bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–11–30
sixty-one papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Defined metabolic states shape T cell fate and function across culture conditions.
  2. A20 restriction of nitric oxide production restores macrophage bioenergetic balance.
  3. Systems analysis reveals alternate metabolic states adopted by Mycobacterium tuberculosis across species.
  4. Itaconate transport across the plasma membrane and Salmonella-containing vacuole via MCT1/4 modulates macrophage antibacterial activity.
  5. Macrophage Immunometabolism in Pulmonary Homeostasis and Chronic Lung Diseases.
  6. Airway immunometabolic responses during pulmonary bacterial and viral infections.
  7. Knockout of Perilipin-2 in Microglia Alters Lipid Droplet Accumulation and Response to Alzheimer's Disease Stimuli.
  8. Immunometabolism in the Tumor Microenvironment: Dual Role in Modulating Anti-Tumor Immunity and Tumor Progression.
  9. Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy.
  10. Semaphorin3A Rewires CD4+ T-Cell Metabolism via AKT/mTORC1 Inhibition in Health and Rheumatoid Arthritis.
  11. Autophagy disruption primes CAR-T cell metabolism for sustained rejection of ovarian tumors.
  12. HCMV infection depends on EGLN1-mediated mitochondrial activation to increase dNTP pools for viral DNA replication.
  13. Plexin C1 modulates metabolic programming for resolution of severe inflammation.
  14. Gut microbiota L-ornithine promotes resistance to obesity through metabolites mediated immunosuppressive macrophages.
  15. Glycolysis inhibition functionally reprograms T follicular helper cells and reverses lupus.
  16. Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
  17. MPP+ disorders Irg1-Itaconate axis to promote M1 polarization of microglia by activating succinate dehydrogenase.
  18. Isoallolithocholic acid ameliorates intestinal inflammation via metabolically reprogrammed macrophages.
  19. L-Phenylalanine is a metabolic checkpoint of human Th2 cells.
  20. Fructose intake driven glycolysis-ROS-EGFR axis specifically promotes the generation and pathogenicity of Th17 cells.
  21. Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis.
  22. Rg1-preconditioned adipose-derived mesenchymal stromal cells alleviate colitis via exosome-mediated Inhibition of macrophage glycolysis through RAS signaling.
  23. Gut microbiota-derived metabolites modulate Treg/Th17 balance: novel therapeutic targets in autoimmune diseases.
  24. Piezo1-mediated mechano-energetics regulate CAR T cell function.
  25. Immunocyte lipid metabolic reprogramming: a novel pathway for targeted intervention in autoimmune diseases.
  26. WSSV-induced reversal of the malate-aspartate shuttle facilitates viral replication in shrimp hemocytes.
  27. Lipid deprivation amplifies type I IFN responses in monocytes through prenylation: insights from familial combined hypolipidemia type 2.
  28. "Rewiring brain immunity: targeting microglial metabolism for neuroprotection in neurodegenerative disorders".
  29. Autofluorescence imaging reveals the impact of cryopreservation on T cell metabolism and activation response.
  30. Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice.
  31. Vitamin B6 preserves the stemness-like phenotypes and antitumor ability of CD8+ T cells.
  32. ANGPTL8 links refeeding to monocyte dynamics and metabolic inflammation via the CCL5-CCR5 axis.
  33. Disruption of metabolic licensing by JAK inhibitors constrains CD8 T cell activation and effector function.
  34. Mitochondrial metabolic reprogramming of microglia in neuroinflammation: Implications for major depressive disorder.
  35. A shift in PKM2 oligomeric state instructs adipocyte inflammatory potential.
  36. Spatial Partitioning of Core Glycolysis Enables Tissue-Specific Metabolic Programs In Vivo.
  37. Amino acid decarboxylation preserves Salmonella fitness during phagocyte-derived oxidative stress.
  38. Acute activation of Gq-signaling in islet macrophages inhibits β-cell insulin secretion through AMPK-sphingolipid axis.
  39. Elevated plasma cholesterol causally improves sepsis outcome by promoting hepatic metabolic reprogramming.
  40. The impact of metabolic reprogramming in hepatocellular carcinoma on T cell.
  41. Integrated multiomics reveals host-virus coadaptation in persistent foot-and-mouth disease virus infection.
  42. Toxoplasma gondii disrupts intestinal microbiota and host metabolism in a rat model.
  43. LDHA facilitates immune escape in bladder cancer through H4K5 lactylation-dependent upregulation of PD-L1.
  44. CD36-mediated long-chain fatty acids transport in keratinocytes promotes psoriasis-like skin inflammation through increasing mitochondrial reactive oxygen species.
  45. Mitochondrial transplantation alleviates acute pancreatitis by suppressing macrophage necroptosis.
  46. A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models.
  47. A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense in lupus.
  48. A noncanonical polyamine from bacteria antagonizes host mitochondrial function.
  49. Bacterial metabolism of tryptophan causes toxicity in Caenorhabditis elegans that is alleviated by sugar supplementation.
  50. Integrated Photoacoustic-Metabolomic Platform for Multimodal Assessment of Sepsis-Induced Brain Dysfunction.
  51. Microbiota-directed lactic acid depleting nanoenzyme reactivates antitumor immunity and chemosensitivity in hypoxic tumor.
  52. Demystifying metabolic‒immune crosstalk: how amino acid metabolic reprogramming shapes the malignant phenotype and macrophage polarization of biliary and pancreatic tumors.
  53. Glutamine-Dependent Biosynthetic Pathways Fuel Autoreactive T and B Cells in Foxp3 Deficiency-mediated Disease.
  54. Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling.
  55. Oxidative stress-induced proinflammatory secretion from retinal pigment epithelium disrupts NAD+ metabolism via CD38 on macrophages leading to immune microenvironment dysregulation.
  56. Zinc, Fe2+ and Fe3+ differentially influence IFN-γ production in human peripheral blood mononuclear cells.
  57. Phenyllactic Acid as a Marker of Antibiotic-Induced Metabolic Activity of Nosocomial Strains of Klebsiella pneumoniae In Vitro Experiment.
  58. HDM and mannose as novel tolerogenic inducers for dendritic cells: mTOR/PPARγ-mediated attenuation of allergic asthma.
  59. Commensal-derived short-chain fatty acids disrupt lipid membrane homeostasis in Staphylococcus aureus.
  60. Macrophage PIM1 Drives Atherosclerosis by Enhancing Foam Cell Formation Via CD36.
  61. High-fat diet promotes colorectal tumorigenesis through gut microbiota-mediated metabolic reprogramming and M2 macrophage polarization.
  1. Front Immunol. 2025 ;16 1703095
    Defined metabolic states shape T cell fate and function across culture conditions.
    Kayla Sylvester, Natasha Karassina, Anthony C Lauer, Gediminas Vidugiris, Jolanta Vidugiriene.
       Introduction: T cell metabolism is a key determinant of immune function and therapeutic efficacy, yet current expansion protocols often neglect how culture conditions influence metabolic programming. We employed a modular, low-input bioluminescent assay platform to profile how media, activation strength, and metabolic perturbation define metabolic trajectories that persist through early expansion and influence downstream outcomes.
    Methods: A multifactorial experimental design was used to evaluate early T-cell activation across media (ICXF, TexMACS, RPMI+FBS) and activators (TransAct, Dynabeads, ImmunoCult). Low-input bioluminescent assays were used to quantify metabolic cofactors (ATP, NAD+, NADP(H)), reducing capacity, and nutrient usage (glucose, lactate, malate). Conditions that yield metabolically distinct phenotypes were selected for deeper analysis of proliferation, cytokine secretion, cytotoxicity, and flow cytometric profiling. To validate and functionally confirm these phenotypes, pathway-specific metabolic inhibitors were introduced in follow-up experiments.
    Results: By measuring intracellular ATP, NAD+, NADP(H), reducing capacity, and nutrient flux, we identified media- and activation-specific metabolic states that emerged upon T-cell activation and persisted through early expansion. ICXF with TransAct promoted a glycolytic, NAD-rich phenotype associated with rapid expansion. In contrast, TexMACS with ImmunoCult supported oxidative metabolism, enriched for TSCM-like cells, and enhanced cytotoxicity despite slower growth. Early lactate levels strongly predicted downstream expansion (r = 0.68, p < 0.0001), highlighting glycolytic activity as a key determinant of proliferative potential. Functional validation with pathway-specific inhibitors revealed media-dependent vulnerabilities, highlighting distinct metabolic wiring.
    Conclusion: This approach enables predictive, multiplexed metabolic profiling using minimal sample input and offers a scalable strategy to optimize T-cell manufacturing for memory enrichment and cytotoxic potency.
    Keywords:  T cell metabolism; adoptive cell therapy; bioluminescent assays; ex vivo expansion; glycolysis; immunometabolism; memory T cells; metabolic profiling
    DOI:  https://doi.org/10.3389/fimmu.2025.1703095
  2. bioRxiv. 2025 Oct 29. pii: 2025.10.26.684676. [Epub ahead of print]
    A20 restriction of nitric oxide production restores macrophage bioenergetic balance.
    Mei-Po Chan, Rommel Advincula, Philip Achacoso, Elizabeth A Grossman, Daniel K Nomura, Barbara A Malynn, Averil Ma.
      Macrophages play critical roles in regulating host responses to microbial pathogens and other forms of tissue stress and can acquire pro-inflammatory or tissue reparative phenotypes. A20, or TNFAIP3, is a potent regulator of innate immune cell functions and is extensively linked to human inflammatory and autoimmune diseases. We now find that A20 is a powerful regulator of both glycolytic and mitochondrial respiration in macrophages. Differentiated macrophages that are acutely rendered A20 deficient exhibit increased glycolytic activity and markedly decreased mitochondrial respiration after LPS stimulation. These cells are unable to repolarize from an M1-like to M2-like phenotype. Compromised mitochondrial oxygen consumption in A20 deficient macrophages is caused by increased nitric oxide production. Inhibition or genetic ablation of inducible nitric oxide synthase (iNOS) restores mitochondrial oxidative phosphorylation and lactate production in these cells. These metabolic perturbations occur independently of exaggerated cytokine production and despite robust production of IL-10. Therefore, A20 prevents Warburg-like aerobic glycolysis and restores macrophage homeostasis.
    DOI:  https://doi.org/10.1101/2025.10.26.684676
  3. bioRxiv. 2025 Nov 15. pii: 2025.11.15.688116. [Epub ahead of print]
    Systems analysis reveals alternate metabolic states adopted by Mycobacterium tuberculosis across species.
    Jonathan Padilla-Gomez, Rachel McGinn, Yisha Liang, Kendra Libby, Alison E Ringel, Charles Evavold, Bryan D Bryson.
      Mycobacterium tuberculosis (Mtb) persists within macrophages, yet how different host species shape bacterial state remains poorly understood. Here, we directly compared the intracellular transcriptome of Mtb during infection of human and mouse macrophages, revealing distinct host-imposed microenvironments that drive the pathogen into separable metabolic states. Lipid metabolism and regulatory circuits were prominently remodeled, with mouse macrophages inducing iron- and oxidative-stress responses while human macrophages promoted fatty acid import programs. Using fluorescent fatty acid tracing, we uncovered a striking species-specific phenotype: Mtb forms intracellular lipid inclusions (ILIs) in murine macrophages but not in human macrophages. This phenotype was independent of culture media, macrophage ontogeny, or host antimicrobial factors such as nitric oxide and itaconate. Access of Mtb to host-derived lipids required the ESX-1 secretion system and was inversely correlated with host triacylglycerol (TAG) synthesis. Inhibition of TAG formation in human macrophages partially restored Mtb ILI formation, revealing a metabolic gate that governs lipid flow between host lipid droplets and intracellular Mtb. Together, these findings establish a cross-species framework for decoding host-driven bacterial metabolic states and identify a key barrier limiting Mtb's access to host lipid stores in human macrophages.
    DOI:  https://doi.org/10.1101/2025.11.15.688116
  4. Nat Commun. 2025 Nov 26. 16(1): 10551
    Itaconate transport across the plasma membrane and Salmonella-containing vacuole via MCT1/4 modulates macrophage antibacterial activity.
    Qingcai Meng, Chengxi Li, Yuping Cai, Ying Chen, Xiaoqing Chen, Xin Wang, Biling Zhang, Yue Zhang, Feng Liu, Meixin Chen.
      Itaconate accumulates in macrophages upon bacterial infection, and manifests antibacterial activity. Convincing evidence substantiates that itaconate is transported across the plasma membrane and vacuolar membrane, but the molecular bases underlying bidirectional transport of itaconate across membranes and its effects on intracellular bacterial replication are less known. Here, we identify MCT1 and MCT4 as bidirectional transporters of itaconate. In addition to modulating itaconate concentration as transporters at the plasma membrane, MCT1 and MCT4 function as itaconate transporters at Salmonella-containing vacuole (SCV). Upon Salmonella infection, MCT1 and MCT4 transport itaconate into SCV facilitated by RAB32. Itaconate is also secreted out of cells through MCT1 and MCT4 as the infection persists. The suppression of MCT1 and MCT4-dependent itaconate secretion increases the overall concentration of itaconate and the proportion of itaconate-targeted Salmonella intracellularly, consequently inhibiting Salmonella replication. Our study thus offers valuable insights into itaconate transport during bacterial infection and provides proof of principle for the development of itaconate-dependent therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-025-65582-6
  5. Int J Biol Sci. 2025 ;21(15): 6580-6598
    Macrophage Immunometabolism in Pulmonary Homeostasis and Chronic Lung Diseases.
    Cong Xie, Maimaititusun Yalikun, Zhenhui Ruan, Hang Yu, Xi Huang, Huahe Zhu, Wenglam Choi, Qingli Luo, Zhen Gao, Jingcheng Dong.
      Macrophages play a central role in maintaining pulmonary immune homeostasis and responding to injury. In the lung, alveolar macrophages modulate their metabolic profiles to support essential functions such as microbial clearance, inflammation resolution, and tissue repair. Recent studies have shown that these metabolic adaptations are not merely byproducts of activation but represent key regulators of macrophage behavior. In chronic lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), macrophage metabolism is pathologically reprogrammed, contributing to persistent inflammation in asthma and COPD, or to unrestrained fibrotic remodeling in IPF, and ultimately leading to ongoing tissue damage. Specifically, in asthma, type 2 cytokine signaling promotes alternative macrophage activation, accompanied by increased fatty acid oxidation and disrupted lipid mediator profiles. COPD-associated macrophages exhibit mitochondrial dysfunction, enhanced glycolysis, and iron overload, impairing bacterial phagocytosis and amplifying oxidative stress. In IPF, macrophages simultaneously engage glycolytic and oxidative pathways while losing regulatory metabolites such as itaconate, supporting persistent fibrogenic signaling. These disease-specific metabolic features sustain maladaptive macrophage phenotypes and constitute promising targets for therapeutic intervention. This review outlines current knowledge of macrophage immunometabolism in the lung and its contribution to chronic respiratory diseases. It also discusses strategies to restore metabolic balance, including the use of antioxidants, metabolic modulators, and targeted drug delivery. Understanding macrophage metabolism may open new avenues for treating chronic lung diseases at the level of cellular function.
    Keywords:  alveolar macrophages; chronic lung diseases; macrophage immunometabolism; metabolic reprogramming; pulmonary homeostasis; therapeutic targets
    DOI:  https://doi.org/10.7150/ijbs.123492
  6. Cell Rep. 2025 Nov 22. pii: S2211-1247(25)01386-5. [Epub ahead of print]44(12): 116614
    Airway immunometabolic responses during pulmonary bacterial and viral infections.
    Ridhima Wadhwa, Eric Tang, Lok Yin Roy Wong, Tania Wong Fok Lung.
      Airway infections caused by viral and bacterial pathogens pose a significant threat to human health, with the COVID-19 pandemic serving as a stark reminder of their detrimental impact. This review explores the critical role of metabolism in determining the outcome of respiratory infections. It covers fundamental concepts in immunometabolism and details how common pathogens exploit the host metabolism to dysregulate immune responses or evade immune clearance. We further consider how immune-signaling metabolites can directly drive pathogen evolution, emphasizing the importance of a better understanding of host-pathogen metabolic interactions in developing effective new therapies.
    Keywords:  CP: immunology; CP: metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2025.116614
  7. Cells. 2025 Nov 13. pii: 1783. [Epub ahead of print]14(22):
    Knockout of Perilipin-2 in Microglia Alters Lipid Droplet Accumulation and Response to Alzheimer's Disease Stimuli.
    Isaiah O Stephens, Lance A Johnson.
      Lipid droplets (LDs) are emerging as key regulators of metabolism and inflammation, with their buildup in microglia linked to aging and neurodegeneration. Perilipin-2 (Plin2) is a ubiquitously expressed LD-associated protein that stabilizes lipid stores; in peripheral tissues, its upregulation promotes lipid retention, inflammation, and metabolic dysfunction. Yet, its role in microglia remains unclear. Using CRISPR-engineered Plin2 knockout (KO) BV2 microglia, we examined how Plin2 contributes to lipid accumulation, bioenergetics, and immune function. Compared to wild-type (WT) cells, Plin2 KO microglia showed markedly reduced LD burden under basal and oleic acid-loaded conditions. Functionally, this was linked to enhanced phagocytosis of zymosan particles, even after lipid loading, indicating improved clearance capacity. Transcriptomics revealed genotype-specific responses to amyloid-β (Aβ), especially in mitochondrial metabolism pathways. Seahorse assays confirmed a distinct bioenergetic profile in KO cells, with reduced basal respiration and glycolysis but preserved mitochondrial capacity, increased spare reserve, and a blunted glycolytic response to Aβ. Together, these findings establish Plin2 as a regulator of microglial lipid storage and metabolic state, with its loss reducing lipid buildup, enhancing phagocytosis, and altering Aβ-induced metabolic reprogramming. Targeting Plin2 may represent a strategy to reprogram microglial metabolism and function in aging and neurodegeneration.
    Keywords:  Alzheimer’s disease; lipid droplets; lipidomics; microglia; neuroinflammation; phagocytosis
    DOI:  https://doi.org/10.3390/cells14221783
  8. Asian Pac J Cancer Prev. 2025 Nov 20. pii: 91914. [Epub ahead of print]26(11): 3881-3893
    Immunometabolism in the Tumor Microenvironment: Dual Role in Modulating Anti-Tumor Immunity and Tumor Progression.
    Casterland Marbaniang, Lakhon Kma, Rajeshwar Nath Sharan.
      Understanding the tumor microenvironment (TME) requires a comprehensive exploration of the interactions between tumor cells and various stromal and immune cells, as these interactions significantly influence tumor growth and treatment response. Immunometabolism, which examines the relationship between immune cell metabolic processes and their behaviour, has become crucial in determining the effectiveness of anti-tumor immune responses. This review explores the intricate relationship between immunometabolism and TME, highlighting how metabolic changes in immune cells can either enhance or impair their capacity to fight cancer. It specifically investigates the metabolic reprogramming of T cells, macrophages, and dendritic cells within the TME and how these alterations affect their anti-tumor roles. The review also examines how tumors utilise metabolic pathways to establish an immunosuppressive environment that fosters tumor growth. Understanding these processes reveals potential therapeutic targets in immunometabolism to improve cancer treatment outcomes. By emphasising the dual role of immunometabolism in both aiding and inhibiting the immune response to cancer, this review underscores the necessity of integrating metabolic strategies into cancer immunotherapy research, which may lead to novel treatments that maximise the immune system's ability to combat cancer.
    Keywords:  Immunometabolism; TME; Tumor; immune cells; immunosuppressive environment
    DOI:  https://doi.org/10.31557/APJCP.2025.26.11.3881
  9. bioRxiv. 2025 Oct 24. pii: 2025.10.23.684261. [Epub ahead of print]
    Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy.
    Lior Goldberg, Eric R Haas, Jiaqi Wu, Bryan Garcia, Ryan Urak, Vibhuti Vyas, Ruby Espinosa, Tamara Munoz, Shirley Bierkatz, Khyatiben V Pathak, Nathaniel P Hansen, Patrick Pirrotte, Jyotsana Singhal, James L Figarola, Ricardo Zerda Noriega, Zhuo Li, Dasol Wi, Erin Tanaka, Ramon Klein Geltink, Min-Hsuan Chen, Xiwei Wu, Jamie R Wagner, Jinny Paul, Mary C Clark, Dat Ngo, Ibrahim Aldoss, Stephen J Forman, Xiuli Wang.
      Although most patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) receiving CD19-targeted chimeric antigen receptor (CAR) T cell therapy achieve remission, loss of CAR T cell functionality and subsequent relapse remains an unmet therapeutic need. We applied an integrative approach to study the immunometabolism of pre- and post-infusion CD19-CAR T cells of patients with relapsed/refractory B-ALL. Pre-infusion CAR T cells of long-term responders (LTR) had increased oxidative phosphorylation, fatty acid oxidation, and pentose phosphate pathway activities, higher mitochondrial mass, tighter cristae, and lower mTOR expression compared to products of short-term responders. Post-infusion CAR T cells in bone marrow (BM) of LTR had high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induced metabolic reprogramming and enhanced anti-tumor activity of CAR T cells. Our findings provide insight into immunometabolic determinants of long-term response and suggest a therapeutic strategy to improve long-term remission.
    DOI:  https://doi.org/10.1101/2025.10.23.684261
  10. Int J Mol Sci. 2025 Nov 19. pii: 11160. [Epub ahead of print]26(22):
    Semaphorin3A Rewires CD4+ T-Cell Metabolism via AKT/mTORC1 Inhibition in Health and Rheumatoid Arthritis.
    Raeda Mubariki, Nasren Eiza, Adi D Sabag, Shiri Keret, Doron Rimar, Gleb Slobodin, Devy Zisman, Elias Toubi, Zahava Vadasz.
      Semaphorin3A (Sema3A) is a regulatory protein found to be expressed on regulatory T and B cells and also secreted into peripheral blood. It has been identified as a potent immune regulator; however, not all its regulatory mechanisms have been evaluated. In this respect, we aim to investigate how Sema3A affects key metabolic pathways in T cells during homeostasis and rheumatoid arthritis (RA), and on the AKT/mTORC1 signaling axis. In this study, peripheral blood samples were collected from 119 healthy donors and 32 rheumatoid arthritis patients. T cells were subjected to Seahorse analysis to evaluate OXPHOS and glycolysis, live cell TMRE staining to evaluate mitochondrial activity, mass spectrometry for metabolite profiling, ATP determination to study ATP production, and Western blot analysis to investigate the signaling pathway activity. This study presents evidence showing that Sema3A inhibits the AKT/mTORC1 pathway, leading to a decreased glucose uptake and glycolysis disruption. Furthermore, we show that Sema3A reduces mitochondrial capacity and OXPHOS in activated T cells of healthy and RA donors, leading to a decreased ATP production. In contrast, Sema3A upregulates fatty acid oxidation (FA), probably as a backup pathway to ensure cell survival. Results with p values of <0.05 were considered significant. Our data may point to Sema3A's ability to convert activated T cells' metabolic profile back to its non-activated state. This may suggest that Sema3A might be a beneficial treatment for immune-mediated diseases by metabolically reprogramming activated T cells.
    Keywords:  Sema3A; activated T cells; fatty acid metabolism; homeostasis; immunometabolism; oxidative phosphorylation; rheumatoid arthritis
    DOI:  https://doi.org/10.3390/ijms262211160
  11. bioRxiv. 2025 Oct 10. pii: 2025.10.09.681473. [Epub ahead of print]
    Autophagy disruption primes CAR-T cell metabolism for sustained rejection of ovarian tumors.
    Gillian A Carleton, Sébastien Levesque, Lauren G Zacharias, Joao San Patricio, Tracey Sutcliffe, Peter H Watson, Ralph J DeBerardinis, Yannick Doyon, Julian J Lum.
      T-cell based immunotherapies such as chimeric antigen receptor T (CAR-T) cell therapy face substantial hurdles when confronting solid tumors such as ovarian cancer, where metabolic constraints in the tumor microenvironment limit T cell infiltration and function. In particular, T cells exposed to nutrient deprivation and hypoxia upregulate autophagy, a lysosomal degradation pathway that negatively regulates effector responses. Here, we used CRISPR-Cas9 to target a folate receptor alpha (αFR) CAR expression cassette into the locus of the essential autophagy gene ATG5, thereby generating autophagy-deficient CAR-T cells in a single editing step. Targeted metabolite profiling revealed that deletion of ATG5 induced widespread metabolic reprogramming characterized by increased glucose and amino acid uptake. Functionally, ATG5-knockout CAR-T cells maintained high cytolytic activity when assayed in patient-derived ascites in vitro, and exhibited superior and long-lasting tumor control against ovarian tumors in vivo. Taken together, our results suggest that deletion of ATG5 metabolically primes CAR-T cells for enhanced cytotoxicity in immune-suppressive conditions, thereby improving the therapeutic potential of αFR CAR-T cells for ovarian cancer immunotherapy.
    DOI:  https://doi.org/10.1101/2025.10.09.681473
  12. bioRxiv. 2025 Oct 31. pii: 2025.10.31.685607. [Epub ahead of print]
    HCMV infection depends on EGLN1-mediated mitochondrial activation to increase dNTP pools for viral DNA replication.
    Lucas A Simpson, Diana M Dunn, Wyatt Fales, Zachary J Moore, Jessica H Ciesla, Nicole Waild, Matthew H Raymonda, Isaac S Harris, Joshua Munger.
      Human cytomegalovirus (HCMV) is a leading cause of congenital infection and morbidity in immunosuppressed populations. Like all viruses, HCMV is an obligate intracellular parasite that extensively remodels host cellular metabolism to support its replication, yet the precise underlying mechanisms and metabolic vulnerabilities remain poorly understood. Using a novel metabolism-focused screening platform, we identified EGLN prolyl hydroxylase activity as critical for HCMV infection. Our studies revealed that HCMV infection depends on EGLN1, which accumulated in mitochondria during infection. Inhibition of EGLN1 expression blocked HCMV-mediated mitochondrial activation, which in turn prevented the production of the dNTP precursors necessary for dNTP pool expansion and viral DNA replication. Further, pharmacological EGLN inhibition attenuated viral infection in a humanized mouse model. Collectively, these data establish EGLN1 as a critical determinant of mitochondrial metabolic remodeling and virally-induced dNTP generation during HCMV infection, highlighting EGLN1 as a promising novel antiviral therapeutic target.
    DOI:  https://doi.org/10.1101/2025.10.31.685607
  13. Cell Commun Signal. 2025 Nov 25.
    Plexin C1 modulates metabolic programming for resolution of severe inflammation.
    Andreas Körner, Michael Koeppen, Jasvir Kaur, Julia C Fitzgerald, Sarantos Kostidis, Torsten Kaussen, Christoph Trautwein, Martin Giera, Tamam Bakchoul, Alice Bernard, Valbona Mirakaj.
      Persistent, unresolved inflammatory processes disrupt the complex homeostatic state and lead to severe disease, ultimately resulting in organ failure, shock, and death. The mediators that monitor and control the programmed mechanisms in tissue homeostasis and repair remain elusive. A recently discovered group of endogenous proteins, termed neuronal guidance proteins (NGPs), has gained attention as important mediators of immunoregulation and tissue homeostasis through their role in the complex interplay between metabolic reprogramming and immunity. In murine peritonitis, the deficiency of the NGP Plexin C1 (PLXC1-/-) led to an increase in neutrophil and Ly6Chi monocyte recruitment to the injury site and a decrease in the phagocytosis rate. This was accompanied by a decrease in the endogenous biosynthesis of specialized proresolving lipid mediators (SPMs) such as Maresin-1 and Protectin DX and finally by a lengthening of the resolution interval. Peritoneal macrophages (MΦs)PLXC1-/- followed specific strategies to adapt their metabolism to catabolic conditions, by reducing fatty acid oxidation and oxidative phosphorylation, increasing aerobic glycolysis and activation of the pentose phosphate pathway, and disrupting the tricarboxylic acid cycle. The decreased MΦsPLXC1-/- citrate levels corresponded with a lipid mediator profile in which PGD2 and PGE2 were greatly decreased in murine PLXC1-/- peritoneal exudates, indicating a lesser effect on lipid mediator class switching and ultimately the formation of SPMs. Analysis of the related signaling networks indicated mTOR and AKT2 phosphorylation pathways are critical determinants of metabolic reprogramming in activated MΦsPLXC1-/-. These findings highlight a novel role for PLXC1 in regulating the crosstalk between immunometabolism and inflammation resolution programs in severe inflammation.
    Keywords:  Inflammation; Leukocytes; Lipid mediators; Macrophage phenotype; Metabolism; Neuronal guidance proteins; Plexin C1; Regeneration; Resolution
    DOI:  https://doi.org/10.1186/s12964-025-02518-z
  14. Cell Mol Life Sci. 2025 Nov 26. 82(1): 426
    Gut microbiota L-ornithine promotes resistance to obesity through metabolites mediated immunosuppressive macrophages.
    Yuanyuan Li, Yuqing Liu, Juanjuan Wang, Yuanhuan Gao, Yuan Zhang, Rongcun Yang.
      The gut microbiota plays a pivotal role in modulating obesity pathogenesis, yet the molecular mechanisms underlying its protective effects remain elusive. In this study, we demonstrate that L-ornithine (L-orn), a metabolite produced by Lactobacillus, confers resistance against high-fat diet (HFD)-induced obesity in mice by modulating macrophage function through its downstream metabolites spermine (SPM) and spermidine (SPD). Mechanistically, SPM suppressed pro-inflammatory cytokine production in macrophages by inhibiting the NF-κB and Akt signaling pathways, while SPD activated Src kinase and upregulated indoleamine 2,3-dioxygenase 1 (IDO-1), thereby promoting the polarization of immunosuppressive IDO-1+ macrophages. Clinically, circulating L-orn levels were inversely correlated with body mass index (BMI) in obese individuals, underscoring its potential relevance in human obesity. Single-cell RNA sequencing (scRNA-seq) analysis further revealed dysregulated macrophage signaling in obese adipose tissue, characterized by hyperactivation of NF-κB and Akt pathways and downregulation of Src signaling in inflammatory macrophages. Collectively, our findings highlight a novel mechanism by which gut microbiota-derived L-orn mitigates obesity through metabolite-driven reprogramming of macrophages toward an anti-inflammatory phenotype, offering new therapeutic avenues for metabolic disorders.
    Keywords:  Indoleamine 2, 3-dioxygenase 1; L-ornithine; Obesity; Spermindine; Spermine
    DOI:  https://doi.org/10.1007/s00018-025-05882-8
  15. Cell Rep. 2025 Nov 22. pii: S2211-1247(25)01372-5. [Epub ahead of print]44(12): 116600
    Glycolysis inhibition functionally reprograms T follicular helper cells and reverses lupus.
    Seung Chul Choi, Yong Ge, Ahmed Elshikha, Yuk Pheel Park, Cenxiao Fang, Milind V Joshi, Maria Montes de Oca Arena, Lauren Padilla, Yanan Zhu, William L Clapp, Eric S Sobel, Mansour Mohamadzadeh, Laurence Morel.
      Systemic lupus erythematosus (SLE) is an autoimmune disease in which the production of pathogenic autoantibodies depends on T follicular helper (TFH) cells. This study investigated the mechanisms by which the glycolysis inhibitor 2-deoxy-d-glucose (2DG) reduces the expansion of TFH cells and the associated production of autoantibodies in lupus-prone mice. Integrated cellular, transcriptomic, epigenetic, and metabolic analyses showed that 2DG reversed the enhanced cell expansion and effector functions, as well as mitochondrial and lysosomal defects in lupus TFH cells, including increased expression of chaperone-mediated autophagy (CMA) markers associated with Toll-like receptor 7 activation. Importantly, adoptive transfer of 2DG-reprogrammed TFH cells protected lupus-prone mice from disease progression. The orthologs of genes responsive to 2DG in murine lupus TFH cells were overexpressed in the TFH cells of SLE patients, suggesting a therapeutic potential for targeting glycolysis to eliminate aberrant TFH cells and curb the production of autoantibodies that induce tissue damage.
    Keywords:  CP: immunology; CP: metabolism; autophagy; follicular helper T cells; glycolysis; lupus; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2025.116600
  16. bioRxiv. 2025 Nov 13. pii: 2025.11.11.687895. [Epub ahead of print]
    Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
    Azusa Terasaki, Alexis T Weiner, Yuhao Tan, Viktoria Szeifert, Keshav Bhatnagar, Cara C Rada, Vishnu Shankar, Courtney Kernick, Mahnoor Mahmood, Lukas Wiggers, Viviana R Rodrigues, Payam A Gammage, Theodore Roth, Jeffrey D Axelrod, Edgar Engleman, Bo Li, Derick Okwan-Duodu.
      Hostile conditions in the tumor microenvironment restrict cellular respiration, yet mitochondrial metabolism remains indispensable for tumor growth and the activity of immunosuppressive cells. How tumor ecosystems sustain mitochondrial output has been unclear. Here, we show that cancer cells resolve this paradox by acting as hubs of intercellular mitochondrial redistribution. Using mitochondrial reporter systems, we demonstrate that cancer cells import host-derived mitochondria, integrate them into their endogenous network, and subsequently relay these hybrid organelles to neighboring immune cells. Mitochondria redistribution reprograms recipient neutrophils, macrophages, and CD4+ T cells into highly suppressive states but drives CD8+ T cell exhaustion. Within cancer cells, fusion of incoming mitochondria induces filamentous P5CS assembly, enhances biosynthetic output, and enables the refurbishment of damaged organelles into fully functional units. Disrupting mitochondrial redistribution collapses the immunosuppressive ecosystem and impairs tumor growth. Thus, cancer cells do not hoard resources but orchestrate a redistribution program that fortifies their own metabolic resilience, derails anti-tumor immunity, and sustains immunosuppressive partners.
    HIGHLIGHTS: Tumor cells regulate their ecosystem by redistributing mitochondriaRedistributed mitochondria expand immunosuppressive cells but exhausts CD8+ T cellsMitochondria fusion within cancer cells, which precedes redistribution, optimizes metabolic output by triggering conformational changes in P5CSMitochondria fusion allows cancer cells to incorporate and refurbish seemingly incompetent host-derived mitochondria, improving efficiency in the tumor ecosystem.
    DOI:  https://doi.org/10.1101/2025.11.11.687895
  17. Mol Biol Rep. 2025 Nov 24. 53(1): 115
    MPP+ disorders Irg1-Itaconate axis to promote M1 polarization of microglia by activating succinate dehydrogenase.
    Lin-Yu Wang, Yi-Yun Tang, Wei Zou, Ping Zhang, Xiao-Qing Tang, Ping Zhang.
       BACKGROUND: The microglial (MG) M1/M2 phenotypic switch plays a crucial role in the neuroinflammation of Parkinson's disease (PD), but the underlying mechanism remains unclear.
    METHODS AND RESULTS: In this study, the BV2 microglial cell line was treated with 1 methyl 4 phenyl pyridinium ion (MPP+) to investigate the mechanism of how to promote microglial M1 polarization in PD. Our study demonstrated that the polarization of microglia was facilitated towards the M1 phenotype, with the expression of immune response gene 1 (Irg1) being upregulated, the level of itaconate decreased, and the activation of succinate dehydrogenase (SDH) was enhanced in MPP+-treated BV2 cells. Conversely, Itaconate inhibited the activation of SDH and reversed the M1 polarization in MPP+-exposed BV2 cells. Importantly, the knockdown of Irg1 augmented the activation of SDH and the M1 polarization in MPP+-exposed BV2 cells.
    CONCLUSIONS: These results reveal that MPP+ disorders the Irg1-Itaconate axis and activates SDH, thereby promoting the M1 polarization of BV2 cells. These insights contribute toward a better understanding of the mechanism underlying the microglial M1 polarization in PD and identify the Irg1-Itaconate axis as a potential therapeutic strategy for treating neuroinflammation in PD.
    Keywords:  Irg1-Itaconate axis; Microglia; Microglia polarization; Parkinson's disease; Succinate dehydrogenase
    DOI:  https://doi.org/10.1007/s11033-025-11191-x
  18. Commun Biol. 2025 Nov 28. 8(1): 1718
    Isoallolithocholic acid ameliorates intestinal inflammation via metabolically reprogrammed macrophages.
    Ying Wang, Weihui Yan, Hongxia Zhao, Ying Lu, Yahui Li, Shicheng Peng, Yongtao Xiao.
      The bile acid isoallolithocholic acid (isoalloLCA) has been observed to be reduced in patients with inflammatory bowel diseases (IBD). However, its role in the pathogenesis of pediatric IBD remains poorly understood. Here we show evidence that isoalloLCA treatment decreases lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production in blood cells from children diagnosed with IBD. In experimental models of IBD, isoalloLCA alleviates acute intestinal inflammation caused by LPS or dextran sulfate sodium (DSS) and shows therapeutic efficacy in a chronic colitis model using Il10 knockout (Il10-/-) mice. Within the mucosa of these murine models, isoalloLCA enhances the expression of the regulatory T cell transcription factor Forkhead box P3 (Foxp3), while simultaneously inhibiting ETS2, a critical regulator of inflammatory macrophages in IBD. In bone marrow-derived macrophages (BMDMs), isoalloLCA mitigates LPS-induced inflammation, potentially through the enhancement of mitochondrial reactive oxygen species (mitoROS) production and inhibition of the ETS2-HIF1A/PFKFB3 signaling pathway. Simultaneously, isoalloLCA metabolically reprograms macrophages by enhancing oxidative phosphorylation (OXPHOS) that is linked to anti-inflammatory effects. Our research indicates that metabolic modulation of macrophages amplifies the anti-inflammatory properties of isoalloLCA, thereby revealing a promising therapeutic avenue for addressing pediatric IBD.
    DOI:  https://doi.org/10.1038/s42003-025-09123-3
  19. Cell Rep Med. 2025 Nov 26. pii: S2666-3791(25)00539-7. [Epub ahead of print] 102466
    L-Phenylalanine is a metabolic checkpoint of human Th2 cells.
    Abhijeet J Kulkarni, Juan Rodriguez-Coira, Nino Stocker, Urszula Radzikowska, Antonio J García-Cívico, María Isabel Delgado Dolset, Nuria Contreras, Inés Jardón Parages, Vanesa Saiz Sanchez, Pilar Serrano, Elena Izquierdo, Cristina Gomez-Casado, Javier Sanchez-Solares, Carmela Pablo-Torres, David Obeso, Carmen Moreno-Aguilar, Maria Luisa Espinazo, Andrzej Eljaszewicz, Jana Koch, Katja Baerenfaller, Anja Heider, Ge Tan, Damir Zhakparov, Maria M Escribese, Berta Ruiz-Leon, Cezmi A Akdis, Rafael J Argüello, Domingo Barber, Alma Villaseñor, Milena Sokolowska.
      After the primary response, circulating memory CD4+T effector and T regulatory (Treg) cells regulate recall responses, typically impaired in allergy. We discovered distinct metabolomes of these cells in humans, differentially enriched in phenylalanine-related metabolites. Energy metabolism assessment in in vitro and ex vivo single-cell analyses revealed that increased intracellular L-phenylalanine boosts glycolysis while limiting oxidative phosphorylation (OXPHOS) in CD4+T, memory CD4+T, and Th2 cells, but not in Th1, Th17, or Treg cells. L-phenylalanine also restrains proliferation of memory CD4+T, Th2, and Th17 cells in an IL4I1-dependent manner and limits Th2 differentiation via inhibition of STAT6 and mechanistic target of rapamycin (mTOR) signaling. RNA sequencing, metabolomics, flow cytometry, and proteomics, validated both in vitro and across patient cohorts, revealed impaired LAT1-dependent transport of L-phenylalanine into Th2 cells in allergy, with increased intracellular processing accompanied by expansion of pathogenic Th2 cells. Thus, our study identifies L-phenylalanine as a checkpoint in Th2 cell development, energy metabolism, and function.
    Keywords:  CD4+T cell; Th2 cells; allergy; amino acid; asthma; immunometabolism; metabolomics; phenylalanine; regulatory T cells; single-cell energy metabolism
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102466
  20. Nat Commun. 2025 Nov 23.
    Fructose intake driven glycolysis-ROS-EGFR axis specifically promotes the generation and pathogenicity of Th17 cells.
    Xiaoyu Liu, Wenhao Hu, Jie Sun, Bing Wu.
      Th17 cells are quite heterogeneous. Treating Th17-related inflammatory disorders requires understanding the functionally diverse subtypes in the context of tissue homeostasis, which is shaped by nutrient availability among other factors. Here, we show that increased consumption of fructose exacerbates colitis and experimental autoimmune encephalomyelitis (EAE), via pathogenic Th17 cells. Fructose selectively enhances the differentiation and function of this pathogenic subtype of Th17 cells, which are induced by a combination of IL1β, IL-6 and IL-23 (pTh17). In contrast, TGFβ1and IL-6-induced homeostatic, non-pathogenic Th17 cells remain unaffected. Notably, fructose enhances metabolic activity in pTh17 cells, leading to increased ROS production and subsequently promoting pathogenic-Th17 cell differentiation. N-acetyl cysteine (NAC), a ROS scavenger, specifically impaired pathogenic-Th17 cell immunity and mitigated high-fructose regulated colitis and EAE disease. Mechanistically, ROS accumulation results in elevated EGFR expression and phosphorylation, which leads to increased nuclear translocation. Nuclear EGFR binds to STAT3, enhancing its transcriptional activity at the CNS6 and CNS9 regions of Rorc. In summary, our work describes here a mechanism through which high fructose intake specifically exacerbates pathogenic Th17-cell-related pathologies and provides potential therapeutic targets for pTh17-mediated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-66064-5
  21. Cell Rep. 2025 Nov 26. pii: S2211-1247(25)01379-8. [Epub ahead of print]44(12): 116607
    Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis.
    Battsetseg Batchuluun, Tinne Thoné, Andre Djalalvandi, Russta Fayyazi, Parneet Deo, Julian M Yabut, Sara Maggiore, Bavo Vanneste, Jaya Gautam, Logan K Townsend, Elham Ahmadi, Maria Joy Therese Jabile, Marisa Morrow, Eric M Desjardins, Evangelia E Tsakiridis, Sonia Rehal, Waliul I Khan, Dongdong Wang, Charlotte L Scott, Gregory R Steinberg.
      Monocyte-derived liver macrophages are critical in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, but their recruitment mechanisms remain unclear. Serotonin (5-hydroxytryptamine [5HT]) is a conserved monoamine synthesized by tryptophan hydroxylase 1 (Tph1) in peripheral tissues and Tph2 in the brain. We show that, in mice housed at thermoneutrality and fed a high-fat, high-fructose diet, inhibition of peripheral serotonin (pe5HT) through genetic deletion of Tph1 prevents MASH independent of reduction in body weight. Liver flow cytometry and single-nucleus sequencing showed reduced pro-inflammatory Ly6Chigh monocytes, monocyte-derived Kupffer cells (moKCs), and lipid-associated macrophages (LAMs) in Tph1 knockout (KO) mice. Tph1 deletion also decreased circulating monocytes, specifically Ly6Chigh monocytes. A single 5HT injection increased Ly6Chigh monocytes, while Tph1 KO mice had reduced monocytes without affecting bone marrow monocytes. Mechanistically, serotonin inhibition increases liver AMP-activated protein kinase (AMPK) activity, and this is important for reducing CCL2 and monocyte recruitment. These findings link two ancient energy sensors, 5HT and AMPK, with obesity-associated liver fibrosis.
    Keywords:  AMPK; CP: Immunology; CP: Metabolism; MASH; immunometabolism; liver fibrosis; macrophage; metabolic syndrome; monocyte; obesity; serotonin
    DOI:  https://doi.org/10.1016/j.celrep.2025.116607
  22. Stem Cell Res Ther. 2025 Nov 28.
    Rg1-preconditioned adipose-derived mesenchymal stromal cells alleviate colitis via exosome-mediated Inhibition of macrophage glycolysis through RAS signaling.
    Yuan Fang, Yanni Chen, Xinlang Yu, Jiakang Zhang, Weina Zhu, Cheng Hong Mou, Dawei Wang, Ao Chen, Rui Zhang, Qizhi Liu, Taosheng Li, Bin Jiang.
       AIMS: The therapeutic potential of adipose-derived mesenchymal stromal cells (ADSCs) in inflammatory bowel disease (IBD) is well established, yet the mechanisms underlying their immunoregulatory effects remain unclear. Ginsenoside Rg1 has been shown to enhance the immunomodulatory properties of ADSCs. Given the key role of macrophages in IBD pathogenesis, this study aimed to explore whether mesenchymal stromal cells (MSCs), particularly following Rg1 pretreatment, alleviate colitis by modulating macrophage immunometabolism.
    MAIN METHODS: In vitro experiments were performed in RAW264.7 macrophages and NCM460 cell. In vivo experiments were performed in C57BL/6 mice.
    KEY FINDINGS: Rg1 pretreatment upregulated stemness-related genes and downregulated immunogenic markers in ADSCs. In vivo, Rg1-preconditioned ADSCs significantly alleviated DSS-induced colitis and inhibited M1 macrophage polarization by reducing glycolytic activity. Mechanistically, ADSC-derived exosomes delivered miRNAs that suppressed glycolysis and RAS signaling in macrophages, thereby limiting pro-inflammatory polarization and ameliorating colitis. This miRNA is presumed to be miR-574-3p.
    SIGNIFICANCE: MSCs alleviate experimental colitis by modulating macrophage immunometabolism, and Rg1 pretreatment further enhances this therapeutic potential. This effect may involve exosomal miRNAs that inhibit macrophage glycolysis by suppressing the RAS pathway, one of which is predicted to be miR-574-3p. These results suggest a possible metabolic mechanism underlying MSC-based immunotherapy for ulcerative colitis.
    Keywords:  Exosomes; Immunometabolism; Inflammatory bowel disease; Macrophage polarization
    DOI:  https://doi.org/10.1186/s13287-025-04822-4
  23. Front Immunol. 2025 ;16 1710733
    Gut microbiota-derived metabolites modulate Treg/Th17 balance: novel therapeutic targets in autoimmune diseases.
    Guolin Li, Yu Xiong, Zhimin Li, Qin Yu, Shiran Li, Jingxian Xie, Siyu Zeng, Dongke Yu, Yong Yang, Jiangping Yu.
      Dysregulation of the homeostasis between regulatory T cell (Treg) and T helper 17 cell (Th17) is increasingly recognized as a pivotal mechanism in the pathogenesis of autoimmune diseases. Emerging evidence indicates that gut microbiota-derived metabolites, including short-chain fatty acids, secondary bile acids, and aromatic metabolites, modulate Treg/Th17 balance by shaping immune cell differentiation and function, thereby revealing novel therapeutic opportunities. This Review synthesizes recent clinical and preclinical findings on the influence of microbial communities and their metabolites on Treg/Th17 dynamics and examines the underlying mechanisms in representative autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, autoimmune hepatitis, and myasthenia gravis. We critically evaluate current microbiome-targeted interventions and discuss their translational potential, highlighting both promises and challenges. Finally, we outline priorities for future research, focusing on multi-omic integration, the development of individualized therapeutic strategies, and rigorous clinical evaluation, to facilitate the development of safe and effective microbiota-based therapies for autoimmune diseases.
    Keywords:  Treg/Th17 balance; autoimmune diseases; gut microbiota; immune regulation; microbial metabolites; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2025.1710733
  24. Res Sq. 2025 Oct 23. pii: rs.3.rs-7776704. [Epub ahead of print]
    Piezo1-mediated mechano-energetics regulate CAR T cell function.
    Weiqiang Chen, Ngoc Luu, Rui Li, Yifei Fang, Huishu Wang, Yujing Song, Ruiqi Chen, Xiangyi Fang, Junru Liao, Katsuo Kurabayashi, Roddy O'Connor, Louis Hodgson, Saba Ghassemi, Tracy Chen, Andre Kelly, Alexander Shestov.
      CAR T cell cytotoxicity requires generating immense mechanical force, but the energetic costs of this process remain poorly defined. While metabolic reprogramming fuels effector function, its mechanistic connection to mechanotransduction remains unclear. By directly measuring the synaptic force and mechanical energy of single CAR T cells and linking them to their metabolic state, we proved that the mechano-energetic efficiency is a fundamental determinant of cytotoxic potency. We discovered that the mechanosensitive ion channel Piezo1 couples cytoskeletal dynamics to metabolic rewiring via Ca²⁺-Wnt-Rac1 signaling. Disrupting Piezo1 cripples glycolytic and mitochondrial ATP production, causing energetic stress and impaired cytotoxicity. Notably, Piezo1 activity follows a Goldilocks principle: intermediate level maximizes activation and cytotoxicity, whereas either hypoactive or hyperactive Piezo1 states impair mechano-metabolic fitness and drive dysfunction in patient and exhausted CAR T cells. Our work establishes mechano-metabolic coupling as a core regulator of CAR T cell fitness and pinpoints Piezo1 tuning as a new strategy to enhance cancer immunotherapy. .
    DOI:  https://doi.org/10.21203/rs.3.rs-7776704/v1
  25. Front Immunol. 2025 ;16 1713148
    Immunocyte lipid metabolic reprogramming: a novel pathway for targeted intervention in autoimmune diseases.
    Yanyu Cui, Zhendong Feng, Qihan Zhao, Haoran Dai, Yang Zheng, Hongliang Rui, Baoli Liu.
      Lipids orchestrate immune signaling beyond structure and energy. In autoimmune diseases (ADs), immune cells rewire fatty-acid and cholesterol pathways under microenvironmental pressures, creating pharmacologically actionable dependencies. This metabolic dysregulation is not merely a passive consequence of immune activation but is a key driver of disease progression. This review synthesizes evidence from human and preclinical studies to systematically outline the core regulatory networks of lipid metabolism. It further dissects the role of lipid metabolism in reshaping the functions of T cells, B cells, macrophages, and dendritic cells, and delineates its organ-specific dysregulation in various ADs (e.g., synovium, skin, central nervous system, gut). Rather than blanket immunosuppression, we propose "immune-metabolic normalization": titrating hyperactive nodes to physiological set-points while preserving host defense. We prioritize targets with high translational potential and evaluate corresponding targeted strategies, including drug repurposing, novel agents in clinical development, and innovative interventional concepts. Our work aims to bridge descriptive immunometabolic research with verifiable, patient-centered interventions, laying the groundwork for precision medicine in autoimmune diseases.
    Keywords:  B cells; T cells; autoimmune diseases; immunometabolism; lipid metabolism; macrophages; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1713148
  26. Cell Commun Signal. 2025 Nov 26. 23(1): 507
    WSSV-induced reversal of the malate-aspartate shuttle facilitates viral replication in shrimp hemocytes.
    Fang-Jyun Guo, Kuan-Lun Huang, Cong-Yan Chen, Shu-Wen Cheng, Yen Siong Ng, Han-Ching Wang.
       BACKGROUND: White spot syndrome virus (WSSV), one of the most devastating pathogens in global shrimp aquaculture, has been shown to hijack and reprogram host metabolic pathways to support its replication. Among the various host metabolic circuits, the malate-aspartate shuttle (MAS) is a key redox-balancing mechanism that facilitates the translocation of cytosolic NADH into mitochondria, thereby sustaining glycolysis and mitochondrial function. To date, however, the involvement of MAS in WSSV pathogenesis has not been documented.
    METHODS: In this study, we investigated the role of the MAS pathway in WSSV replication. We first assessed the mRNA level changes of MAS-related genes in WSSV infected shrimp. dsRNA-mediated gene silencing was also employed to examine its impact on the virus replication. To determine the direction of MAS during WSSV infection, we first silenced the MAS-related genes (e.g., GOT1 or GOT2), and subsequently replenished the corresponding metabolite to assess whether it could rescue the virus replication.
    RESULTS: At the viral genome replication stage of WSSV infection (12 hpi), significant upregulation of key MAS-related genes, including LvGOT1, LvGOT2, LvMDH1, LvAGC, and LvOGC, was observed in hemocytes of infected shrimp. Functional knockdown of these genes by in vivo dsRNA-mediated gene silencing significantly reduced WSSV gene expression and viral genome copy number, indicating that MAS activity is required for efficient WSSV replication. Furthermore, metabolite rescue experiments revealed a potential reversal of the MAS flux during the infection: supplementation with aspartate or α-ketoglutarate restored viral replication in LvGOT1-silenced shrimp, while oxaloacetate supplementation reversed the lowered replication caused by LvMDH1 silencing.
    CONCLUSION: This study demonstrates that WSSV activates the host MAS pathway to facilitate its replication and highlights the dynamic reprogramming of redox-associated mitochondrial metabolism in response to WSSV infection. The WSSV-induced reversed MAS might supply specific metabolites such as aspartate needed for virus replication or to prevent the TCA shut down.
    Keywords:   Litopenaeus vannamei ; Aspartate-glutamate carrier; Glutamate-oxaloacetate transaminase; Malate dehydrogenase; Malate-aspartate shuttle; Oxoglutarate carrier; White spot syndrome virus
    DOI:  https://doi.org/10.1186/s12964-025-02506-3
  27. J Transl Med. 2025 Nov 25.
    Lipid deprivation amplifies type I IFN responses in monocytes through prenylation: insights from familial combined hypolipidemia type 2.
    Alessandra Pinzon Grimaldos, Ilenia Pacella, Tiziano Giacomelli, Simone Bini, Alessia Di Costanzo, Ilenia Minicocci, Laura D'Erasmo, Giuseppe Pietropaolo, Valerio Licursi, Marcello Arca, Silvia Piconese.
      Familial Combined Hypolipidemia (FHBL2) is a genetic disorder caused by loss-of-function mutations in the Angiopoietin-like 3 (ANGPTL3) gene. FHBL2 subjects exhibit hypolipidemia and protection from atherosclerotic cardiovascular diseases. Here, we explored the hypothesis that immunometabolic events contribute to this atheroprotective phenotype. To this aim, circulating monocytes from FHBL2 subjects and controls were profiled through gene expression and phenotypic analysis in vivo and ex vivo. In parallel, immune responses were analyzed in monocytes that were lipid-deprived in vitro. In FHBL2 subjects, leukocytes exhibited lower content of intracellular lipids, together with a spontaneous type I IFN signature in vivo and higher sensitivity to IFN stimulation ex vivo. Lipid restriction in vitro was sufficient to recapitulate the higher IFN sensitivity in monocytes, while activating the mevalonate and isoprenoid synthetic pathway. These two events were linked, since a prenylation inhibitor reverted the high IFN response under lipid deprivation. Finally, we found that lipid restriction repressed, in a prenylation- and IFN-dependent fashion, the production of the inflammatory and proatherogenic cytokine IL-1β, and suppressed mitochondrial metabolism, which is a known trigger for inflammasome activation. In summary, we uncovered a novel immunometabolic mechanism linking lipid deprivation in monocytes, isoprenoid synthesis, enhanced IFN response, and IL-1β control. This circuit may provide an immunometabolic basis for the protection from atherosclerotic diseases in hypolipidemic subjects.
    Keywords:  Cholesterol; Immunometabolism; Interferon signature; Isoprenoids
    DOI:  https://doi.org/10.1186/s12967-025-07448-5
  28. Metab Brain Dis. 2025 Nov 25. 40(8): 326
    "Rewiring brain immunity: targeting microglial metabolism for neuroprotection in neurodegenerative disorders".
    Mustafa M Shokr.
      Neuroinflammation, a pervasive hallmark in many neurological and neuropsychiatric diseases, is largely dictated by the functional phenotypic dynamics of microglia, the immune system of the brain. Recent data illustrate that these phenotypic changes, from neuroprotective scavenging to neurotoxic pro-inflammatory effects, are intrinsically regulated by microglial metabolic repolarization. This review synthesizes understanding of discrete microglial metabolic phenotypes like the glycolytic reliance of pro-inflammatory (M1-like) microglia and the oxidative phosphorylation/fatty acid oxidation bias of anti-inflammatory/resolving (M2-like) microglia. We discuss how central metabolic sensors like AMPK, mTOR, and HIF-1α oversee these metabolic shifts in response to disease-targeted pathologies in Alzheimer's, Parkinson's, Multiple Sclerosis, ischemic stroke, and traumatic brain injury. Moreover, we review innovative therapeutic strategies directed toward microglial metabolism, involving pharmacological modulators (e.g., metformin, rapamycin, and ketone bodies), nutritional interventions (e.g., ketogenic diets), and modulation of gut microbiota. By tightly specific re-tuning of microglial cells' bioenergetics, these approaches enable unprecedented opportunities to counteract neuroinflammation, enhance pathological clearance, and induce neuroprotection, paving the way for a new generation of disease-modifying therapies of neurodegenerative disorders.
    Keywords:  Metabolic reprogramming; Microglial metabolism; Neurodegeneration; Neuroinflammation
    DOI:  https://doi.org/10.1007/s11011-025-01739-y
  29. bioRxiv. 2025 Nov 16. pii: 2025.11.14.688556. [Epub ahead of print]
    Autofluorescence imaging reveals the impact of cryopreservation on T cell metabolism and activation response.
    Dan L Pham, Meghana Kalluri, Cole Weaver, Angela Hsu, Amani Gillette, Wenxuan Zhao, Tyce Kearl, Peiman Hematti, Nirav Shah, Melissa C Skala.
      Cryopreservation or the process of freezing cells is a cornerstone of most cell therapy protocols. Optimization of cryopreservation protocols and cryoprotectant agents to improve cell viability and functionality is under further investigation. However, the impact of cryopreservation on cellular metabolism and function immediately post-thaw is not fully understood. Here, we used label-free, non-invasive optical metabolic imaging (OMI) of NAD(P)H and FAD to characterize the activation response of frozen T cells from healthy donors and lymphoma patients post-thaw. Using OMI, we identified significant metabolic shift, along with delayed and diminished activation response in healthy donor T cells throughout the first 4.5 hours upon thawing. In cryopreserved peripheral T cells from lymphoma patients in our bispecific CD19/CD20 CAR T therapy clinical trial, OMI could identify early metabolic stress and allowed gating of metabolically-fit cells associated with post-thaw viability. Notably, in our pilot study, only metabolically-fit T cells from complete responders exhibited metabolic responses to activating stimuli within the first 4.5 hours post-thaw. Overall, our findings suggest that 4-5 hours post-thaw is a critical time window to assess the impact of cryopreservation and thawing, and support the potential of OMI to optimize cryopreservation protocols and evaluate patient T cell quality for cell therapy.
    DOI:  https://doi.org/10.1101/2025.11.14.688556
  30. Geroscience. 2025 Nov 22.
    Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice.
    Ramkumar Thiyagarajan, Rupadevi Muthaiah, Bhavana Sreevelu, Owen P Treanor, Yonas Redae, Reem Berman, Anna L Davis, Nanda Yellapu, Spencer R Rosario, Lee D Chaves, Kenneth L Seldeen, Bruce R Troen.
      Cognitive impairment affects 1 in 6 individuals over 60, with over 75 million projected by 2030. Age-related changes in microglial function and declining nicotinamide adenine dinucleotide (NAD+) levels may contribute to cognitive decline. Although nicotinamide riboside (NR) supplementation can restore NAD+ levels in aged mice, its effects on microglial phenotype and cognition during normal aging remain unclear. We assessed cognitive function, neuroinflammation, and microglial gene expression in 6-month (Young) and 22-month (Aged) mice, along with aged mice supplemented with NR (Aged + NR; 400 mg/kg body weight) for 8 weeks. Aged mice exhibited impaired cognition and increased gene expression related to neuroinflammation. NR supplementation improved or prevented the decline in nest-building ability, Y-maze spontaneous alternation, and novel object recognition, which are reflective of instrumental activities of daily living, spatial working memory, and recognition memory. NR supplementation diminished microglial (IBA1) and astrocytic (GFAP) activation, resembling the young phenotype. Gene expression profiling revealed reduced microglial activation, inflammatory pathways, and chemokine production in Aged + NR mice, along with upregulation of genes associated with learning, memory, and gliogenesis. NR lowered transcriptional signatures from age-dependent (ADEM) and disease-associated (DAM) microglia and enhanced homeostatic state profiles. Metabolic pathway analysis of microglial transcripts indicated that NR suppressed age-induced increases in fatty acid metabolism. This was supported by immunostaining, which showed reduced lipoprotein lipase (LPL), a DAM marker, in the cortex and hippocampus. Overall, NR appeared to mitigate age-related cognitive decline by shifting microglial gene expression and metabolism toward a younger phenotype, suggesting potential therapeutic relevance for healthy brain aging.
    Keywords:  Aging; Cognition decline; Disease-associated microglia; Microglia; NAD metabolism
    DOI:  https://doi.org/10.1007/s11357-025-01959-1
  31. Dev Cell. 2025 Nov 27. pii: S1534-5807(25)00691-4. [Epub ahead of print]
    Vitamin B6 preserves the stemness-like phenotypes and antitumor ability of CD8+ T cells.
    Jun Wu, Gen Li, Jiawen Zhou, Xuan Sun, Haoyu Wang, Haipeng Gong, Peng Jiang.
      Tumor-infiltrating lymphocytes are usually dysfunctional but demonstrate stem cell-like behavior through unclear mechanisms. Here, we report that administration of vitamin B6 or its active form, pyridoxal phosphate (PLP), endows mouse and human CD8+ T cells with improved persistence, stemness-like phenotypes, and tumor clearance capabilities. Lowering PLP by pyridoxal kinase (PDXK) heterozygosity results in reduced T cell stemness-like properties and increased exhaustion phenotypes in tumors. Mechanistically, PLP preserves T cell function by directly binding to and inhibiting p70S6 kinase (p70S6K). Through limiting p70S6K-mediated BTB domain and CNC homolog 2 (BACH2) phosphorylation, PLP increases nuclear retention and functional activation of BACH2, promoting stemness gene expression while dampening exhaustion gene expression. In preclinical tumor models, PLP treatment improves the efficacy of anti-programmed death receptor 1 (PD-1) antibody therapy. Thus, our study reveals a pathway that preserves T cell functional stemness-like phenotypes to drive the acquisition of antitumor immunity, highlighting the clinical potential of vitamin B6/PLP-enhanced T cell function strategies in cancer immunotherapy.
    Keywords:  T cell differentiation; antitumor immunity; metabolite signaling; p70S6K; vitamin B6
    DOI:  https://doi.org/10.1016/j.devcel.2025.10.017
  32. JCI Insight. 2025 Nov 25. pii: e196605. [Epub ahead of print]
    ANGPTL8 links refeeding to monocyte dynamics and metabolic inflammation via the CCL5-CCR5 axis.
    Ran-Ran Kan, Si-Yi Wang, Xiao-Yu Meng, Li Huang, Yu-Xi Xiang, Bei-Bei Mao, Hua-Jie Zou, Ya-Ming Guo, Li-Meng Pan, Pei-Qiong Luo, Yan Yang, Zhe-Long Liu, De-Lin Ma, Wen-Jun Li, Yong Chen, Dan-Pei Li, Xue-Feng Yu.
      Metabolic inflammation is closely linked to dynamic changes in circulating monocyte populations, yet how nutritional signals regulate this process remains unclear. ANGPTL8, a hepatokine rapidly induced by refeeding, emerged as a key regulator of postprandial monocyte dynamics. We examined ANGPTL8 expression in human and murine fasting-refeeding models and manipulated ANGPTL8 expression specifically in hepatocytes to assess its role in metabolic inflammation and insulin resistance in obese mice. ANGPTL8 overexpression elevated circulating monocytes and proinflammatory cytokines, while its deletion reduced these parameters and conferred metabolic benefits. Mechanistically, recombinant ANGPTL8 stimulated CCL5 production in bone marrow-derived macrophages via P38 signaling activation, promoting monocyte recruitment and proinflammatory macrophage polarization. These effects were mitigated by CCR5 antagonism. Rescue experiments demonstrated that CCL5 supplementation in Angptl8-deficient mice restored monocyte levels and inflammatory responses. Functionally, ANGPTL8 worsened insulin resistance and glucose intolerance in obese mice, effects that were reversed by its deletion and recapitulated by CCL5 administration. These findings suggest that ANGPTL8 functions as a nutritional checkpoint linking feeding status to monocyte-mediated inflammation through the CCL5-CCR5 axis. By driving monocytosis and proinflammatory macrophage activation, ANGPTL8 exacerbates metabolic dysfunction. Targeting the ANGPTL8-CCL5-CCR5 pathway may therefore offer a promising therapeutic strategy for managing obesity-related metabolic diseases.
    Keywords:  Cell migration/adhesion; Chemokines; Immunology; Metabolism; Monocytes
    DOI:  https://doi.org/10.1172/jci.insight.196605
  33. Res Sq. 2025 Oct 27. pii: rs.3.rs-7794494. [Epub ahead of print]
    Disruption of metabolic licensing by JAK inhibitors constrains CD8 T cell activation and effector function.
    Eva Acosta Rodriguez, Luisina Onofrio, Carolina Abrate, Ingrid Strusberg, Liliana Morales, Danilo Ceschin, Carolina Montes, Cinthia Stempin.
      Janus kinase inhibitors (JAKis) are widely prescribed for autoimmune diseases, but their use is associated with increased infection risk. The mechanisms underlying this susceptibility remain unclear. CD8 T cells play a central role in antimicrobial defense, yet little is known about how JAKis reprogram their activation and effector programs. Here, we investigated naïve and memory CD8 T cells from healthy donors stimulated in vitro with baricitinib, tofacitinib, or upadacitinib. Flow cytometry, SCENITH, transmission electron microscopy, and RNA-seq were used to evaluate metabolic and functional programs. We found that JAKis uncoupled phenotypic activation from metabolic reprogramming. Functionally, JAKi-treated CD8 T cells exhibited reduced activation and produced lower amounts of cytokines and cytotoxic molecules. Notably, even JAKi-treated memory CD8 T cells that upregulated CD69 and CD25 failed to engage glycolysis, showing decreased GLUT1 expression and glucose uptake. SCENITH profiling confirmed diminished glucose dependence and a shift toward mitochondrial reliance, despite reduced mitochondrial potential and structural alterations. Transcriptomic and protein analyses further revealed decreased mTOR activity and increased p53-associated transcripts, consistent with impaired growth and stress signaling. CD8 T cells from rheumatoid arthritis patients under JAKi therapy were analyzed ex vivo for translational validation. These cells showed similar metabolic and signaling alterations, underscoring their clinical relevance. Altogether, these findings identify JAKis as disruptors of metabolic and signaling pathways in CD8 T cells, providing a mechanistic link between impaired effector function and the increased infection risk observed in treated patients.
    DOI:  https://doi.org/10.21203/rs.3.rs-7794494/v1
  34. Prog Neuropsychopharmacol Biol Psychiatry. 2025 Nov 26. pii: S0278-5846(25)00320-3. [Epub ahead of print] 111566
    Mitochondrial metabolic reprogramming of microglia in neuroinflammation: Implications for major depressive disorder.
    Yu-Fei Wang, Cong-Ya Chen, Xuan-Yang, Lan Lei, Yi Zhang.
      Major depressive disorder (MDD) is a recurrent episodic mood disorder characterized by persistent low mood and loss of interest. The pathogenesis of major depressive disorder (MDD) involves a neuroinflammatory response, neurotransmitter dysfunction, blood-brain barrier disruption, oxidative stress, and mitochondrial dysfunction. Neuroinflammation, caused by the overactivation of microglia, is considered a key factor in the development of the disease. Metabolic reprogramming has been shown to play a crucial role in microglial activation and executive function. In MDD, microglia have the potential to become activated and transform into either pro-inflammatory or anti-inflammatory phenotypes. These variations in cellular phenotypes lead to differences in cellular energy metabolism. Mitochondria are involved in the energy metabolism of microglia and have intricate connections with microglia-mediated metabolic reprogramming and neuroinflammation. However, the specific changes in the metabolic reprogramming of microglia in depression, the numerous signaling pathways and cytokines involved, and the mechanisms by which they mediate phenotypic transitions remain unclear. Therefore, this review summarizes the metabolic reprogramming of microglia in MDD, as well as the involved signaling pathways, mitochondrial involvement and cytokines, and elaborates on their interaction with phenotypic transformation. The effects of drugs on regulating immune metabolic reprogramming to suppress neuroinflammation were summarized, providing potential for new research approaches in the treatment of MDD.
    Keywords:  Immunometabolic reprogramming; Major depressive disorder; Microglia; Mitochondria; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.pnpbp.2025.111566
  35. JCI Insight. 2025 Nov 24. pii: e185914. [Epub ahead of print]10(22):
    A shift in PKM2 oligomeric state instructs adipocyte inflammatory potential.
    Michelle Sma Damen, Pablo C Alarcon, Calvin C Chan, Traci E Stankiewicz, Hak Chung, Keisuke Sawada, Cassidy J Ulanowicz, John Eom, Jarren R Oates, Jennifer L Wayland, Jessica R Doll, Rajib Mukherjee, Miki Watanabe-Chailland, Lindsey Romick-Rosendale, Sara Szabo, Michael A Helmrath, Joan Sanchez-Gurmaches, Maria E Moreno-Fernandez, Senad Divanovic.
      Processes that promote white adipocyte inflammatory function remain incompletely defined. Here, we demonstrated that type I interferon-dependent (IFN-I-dependent) skewing of adipocyte glycolysis, nicotinamide adenine dinucleotide (NAD+) utilization, and pyruvate kinase isozyme M2 (PKM2) function may contribute to increased systemic and tissue inflammation and disease severity in obesity. Notably, chemical and/or genetic inhibition of glycolysis, the NAD+ salvage pathway, or PKM2 restricted IFN-I-dependent increase in adipocyte inflammatory cytokine production. Further, genetic or small molecule targeting of PKM2 function in vivo was sufficient to reduce systemic and tissue inflammation and metabolic disease severity in obese mice, in an adipocyte PKM2-dependent manner. Further, white adipose tissue of individuals living with obesity and metabolic disease, compared with metabolically healthy individuals with obesity, showed an increase in expression of inflammatory and metabolic genes, while small molecule targeting of PKM2 function contributed to reduced IFN-I-driven inflammatory cytokine production by primary human adipocytes. Together, our findings invoke the IFN-I/PKM2 axis as a potential target for modulating adipocyte dysregulated inflammation.
    Keywords:  Adipose tissue; Cytokines; Immunology; Inflammation; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.185914
  36. bioRxiv. 2025 Nov 10. pii: 2025.11.09.687253. [Epub ahead of print]
    Spatial Partitioning of Core Glycolysis Enables Tissue-Specific Metabolic Programs In Vivo.
    Ian J Gonzalez, Aaron D Wolfe, Benjamin Clark, Michael Hanna, Quishi Sun, Snusha Ravikumar, Anastasia Tsives, Sarah E Emerson, Stephan Siebel, Richard Kibbey, Daniel Colón-Ramos.
      Tissues exhibit metabolic heterogeneity that tailors metabolism to their physiological demands. How the conserved pathways of metabolism achieve metabolic heterogeneity is not well understood, particularly in vivo. We established a system in Caenorhabditis elegans to investigate tissue-specific requirements for glucose 6-phosphate isomerase (GPI-1), a conserved glycolytic enzyme that also regulates the pentose phosphate pathway (PPP). Using CRISPR-Cas9 genome editing, we found that gpi-1 knockout animals display germline defects consistent with impaired PPP, and somatic defects consistent with impaired glycolysis. We discovered that two GPI-1 isoforms are differentially expressed and localized: GPI-1A is expressed in most tissues, where it displays cytosolic localization, whereas GPI-1B is primarily expressed in the germline, where it localizes to subcellular foci near the endoplasmic reticulum. GPI-1B expression alone is sufficient to maintain wild type levels of reproductive fitness, but insufficient to reconstitute wild-type glycolytic dynamics. Our findings uncover isoform-specific, spatially-compartmentalized functions of GPI-1 that underpin tissue-specific anabolic and catabolic metabolism in vivo , underscoring roles for subcellular localization in achieving tissue-specific metabolic flux.
    DOI:  https://doi.org/10.1101/2025.11.09.687253
  37. mBio. 2025 Nov 24. e0314725
    Amino acid decarboxylation preserves Salmonella fitness during phagocyte-derived oxidative stress.
    Alyssa Margolis, Lin Liu, Ju-Sim Kim, Steffen Porwollik, Michael McClelland, Andrés Vázquez-Torres.
      Successful establishment of infection by non-typhoidal Salmonella depends upon its ability to resist the antimicrobial defenses of the host innate immune response. To withstand the membrane depolarization that potentiates the killing activity of reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase, Salmonella employs metabolic adaptations that maintain intracellular pH homeostasis and membrane energetics. Here, we identify amino acid decarboxylation as a critical determinant of Salmonella virulence and resistance to the oxidative pressures within the host environment. The proton-consuming decarboxylation of L-arginine preserves intracellular ∆pH and enhances Salmonella survival against the bactericidal effects of ROS, while downstream polyamine biosynthesis aids in bacterial recovery following ROS exposure. Polyamines alone cannot substitute for the immediate, protective impact of proton-consuming decarboxylation during oxidative stress killing. Specifically, we show that Salmonella relies on the combined activity of the inducible arginine AdiA and the ornithine SpeF decarboxylases for resistance to oxidative stress, and that this activity is essential for Salmonella virulence during systemic infection. Together, amino acid decarboxylation and polyamine biosynthesis play complementary, but distinct roles in Salmonella adaptation to phagocyte-derived oxidative stress, providing a new framework for understanding how amino acid catabolism influences bacterial survival in the host.
    IMPORTANCE: Salmonellae have been causing disease in humans since at least the Neolithic Revolution, yet non-typhoidal Salmonella infections remain a significant public health challenge. The success of Salmonella as a pathogen stems, in part, from its ability to subvert and survive the host response of macrophages. The amino acid L-arginine is critical for Salmonella enterica serovar Typhimurium virulence and resistance to reactive oxygen species produced by the phagocyte NADPH oxidase. The precise mechanisms by which L-arginine fosters oxidative stress resistance have remained unclear. In this report, we demonstrate that Salmonella relies on the proton-consuming decarboxylation of L-arginine and ornithine to promote resistance against the acute cytotoxicity emanating from the phagocyte NADPH oxidase. On the other hand, polyamines synthesized downstream of L-arginine and ornithine decarboxylation aid in the recovery phase. Our findings redefine the physiological role of amino acid decarboxylation, establishing it as a critical defense mechanism against oxidative stress that is functionally distinct from polyamine biosynthesis. By disentangling the regulatory and functional roles of individual decarboxylases, our study clarifies a long-standing ambiguity in the field and highlights how Salmonella exploits complementary metabolic pathways during its adaptation to oxidative stress in the host.
    Keywords:  Salmonella; gram-negative bacteria; host-pathogen interactions; intracellular pathogens; macrophages; metabolism; oxidative stress; pathogenesis
    DOI:  https://doi.org/10.1128/mbio.03147-25
  38. bioRxiv. 2025 Oct 30. pii: 2025.10.29.680858. [Epub ahead of print]
    Acute activation of Gq-signaling in islet macrophages inhibits β-cell insulin secretion through AMPK-sphingolipid axis.
    Simran Singh, Ashish Kumar, Sudipta Paul, Mriganka Sarkar, Santhosh Duraisamy, Harender Yadav, Seema Kuldeep, Soumita Bhaumik, Kunj Kumar Prajapati, Saahiba Thaleshwari, Anuj Gargya, Tamojit Santra, Sonal Amit, Rashmi Parihar, Santosh K Misra, Hamim Zafar, Luiz F Barella, Dharmaraja Allimuthu, Sai Prasad Pydi.
      Obesity-associated inflammation disrupts pancreatic β-cell function, but the immune-derived signals that directly regulate insulin secretion remain incompletely defined. Here, we identify myeloid Gq signaling as a critical immunometabolic node that links macrophage activation to β-cell dysfunction. For the first time, we employed a chemogenetic approach (DREADDs) to selectively and temporally activate Gq-coupled GPCR signaling in myeloid cells to examine its effect on islet function. Our findings reveal that acute Gq activation in islet-resident macrophages impaired glucose-stimulated insulin secretion, uncovering a previously unrecognized immune-endocrine axis. Conversely, myeloid-specific Gαq deletion improves systemic glucose homeostasis, underscoring the physiological relevance of this pathway. Mechanistic analysis revealed that Gq activation in macrophages stimulates AMPK signaling and drives the secretion of sphingolipids. These lipids suppress insulin secretion and introduce a new mechanism for immune-islet communication, extending beyond traditional cytokine-based models. We further identify the lipid-sensing receptor GPR18 as an upstream activator of the Gq-AMPK pathway in macrophages. GPR18 stimulation recapitulated the Gq-dependent sphingolipid secretion and β-cell inhibitory phenotype, which was abolished in myeloid Gαq-deficient mice. Collectively, these findings establish a mechanistic framework whereby macrophage Gq signaling integrates lipid sensing and metabolic stress to modulate β-cell function. This work reveals a previously unrecognized macrophage-β-cell communication axis with therapeutic potential for restoring insulin secretion in metabolic diseases such as obesity and type 2 diabetes.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2025.10.29.680858
  39. bioRxiv. 2025 Oct 27. pii: 2025.10.22.683940. [Epub ahead of print]
    Elevated plasma cholesterol causally improves sepsis outcome by promoting hepatic metabolic reprogramming.
    Qian Wang, Jianyao Xue, Ling Guo, Dan Hao, Misa Ito, Rianna Reese, Bin Huang, Congqing Wu, Xiang-An Li.
       Rationale: Sepsis is a life-threatening condition with high mortality and limited therapeutic options. While hypocholesterolemia is associated with poor outcomes, the causal role of cholesterol and its underlying mechanisms remain unclear.
    Objectives: To determine whether elevated plasma cholesterol improves sepsis survival and to elucidate the mechanistic basis of this effect.
    Methods: We analyzed septic patients from the MIMIC-IV database. Total cholesterol levels were compared between 28-day survivors and non-survivors using Wilcoxon rank-sum tests. Cox proportional hazards regression assessed the association between cholesterol levels and mortality, adjusting for age, sex, race, SOFA score, and Charlson comorbidity index. To establish causality, C57BL/6J mice were randomized to receive either a high-cholesterol diet (HCD) or regular diet (RD) for three days prior to cecal ligation and puncture (CLP) to induce sepsis.
    Measurements and Main Results: Survivors had significantly higher cholesterol levels than non-survivors (median, 135 vs. 126 mg/dL, p < 0.001). High cholesterol (≥ 133 mg/dL) was independently associated with reduced 28-day mortality (adjusted HR = 0.80, 95% CI: 0.67-0.95, p = 0.012). In mice, HCD elevated plasma cholesterol and significantly improved survival (52.5% to 90%), independent of immune modulation.Hepatic transcriptomics revealed metabolic reprogramming, including upregulation of oxidative phosphorylation and glutathione-mediated antioxidant pathways, and suppression of endoplasmic reticulum proteostasis. Notably, inhibition of mitochondrial respiration abolished the survival benefit.
    Conclusions: Elevated plasma cholesterol causally improves sepsis outcomes by promoting hepatic metabolic reprogramming. These findings offer mechanistic insight into clinical observations and suggest hepatic bioenergetics as a novel therapeutic target in sepsis.
    DOI:  https://doi.org/10.1101/2025.10.22.683940
  40. Front Immunol. 2025 ;16 1696113
    The impact of metabolic reprogramming in hepatocellular carcinoma on T cell.
    Dong-Xu Liao, Xiang An, Gui-Xiang Huang, Tong-Ling Yuan.
      Hepatocellular carcinoma (HCC) is the predominant type of liver cancer, characterized by high incidence and mortality rates. Despite advancements in surgical and systemic therapies, the prognosis remains poor due to the asymptomatic nature of early-stage HCC. Metabolic reprogramming in HCC cells usually creates an immunosuppressive tumor microenvironment (TME), thereby impeding T cell-mediated antitumor immunity. This review focuses on the metabolic reprogramming patterns in HCC, their impact on T cell function, and the potential of metabolic-immune targeted combination therapies. We emphasize that nutrient competition and the accumulation of inhibitory metabolites are key mechanisms underlying T cell suppression in the TME. This review provides an update on the complex metabolic-immune interactions and helps to identify new therapeutic targets to improve the efficacy of immunotherapy for HCC.
    Keywords:  T cell-mediated antitumor immunity; hepatocellular carcinoma (HCC); metabolic reprogramming; metabolic-immune targeted combination therapies; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1696113
  41. Cell Mol Life Sci. 2025 Nov 24.
    Integrated multiomics reveals host-virus coadaptation in persistent foot-and-mouth disease virus infection.
    Shuang Wang, Zhihui Zhang, Sumin Wei, Guoliang Huang, Shuanghui Yin, Suyu Mu, Hu Dong, Shiqi Sun, Huichen Guo.
      A comprehensive understanding of host-virus interactions during persistent foot-and-mouth disease virus (FMDV) infection is essential for elucidating the mechanisms that underpin disease causation by this highly contagious pathogen. This understanding necessitates the development of stable in vitro models. In this study, we established a model of persistent FMDV serotype O infection in Madin-Darby bovine kidney epithelial cells followed by integrated multiomics analyses. These analyses revealed that host cells adapt to persistent viral infection by reprogramming mitochondrial metabolism. This reprogramming is accompanied by alterations in mitochondrial structure and function, as well as the suppression of the apoptotic response in host cells. In particular, bystander cells, which are devoid of active viral replication, display enhanced proliferative capacity and possess a distinct microenvironmental signature that potentially increases viral susceptibility, facilitating sustained virus persistence within the cell population. Moreover, persistent viruses have evolved enhanced replicative fitness. Our findings elucidate the biological characteristics of FMDV-infected cell populations that persistently harbour the virus, reveal host-virus coadaptation, and highlight the critical role of bystander cells in sustaining persistent FMDV infection. These discoveries establish the foundation for further mechanistic studies of FMDV persistence maintenance.
    Keywords:  Host adaptation; Mitochondrial damage; Systems biology; Viral fitness; Virus-eliminated cells
    DOI:  https://doi.org/10.1007/s00018-025-05997-y
  42. PLoS Negl Trop Dis. 2025 Nov 25. 19(11): e0013768
    Toxoplasma gondii disrupts intestinal microbiota and host metabolism in a rat model.
    Ji-Xin Zhao, Wen-Bin Zheng, Shi-Chen Xie, He Ma, Xiao-Tong Chen, Ying-Qian Gao, Lu-Yao Tang, Meng-Ting Yang, Fu-Long Nan, Jing Jiang, Hany M Elsheikha, Xiao-Xuan Zhang.
      Toxoplasma gondii infection disrupts the gut microbiota and host systemic metabolism, which plays a key role in the pathophysiology of toxoplasmosis. To investigate these interactions, we conducted metagenomic sequencing and untargeted serum metabolomics on 18 Sprague-Dawley rats across control, acute, and chronic stages of infection. De novo assembly of 148 Gb of high-quality reads produced a comprehensive non-redundant microbial gene catalog comprising over 5.7 million genes. Infection led to a marked reduction in microbial diversity and significant shifts in community structure. Chronic infection, in particular, was characterized by the enrichment of Lactobacillus johnsonii, Lactobacillus intestinalis, and Limosilactobacillus reuteri, alongside a marked depletion of Akkermansia muciniphila and Rothia nasimurium. These compositional changes coincided with reduced abundance of carbohydrate-active enzymes, suggesting impaired microbial metabolic capacity. Pathway analysis revealed distinct, stage- and gut-region-specific metabolic disruptions, including suppressed amino acid and energy metabolism, and enhanced glycan and carbohydrate pathways during chronic infection. Untargeted LC-MS/MS profiling uncovered 883 differentially abundant serum metabolites, enriched in pathways related to amino acid metabolism, bile acid transformation, and aromatic compound processing. Importantly, L. johnsonii and L. reuteri were positively correlated with metabolites implicated in immune modulation and oxidative stress response, whereas A. muciniphila showed negative associations. These findings demonstrate that T. gondii infection orchestrates a coordinated host-microbiota-metabolome network, advancing our understanding of disease mechanisms and pointing to novel microbial and metabolic targets for therapy.
    DOI:  https://doi.org/10.1371/journal.pntd.0013768
  43. Biochem Pharmacol. 2025 Nov 20. pii: S0006-2952(25)00818-4. [Epub ahead of print]243(Pt 2): 117553
    LDHA facilitates immune escape in bladder cancer through H4K5 lactylation-dependent upregulation of PD-L1.
    Sensheng Tang, Yu Liu, Bo Jin, Tianyang Zhang, Xingbo Wang, Jie Zhao, Zhibin Xu, Wenchao Zhao, Hao Bian, Kai Li, Yuan Xia, Hui Wang, Maomao Guo.
      Metabolic reprogramming, characterized by hyperactive glycolysis, is a hallmark of bladder cancer (BCa) progression. Here, we identify lactate dehydrogenase A (LDHA) as a central metabolic node coupling glycolytic flux to epigenetic regulation of the immune checkpoint molecule PD-L1. Transcriptomic and survival analyses reveal that dysregulated glycolytic enzymes, particularly LDHA, correlate with poor prognosis and immunotherapy response in BCa patients. Mechanistically, LDHA-driven lactate production induces histone H4K5 lactylation (H4K5la), facilitated by the acetyltransferase EP300, which directly activates PD-L1 transcription. Depletion of LDHA or EP300 reduces H4K5la levels and suppresses PD-L1 expression. Critically, EP300 knockdown reverses PD-L1 upregulation induced by LDHA overexpression, establishing a causal LDHA-EP300-H4K5la-PD-L1 axis that drives immune evasion. Furthermore, RNA immunoprecipitation and luciferase reporter assays suggest that m6A RNA modification may potentiate LDHA overexpression. Collectively, this work unveils a dual-layered mechanism-metabolic lactate flux and histone lactylation that orchestrates immune evasion in BCa, proposing LDHA and EP300 as actionable targets to restore antitumor immunity.
    Keywords:  Bladder cancer; Histone lactylation; Immune escape; Immunotherapy; LDHA; PD-L1
    DOI:  https://doi.org/10.1016/j.bcp.2025.117553
  44. J Invest Dermatol. 2025 Nov 20. pii: S0022-202X(25)03555-9. [Epub ahead of print]
    CD36-mediated long-chain fatty acids transport in keratinocytes promotes psoriasis-like skin inflammation through increasing mitochondrial reactive oxygen species.
    Jiajia Lan, Biling Jiang, Xinyue Zhang, Yuting Xia, Zhen Cai, Yan Xiong, Jing Yang, Yan Li, Juan Tao.
      Altered epidermal lipid metabolism along with keratinocyte dysfunction is a characteristic feature of psoriasis. CD36, a key fatty acid translocase, has been implicated in various inflammatory diseases through its regulation of lipid metabolism, but its role in the keratinocytes of psoriasis remains unclear. Here, we found that CD36 was significantly elevated in the lesional epidermis of psoriasis patients and positively correlated with the disease severity. Mice with keratinocyte-specific CD36 knockout or sulfosuccinimidyl oleate (the blocker of CD36) ointment topical treatment, exhibited relieved imiquimod (IMQ)-induced psoriasis-like inflammation visually and histologically. Furthermore, gas chromatography tandem mass spectrometry (GC-MS) analysis revealed significant increase of CD36 ligands, particularly long-chain fatty acids (LCFAs), in lesional skin from both psoriasis patients and IMQ-induced psoriatic mice. In vitro, CD36 facilitated LCFAs transport into keratinocytes, leading to lipid accumulation and elevated expression of chemokines, notably CXCL2 and CCL20, which recruit neutrophils and CCR6+ T cells, respectively. Mechanistically, CD36-mediated LCFAs uptake impaired mitochondrial function and induced mitochondrial reactive oxygen species (mtROS) generation, thereby activating the NF-κB signaling pathway and promoting chemokine production. These findings demonstrate an essential role of CD36 in lipid metabolic‒inflammatory crosstalk in keratinocytes, suggesting it could be a potentially effective therapeutic target in inflammatory skin diseases.
    Keywords:  CD36; Keratinocytes; Long-chain fatty acids; Mitochondrial reactive oxygen species; Psoriasis
    DOI:  https://doi.org/10.1016/j.jid.2025.10.615
  45. Biochem Biophys Res Commun. 2025 Nov 24. pii: S0006-291X(25)01760-7. [Epub ahead of print]794 153044
    Mitochondrial transplantation alleviates acute pancreatitis by suppressing macrophage necroptosis.
    Cai Sun, Liang Pan, Chengsi Tang, Yiyuan Liu, Sha Ran, Ying Li, Yan Shen.
      Acute pancreatitis (AP) is a multifactorial disease in which mitochondrial dysfunction plays a key role by triggering inflammatory cascades and necrotic cell death. Mitochondrial transplantation has been reported to alleviate AP, however its underlying mechanisms remain unclear. To investigate the effect of mitochondrial transplantation on macrophage during AP, we stimulated macrophages with supernatant of damaged pancreatic acinar cells to mimic the inflammatory microenvironment. Upon stimulation, macrophages exhibited an enhanced capacity to internalize exogenous mitochondria. These exogenous mitochondria restored mitochondrial function in damaged macrophages by maintaining mitochondrial membrane potential, suppressing excessive reactive oxygen species production, and restoring ATP levels. Furthermore, mitochondria transplantation significantly inhibited macrophages necroptosis, as evidenced by the decreased protein expression and phosphorylation levels of the necroptosis markers RIPK1 and MLKL in macrophages and pancreatic tissue, and decreased cell necrosis. In terms of inflammation, exogenous mitochondria suppressed macrophage polarization toward the pro-inflammatory M1 phenotype and reduced the expression of pro-inflammatory cytokines. Collectively, these findings demonstrate that macrophage-centered inflammatory regulation constitutes a central mechanism underlying the therapeutic effects of mitochondrial transplantation in AP, providing a theoretical foundation for developing mitochondria-based therapeutic strategies.
    Keywords:  Acute pancreatitis; Macrophage; Mitochondrial transplantation; Necroptosis
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153044
  46. Nat Commun. 2025 Nov 26. 16(1): 10580
    A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models.
    Dongming Lv, Lei Ren, Zirui Zhao, Yanchao Rong, Miao Chen, Hao Yang, Rong Yin, Ruixi Zeng, Hua Chao, Xiaohui Li, Zhongye Xu, Zhicheng Hu, Xiaoling Cao, Wuguo Deng, Qing Tang, Bing Tang.
      Timely infiltration and effective turnover of macrophages after trauma are essential for wound regeneration. In pathological conditions, such as diabetic wounds, how disturbances in cellular collaboration leads to persistent inflammatory infiltration remains unclear. Herein, we identify that the expression of methionine adenosyltransferase 2 A (MAT2A), which is downregulated in pericytes, is negatively correlated with inflammatory macrophage infiltration in diabetic wounds. Cspg4-CreERT2/+; Mat2aflox/flox female mouse model and single-cell sequencing of its wound tissue reveal that TAM induced-Mat2a deficiency in pericytes induces cell senescence and further drives the inflammatory trained immunity of infiltrating macrophages through senescence-associated secretory phenotype factors and cellular mitochondrial transfer. Mechanistically, MAT2A downregulation in pericyte reduces the recruitment of the deubiquitinase OTUB1 to HMGCS1 and thus reduces HMGCS1 expression level, thereby interfering with coenzyme Q synthesis, affecting mitochondrial function, and inducing cell senescence. We then coat self-amplifying RNA-loaded nanoparticles with pericyte membrane to restore stable MAT2A expression in senescent pericytes, effectively alleviating the persistent inflammatory macrophage infiltration and promoting wound regeneration. Our results reveal MAT2A as a potential therapeutic target in chronic inflammatory wounds and suggest a targeting senotherapy based on a biomimetic strategy.
    DOI:  https://doi.org/10.1038/s41467-025-65659-2
  47. bioRxiv. 2025 Oct 07. pii: 2025.10.07.680928. [Epub ahead of print]
    A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense in lupus.
    Eden G TenBarge, Ashley D Wise, Morgan L Hetzel, Helene A Hoover, Helia Esfandiari, Bailey E Holder, Eva Belevska, Ellie C Mennen, Sarah R McDaniel, Nicole M Vaccaro, Courtney C Lucca, Jonathan M Williams, Jennifer Ferris, Timothy E Sparer, Leslie J Crofford, Jeffry D Bieber, Andrew J Monteith.
      Patients with systemic lupus erythematosus (SLE) are susceptible to bacterial infections, but the underlying dysfunction remains unclear. We found that Staphylococcus aureus triggers mitochondria-dependent suicidal NETosis via lactate sensing in healthy neutrophils, but this response is defective in SLE. Herein, we show that chronic Toll-like receptor (TLR) 7/9 signaling represses mitochondrial lactate dehydrogenase B (LDHB), thereby impairing lactate sensing and downstream suicidal NETosis. Instead, SLE neutrophils default to vital NET release; a less bactericidal, type I interferon (IFN)-driven process amplified by staphylococcal pore-forming toxins and sustained by elevated systemic IFNα levels observed in SLE. Combined treatment with hydroxychloroquine (HCQ) and interferon-alpha/beta receptor (IFNAR) blockade restores LDHB expression, NET homeostasis, and bacterial clearance in lupus-prone mice. Neutrophils from SLE patients exhibit similar defects, which are reversed by HCQ and the IFNAR-blocking antibody anifrolumab. These findings identify a clinically actionable immunometabolic checkpoint linking chronic autoimmune signaling to defective antibacterial defense in SLE.
    DOI:  https://doi.org/10.1101/2025.10.07.680928
  48. Nat Commun. 2025 Nov 26.
    A noncanonical polyamine from bacteria antagonizes host mitochondrial function.
    Kelsie M Nauta, Darrick R Gates, Matthew Weiland, Marco E Mechan-Llontop, Xiao Wang, Christine Isaguirre, Megan R Gendjar, Jason Cooper, Sawyer F Barton, Kim P Nguyen, Ryan D Sheldon, Connie M Krawczyk, Nicholas O Burton.
      Interactions between gut bacterial polyamines and intestinal cells have been proposed to contribute to inflammatory bowel diseases, but the underlying molecular mechanisms are often unclear. Here, we use a derivatization-based LC-MS approach and the model animal Caenorhabditis elegans to study microbiome-derived polyamine bioactivity. We show that aberrant polyamine metabolism in two diverse bacterial species (Escherichia coli K12 and Bacillus subtilis 168) can result in the accumulation of a noncanonical polyamine intermediate, N1-aminopropylagmatine (N1-APA). N1-APA is produced via spermidine synthase (SpeE) and is bioactive in C. elegans intestinal cells and mouse bone marrow macrophages. Specifically, bacterial N1-APA can be transported into intestinal cells via the polyamine transporter CATP-5, where it antagonizes C. elegans development and activates the mitochondrial unfolded protein response. N1-APA functions analogously to the deoxyhypusine synthase inhibitor GC7 in C. elegans and, like GC7, it antagonizes eIF5A hypusination and inhibits the alternative activation of mouse macrophages in vitro. Our results indicate that bacterial N1-APA is a bioactive metabolite that functions similarly to deoxyhypusine synthase inhibitors but has other unidentified targets that likely play roles in mitochondrial stress responses. We hypothesize that N1-APA production by the gut microbiome, caused by either high dietary agmatine or loss of agmatinase activity, might contribute to inflammatory bowel diseases.
    DOI:  https://doi.org/10.1038/s41467-025-66499-w
  49. bioRxiv. 2025 Nov 05. pii: 2025.06.09.658597. [Epub ahead of print]
    Bacterial metabolism of tryptophan causes toxicity in Caenorhabditis elegans that is alleviated by sugar supplementation.
    Shivani Gahlot, Subodh, Jogender Singh.
      Tryptophan is an essential amino acid required not only for protein biosynthesis but also for the production of several physiologically important metabolites, including serotonin, kynurenine, and nicotinamide. Although dietary tryptophan is associated with various health benefits, excessive intake can result in adverse physiological effects. The specific tryptophan- derived metabolites responsible for such toxicity, however, remain incompletely characterized. Here, we investigate the mechanisms underlying tryptophan-induced toxicity in Caenorhabditis elegans . We observe that tryptophan concentrations of 1 mM or higher are highly toxic to C. elegans , blocking egg hatching. Notably, supplementation with various sugars, including glucose, fructose, mannose, galactose, rhamnose, and lactose, alleviates this toxicity. Genetic analyses reveal that host tryptophan metabolism is dispensable for the observed effects. Instead, bacterial metabolism, particularly the conversion of tryptophan to indole, is essential for mediating toxicity. Bacterial strains deficient in indole production abolished tryptophan-induced toxicity, and all sugars that conferred protection also suppressed bacterial indole synthesis. These findings demonstrate that tryptophan toxicity in C. elegans is primarily mediated by bacterial metabolism.
    DOI:  https://doi.org/10.1101/2025.06.09.658597
  50. IEEE Trans Med Imaging. 2025 Nov 25. PP
    Integrated Photoacoustic-Metabolomic Platform for Multimodal Assessment of Sepsis-Induced Brain Dysfunction.
    Cong Mai, Xiaoxuan Zhong, Xiaoran Huang, Huan Cheng, Huifang Wang, Xin Qi, Yongji Cui, Yukai Xu, Haoying Lan, Xue Bai, Yizhi Liang, Long Jin, Bai-Ou Guan, Xin Li.
      Sepsis-induced brain dysfunction (SIBD), a critical determinant of mortality and long-term neurological sequelae in sepsis patients. The mechanistic understanding of SIBD has been limited by conventional single-modality approaches, which fail to capture the complex oxygenation-metabolism interplay. Here, we present an integrated photoacoustic-metabolomic platform that combines high-resolution photoacoustic imaging with targeted metabolomics to comprehensively assess cerebral oxygenation and metabolic alterations during sepsis. Our imaging system provides high spatiotemporal resolution, enabling mapping of key parameters, including cerebral oxygen saturation (sO2), oxygen extraction fraction (OEF), and the spatial heterogeneity of oxygen metabolism. By integrating these imaging capabilities with region-specific metabolomic profiling, we uncover a dynamic relationship between sepsis-driven oxygenation disruptions and metabolic reprogramming. Specifically, we demonstrate that sepsis induces heterogeneous cortical hypoxia, dysregulated OEF dynamics, and a metabolic shift marked by enhanced glycolysis and suppressed pentose phosphate pathway activity in high-OEF regions. This multimodal platform not only advances our understanding of the pathophysiology of SIBD but also offers a powerful tool for early diagnosis, personalized therapeutic strategies, highlighting the promise in bedside monitoring and precision medicine applications in sepsis management.
    DOI:  https://doi.org/10.1109/TMI.2025.3637090
  51. Mater Today Bio. 2025 Dec;35 102493
    Microbiota-directed lactic acid depleting nanoenzyme reactivates antitumor immunity and chemosensitivity in hypoxic tumor.
    Xinyue Lan, Fengling Zhang, Guangman Cui, Ben Hu, Yufang Lai, Huimin Lin, Huiqi Huang, Dan Zhou, Meng Yu, Guangyu Yao.
      The acidification of the tumor microenvironment (TME) remains a major obstacle contributing to malignant progression and impeding therapeutic development. While traditionally attributed to anaerobic glycolysis, increasing evidence suggests that hypoxia-induced colonization of intratumoral symbiotic microbiota, particularly anaerobes, produce lactic acid (LA) metabolites serves as a significant contributor to TME acidification. Although antibiotic-based combination therapies have been explored for the hypoxic tumor treatment, the efficiency was restricted in reversing acidification-induced immunosuppression and chemoresistance. To tackle this challenge, we engineered a delivery platform (TML NPs) for lactate oxidase (LOX) and chemotherapeutic drug tirapazamine (TPZ) by modifying the carrier with metronidazole (MTZ), an antibiotic bearing hypoxia-responsive functional group. By directly targeting the symbiotic anaerobic bacterial metabolism, this strategy introduces a novel paradigm for modulating TME acidification, reversing the LA-mediated suppression of anti-tumor immune responses and chemosensitivity. Our strategy offers a promising translational platform for the precise treatment of TNBC and other hypoxic malignancies.
    Keywords:  Anaerobic bacteria; Anti-tumor immunity; Drug delivery; Lactate metabolism; Nanomedicine
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102493
  52. Int J Biol Sci. 2025 ;21(15): 6952-6977
    Demystifying metabolic‒immune crosstalk: how amino acid metabolic reprogramming shapes the malignant phenotype and macrophage polarization of biliary and pancreatic tumors.
    Jinglei Zhang, Zhuohuan Chu, Jiawen Li, Lu Xie, Cong Ding, Zihui An, Xiang Wang, Hangbin Jin, Xiaofeng Zhang, Qiang Liu, Jianfeng Yang.
      Biliary and pancreatic malignant tumors refer to biliary tract carcinoma (BTC) and pancreatic cancer (PC), among which BTC mainly includes cholangiocarcinoma (CCA) and gallbladder cancer (GBC), and their prognosis is poor because of the lack of effective early diagnostic methods. Although surgical resection is the preferred method for a cure, treatment options are limited for patients with advanced tumors. Therefore, the exploration of other new treatment methods is urgently needed. Currently, metabolic reprogramming is a key mechanism in the process of tumor development and progression and is closely related to cancer cell proliferation, metastasis and drug resistance. As an indispensable part of metabolic reprogramming in tumor cells, amino acid (AA) metabolic reprogramming provides an energy source for tumor cells and participates in regulating the tumor microenvironment (TME). Moreover, as important intrinsic myeloid cells, macrophages play indispensable physiological roles in malignant tumor progression. In the TME, tumor cells can not only induce peripheral immune tolerance by releasing extracellular signals but also compete with tumor-associated macrophages (TAMs) for AAs and release the resulting downstream metabolites into the TME, directly targeting and damaging immune cells and influencing macrophage polarization. Consequently, a more profound understanding of the function of AA metabolic reprogramming in biliopancreatic malignancies and their associated macrophage polarization holds the potential to facilitate the development of effective strategies for early diagnosis, prognostic assessment and targeted therapy in patients with biliopancreatic malignancies. In this paper, we review the impact of AA metabolic reprogramming on the occurrence and development of biliary and pancreatic malignant tumors, summarize the relevant mechanisms of AA metabolic reprogramming on the polarization of TAMs, and provide new therapeutic targets for AA metabolic therapies and immunotherapies for biliary and pancreatic malignant tumors.
    Keywords:  amino acid metabolism; cholangiocarcinoma; metabolic reprogramming; pancreatic cancer; tumor-associated macrophages
    DOI:  https://doi.org/10.7150/ijbs.122325
  53. bioRxiv. 2025 Nov 05. pii: 2025.11.04.686569. [Epub ahead of print]
    Glutamine-Dependent Biosynthetic Pathways Fuel Autoreactive T and B Cells in Foxp3 Deficiency-mediated Disease.
    Mohammad Adeel Zafar, Charlotte Nicole Hill Machado, Jyotirmaya Behera, Yuelin Zhong, Xiao Li, Shakchhi Joshi, Yassine El Fazaa, Virginia Camacho, Peter Georgiev, Kiran Kurmi, Marcia Carmen Haigis, Louis-Marie Charbonnier.
      Foxp3 deficiency causes a profound loss of immune tolerance, unleashing autoreactive T and B cells, lymphoproliferation, cytokine-driven inflammation, and autoantibody production. This autoimmune pathology is fueled by increased glutamine usage, but it remains unresolved whether glutamine is necessary to produce energy, or for biosynthetic pathways leading to inosine and asparagine production. Here, we demonstrate that glutamine utilization supports Foxp3-deficiency mediated disease independently of pathogenic Foxp3-deficient Treg cell energetic reprogramming. Mechanistically, glutamine biosynthetic pathways sustain conventional T cell activation and proinflammatory cytokine production preventing inosine accumulation and signaling, thus implicating adenosine pathway modulation in autoreactive T cell dysregulation. Conversely, autoreactive B cell activation and autoantibody production depend on glutamine-dependent asparagine synthesis, which we reveal as a targetable vulnerability for autoantibody formation. These findings highlight glutamine-driven biosynthetic processes as critical drivers of autoimmunity and reveal distinct metabolic vulnerabilities in autoreactive T and B cells that can be targeted for therapeutic intervention.
    DOI:  https://doi.org/10.1101/2025.11.04.686569
  54. bioRxiv. 2025 Oct 29. pii: 2025.10.29.685332. [Epub ahead of print]
    Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling.
    Drew Adler, Alejandro Martín-Ávila, Evan Cheng, Mauricio M Oliveira, Muxian Zhang, Harrison T Evans, Deliang Yuan, Richard Sam, Nicole D Zhang, Maria Clara Selles, Olivia Mosto, Wendy J Liu, Amy X Guo, Shane A Liddelow, Robert C Froemke, Moses V Chao, Wen-Biao Gan, Eric Klann.
      De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here we demonstrate that microglia, resident macrophages of the brain, coordinate metabolic coupling between endothelial cells, astrocytes, and neurons to fuel protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, increasing glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit required for on-demand protein synthesis in mouse motor cortex.
    DOI:  https://doi.org/10.1101/2025.10.29.685332
  55. Free Radic Biol Med. 2025 Nov 25. pii: S0891-5849(25)01386-3. [Epub ahead of print]243 434-451
    Oxidative stress-induced proinflammatory secretion from retinal pigment epithelium disrupts NAD+ metabolism via CD38 on macrophages leading to immune microenvironment dysregulation.
    Ruoyi Lin, Feng Liang, Chengyu Hu, Lei Jiang, Zhongqi Wan, Zihang Xu, Yunhong Luo, Jingyang Ma, Yan Wu, Wenting Cai, Jing Yu.
       PURPOSE: Oxidative damage at the retinochoroidal interface manifests as retinal pigment epithelium (RPE) damage and subretinal macrophage accumulation. This study aimed to explore the role of oxidative stress (OS) in the RPE cells affecting metabolic reprogramming and associated molecular mechanisms in macrophages.
    METHODS: In vivo, RPE damage models in C57BL/6J mice were generated via the intraperitoneal injection of sodium iodate (SI). Following oral gavage intervention with or without the cluster of differentiation 38 (CD38) inhibitor 78c, macrophage infiltration and polarization, inflammatory markers, the NAD+ content, and the structure of Bruch's membrane (BrM) were observed in this model. In vitro, macrophages were co-cultured with OS-induced RPE. Comprehensive transcriptomics, targeted metabolomics, functional assays, and molecular mechanism studies were employed to clarify key NAD+ metabolic enzyme expression changes, metabolite alterations, macrophage cellular processes and intracellular molecular changes.
    RESULTS: In the RPE damage mouse model, the proportion of circulating non-tissue-resident infiltrating CD38+ macrophages significantly increased, with these cells primarily accumulating in the subchoroidal space, accompanied by elevated inflammatory marker levels and disrupted structure, which were reversed by 78c gavage intervention. In vitro, after co-cultured with OS-induced RPE, macrophages exhibited proinflammatory changes and intracellular NAD+ depletion, along with dysregulated extracellular matrix (ECM) interactions. Molecular mechanism experiments revealed that CD38 upregulation inhibited fibronectin expression via the NAD+/PARP1/FOS pathway, which led to a decrease in migration and adhesion functions.
    CONCLUSIONS: OS in the RPE drives metabolic reprogramming in macrophages via cytokine secretion, altering their transcriptional profiles and cellular functions. Our study established CD38 as a promising therapeutic target for modulating macrophage-driven pathology in OS-associated ocular disorders.
    Keywords:  Cluster of differentiation 38 (CD38); Extracellular matrix; Macrophages; Nicotinamide adenine dinucleotide (NAD(+)); Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.041
  56. J Nutr Biochem. 2025 Nov 24. pii: S0955-2863(25)00356-0. [Epub ahead of print] 110194
    Zinc, Fe2+ and Fe3+ differentially influence IFN-γ production in human peripheral blood mononuclear cells.
    Evelyn Fast, Jana Jakobs, Jens Bertram, Inga Weßels, Judith Sailer, Bernhard Michalke, Lothar Rink.
       BACKGROUND: Iron overload is a common phenomenon in patients undergoing transfusions or organ transplantation. Clinical studies indicate that iron overload interferes with immune function. Baseless supplementation of iron leads to higher morbidity and mortality. In iron overload T-cell differentiation is skewed towards a Th2 response, with lower levels of interferon (IFN)-γ. Zinc is known for its immune balancing abilities, e.g. by induction of regulatory T cells. This study aims to investigate the interaction of iron and zinc in mixed lymphocyte cultures (MLC).
    METHODS: MLC, peripheral blood mononuclear cells (PBMC) stimulation with phytohemagglutinin, ELISA, PCR, ICP-MS RESULTS: Zn2+ supplementation leads to a significantly lower IFN-γ production in MLC compared with control (p<0.03). Fe2+ supplementation lowers the IFN-γ production in MLC (P<0.0017), too. However, Fe3+ has a slightly increasing effect on IFN-γ release which differs significantly from Fe2+ (p<0.03). In 2,2-Bipyridyl-induced iron deficiency IFN-γ production is lowered (p<0.0003), whereas zinc deficiency does not significantly affect IFN-γ production. Examinations of Interleukin (IL)-2 and IL-6 show comparable tendencies. The Fe2+ effect can be imitated by sodium sulfite. Fe3+ treatment increases intracellular free iron in PBMC significantly compared to Fe2+ treatment (p<0.02).
    CONCLUSION: Iron (II) and zinc both suppress cytokine production in MLC. Fe3+ shows a significantly different effect on IFN-γ production. The underlying mechanism is likely a donation of electrons by Fe2+ or oxidative stress. These findings provide mechanistic insights on how the oxidation state of iron differentially modulates human immune cell function and highlights the importance of iron speciation in nutritional immunology.
    Keywords:  cytokine production; immunology; iron; mixed lymphocyte culture; zinc
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.110194
  57. Microorganisms. 2025 Nov 15. pii: 2599. [Epub ahead of print]13(11):
    Phenyllactic Acid as a Marker of Antibiotic-Induced Metabolic Activity of Nosocomial Strains of Klebsiella pneumoniae In Vitro Experiment.
    Maria Getsina, Ekaterina Chernevskaya, Ekaterina Sorokina, Tatiana Chernenkaya, Natalia Beloborodova.
      Klebsiella pneumoniae (K. pneumoniae) is a major nosocomial pathogen with increasing antibiotic resistance. Treatment failures and high mortality rates in sepsis caused by K. pneumoniae are associated with difficulties in choosing an adequate antibacterial therapy in the presence of resistance to all available antibiotics, based on the results of susceptibility tests. This study aimed to identify "weak points" in the metabolism of K. pneumoniae, to be able to use these features in the future. Ten nosocomial K. pneumoniae strains were incubated with fourteen broad-spectrum antibiotics representing major drug classes. Aromatic metabolites were analyzed using gas chromatography-mass spectrometry after 24 h exposure. Phenyllactic acid (PhLA), comprising 86% of detected phenylcarboxylic acids, served as the metabolic activity marker. Antibiotics demonstrated multidirectional effects on aromatic compound metabolism. Doxycycline, nitrofurantoin, rifampicin, and tigecycline significantly suppressed metabolic activity, confirmed by decreased PhLA levels. Conversely, meropenem, cephalosporins (ceftriaxone, cefepime, cefotaxime, and ceftazidime), ciprofloxacin, and amikacin stimulated PhLA production, suggesting that bacterial metabolic activity was maintained despite the presence of antibiotics. PhLA is a promising biomarker for quantifying K. pneumoniae's metabolic response to antibiotics. This potentially introduces a novel approach for future investigations into resistance mechanisms and has the potential to increase the effectiveness of therapies for multidrug-resistant K. pneumoniae infections by providing an additional analytical tool to traditional susceptibility testing methodologies.
    Keywords:  GC-MS; Klebsiella pneumoniae; antibiotics; hospital infection; metabolic activity of bacteria; microbial metabolites; multidrug-resistant strains; phenyllactic acid
    DOI:  https://doi.org/10.3390/microorganisms13112599
  58. Eur J Med Res. 2025 Nov 25.
    HDM and mannose as novel tolerogenic inducers for dendritic cells: mTOR/PPARγ-mediated attenuation of allergic asthma.
    Fang Wang, Zhihui Min, Jiameng Gao, Yuhao Qian, Zhilong Jiang, Xiwen Gao, Zhihong Chen.
      Dendritic cells (DCs) are pivotal in balancing immunity and tolerance in allergic asthma. This study reveals that both house dust mite (HDM) and mannose induce a potent tolerogenic phenotype in bone marrow derived DCs (BMDCs). These DCs display hallmark tolerogenic features, including a reduced proportion of DC-SIGN⁺ cells, downregulation of co-stimulatory molecules (MHC-II, CD80, and CD86) and key Th2-promoting factors (Jagged-1, OX40L), coupled with impaired phagocytosis and a reduced capacity to stimulate naïve CD4+ T cell proliferation. Crucially, HDM- and mannose-induced DCs effectively promoted the differentiation of naïve CD4+ T cells into Foxp3+ regulatory T (Treg) cells, demonstrating their direct role in actively enforcing immune tolerance. Adoptive transfer of these tolerogenic DCs significantly alleviated airway inflammation in a murine asthma model. Mechanistically, we identified a novel metabolic checkpoint that involves HDM-mediated activation of mTOR/PPARγ signaling. Inhibition of mTOR disrupted this axis and reversed the tolerogenic state, while pharmacological activation of PPARγ with pioglitazone mitigated asthma pathology in vivo. In conclusion, our work establishes HDM and mannose as novel tolerogenic inducers, providing a new strategy for the immunotherapy of asthma.
    Keywords:  Asthma; Dendritic cells; House dust mite; Immunological tolerance
    DOI:  https://doi.org/10.1186/s40001-025-03547-7
  59. mBio. 2025 Nov 28. e0139225
    Commensal-derived short-chain fatty acids disrupt lipid membrane homeostasis in Staphylococcus aureus.
    Joshua R Fletcher, Lisa A Hansen, Julia R Hoyser, Allison E Hanna, Richard Martinez, Christian D Freeman, Niall T Thorns, Mitchell R Penningroth, Alex R Villarreal, Grace A Vogt, Matthew A Tyler, Kelly M Hines, Ryan C Hunter.
      The role of commensal anaerobic bacteria in chronic respiratory infections is unclear, yet they can exist in abundances comparable to canonical pathogens in vivo. Their contributions to the metabolic landscape of the host environment may influence pathogen behavior by competing for nutrients and creating inhospitable conditions via toxic metabolites. Here, we show that the anaerobe-derived short-chain fatty acids (SCFAs) propionate and butyrate negatively affect Staphylococcus aureus physiology by disrupting branched-chain fatty acid (BCFA) metabolism. In turn, alterations to BCFA abundance impair S. aureus growth, compromise membrane integrity, diminish expression of the accessory gene regulator quorum-sensing system, and increase sensitivity to membrane-targeting antimicrobials. Disrupted BCFA metabolism also reduced S. aureus fitness in competition with Pseudomonas aeruginosa, suggesting that airway microbiome composition and the metabolites they exchange can directly impact pathogen succession over time. The pleiotropic effects of SCFAs on S. aureus fitness and their ubiquity as metabolites in the human host also suggest that they may be effective as adjuvants to traditional antimicrobial agents when used in combination.IMPORTANCEStaphylococcus aureus is a primary pathogen of chronic airway disease yet is also found in the upper airways of 30%-50% of the population to no obvious detriment. Thus, identifying the host and/or microbial factors that tip the balance between its commensal and pathogenic states may be key to its control. Here, we reveal that short-chain fatty acids produced by commensal microbiota promote a marked remodeling of the S. aureus lipid membrane that, in turn, sensitizes the pathogen to antimicrobials, disrupts accessory gene regulator quorum signaling, and reduces its competitive fitness. Altogether, these data suggest that co-colonizing microbiota and the metabolites they exchange with S. aureus may be key players in the microbial ecology of airway disease.
    Keywords:  Staphylococcus aureus; anaerobes; branched-chain fatty acids; lipidomics; short-chain fatty acids
    DOI:  https://doi.org/10.1128/mbio.01392-25
  60. bioRxiv. 2025 Nov 03. pii: 2025.10.31.685966. [Epub ahead of print]
    Macrophage PIM1 Drives Atherosclerosis by Enhancing Foam Cell Formation Via CD36.
    Mirza Ahmar Beg, Quoc Quang Luu, Vaya Chen, Yaxin Wang, Gang Xin, Weiguo Cui, Roy L Silverstein, Yiliang Chen.
       Background: Atherosclerosis is characterized by the buildup of fatty plaques that thicken and stiffen arterial walls. Macrophages (Mφs) significantly contribute to this process through their scavenger receptor CD36. PIM1 is a serine/threonine kinase known to modulate immune responses and cell metabolism. However, its role in Mφ lipid handling and atherogenesis is not well defined. This study examines the role of PIM1 in regulating CD36 expression and function in Mφs during foam cell formation and atherosclerosis progression.
    Methods: We performed in vitro studies by treating murine peritoneal Mφs from Pim1 -/- and wild-type (WT) mice with oxidized low-density lipoprotein (oxLDL). We measured CD36, PIM1, and plaque-associated proteins and mRNA levels, oxLDL binding and uptake rates, as well as foam cell formation. For in vivo studies, we fed Mφ-specific PIM1-deficient ( Apoe -/- Lyz2 Cre/+ Pim1 fl/fl ) and their littermate control ( Apoe ⁻/⁻ Pim1 fl/fl ) mice a high-fat diet for 12 weeks. We then evaluated the plaque formation in their aortic sinuses and arches.
    Results: Deletion of Pim1 in Mφs reduced CD36 protein expression by up to 96.7% compared to WT controls. This led to a 49.6% decrease in foam cell formation and a 25.5% reduction in cellular cholesterol after oxLDL treatment. Pharmacological inhibition of PIM kinase activity in WT Mφs also impaired oxLDL handling, with a 64.5% reduction in binding and a 57.9% in uptake. Bulk RNA-seq revealed that Pim1 deficiency downregulated PPARγ signaling. Treatment with a PPARγ agonist restored CD36 levels in the PIM1 knockdown Mφs, suggesting that PIM1 regulates CD36 through PPARγ. Moreover, PIM1 Mφ-specific deficiency caused a 69.4% reduction in atherosclerotic plaque formation.
    Conclusion: PIM1 acts as a key upstream regulator of CD36 by enhancing PPARγ activity in Mφs. The PIM1-CD36 axis promotes oxLDL binding, uptake, and foam cell formation. Targeting the PIM1/PPARγ/CD36 pathway could offer new ways to modulate Mφ lipid metabolism and reduce atherosclerotic plaque progression.
    Non-standard Abbreviations and Acronyms: ELISA: enzyme-linked immunosorbent assay; HFD: high-fat diet; Mφs: macrophages; MCP-1: monocyte chemoattractant protein-1; ORO: oil red O; oxLDL: oxidized low-density lipoprotein; PBS: phosphate-buffered saline; PPARγ: peroxisome proliferator-activated receptor gamma; WT: wild type.
    DOI:  https://doi.org/10.1101/2025.10.31.685966
  61. Biochem Biophys Res Commun. 2025 Nov 19. pii: S0006-291X(25)01730-9. [Epub ahead of print]794 153014
    High-fat diet promotes colorectal tumorigenesis through gut microbiota-mediated metabolic reprogramming and M2 macrophage polarization.
    Liangfei Xu, Jiajia Zhang, Yuhan Xiao, Peipei Jin, Ju Zhang.
       BACKGROUND: High-fat diet (HFD) drives colorectal cancer (CRC) progression through gut microbiota dysbiosis and M2 macrophage polarization, yet the microbiota-immunity crosstalk remains mechanistically unresolved.
    METHODS: APCmin/+ (CRC model, n = 8) and wild-type controls (n = 7) received 12-weeks HFD. We employed integrated metagenomic sequencing (Illumina NovaSeq) and immunohistochemistry (targeting CD206+ M2 macrophages) to investigate the linkages between the gut microbiota and the host.
    RESULTS: CRC mice exhibited colonic adenocarcinoma with increased M2 macrophages. Gut microbiota in CRC mice showed enrichment of pro-inflammatory taxa (e.g., Bacteroides massiliensis, Vampirovibrion) and upregulated pathways (carbohydrate metabolism, mucin degradation). Strikingly, the relative abundances of Bacteroides massiliensis and Vampirovibrion showed significant positive correlations with CD206+ M2 macrophage infiltration levels.
    CONCLUSION: HFD induces microbiota-directed metabolic reprogramming and M2 polarization, synergistically accelerating CRC. Notably, targeting key pro-inflammatory taxa (e.g., B. massiliensis) or glycan hydrolysis pathways (e.g. GH95 enzyme) may provide mechanism-guided anti-CRC strategies.
    Keywords:  CRC; Gut microbiota; M2 macrophage,CD206
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153014
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