.
    Clara Hennot, Marine Leroux, Remi Lambert, Fanny Boukherrouba, Marion Guichard, Karen Gaget, Federica Calevro, Isabelle Delton, Samira Azzouz-Maache, Celine Luquain-Costaz.
      Leishmania spp., the causative agents of leishmaniasis, are protozoan parasites displaying two life stages: promastigote in the insect vector and amastigote in host macrophages. After inoculation, the promastigote differentiates into the amastigote which multiplies within a parasitophorous vacuole formed by the fusion of the phagosome with the macrophage endolysosome. This compartment is characterized by a specific enrichment in bis(monoacylglycerol)phosphate (BMP), an atypical phospholipid that regulates endosomal dynamics and cholesterol trafficking. Host cell cholesterol is essential for parasite intracellular development. In this study, we examined the relationships between cholesterol, BMP, and the parasitophorous vacuole during the infection of J774 murine macrophages with L. infantum. Our results showed that cholesterol is redistributed in the vicinity of the parasite within infected cells. BMP is redistributed along with the same pattern and colocalizes with markers of the parasitophorous vacuole. Transcriptomic analyses revealed an upregulation of key genes governing cholesterol uptake and synthesis (HMGCR, SREBP2, LDLR) during infection and conversely a downregulation of ABCA1 involved in cholesterol efflux. Noteworthy, the overexpressions of HMGCR, SREBP2, LDLR were significantly attenuated by macrophage BMP enrichment. As for functional impact, BMP enrichment was associated with a significant increase of the parasite infectivity toward macrophages, assessed by infection rate and parasite load. Together, our results confirm the essentiality of macrophage cholesterol and demonstrate the involvement of BMP during Leishmania infection likely by facilitating parasitophorous vacuole remodeling and cholesterol trafficking.
    Keywords:  Bis(monoacylglycerol)phosphate; Cholesterol; Leishmania; Macrophages; Parasitophorous vacuole
    DOI:  https://doi.org/10.1016/j.biochi.2026.02.017
  45. Antioxid Redox Signal. 2026 Feb 27. 15230864261425887
    Dysregulated Copper Metabolism-Induced Cuproptosis Contributes to Mitochondrial Dysfunction and Macrophage Inflammatory Response in Acute Lung Injury.
    Shuyang Chen, Zheng Zhou, Yajun Wang, Dong Yang, Jinjun Jiang, Shujing Chen.
       AIMS: To determine whether dysregulated copper metabolism and cuproptosis contribute to acute lung injury (ALI), and to evaluate whether targeting copper homeostasis mitigates lung inflammation and injury.
    RESULTS: Integrative analysis of RNA-seq data from patients with severe community-acquired pneumonia revealed increased enrichment of copper metabolism-related gene sets and differential expression of cuproptosis-related genes. Notably, immune deconvolution of patient RNA-seq data demonstrated prominent macrophage enrichment, suggesting that macrophages represent a major cell group in which dysregulated copper metabolism may occur during ALI. In a lipopolysaccharide (LPS)-induced mouse ALI model, lung copper levels were elevated, accompanied by molecular features of cuproptosis, including increased DLAT oligomerization and destabilization of Fe-S cluster proteins. Pretreatment with the copper chelator tetrathiomolybdate alleviated lung injury and inflammatory response, while suppressing cuproptosis-related molecular features in vivo. In alveolar macrophages, LPS challenge increased intracellular Cu+ concentration and promoted DLAT oligomerization, and impaired Fe-S protein stability. Mechanistically, both copper chelation and knockdown of upstream cuproptosis regulator reduced DLAT oligomerization, restored Fe-S proteins, alleviated mitochondrial dysfunction, and decreased CD86+ macrophage polarization. Importantly, altered expression of copper transporters was observed, suggesting a remodeling of copper metabolic homeostasis during ALI.
    INNOVATION AND CONCLUSION: This study identifies cuproptosis as a previously unrecognized driver of ALI, mechanistically linking copper dysregulation to mitochondrial damage and inflammatory activation of alveolar macrophages, and demonstrates the therapeutic benefit of copper chelation or cuproptosis suppression. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  acute lung injury; alveolar macrophages; copper metabolism; cuproptosis; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1177/15230864261425887
  46. Mol Cell. 2026 Feb 24. pii: S1097-2765(26)00071-7. [Epub ahead of print]
    The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
    Dominic A Ritacco, Hamna Shahnawaz, Antonia Oduguwa, Jacob Hawk, Brianna Vizcaino, Donna L Farber, Ryan G Gaudet.
      Lysosomal damage is an endogenous danger signal, but its significance for innate immunity and the specific signaling pathways it engages remain unclear. Here, we uncover an immune-inducible pathway that connects lysosomal damage to mitochondrial DNA (mtDNA) efflux and type I IFN production. We find that transient lysosomal damage elicits sub-lethal mitochondrial outer membrane permeabilization (MOMP) via BAK/BAX macropores; however, the inner mitochondrial membrane (IMM) maintains a barrier against wholesale mtDNA release. Priming with type II IFN (IFN-γ) induced the antibacterial factor APOL3, which, upon sensing lysosomal damage, targets mitochondria undergoing MOMP to selectively permeabilize the IMM, enhance mtDNA release, and potentiate downstream cGAS signaling. Biochemical and cellular reconstitution revealed that, analogous to its bactericidal detergent-like mechanism, APOL3 permeabilized the IMM by solubilizing cardiolipin. Our findings illustrate how cells enlist an antibacterial protein to expedite the breakdown of endosymbiosis and facilitate a heightened response to injury and infection.
    Keywords:  DNA; damage; innate immunity; interferon; intracellular bacteria; lysosome; mitochondrion; viruses
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.029
  47. NAR Mol Med. 2026 Jan;3(1): ugag012
    Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation.
    Rodolphe Suspène, Béibhinn O'Hora, Constance de Maere d'Aertrycke, Lydie Couturier, Théo Defresne, Pierre Khalfi, XiongXiong Li, Jean-Pierre Vartanian.
      Hypoxia is a hallmark of the tumour microenvironment, driving metabolic reprogramming, immune activation, and genome instability. Here, we showed that cobalt chloride (CoCl2), a hypoxia-mimicking agent, potently induces the expression of the DNA cytidine deaminase APOBEC3A (A3A) in THP-1, a human monocytic cell line. A3A upregulation occurred in a dose-dependent manner, independently of type I interferon signalling, and was accompanied by increased double-strand DNA breaks. Transcriptomic profiling revealed broad hypoxia-driven reprogramming, characterized by activation of the stress response and downregulation of mitochondrial signalling pathways. Mechanistically, cobalt chloride induced mitochondrial dysfunction, metabolic reprogramming, and cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA was transcribed by RNA polymerase III into immunostimulatory RNA, which activated the RIG-I/TRAF6/NF-κB signalling cascade to drive A3A expression. Inhibition or knockdown of RNA polymerase III markedly reduced both A3A levels and DNA damage, highlighting the central role of this pathway. All together, our findings reveal a novel interferon-independent signalling route through which hypoxia-induced mitochondrial stress activates A3A, directly linking metabolic dysfunction to genome instability. This mechanism involves mitochondrial perturbation as a key driver of APOBEC3-mediated mutagenesis in hypoxic tumours and other diseases associated with mitochondrial stress.
    DOI:  https://doi.org/10.1093/narmme/ugag012
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