bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–09–28
forty-two papers selected by
Dylan Ryan, University of Cambridge
  1. Beyond energy: how TCA cycle-derived metabolites regulate gene expression and inflammation in the nucleus.
  2. Lactate metabolism is exploited by Francisella tularensis via its O-antigen capsule to limit macrophage-mediated activation and cell death.
  3. CD8+ T cell stressors converge on shared metabolic-epigenetic networks.
  4. Metabolomics and Cytokine Signatures in COVID-19: Uncovering Immunometabolism in Pathogenesis.
  5. Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power.
  6. Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.
  7. Adenosine 2A receptor-dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming.
  8. Inhibiting arginine metabolism via ALDH2/ARG2 axis blockade potentiates immune checkpoint inhibitors in colorectal cancer.
  9. Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints.
  10. Targetable axes of tumor-associated macrophages: An MSF framework for precision immunotherapy.
  11. Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.
  12. Taurine transport is a critical modulator of ionic fluxes during NLRP3 inflammasome activation.
  13. Obesity Risk Factors Promote Metabolic Reprogramming and Viral Infection in Airways with Type 1 High Inflammation.
  14. STK11 coordinates IL-4 signaling with metabolic reprogramming to control M2 macrophage polarization and antitumor immunity.
  15. Succinate metabolism: underlying biological mechanisms and emerging therapeutic targets in inflammatory bowel disease.
  16. Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.
  17. Cholesterol fuels microglia in chronic stroke.
  18. Metabolic regulation of host defence against viral infection through sensing oxaloacetate.
  19. Itaconate promotes the differentiation of murine stress erythroid progenitors by increasing Nrf2 activity.
  20. Metabolic reprogramming in efferocytosis.
  21. Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
  22. Metformin improves CD8+ T cell responses and parasitemia control via macrophage modulation during Trypanosoma cruzi infection.
  23. Investigation of the Impact of Tryptophan-Metabolizing Enzymes and Kynurenic Acid on Antibody-Mediated Glomerulonephritis.
  24. The Glycolysis-HIF-1α axis induces IL-1β of macrophages in rheumatoid arthritis.
  25. Glucose-Fueled Histone Modifications Drive HIV-1 Latency Reversal at Hypoxia.
  26. Dietary Selenium deficiency activates the NLRP3 inflammasome to induce gallbladder pyroptosis by regulating glycolysis and histone lactylation through ROS/HIF-1α pathway.
  27. Intracellular pH links energy metabolism to lymphocyte death and proliferation.
  28. Research on Sepsis and Metabolic Reprogramming from 1998 to 2025: A Bibliometric and Visualized Analysis.
  29. Microglial metabolic reprogramming drives cognitive decline in heart failure with preserved ejection fraction.
  30. Synthetic anticoagulant octaparin targets mitochondrial cardiolipin-GSDMD axis to rescue redox homeostasis in sepsis.
  31. Intra-tumoral hypoxia promotes CD8+ T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.
  32. HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.
  33. ICAT drives lactylation of tumor-associated macrophages via the c-Myc-ENO1 axis to promote cervical cancer progression.
  34. Dysregulation of cellular metabolism within the gut-brain axis is associated with behavioural changes in chronic intestinal inflammation.
  35. PPP1R3B Suppresses Atherosclerosis by Promoting the M2 Polarization of Macrophages Through Glycogen Metabolic Reprogramming.
  36. Histone demethylase LSD1 regulates lipid homeostasis during Cryptococcus neoformans infection.
  37. Mitochondria expel tainted DNA - spurring age-related inflammation.
  38. Modulating Glutamine Metabolism Reprograms Pro-Inflammatory Differentiation in Macrophages.
  39. Copper overload worsens the inflammatory response of microglia to amyloid beta (Aβ) by impairing phagocytosis and promoting mitochondrial DNA-mediated NLRP3 inflammasome activation.
  40. Metabolic Regulation of Influenza Vaccine Responses in Racially Diverse Hispanics.
  41. Tryptophan catabolites from microbiota ameliorate immune-mediated hepatitis through activating aryl hydrocarbon receptor of T cells.
  42. ENO2 regulates CD4+ T cell pyroptosis via mitochondrial ROS to drive immunological non-response in HIV infection.
  1. J Inflamm (Lond). 2025 Sep 26. 22(1): 39
    Beyond energy: how TCA cycle-derived metabolites regulate gene expression and inflammation in the nucleus.
    Jaiya Randhawa, Eva M Pålsson-McDermott.
      Immune cells can rewire their metabolism in response to various stimuli. Crosstalk between the nucleus and mitochondria allows for tight regulation of this metabolic reprogramming. Research has emerged showing several TCA cycle-derived metabolites exhibiting moonlighting functions in the nucleus, modulating chromatin modifications in order to control inflammation. These TCA cycle-derived metabolites include acetyl-CoA, α-ketoglutarate, succinate, fumarate, itaconate, and succinyl-CoA which can modify DNA or histone to drive or inhibit gene expression. In this review, we look at the mechanisms of TCA cycle metabolites' non-canonical functions in the nucleus in the context of inflammation. In addition, we discuss the known and possible links between these metabolites' nuclear moonlighting functions and the pathogenesis of diseases, including inflammatory diseases and cancers.
    Keywords:  Epigenetics; Immunometabolism; Inflammation; Metabolites; TCA cycle
    DOI:  https://doi.org/10.1186/s12950-025-00461-x
  2. mBio. 2025 Sep 22. e0068125
    Lactate metabolism is exploited by Francisella tularensis via its O-antigen capsule to limit macrophage-mediated activation and cell death.
    Forrest Jessop, Eric Borhnsen, Benjamin Schwarz, Kaitlin A Stromberg, Molly Miltko, Tyler Jones, Tara Wehrly, Catharine M Bosio.
      Intracellular pathogens manipulate host metabolic systems to establish a replicative niche and evade immune responses. However, mechanisms by which metabolism can be altered for successful infection remain poorly understood. Here, we identify a metabolism-based strategy used by the intracellular pathogen Francisella tularensis subsp. tularensis (FTT) to condition its host cell for optimal replication. FTT, through its associated O-antigen capsule, augmented lactate oxidation in macrophages, thereby improving mitochondrial bioenergetics, reducing redox imbalances and production of pro-inflammatory cytokines, and maintaining cellular viability. Heavy isotope tracing and extracellular flux analysis confirmed lactate incorporation into the TCA cycle with increased mitochondrial ATP production, and these outcomes were associated with upregulation of lactate import and conversion systems, specifically monocarboxylate transporter 4 (MCT4) and LDHB, respectively. Targeting MCT4 using the small molecule inhibitor MSC-4381, controlled FTT infection-mediated manipulation of mitochondrial function and increased cell death in infected macrophages, thereby controlling infection. MSC-4381 also directly controlled FTT infection in defined medium implicating a critical role of short-chain carbon intermediates among the bacteria. Ultimately, these data demonstrate that the lactate oxidation metabolic node, including MCT4 activity, is integral for successful FTT infection and contributes to the pleiotropic effects of the FTT capsule on immune evasion.IMPORTANCEFrancisella tularensis subsp. tularensis (FTT) is an extremely virulent pathogen for which antibiotic intervention must be delivered early, often before proper diagnosis and effective, durable vaccines do not exist. Part of what makes FTT so problematic is that it is proficient at manipulating host metabolic pathways that govern immune activation. However, specific mechanisms by which this manipulation occurs have remained elusive. Discovering new ways in which FTT modulates host cell metabolism will reveal new therapeutic targets to help treat this difficult-to-control infection. We show here that FTT, through its O-antigen polysaccharide capsule, increased lactate oxidation, which in turn reduced inflammatory cytokine production, redox imbalance, and cell death. Targeting proteins responsible for lactate transport controlled FTT infection and blocked the capsule's ability to manipulate the host cell. These data are the first to show lactate oxidation as a potential target for pathogen success and may be a therapeutic target for FTT infection.
    Keywords:  capsule; intracellular bacteria; lactate; macrophages; metabolism; mitochondria
    DOI:  https://doi.org/10.1128/mbio.00681-25
  3. Trends Endocrinol Metab. 2025 Sep 22. pii: S1043-2760(25)00190-0. [Epub ahead of print]
    CD8+ T cell stressors converge on shared metabolic-epigenetic networks.
    Yangtao Shangguan, Jianxiang Wang, Ping-Chih Ho, Yingxi Xu.
      CD8+ T cells are vital for antiviral and antitumor immunity, yet in hostile microenvironments, they experience metabolic stress, leading to mitochondrial damage, metabolic dysregulation, and chromatin remodeling that cause immune dysfunction. Aging further exacerbates these processes, with intrinsic metabolic collapse and extrinsic environmental factors jointly impairing T cell immunity. Metabolites orchestrate key epigenetic modifications, shaping transcriptional programs essential for T cell differentiation and memory formation. This review explores the interconnected metabolic and epigenetic mechanisms governing CD8+ T cell fate decisions, emphasizing how mitochondrial dysfunction, metabolic inflexibility, and nutrient competition drive CD8+ T cell exhaustion, senescence, and age-associated dysfunction. Understanding these metabolic-epigenetic circuits offers novel therapeutic avenues, including metabolic reprogramming and senescence-targeted strategies, to rejuvenate immune responses and enhance immunotherapy outcomes.
    Keywords:  T cell; aging; exhaustion; metabolism; senescence
    DOI:  https://doi.org/10.1016/j.tem.2025.08.009
  4. Metabolites. 2025 Sep 11. pii: 608. [Epub ahead of print]15(9):
    Metabolomics and Cytokine Signatures in COVID-19: Uncovering Immunometabolism in Pathogenesis.
    Mohammad Mehdi Banoei, Abdulrazagh Hashemi Shahraki, Kayo Santos, Gregory Holt, Mehdi Mirsaeidi.
       BACKGROUND: This study aimed to analyze metabolic changes in blood samples from patients with confirmed COVID-19 to explore the correlation between metabolomics and cytokines in survivors and non-survivors of SARS-CoV-2 infection. Understanding the complex biochemical and immunometabolic mechanisms underlying SARS-CoV-2 infection is essential for elucidating the pathophysiology and virulence of COVID-19.
    METHODS: This study included 40 hospitalized COVID-19 patients and 40 healthy controls. Serum metabolic profiles were analyzed using ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC-MS), and cytokine levels were measured using ELISA.
    RESULTS: Our study defined three clear metabolic phenotypes among survivors and non-survivors of COVID-19 compared with healthy controls, which might be related to mortality, severity, and disease burden. A strong relationship was observed between certain inflammatory markers, including IL-1β, IL-2, IFN-β, IFN-γ, IL-17, and GM-CSF, as well as several metabolites, particularly in COVID-19 non-survivors, such as LysoPCs, 3-hydroxykynurenine, and serotonin. Different metabolite-cytokine correlation patterns were observed according to patient outcomes, indicating unique correlations between metabolic and immune responses in survivors and non-survivors. Metabolic phenotypes were associated with clinical outcomes, comorbidities, and sex-related differences. Kynurenine and related metabolites of tryptophan metabolism were closely correlated with COVID-19 severity, age, and mortality. Compared with survivors and healthy controls, non-survivors displayed higher IL-6, together with distinct metabolic changes. These included increased kynurenine through the IDO1 pathway, elevated glucose and lactate reflecting hyperglycolysis and energy stress, and higher xanthosine from purine turnover. Stronger cytokine-metabolite correlations in this group point to tightly linked immunometabolic activation.
    CONCLUSIONS: Metabolomic profiling revealed distinct metabolic phenotypes that could be associated with the severity and inflammation levels of COVID-19. Correlation analysis between metabolites and cytokines demonstrated strong intercorrelations between specific metabolites and cytokines, indicating a strong interrelationship between inflammatory markers and metabolic alterations. Specific metabolic pathways associated with cytokines and their clinical relevance may serve as potential therapeutic targets.
    Keywords:  COVID-19; cytokines biosignatures; immunometabolism; metabolic biosignatures; metabolites-cytokine correlation
    DOI:  https://doi.org/10.3390/metabo15090608
  5. Annu Rev Virol. 2025 Sep;12(1): 157-178
    Cellular Titanomachy: Viral Forces Clash with Mitochondrial Power.
    Théo Defresne, Rodolphe Suspène, Jean-Pierre Vartanian.
      Mitochondria play a vital role in cellular metabolism, energy production, and immune signaling, making them key targets for viral manipulation. Viruses exploit mitochondrial functions to enhance replication and evade immune responses. They also disrupt mitochondrial dynamics by altering fission/fusion balance and modulating mitophagy, which is essential for mitochondrial quality control. Additionally, they reprogram mitochondrial metabolism, affecting pathways such as oxidative phosphorylation and glycolysis to support replication. Viruses regulate apoptosis, either inhibiting or activating mitochondria-mediated apoptosis to prolong host cell survival or facilitate viral spread. Viral infections also induce oxidative stress through reactive oxygen species generation, affecting cellular integrity. Furthermore, viruses manipulate mitochondrial antiviral immunity by degrading mitochondrial antiviral signaling protein and triggering the release of mitochondrial DNA, modulating immune responses. Understanding these interactions offers valuable insights into viral pathogenesis and presents therapeutic opportunities. Targeting mitochondrial dysfunction and enhancing antiviral immunity could provide new strategies to mitigate viral damage and enhance cellular resilience.
    Keywords:  antiviral immunity; metabolic pathways; mitochondria; mitochondrial dynamics; oxidative stress; virus
    DOI:  https://doi.org/10.1146/annurev-virology-092623-090901
  6. Nat Metab. 2025 Sep 23.
    Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.
    Qiang Zhao, Jiajian Li, Jingjing Feng, Xin Wang, Yueting Liu, Fei Wang, Liang Liu, Bingxue Jin, Ming Lin, Ya-Chao Wang, Xiuhua Guo, Jieli Chen, Junwei Hao.
      Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes.
    DOI:  https://doi.org/10.1038/s42255-025-01379-7
  7. Sci Signal. 2025 Sep 23. 18(905): eadr3177
    Adenosine 2A receptor-dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming.
    Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A J O'Neill, Georgina Xanthou.
      Metabolic reprogramming controls protective and pathogenic T helper 17 (TH17) cell responses. When naïve T cells are differentiated into TH17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic TH17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A2A receptor (A2AR) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic TH17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic TH17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys9 (H3K9ac) of genes involved in aerobic glycolysis and TH17 pathogenic programs. In contrast, in nonpathogenic activin A-treated TH17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic TH17 programs. Together, our findings uncover A2AR-AMPK signaling as a central metabolic checkpoint that suppresses TH17 cell pathogenicity.
    DOI:  https://doi.org/10.1126/scisignal.adr3177
  8. Mol Cancer Ther. 2025 Sep 26.
    Inhibiting arginine metabolism via ALDH2/ARG2 axis blockade potentiates immune checkpoint inhibitors in colorectal cancer.
    Lu Cai, Yonglong Cao, Jiawei Zhang, Kaiwen Xi, Aimin Li, Hong Zhang.
      Metabolic reprogramming constitutes a key mechanism driving immunotherapy resistance in colorectal cancer (CRC), though the immunomodulatory role of L-arginine metabolism remains poorly defined. Through metabolomic profiling, we identified aldehyde dehydrogenase 2 (ALDH2) as a critical regulator depleting intracellular L-arginine pools in CRC cells. High Performance Liquid Chromatography (HPLC) analysis of cell supernatants further demonstrated that ALDH2 overexpression significantly diminishes extracellular L-arginine availability. Functionally, this arginine deficiency suppressed CD8+ T cell proliferation while inducing the attenuation of anti-tumor efficacy. Mechanistic studies revealed that ALDH2 upregulates Pre-B-Cell Leukemia Homeobox 3 (PBX3), which enhances arginase 2 (ARG2) transcription to promote L-arginine catabolism. This process suppresses glycolysis in CD8+ T cells, ultimately compromising their effector functions. Notably, ALDH2-high tumors exhibited resistance to immune checkpoint blockade (ICB), whereas combinatorial ARG2 inhibition and ICB therapy synergistically restored antitumor immunity. These findings nominate ARG2 as a novel therapeutic target and propose dual metabolic-immunologic intervention as a promising strategy for ICB-resistant CRC.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0404
  9. J Adv Res. 2025 Sep 18. pii: S2090-1232(25)00729-5. [Epub ahead of print]
    Dynamic remodeling of amino acid metabolism in tumor-associated macrophages: Fueling immunosuppression, reshaping tumor niches, and unlocking metabolic checkpoints.
    Beibei Ran, Lingjun Xiao, Yan Liu, Chenglin Zhang, Lingkai Kong, Yuxin Zhang, Xiaosong Gu, Chunping Jiang, Junhua Wu.
       BACKGROUND: Tumor-associated macrophages (TAMs) depend on their amino acid metabolism to determine their properties and immune function and play important roles in the tumor microenvironment (TME). Although in previous studies, targeting amino acid metabolism to transform the protumor function of TAMs into antitumor immune function has shown promising application as a tumor therapy, current clinical research is still limited. There is a lack of discussion on the mechanism and treatment strategy for determining tumor progression by controlling amino acid metabolism in TAMs, as does a summary of studies on promoting tumor progression by reshaping amino acid metabolism in TAMs.
    AIM OF REVIEW: This review aims to systematically review and summarize the crosstalk between amino acid metabolism in TAMs and the TME, analyze the determining role of its metabolic network in tumor occurrence and development, and summarize therapies on this basis to help determine the development status and emerging technologies in the field of amino acid metabolism in TAMs for tumor therapy.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: This review dissects how TAMs exploit amino acid dynamics via transporters, enzymes, and sensors to adopt protumoral phenotypes, depleting critical metabolites and crippling antitumor T-cell responses. We map the immunometabolic crosstalk through which TAMs reshape immunity, highlighting nutrient competition and metabolic byproducts as dual drivers of immune dysfunction. Emerging therapeutic strategies targeting these pathways (IFN-γ-JAK-STAT1 and IL-6/JAK2/STAT3) have been critically evaluated for their potential to reprogram TAMs and reverse immunosuppression. Key challenges, such as TAM heterogeneity, metabolic plasticity, and therapy resistance, are addressed, emphasizing the need for single-cell-resolution mapping of TAM metabolic states to identify context-dependent vulnerabilities. Finally, we advocate for combinatorial approaches that couple metabolic rewiring with immunotherapies, proposing that disrupting amino acid dependencies in TAMs could dismantle the immunosuppressive TME.
    Keywords:  Amino acid; Immunometabolic crosstalk; Immunotherapy; M1-like TAMs; M2-like TAMs; Metabolic crosstalk; Metabolic reprogramming; Therapeutic target; Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1016/j.jare.2025.09.025
  10. Biochim Biophys Acta Rev Cancer. 2025 Sep 23. pii: S0304-419X(25)00200-8. [Epub ahead of print] 189458
    Targetable axes of tumor-associated macrophages: An MSF framework for precision immunotherapy.
    Zhenting Lu, Midie Xu, Junzhe Tang, Xinyi Wang, Xinxiang Li, Qingguo Li.
      Tumor-associated macrophages (TAMs) are a central component of the tumor microenvironment and exert dual, context-dependent effects on cancer progression. This review synthesizes the mechanisms that govern TAM polarization, their bidirectional crosstalk with tumor and stromal cells, and the consequences of metabolic reprogramming. Molecular and metabolic circuits that shape TAM phenotypes and sustain immune suppression are highlighted, and therapeutic strategies targeting TAM checkpoints, metabolism, and lineage pathways are summarized. To integrate immunometabolism with single-cell and spatial profiling, we introduce a Metabolic-Spatial-Functional Axis that links dominant metabolic programs, anatomic niches, and measurable effector functions. This framework organizes TAM heterogeneity and prioritizes biomarker-guided therapeutic combinations with clear translational readouts. Collectively, these advances support precision approaches that reprogram or constrain TAMs to enhance antitumor immunity and overcome therapeutic resistance.
    Keywords:  Immune evasion; Macrophage polarization; Macrophage-stromal interaction; Metabolic reprogramming; Metabolic-spatial-functional (MSF) axis; Precision immunotherapy; Single-cell RNA sequencing; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189458
  11. Nat Microbiol. 2025 Sep 22.
    Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.
    Shouheng Jin, Xing He, Zheyu Wang, Tao Zhou, Jun Wang, Guihong Pan, Yin Zhang, Ling Ma, Shuai Yang, Liqiu Wang, Yaoxing Wu, Yilin Zou, Nan Qi, Jun Cui.
      Metabolic pathways determine cellular fate and function; however, the exact roles of metabolites in host defence against influenza virus remain undefined. Here we employed pharmacological inhibition and metabolomics analysis to show that the metabolic pathways of oxaloacetate (OAA) are integrated with antiviral responses to influenza virus. Cytosolic malate dehydrogenase 1 senses intracellular OAA to undergo dimerization and functions as a scaffold to recruit the transcription factor ETS2 for phosphorylation by the kinase TAOK1 at serine 313. The phosphorylated ETS2 translocates into the nucleus and supports optimal expression of TBK1, an indispensable activator of type I interferon responses. OAA supplementation provides a broad-spectrum antiviral ability, and OAA deficiency caused by Acly genetic ablation decreases antiviral immunity and renders mice more susceptible to lethal H1N1 virus infection. Our results uncover a signalling pathway through cellular OAA sensing that links metabolism and innate immunity to coordinate defence against viral challenge.
    DOI:  https://doi.org/10.1038/s41564-025-02107-3
  12. Cell Rep. 2025 Sep 18. pii: S2211-1247(25)01088-5. [Epub ahead of print]44(10): 116317
    Taurine transport is a critical modulator of ionic fluxes during NLRP3 inflammasome activation.
    Peter Rossi-Smith, Joohee Kim, Kamil Skirlo, Trevor Ferris, Jack P Green, Cari Stek, Kristin K Huse, Paige M Mortimer, Antoni Olona, Cecilia Wieder, Raymond Moseki, Mariana Silva Dos Santos, James I MacRae, Shiranee Sriskandan, Timothy M D Ebbels, Robert J Wilkinson, Alice E Denton, Nicolas J Matheson, Paras K Anand, Graeme Meintjes, David C Thomas, Rachel P J Lai.
      Metabolic regulation is a key feature of inflammasome activation and effector function. Using metabolomic approaches, we show that downregulation of taurine metabolism is crucial for NLRP3 inflammasome activation. Following NLRP3 activation stimuli, taurine rapidly egresses to the extracellular compartment. Taurine efflux is facilitated primarily by the volume-regulated anion channel (VRAC). Loss of intracellular taurine impairs sodium-potassium ATPase pump activity, promoting ionic dysregulation and disrupting ionic fluxes. Inhibiting VRAC, or supplementation of taurine, restores the ionic balance, abrogates IL-1β release, and reduces cellular cytotoxicity in macrophages. We further demonstrate that the protective effect of taurine is diminished when sodium-potassium ATPase is inhibited, highlighting the pump's role in taurine-mediated protection. Finally, taurine metabolism is significantly associated with the development of tuberculosis-associated immune reconstitution inflammatory syndrome, a systemic hyperinflammatory condition known to be mediated by inflammasome activation. Altogether, we identified a critical metabolic pathway that modulates inflammasome activation and drives disease pathogenesis.
    Keywords:  ATPase; CP: Metabolism; inflammasome; inflammation; ion channels; ionic fluxes; metabolism; metabolomics; taurine; tuberculosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116317
  13. Biomolecules. 2025 Aug 26. pii: 1229. [Epub ahead of print]15(9):
    Obesity Risk Factors Promote Metabolic Reprogramming and Viral Infection in Airways with Type 1 High Inflammation.
    Paige Hartsoe, Niccolette Schaunaman, Taylor Nichols, Diana Cervantes, Stephanie Dawrs, Fernando Holguin, Hong Wei Chu.
      Obesity is a significant health issue, as it is related to human diseases such as asthma and respiratory viral infections. Asthma patients with obesity have more severe diseases, which can be presented with type 1 (e.g., IFN-γ) high inflammation. The interactions of obesity or saturated fatty acids (e.g., palmitic acid, PA) with IFN-γ in airway viral infections have not been clear. In this study, we determined the role of obesity risk factors high-fat diet (HFD) and PA in rhinovirus infection in the context of IFN-γ stimulation in mice and cultured human tracheobronchial epithelial cells. We further examined the therapeutic effect of a glycolytic inhibitor on metabolic reprogramming and viral infection in our experimental models. In mice, HFD in combination with IFN-γ significantly increased lung rhinovirus levels as well as neutrophilic inflammation. Similarly, PA and IFN-γ combination increased viral infection in mice, but HFD or PA alone had a minimal effect on viral infection. Mouse model data were confirmed in cultured primary healthy human airway epithelial cells where PA and IFN-γ together increased viral load. Mechanistically, HFD or PA in combination with IFN-γ up-regulated the glycolytic pathway and generated metabolites favoring viral replication. Inhibition of glycolysis by 2-DG effectively reduced viral infection in human airway epithelial cells. Our data suggest that hosts with obesity along with type 1 high inflammation may be at an increased risk of respiratory viral infections. Intervention of the glycolytic pathway or its metabolites may reduce the severity of viral infection.
    Keywords:  asthma; high-fat diet; interferon-gamma; metabolic reprogramming; obesity; palmitic acid; rhinovirus
    DOI:  https://doi.org/10.3390/biom15091229
  14. Sci Adv. 2025 Sep 26. 11(39): eadx5495
    STK11 coordinates IL-4 signaling with metabolic reprogramming to control M2 macrophage polarization and antitumor immunity.
    Jing Yang, Naresh Singh, Chengxian Xu, Dehui Kong, Samantha Sharma, Sheng Liu, Joseph Lechner, Ankhbayar Lkhagva, Haiyan Tan, Zhiping Wu, Martin J Richer, Yong Zang, Xiumei Huang, Reuben Kapur, Jun Wan, Anthony A High, Xinna Zhang, Xusheng Wang, Xiongbin Lu, Kai Yang.
      Macrophages integrate microenvironmental cues to orchestrate complex transcriptional and metabolic programs that drive functional polarization. Here, we demonstrate that STK11 links interleukin-4 (IL-4) signaling with metabolic reprogramming to restrain alternatively activated (M2) macrophage polarization. Through integrative transcriptomic and metabolomic analyses, we identified STK11 as a key transcriptional and metabolic regulator during M2 polarization. STK11 deficiency enhanced the expression of M2-associated markers and promoted glutamine metabolism in IL-4-stimulated macrophages. Mechanistically, STK11 deficiency led to increased FOXO1 activation, thereby promoting M2 polarization. Pharmacological inhibition of FOXO1 or glutamine metabolism effectively reversed the enhanced M2 polarization. In an orthotopic model of pancreatic ductal adenocarcinoma, myeloid-specific deletion of STK11 resulted in increased accumulation of M2-like tumor-associated macrophages, impaired antitumor immunity, and accelerated tumor progression. These findings uncover a previously unrecognized role for STK11 in modulating M2 macrophage polarization, offering mechanistic insights that may inform the development of immunometabolic therapies for pancreatic cancer.
    DOI:  https://doi.org/10.1126/sciadv.adx5495
  15. Front Immunol. 2025 ;16 1630310
    Succinate metabolism: underlying biological mechanisms and emerging therapeutic targets in inflammatory bowel disease.
    Mingzhu Dai, Shu Bu, Zhiwei Miao.
      The global incidence of inflammatory bowel disease (IBD) continues to rise, yet its precise pathogenesis remains incompletely understood. In recent years, various gut microbiota-derived metabolites have been implicated in the development of IBD. Among them, succinic acid is a key metabolite produced by intestinal flora and serves as a central intermediate in the tricarboxylic acid (TCA) cycle, which plays a pivotal role in the IBD pathogenesis by modulating the intestinal mucosal barrier function, immune-metabolic reprogramming and cellular energy homeostasis. Abnormal succinate metabolism has also been linked to a range of metabolic disorders, including hepatitis, arthritis, diabetes mellitus, and cardiovascular diseases. Recently, its role in IBD has attracted growing interest. This review systematically elucidates the mechanisms by which succinate promotes pro-inflammatory immune phenotypes through a multifaceted network involving macrophage polarization, T-cell metabolic reprogramming, and epithelial-immune cell interactions, largely mediated via the SUCNR1 signaling axis. Furthermore, we explore the therapeutic potential of targeting succinate metabolism, offering new insights into IBD prevention and treatment.
    Keywords:  HIF-1α; SUCNR1; immunometabolism; inflammatory bowel disease; intestinal flora; succinic acid
    DOI:  https://doi.org/10.3389/fimmu.2025.1630310
  16. Nat Metab. 2025 Sep;7(9): 1924-1938
    Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.
    Saloua Benhmammouch, Coraline Borowczyk, Clara Pierrot-Blanchet, Thibault Barouillet, Florent Murcy, Sébastien Dussaud, Marina Blanc, Camille Blériot, Tiit Örd, Lama Habbouche, Nathalie Vaillant, Yohan Gerber, Clément Cochain, Emmanuel L Gautier, Florent Ginhoux, Edward B Thorp, Erik A L Biessen, Judith C Sluimer, Susanna Bodoy, Manuel Palacin, Béatrice Bailly-Maitre, Minna U Kaikkonen, Laurent Yvan-Charvet.
      Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages: Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion of Slc7a7 accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability.
    DOI:  https://doi.org/10.1038/s42255-025-01354-2
  17. Nat Metab. 2025 Sep 23.
    Cholesterol fuels microglia in chronic stroke.
    Stefano Pluchino, Cory M Willis.
      
    DOI:  https://doi.org/10.1038/s42255-025-01362-2
  18. Nat Microbiol. 2025 Sep 25.
    Metabolic regulation of host defence against viral infection through sensing oxaloacetate.
      
    DOI:  https://doi.org/10.1038/s41564-025-02129-x
  19. Blood Red Cells Iron. 2025 Jun;pii: 100001. [Epub ahead of print]1(1):
    Itaconate promotes the differentiation of murine stress erythroid progenitors by increasing Nrf2 activity.
    Baiye Ruan, Yuanting Chen, Sara Trimidal, Meghna Chakraborty, Aashka Shah, Hangdi Gong, Imhoi Koo, Jingwei Cai, John Mcguigan, Molly A Hall, Andrew D Patterson, K Sandeep Prabhu, Robert F Paulson.
      Steady-state erythropoiesis produces new erythrocytes at a constant rate to replace senescent erythrocytes removed in the spleen and liver. Inflammation caused by infection or tissue damage skews bone marrow hematopoiesis, increasing myelopoiesis at the expense of steady-state erythropoiesis. To compensate for the loss of production, stress erythropoiesis is induced. Stress erythropoiesis is highly conserved between mice and humans. It uses a strategy different to the constant production of steady-state erythropoiesis. Inflammatory signals promote the proliferation of immature stress erythroid progenitors (SEPs), which then commit to differentiation. This transition relies on signals made by niche macrophages in response to erythropoietin. Nitric oxide-dependent signaling drives the proliferation of SEPs, and nitric oxide production must be decreased so that progenitor cells can differentiate. Here, we show that as progenitor cells transition to differentiation, increased production of the anti-inflammatory metabolite itaconate activates nuclear factor erythroid 2-related factor 2, which decreases nitric oxide synthase 2 expression, leading to decreased nitric oxide production. Mutation of immunoresponsive gene 1, the enzyme that catalyzes the production of itaconate, causes a delayed recovery from inflammatory anemia induced by heat-killed Brucella abortus. These data show that the differentiation of SEPs relies on a switch to an anti-inflammatory metabolism and increased expression of proresolving cytokines.
    DOI:  https://doi.org/10.1016/j.brci.2025.100001
  20. Front Cell Dev Biol. 2025 ;13 1677028
    Metabolic reprogramming in efferocytosis.
    Qing Yan, Kuo Li, Lu Chen, Aowei Wang, Yingying Xi, Hui Xiao, Lei Yuan.
      Efferocytosis refers to the process by which phagocytes specifically identify and eliminate apoptotic cells. This process is essential for both maintaining tissue homeostasis and suppressing inflammatory responses, as well as facilitating tissue repair. When phagocytes internalize apoptotic cells, which act as "nutrient packages," they undergo significant metabolic reprogramming. This reprogramming not only supplies energy and biosynthetic precursors necessary for engulfment but also critically influences the functional phenotype of phagocytes through complex molecular networks. These networks ultimately determine whether phagocytes adopt an anti-inflammatory resolution or a pathological pro-inflammatory state. This article offers a comprehensive analysis of the molecular regulatory mechanisms that underpin metabolic reprogramming during efferocytosis, aiming to elucidate the intricate regulatory networks formed by the interaction of metabolites as signaling molecules and classical signaling pathways. We examine how the three primary metabolic pathways-glucose, lipid, and amino acid metabolisms-are regulated by signals from efferocytosis and, in turn, modulate phagocyte function. A deeper understanding of the interplay between metabolic reprogramming and efferocytosis will provide a theoretical foundation and novel targets for treating diseases associated with impaired clearance of apoptotic cells.
    Keywords:  apoptotic cell clearance; efferocytosis; fatty acid oxidation; glycolysis; macrophages; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fcell.2025.1677028
  21. Nature. 2025 Sep 24.
    Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
    Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.
      Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.
    DOI:  https://doi.org/10.1038/s41586-025-09541-7
  22. J Leukoc Biol. 2025 Sep 26. pii: qiaf134. [Epub ahead of print]
    Metformin improves CD8+ T cell responses and parasitemia control via macrophage modulation during Trypanosoma cruzi infection.
    Ruth Eliana Baigorri, María Belén Brugo, Florencia Hellriegel, María Estefanía Viano, Yanina Luciana Mazzocco, Yamile Ana, Camila Fontanari, Matías Vazquez-Vignale, Maria Pilar Aoki, María Cecilia Rodriguez-Galán, Claudia Cristina Motrán, Cinthia Carolina Stempin, Fabio Marcelo Cerbán.
      The immune response to Trypanosoma cruzi infection relies on robust inflammatory activation of macrophages and proper CD8+ T cells function to control parasite replication. However, an exacerbated respiratory burst from macrophages can damage tissues where parasites reside, such as the heart and liver. Subsequent fibrotic repair in the heart contributes to cardiomyopathy in patients with chronic Chagas disease and in mouse models. Additionally, respiratory burst metabolites are implicated in the impairment of CD8+ T cell responses. While excessive reactive oxygen species (ROS) production is associated with increased differentiation of Foxp3+ regulatory T cells (Tregs), T cell receptor (TCR) nitration occurs in the presence of high extracellular nitric oxide (NO) levels. Both mechanisms contribute to CD8+ T cell suppression during T. cruzi infection. In this study, we use metformin (Metf) to balance parasite control and immune-mediated tissue damage by modulating macrophage activation. We found that Metf ex vivo treatment in peritoneal macrophages (PEMs) from acutely infected mice led to reduced iNOS expression, decreased NO production and lower secretion of IL-1β, TNF and IL-6. However, IL-12 levels increased and CD8+ T cells co-cultured with these PEMs showed enhanced proliferation and IFN-γ production. In vivo, Metf-treated infected mice exhibited lower parasitemia and improved CD8+ T cell functionality, potentially linked to reduced TCR nitration and decreased Treg frequencies in the peritoneum, as well as reduced cardiac inflammation. These findings provide new insights into the inflammatory modulation exerted by Metf and its potential impact on CD8+ T cell response and Chagas disease outcome.
    Keywords:  CD8 T cell; T. cruzi; macrophages; meta-inflammation; metformin
    DOI:  https://doi.org/10.1093/jleuko/qiaf134
  23. FASEB J. 2025 Sep 30. 39(18): e71076
    Investigation of the Impact of Tryptophan-Metabolizing Enzymes and Kynurenic Acid on Antibody-Mediated Glomerulonephritis.
    Ryosuke Umeda, Yoshimasa Ito, Shun Minatoguchi, Shigehisa Koide, Kazuo Takahashi, Hiroki Hayashi, Midori Hasegawa, Yukio Yuzawa, Yasuko Yamamoto, Kuniaki Saito, Naotake Tsuboi.
      Tryptophan (TRP) metabolism through the kynurenine pathway generates multiple biologically active metabolites with diverse immunomodulatory effects, but their roles in glomerulonephritis (GN), particularly in innate immunity, remain poorly understood. Using a nephrotoxic serum-induced GN (NTS-GN) model, we first analyzed mice deficient in key TRP-metabolizing enzymes of the kynurenine pathway: Indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2), and kynurenine 3-monooxygenase (KMO), and found that Ido1-deficient mice exhibited exacerbated kidney injury and glomerular neutrophil infiltration, whereas Ido2 deficiency had no significant impact. In contrast, Kmo-deficient mice showed reduced crescent formation. Unexpectedly, the concentration of kynurenic acid (KYNA), a downstream metabolite of IDO1, was elevated in the kidney cortex of Ido1-deficient mice. Exogenous KYNA administration improved survival, ameliorated renal injury, and reduced neutrophil infiltration in Ido1-deficient mice, indicating its protective effect against antibody-mediated injury. Moreover, KYNA suppressed immune complex-mediated neutrophil spreading, attenuated FcγR-dependent Syk phosphorylation, and reduced VEGF secretion in vitro. Our results position KYNA as a key modulator of neutrophil-driven inflammation in antibody-mediated GN. This study uncovers distinct roles for kynurenine pathway enzymes and highlights the TRP-KYNA pathway as a promising immunometabolic target for controlling innate immune responses in GN.
    Keywords:  Indoleamine 2,3‐dioxygenase; RRID:AB_2337118; RRID:IMSR_JAX:005867; RRID:MGI:2159965; RRID:MGI:3028467; RRID:MGI:5759308; glomerulonephritis; kynurenic acid; neutrophils; tryptophan
    DOI:  https://doi.org/10.1096/fj.202501800R
  24. Arthritis Res Ther. 2025 Sep 26. 27(1): 180
    The Glycolysis-HIF-1α axis induces IL-1β of macrophages in rheumatoid arthritis.
    Yimeng Jia, Rongli Li, Linfang Huang, Xunyao Wu, Lidan Zhao, Huaxia Yang, Xin You, Yunyun Fei.
       BACKGROUND: Rheumatoid arthritis (RA) is an aggressive, systemic autoimmune disease in which overactivated macrophages play a critical role in its pathogenesis. This study aimed to explore the potential role of glycolytic reprogramming in the production of proinflammatory cytokines by macrophages in RA.
    METHODS: The Seahorse assay was conducted on RA or healthy control (HC) serum-treated human monocyte-derived macrophages (HMDMs) to evaluate glycolysis levels. RNA sequencing was performed to identify activated signaling pathways and key molecules in HMDMs stimulated by RA serum. The proinflammatory cytokines and hypoxia-inducible factor 1α (HIF-1α) were verified by Western blotting and quantitative polymerase chain reaction (qPCR).
    RESULTS: We found that HMDMs stimulated with RA serum showed higher aerobic glycolysis levels than those treated with HC serum, along with higher expression of glycolysis-related genes, including hexokinase2 (HK2), pyruvate kinase L/R (PKLR), and phosphoglycerate kinase 1 (PGK1). Furthermore, RA serum-treated macrophages exhibited a higher level of interleukin-1 beta (IL-1β), and the expression of IL-1β positively correlated with HK2. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) or HK2 knockdown significantly suppressed IL-1β production in macrophages. The HIF-1α-associated signaling pathways and HIF-1α protein levels were also elevated in RA serum-treated macrophages. Inhibition of glycolysis by 3BrPA or knockdown of HK2 reduced HIF-1α. Inhibiting HIF-1α can suppress IL-1β production of RA serum-treated macrophages, and vice versa. TNF-α and IL-1β enhanced HIF-1α and IL-1β expression in macrophages, an effect attenuated by glycolysis inhibition. Blocking TNF-α and IL-1β in RA serum diminished both glycolysis and IL-1β production.
    CONCLUSION: Our findings demonstrate that RA serum triggers aerobic glycolysis in macrophages, which promotes HIF-1α to drive IL-1β production. Notably, IL-1β within RA serum amplifies its own expression via this glycolysis-HIF-1α axis, establishing a pathogenic positive feedback loop in RA.
    Keywords:  Glycolysis; HIF-1α; IL-1β; Macrophage; Rheumatoid arthritis
    DOI:  https://doi.org/10.1186/s13075-025-03647-z
  25. bioRxiv. 2025 Sep 16. pii: 2025.09.14.676169. [Epub ahead of print]
    Glucose-Fueled Histone Modifications Drive HIV-1 Latency Reversal at Hypoxia.
    Yetunde I Kayode, Deanna C Clemmer, Adebola A Owolabi, AbdulKareem A AlShaheeb, Elyse K McMahon, Anna Tangiyan, Lauren Clark, Glenn E Simmons, Alberto Bosque, Melanie R McReynolds, Harry E Taylor.
      The major barrier to curing HIV-1 infection is the persistence of a latent reservoir in CD4 T cells within tissues which readily fuel viral rebound upon antiretroviral therapy (ART) interruption. Clinical trials aimed at purging these viral reservoirs with latency reversal agents (LRAs) have been unsuccessful owing to our incomplete understanding of the molecular and physiological determinants that underlie latency reversal in these virus-harboring tissues. Here, using a combination of complementary pharmacological and metabolomic approaches, we uncover glucose as a conditionally essential nutrient for HIV-1 latency reversal at hypoxic conditions. By modelling physiological variations in both glucose and oxygen availability as found in vivo within tissues that may harbor the HIV reservoir, we show that hyperglycemic conditions potentiate HIV-1 latency reversal. Importantly, we found major classes of clinically relevant LRAs, PKC agonists (PKCags) and histone deacetylase inhibitors (HDACis) have disparate efficacies under glucose-limiting conditions. Mechanistically, we show that this differential glycolytic dependency is due to distinct capacities of LRAs to induce glycolytic flux during adaptation to hypoxia, a condition that increases glycolytic dependence. Furthermore, we show that PKCag-induced glycolysis drives histone lactylation, a post-translational modification (PTM) we found to be associated with HIV-1 latency reversal and promotes increased chromatin accessibility at the HIV promoter. Importantly, we identify KAT2A as a lactyl-transferase critical for histone lactylation induced upon latency reversal. Taken together, our findings uncover glucose and oxygen availability as critical metabolic determinants of HIV-1 latency reversal and underscore the importance of modeling physiologically relevant experimental conditions in vitro aimed at identifying therapeutic agents that effectively target the latent reservoir in vivo .
    DOI:  https://doi.org/10.1101/2025.09.14.676169
  26. J Nutr Biochem. 2025 Sep 18. pii: S0955-2863(25)00280-3. [Epub ahead of print] 110118
    Dietary Selenium deficiency activates the NLRP3 inflammasome to induce gallbladder pyroptosis by regulating glycolysis and histone lactylation through ROS/HIF-1α pathway.
    Zhaoyang An, Haodong Hu, Qian Wang, Yaning Qiu, Jiahong Chu, Yu Xia, Shu Li.
      Selenium (Se) is an essential micronutrient, and inadequate intake can disrupt redox balance in digestive organs, promoting inflammation. Enhanced glycolysis leads to lactate accumulation, exacerbating the inflammatory response through inflammation-related pathways. Histone lysine lactylation plays a key role in epigenetic regulation. The effect of Se deficiency on the gallbladder remains unclear. To explore the mechanism of Se deficiency on gallbladder injury and the regulatory role of histone lactylation, we established Se-deficient swine models and in vitro cell models. Histopathological observation of the gallbladder found that Se deficiency led to inflammatory damage to the gallbladder. Metabolomics and proteomics results showed that Se deficiency led to significant enrichment of "glycolytic flux", "oxidative stress", and "hypoxia-inducible factor-1 α (HIF-1α) signaling pathway". Further studies have found that Se deficiency led to oxidative stress in gallbladder tissue, abnormal expression of HIF-1α factor, increased glycolysis levels, excessive lactate production, increased histone lactylation, and pyroptosis. HIF-1α knockdown suppressed Se deficiency-induced glycolysis and reduced lactate accumulation. In vitro studies using N-acetylcysteine (NAC), 2-deoxyglucose (2-DG), Oxamate and A-485 showed that Reactive oxygen species (ROS) regulated increased glycolysis through HIF-1α and increased H3K18 lactylation (H3K18la) levels through substrate-dependent modifications. Furthermore, H3K18la activated NLRP3 inflammasome, triggering pyroptosis and inflammatory cascades. In conclusion, the results of this study showed that dietary Se deficiency promotes glycolysis-dependent histone lactylation via the ROS/HIF-1α pathway, activating NLRP3 inflammasome, leading to pyroptosis and inflammation in gallbladder. These findings provide insights into targeted therapies for Se deficiency-related metabolic disorders and pathological changes in organs.
    Keywords:  Gallbladder; Glycolysis; Histone lactylation; NLRP3 inflammasome; Pyroptosis; ROS/HIF-1α pathway; Selenium deficiency
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.110118
  27. Sci Rep. 2025 Sep 25. 15(1): 32878
    Intracellular pH links energy metabolism to lymphocyte death and proliferation.
    Wei-Ping Zeng, Shuangshuang Yang, Baohua Zhou.
      The role of intracellular pH (pHi) of lymphocytes in the control of the magnitude of immune response is unknown. The central question addressed in this report is whether energy metabolism affects pHi, which in turn regulates the death and proliferation of the lymphocytes and hence the magnitude of the immune response. To this end, we studied lymphocytes in the in vitro model of anti-CD3 activation and the in vivo mouse model of ovalbumin sensitization and challenge. We found that low pHi induces apoptosis of proliferating lymphocytes, whereas high pHi is conducive to their survival. In the in vivo model, treating the mice with the metabolic regulators dichloroacetate or C75 that increase the influx of carbons derived from pyruvate and fatty acid to the TCA cycle, respectively, lowered pHi. Treatments with the metabolic regulators CB-839 or GSK2837808A that inhibit glutaminolysis and aerobic glycolysis, respectively, also lowered pHi. Proliferation powered by high mitochondrial membrane potentials (MMPs) in lymphocytes of low but not high pHi was accompanied by apoptosis. After antigenic challenge, lymphocytes of high pHi increased and assumed a positive relation between pHi and MMPs, while lymphocytes of low pHi and with an inverse relation between pHi and MMPs diminished. These changes were largely dependent on glutaminolysis and aerobic glycolysis. It is therefore concluded that glutaminolysis and aerobic glycolysis are important for counterbalancing the acidic effects of pyruvate and fatty acid energy metabolism to promote a favorable pHi environment for lymphocyte survival and the progression of the immune response.
    DOI:  https://doi.org/10.1038/s41598-025-16862-0
  28. Shock. 2025 Sep 23.
    Research on Sepsis and Metabolic Reprogramming from 1998 to 2025: A Bibliometric and Visualized Analysis.
    Yipeng Fang, Aizhen Dou, Yunfei Zhang, Ying Zhang, Ying Gao, Keliang Xie.
       BACKGROUND: Metabolic reprogramming has emerged as a central mechanism in sepsis pathogenesis, influencing immune responses, organ dysfunction, and therapeutic outcomes. This study conducts a comprehensive bibliometric analysis to map the research landscape, identify key trends, and highlight future directions in this field.
    METHODS: Based on the Science Citation Index Expanded database in Web of Science Core Collection (WOSCC) database, we retrieved and analyzed 672 English-language original research articles and reviews. Using R-bibliometrix, VOSviewer, and CiteSpace we performed a multidimensional analysis of academic output trends, geographical distribution, institutional and author collaboration networks, burst detection and the evolution of research hotspots.
    RESULTS: The analysis reveals a consistent upward trend in both publication output and citation frequency within this research domain. The United States (24.3% of total publications) and China (23.4%) have emerged as the most productive contributing nations. Notably, the United States maintains superior academic influence as evidenced by its highest citation frequency. Among institutions, Wake Forest University in the United States holds a preeminent position, having published 54 high-impact articles in this field. The journals Frontiers in Immunology, Shock, and Critical Care, represent the premier academic platforms in this research domain. Immunometabolism, mitochondrial regulation, gut microbiota imbalance, epigenetic modifications, along with the mTOR/AMPK/HIF-1α axis and the Sirtuin family pathway has been identified as the key research hotspots. Novel therapeutic approaches targeting metabolic regulation are rapidly emerging, including pharmacological agents, natural compounds, stem cell-based therapies, and non-coding RNA interventions.
    CONCLUSION: Research on metabolic reprogramming in sepsis shows promising prospects, with investigations into key mechanisms focusing on current research hotspots and the development of metabolism-targeted interventions emerging as critical priorities for future sepsis prevention and treatment strategies.
    Keywords:  Glycolysis; Gut microbiota; Immunometabolism; Lactylation; Macrophage; Metabolic reprogramming; Mitochondria; Sepsis
    DOI:  https://doi.org/10.1097/SHK.0000000000002714
  29. bioRxiv. 2025 Sep 16. pii: 2025.09.10.675257. [Epub ahead of print]
    Microglial metabolic reprogramming drives cognitive decline in heart failure with preserved ejection fraction.
    Swapna Patil, Connor Lantz, Angela Marinovic, Ripon Sarkar, Bo Ryung Lee, Matthew DeBerge.
      Heart failure with preserved ejection fraction (HFpEF) is a rapidly growing public health concern and an emerging contributor to dementia, yet the mechanisms linking cardiometabolic dysfunction to neurodegeneration remain poorly understood. Here, we demonstrate that HFpEF drives a sustained neuroinflammatory state through microglial metabolic reprogramming. Using a clinically relevant murine model of HFpEF, we identified robust induction of HIF-1α signaling in microglia via integrated transcriptomics and metabolomics, coupled with increased glycolytic metabolism revealed by extracellular flux analysis. Conditional deletion of Hif1a in microglia during HFpEF attenuated neuroinflammation, preserved white matter integrity, and rescued cognitive performance. We further identify Sema4D as a HIF-1α-dependent, microglia-derived effector linking metabolic stress to white matter injury. These findings establish a mechanistic bridge between cardiovascular disease and cognitive dysfunction and reveal microglial HIF-1α signaling as a tractable therapeutic strategy for preventing cognitive decline in cardiometabolic disease.
    DOI:  https://doi.org/10.1101/2025.09.10.675257
  30. Redox Biol. 2025 Sep 22. pii: S2213-2317(25)00390-8. [Epub ahead of print]87 103877
    Synthetic anticoagulant octaparin targets mitochondrial cardiolipin-GSDMD axis to rescue redox homeostasis in sepsis.
    Shule Zhang, Cong Feng, Ning Yu, Rui Fang, Yingxin Zhang, Simeng Chen, Lijuan Cao, Jianfa Zhang.
      Sepsis, characterized by dysregulated immune responses and mitochondrial dysfunction, currently has few effective therapies that directly target these cellular mechanisms, and conventional heparin and related analogues provide inadequate immunomodulatory benefits. Here, we investigated the synthetic heparin analogue octaparin, which exhibits enhanced anticoagulant safety, for its potential to mitigate sepsis by targeting mitochondrial and redox pathways. Using murine models of lipopolysaccharide (LPS)-induced endotoxemia and Salmonella typhimurium-induced sepsis, along with in vitro studies performed using murine bone marrow-derived macrophages (BMDMs) and the human acute monocytic leukemia THP-1 cell line, we demonstrate that octaparin significantly improves survival and attenuates multi-organ (lung, liver, kidney) damage. Octaparin outperformed heparin, enoxaparin, and fondaparinux in suppressing systemic inflammation including TNF-α, IL-6, IL-1β and bacterial burden. Transcriptomic analysis revealed octaparin reprograms macrophage immunometabolism, suppressing pro-inflammatory pathways while enhancing phagocytosis. Crucially, octaparin inhibited both canonical and non-canonical inflammasome activation, reduced generation of the pyroptotic executor GSDMD-N-terminal fragment (GSDMD-NT), and specifically diminished mitochondrial localization of GSDMD-NT by downregulating key cardiolipin synthesis and transport genes. Furthermore, octaparin uniquely reversed LPS-induced mitochondrial dysfunction. This restoration was accompanied by improvements in mitochondrial quality and the reestablishment of redox homeostasis. Collectively, octaparin confers multifaceted protection in sepsis, positioning it as a promising redox-targeted therapeutic for sepsis.
    Keywords:  Cardiolipin; Mitochondria; Octaparin; Pyroptosis; Redox homeostasis; Sepsis
    DOI:  https://doi.org/10.1016/j.redox.2025.103877
  31. Immunity. 2025 Sep 25. pii: S1074-7613(25)00414-5. [Epub ahead of print]
    Intra-tumoral hypoxia promotes CD8+ T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.
    Coral Del Mar Alicea Pauneto, Brian P Riesenberg, Evelyn J Gandy, Andrew S Kennedy, Genevieve T Clutton, Jessica W Hem, Katie E Hurst, Elizabeth G Hunt, Jarred M Green, Brian C Miller, Steven P Angus, Gary L Johnson, Robert J Esther, Jennifer L Guerriero, Peng Gao, David R Soto-Pantoja, Robert L Ferris, Jennifer L Modliszewski, Michael F Coleman, H Kay Chung, J Justin Milner, Stergios J Moschos, R Luke Wiseman, Jessica E Thaxton.
      Metabolic stress in the tumor microenvironment (TME) promotes T cell dysfunction and immune checkpoint inhibitor (ICI) resistance. We examined the contribution of activating transcription factor 4 (ATF4), the central node of the integrated stress response (ISR), to T cell dysfunction in tumors. CD8+ tumor-infiltrating lymphocytes (TILs) in patient samples exhibited chronic ATF4 activity, which was reflected across various tumor models. Hypoxia in the TME imposed chronic ATF4 activity via the ISR kinases. ATF4 overexpression in CD8+ T cells induced metabolic polarity, mitochondrial oxidative stress, and cell death, impairing antitumor immunity. Chronic ATF4 transcriptional activity replicated the terminal exhaustion CD8+ T cell state independent of T cell receptor (TCR) stimulation. Genetic or pharmacologic attenuation of ATF4 reduced mitochondrial oxidative stress and promoted CD8+ TIL viability, enabling response to programmed cell death protein-1 (PD-1) inhibitor therapy and conferring protection from re-emergent disease. Thus, the ISR converges on chronic ATF4 activity in CD8+ TILs as a barrier to ICI response, positioning ISR therapeutics as candidates for immunotherapy.
    Keywords:  ATF4; T cell; hypoxia; immunotherapy; integrated stress response; metabolism; mitochondria; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2025.09.003
  32. Cell Metab. 2025 Sep 23. pii: S1550-4131(25)00382-1. [Epub ahead of print]
    HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.
    Yi Xiao, Ying Xu, Han Wang, Fan Yang, Xiao-Hong Ding, Tong Fu, Li Chen, Xi Jin, Ya-Xin Zhao, Ying Wang, Fenfang Chen, Zhi-Ming Shao, Yi-Zhou Jiang.
      Immunotherapy demonstrates limited efficacy in triple-negative breast cancer (TNBC), influenced by intricate metabolic interactions within the tumor microenvironment. Here, we developed a single-cell RNA sequencing (scRNA-seq) immunotherapy cohort (N = 27) and a spatial transcriptomics cohort (N = 88) to elucidate metabolic crosstalk associated with therapeutic efficacy in TNBC. We illustrated that heme binding protein 2 (HEBP2)high tumor cells (featured by active glutathione metabolism) and CCL3+ macrophages (characterized by oxidative metabolism) indicated immunotherapy efficacy and were quantitatively and spatially negatively correlated. HEBP2-mediated glutamine face-off between these cell types induced this phenomenon. Mechanistically, HEBP2 disrupted FOXA1 cytoplasmic phase separation, promoting its nuclear translocation to upregulate glutathione S-transferase P1 (GSTP1) expression and glutamine consumption in tumor cells. This metabolic shift induced ferroptosis of CCL3+ macrophages, impairing the antitumor immunity. The utilization of a GSTP1 inhibitor sensitized TNBC to immunotherapy. Collectively, we delineate a tumor-macrophage metabolic checkpoint governed by the HEBP2/GSTP1 axis and pioneer single-cell-level immunometabolism as a paradigm for evaluating immunotherapeutic vulnerabilities.
    Keywords:  immunometabolic crosstalk; immunotherapy; precision immunotherapy; single-cell metabolism; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.cmet.2025.08.009
  33. Free Radic Biol Med. 2025 Sep 19. pii: S0891-5849(25)00988-8. [Epub ahead of print]
    ICAT drives lactylation of tumor-associated macrophages via the c-Myc-ENO1 axis to promote cervical cancer progression.
    Tingting Dang, Yiqing You, Lan Wei, Qian Li, Haoli Sun, MengXin Sun, Xiaolu Li, Shiyu Yang, Tao Zeng, Liang Zhang, Xiran He, Ke Wang, Jiafeng Tang, Yan Zhang.
      The effectiveness of immunotherapy in cervical cancer (CC) is profoundly influenced by the tumor microenvironment (TME), where a high infiltration of M2-type tumor-associated macrophages (TAMs) correlates with poor therapeutic responses. Therefore, understanding the molecular mechanisms driving M2-type TAM polarization and identifying novel therapeutic targets are essential for enhancing immunotherapy outcomes in CC. In this study, ICAT was revealed to be significantly upregulated in CC, correlating with poor prognosis. Mechanistically, ICAT facilitated the nuclear translocation of c-Myc, enhancing ENO1 transcription, thereby promoting glycolytic activity and lactate accumulation in the TME. Tumor-derived lactate induced H3K18 lactylation in TAMs, which in turn activated ARG1 expression, driving M2 polarization and establishing an immunosuppressive microenvironment that supports immune evasion. In summary, this study demonstrates that ICAT, by regulating the c-Myc-ENO1 axis, mediates the interaction between tumor cells and macrophages, thereby reshaping the TME and promoting the migration, invasion, and glycolysis of CC. These findings demonstrate that ICAT represents a potential therapeutic target for the treatment of CC.
    Keywords:  Cervical cancer; ICAT; lactylation; polarization; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.031
  34. J Neuroinflammation. 2025 Sep 26. 22(1): 216
    Dysregulation of cellular metabolism within the gut-brain axis is associated with behavioural changes in chronic intestinal inflammation.
    Jeannie Devereaux, Ainsley M Robinson, Rhian Stavely, Majid Davidson, Rhiannon T Filippone, Ramya Ephraim, Dimitros Kiatos, Vasso Apostolopoulos, Kulmira Nurgali.
       BACKGROUND: Inflammatory bowel disease (IBD) is a chronic debilitating condition significantly affecting patient quality of life. Although the exact aetiology remains unknown, accumulating evidence has shown that disruption of the gut-brain axis may be related to the occurrence and development of chronic intestinal inflammation. Psychological disorders are highly prevalent in patients with IBD. However, an association between altered behaviour and dysregulated metabolic pathways within the gut-brain axis is yet to be explored.
    METHODS: Metabolic multiplexed phenotyping system involving indirect calorimetry and flow-through respirometry monitors was used to assess energy metabolism in Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Depressive and anxiety-like behaviours were evaluated with light dark, open field, grooming, elevated plus maze, and forced swimming tests. To investigate underlying mechanisms of the metabolic changes in Winnie mice, glycolysis/gluconeogenesis, fatty acid ß-oxidation, tricarboxylic acid cycle and oxidative phosphorylation gene expressions were determined by transcriptome analysis using high-throughput sequencing of mRNA extracted from the distal colon and brain samples.
    RESULTS: Our findings showed that energy metabolism and spontaneous activity were reduced in Winnie mice corresponding to alterations in the expression of cellular metabolism-associated genes in the distal colon. Winnie mice displayed depressive and anxiety-like behaviours reflecting downregulation of glycolysis/gluconeogenesis, fatty acid ß-oxidation, tricarboxylic acid cycle and oxidative phosphorylation in the distal colon and brain. Subsequent analyses showed pro-inflammatory cytokine expression was upregulated in the Winnie mouse brain.
    CONCLUSIONS: These data provide evidence that the dysregulation of cellular metabolism within the gut-brain axis underlies changes in behaviour and energy metabolism in chronic intestinal inflammation.
    Keywords:  Cellular metabolism; Chronic colitis; Depression; Energy metabolism; Gut-brain axis; Inflammatory bowel disease (IBD)
    DOI:  https://doi.org/10.1186/s12974-025-03536-x
  35. Adv Sci (Weinh). 2025 Sep 23. e06345
    PPP1R3B Suppresses Atherosclerosis by Promoting the M2 Polarization of Macrophages Through Glycogen Metabolic Reprogramming.
    Lin Shen, Junchao Yu, Weiqian Chen, Yanran Bi, Zhangyu Yang, Chenying Lu, Chengli Jiang, Yang Yang, Minjiang Chen, Jianhua Zou, Lingchun Lv, Xiaoyuan Chen, Jiansong Ji.
      Identifying targets that promote M2 macrophage polarization in the hypoxic plaque microenvironment is crucial for modulating immune metabolism and optimizing energy dynamics in atherosclerotic cardiovascular disease (ASCVD) treatment. The high phagocytic activity of M2 macrophages reduces foam cell formation. Their secretion of anti-inflammatory cytokines enhances plaque stability, mitigating atherosclerosis progression. Through high-throughput sequencing and multi-omics bioinformatics analysis, protein phosphatase 1 regulatory subunit 3B (PPP1R3B) is identified as a key regulator linking glycogen metabolism to macrophage polarization. The integrated approach combined transcriptomic analysis of human atherosclerotic plaques (GSE57614) with RNA-seq of PPP1R3B-modulated macrophages, revealing its dual role. PPP1R3B induces anti-inflammatory M2 macrophage polarization and maintains energy supply in plaques. Its absence accelerates plaque progression. PPP1R3B regulates M2 macrophage polarization and energy metabolism via phosphorylated STAT3 (p-STAT3), which plays a dual role by activating anti-inflammatory transcriptional programs through the PPAR-γ/PGC-1α/CD206 axis in the nucleus and enhancing glycogenolysis-mediated metabolic activity via the p-GSK-3β/p-PYGL/p-GYS2 axis in mitochondria. STAT3 plays a dual role in metabolic regulation and macrophage phenotype modulation. By orchestrating glycogen metabolic reprogramming, PPP1R3B-induced M2 polarization presents a novel strategy for anti-ASCVD drug development, with significant potential for clinical translation.
    Keywords:  ASCVD; M2 macrophage polarization; PPP1R3B; glycogen metabolic reprogramming
    DOI:  https://doi.org/10.1002/advs.202506345
  36. iScience. 2025 Sep 19. 28(9): 113405
    Histone demethylase LSD1 regulates lipid homeostasis during Cryptococcus neoformans infection.
    Gaurav Kumar Lohia, Awantika Shah, Kithiganahalli Narayanaswamy Balaji.
      An opportunistic fungal pathogen, Cryptococcus neoformans, causes cryptococcal meningitis and is frequently associated with high mortality in immunocompromised individuals. The formation of metabolically altered lipid-rich foamy macrophages is a successful strategy used by various intracellular pathogens to secure a nutrient source and niche within the host. Herein, we elucidate the involvement of macroautophagy, specifically lipophagy, in lipid dysregulation during C. neoformans infection. C. neoformans driven activation of WNT-signaling leads to an aberrant lipid accumulation in host macrophages under the regulatory role of a histone modifier, Lysine Specific Demethylase 1 (LSD1). In a murine model of pulmonary infection, targeting host LSD1 led to a significant reduction in lung fungal burden, accompanied by improved lung pathology and reduced lipid content in the lungs. The study highlights the significance of host epigenetic regulation in modulating foamy macrophage formation through the regulation of lipophagy during C. neoformans pathogenesis.
    Keywords:  Immune response; Lipid; Model organism; Mycology
    DOI:  https://doi.org/10.1016/j.isci.2025.113405
  37. Nature. 2025 Sep 26.
    Mitochondria expel tainted DNA - spurring age-related inflammation.
    Gemma Conroy.
      
    Keywords:  Ageing; Cell biology; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-03064-x
  38. bioRxiv. 2025 Sep 18. pii: 2025.09.16.675216. [Epub ahead of print]
    Modulating Glutamine Metabolism Reprograms Pro-Inflammatory Differentiation in Macrophages.
    Sumeng Qi, Jiawei Fan, Dao-Sian Wu, Sudipto Ganguly, Ie-Ming Shih, Tian-Li Wang.
      Previous in vivo studies demonstrated that JHU083/DON, a glutamine analog drug, potently reprograms M1/M2 macrophages. To determine whether these effects are direct or indirect, we utilized an in vitro murine bone marrow-derived macrophage (BMDM) model, which recapitulates macrophage differentiation and polarization processes, to examine the impact of DON on the M1 macrophages. DON was applied during M1 differentiation or to fully polarized M1 macrophages, revealing that glutamine inhibition initially suppressed M1 activity but later enhanced it, resulting in sustained pro-inflammatory activation. Multi-omics analyses (bulk RNA-seq and LC-MS), time-course assays, and glutamine depletion experiments consistently suggested that prolonged glutamine inhibition elevates glutamine levels, which sustain pro-inflammatory gene transcription. In contrast, M2 and tumor-associated macrophages (TAM), which are immunosuppressive, were more susceptible to DON, leading to functional suppression. Collectively, our findings uncover stage-specific mechanisms by which glutamine inhibition modulates M1 polarization, offering a mechanistic rationale for therapeutic strategies that sustain pro-inflammatory, anti-tumor macrophage activity while concurrently suppressing immunosuppressive myeloid subsets in cancer.
    DOI:  https://doi.org/10.1101/2025.09.16.675216
  39. Redox Biol. 2025 Sep 17. pii: S2213-2317(25)00385-4. [Epub ahead of print]87 103872
    Copper overload worsens the inflammatory response of microglia to amyloid beta (Aβ) by impairing phagocytosis and promoting mitochondrial DNA-mediated NLRP3 inflammasome activation.
    Marlene Zubillaga, Xenia Abadin, Elia Ivars, Margalida Puigròs, Ramon Trullas, M José Bellini, Nathalie Arnal, Anna Colell.
      Microglia play a significant role in the development and progression of Alzheimer's disease (AD). These brain-resident immune cells efficiently clear neurotoxic amyloid beta (Aβ) peptides; however, chronic activation may overwhelm their protective abilities, resulting in persistent neuroinflammation. The causes of aberrant microglial activation in AD remain elusive. Emerging evidence indicates that copper (Cu) accumulation, which can arise from prolonged exposure to various environmental sources, modifies the innate immune response in AD. Here, we sought to explore the mechanisms by which Cu overload regulates the microglial phenotype when exposed to Aβ. Our findings showed that exposure to sublethal doses of Cu led to the accumulation of this transition metal in the mitochondria. Elevated mitochondrial Cu (mtCu) levels were accompanied by reduced mitochondrial glutathione (mtGSH) and high oxidative stress, leading to Aβ-induced inflammasome activation through the release of oxidized mitochondrial DNA (ox-mtDNA). Moreover, increased intracellular Cu levels enhanced cholesterol biosynthesis and facilitated its transport to mitochondria. The combination of elevated cholesterol and mitochondrial oxidative stress hindered the ability of microglia to phagocytose Aβ effectively. As expected, conditioned medium from Cu-activated microglia reduced neuronal viability. The neurotoxicity caused by Cu-overloaded microglia was prevented by inhibiting inflammasome activation and restoring mtGSH levels. In conclusion, our study outlines a mechanistic pathway by which chronic exposure to environmental Cu may lead to neuroinflammation and Aβ accumulation in AD, underscoring the crucial role of mitochondrial oxidative stress.
    Keywords:  ABCA7; Alzheimer's disease; Cholesterol; Mitochondrial oxidative stress; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.redox.2025.103872
  40. Vaccines (Basel). 2025 Sep 02. pii: 938. [Epub ahead of print]13(9):
    Metabolic Regulation of Influenza Vaccine Responses in Racially Diverse Hispanics.
    Daniela Frasca, Maria Romero, Suresh Pallikkuth.
       BACKGROUND: Racial and ethnic differences in vaccine responses, particularly within Hispanic populations, remain underexplored. Disparities in immune function may be influenced by metabolic and inflammatory mechanisms.
    METHODS: The current study investigated humoral immune responses to influenza vaccination in a diverse cohort of Hispanic individuals from South Florida, encompassing both White and Black Hispanics. Antibody responses were assessed post-vaccination, and B cell phenotypes were analyzed to evaluate inflammatory and metabolic characteristics. In vitro experiments were conducted to determine whether blocking metabolic pathways could alter the inflammatory phenotype of B cells. Data were analyzed using an unpaired Student's t-test (two-tailed), and correlation analysis was conducted with Pearson correlation.
    RESULTS: Our findings indicated that Black Hispanic individuals exhibited significantly reduced antibody responses compared to White Hispanics (p < 0.01) following influenza vaccination. This diminished humoral response correlated with inversely with serum LDH (r = -0.58; p = 0.0005) and other intrinsic inflammatory phenotypes in blood-derived B cells and was supported by changes in metabolic activity. In vitro blockade of metabolic pathways effectively reduced the inflammatory phenotype of B cells from Black Hispanic individuals, suggesting a mechanistic link between metabolic dysfunction and impaired vaccine-induced immunity.
    CONCLUSION: This study is the first to reveal racial disparities in influenza vaccine responses within a Hispanic population, highlighting reduced antibody production in Black Hispanics. These findings suggest that metabolically driven B cell inflammation may play a critical role and point to potential therapeutic strategies to address disparities in vaccine-induced immunity.
    Keywords:  health disparities; humoral immunity; influenza vaccine
    DOI:  https://doi.org/10.3390/vaccines13090938
  41. Gut Microbes. 2025 Dec;17(1): 2557979
    Tryptophan catabolites from microbiota ameliorate immune-mediated hepatitis through activating aryl hydrocarbon receptor of T cells.
    Bo Li, Xueying Liang, Yikang Li, Rui Wang, Yiran Wei, Qiaoyan Liu, Jun Zhang, Qixia Wang, Qi Miao, Xiao Xiao, Min Lian, Zhi Wang, Yufeng Zhou, M Eric Gershwin, Zhengrui You, Ruqi Tang, Xiong Ma.
      Intestinal dysbiosis and T cell-mediated immune attack are implicated in the pathogenesis of autoimmune hepatitis (AIH). However, the mechanisms by which microbiota-derived metabolites modulate immune homeostasis in AIH remain elusive. Here, we demonstrated that microbiota-derived indole-3-carboxaldehyde (ICA) was significantly reduced in patients with AIH. Treatment with ICA restricted the activation of effector T cells by activating AhR in T lymphocytes. Nuclear translocation of AhR induced the transcription of PI3K interacting protein 1 (Pik3ip1), which inhibited the PI3K/Akt/mTOR signaling pathway. In vivo supplementation of ICA suppressed effector T cells and mitigated the tissue damage and hepatic inflammation in two mouse models of T cell-mediated hepatitis. Importantly, T cell-specific deletion of AhR abrogated the protective effects of ICA in AIH-like mouse model. Finally, administration of Lactobacillus reuteri resulted in elevated level of ICA and protected mice from liver damage. Our data suggest that ICA supplementation ameliorates immune-mediated hepatitis through agonizing AhR in T cells, presenting a promising therapeutic strategy for AIH.
    Keywords:  Indole-3-carboxaldehyde; PI3K interacting protein 1; aryl hydrocarbon receptor; immune-mediated hepatitis; lactobacillus reuteri
    DOI:  https://doi.org/10.1080/19490976.2025.2557979
  42. mBio. 2025 Sep 25. e0170225
    ENO2 regulates CD4+ T cell pyroptosis via mitochondrial ROS to drive immunological non-response in HIV infection.
    Siyao Li, Heqiao Wang, Pan Wang, Tianling Yang, Jiaqi Li, Mei Liu, Yajing Fu, Yongjun Jiang, Zining Zhang, Hong Shang.
      Approximately 10-40% of patients with acquired immune deficiency syndrome (AIDS) fail to restore the number of CD4+ T cells after antiretroviral therapy (ART). They are referred to as immunological non-responders (INRs) and have increased morbidity and mortality of AIDS and non-AIDS events. Pyroptosis is one of the key factors driving CD4+ T cell death in human immunodeficiency virus (HIV) infection, but its relationship with immune reconstitution and the underlying mechanisms is poorly understood. Through our in vitro experiments, we showed that the expression of enolase 2 (ENO2) decreased in INRs and inhibited ENO2-enhanced CD4+ T cell pyroptosis through the regulation of reactive oxygen species (ROS). Furthermore, we discovered that supplementation with phosphoenolpyruvate (PEP), the catalytic product of ENO2, could restore mitochondrial function and reduce the pyroptosis of CD4+ T cells. Our study clarified the ENO2-PEP-ROS-pyroptosis axis of CD4+ T cells in INRs and provided a novel therapeutic target for enhancing immune reconstitution in HIV infection.IMPORTANCEThe decrease in CD4+ T cell count is an important cause of poor immune reconstitution in HIV-infected patients. In this study, we analyzed the pyroptosis of T cells in HIV-infected patients with poor immune reestablishment and demonstrated how ENO2, a key enzyme in the glycolytic pathway, affects pyroptosis through mitochondrial ROS. Our results clarified the role of ENO2 in regulating CD4+ T cell pyroptosis in INRs and discussed its possible mechanism. This provides a new target for improving immune reconstitution and intervention in HIV infection.
    Keywords:  ENO2; HIV; immune response; mitochondrial ROS; pyroptosis
    DOI:  https://doi.org/10.1128/mbio.01702-25
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