bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–11–23
forty-two papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Digitally Assessed Long COVID Symptomatology Is Associated With Lymphocyte Mitochondrial Dysfunction and Altered Immune Potential.
  2. The Drosophila PDGF/VEGF signaling pathway regulates host immunometabolism in response to parasitoid infection.
  3. Metabolic deficits and immune dysfunction in aging people living with HIV.
  4. Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
  5. CAR-T cell therapy for solid tumors: HIF-1α as a potential enhancement strategy.
  6. An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
  7. Puerarin Targets MIC19 to Suppress Mitochondrial Metabolism of Tumor-Infiltrating Tregs and Enhance Anti-tumor Immunity.
  8. Host immunometabolic regulation through viral sensing pathways.
  9. The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity.
  10. Proteome profiling indicates a link between mitochondrial pathways and the host-microbial sensor ELMO1 following Salmonella infection.
  11. Analysis of Cellular Metabolism Using Flow Cytometry.
  12. CTRP9 engages AdipoR1 and promotes T cell glycolysis and immunity.
  13. SLC7A8 is essential for metabolic fitness and function of Th2 cells.
  14. Obesity rewires CD8+ T cell iron metabolism in adipose tissue to fuel metabolic inflammation.
  15. Atg16l1 promotes lung transplant tolerance by regulating glycolysis in macrophages.
  16. High glucose-induced mitophagy accelerates premature aging of T cells in patients with rheumatoid arthritis.
  17. Mycobacterium tuberculosis curli pili (MTP) facilitates pathogenicity by modulating oxidative phosphorylation and carbon flux during early infection of A549 epithelial cells.
  18. The metabolic engine of cognition: microglia-neuron interactions in health, ageing and disease.
  19. Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.
  20. PLA2G16-Mediated Tetracosatetraenoic Acid Rewires Fatty Acid Oxidation to Impair CD8+ T Cell Immune Function in Promoting Breast Cancer Lung Metastasis.
  21. tRF-His-GTG-1 promotes Salmonella survival through modulation of lipid metabolism and immune signaling.
  22. Mapping real-time metabolic kinetics of expanded CAR T cells using hyperpolarized 13C-glucose and metabolomics.
  23. Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.
  24. Lipocalin 2 deficiency attenuates NLRP3 inflammasome activation through glycolysis impairment and MGST1-mediated mitochondrial ROS reduction.
  25. Fibulin7 C-terminal bioactive peptide regulates metabolic profiling of macrophages during inflammation via integrin α5β1.
  26. The role of metabolic reprogramming in inflammatory bone diseases.
  27. High Extracellular Glucose Concentration Drives Palmitate-Induced Toxicity and Metabolic Dysfunction in BV2 Microglia Cells.
  28. Mechanism of LEPR-mediated cholesterol metabolism involved in NK cell function suppression under simulated microgravity.
  29. Sucrose supplementation mitigates heat stress-induced alterations in rumen metabolism and immunity in dairy cows.
  30. Polyphenols-mediated immune regulation: Metabolite-driven epigenetic regulatory mechanisms.
  31. Ethanol consumption mediates parasitoid resistance via effects on host metabolism.
  32. Sodium butyrate inhibits colorectal cancer development by reducing M2 macrophage polarization and PD-L1 expression.
  33. Methionine regulates antitumor function of CD8 + T cells through polyamine synthesis.
  34. Induction of endogenous IL-10 promotes resolution and tolerance of nitric oxide in microglia.
  35. Reprogramming of lipid metabolism by ORF3a-induced microlipophagy enhances biogenesis of SARS-CoV-2 replication organelle.
  36. NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice.
  37. Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids.
  38. Purinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic brown adipose tissue.
  39. Monocyte Iron Load Correlates with Immune Suppression and Sepsis Severity: A Longitudinal Analysis.
  40. Gut-lung immunometabolic crosstalk in sepsis: from microbiota to respiratory failure.
  41. Bacterial CipB is an exogenous receptor to drive the mitophagy-TFEB axis and promote pathogenesis.
  42. Mitochondrial targeting by measles virus nucleoprotein modulates viral spread in human airway epithelium.
  1. Open Forum Infect Dis. 2025 Nov;12(11): ofaf447
    Digitally Assessed Long COVID Symptomatology Is Associated With Lymphocyte Mitochondrial Dysfunction and Altered Immune Potential.
    Vasile Mihai Sularea, Liam Townsend, Cian Reid, Andreea V Atanasescu, Adam H Dyer, Federica Giangrazi, Roman Rocha Lawrence, Manoj Sivan, Barry Moran, Derek G Doherty, Niall P Conlon, Aideen Long, Cliona O'Farrelly.
       Background: Postacute sequelae of SARS-CoV-2 infection, also known as long COVID (LC), is a complex and heterogenous condition affecting millions worldwide with a poorly understood underlying pathology. Although metabolic dysregulations have been described in LC, it remains unclear whether circulating immune cells exhibit immunometabolic alterations.
    Methods: We conducted a detailed clinical, immunologic, and mitochondrial analysis on 27 patients with LC and 27 who recovered from COVID-19 and were healthy. Symptom burden and severity were assessed and quantified via a digital platform with the modified COVID-19 Yorkshire Rehabilitation Scale. Mitochondrial function of circulating immune cell populations (lymphocytes and monocytes) was analyzed by measuring mitochondrial mass and mitochondrial membrane potential. Production of 11 cytokines after whole blood stimulation with bacterial and viral agonists was measured by multiplex immunoassay. Relationships between mitochondrial and immune parameters with LC symptoms were investigated.
    Results: Patients with LC exhibited significant symptom burden, with worsening across all symptom domains as compared with their health state before SARS-CoV-2 infection. They also had a decreased mitochondrial membrane potential of CD56bright natural killer cells, particularly in patients experiencing dizziness, whereas reduced mitochondrial membrane potential in CD4+ lymphocytes was found in patients with worsening breathlessness. Upon LPS stimulation, patients with LC demonstrated significantly lower IFN-γ production. In response to viral ligand R848, impaired IFN-β and IL-10 responses were associated with worsening cough and executive functions.
    Conclusions: Symptom severity in LC is associated with immune cell mitochondrial dysfunction and altered cytokine responses, highlighting potential disease biomarkers and targets for future therapeutic strategies.
    Keywords:  Immunometabolism; Long COVID; Lymphocyte; Mitochondria; Natural Killer cell
    DOI:  https://doi.org/10.1093/ofid/ofaf447
  2. bioRxiv. 2025 Oct 01. pii: 2025.10.01.679819. [Epub ahead of print]
    The Drosophila PDGF/VEGF signaling pathway regulates host immunometabolism in response to parasitoid infection.
    Ashley L Waring-Sparks, Abraham Y Kpirikai, Jun Yang, Riitvek Baddireddi, Najeeb Marun, Nicholas M Bretz, Hayden Gosnell, Humayl Malik, David A Hendrix, Nathan T Mortimer.
      Mounting an immune response requires energy, but how that energy is reallocated at the organismal level remains poorly understood. In Drosophila melanogaster, infection by a parasitoid wasp triggers a systemic metabolic switch known as immunometabolism which is characterized by a shift in metabolic activity and the redistribution of resources away from organismal development and toward the production of a cellular immune response. We identify the PDGF/VEGF (PVF) signaling pathway as a key initiator of this immunometabolic switch. Genetic manipulation of PVF signaling alters infection outcomes, modulates systemic metabolite profiles, and reveals a direct trade-off between immune function and development. Our findings establish the Drosophila-parasitoid wasp system as a genetically tractable model for understanding the molecular basis of immunometabolism.
    Keywords:  Drosophila melanogaster; Immunometabolism; PDGF/VEGF signaling pathway; cellular immunity; innate immunity; metabolic reallocation; metabolites; metabolomics
    DOI:  https://doi.org/10.1101/2025.10.01.679819
  3. Immunometabolism (Cobham). 2025 Oct;7(4): e00071
    Metabolic deficits and immune dysfunction in aging people living with HIV.
    Daniela Frasca, Suresh Pallikkuth.
      Cellular metabolism is crucial for energy production, which regulates cell function and survival. In recent years, the importance of metabolism in modulating immune cell proliferation, differentiation, and function has become a prominent area of research. However, little is still known about the metabolic regulation of B cell function and humoral immunity, both in healthy individuals as well as in those with various conditions and diseases. In this viewpoint, we will discuss the current understanding of immunometabolic regulation of humoral responses in aging people living with HIV, and in people without HIV. We propose the possibility to target metabolic molecules and pathways to prevent the negative effects of aging and HIV and progress towards an overall better immune system, not only in individuals with HIV but also in those living with other inflammatory conditions and diseases.
    Keywords:  B cells; HIV; aging; metabolism
    DOI:  https://doi.org/10.1097/IN9.0000000000000071
  4. Int Rev Immunol. 2025 Nov 17. 1-30
    Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
    Thao Hoang Nhu Le, Van Thi Tuong Nguyen.
      Mitochondria serve as the powerhouses of living cells, supplying energy and essential building blocks for cellular activities. The immune system exhibits a dynamic and active characteristic within the body, wherein immune cells are constantly activated and primed for pathogens without causing harmful effects on the self-body. These characteristics necessitate that immune cells function effectively and correctly, supported by a sufficient energy supply and metabolism from the mitochondria. Mitochondrial dysfunction leads to immune dysregulation, resulting in inappropriate inflammation, autoimmunity, immunodeficiency, and hypersensitive responses, all of which contribute to the development of illness and disease. Recent studies on mitochondrial transfer in immune cells indicate that mitochondrial replacement could emerge as a promising tool for rectifying immune cell function. This review will emphasize the role of mitochondria in various immune cell types and explore how mitochondrial dysfunction can result in pathogenesis in different conditions. We also discuss the potential application of mitochondrial transfer and transplantation to- and from immune cells in the context of health and disease.
    Keywords:  Immunology; immunometabolism; mesenchymal stem cells; metabolism; mitochondria transfer
    DOI:  https://doi.org/10.1080/08830185.2025.2577986
  5. Autoimmunity. 2025 Dec;58(1): 2579069
    CAR-T cell therapy for solid tumors: HIF-1α as a potential enhancement strategy.
    Hai Rong Li, Jie Xiong, Chun Hui Wang, Li Bing Hu, Ying Bao Wang, Qin Rong Ping, Meng Yang, Jun Tan, Ting Ting Li, Yang Yang.
      The advent of chimeric antigen receptor (CAR) T cell therapy has yielded transformative efficacy in hematological malignancies, yet its application in solid tumors remains constrained by the immunosuppressive tumor microenvironment (TME). Characterized by hypoxia, acidosis, and nutrient deprivation, the TME critically compromises CAR-T cell infiltration, persistence, and effector functions. Hypoxia-inducible factor 1α (HIF-1α), a central regulator of cellular adaptation to hypoxia within the TME, modulates T cell metabolism and functionality-presenting a strategic framework for enhancing CAR-T cell efficacy in solid malignancies. This review characterizes the role of HIF-1α in reprogramming the tumor-immune microenvironment, with specific emphasis on its metabolic regulation of T cells and translational implications for CAR-T therapy. Under hypoxic stress, HIF-1α orchestrates a metabolic shift toward glycolysis in effector T cells by suppressing oxidative phosphorylation (OXPHOS) while upregulating key glycolytic enzymes (e.g. GLUT1, HK2, LDHA). This adaptation sustains ATP production while attenuating mitochondrial reactive oxygen species (ROS) accumulation, thereby mitigating T cell exhaustion and augmenting cytotoxic persistence. This HIF-1α-mediated metabolic reprogramming provides critical insights for overcoming barriers to CAR-T cell efficacy in solid tumors.
    Keywords:  CAR-T cells; HIF-1α; immunotherapy; solid tumor treatment; tumor microenvironment
    DOI:  https://doi.org/10.1080/08916934.2025.2579069
  6. Nat Commun. 2025 Nov 20. 16(1): 10222
    An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
    Eloïse Marques, Stephen P Burr, Alva M Casey, Richard J Stopforth, Chak Shun Yu, Keira Turner, Dane M Wolf, Marisa Dilucca, Vincent Paupe, Suvagata Roy Chowdhury, Victoria J Tyrrell, Robbin Kramer, Yamini M Kanse, Chinmayi Pednekar, Chris A Powell, James B Stewart, Julien Prudent, Michael P Murphy, Michal Minczuk, Valerie B O'Donnell, Clare E Bryant, Patrick F Chinnery, Arthur Kaser, Alexander von Kriegsheim, Dylan G Ryan.
      Impaired mitochondrial bioenergetics in macrophages promotes hyperinflammatory cytokine responses, but whether inherited mtDNA mutations drive similar phenotypes is unknown. Here, we profiled macrophages harbouring a heteroplasmic mitochondrial tRNAAla mutation (m.5019A>G) to address this question. These macrophages exhibit combined respiratory chain defects, reduced oxidative phosphorylation, disrupted cristae architecture, and compensatory metabolic adaptations in central carbon metabolism. Upon inflammatory activation, m.5019A>G macrophages produce elevated type I interferon (IFN), while exhibiting reduced pro-inflammatory cytokines and oxylipins. Mechanistically, suppression of pro-IL-1β and COX2 requires autocrine IFN-β signalling. IFN-β induction is biphasic: an early TLR4-IRF3 driven phase, and a later response involving mitochondrial nucleic acids and the cGAS-STING pathway. In vivo, lipopolysaccharide (LPS) challenge of m.5019A>G mice results in elevated type I IFN signalling and exacerbated sickness behaviour. These findings reveal that a pathogenic mtDNA mutation promotes an imbalanced innate immune response, which has potential implications for the progression of pathology in mtDNA disease patients.
    DOI:  https://doi.org/10.1038/s41467-025-65023-4
  7. Adv Sci (Weinh). 2025 Nov 18. e12793
    Puerarin Targets MIC19 to Suppress Mitochondrial Metabolism of Tumor-Infiltrating Tregs and Enhance Anti-tumor Immunity.
    Yu Li, Ziyan Song, Jianjun Ding, Yiheng Zhou, Tianning Huang, Qufei Qian, Miao Yu, Wenzhao Chen, Jiazheng Liu, Ling Lu, Qiuyang Chen.
      Regulatory T cells (Tregs) are pivotal mediators of immunosuppression in hepatocellular carcinoma, but strategies for selectively disrupting their function remain underdeveloped. Here, puerarin, a natural isoflavone is identifed as a selective immunometabolic modulator. It impairs mitochondrial metabolism in tumor-infiltrating Tregs (Ti-Tregs) without affecting conventional T cells. Mechanistically, puerarin directly binds to MIC19-a core subunit of the mitochondrial contact site and cristae organizing system-leading to its degradation and disruption of the MIC19-MIC60 complex. This disruption causes cristae disorganization, reduces oxidative phosphorylation, and weakens the immunosuppressive function of Ti-Tregs. In vivo, puerarin decreases Ti-Treg infiltration, thereby enhancing antitumor immunity without causing systemic toxicity. Furthermore, MIC19 knockdown and site-directed mutagenesis studies validate the role of critical MIC19 residues (His180, Gln187, and Tyr211) in puerarin's activity. These results reveal a mechanism by which puerarin suppresses mitochondrial metabolism of Ti-Tregs and emphasize the therapeutic potential of natural compounds in metabolic targeting for cancer immunotherapy.
    Keywords:  Regulator T cells; hepatocellular carcinoma; immunotherapy; mitochondrial metabolism; puerarin
    DOI:  https://doi.org/10.1002/advs.202512793
  8. Curr Opin Microbiol. 2025 Nov 18. pii: S1369-5274(25)00105-5. [Epub ahead of print]88 102683
    Host immunometabolic regulation through viral sensing pathways.
    Ana Julia Estumano Martins, Thaís Pirola Dos Santos, Wilias Greison Silva Santos, Enzo Triozzi, Pedro M Moraes-Vieira.
      Viruses are intracellular pathogens that have profoundly influenced biological evolution and continue to threaten global health through outbreaks such as influenza and COVID-19. Their ability to evade host immunity stems from evolutionary adaptations that manipulate cellular defense mechanisms. A critical aspect of virus-host interactions involves cellular receptors, which facilitate viral entry and trigger immune signaling. Among these, pattern recognition receptors (PRRs) and other proteins serve as key sensors of viral components, coordinating immune responses while reprogramming host metabolism to sustain antiviral defenses. However, many viruses hijack these metabolic changes to enhance replication, evade immune surveillance, or dysregulate cytokine production. This review explores how host cell virus-sensitive proteins, particularly PRRs and metabolically active proteins, modulate cellular metabolism during infection, shaping immune outcomes and revealing potential therapeutic targets for antiviral intervention.
    DOI:  https://doi.org/10.1016/j.mib.2025.102683
  9. Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2518190122
    The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity.
    Paôline Laurent, Vidyanath Chaudhary, Daqiang Li, Marie Dominique Ah Kioon, Chen Zhang, William H Miller, Hua Liao, Gang Lin, Carl F Nathan, Franck J Barrat.
      Type 2 innate lymphoid cells (ILC2s) contribute to type 2 immunity but have also been associated with multiple inflammatory diseases, including airway inflammation and asthma. We report that beyond its function of degrading poly-ubiquitinylated proteins, the immunoproteasome (i-20S) is required for the proper function of ILC2s by controlling their mitochondrial capacity. We found that 90% of the catalytic β subunits of proteasomes in human ILC2s (hILC2s) are the immuno- (β5i) rather than constitutive (β5c) isoform. Specific, noncovalent, reversible inhibition of i-20S β5i (LMP7) in hILC2s induced ROS production, which inhibited aconitase, leading to altered mitochondrial function and reduced levels of ATP. Reprogramming of metabolic status by an LMP7 inhibitor impaired ILC2 activation, without significant cytotoxicity or preventing their recovery. Hence, the selective inhibition of i-20S in ILC2 cells did not kill them but reversibly depleted their ATP, preventing their activation and cytokine secretion. In mice, proteasome inhibition similarly blocked mitochondrial function and ILC2 activation, preventing airway inflammation in response to IL33 and asthma in response to house dust mites. These findings reveal a previously unappreciated linkage between proteasome blockade, central carbon metabolism, and mitochondrial function and identify a strategy to regulate immune cell metabolism in inflammatory diseases.
    Keywords:  airway inflammation; innate lymphoid cells; metabolism; proteasome
    DOI:  https://doi.org/10.1073/pnas.2518190122
  10. Gut Microbes. 2025 Dec 31. 17(1): 2580708
    Proteome profiling indicates a link between mitochondrial pathways and the host-microbial sensor ELMO1 following Salmonella infection.
    Sajan C Achi, Dominic McGrosso, Stefania Tocci, Isaac Amao, Baibaswata Saha, Stella-Rita Ibeawuchi, Ibrahim M Sayed, David J Gonzalez, Soumita Das.
      The host EnguLfment and cell MOtility protein 1 (ELMO1) is a cytosolic microbial sensor that binds bacterial effector proteins, including pathogenic effectors from Salmonella (Salmonella enterica serovar Typhimurium) and controls host innate immune signaling. To understand the ELMO1-regulated host pathways, we have performed liquid chromatography Multinotch MS3-Tandem Mass Tag (TMT) multiplexed proteomics to determine the global quantification of proteins regulated by ELMO1 in macrophages during Salmonella infection. Comparative proteome analysis of control and ELMO1-depleted murine J774 macrophages after Salmonella infection quantified more than 7000 proteins with a notable enrichment in mitochondrial-related proteins. Gene ontology enrichment analysis revealed 19 upregulated and 11 downregulated proteins exclusive to ELMO1-depleted cells during infection, belonging to mitochondrial functions, metabolism, vesicle transport, and the immune system. Seahorse analysis showed that Salmonella infection alters mitochondrial metabolism from oxidative phosphorylation to glycolysis-a shift significantly influenced by the depletion of ELMO1. Furthermore, ELMO1 depletion decreased the ATP rate index following Salmonella infection, indicating its importance in counteracting the effects of Salmonella on immunometabolism. Among the proteins involved in mitochondrial pathways, the mitochondrial fission protein DRP1 was significantly upregulated in ELMO1-depleted cells and ELMO1-KO mice intestine following Salmonella infection. Pharmacological inhibition of DRP1 identified the role of ELMO1-DRP1 pathway in the regulation of pro-inflammatory cytokine TNF-α following infection. The role of ELMO1 has been further characterized by a Proteome profiling of ELMO1-depleted macrophage infected with SifA mutant displayed the involvement of ELMO1-SifA in mitochondrial function, metabolism and host immune/defense responses. Collectively, these findings reveal a novel role for ELMO1 in modulating mitochondrial functions, potentially pivotal in modulating inflammatory responses.
    Keywords:  DRP1; ELMO1; Microbial sensor; SifA; bacterial effector; macrophages; mitochondrial dynamics; mitochondrial fission; proteomics
    DOI:  https://doi.org/10.1080/19490976.2025.2580708
  11. Methods Mol Biol. 2026 ;2990 119-125
    Analysis of Cellular Metabolism Using Flow Cytometry.
    Christos Aronis, Matteo Villa.
      The understanding that cellular metabolism underlines the differentiation, activation, and function of immune cells has opened new avenues to modulate immunity. Here, we describe a method to analyze cellular metabolism using the quintessential immunological technique: flow cytometry. We analyze single cell suspensions, by combining the staining of surface immune cell markers and nutrient transporters, with the staining using metabolic dyes, to readout surrogates of metabolic pathway utilization with cell subset resolution.
    Keywords:  Cellular metabolism; Flow cytometry; Metabolic dyes; Single cell analysis; Surface nutrient transporters
    DOI:  https://doi.org/10.1007/978-1-0716-4997-8_10
  12. EMBO Rep. 2025 Nov 17.
    CTRP9 engages AdipoR1 and promotes T cell glycolysis and immunity.
    Kunming Li, Jiansong Zhang, Kang Li, Haokai Chen, Wenhai Deng, Wenzhuo Rao, Ming Geng, Yuying Zheng, Xiumei Wei, Jialong Yang.
      The adiponectin (ADPN) receptor (AdipoR) modulates T-cell responses, but its effects remain controversial since signaling can either promote or inhibit T-cell function. Interaction with the ligand ADPN inhibits T-cell responses, but given the existence of multiple AdipoR ligands, we hypothesize that ligand diversity underlies its differential effect in T-cell immunity. To test this, we use tilapia and mouse models. Tilapia encodes AdipoR1 but lacks ADPN. Instead, an alternative adipokine, CTRP9, engages AdipoR1. We find CTRP9-AdipoR1 interaction triggers Ca2+ influx and activates the CaM-CaMKKβ-AMPK pathway, facilitating crosstalk with TCR signaling. This cascade enhances T-cell activation, proliferation, and antimicrobial immunity by promoting glycolysis. In mice, CTRP9 similarly enhances T-cell activation, proliferation, and cytokine production and improves the efficacy of anti-CD19 CAR-T cells in eliminating B-cell lymphoma in vitro. These findings reveal an evolutionarily conserved role of CTRP9 in promoting T-cell immunity, in contrast to the inhibitory effect exerted by ADPN. Mechanistically, CTRP9 and ADPN exert distinct effects on T-cell metabolism; CTRP9 enhances T-cell glycolysis, whereas ADPN suppresses it. We therefore propose ligand selectivity as a determinant of AdipoR1-dependent T-cell immune outcomes.
    Keywords:  AdipoR1; Adiponectin; CTRP9; Glycolysis; T Cell Immunity
    DOI:  https://doi.org/10.1038/s44319-025-00640-0
  13. J Exp Med. 2026 Feb 02. pii: e20250439. [Epub ahead of print]223(2):
    SLC7A8 is essential for metabolic fitness and function of Th2 cells.
    Santosh K Panda, Do-Hyun Kim, Pritesh Desai, Shitong Wu, Patrick Fernandes Rodrigues, Raki Sudan, Yizhou Liu, Haerin Jung, Intelly Lee, Susan Gilfillan, Marina Cella, Steven J Van Dyken, Marco Colonna.
      Amino acids are essential for the activation and function of CD4 T helper (Th) cells, which differentiate into Th1, Th2, Th17, and Treg subsets to coordinate immune responses. While specific amino acid transporters have been identified for Th1, Th17, and Tregs, a transporter regulating Th2 cells remains unknown. This study identifies SLC7A8 as a Th2-specific amino acid transporter in the Th compartment. We found that Slc7a8 expression is upregulated in Th2 cells compared with other T helper subsets, and Slc7a8 deficiency impairs Th2 cell proliferation and cytokine production. Furthermore, SLC7A8 was found to be crucial for an effective type 2 immune response to helminth infection and allergen-induced lung inflammation. Mechanistically, Slc7a8 deficiency disrupted Th2 cell metabolism, leading to reduced mTOR activation and, consequently, diminished mitochondrial function along with an impaired c-Myc pathway; these defects cumulatively induced cellular stress that curtailed cell growth and survival. Collectively, these findings highlight a previously unknown role for SLC7A8 in Th2 cells, with potential implications for understanding and treating type 2 immune-related diseases.
    DOI:  https://doi.org/10.1084/jem.20250439
  14. Metabolism. 2025 Nov 13. pii: S0026-0495(25)00307-5. [Epub ahead of print]175 156438
    Obesity rewires CD8+ T cell iron metabolism in adipose tissue to fuel metabolic inflammation.
    Jinfen Dai, Zixuan Zeng, Lishuan Wang, Wei Yuan, Karina Cunha E Rocha, Junho Park, Garam An, Ke Wang, Jisoo Song, Qian Xiang, Ying Duan, Chengjia Qian, Varsha Beldona, Whasun Lim, Enfu Hui, Michael Karin, Wei Ying.
      Sufficient nutrient supply is important for the maintenance of non-lymphoid tissue resident CD8+ T cell homeostasis, but the role of labile iron remains unclear. Here, we find adipose tissue CD8+ T cells exhibit elevated labile iron and mitochondrial Fe2+ compared to splenic counterparts, driving high ROS and IFNγ production. In obesity, an increase in Fe2+ influx into mitochondria enhances adipose tissue CD8+ cell functions, but weight loss normalizes CD8+ cell iron metabolism. Ncoa4 knockout reduces labile iron, blunting ROS and IFNγ production, while Fth1 knockout elevates Fe2+ and ROS, elevating IFNγ production. CD8+ cell-specific activation of NRF2 restores iron homeostasis by upregulating ferritin and promoting oxidative detoxification, suppressing adipose tissue CD8+ T cell accumulation and IFNγ production. Finally, NRF2 overexpression in CD8+ T cells attenuates obesity-related adipose tissue inflammation and metabolic disorders. These results highlight the crucial role of labile iron supply in adipose tissue CD8+ T cell homeostasis.
    Keywords:  Adipose tissue; CD8+ T cells; Insulin resistance; Iron metabolism; Obesity
    DOI:  https://doi.org/10.1016/j.metabol.2025.156438
  15. bioRxiv. 2025 Oct 04. pii: 2025.10.02.679826. [Epub ahead of print]
    Atg16l1 promotes lung transplant tolerance by regulating glycolysis in macrophages.
    Marlene Cano, Fuyi Liao, Dequan Zhou, Catherine Chen, Zhiyi Liu, Jihong Zhu, Cory Bernadt, Ricky Ebenezer, Victoria Davis, Katy N Pugh, Yan Tao, Laneshia K Tague, Howard J Huang, Derek E Byers, Ramsey R Hachem, Steven L Brody, Alexander S Krupnick, Daniel Kreisel, Andrew E Gelman.
      Lung transplant survival is limited by the development of chronic lung allograft dysfunction (CLAD), a type of graft rejection that lacks effective treatments. Autophagy plays a crucial role in maintaining cellular homeostasis. In a single-nucleotide polymorphism screen, we found that lung recipients with two copies of a common hypofunctional genetic variant of autophagy-related 16-like 1 rs2241880 ( ATG16L1 T300A/T300A ), known to deplete this protein from macrophages, were more likely to develop early CLAD. To understand this, we used a mouse orthotopic lung transplant model. Recipients encoding myeloid cell-specific deletion of Atg16l1 ( Atg16l1 Δ/Δ ) or who harbor an engineered orthologous mutation ( Atg16l1 T316A/T316A ) showed similar susceptibility to CLAD. Transcript profiling and mitochondrial tracking studies indicated that increased mitochondrial damage and decreased autophagic removal of mitochondria in Atg16l1-deficient macrophages were associated with heightened activation of the hypoxia-inducible factor 1α (Hif1α) pathway and accumulation of glycolytic transcripts. Metabolic analysis revealed reduced oxidative phosphorylation, increased glycolytic activity, and higher IL-1β expression in Atg16l1-deficient macrophages. Notably, the development of CLAD in Atg16l1 Δ/Δ lung recipients could be significantly prevented by additionally deleting Hif1α in myeloid cells or by treating with the glycolysis inhibitor 2-deoxyglucose. Our results show how a common autophagy-related genetic variant disrupts macrophage metabolism and impairs lung transplant tolerance, pointing toward potential therapeutic strategies to combat CLAD.
    DOI:  https://doi.org/10.1101/2025.10.02.679826
  16. Clin Rheumatol. 2025 Nov 20.
    High glucose-induced mitophagy accelerates premature aging of T cells in patients with rheumatoid arthritis.
    Jiaxin Lei, Yongao Wen, Lingyi Li, Huiyan Ji.
       OBJECTIVES: Premature T cell aging, marked by telomere shortening and cell cycle arrest, plays a key role in the pathogenesis of rheumatoid arthritis (RA). Growing evidence suggests that high glucose-induced metabolic dysfunction critically regulates both cellular aging and RA progression. This study explores how high glucose exacerbates T cell aging, providing novel insights into the mechanisms underlying RA development.
    METHODS: CD4+ T cells isolated from RA patients and healthy controls, along with HC-derived CD4+ T cells cultured in either low- or high-glucose conditions, were analyzed for aging markers including telomere length and cell cycle regulatory proteins to evaluate glucose-dependent effects. Cellular metabolism was characterized through: (1) glucose uptake (2-NBDG assay), (2) mitochondrial respiration (oxygen consumption rate analysis), and (3) mitophagy activity (DRP1/PINK1/parkin protein levels by immunoblotting). Mechanistic studies employed both pharmacological interventions (2-DG for glycolysis inhibition, succinyl phosphonate for OGDH inhibition, Mdivi-1 for DRP1 blockade) and genetic manipulation (DRP1 knockdown and overexpression) to delineate the roles of glucose metabolism and DRP1-mediated mitophagy in T cell aging.
    RESULTS: RA-derived CD4+ T cells exhibited increased glucose uptake and mitochondrial dysfunction. Enhanced mitophagy accelerated T-cell aging in RA. Mechanistically, high glucose promoted succinate accumulation, a key TCA cycle metabolite, leading to succinylation of Zinc Finger Protein 76 (ZNF76), a DRP1 transcription factor. This activated ZNF76, upregulating DRP1-mediated mitophagy and driving T-cell aging. Targeting glucose uptake and mitophagy may thus reverse T-cell dysfunction and ameliorate RA severity.
    CONCLUSION: Elevated mitophagy induced by high glucose represents a cell-autonomous mechanism driving premature T cell aging in RA, presenting a novel therapeutic avenue for disease management. Key Points • Dysregulated glucose metabolism is a key driver of T cell aging and RA pathogenesis. • High glucose exposure triggers metabolic reprogramming, leading to succinate accumulation. • Accumulated succinate induces ZNF76 succinylation and enhances DRP1-dependent mitophagy-a phenotype consistently observed in CD4+ T cells from RA patients. • DRP1-dependent mitophagy drives T cell aging in RA.
    Keywords:  CD4+ T cells; DRP1; Rheumatoid Arthritis; Succinylation
    DOI:  https://doi.org/10.1007/s10067-025-07815-z
  17. Metabolomics. 2025 Nov 15. 21(6): 173
    Mycobacterium tuberculosis curli pili (MTP) facilitates pathogenicity by modulating oxidative phosphorylation and carbon flux during early infection of A549 epithelial cells.
    Tarien J Naidoo, Shinese Ashokcoomar, Barry Truebody, Jared S Mackenzie, Bridgette M Cumming, Adrie J C Steyn, Manormoney Pillay.
       BACKGROUND: The Mycobacterium tuberculosis (Mtb) curli pili (MTP) adhesin has been reported as a significant target for TB diagnostic and intervention strategies. The precise contribution of MTP in modulating oxidative phosphorylation (OXPHOS) and central carbon metabolism (CCM) within host epithelial cells is currently unknown.
    OBJECTIVES: This study aimed to investigate the impact of MTP in whole cell bioenergetics during early stages of infection.
    METHODS: Extracellular flux analysis was used to determine the role of MTP in modulating OXPHOS in A549 epithelial cells. 13C-metabolic flux analysis was performed on Mtb mtp proficient/deficient infected A549 epithelial cells to determine whether any specific changes in carbon flux through CCM are induced by the adhesin.
    RESULTS: The absence of MTP led to an increase in OXPHOS in infected A549 cells, thereby increasing ATP synthesis. The Δmtp-infected A549 cells displayed a similar metabolic profile to the uninfected A549 cells. 13C-isotopomer metabolomic analysis of infected A549 cells suggested that MTP plays a role in decreasing glycolytic flux, enhancing flux through the pentose phosphate pathway (PPP), and modulating tricarboxylic acid (TCA) cycle intermediates by increasing flux through succinate.
    CONCLUSIONS: The decreased basal respiration and flux through glycolysis and PPP of Mtb-infected A549 cells potentially decreased innate immune responses and production of signalling molecules to interact with immunocytes and activate adaptive immune responses. The similar metabolic profile of Δmtp-infected A549 cells and uninfected A549 cells suggests that the absence of the adhesin decreases virulence of Mtb. These findings substantiate MTP as an eminent biomarker for TB diagnostics/intervention strategies, and a novel target for vaccine development.
    Keywords:   Mycobacterium tuberculosis ; A549 pulmonary epithelial cells; Bioenergetics; LC-MS/MS
    DOI:  https://doi.org/10.1007/s11306-025-02366-5
  18. Nat Metab. 2025 Nov 21.
    The metabolic engine of cognition: microglia-neuron interactions in health, ageing and disease.
    Evridiki Asimakidou, Stefano Pluchino, Bianca Ambrogina Silva, Luca Peruzzotti-Jametti.
      Cognitive impairment is associated with perturbations of fine-tuned neuroimmune interactions. At the molecular level, alterations in cellular metabolism can compromise brain function, driving structural damage and cognitive deficits. In this Review, we focus on the bidirectional interactions between microglia, the brain-resident immune cells and neurons to dissect the metabolic determinants of brain resilience and cognition. We first outline these metabolic pathways during development and adult life. Then, we delineate how these processes are perturbed in ageing, as well as in metabolic, neuroinflammatory and neurodegenerative disorders. By doing so, we provide a mechanistic understanding of the metabolic pathways relevant to cognitive function in health and disease, thus paving the way for novel therapeutic targets based on the emerging field of neuroimmunometabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01409-4
  19. J Neurochem. 2025 Nov;169(11): e70304
    Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.
    Emil W Westi, Rebecca Birch Carlsen, Jens Velde Andersen, Zeliha Kilic, Dana Alnajar, Nadia K Holmgaard, Belén García Sintes, Agustin Cota-Coronado, Sonia Sanz Muñoz, Céline Galvagnion, Blanca I Aldana.
      Microglia, the main resident immune cells of the brain, play critical roles in maintaining neuronal function and homeostasis. Microglia's metabolic flexibility enables rapid adaptation to environmental changes, yet the full extent of their metabolic capabilities and influence on neuronal metabolism remains unclear. While microglia predominantly rely on glucose oxidative metabolism under homeostatic conditions, they shift towards glycolysis upon proinflammatory activation. In this study, we investigated microglial metabolism and its impact on neuronal metabolic homeostasis using isotope tracing with stable carbon 13C-enriched substrates and gas chromatography-mass spectrometry (GC-MS) analysis. Primary microglia were incubated with 13C-labeled glucose, glutamine, or GABA in the presence or absence of lipopolysaccharide (LPS) to assess metabolic adaptations upon an inflammatory challenge. Additionally, neurons co-cultured with quiescent or activated microglia (either with LPS or amyloid-β) were incubated with 13C-enriched glucose to examine microglia-neuron metabolic interactions. Our findings confirm that microglia readily metabolize glucose and glutamine, with LPS stimulation slightly changing the glycolytic activity, as indicated by subtle changes in extracellular lactate. Importantly, we demonstrate for the first time that microglia take up and metabolize the inhibitory neurotransmitter GABA, suggesting a novel metabolic function. Furthermore, microglial presence directly influences neuronal metabolism and neurotransmitter homeostasis, highlighting a previously unrecognized aspect of neuron-microglia metabolic crosstalk. Collectively, these findings provide new insights into microglial metabolism and its role in neuronal function, with implications for neuroinflammatory and neurodegenerative diseases in which microglial metabolism is dysregulated.
    Keywords:  GABA metabolism; amyloid‐beta; glutamine; metabolic flexibility; neuroimmune interactions; neurons
    DOI:  https://doi.org/10.1111/jnc.70304
  20. Adv Sci (Weinh). 2025 Nov 16. e10224
    PLA2G16-Mediated Tetracosatetraenoic Acid Rewires Fatty Acid Oxidation to Impair CD8+ T Cell Immune Function in Promoting Breast Cancer Lung Metastasis.
    Yubi Gan, Die Meng, Lei Lang, Jing Luo, Peijin Dai, Chao Chang, Zexiu Lu, Yuetong Guo, Rui Wang, Shanchun Chen, Xi Tang, Yixuan Hou, Dongmei Tan, Manran Liu.
      Tumor-related metabolites in the tumor microenvironment may induce immune dysfunction, leading to malignant progression and metastasis of tumors. Here, it is demonstrated that tumoral PLA2G16, a phospholipase catalyzes phospholipids to generate free fatty acid (FFA) or lysophosphatidic acid (LPA), is an important contributor to triple-negative breast cancer (TNBC) lung metastasis in an immune-dependent pattern by improving tetracosatetraenoic acid (C24:4 (n-6)) accumulation in the early metastatic niche of lung and impairing immune function of pulmonary CD8+ T cells. C24:4 (n-6) induces nuclear import of PPARα in pneumal CD8+ T cells, which regulates the transcription of Cpt1a, Dgat1, Cd36, and Fabp1, leading to the activation of fatty acid oxidation (FAO). The robust FAO results in suppression of CD8+ T cells. Genetically depleting PPARα in mice, pharmacologically inhibiting C24:4 (n-6)-induced PPARα in the nucleus or directly suppressing PPARα activity effectively attenuates PLA2G16-C24:4 (n-6) axis-based immune dysfunction of CD8+ T cells and their according anti-tumor activities. These results imply that PLA2G16-mediated C24:4 (n-6) accumulation in the lung acts as a metabolic disorder to CD8+ T cell antitumor activity and highlights a critical role of PLA2G16 in promoting TNBC lung metastasis. Targeting PLA2G16 and combination with anti-PD-1-based immunotherapy may be an effective strategy for clinical tumor immunotherapy.
    Keywords:  PLA2G16; T cell; lipid metabolism; lung metastasis; tetracosatetraenoic acid
    DOI:  https://doi.org/10.1002/advs.202510224
  21. Cell Commun Signal. 2025 Nov 18. 23(1): 497
    tRF-His-GTG-1 promotes Salmonella survival through modulation of lipid metabolism and immune signaling.
    Yi-Ming Chen, Kuo-Tung Tang, Shih-Ting Huang, Hung-Jen Liu, Tsai-Ling Liao.
       BACKGROUND: Patients with systemic lupus erythematosus (SLE) are highly susceptible to severe infections, with non-typhoidal Salmonella (NTS) often progressing to life-threatening bacteremia. However, the mechanisms underlying this heightened vulnerability remain unclear. Lipid droplets (LDs), key immunometabolic hubs, have been implicated in facilitating Salmonella survival within phagocytes. We identified the tRNA-derived small RNA (tsRNA) tRF-His-GTG-1 as upregulated in SLE and correlated with disease activity. This study investigates the signaling and functional roles of tRF-His-GTG-1 in LD formation and Salmonella persistence in SLE.
    METHODS: LDs and tRF-His-GTG-1 expression were analyzed in peripheral blood mononuclear cells (PBMCs) from SLE patients with or without NTS bacteremia and from controls. Bacterial survival, tsRNA function, and signaling pathways were assessed using immunofluorescence, qRT-PCR, colony-forming unit assays, and pharmacological or genetic inhibition.
    RESULTS: LDs were elevated in SLE PBMCs and further increased by NTS infection, correlating with enhanced bacterial survival. SLE immune complexes (ICs) and IC-primed platelet-derived extracellular vesicles (pEVs) induced LD formation via FcγRIIA-mediated uptake and Toll-like receptor (TLR) 7/8 activation. Both SLE ICs and NTS infection upregulated tRF-His-GTG-1. Mechanistically, tRF-His-GTG-1 directly bound to TLR7/8, activating ERK/p38 signaling to induce PPARδ expression and LD biogenesis. Concurrently, tRF-His-GTG-1 promoted ERK/p38 phosphorylation and IL-10 production. Inhibition of tRF-His-GTG-1 suppressed both LD- and IL-10-dependent pathways, thereby reducing Salmonella survival.
    CONCLUSIONS: tRF-His-GTG-1 enhances Salmonella persistence through a TLR7/8-ERK/p38-PPARδ/IL-10 signaling axis. These findings identify a tsRNA-mediated immunometabolic mechanism linking SLE with bacterial susceptibility and highlight tRF-His-GTG-1 as a potential therapeutic target to improve antibacterial immunity in high-risk patients.
    Keywords:  IL-10 immune modulation; Lipid droplets; Non-typhoidal Salmonella bacteremia; Systemic lupus erythematosus; TRF-His-GTG-1
    DOI:  https://doi.org/10.1186/s12964-025-02490-8
  22. Sci Rep. 2025 Nov 20. 15(1): 40929
    Mapping real-time metabolic kinetics of expanded CAR T cells using hyperpolarized 13C-glucose and metabolomics.
    Thomas B Wareham Mathiassen, Mikkel Rasmus Hansen, Magnus Karlsson, Sine Reker Hadrup, Maria Ormhøj, Pernille Rose Jensen.
      Chimeric Antigen Receptor (CAR) T cell therapy has advanced cancer treatment, providing options for patients with refractory hematological malignancies. Understanding the metabolic changes in CAR T cells during their activation, proliferation, and therapeutic application is essential for improving efficacy. In this study, human CD19 CAR T cells were expanded from three healthy donors under a standard manufacturing protocol. Hyperpolarized 13C dDNP-NMR spectroscopy was used to measure glycolytic flux at key time points (days 1, 7, 14, and 21), and 1H NMR metabolomics was employed to monitor nutrient depletion in the culture medium. The results showed that CAR T cells underwent a metabolic transition from oxidative phosphorylation to aerobic glycolysis by day 7, followed by a return to oxidative phosphorylation by day 21. Glucose depletion was most pronounced during the first week, whereas amino acids were substantially consumed, with a decline in consumption observed after day 12. Real-time NMR spectroscopy revealed large metabolic flux changes that metabolomics did not capture. This study demonstrates the dynamic metabolic plasticity of CAR T cells and highlights the utility of hyperpolarized 13C-NMR for tracking glycolytic activity. Addressing metabolic bottlenecks, such as nutrient depletion during early expansion, may improve CAR T cell manufacturing and therapeutic outcomes.
    Keywords:  CAR T cells; Immunotherapy; Metabolism; NMR spectroscopy; dDNP-NMR
    DOI:  https://doi.org/10.1038/s41598-025-24712-2
  23. J Transl Med. 2025 Nov 19. 23(1): 1321
    Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.
    Cristina Algieri, Salvatore Nesci, Francesca Oppedisano.
      Mitochondria, in addition to their classic role in energy production, have emerged as central hubs in the regulation of innate immunity. Under conditions of cellular stress, mitochondrial dysfunction triggers the release of mitochondrial DNA (mtDNA) into the cytosol or extracellular space, activating potent inflammatory pathways such as cGAS-STING, NLRP3 and TLR9. mtDNA release, driven by factors such as oxidative damage, membrane permeabilization, and various cell death pathways, is involved in immune surveillance and the pathogenesis of various diseases. At the same time, this downstream event leads to profound reorganization of immune cell metabolism, influencing functional polarization and inflammatory outcomes. This review presents the mitochondrion as an interface between metabolism, immunity, immunometabolites, and danger signalling. We explore the molecular mechanisms of mtDNA release, its conversion into immune signals, and its impact on metabolism in immune cells. Translational implications for pathologies such as neurodegenerative, autoimmune, and neoplastic diseases are also discussed. Deciphering the interconnection between mitochondrial stress, mtDNA release, and immunometabolic rewiring could open new avenues for the treatment of complex diseases and drive innovation in immunotherapy and regenerative medicine.
    Keywords:  Complex diseases; Immunity; Inflammation; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1186/s12967-025-07392-4
  24. Int J Biol Macromol. 2025 Nov 17. pii: S0141-8130(25)09578-9. [Epub ahead of print]334(Pt 1): 149021
    Lipocalin 2 deficiency attenuates NLRP3 inflammasome activation through glycolysis impairment and MGST1-mediated mitochondrial ROS reduction.
    Shouchuan Jiang, Yecheng Xu, Xin Wen, Yuhui Zhang, Jianjun Chen, Yu Han, Yi Zheng, Xi Qiao, Yunqin Li, Hong Yu, Huahua Du.
      Lipocalin 2 (Lcn2), a multifunctional innate immune protein, plays a critical role in many biological processes, especially in mediating inflammation. However, its role in the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome remains elusive. In this study, we generated whole-body Lcn2-knockout mice and demonstrated that Lcn2 deficiency reduced the secretion of interleukin (IL)-1β and IL-18 in murine models of sepsis, gouty arthritis and colitis. Using Lcn2-deficient bone marrow-derived macrophages (BMDMs), we showed that Lcn2 deficiency mostly inhibited the inflammatory response by modifying transcriptional priming and posttranslational activation of NLRP3 inflammasome. At the transcriptional level, Lcn2-deficient BMDMs exhibited reduced priming of the NLRP3 inflammasome, as provided by decreased activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), alongside diminished transcription of NLRP3 and IL-1β. At the posttranslational level, Lcn2 deficiency attenuated NLRP3 inflammasome activation by reducing glycolytic activity and mitochondrial reactive oxygen species (mt-ROS) production. Furthermore, upregulation of microsomal glutathione S-transferase 1 (MGST1) in Lcn2-deficient BMDMs mitigated NLRP3 inflammasome activation by suppressing mt-ROS accumulation. Collectively, these findings uncover Lcn2 as an important mediator of inflammatory responses and it could be a prospective target for treating NLRP3-associated inflammatory disorders.
    Keywords:  Glycolysis; Lipocalin 2; MGST1; Mitochondrial ROS; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149021
  25. Biochem Biophys Res Commun. 2025 Nov 19. pii: S0006-291X(25)01721-8. [Epub ahead of print]793 153005
    Fibulin7 C-terminal bioactive peptide regulates metabolic profiling of macrophages during inflammation via integrin α5β1.
    Saloni Gupta, Shubham Kumar Rai, Rama N Behera, Saikat Roy, Kiran Ambatipudi, Pranita P Sarangi.
      Inflammation can trigger metabolic changes in monocytes and macrophages. Previous studies have shown that a C-terminal fragment of the adhesion protein Fibulin7 (Fbln7-C) and its bioactive peptide (FC-10) can regulate their migration and inflammatory functions of monocytes and macrophages via integrin α5β1, which is associated with the modulation of metabolic pathways in pathological conditions. This study investigates the possible correlation between FC-10-integrin α5β1-mediated cellular and immuno-metabolic programming in macrophages under inflammation. Our results show that FC-10 promoted the anti-inflammatory state in THP-1 and blood monocyte-derived macrophages stimulated with Lipopolysaccharide (LPS), with higher expression of M2 markers (e.g., CD206, IL-10). Further, liquid chromatography coupled tandem mass spectrometry LC-MS/MS based proteomics, metabolomics, and gene expression studies showed a reduced expression of inflammatory, differentiation, and glycolytic proteins (hexokinase and pyruvate kinase). Conversely, expression of the TCA cycle (citrate synthase) and glutamine metabolism proteins (Glutamate Dehydrogenase (GDH1) and SLC1A5) were elevated in the presence of FC-10, depicting an anti-inflammatory phenotype, compared to the control peptide. Furthermore, blocking integrin α5β1 increased the expression of glycolytic proteins (hexokinase) and decreased the glutamine-metabolism-associated proteins (GDH1). In conclusion, our data suggest that FC-10 can regulate metabolic processes in monocytes and macrophages during inflammation and has potential for anti-inflammatory therapeutics.
    Keywords:  FC-10; Inflammation; Integrins; Macrophages; Metabolism
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153005
  26. Biochem Pharmacol. 2025 Nov 16. pii: S0006-2952(25)00806-8. [Epub ahead of print] 117541
    The role of metabolic reprogramming in inflammatory bone diseases.
    Yu-Han Wang, Lu Zhou, Lu Zhang.
      Inflammatory bone diseases are characterized by bone destruction, resulting from an imbalance between bone resorption and formation due to chronic inflammation. The dynamic equilibrium among osteoblasts, osteoclasts, and various immune cells is crucial for disease progression. Metabolic reprogramming is a key factor involved in regulating the differentiation and function of these cells, and recent research has increasingly revealed its role in inflammatory bone diseases. This review focuses on the complex roles of glucose, lipid, and amino acid metabolic reprogramming in cellular processes, contributing to a deep understanding of the pathogenesis of inflammatory bone diseases. More importantly, targeting metabolic pathways to regulate the balance among osteoblasts, osteoclasts, and immune cells represents a promising therapeutic strategy for inflammatory bone diseases. Many preclinical studies have explored small-molecule compounds and nanoparticle-based drug-delivery systems targeting metabolism to restore bone homeostasis, suppress inflammation and bone destruction, and even promote tissue regeneration. However, the potential for clinical translation requires further validation in large animal models and human trials. This review highlights the critical role of metabolic reprogramming in inflammatory bone diseases and underscores the therapeutic potential of metabolism-based interventions.
    Keywords:  Amino acid metabolism; Glucose metabolism; Inflammatory bone diseases; Lipid metabolism
    DOI:  https://doi.org/10.1016/j.bcp.2025.117541
  27. Mol Neurobiol. 2025 Nov 21. 63(1): 118
    High Extracellular Glucose Concentration Drives Palmitate-Induced Toxicity and Metabolic Dysfunction in BV2 Microglia Cells.
    Wembley Rodrigues Vilela, Nicolle Platt, Luiz Roberto Grassmann Bechara, Gabriela Cristina de Paula, Julio Cesar Batista Ferreira, Jade de Oliveira, João M N Duarte, Andreza F de Bem.
      Microglia exhibit targeted responses to different stimuli, including lipids, which can differ depending on the environmental conditions they encounter. These responses involve inflammatory mediators and are crucial for maintaining brain homeostasis. This study investigated whether inflammatory, metabolic, and phagocytic responses of microglia to the saturated fatty acid palmitate depend on extracellular glucose concentrations. BV2 microglial cells were cultured in low glucose (LG; 5.5 mmol/L) or high glucose (HG; 25 mmol/L) concentrations, and then exposed to palmitate (100 or 200 µmol/L) or vehicle for 24 h. Under HG, palmitate decreased cell viability, which was accompanied by an increase in inflammatory markers, which are associated with an activated state. Additionally, palmitate induced higher expression of genes related to lipid metabolism in both LG and HG, without affecting enzymes linked to glucose metabolism. HG condition led to an increase in the oxygen consumption rate (OCR) and glycolytic flux (i.e., extracellular medium acidification) compared to LG-cultured cells, with palmitate reducing OCR and glycolytic flux in both conditions. The short-chain fatty acid butyrate did not prevent palmitate-induced mitochondrial dysfunction in BV2 cells. In primary microglia, palmitate did not affect mitochondria density and cargo metabolism. Altogether, our results indicate that BV2 cells are prone to palmitate-induced stress on viability assays under HG but not LG in the medium.
    Keywords:  Glucolipotoxicity; Microglia; Mitochondria; Palmitate; Phagocytosis
    DOI:  https://doi.org/10.1007/s12035-025-05455-7
  28. NPJ Microgravity. 2025 Nov 21. 11(1): 83
    Mechanism of LEPR-mediated cholesterol metabolism involved in NK cell function suppression under simulated microgravity.
    Hongfang Lv, Huan Yang, Xiaojia Guo, Jing Li, Yuanyuan Xie, Chunmei Jiang, Junling Shi, Qingsheng Huang, Dongyan Shao.
      Natural killer (NK) cells play an important role in antitumor and viral resistance. However, the mechanism of impaired NK cell function in microgravity remains unclear. Cholesterol metabolism, a new research hotspot, plays a critical role in NK cells function. This study found that simulated microgravity downregulate NK cell membrane cholesterol levels by disrupting cholesterol biosynthesis and transport to the membrane, leading to the obstruction of activated immune synapse formation, which inhibit the release of NK cell cytotoxic particles and ultimately decreasing NK cell immune function. Most importantly, this study identified a new target for regulating NK cell function, LEPR (leptin receptor). LEPR affected NK cell membrane cholesterol levels by influencing the CAMKK-SREBP1-HMGCR cholesterol endogenous synthesis pathway and regulating the expression of NPC1 and NPC2 genes, which ultimately influencing NK cell cytotoxic function. The study is significant for understanding the mechanism of NK cell activity in microgravity and offers new targets for clinical immunotherapy of NK cells.
    DOI:  https://doi.org/10.1038/s41526-025-00473-0
  29. Sci Rep. 2025 Nov 21.
    Sucrose supplementation mitigates heat stress-induced alterations in rumen metabolism and immunity in dairy cows.
    Byeongcheol Ban, Sejin Ki, Seonho Kim, Jihoo Park, Sangbum Kim, Mooyoung Jung, Joonpyo Oh, Sangsuk Lee, Myunghoo Kim.
      Rapid global warming is affecting the metabolic and immune responses of dairy cows, making heat stress a major challenge in the industry. This study aimed to develop nutritional strategies to mitigate these effects. Sucrose has been identified as a carbohydrate that not only provides immediate energy to the rumen. Specifically, we investigated whether sucrose supplementation could alleviate heat stress-induced changes in rumen metabolism and blood immune parameters. A total of 12 Holstein cows were used in this study. All cows were initially maintained under the optimal temperature period (OTP, n = 12). They were then assigned to either the high-temperature period control group (HTP-CON, n = 6) or the high-temperature period treatment group (HTP-TRT, n = 6). The feeding trial lasted for four weeks. Heat stress reduced milk yield by 22.36%, and sucrose supplementation tended to attenuate this reduction to 10.75%; heat stress decreased milk yield, whereas sucrose supplementation has minor mitigating effect on milk yield reduction. Furthermore, heat stress altered rumen metabolites, leading to metabolic imbalances, particularly in amino acid and fatty acid metabolism. Sucrose supplementation improved amino acid metabolic pathways, including phenylalanine and glutamate metabolism, which are essential for immune and metabolic homeostasis. Key metabolites such as aspartic acid, tyrosine, and isobutyrate were restored. Additionally, heat stress induced an inflammatory response, increasing the proportion of Th1 cells and upregulating IL-1β and IL-2 expression in PBMCs. Sucrose supplementation alleviated inflammation by reducing pro-inflammatory cytokine expression and normalizing the Th1 cell proportion. In conclusion, sucrose supplementation improved the resilience of dairy cows by alleviating metabolic imbalances and inflammatory responses caused by heat stress. These findings enhance our understanding of the relationship between immunity and metabolism under environmental stress and support the development of improved dairy management strategies.
    Keywords:  Feed additive; Heat stress; Holstein; Immune; Metabolite
    DOI:  https://doi.org/10.1038/s41598-025-21840-7
  30. Phytomedicine. 2025 Nov 09. pii: S0944-7113(25)01171-7. [Epub ahead of print]149 157535
    Polyphenols-mediated immune regulation: Metabolite-driven epigenetic regulatory mechanisms.
    Boya Ouyang, Quanyong Wu, Jingyimei Liang, Hui Cao, Jianbo Xiao.
       BACKGROUND: Dietary polyphenols are recognized modulators of immune function. Although metabolic and epigenetic effects have been examined separately, relationships and implications for immune regulation remain unclear. Addressing the gap is critical to understanding how diet shapes immune homeostasis and disease risk. Previous studies examined metabolic and epigenetic effects separately, leaving their interconnections-and implications for immune regulation-unclear.
    PURPOSE: This review aims to elucidate, from a novel perspective, the polyphenols-metabolic-epigenetic modification-immunity regulatory axis that underlies polyphenols-mediated immunoregulation. By emphasizing this framework, we highlight mechanistic insights into the interplay among diet, metabolism, and immune homeostasis, providing potential strategies for preventing and treating chronic inflammatory and metabolic diseases.
    METHODS: A comprehensive search of peer-reviewed publications was performed from core collections of electronic databases such as PubMed, Web of Science, Google Scholar, and Science Direct.
    RESULTS: Polyphenols regulate immunity by reprogramming metabolic pathways and modulating epigenetic mechanisms. Metabolite-driven crosstalk between metabolism and epigenetics offers insights into immune phenotype stability, particularly across generations. These mechanisms are relevant to clinical phenotypes highlighted in the manuscript, including obesity, features of metabolic syndrome, and autoimmune conditions. Challenges remain in translation, including bioavailability, dose-response variability, and limited evidence on transgenerational effects. Future studies should explore how polyphenols-mediated metabolic shifts affect epigenetic regulators during early development and immune inheritance. Integrating polyphenols into immunometabolism and epigenetic regulation offers novel strategies for disease prevention and precision nutrition.
    CONCLUSION: This review provides a new perspective on polyphenols-mediated immune regulation, offering a theoretical basis for understanding how small molecules influence immunity through metabolism and epigenetics. This framework, rarely highlighted in current studies, may also guide future research in epigenetics.
    Keywords:  Epigenesis; Immunity; Metabolic networks and pathways; Phenolic compounds
    DOI:  https://doi.org/10.1016/j.phymed.2025.157535
  31. bioRxiv. 2025 Oct 03. pii: 2025.10.01.679850. [Epub ahead of print]
    Ethanol consumption mediates parasitoid resistance via effects on host metabolism.
    Carrie L Marean-Reardon, Patrick N Reardon, Nathan T Mortimer.
      Many insect species use self-medication, the consumption of an environmental compound with antipathogen activity, as a defense against pathogen infection. One well-studied example is the interaction between Drosophila melanogaster and parasitoid wasps, in which D. melanogaster larvae consume ethanol-laden food to kill the developing parasitoid. Despite research into self-medication as a behavioral immune response to parasitoid infection, the parasitoid-killing mechanism remains elusive. To test the impact of ethanol consumption and infection on host metabolism, we used untargeted Nuclear Magnetic Resonance (NMR) metabolomics of hemolymph samples isolated from naïve and parasitoid infected larvae fed ethanol-containing or control food. Surprisingly, we found that the consumption of dietary ethanol did not result in an elevated hemolymph ethanol abundance. Instead, we found evidence that host carbohydrate-derived energy production and amino acid metabolism were altered by ethanol consumption. Our results suggest that these ethanol-mediated changes in host metabolism, rather than a direct effect of dietary ethanol, confers parasitoid resistance.
    Keywords:  Drosophila melanogaster; insect immunity; metabolomics; parasitoid wasp; self-medication
    DOI:  https://doi.org/10.1101/2025.10.01.679850
  32. mSystems. 2025 Nov 18. e0069225
    Sodium butyrate inhibits colorectal cancer development by reducing M2 macrophage polarization and PD-L1 expression.
    Bing Han, Qiong Chai, Qian Chen, Min Liu, Ting Wang, Yu-Li Zhang, Zan Li, Zhen Chen, Bo-Wang Li, Xian Li, Hua Sui, Qingfeng Tang.
      Short-chain fatty acids (SCFAs), produced by gut bacteria, are being recognized as an important form of anticancer therapy; however, their antitumor potency and underlying mechanisms remain unclear. Here, we used single-cell transcriptomics to identify the mechanism by which the SCFA sodium butyrate (NaB) inhibited the development of colorectal cancer (CRC) and explored new strategies for combining NaB with existing immunotherapies against CRC. An azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model of colitis and a macrophage-deficient subcutaneous tumor model were used to determine NaB effects on CRC. RNA-sequencing profiled CRC immune landscape changes following NaB treatment. The potential synergy between NaB and programmed death receptor ligand 1 (PD-L1) blockade was explored in macrophage and CRC coculture systems. We showed that NaB markedly reduced inflammation, especially M2 macrophage polarization, tumor burden, histopathological damage, and disease activity index in AOM/DSS mice, and diminished PD-L1+ tumor-associated macrophage (TAM) infiltration in CRC tissues. These effects depended on macrophage presence and HDAC/TLR4/MyD88 signaling. The synergy with PD-L1 blockade underscores the need for clinical evaluation of this combination therapy.IMPORTANCECRC remains a leading cause of cancer death worldwide, and new therapeutic approaches are urgently needed. Our study reveals that NaB, a natural gut-derived metabolite, can reshape the tumor immune environment by limiting pro-tumor M2 macrophages and reducing PD-L1+ macrophage infiltration. By combining single-cell transcriptomics with mouse models, we pinpoint how butyrate acts through the HDAC/TLR4/MyD88 pathway and demonstrate its synergy with PD-L1 blockade. These findings highlight butyrate's potential as an accessible, low-toxicity agent to boost existing immunotherapies and offer a clear rationale for clinical trials exploring butyrate-immune checkpoint inhibitor combinations in CRC.
    Keywords:  NaB; PD-L1; TLR/MyD88 signaling; colorectal cancer; sodium butyrate; tumor-associated macrophages
    DOI:  https://doi.org/10.1128/msystems.00692-25
  33. bioRxiv. 2025 Oct 05. pii: 2025.10.03.680201. [Epub ahead of print]
    Methionine regulates antitumor function of CD8 + T cells through polyamine synthesis.
    Tian Zhao, Gillian A Carleton, Sarah Macpherson, Madison Shiyuk, Joseph Monaghan, Jun Han, Oro Uchenunu, Robert Rottapel, Ralph J DeBerardinis, Kelly M Stewart, Bo-Hyun Kim, Juan Ausió, David R Goodlett, Helena Pětrošová, Kyle D Duncan, Julian J Lum.
      Methionine is an essential amino acid critical for T cell activation. While methionine restriction (MR) combined with immune checkpoint blockade has been shown to enhance T cell function, the impact of methionine on adoptive T cell therapies is largely unexplored. Here, we examined the functionality of T cells under MR and pharmaceutical inhibition of the methionine cycle (MAT2Ai), using primary T cells and a murine adoptive T cell therapy model. In vitro , transient MR or MAT2Ai treatment increased interferon gamma (IFNγ) expression in CD8 + T cells, whereas sustained MR led to the upregulation of T cell exhaustion-associated markers. Mechanistically, transient MR suppressed the polyamine synthesis pathway, and supplementation with polyamines reversed MR-induced IFNγ expression. Genetic ablation of s-adenosylmethionine decarboxylase, an enzyme in the polyamine synthesis pathway, recapitulated the effect of MR, indicating that transient MR enhances T cell function by inhibiting polyamine synthesis. Despite this, transient MR treatment of ovalbumin (OVA)-specific (OT-I) CD8 + T cells prior to adoptive transfer did not improve antitumor efficacy against EG7-OVA tumors in vivo . In contrast, sustained dietary MR accelerated EG7-OVA tumor growth in mice treated with OT-I T cells, demonstrating that methionine availability is essential for the activity of adoptively transferred T cells. These findings suggest that enhancing methionine availability in the tumor microenvironment may improve the efficacy of adoptive T cell therapies.
    DOI:  https://doi.org/10.1101/2025.10.03.680201
  34. Brain Behav Immun Health. 2025 Nov;49 101094
    Induction of endogenous IL-10 promotes resolution and tolerance of nitric oxide in microglia.
    Hsing-Chun Kuo, Jia-Shing Chen, Chun-Nun Chao, Kam-Fai Lee, Yi-Te Huang, Pin-Cheng Mao, Tzu-Chia Lin, Shu-Chen Chiu, Ya-Ling Huang, Chun-Hsien Chu.
      Endogenous interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is induced in a timely and coordinated manner to dampen microglia-mediated brain inflammation. However, it remains unclear how it alters the inflammatory process to shape the immune polarization of microglia. This study aimed to investigate the anti-inflammatory mechanisms of endogenous IL-10 in activated and tolerized microglia using in vitro multiple-reconstituted primary brain cell cultures and an in vivo IL-10 knockout (IL-10KO) animal model. Upon a single or repeated lipopolysaccharide (LPS) treatment regimen, the expression levels of the inflammatory factors during the neuroinflammatory/tolerance process were measured by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and Griess reagent assay. ELISA data showed that cell-autonomous induction of endogenous IL-10 occurs in LPS-activated and LPS-tolerized microglia. Furthermore, comparing the LPS-elicited pro-inflammatory factor expressions at different neuroinflammatory stages between the wild-type and IL-10KO groups, our data revealed the failure of negative-feedback suppression of inducible nitric oxide synthesis (iNOS) during immune resolution in the IL-10KO brains. Moreover, LPS-treated IL-10KO microglia increase the supernatant level of nitrite and become overactive during late-stage inflammation, despite no changes in cell number; in contrast, LPS-tolerized IL-10KO microglia fail to program endotoxin tolerance of nitric oxide/inducible nitric oxide synthesis (iNOS). In summary, our data demonstrate that the cell-autonomous induction of endogenous IL-10 in microglia is crucial for mitigating brain immune responses, particularly in the resolution and tolerance of nitric oxide.
    Keywords:  Endotoxin tolerance; IL-10; Immune resolution; Microglia; Neuroinflammation; Nitric oxide
    DOI:  https://doi.org/10.1016/j.bbih.2025.101094
  35. PLoS Pathog. 2025 Nov 21. 21(11): e1013676
    Reprogramming of lipid metabolism by ORF3a-induced microlipophagy enhances biogenesis of SARS-CoV-2 replication organelle.
    Zhifei Li, Xianfeng Hui, Miaomiao Zheng, Zhicheng He, Wenjing Huai, Binbin Ding, Meilin Jin, Yali Qin, Mingzhou Chen.
      Infection by positive-strand RNA viruses necessitates membrane expansion and elevated phospholipid biosynthesis, whereby fatty acids stored as triacylglycerols in lipid droplets (LDs) are mobilized to promote metabolic processes and membrane biogenesis. The replication organelles (ROs) of coronavirus associate with modified host endomembrane; however, the molecular mechanisms underlying the expansion and modification of these membranes remain poorly understood. Here, we show that viral protein orf3a collaborates with nsp3, nsp4, nsp6 to facilitate the formation of ROs in SARS-CoV-2. Importantly, orf3a targets LDs to ROs, establishing novel membrane contact sites and induces host cell microlipophagy, which supplies essential lipids for RO biogenesis. Subsequently, Following the formation of ROs, nsp3, with assistance from nsp12, indirectly recruits phosphatidylinositol 4-kinase beta (PI4KB) to ROs, to produce phosphatidylinositol 4-phosphate (PI4P). This action creates a PI4P-enriched microenvironment that enhances SARS-CoV-2 replication. Our findings elucidate the mechanism governing RO generation during SARS-CoV-2 infection and suggest that targeting microlipophagy pharmacologically may represent a promising strategy for the development of anti-coronaviruses therapies.
    DOI:  https://doi.org/10.1371/journal.ppat.1013676
  36. Mol Metab. 2025 Nov 14. pii: S2212-8778(25)00189-9. [Epub ahead of print] 102282
    NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice.
    Jennyfer Bultinck, Shendong Yuan, Ludovico Cantuti-Castelvetri, Lander Brosens, Debby Bracke, James Collins, Jens Goethals, Christina Christianson, John Nuss, Kathleen Ogilvie.
      The NLRP3 inflammasome is a key innate immune sensor that orchestrates inflammatory responses to diverse stress signals, including metabolic danger cues. Dysregulated NLRP3 activation has been implicated in chronic diseases such as type 2 diabetes, atherosclerosis, and neurodegeneration, underscoring the broad pathophysiological role of the NLRP3 pathway. In the context of obesity and its associated conditions, NLRP3 inhibition by VTX3232, an oral, selective, and brain-penetrant NLRP3 inhibitor, potently suppressed the release of proinflammatory cytokines (IL-1β, IL-18, IL-1α, IL-6, and TNF) from macrophages and microglia stimulated with metabolic stressors including palmitic acid and cholesterol crystals. Moreover, NLRP3 inhibition by VTX3232 also blocked NLRP3-driven insulin resistance in primary human hepatocytes and adipocytes while normalizing the acute phase response and FGF-21 secretion in hepatocytes under palmitic acid-induced inflammation. In vivo, NLRP3 inhibition by VTX3232 reduced systemic and tissue-specific inflammation in a mouse model of diet-induced obesity, reflected by decreased circulating inflammatory mediators, reduced hepatic inflammation, fewer crown-like structures in adipose tissue, and diminished hypothalamic gliosis. These anti-inflammatory effects were accompanied by improvements in body weight, food intake, and obesity-associated comorbidities such as hyperglycemia, hepatic steatosis, and markers of cardiovascular and renal disease. Notably, these effects were confined to the context of obesity, as no impact was observed in lean mice. When combined with glucagon-like peptide-1 receptor agonism by semaglutide, NLRP3 inhibition by VTX3232 yielded additive metabolic benefits, highlighting complementary mechanisms of action. Together, these findings reinforce the biological rationale for targeting NLRP3 in inflammatory conditions such as obesity, expand on the role of NLRP3 in metabolic inflammation, and underscore the importance of continued investigation into the NLRP3 pathway as a central node in cardiometabolic disease.
    Keywords:  Drug Therapy; Inflammation; Insulin Resistance; Metabolism; Obesity; Steatosis
    DOI:  https://doi.org/10.1016/j.molmet.2025.102282
  37. Nat Commun. 2025 Nov 20.
    Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids.
    Robert M Gray, Debbie M Hunt, Mariana Silva Dos Santos, Jiuyu Liu, Aleksandra Agapova, Angela Rodgers, Antony Fearns, Julio Ortiz Canseco, Acely Garza-Garcia, James I MacRae, Maximiliano G Gutierrez, Richard E Lee, Luiz Pedro S de Carvalho.
      Tuberculosis (TB) is the biggest cause of death from infectious disease worldwide. The causative agent, Mycobacterium tuberculosis (Mtb), possesses a complex cell envelope comprised of multiple classes of unique lipids. The macrophage phagosome is a key reservoir of infection in pulmonary TB and multiple studies have shown that inorganic phosphate (Pi) is limiting in this environment. Here, we show that during Pi restriction the Mtb lipidome markedly remodels such that phospholipids are replaced with multiple classes of phosphorus-free lipids. This envelope lipidome remodelling suggests that standard Mtb culture conditions that use media with high concentrations of Pi do not reflect the physiologic environment during infection, thereby undermining vaccine and drug development for tuberculosis. Further, we discover that Mtb can metabolise phospholipid polar heads abundant in host pulmonary surfactant as an alternative phosphate source. Therefore, we present two mechanisms where Mtb manipulates lipid metabolism to overcome host restriction.
    DOI:  https://doi.org/10.1038/s41467-025-66437-w
  38. EMBO Rep. 2025 Nov 19.
    Purinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic brown adipose tissue.
    Michelle Y Jaeckstein, Alexander W Fischer, Björn Rissiek, Tobias Staehler, Markus Heine, Janina Behrens, Oliver Mann, Alexander Pfeifer, Tim Magnus, Christian Schlein, Anna Worthmann, Ludger Scheja, Friedrich Koch-Nolte, Joerg Heeren.
      Loss of brown adipose tissue (BAT) activity observed during ageing, obesity and living at thermoneutrality is associated with lipid accumulation, fibrosis and tissue inflammation in BAT. The mechanisms that promote this degenerative process of BAT remain largely enigmatic. Here, we show that an imbalance between sympathetic activation and mitochondrial energy handling causes BAT degeneration, which leads to impaired energy expenditure and systemic metabolic disturbances. Mechanistically, we demonstrate that brown adipocytes secrete ATP in response to imbalanced thermogenic activation, which activates P2X4 and P2X7 of BAT-resident macrophages. Notably, mice lacking activity of these purinergic receptors in myeloid cells are protected against BAT inflammation, thermogenic dysfunction and systemic metabolic disturbances under conditions of imbalanced BAT activation, thermoneutrality or overnutrition. These results highlight the relevance of extracellular ATP released by brown adipocytes as a paracrine signal for myeloid cells to initiate BAT degeneration.
    Keywords:  Adaptive Thermogenesis; Dyslipidemia; Hyperglycemia; Inflammation; P2X Receptors
    DOI:  https://doi.org/10.1038/s44319-025-00642-y
  39. J Infect. 2025 Nov 15. pii: S0163-4453(25)00260-9. [Epub ahead of print] 106660
    Monocyte Iron Load Correlates with Immune Suppression and Sepsis Severity: A Longitudinal Analysis.
    Christina Mertens, Diana Reuter, Anand Ruban Agarvas, Judith Schenz, Bastian Winkelhausen, Anna Hafner, Christoph Kahlert, Maximilian Dietrich, Mascha O Fiedler-Kalenka, Markus A Weigand, Martina U Muckenthaler, Dania Fischer.
       BACKGROUND: Sepsis is a life-threatening condition caused by a dysregulated immune response to infection. In critically ill patients, iron biomarkers are closely linked to outcomes; yet the mechanistic role of iron metabolism in sepsis progression remains unclear.
    METHOD: To address this knowledge gap, we conducted a longitudinal clinical study in 20 sepsis patients, tracking plasma iron biomarkers together with monocyte function and iron content over five consecutive days following sepsis onset. Some patients required red blood cell transfusions during the study period.
    RESULTS: We show that anemia of inflammation is an early and prominent feature of sepsis hallmarked by iron sequestration in blood monocytes, reduced plasma iron levels and anemia. Importantly, increased iron levels in monocytes are detected already at day one following the sepsis diagnosis and the degree of iron accumulation directly correlates with sepsis severity. High monocytic iron levels further correlate with decreased human leukocyte antigen DR (HLA-DR) expression on day one, suggestive of monocyte immunosuppression. Furthermore, in iron-loaded septic monocytes mRNA levels of the non-transferrin bound iron (NTBI) transporter ZRT/IRT-like Protein 8 were significantly increased, suggesting enhanced uptake of non-transferrin bound iron that may arise from hemolysis. Interestingly, we also show that the total iron binding capacity is an important predictor of sepsis mortality, while transfusions did not correlate with an altered iron and/or inflammatory status.
    CONCLUSIONS: The study highlights that early iron accumulation in monocytes is a hallmark of sepsis and is closely linked to disease severity and progression. We expect that improved insights into iron metabolism in sepsis patients may pave the way to improving therapeutic options that balance iron levels and their effects on organ functions in the future.
    Keywords:  Anemia; Iron; Monocytes; Nutritional Immunity; Sepsis
    DOI:  https://doi.org/10.1016/j.jinf.2025.106660
  40. Front Med (Lausanne). 2025 ;12 1685044
    Gut-lung immunometabolic crosstalk in sepsis: from microbiota to respiratory failure.
    Qixiu Li, Xi-Cheng Song, Kefeng Li, Jing Wang.
      Sepsis is a systemic immune-metabolic disorder syndrome caused by infection, in which gut microbiota dysbiosis plays a central role in the occurrence and development of multi-organ dysfunction. This paper systematically elaborates on the bidirectional regulatory mechanism of the "gut-lung axis" in sepsis. Gut microbiota dysregulation damages the gut barrier function, reduces the production of short-chain fatty acids (SCFAs), and increases endotoxin translocation. Subsequently, it activates alveolar macrophage polarization, promotes the formation of neutrophil extracellular traps (NETs), and leads to an imbalance in the Treg/Th17 cell ratio, ultimately exacerbating the pathological process of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Conversely, the pulmonary inflammatory response can also aggravate gut barrier damage through circulating inflammatory mediators, forming a vicious cycle. Mechanistically, HIF-1α, mTOR, and Sirtuins do not act in isolation. Instead, they jointly regulate the metabolic fate of immune cells through spatiotemporally dynamic interactions. During the evolution of sepsis, these signals exhibit opposite regulatory polarities during the hyper-inflammatory phase and the immunosuppressive phase, and mitochondrial dysfunction and oxidative stress further amplify the inflammatory cascade reaction. Preclinical research evidence shows that microbiota-based intervention measures (including probiotic preparations, fecal microbiota transplantation, and SCFA supplementation) and vagus nerve electrical stimulation can effectively alleviate sepsis-related lung injury and improve prognosis, but there is significant individual heterogeneity in their therapeutic effects. Future research should not be restricted to descriptive associations. Instead, it is essential to conduct in-depth analyses of the specific logic of the aforementioned signaling networks in terms of cell types, subcellular compartments, and disease course timings, and clarify their context-dependent controversies to promote the transformation of mechanistic understanding into precision treatment. Meanwhile, research efforts should focus on constructing a multi-omics dynamic biomarker system integrating metagenomics, metabolomics, and immunophenotyping analysis and designing clinical trials through precise patient stratification to facilitate the clinical translation of individualized treatment strategies based on gut-lung axis regulation.
    Keywords:  gut-lung axis; immunometabolism; intensive care unit; microbiota dysbiosis; sepsis
    DOI:  https://doi.org/10.3389/fmed.2025.1685044
  41. J Cell Biol. 2026 Jan 05. pii: e202503028. [Epub ahead of print]225(1):
    Bacterial CipB is an exogenous receptor to drive the mitophagy-TFEB axis and promote pathogenesis.
    Shuai Liu, Lina Ma, Ruiqi Lv, Liangting Guo, Xing Pan, Shufan Hu, Shan Li.
      Mitophagy transports mitochondria to lysosomes for degradation to maintain energy homeostasis, inflammation, and immunity. Here, we identify CipB, a type III secretion system (T3SS) effector from Chromobacterium violaceum, as a novel exogenous mitophagy receptor. CipB targets mitochondria by the mitochondrial protein TUFM and recruits autophagosomes via its LC3-interacting region (LIR) motifs. This process initiates the mitophagy-TFEB axis, triggering TFEB nuclear translocation and suppression of proinflammatory cytokines, thereby promoting bacterial survival and pathogenesis. CipB represents a conserved family of T3SS effectors employed by diverse pathogens to manipulate host mitophagy. Using a mouse model, CipB's mitophagy receptor function is critical for C. violaceum colonization in the liver and spleen, underscoring its role in bacterial virulence. This study reveals a novel mechanism by which bacterial pathogens exploit host mitophagy to suppress immune responses, defining CipB as a paradigm for exogenous mitophagy receptors. These findings advance our understanding of pathogen-host interactions and highlight the mitophagy-TFEB axis as a potential signaling pathway against bacterial infection.
    DOI:  https://doi.org/10.1083/jcb.202503028
  42. PLoS Pathog. 2025 Nov 20. 21(11): e1013713
    Mitochondrial targeting by measles virus nucleoprotein modulates viral spread in human airway epithelium.
    Lorellin A Durnell-Bettis, Stephanie E Clark, Camilla E Hippee, Angela Liu, Justin W Kaufman, Sydney R Winecke, Kalpana Yadav, Brajesh K Singh, Roberto Cattaneo, Patrick L Sinn.
      Measles is the most infectious human respiratory virus: on average, one individual with measles infects 12-18 susceptible people in a population without immunity. However, how measles virus (MeV) establishes infection in the human respiratory epithelium is insufficiently understood. Since our analyses of MeV infections of well-differentiated primary human airway epithelial cells (HAE) revealed perturbations of mitochondrial gene expression, we tested mitochondrial function. MeV replication disrupted mitochondrial membrane potential and induced superoxide production. This resulted in cGAS-dependent interferon-stimulated gene expression without interferon induction. We then assessed by differential centrifugation whether MeV replicates in mitochondrial proximity. Indeed, MeV proteins and genome were enriched in mitochondrial fractions. We identified a previously unrecognized potential mitochondrial localization signal (MLS) in the MeV nucleoprotein (N), the first protein expressed during infection and showed that the first 70 amino acids of N are sufficient to deliver a GFP reporter to mitochondria. Mutational analyses revealed that arginine 6 and arginine 13 of the N protein are critical for targeting. Recombinant MeV mutants harboring single MLS amino acid substitutions exhibited altered replication kinetics and infectious center formation in HAE, despite similar ISG expression profiles to wild-type MeV. Thus, the MeV N protein amino-terminal arm, previously known only to promote formation of the helical ribonucleocapsid protecting the viral genome, also codes for an MLS. In newly infected cells, this signal may target the formation of MeV replication factories near mitochondria without provoking a canonical RNA sensing pathway. Notably, the MLS appears unique to Morbillivirus N proteins within the Paramyxoviridae family, which are also distinguished by the unique ability to form infectious centers in HAE. Our findings reveal a novel mechanism by which MeV exploits mitochondrial proximity to coordinate replication and modulate host responses, offering new insights into virus-host interactions at the organelle level.
    DOI:  https://doi.org/10.1371/journal.ppat.1013713
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