bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–11–01
fifty papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Targeting Immune Cell Metabolism for Tolerance.
  2. T-cell metabolic reprogramming in systemic lupus erythematosus: linking intracellular metabolism to effector differentiation and senescent-like/exhausted-like states.
  3. Immunometabolic reprogramming of macrophages and neutrophils in acute pancreatitis: from metabolic stress to amplification and endogenous braking.
  4. The fate of cysteine's sulfur in CD8+ T cell function.
  5. Lactate dynamics at the Pseudomonas aeruginosa-host interface: bacterial metabolism, host defense, and emerging links to histone lactylation.
  6. Immunometabolic checkpoint: The dual regulatory role of macrophages in islet destruction in type 1 diabetes.
  7. Hyperuricemia aggravates acute colitis through NLRP3-associated macrophage-lineage inflammatory responses.
  8. SLC3A2 Drives an Immunosuppressive Metabolic Axis that Limits Oncolytic Virotherapy Efficacy.
  9. Broken Engines of Immunity: Mitochondrial Dysfunction in T Cells Across Cancer and Complex Pathologies.
  10. Deoxycorticosterone Reshapes CD8+ T Cell State and Effector Function Through Distinct Metabolic Signaling Programs.
  11. Mycobacterium tuberculosis inactivates host oxysterols to impair macrophage cholesterol homeostasis.
  12. Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling.
  13. PEDF alleviates autoimmune uveitis and reprograms Treg metabolism.
  14. Metabolic Dysfunction and T-Cell Exhaustion in Colorectal Cancer: Mechanisms, Microenvironment Remodeling, and Therapeutic Opportunities.
  15. Neutrophil metabolic heterogeneity as a novel target in diseases.
  16. Glucose restriction induced by intermittent fasting promotes alternative metabolic fluxes leading to memory CD8+ T cell development.
  17. Arginine rewires eIF4F translation initiation to overcome fever-induced CAR T cell dysfunction.
  18. Tumour rewires host tryptophan metabolism to promote organism-wide immune suppression.
  19. Integrative single-cell transcriptomic and metabolic profiling reveals lactate-driven glycolytic reprogramming and histone lactylation in colorectal cancer liver metastasis.
  20. Lactate-Driven Biphasic Reprogramming of Macrophage Immune Responses.
  21. Gut microbial metabolism in aging: from metabolite production to organ-specific immunometabolic effects.
  22. Nuclear NAD+ promotes innate immune memory by inhibiting KDM5A-dependent histone demethylation.
  23. Immunometabolic crosstalk between dysfunctional adipose tissue and the brain: implications for postoperative cognitive dysfunction in obesity.
  24. Taurine preserves γδ T cell fitness in triple-negative breast cancer.
  25. Lipid-sensing GPR183-KRAS signaling mediates TH17 autoimmunity and identifies fluvoxamine repurposing in uveitis.
  26. Macrophage GLUD1 is Essential for Redox Balance and Immune Homeostasis in Cardiac Injury.
  27. c-Myc Links TGF-β Signaling to Metabolic Control of HIV Reactivation in OM10.1 Cells.
  28. Vanin-pantethine metabolic axis shapes dendritic cell function and affects inflammatory disorder progression.
  29. Nutrient-sensitive histone propionylation regulates T cell fate and function.
  30. Proteomics analysis reveals headgroup-dependent modulation of lipopolysaccharide-induced inflammation by arachidonoyl phospholipids in macrophages.
  31. Exogenous lactate exacerbates adverse cardiac remodeling following myocardial infarction via impaired macrophage activation and myocardial ER stress.
  32. A synthetic PGC1α co-activator reprograms microglial immunometabolism to preserve cone function in retinal degeneration.
  33. Multi-Omics Insights Into Circulating T-Cell Metabolic Reprogramming and Treg Dysfunction in Moyamoya Disease.
  34. Integrated transcriptomic and metabolomic analysis reveals ApoLp-III-mediated BmNPV suppression via host energy and lipid reprogramming.
  35. Targeting SLC6A14-mediated nutrient competition reverses an immunosuppressive metabolic niche in pancreatic cancer.
  36. Metabolic licensing of innate immune memory.
  37. T cell metabolic ageing as a factor for therapeutic research.
  38. Global carbohydrate metabolism is increased and beta hydroxybutyrate decreased in sepsis vulnerable children compared to sepsis tolerant children; a cohort study.
  39. Neutrophil-Derived Arg1 Impairs CD8+ T Cell Activity in Sepsis Through mTOR-Mediated Mitochondrial Dysfunction.
  40. Sex-Dependent Microbiome-Metabolome Remodeling Associated with Bacteroides acidifaciens Modulation of Acute Respiratory Distress Syndrome.
  41. One-carbon metabolism sustains effector T cell function through cell-surface glycosylation.
  42. Dopamine turns mitochondrial stress into inflammation.
  43. Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma.
  44. Spermidine disrupts mitochondrial respiration and redox homeostasis in aged CD44+ CD49d- CD8+ T cells.
  45. Mitochondrial Lactate Signaling and Protein Lactylation in Neurological Diseases.
  46. Single-cell transcriptomics uncovers persistent hepatic immunometabolic remodeling following SARS-CoV-2 infection in obese hosts.
  47. MIF-CD74 orchestrates synovial macrophage metabolic-inflammatory reprogramming by ENO2 interaction to drive osteoarthritis pathogenesis.
  48. Prophylactic Soraphen A Treatment Attenuates Western Diet-Exacerbated IMQ-Induced Psoriasiform Inflammation.
  49. Gαi3 acts as a metabolic checkpoint orchestrating TAMs immunosuppression and lipid metabolism in glucose-deprived hepatocellular carcinoma.
  50. Biotin-dependent metabolism controls germinal center fate and vaccine-induced antibody diversification.
  1. Clin Exp Immunol. 2026 Oct 30. pii: uxag071. [Epub ahead of print]
    Targeting Immune Cell Metabolism for Tolerance.
    Nicholas Jones.
      
    Keywords:  Autoimmunity; immunometabolism; metabolism; mitochondria
    DOI:  https://doi.org/10.1093/cei/uxag071
  2. Front Immunol. 2026 ;17 1961063
    T-cell metabolic reprogramming in systemic lupus erythematosus: linking intracellular metabolism to effector differentiation and senescent-like/exhausted-like states.
    Yi Zou, Zhichu Ren, Yuki Kudo, Michihito Kono.
      Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and multiorgan inflammation. T-cell metabolic reprogramming has recently emerged as an active area of investigation in the pathogenesis of SLE. This metabolic reprogramming, which involves glycolysis, mitochondrial oxidative phosphorylation, glutamine metabolism, and lipid metabolism, is associated not only with functional alterations in SLE T cells but also with changes in their differentiation and proliferation, potentially contributing to disease pathogenesis and progression. Moreover, metabolic alterations, including mitochondrial dysfunction and reactive oxygen species accumulation, in the context of persistent T-cell activation may contribute to phenotypic transitions toward senescent-like or exhausted-like states. These two partially overlapping but biologically distinct cellular phenotypes may represent divergent cellular responses to chronic inflammatory stimulation. Rather than representing mutually exclusive states or a simple loss of function, both may contribute to the perpetuation of chronic inflammation, immune imbalance and disease activity. This review summarizes recent advances in T-cell metabolic reprogramming in SLE and its potential relationship to senescent-like and exhausted-like T-cell states.
    Keywords:  exhausted-like T cells; immunometabolism; metabolic reprogramming; senescent-like T cells; systemic lupus erythematosus
    DOI:  https://doi.org/10.3389/fimmu.2026.1961063
  3. Front Immunol. 2026 ;17 1976931
    Immunometabolic reprogramming of macrophages and neutrophils in acute pancreatitis: from metabolic stress to amplification and endogenous braking.
    Yuanhang Ai, Longze Zhang, Aiping Wei, Jiayan Dong, Tianjing Pang, Yuanyu Zhang, Kaifeng Wu, Shifei Yao.
      Acute pancreatitis (AP) progression involves both the initiating acinar injury and immune responses that sustain or contain subsequent damage. This review integrates evidence on metabolic regulation in macrophages and neutrophils to examine its links to inflammatory effectors, clearance, and tissue protection. Glycolytic regulation can support inflammatory activation, while non-AP neutrophil studies show how substrate allocation supports oxidant production and neutrophil extracellular trap (NET) release. Metabolite signaling also participates in macrophage efferocytosis, repair-associated responses, and tissue antioxidant defense. Contrasting lactate effects in acinar injury and macrophage repair indicate that metabolic changes must be interpreted through their effects on particular cells and functions. We propose an integrated amplification-braking framework that connects metabolically supported inflammatory effectors to continued generation of injury-derived stimuli, and clearance, antioxidant, and repair functions to damage containment. These functions can coexist without receiving equivalent metabolic support, and protective braking is distinct from generalized immunosuppression. Evidence differs across cells and experimental systems; metabolic regulation of inflammatory activation does not by itself establish metabolic control of NET-mediated injury in AP. The framework provides a basis for evaluating whether metabolic interventions can limit damaging activity while preserving protective functions, but it is not a validated clinical model. Pairing metabolic changes with specific cellular functions and subsequent injury is central to testing these relationships.
    Keywords:  acute pancreatitis; immunometabolism; macrophage; metabolic reprogramming; metabolic stress; neutrophil
    DOI:  https://doi.org/10.3389/fimmu.2026.1976931
  4. Trends Endocrinol Metab. 2026 Oct 27. pii: S1043-2760(26)00274-2. [Epub ahead of print]
    The fate of cysteine's sulfur in CD8+ T cell function.
    Beth Kelly, Erika L Pearce.
      CD8+ T cells modulate their metabolism to support activation, proliferation, and effector function. The sulfur-containing amino acid cysteine is essential for these processes, but beyond its role in protein synthesis, cysteine is metabolized into multiple products that differentially regulate T cell immunity. Here, we review recent advances in understanding how intracellular cysteine routing controls CD8+ T cell function. Cysteine-derived glutathione, iron-sulfur clusters, coenzyme A, hydrogen sulfide, and taurine each have distinct effects on T cell activation, mitochondrial metabolism, and antitumor immunity. Additionally, cysteine-dependent post-translational modifications-including sulfenylation and persulfidation-modulate signaling and gene expression. Understanding how cells balance competing cysteine fates may reveal new therapeutic strategies to enhance T cell responses in cancer and other diseases.
    Keywords:  CD8(+) T cell; Fe–S cluster; cysteine; glutathione; immunometabolism; sulfur
    DOI:  https://doi.org/10.1016/j.tem.2026.10.002
  5. Front Immunol. 2026 ;17 1979311
    Lactate dynamics at the Pseudomonas aeruginosa-host interface: bacterial metabolism, host defense, and emerging links to histone lactylation.
    Yi Jian, Zhijie Wu, Yuqiang Liang, Jin Cao, Mei Li, Fashuang Yang, Ke Wang.
      At the Pseudomonas aeruginosa-host interface, lactate is both a host immunometabolic product and a preferred bacterial carbon source. Its local concentration reflects host production, bacterial utilization, transport, and clearance rather than inflammation alone. P. aeruginosa uses D- and L-lactate through stereospecific, conditionally regulated systems. It preferentially consumes lactate in human burn-wound exudate, and this capacity contributes to early intracellular survival in macrophages. Lactate-associated acidity also increases bacterial vesicle release and quinolone signaling, weakening antimicrobial-peptide activity independently of chromatin modification. On the host side, bacterial L-lactate utilization and virulence-factor-associated suppression of epithelial glycolysis lower epithelial lactate and histone H3 lysine 18 lactylation (H3K18la). These changes are linked to disrupted RNA regulation and impaired ciliary clearance. In macrophages, the quorum-sensing signal 2-aminoacetophenone (2-AA) reprograms bioenergetics, autophagy, and lipid metabolism, promoting tolerance and intracellular persistence. A separate hypothesis connecting 2-AA to increased macrophage lactate and H3K18la is supported only by a supplement abstract and requires full-length validation. Histone lactylation is therefore an emerging extension of this biology. This narrative review follows two linked strands: bacterial lactate utilization and lactate-associated changes in host defense. It distinguishes established metabolic effects from proposed lactylation-dependent mechanisms and considers potential therapeutic directions and their trade-offs. These include targeting bacterial lactate utilization, airway acidity, host transport or modification enzymes, and 2-AA-associated tolerance. Any benefit must be assessed against the possibility of supplying bacterial nutrients or worsening host injury.
    Keywords:  H3K18la; Pseudomonas aeruginosa; bacterial metabolism; biofilm; histone lactylation; host defense; lactate dynamics
    DOI:  https://doi.org/10.3389/fimmu.2026.1979311
  6. Life Sci. 2026 Oct 24. pii: S0024-3205(26)00558-8. [Epub ahead of print]406 124749
    Immunometabolic checkpoint: The dual regulatory role of macrophages in islet destruction in type 1 diabetes.
    Jin Deng, Jianliang Lu, Wei Wang, Qingyang Liu.
      Macrophage immunometabolic states are important determinants of inflammatory and reparative responses in type 1 diabetes (T1D). Within the diabetic islet, glycolysis, lipid metabolism, mitochondrial function, and metabolite-dependent epigenetic and post-translational mechanisms converge to regulate macrophage signaling, chromatin accessibility, and inflammatory output. M1-like/pro-inflammatory macrophages promote β-cell injury through nitric oxide and cytokine production, whereas M2-like/reparative states support efferocytosis, immune tolerance, and tissue homeostasis. These interconnected pathways form immunometabolic checkpoints that may be therapeutically targeted to reshape the islet immune microenvironment. Precision delivery strategies may further enable cell- and context-specific modulation while limiting systemic effects.
    Keywords:  Epigenetics; Immunometabolism; Inflammation; Macrophages; Metabolic reprogramming; Trained immunity; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.lfs.2026.124749
  7. Inflamm Bowel Dis. 2026 Oct 27. pii: izag227. [Epub ahead of print]
    Hyperuricemia aggravates acute colitis through NLRP3-associated macrophage-lineage inflammatory responses.
    Junyi Ji, Yize Wang, Tianyu Zhou, Jie Zhang, Zixin Xu, Zhe Shen, Chaohui Yu.
       BACKGROUND: Inflammatory bowel diseases (IBDs) are chronic, relapsing inflammatory disorders of the gastrointestinal tract with rising prevalence. Hyperuricemia has been associated with IBD, but whether elevated uric acid (UA) directly aggravates intestinal inflammation and how it affects immune responses remain unclear.
    METHODS: We used hepatocyte-specific Glut9 knockout mice, allopurinol intervention, and acute UA administration in wild-type mice to assess dextran sulfate sodium (DSS)-induced acute colitis. Lamina propria immune cells were profiled by expanded flow cytometry; phagocytic/macrophage-lineage and NLRP3 pathways were perturbed with clodronate liposomes, MCC950, and Nlrp3 siRNA. Bone marrow-derived macrophages (BMDMs) and public human IBD mucosal transcriptomic datasets were analyzed.
    RESULTS: Glut9 HKO mice developed higher serum UA and more severe DSS-induced colitis than controls, whereas allopurinol reduced serum UA and ameliorated disease. Acute UA administration during DSS exposure similarly worsened colitis in wild-type mice. Hyperuricemia expanded colonic monocyte/macrophage-lineage cells during DSS challenge, increased pro-inflammatory cells, and enhanced NLRP3 inflammasome-associated signaling. Clodronate-sensitive macrophage depletion and MCC950 attenuated disease severity. In BMDMs, soluble UA enhanced LPS-primed inflammatory activation and inflammasome-associated readouts, which were reduced by NLRP3 inhibition or knockdown. In human IBD mucosal transcriptomic datasets, purine metabolism scores positively correlated with inflammatory macrophage and NLRP3 inflammasome signatures.
    CONCLUSIONS: Elevated UA aggravates DSS-induced acute colitis and amplifies inflammatory monocyte/macrophage-lineage responses associated with NLRP3 inflammasome signaling. These findings identify hyperuricemia as a metabolic modifier of acute intestinal injury and support further investigation of UA-linked innate immune activation in IBD.
    Keywords:  NLRP3 inflammasome; colitis; macrophages; uric acid
    DOI:  https://doi.org/10.1093/ibd/izag227
  8. Cancer Res. 2026 Oct 27.
    SLC3A2 Drives an Immunosuppressive Metabolic Axis that Limits Oncolytic Virotherapy Efficacy.
    Weiwei Dai, Rihan Hai, Shasha Bian, Yan Dong, Bowen Yin, Yuling Chen, Xi Chen, Zhuoyang Fan, Yiheng Cai, Minfeng Shu.
      Oncolytic virotherapy is a promising cancer treatment that elicits antitumor immunity. However, the efficacy of virotherapy is often constrained by tumor-intrinsic immune suppression. To identify conserved virus-induced programs driving immune escape, we applied multi-omics and functional assays across multiple tumor and virus models, uncovering an SLC3A2-driven immunosuppressive metabolic barrier. In oncolytic herpes simplex virus (oHSV)-infected tumors, a biphasic immune trajectory emerged: early CD8+ T cell activation was followed by SLC3A2-mediated methionine and tryptophan uptake, driving T cell exhaustion. Mechanistically, oHSV upregulated SLC3A2 via the m6A-IGF2BP3 axis, while tumor-intrinsic tryptophan metabolism engaged the AHR/ARNT/ICP4 cascade to amplify viral replication and reinforce the immunosuppressive program. Importantly, dietary methionine supplementation disrupted the metabolic checkpoint, restored T cell effector function, and synergized with oHSV expressing anti-PD1 to enhance tumor control in humanized preclinical models. Notably, a parallel SLC3A2-centered metabolic-immunologic circuit operated in vesicular stomatitis virus (VSV) infection. Together, these findings delineate an actionable, conserved metabolic checkpoint and provide a framework for integrating metabolic modulation into cancer viroimmunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1659
  9. Eur J Immunol. 2026 Oct;pii: e70300. [Epub ahead of print]56(10):
    Broken Engines of Immunity: Mitochondrial Dysfunction in T Cells Across Cancer and Complex Pathologies.
    Carolina Brescia, Giuseppe Viglietto, Rosario Amato.
      Mitochondria have traditionally been viewed as the cellular 'powerhouses' responsible for energy production; however, they also play essential roles in a wide range of cellular processes, including macromolecule biosynthesis and the regulation of apoptosis. Accumulating evidence highlights their importance in immune regulation, particularly through their influence on T cell activation, proliferation, and effector function. In addition to ATP generation, mitochondria regulate redox and calcium homeostasis and produce metabolites that modulate the transcriptional and epigenetic programs of immune cells. Upon antigen recognition, T lymphocytes undergo marked metabolic reprogramming, characterised by increased glycolysis while preserving mitochondrial metabolism as a critical pathway. Mitochondrial dysfunction disrupts intracellular signalling and contributes to T cell exhaustion in diverse pathological contexts, including cancer and chronic viral infections. Consequently, strategies aimed at restoring mitochondrial function are emerging as promising therapeutic approaches to correct immune dysfunction driven by impaired T cell responses. Importantly, these alterations should not be interpreted solely as downstream consequences of chronic immune stimulation; rather, mitochondrial dysfunction can actively determine T-cell fate, stabilise exhaustion-associated programs, and define the extent to which dysfunctional T cells remain therapeutically reversible. This review first outlines mitochondrial structure, bioenergetics, dynamics, and quality-control pathways and then examines how these processes are remodelled across naïve, effector, circulating-memory, tissue-resident-memory, and exhausted T-cell states. It subsequently integrates evidence from cancer, chronic viral infection, and ageing and evaluates mitochondria-directed strategies for restoring T-cell function.
    Keywords:  T cell; T‐cell exhaustion; cancer; metabolism; mitochondria; mitochondrial dysfunction
    DOI:  https://doi.org/10.1002/eji.70300
  10. Biomedicines. 2026 Oct 15. pii: 2347. [Epub ahead of print]14(10):
    Deoxycorticosterone Reshapes CD8+ T Cell State and Effector Function Through Distinct Metabolic Signaling Programs.
    Tao Li, Anqi Chen, Siqi Zhou, Gang Xue.
      Background/Objectives: Whether individual endogenous corticosteroids exert distinct immunoregulatory effects on CD8+ T cells remains poorly understood. We investigated how deoxycorticosterone (DOC) affects CD8+ T cell state and function. Methods: Primary mouse CD8+ T cells were activated with anti-CD3/CD28 and IL-2 in the presence or absence of DOC. Flow cytometry was used to assess exhaustion-associated markers and effector function, and pharmacological perturbations were used to examine the involvement of AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and protein kinase B (AKT) signaling. Results: DOC promoted an exhaustion-associated phenotype characterized by increased frequencies of PD-1+LAG-3+ and PD-1+TIM-3+ cells and elevated TOX expression. DOC concurrently impaired effector function, reducing IFN-γ/TNF co-production, granzyme B expression, and IL-2 production. Pharmacological inhibition of AMPK or activation of mTOR partially attenuated exhaustion-associated features induced by DOC, whereas AKT activation partially restored effector function. Conclusions: DOC directly reshapes CD8+ T cell state and function in vitro, with exhaustion-associated and effector responses exhibiting distinct pharmacological signaling dependencies. These findings identify DOC as a previously underappreciated endogenous corticosteroid capable of modulating CD8+ T cell biology.
    Keywords:  CD8+ T cells; T cell exhaustion; deoxycorticosterone; immunometabolism; metabolic signaling
    DOI:  https://doi.org/10.3390/biomedicines14102347
  11. bioRxiv. 2026 Oct 05. pii: 2026.10.04.756586. [Epub ahead of print]
    Mycobacterium tuberculosis inactivates host oxysterols to impair macrophage cholesterol homeostasis.
    Andrew T Roth, Mohsen Ali Asgari, Pallavi Chandra, Jalalah Muhammad, Amy Lopez, Sourav Bhattacharya, Isabelle A Williams, Brian T Edelson, Charles W Goss, Dmitri I Kotov, Mingxing Qian, Douglas F Covey, Xuntian Jiang, William J Griffiths, Yuqin Wang, Jennifer A Philips.
      Host oxysterols coordinate macrophage cholesterol homeostasis and antimicrobial defense, but whether pathogens directly target oxysterol signaling is unknown. Here, we identify pathogen-mediated enzymatic oxysterol inactivation as a mechanism by which Mycobacterium tuberculosis (Mtb) subverts host cholesterol metabolism. Mtb oxidizes the endogenous oxysterols 27-hydroxycholesterol (27-HC) and 3β-hydroxycholest-5-enoic acid (3β-HCA) into 3-oxo-Δ 4 metabolites. Sputum lipidomics across TB cohorts on three continents revealed an active-disease signature characterized by 27-HC depletion and accumulation of 27-hydroxycholest-4-en-3-one (27-HCO) and 3-oxocholest-4-enoic acid (3O-CA), which normalized with treatment. In infected human macrophages, Mtb 3β-hydroxysteroid dehydrogenase (3β-Hsd) generated 27-HCO. Unlike their parent oxysterols, 27-HCO and 3O-CA did not activate liver X receptor (LXR), and 3O-CA failed to suppress sterol regulatory element-binding protein 2 (SREBP2) target genes. Accordingly, 3β-Hsd-deficient Mtb did not induce macrophage cholesterol retention, a phenotype restored by LXR antagonism. Thus, Mtb enzymatically inactivates host oxysterols, disrupting macrophage cholesterol homeostasis and generating treatment-responsive metabolic signatures in human TB.
    DOI:  https://doi.org/10.64898/2026.10.04.756586
  12. Elife. 2026 Oct 29. pii: RP107627. [Epub ahead of print]14
    Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling.
    Sung Hoon Cho, Shawna K Brookens, Ariel L Raybuck, Kaylor Meyer, Yeeun Paik, Jennie Hamilton, Jingxin Li, Karel Kalecky, Chloe Park, Juyeon Lim, Sakeenah L Hicks, John Karijolich, Teodoro H Bottiglieri, Jeffrey C Rathmell, Denis Mogilenko, Christopher D Scharer, Mark R Boothby.
      The proliferation and development of activated B lymphocytes into antibody (Ab)-secreting plasma cells are critical determinants of humoral immunity and sustain certain autoimmune diseases. Specific pathways and substrate supplies in intermediary metabolism influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases B cell proliferation and differentiation into plasma cells, glutaminolysis - a major metabolic use of this amino acid - was only conditionally crucial in B cells and the Ab responses derived from them. Gls, the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases if either glucose uptake into mouse B cells or pyruvate into their mitochondria was also impaired. Otherwise, it was dispensable. This synthetic auxotrophy, that is, the conditional requirement of glutaminase for processes in addition to survival, involved supporting progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel decreased IL-21 stimulation of STAT3 phosphorylation as well as interferon stimulation of STAT1 activation. Together, our findings establish a powerful collaboration of metabolic pathways in programming increased respiration and the development of Ab-secreting cells, but also reveal modulation of cytokine receptor signaling by metabolism.
    Keywords:  B lymphocyte; cytokine receptor signaling; immunology; immunometabolism; inflammation; mitochondria; mouse; plasma cell; regulation of antibodies
    DOI:  https://doi.org/10.7554/eLife.107627
  13. J Neuroinflammation. 2026 Jul 31. pii: 356. [Epub ahead of print]23(1):
    PEDF alleviates autoimmune uveitis and reprograms Treg metabolism.
    Zhihui Zhang, Yongtao Li, Huan Li, Mi Zhang, Zhen Qian, Baiyi Li, Nu Chen, Jiawei Wang, Xuexue Cui, Mengjuan Zhang, Song Zhang, Lai Wei, Xiaomin Zhang.
      T cell-mediated autoimmune diseases remain difficult to manage owing to limited options and adverse effects of current immunosuppressants; safer, tolerance-preserving approaches are needed. We identify pigment epithelium-derived factor (PEDF) as an endogenous regulator of ocular immunity with therapeutic potential. PEDF expression was induced during autoimmune uveitis (AU) in patients and during experimental autoimmune uveitis (EAU) progression, suggesting an endogenous compensatory response to inflammatory stress. Loss of PEDF did not substantially alter early peripheral immune activation but impaired inflammatory control during established disease, leading to persistent retinal inflammation and reduced Foxp3⁺ regulatory T (Treg) responses. Conversely, intravitreal administration of recombinant PEDF enhanced Treg responses and promoted inflammatory resolution, thereby alleviating EAU severity. Mechanistically, we delineate a PEDF-ATGL-DHA-PPARγ axis that reprograms Treg metabolism: PEDF activates adipose triglyceride lipase (ATGL) to mobilize docosahexaenoic acid (DHA), enhancing mitochondrial oxidative metabolism and stabilizing Foxp3 via PPARγ. Together, these findings establish PEDF as a physiological checkpoint that links lipid utilization to immune tolerance, and demonstrate a metabolism-centered, cytokine-independent strategy to reinforce Treg stability in vivo. Having shown efficacy in an ocular model of T cell-driven autoimmunity, PEDF-based immunometabolic modulation defines a broadly applicable strategy for restoring immune tolerance across T cell-mediated autoimmune diseases.
    Keywords:  ATGL; Autoimmune uveitis; DHA; Immunometabolism; PEDF; Regulatory T cells
    DOI:  https://doi.org/10.1186/s12974-026-03980-3
  14. Int J Mol Sci. 2026 Oct 15. pii: 9134. [Epub ahead of print]27(20):
    Metabolic Dysfunction and T-Cell Exhaustion in Colorectal Cancer: Mechanisms, Microenvironment Remodeling, and Therapeutic Opportunities.
    Jieun Jeon, Hye Suk Baek, Kibeom Park, Mee-Na Park, Na Hyeon Heo, Sohyeon Cheon, Gahyeon Kim, Shin Kim.
      Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide. Metabolic disorders such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome are associated with CRC risk. Metabolic abnormalities may contribute to colorectal tumorigenesis and reshape the tumor immune microenvironment, which in turn influence immune dysfunction and therapeutic resistance. Exhausted CD8+ T cells exhibit impaired effector function, sustained inhibitory receptor expression, and transcriptional and epigenetic reprogramming. Metabolic stressors within the CRC microenvironment may modulate T-cell function and exhaustion-associated states. Additionally, other immune populations (natural killer cells, macrophages, myeloid-derived suppressor cells, dendritic cells, and regulatory T cells) may develop distinct dysfunctional or immunosuppressive states. Recent single-cell and spatial studies have indicated the heterogeneity of these immunometabolic interactions in CRC. This review examines the interactions of the systemic and tumor-associated metabolic alterations with T-cell exhaustion and other forms of immune dysfunction in CRC. We discuss the influence of glucose, lipid, amino acid, and mitochondrial metabolism, hypoxia, microbiota-derived metabolites, and chronic inflammation in shaping tumor-immune interactions. Finally, we reviewed therapeutic strategies targeting immunometabolic pathways and their potential integration with immune checkpoint blockade. Overall, understanding these interactions may help identify immunometabolic vulnerabilities for informing precise therapeutic strategies for CRC.
    Keywords:  T-cell exhaustion; colorectal cancer; diabetes mellitus; immune checkpoint blockade; immunometabolism; metabolic dysfunction; microbiota; obesity; therapeutic resistance; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27209134
  15. Cell Commun Signal. 2026 Jul 29. pii: 577. [Epub ahead of print]24(1):
    Neutrophil metabolic heterogeneity as a novel target in diseases.
    Yuting Zhang, Minjie Guo, Danni Zhao, Hele Liu, Xuanyin Ding, Xiao Yuan, Ying Jiang, Dan Feng, Xu Wang.
       BACKGROUND: Neutrophils, pivotal effector cells of the immune system, are increasingly recognized to have considerable functional and phenotypic heterogeneity. The emergence of immunometabolism has offered a framework for understanding this diversity. Accumulating evidence indicates that shifts in metabolic pathways and their byproducts can reshape the fate and function of neutrophils.
    MAIN BODY: Neutrophil heterogeneity arises from both distinct developmental stages and specific signals within peripheral tissue microenvironments. Functionally, glycolysis is the central metabolic pathway that fuels core effector responses, while metabolites such as lactate, lipids, and amino acids can further modulate neutrophil phenotypes. In pathological contexts of metabolic dysregulation, metabolic stress induces extensive reprogramming of neutrophils. This process drives the accumulation of specific metabolites, which in turn trigger transcriptional reprogramming through epigenetic remodeling, establishing a self-reinforcing loop that sustains pro-pathological neutrophil states. Targeting key nodes within these dysregulated metabolic pathways has potential as a therapeutic strategy.
    CONCLUSIONS: Here, we review the metabolic heterogeneity of neutrophil subpopulations and the mechanisms by which distinct metabolic programs drive disease progression in pathological settings. We further discuss current therapeutic strategies targeting these pathways. Through this analysis, we aim to provide a refined perspective on the immune landscape and to identify new possibilities for therapeutic intervention.
    Keywords:  Heterogeneity; Immunometabolism; Neutrophils; Transcriptomics; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1186/s12964-026-03112-7
  16. Sci Adv. 2026 Oct 30. 12(44): eaeg0361
    Glucose restriction induced by intermittent fasting promotes alternative metabolic fluxes leading to memory CD8+ T cell development.
    Da-Jeong Park, Young-Jun Ju, Young Jin Pyung, Cheol Gyun Kim, Narae Kim, MinJi Lim, Hyungseok Seo, Seung Hyun Han, Jae-Ho Cho, Cheol-Heui Yun.
      Dietary restrictions are increasingly recognized as modulators of immune cell function. However, how they shape CD8+ T cell fate decisions remains incompletely understood. Here, we investigated the impact of intermittent fasting (IF) on differentiation of heterogeneous effector T cell subsets and the formation of a long-lived homeostatic memory pool. We found that IF skewed CD8+ T cell differentiation toward memory precursor effector cells (MPECs) and enhanced the central memory CD8+ T cell development and functions. Mechanistically, glucose restriction induced by IF promotes alternative metabolic fluxes leading to fatty acid oxidation. This metabolic shift enhanced mitochondrial fitness and supported MPEC differentiation via metabolic-epigenetic cross-talk, culminating in durable and functionally robust memory CD8+ T cell responses. Applying this strategy in adoptive transfer therapy, intratumoral defects could be circumvented by imprinting a memory phenotype under IF-mimicking conditions, resulting in improved and long-lasting antitumor activity. Collectively, these findings underscore the importance of IF in orchestrating metabolic-epigenetic cross-talk to enhance memory formation and antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.aeg0361
  17. Cell Metab. 2026 Oct 28. pii: S1550-4131(26)00439-0. [Epub ahead of print]
    Arginine rewires eIF4F translation initiation to overcome fever-induced CAR T cell dysfunction.
    Taisuke Kondo, Makoto Ando, Josquin Moraly, Justyn DuSold, Abdallah Abdelmaksoud, Hannah W Song, Lakshmi Balagopalan, Dongya Jia, Laetitia Racine, Andy D Tran, Sooraj Achar, Serifat O Adebola, Pedro Gonzalez-Menendez, John Buckley, Anjali Chandroth, Alka Dwivedi, Nikolaos Svoronos, Angela Su, Christopher D Chien, Alexander D Clark, Xiyuan Zhang, Bonnie Yates, King Chan, Stephen D Fox, Xia Xu, Nicholas P Restifo, Neeraja Syed, Michael C Kelly, Michael Kruhlak, Yuki Kagoya, Rémy Bosselut, Jack F Shern, Thorkell Andresson, Valérie Dardalhon, Craig J Thomas, Steven L Highfill, Nirali N Shah, Grégoire Altan-Bonnet, Naomi Taylor.
      Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment of hematological malignancies, but cytokine release syndrome (CRS) remains a major toxicity. Fever-a hallmark of CRS-has been understudied as a modifier of therapeutic efficacy. In a retrospective cohort of patients with B cell acute lymphoblastic leukemia treated with CD22-directed CAR T cells (NCT02315612), sustained high-grade fever inversely correlated with clinical response. Mechanistically, experimental hyperthermia impaired proximal CAR signaling, reduced cytotoxicity, and compromised metabolic fitness through dysregulated arginine metabolism. Arginine supplementation restored CAR T cell function following hyperthermic stress and enhanced cytotoxicity under normothermic conditions. This effect required mTOR-dependent recruitment of the eIF4F translation-initiation complex and downstream c-MYC-driven metabolic reprogramming. Importantly, arginine enhanced good manufacturing practice (GMP)-manufactured CAR T cell function under normothermia, while oral supplementation improved in vivo efficacy. These findings identify metabolic control of translation as a fever-sensitive checkpoint and establish arginine supplementation as a tractable strategy to enhance CAR T cell efficacy.
    Keywords:  CD22; arginine; c-MYC; chimeric antigen receptor T cell therapy; cytokine release syndrome; fever; mTOR; metabolic fitness; mitochondrial function; translation initiation
    DOI:  https://doi.org/10.1016/j.cmet.2026.10.001
  18. bioRxiv. 2026 Sep 03. pii: 2026.09.02.748262. [Epub ahead of print]
    Tumour rewires host tryptophan metabolism to promote organism-wide immune suppression.
    Lucia Garcia-Lopez, Ernesto Saez-Carrion, Mary L Uribe, Carmen Gomez-Escolar, Esther Ballesta-Illan, Jason M Tennesen, Maria Dominguez.
      How tumour genotype reshapes systemic metabolism to drive immune tolerance and tumour progression remains unclear. Here, we show that Pten -deficient Drosophila tumours reprogram host tryptophan metabolism, triggering systemic and local changes in immune compartments to foster tolerance. Tumour-derived nitric oxide activates the kynurenine pathway in liver-like tissue, selectively increasing the 3-hydroxykynurenine (3-HK) branch. Host 3-HK promotes tumour progression and suppresses immune function via aryl hydrocarbon receptor (AhR) signalling. These results identify the kynurenine pathway as a central tumour-host nexus and reveal how tumour genotype creates immune vulnerabilities.
    DOI:  https://doi.org/10.64898/2026.09.02.748262
  19. J Pathol. 2026 Oct 27.
    Integrative single-cell transcriptomic and metabolic profiling reveals lactate-driven glycolytic reprogramming and histone lactylation in colorectal cancer liver metastasis.
    Yichao Liang, Xiaoxu Deng, Tao Wang, Xiaoying Chang, Zhe Zhang.
      Metabolic reprogramming and immune evasion are hallmarks of cancer metastasis, but how tumor metabolism shapes the immune microenvironment during colorectal cancer (CRC) liver metastasis remains poorly understood. The role of E-cadherin (CDH1) beyond cell adhesion is unexplored. We integrated single-cell RNA sequencing, pseudotime trajectory inference, and in vivo/in vitro functional assays in primary and liver-metastatic CRC models. CellChat was used to map intercellular communication. Histone lactylation, ADAM10 activation, and CDH1 shedding were validated by biochemical and immunohistochemical assays. PGK1-driven glycolysis is upregulated in liver metastases and promotes metastatic progression. Elevated lactate induces histone H3K18 lactylation, activating ADAM10 expression. ADAM10 cleaves CDH1, releasing its soluble ectodomain. This fragment acts as a ligand for KLRG1 on T cells, driving exhaustion and immunosuppression. Cell-cell communication analysis confirmed CDH1-KLRG1 as a top differentially activated pathway in metastasis. Functionally, targeting PGK1 or blocking CDH1 shedding inhibits liver metastasis and restores T-cell function. We identify a metabolic-epigenetic-immune axis in which tumor glycolysis reprograms immunity via lactate-induced CDH1 shedding. Soluble CDH1 functions as an immunomodulatory signal, linking metabolic activity to T-cell exhaustion. This redefines CDH1 as a dual-function molecule and reveals actionable targets for metastatic CRC. © 2026 The Pathological Society of Great Britain and Ireland.
    Keywords:  ADAM10; CDH1–KLRG1 axis; PGK1; T‐cell exhaustion; colorectal cancer; histone lactylation; liver metastasis; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1002/path.70138
  20. Metabolites. 2026 Oct 16. pii: 788. [Epub ahead of print]16(10):
    Lactate-Driven Biphasic Reprogramming of Macrophage Immune Responses.
    Qingshuang Guo, Pan Ren, Lanqi He, Jiaying Gao, Ruiqi Lu, Yitian Wang, Zhiheng Zhang, Xiaohui Han, Xi Zhang, Chao Fang.
      Lactate is a metabolic substrate, an extracellular signaling molecule, and a precursor for protein lactylation, with diverse effects on macrophage immunity. Evidence from infection, tissue injury, efferocytosis, and cancer indicates that lactate-associated pathways can amplify inflammation, support resolution and tissue repair, or sustain immune suppression. These outcomes depend on the timing, cellular source and compartment, chemical formulation and pH, transport and receptor engagement, and the chemistry and targets of lactylation. In this narrative review, we critically synthesize the biochemical foundations of lactate metabolism and lactyl-group donation and examine the mechanisms underlying these distinct macrophage responses. We distinguish model-specific biphasic responses from a universal sequence of early inflammation followed by resolution, and separate reparative programs from impaired antimicrobial or antitumor immunity. We also evaluate evidence for histone and non-histone lactylation, emphasizing the limits of metabolic perturbations and chromatin associations for establishing site-specific causality. This framework identifies experimental variables that should be controlled and supports context-selective investigation of lactate-related therapeutic targets in inflammatory diseases and cancer.
    Keywords:  immune regulation; immunometabolism; lactate; lactylation; macrophage plasticity
    DOI:  https://doi.org/10.3390/metabo16100788
  21. Front Nutr. 2026 ;13 1984798
    Gut microbial metabolism in aging: from metabolite production to organ-specific immunometabolic effects.
    Zhen Wang, Yang Liu.
      Age-related changes in gut microbiota metabolism are heterogeneous across populations and pathways, and their relationships with immunometabolism and organ phenotypes should be interpreted in the context of health status and disease. Microbial abundance or the concentration of a single metabolite does not, by itself, capture microbial production, host exposure, or effects in target tissues. This narrative review summarizes upstream influences, including gastrointestinal physiology, dietary substrates, comorbidities, and medications, and discusses the origins and host processing of major metabolites, their immunometabolic effects, and associated organ phenotypes. Studies in some older populations report lower fecal short-chain fatty acid concentrations. Microbiota-derived indole derivatives and host-synthesized, microbiota-modified bile acids show molecule- and population-specific patterns. Circulating concentrations of some host-microbe co-metabolites are higher in selected older or disease populations, but are also shaped by host biotransformation and clearance. Human evidence is predominantly observational and links metabolic features to health status or clinical phenotypes, whereas animal and cell studies support effects on barrier function, inflammation, and cellular metabolism under specific experimental conditions. Personalized nutrition, metabolite supplementation, selective targeting of microbial enzymes, and multi-omics-based responder stratification are promising research directions; prospective evidence that these strategies improve functional outcomes in older adults remains limited.
    Keywords:  aging; gut microbiota; gut-organ axis; immunometabolism; inflammaging; microbial metabolites; personalized nutrition
    DOI:  https://doi.org/10.3389/fnut.2026.1984798
  22. Sci Immunol. 2026 Oct 30. 11(124): eaea5625
    Nuclear NAD+ promotes innate immune memory by inhibiting KDM5A-dependent histone demethylation.
    Huan Jin, Zining Wang, Yongxiang Liu, Zifeng Wang, Mengyun Li, Ju Xue, Yiqun Zhang, Tiantian Yu, Shoujie Wang, Bitao Huo, Chunwei Li, Xiaojuan Wang, Ruhui Yao, Huanling Zhang, Jiahong Yi, Yanxun Lin, Lei Cui, Hui Guo, Zixuan Guo, Ling Zhang, Chaoyun Pan, Xuetong Shen, Gelin Wang, Gaofeng Fan, Zhiming Wu, Jing Tan, Song Gao, Jin-Xin Bei, Peng Huang, Jinyun Liu, Xiaojun Xia.
      Trained immunity is tightly regulated by metabolic and epigenetic reprogramming, yet how these changes are orchestrated at the chromatin level to establish long-term innate immune memory is not fully understood. Here, we show that induction of trained immunity elevates nuclear levels of nicotinamide adenine dinucleotide (NAD+), which directly binds to KDM5A demethylase and inhibits its activity, thereby sustaining H3K4me3 (histone H3 lysine 4 trimethylation) levels and chromatin accessibility at inflammatory gene promoters to enhance "memory" responsiveness upon restimulation. Genetic deletion or pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ synthesis, impaired trained immunity and associated antitumor activity. Nicotinamide mononucleotide (NMN) supplementation rescued defective trained immunity-mediated antitumor activity in NAMPT-deficient and aged mice. In human cancer, NAMPT expression in myeloid cells correlated with an inflammatory tumor microenvironment. Our findings identify KDM5A as a nuclear NAD+ sensor that orchestrates histone methylation and chromatin accessibility required for trained immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.aea5625
  23. Front Immunol. 2026 ;17 1965479
    Immunometabolic crosstalk between dysfunctional adipose tissue and the brain: implications for postoperative cognitive dysfunction in obesity.
    Ya-Jiao Hu, Juan Ni, Jin-Xi Zhang.
      Postoperative cognitive dysfunction (POCD) is an important complication after surgery, particularly in patients with pre-existing metabolic and inflammatory vulnerability. Obesity may increase susceptibility to postoperative cognitive decline, but its independent association with POCD and the underlying mechanisms remain uncertain. This review critically examines a proposed adipose-immune-brain pathway linking obesity-associated adipose dysfunction to perioperative neurocognitive outcomes. In obesity, adipocyte hypertrophy, hypoxia, fibrosis, macrophage accumulation, T-cell imbalance, and activation of inflammasome and innate immune signaling pathways promote chronic low-grade inflammation and altered endocrine function. The resulting changes in cytokines, adipokines, free fatty acids, lipid mediators, insulin sensitivity, and glucose and lipid metabolism may establish a systemically primed immunometabolic state. Surgical trauma may then act as a second inflammatory hit, amplifying peripheral immune activation and promoting blood-brain barrier dysfunction, glial activation, oxidative stress, and impaired neuronal function. However, direct clinical evidence linking adipose tissue inflammation to POCD remains limited; current support is derived largely from preclinical studies, indirect biomarker associations, and heterogeneous clinical studies that sometimes combine postoperative delirium with longer-term cognitive outcomes. Accordingly, the adipose-immune-brain axis should be regarded as a biologically plausible framework rather than an established causal pathway. Better phenotyping of visceral adiposity and metabolic dysfunction, standardized neurocognitive outcomes, and integrated assessment of adipose, circulating, and blood-brain barrier biomarkers are needed. Potential interventions include weight and metabolic optimization, incretin-based therapies, modulation of inflammatory and pro-resolving pathways, and perioperative physiological management, although their efficacy for preventing POCD remains to be established.
    Keywords:  adipose tissue immune remodeling; blood–brain barrier; immunometabolism; neuroinflammation; obesity; peripheral immune activation; postoperative cognitive dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2026.1965479
  24. Cell Commun Signal. 2026 Aug 01. pii: 586. [Epub ahead of print]24(1):
    Taurine preserves γδ T cell fitness in triple-negative breast cancer.
    Haibo Duan, Ke Li, Wenhui Yuan, Lanhong Pan, Min Su, Qiang Quan, Jianfu Zhao, Peng Li.
      Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options. Here, we identified a marked exhaustion phenotype in peripheral Vγ9Vδ2 (Vδ2) T cells from patients with TNBC, characterized by elevated PD-1 and TIM-3 expression. Untargeted serum metabolomics revealed significantly reduced taurine levels, which were inversely associated with Vδ2 T-cell exhaustion. Bioinformatic analyses further showed that higher expression of the taurine transporter SLC6A6 correlated with enhanced immune infiltration and favorable prognosis in TNBC. Mechanistically, taurine uptake via SLC6A6 alleviated immune exhaustion in Vδ2 T cells and enhanced PLCγ1 phosphorylation, thereby promoting IFN-γ and TNF-α production. In vitro, taurine-treated Vδ2 T cells exhibited enhanced cytotoxicity against TNBC cells. In vivo, taurine supplementation suppressed tumor growth in a γδ T cell-dependent manner. Collectively, these findings identify the taurine-SLC6A6 axis as a key regulator of Vδ2 T-cell function in TNBC and suggest taurine supplementation as a potential strategy to enhance γδ T cell-mediated antitumor immunity.
    Keywords:  Antitumor immunity; Immune exhaustion; Taurine; Triple-negative breast cancer; γδ T cell
    DOI:  https://doi.org/10.1186/s12964-026-03125-2
  25. Sci Adv. 2026 Oct 30. 12(44): eaeh8465
    Lipid-sensing GPR183-KRAS signaling mediates TH17 autoimmunity and identifies fluvoxamine repurposing in uveitis.
    Chun Zhang, Xiuxing Liu, Nanwei Xu, Hui Chen, Yuehan Gao, Chenyang Gu, Xinyue Shen, Junying Wu, Xuejing Lu, Pei Zhang, Yuxuan He, Zhuping Xu, Wenru Su.
      Autoimmune uveitis (AU) is a leading cause of irreversible blindness driven by pathogenic T helper 17 (TH17) cell-mediated inflammation, yet current therapies are limited by efficacy and side effects, with immunometabolic mechanisms remaining poorly defined. By integrating single-cell RNA sequencing and multilayered metabolomic profiling in patients with AU and experimental AU models, we identified the lipid-sensing G protein-coupled receptor GPR183 as a key immunometabolic regulator in pathogenic CD4+ T cells. Upon activation, GPR183 modulates intracellular signaling via suppression of cyclic adenosine monophosphate-cAMP-dependent protein kinase activity and promotion of son-of-sevenless-dependent KRAS activation, which in turn elicits copper overload-induced mitochondrial oxidative stress, structural impairment, and metabolic rewiring toward glycolysis, thereby promoting TH17 cell pathogenicity. For clinical translation, virtual screening of Food and Drug Administration-approved drugs coupled with molecular docking and microscale thermophoresis validation identified fluvoxamine (FLV) as a direct GPR183 antagonist. In in vivo and in vitro uveitis and colitis models, FLV attenuated GPR183-KRAS signaling, dampened pathogenic TH17 cell responses, and alleviated tissue inflammation. These findings delineate a unique GPR183-KRAS-mitochondrial damage axis governing TH17-driven autoimmunity and support repurposing FLV as a translatable therapeutic approach for AU and other autoimmune inflammatory disorders.
    DOI:  https://doi.org/10.1126/sciadv.aeh8465
  26. Adv Sci (Weinh). 2026 Oct 28. pii: e78416. [Epub ahead of print]
    Macrophage GLUD1 is Essential for Redox Balance and Immune Homeostasis in Cardiac Injury.
    Tingting Jin, Chaojie Lai, Qingyan Zhou, Ruilin Wang, Yiping Tong, Wentao Chen, Nikola Rabrenovic, Tingyu Zhang, Xinrong Ren, Chengchen Huang, Jiawen Chen, Ran Li, Luyang Yu, Massimiliano Mazzone, Wenbin Zhang, Guosheng Fu, Min Shang.
      Excessive free radical production and dysregulated immune responses contribute to myocardial ischemia-reperfusion (IR) injury. However, the mechanisms by which macrophages regulate reactive oxygen species (ROS) homeostasis and orchestrate immune responses during IR injury remain elusive. Here, we show that glutamate dehydrogenase 1 (GLUD1) expression is induced in monocytes from patients with acute myocardial infarction after interventional therapy and in cardiac-recruited macrophages from mice subjected to IR injury. GLUD1-deficient macrophages exacerbate IR injury by increasing mitochondrial ROS accumulation and amplifying pro-inflammatory responses. Mechanistically, GLUD1 deficiency leads to mitochondrial ROS accumulation due to reduced NADPH/NADP+ and GSH/GSSG ratios during IR injury. Elevated mitochondrial ROS inhibits PHD2 activity, stabilizing HIF-1α and enhancing NF-κB signaling, promoting the release of pro-inflammatory factors and exacerbating myocardial damage. Systemic activation of GLUD1 or adoptive transfer of monocytes pre-treated with a GLUD1 activator preserved cardiac function and mitigated IR injury. These findings highlight macrophage GLUD1 as a critical regulator of redox balance and immune homeostasis, presenting a promising therapeutic target for alleviating IR injury and preserving cardiac function.
    Keywords:  acute myocardial infarction; cardiac Injury; cell metabolism; glutamate dehydrogenase 1 (GLUD1); immune homeostasis; immunometabolism; ischemia‐reperfusion injury; monocytes and macrophages; reactive oxygen species
    DOI:  https://doi.org/10.1002/advs.78416
  27. Microorganisms. 2026 Oct 16. pii: 2368. [Epub ahead of print]14(10):
    c-Myc Links TGF-β Signaling to Metabolic Control of HIV Reactivation in OM10.1 Cells.
    Jakob Harrison-Gleason, Jinhee Kim, Elena Martinelli.
      Antiretroviral therapy (ART) suppresses HIV replication but does not eliminate persistent viral reservoirs, which can rapidly reseed viremia following treatment interruption. We previously showed that blockade of transforming growth factor beta (TGF-β) signaling in vivo promotes SIV latency reversal and is associated with reversal of cellular metabolic quiescence. Here, using the provirally infected promyelocytic OM10.1 cell line, we investigated the cell-intrinsic mechanisms through which TGF-β regulates HIV reactivation. TGF-β inhibited proviral reactivation following stimulation with distinct latency-reversing agents, and this effect was reversed by pharmacologic inhibition of TGF-β signaling. TGF-β reduced HIV transcription without suppressing TNF-α-induced NF-κB activation, suggesting inhibition through an alternative mechanism. Bulk RNA sequencing revealed broad suppression of c-Myc-associated pathways, oxidative phosphorylation, and mTORC1 signaling. Functional metabolic profiling confirmed marked reductions in both glycolytic and mitochondrial ATP production and decreased mitochondrial membrane polarization. Consistent with a functional link between metabolism and viral reactivation, mitochondrial uncoupling strongly inhibited HIV expression. Finally, MYC overexpression completely rescued HIV transcription and partially restored p24 production in TGF-β-treated cells. Together, these findings identify a cell-intrinsic mechanism through which TGF-β restrains HIV reactivation by imposing a metabolically quiescent state, mediated at least in part through suppression of c-Myc.
    Keywords:  HIV; Myc; SIV; TGF-β; immunometabolism
    DOI:  https://doi.org/10.3390/microorganisms14102368
  28. J Exp Med. 2026 Nov 02. pii: e20252558. [Epub ahead of print]223(11):
    Vanin-pantethine metabolic axis shapes dendritic cell function and affects inflammatory disorder progression.
    Ai-Ping Cao, Jun-Cheng Li, Rui Wang, Yun-Ying Wang, Nan Wu, Yan-Hong Liu, Zhi Jin, Jia-Yu Liu, Yan-Yan Shen, Yue Guo, Qi Qi, Yao Wang, Rui-Bo Wang, Bo-Yang Xie, Chun-Yan Yan, Qiu-Ying Han, Shao-Yi Huang, Sheng-Ming Wu, Na Wang, Xin Pan, Cheng-Xin Li, Tao Zhou, Ai-Ling Li, Qing Xia, Wei-Na Zhang.
      Aberrant activation of dendritic cells (DCs) is intricately associated with inflammatory diseases, rendering DCs an appealing therapeutic target. Metabolites are emerging as crucial regulators of DCs, yet therapeutic strategies targeting DC metabolism for inflammatory diseases remain underexplored. Our study identifies the Vanin-pantethine-cholesterol axis as a key metabolic pathway that governs DC activation-a classical APC function. We found that Vanin is upregulated in activated DCs from autoimmune patients and mice; DC-specific Vanin deficiency significantly alleviates psoriasiform inflammation in mice. Mechanistically, Vanin hydrolyzes pantethine, leading to cholesterol and lipid raft accumulation on the cell membrane and promoting DC hyperactivation. Pantethine supplementation or pharmacologically induced Vanin inhibition reduces cholesterol overload, impedes DC activation, and mitigates psoriasiform inflammation. Notably, pantethine or RR6 treatment impairs activation of patient-derived DCs, and our investigator-initiated trial shows that pantethine combination therapy relieves clinical symptoms in psoriasis patients. Collectively, these findings establish the Vanin-pantethine-cholesterol axis as a key modulator of APC function, offering a promising metabolic approach for inflammatory diseases.
    DOI:  https://doi.org/10.1084/jem.20252558
  29. bioRxiv. 2026 Oct 06. pii: 2026.10.01.756002. [Epub ahead of print]
    Nutrient-sensitive histone propionylation regulates T cell fate and function.
    Alison Jaccard, Kelly Rome, Qihua Yang, Shuo Zhang, Noah Ford, Adam Chatoff, Tran Ngoc Van Le, Michael Noji, Andrea Andress Huacachino, Stephanie Stransky Lauar, Carlos Pondevida, Krittin Trihemasava, Laura V Pinheiro, Sanat Bhadsalve, Eun Kyung Ko, Charles Salinas, Mariola M Marcinkiewicz, Brian C Capell, Golnaz Vahedi, Simone Sidoli, Roddy S O'Connor, Will Bailis, Nathaniel W Snyder, Kathryn E Wellen.
      Tissue microenvironments differ widely in nutrient composition; yet how local nutrient conditions shape epigenetic programs that direct immune cell fate is poorly understood. We identify histone lysine propionylation (Kpr) as a chromatin mechanism linking nutrient availability to T cell fate decisions. Proteomic analysis reveals that Kpr is broadly reduced in exhausted T cells. H3K18pr is enriched at stemness-associated loci in effector T cells and depleted upon exhaustion. Isoleucine and propionate supply propionyl-CoA in T cells, and restricted nutrient availability within the tumor microenvironment limits histone Kpr, promoting T cell exhaustion. Disrupting isoleucine catabolism in T cells further suppresses Kpr, without altering histone acetylation, and impairs T cell function and antitumor immunity in a manner rescued by propionate. Dietary supplementation of isoleucine and propionate increases Kpr in tumor infiltrating lymphocytes, limits exhaustion, and improves tumor control. These findings establish a microenvironment-chromatin axis crucial for antitumor immunity and amenable to nutritional intervention.
    DOI:  https://doi.org/10.64898/2026.10.01.756002
  30. J Proteomics. 2026 Oct 24. pii: S1874-3919(26)00158-2. [Epub ahead of print]333 105755
    Proteomics analysis reveals headgroup-dependent modulation of lipopolysaccharide-induced inflammation by arachidonoyl phospholipids in macrophages.
    Tatiana Maurício, Bruno M Neves, M Rosário Domingues, Pedro Domingues.
      Aminophospholipids, including phosphatidylserines (PS) and phosphatidylethanolamines (PE), are major components of the inner leaflet of cellular membranes with emerging immunomodulatory functions, yet the contribution of their polar headgroups remains poorly defined. To address this, we compared PS16:0/20:4 and PE16:0/20:4, two phospholipids with identical fatty-acyl composition, in resting and lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages using LC-MS/MS proteomics, gene set enrichment analysis, and targeted qPCR. Among the 1611 proteins retained for statistical analysis, both phospholipids produced distinct basal proteomic profiles and substantially modified the subsequent response to LPS. A core of 667 LPS-responsive proteins was preserved across control, PS-, and PE-supplemented macrophages, while interaction analyses revealed marked headgroup-dependent differences in response magnitude. These differences mapped onto distinct pathways. PS supplementation was associated with vesicle trafficking, lipid recognition, redox regulation, and ER proteostasis, whereas PE preferentially affected glutathione and redox-related proteins. Both phospholipids reduced selected inflammatory markers and LPS-induced nitric oxide production. Together, these findings demonstrate headgroup-dependent modulation of macrophage proteomic responses by matched arachidonoyl phospholipids, underscoring the functional relevance of phospholipid headgroup. Significance: Membrane phospholipids are increasingly recognized as active regulators of immune cell function, yet the contribution of the polar headgroup remains poorly defined. By directly comparing PS16:0/20:4 and PE16:0/20:4, this study shows that two native phospholipids carrying identical acyl chains generate distinct macrophage proteomic responses. Both lipids remodel the resting proteome and modify subsequent LPS responsiveness, but with different associations with redox regulation, membrane trafficking, ER proteostasis, and inflammatory signalling. These findings advance our understanding of the role of phospholipid headgroup as an important modulator of macrophage responses and support the development of phospholipid-based approaches to modulate inflammation and immunometabolism.
    Keywords:  Immunometabolism; Inflammation; Macrophages; Phosphatidylserine; Phospholipids; Proteomics
    DOI:  https://doi.org/10.1016/j.jprot.2026.105755
  31. Am J Physiol Heart Circ Physiol. 2026 Oct 20.
    Exogenous lactate exacerbates adverse cardiac remodeling following myocardial infarction via impaired macrophage activation and myocardial ER stress.
    Mursalin Khan, Nadiyeh Rouhi, Katherine R O'Quinn, Catharyne Wright, Rob W Spitz, Emily C Ladnier, Jussara M do Carmo, Ana C M Omoto, Alex A da Silva, Zhen Wang, John E Hall, Alan J Mouton.
      Myocardial infarction (MI) induces cardiac remodeling characterized by inflammation, scar formation, and metabolic remodeling of surviving tissue. Emerging evidence suggests that lactate, an alternative metabolic fuel, may also have therapeutic effects by mitigating damaging inflammation. To investigate the effects of lactate on post-MI remodeling, male and female mice underwent permanent coronary artery ligation for up to 7-days post-MI. In untreated animals, MI induced progressive myocardial lactate accumulation, accompanied by increased Lactate Dehydrogenase-A (LDHA) and reduced LDHB expression in both male and female. In untreated male, cardiac macrophages exhibited dynamic changes in Ldha, Ldhb, and Mct1 gene expression between Day-1, 3, and 7. Repeated sodium lactate administration significantly reduced Day-7 survival in male and promoted ventricular wall thinning, reduced collagen deposition, increased myocardial inflammatory markers (Ccl2, Il18, Il6) and reduced CD206+ reparative macrophages in both infarct and remote regions at Day-3. To distinguish acute from sustained lactate effects, we administered a single sodium lactate injection 30 minutes before tissue collection at Day-3 post-MI (D3-30min), which rapidly increased myocardial lactate levels and induced inflammatory and endoplasmic reticulum stress-associated gene expression. Moreover, acute lactate treatment (D3-30min) increased circulating and bone marrow neutrophils, increased bone marrow and cardiac monocytes, and reduced ATP-linked mitochondrial respiration in isolated cardiac macrophages. In parallel experiments, sodium oxamate (a lactate dehydrogenase inhibitor), displayed a trend towards improving post-MI survival (p=0.09) but otherwise did not significantly impact cardiac functional or remodeling parameters. These findings demonstrate that exogenous lactate exacerbates adverse post-MI remodeling, promoting extracellular matrix disruption, inflammatory activation, and macrophage metabolic dysregulation. Collectively, our results suggest that lactate metabolic signaling, production, accumulation or downstream may represents a potential therapeutic strategy for limiting adverse cardiac remodeling after MI.
    Keywords:  ER stress; LDHA; cardiac remodeling; extracellular matrix; heart failure; immunometabolism; infarct healing; inflammation; macrophages; mitochondrial respiration
    DOI:  https://doi.org/10.1152/ajpheart.90312.2026
  32. bioRxiv. 2026 Oct 05. pii: 2026.09.29.753881. [Epub ahead of print]
    A synthetic PGC1α co-activator reprograms microglial immunometabolism to preserve cone function in retinal degeneration.
    Thomas Winogrodzki, Jayvin Hernandez-Reyes, Rajvir Solanky, Richard Lowery, Georgy Komissarov, Wen Huang, Boyuan Wang, Neoklis Makrides, Sharifa Davis, Siyuan Liu, Yong-Shi Li, Wen-Hsuan Wu, Nicholas Nolan, Robert van de Werken, Aykut Demirkol, Anders Knudsen, Nuntachai Surawatsatien, Yao Li, James Hurley, Stephen H Tsang.
      Retinitis pigmentosa (RP) is genetically heterogeneous, yet initiating mutations converge on primary rod degeneration followed by cone dysfunction and loss. Activated microglia are implicated in this secondary phase, but whether selective immunometabolic reprogramming of microglia preserves retinal function remains unknown. In human iPSC-derived microglia and retinal CD11b+ cells, PGC1α induction suppressed LPS-driven interferon signaling and cytokine release, yet Seahorse analysis and isotopologue tracing showed that energy metabolism remained altered. We therefore fused PGC1α to a multivalent p65-HSF1 module, yielding ~2.5-fold higher nuclear receptor output than native PGC1α and coordinated engagement of oxidative and anti-inflammatory programs in mouse retinal CD11b+ cells. Microglia-restricted expression in humanized RHO P347L mice preserved photopic responses through six months, increased retinal thickness and promoted ramified subretinal IBA1+ morphology. Microglial immunometabolism thus represents a potentially genotype-independent neuroprotective target in RP, and engineered PGC1α co-activators provide a means to sustain oxidative metabolism under inflammatory pressure.
    DOI:  https://doi.org/10.64898/2026.09.29.753881
  33. MedComm (2020). 2026 Nov;7(11): e71088
    Multi-Omics Insights Into Circulating T-Cell Metabolic Reprogramming and Treg Dysfunction in Moyamoya Disease.
    Zhiyao Zheng, Qiheng He, Xinyu Ma, Bojian Zhang, Junsheng Li, Chenglong Liu, Siqi Mou, Wei Sun, Xiangjun Shi, Wenjing Wang, Dong Zhang, Peicong Ge, Jizong Zhao.
      Moyamoya disease (MMD) is a progressive cerebrovascular disease linked to immune dysregulation, yet T-cell metabolic reprogramming and regulatory T-cell (Treg) function remain poorly understood. Here, we integrated multi-omics approaches, including mass cytometry, single-cell RNA sequencing, bulk RNA sequencing, metabolomics, and flow cytometry to characterize T-cell metabolic alterations and Treg dysfunction in MMD, uncovering a key metabolic-immune axis. Compared with healthy controls, MMD patients showed chronic immune activation and broad suppression of amino acid, glycolytic, and fatty acid metabolic pathways. Although Tregs were aberrantly expanded, they displayed metabolic inflexibility, together with impaired intercellular communication. Single-cell transcriptomics indicated Treg-to-Th17 conversion, while flow cytometry confirmed increased IL-17A+ cells within the CD4+FOXP3+ compartment. Besides, these dysfunctional Tregs correlated with advanced Suzuki stages, ischemic stroke, and posterior cerebral artery involvement. Bulk transcriptomic and serum metabolomic analyses further confirmed coordinated immune activation and metabolic suppression at the gene, protein, pathway, and metabolite levels. These findings define a metabolic-immune axis in MMD in which metabolically constrained, functionally unstable Tregs may contribute to neuroinflammation and vascular remodeling, suggesting that restoring Treg metabolic fitness could represent a therapeutic strategy.
    Keywords:  Moyamoya disease; metabolic reprogramming; neuroinflammation; regulatory T‐cell
    DOI:  https://doi.org/10.1002/mco2.71088
  34. Insect Mol Biol. 2026 Oct 28.
    Integrated transcriptomic and metabolomic analysis reveals ApoLp-III-mediated BmNPV suppression via host energy and lipid reprogramming.
    Quadsia Jabeen, Xinhao Jiao, Zi Liang, Na Zhang, Shengyan Xiao, Wenwen Jiang, Shuyi Liu, Aniqa Shakoor Butt, Ping Wu.
      In global sericulture, the most economically important and primary causative pathogen is Bombyx mori nucleopolyhedrovirus (BmNPV), but the host immune metabolism that restricts the viral replication is not completely defined. A recently identified insect multifunctional apolipoprotein (apolipophorin-III [ApoLp-III]) was shown to suppress BmNPV proliferation by enhancing ceramide accumulation. However, it is unknown how this antiviral action is mediated through coordinated transcriptional and metabolic changes. In this study, we dissect the ApoLp-III-mediated antiviral mechanism by constructing an ApoLp-III-overexpressing BmN cell line and integrating RNA-seq data with a previously published metabolomic profile. A total of 1067 differentially expressed genes (DEGs) with significantly opposing expression trends were identified. These DEGs were prominent in DNA replication, oxidative phosphorylation (OXPHOS) and amino sugar nucleotide sugar metabolism. Genes associated with amino acid metabolism were down-regulated, while genes linked with DNA replication and OXPHOS were up-regulated. Bidirectional regulation of sphingolipids was also confirmed by quantitative real-time PCR (qRT-PCR) and transcriptomic data. Ceramide accumulation resulted from the down-regulation of alkaline ceramidase (ACER) and up-regulation of regulatory subunit of the rate-limiting ceramide synthesis enzyme, SPTssA. Integrated multi-omics correlation analysis further showed that ceramide species positively correlated with OXPHOS and negatively correlated with amino sugar metabolism. Meanwhile, down-regulated triglycerides showed negative correlation with DNA replication and OXPHOS genes. In addition, we identified ApoLp-III interacting proteins, that is, the integrin-associated cytoskeletal regulator, Talin-1 and lepidopteran-specific immune receptor Haemolin, using Flag-based co-immunoprecipitation coupled with mass spectrometry. Our results show that ApoLp-III suppresses BmNPV replication by the coordinated reprogramming of host cellular energy (OXPHOS) and lipid (sphingolipid) metabolism. Thus, ApoLp-III acts as an important immunometabolic hub in the antiviral defence of lepidopterans, and our research also offers a theoretical foundation for controlling silkworm diseases by targeting sphingolipid-energy pathway.
    Keywords:  BmNPV; apolipophorin‐III; immunometabolism; metabolic reprogramming; multi‐omics integration
    DOI:  https://doi.org/10.1111/imb.70072
  35. Exp Hematol Oncol. 2026 Aug 14. pii: 118. [Epub ahead of print]15(1):
    Targeting SLC6A14-mediated nutrient competition reverses an immunosuppressive metabolic niche in pancreatic cancer.
    Lihong He, Zihao Lin, Lingyue Liu, Shicheng Yao, Jiawei Wang, Jingpeng Guo, Changxin Zhong, Hanjia Zhang, Xiaozhen Zhang, Tingbo Liang, Xueli Bai.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive and nutrient-deficient tumor microenvironment (TME), where solute carrier (SLC) transporters are critical in metabolic reprogramming and intercellular communication. However, the precise mechanisms by which specific SLCs contribute to therapeutic resistance through the TME remain unclear.
    METHODS: We integrated transcriptomic data from clinical cohorts with computational analysis and expression validation to identify the SLC family members most closely linked to PDAC patient outcomes. Using in vitro and in vivo experiments along with multi‑omics approaches, we further clarified its functional roles in stromal-immune-metabolic networks within the TME. Following virtual screening of a million‑compound library and validated by binding assays, two target‑specific inhibitors were identified. Using pharmacological and genetic methods, the therapeutic potential of targeting this pathway was systematically evaluated.
    RESULTS: SLC6A14 is identified as a prognostic biomarker and functional driver of PDAC progression, with higher expression levels correlating with poor patient outcomes; it facilitates tumor growth by modifying amino acid metabolic reprogramming and exerting immunosuppressive effects by competitively impairing amino acid uptake in dendritic cells and CD8⁺ T cells. STOCK1N-75990 is a specific SLC6A14 inhibitor that competitively blocks amino acid binding, induces intracellular nutrient deprivation, and causes profound metabolic collapse; it exhibits marked anti-tumor activity and limited toxicity in preclinical models, synergizing with anti-PD1 therapy.
    CONCLUSION: These findings establish SLC6A14 as a potent multifunctional therapeutic target and demonstrate the clinical relevance of its inhibitors as a metabolic immunotherapy for PDAC.
    Keywords:  Immune metabolism; Immunotherapy; Metabolic remodeling; SLC6A14; STOCK1N-75990; Sophoricoside; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-026-00818-9
  36. Sci Immunol. 2026 Oct 30. 11(124): eaek9099
    Metabolic licensing of innate immune memory.
    Musa M Mhlanga, Andrew A Pieper.
      NAD+ is revealed to be a metabolic signal that preserves an epigenetic mark central to trained immunity by inhibiting the histone demethylase KDM5a (see related Research Article by Jin et al.).
    DOI:  https://doi.org/10.1126/sciimmunol.aek9099
  37. Clin Exp Immunol. 2026 Oct 27. pii: uxag066. [Epub ahead of print]
    T cell metabolic ageing as a factor for therapeutic research.
    Ellen King, Bahar Zinali Sohanaki, Anna Schurich.
      Ageing is an important determinant of immune function across the lifespan, yet it remains underappreciated in the design and interpretation of much basic T cell research. As the immune system ages, T cell responses become less diverse, less efficient, and less adaptable, with consequences for infection control, vaccine responsiveness, cancer immunosurveillance, and the performance of T cell-based immunotherapies. This issue is particularly acute because many fundamental studies still rely on T cells from, mostly, healthy young donors. These controls are indispensable, but the field has built much of its pre-clinical logic on immune systems that are younger, fitter, and biologically distinct from the patients for whom T cell therapies are intended. We argue that this mismatch between experimental systems and clinical reality could be overcome by considering age as a routine variable from the start.
    Keywords:  T cell; ageing; metabolism
    DOI:  https://doi.org/10.1093/cei/uxag066
  38. Res Sq. 2026 Sep 01. pii: rs.3.rs-10732509. [Epub ahead of print]
    Global carbohydrate metabolism is increased and beta hydroxybutyrate decreased in sepsis vulnerable children compared to sepsis tolerant children; a cohort study.
    Ruth A Carcillo, Rebecca I Caldino Bohn, Aditya Sriram, Kate F Kernan, Ivan Saraiva, Lina Ghaloul-Gonzalez, Dana Y Fuhrman, Christopher M Horvat, Jeremy R Herrman, Yong Y Han, Trung C Nguyen, Brian Ingram, Robert A Berg, Kathy L Meert, Mark W Hall, Christopher Jl Newth, Hernando Gomez, Jerry Vockley, Hyun Jung Park, Joseph A Carcillo.
       Background: Sepsis investigators propose tolerance is conferred when the dormancy response increases beta hydroxybutyrate to protect organs; whereas, vulnerability occurs when a 'metabolic switch' to aerobic glycolysis decreases beta hydroxybutyrate promoting persistent immune cell activation without organ protection. We previously identified tolerant (PedSep A 2% mortality), susceptible (PedSep B 12% mortality and PedSep C 10% mortality) and vulnerable (PedSep D 34% mortality) phenotypes in the PHENOtyping pediatric sepsis induced Multiple organ failure Study (PHENOMS). We hypothesized that carbohydrate metabolism was increased and beta hydroxybutyrate decreased in PedSep D compared to PedSep A in this study.
    Methods: Metabolomics were assayed in biobanked plasma samples previously collected at 24-48 hours of sepsis in 375 children ages 44 weeks post gestation to 17 years, using the Metabolon Discovery Panel. Welch's t-tests identified differences between PedSep B, C, and D with A.
    Results: Compared to PedSep A (n =130) PedSep B had similar carbohydrate metabolism and beta hydroxybutyrate but dysregulated branch chain amino acid metabolism (n = 92; p < 0.05); PedSep C had similar carbohydrate metabolism but decreased beta hydroxybutyrate (n = 100; p< 0.05); and, PedSep D had increased carbohydrate metabolism with decreased beta hydroxybutyrate (n = 53; p < 0.05). Causal inference analysis found direct associations of increased glycolysis with decreased beta hydroxybutyrate, and death.
    Conclusions: Only PedSep D had increased carbohydrate metabolism with decreased beta hydroxybutyrate providing rationale for designing clinical trials of low carbohydrate ketogenic nutrition to decrease glycolysis, restore dormancy, and improve outcome in these high-risk children.
    Keywords:  beta hydroxybutyrate; carbohydrate metabolism; immunometabolism; metabolomics; multiple organ failure; pediatric sepsis; sepsis tolerance; sepsis vulnerability
    DOI:  https://doi.org/10.21203/rs.3.rs-10732509/v1
  39. Immunol Invest. 2026 Oct 28. 1-25
    Neutrophil-Derived Arg1 Impairs CD8+ T Cell Activity in Sepsis Through mTOR-Mediated Mitochondrial Dysfunction.
    Qiulin Peng, Liuqing Yang.
       BACKGROUND: This research aimed to elucidate the contribution of Arginase 1 (Arg1) to pediatric sepsis progression, specifically impacting the effector functions of CD8+ T lymphocytes.
    METHODS: Arg1 expression was assessed in venous blood from pediatric sepsis patients (n = 21) and healthy volunteers (n = 21). Pharmacological inhibition of Arg1 was achieved using Nor-NOHA in both sepsis patients-derived neutrophils and LPS-stimulated healthy neutrophils, followed by co-culture with CD8+ T cells. Sepsis-derived neutrophils were also treated with hArg1 monoclonal antibody (mAb). CD8+ T cell viability, exhaustion markers (PD-1/TIM-3), mitochondrial membrane potential, ATP production, autophagy, and inflammatory cytokine secretion were systematically evaluated.
    RESULTS: Arg1 expression was markedly upregulated in sepsis patients correlated positively with neutrophil counts but negatively with CD8+ T cell numbers and mitochondrial function. Strikingly, CD8+ T cells from Arg1-high patients exhibited increased PD-1+TIM-3+ double-positive populations. Both Nor-NOHA-mediated Arg1 inhibition and hArg1-mAb neutralization significantly restored CD8+ T cell mitochondrial membrane potential (MMP), ATP production, and effector cytokine secretion, while concurrently reducing PD-1/TIM-3 expression.
    CONCLUSION: Our findings indicate that overexpression of Arg1 derived from neutrophils leads to a highly inflammatory response suggesting that Arg1 is a potential prognostic biomarker and therapeutic target in pediatric sepsis.
    Keywords:  Arg1; CD8+ T cell; mitochondrial impairment; neutrophil; sepsis
    DOI:  https://doi.org/10.1080/08820139.2026.2750409
  40. bioRxiv. 2026 Oct 06. pii: 2026.10.05.756742. [Epub ahead of print]
    Sex-Dependent Microbiome-Metabolome Remodeling Associated with Bacteroides acidifaciens Modulation of Acute Respiratory Distress Syndrome.
    Shanieka Staley, Carly Cooper, Stacey Oxendine, Jordan Williams, Alissa Armstrong, Kiesha Wilson.
      Acute respiratory distress syndrome (ARDS) is a severe lung disorder influenced by the interplay between the intestinal microbiome, host metabolism, and immune function. We previously found that Bacteroides acidifaciens (BA) has opposing effects on staphylococcal enterotoxin B (SEB)-induced ARDS, worsening the condition in female mice while alleviating it in males. This study aimed to examine whether these outcomes are linked to sex-dependent changes in the intestinal microbiome and gut-lung metabolome. C3H/HeJ mice of both sexes were orally colonized with Bacteroides acidifaciens before SEB exposure. Stool and bronchoalveolar lavage fluid (BALF) were collected for analysis using 16S rRNA sequencing and untargeted liquid chromatography mass spectrometry metabolomics. Our findings revealed distinct sex-dependent metabolic and microbial responses. In females, disease exacerbation correlated with elevated lipid mediators (leukotriene B4, 13-oxoODE, and 13S-HODE) alongside shifts in bile acid and redox metabolism. The intestinal microbiome showed changes in Bacteroides, Akkermansia, and Lachnospiraceae. Conversely, males showed a protective phenotype characterized by increased butyrate and alterations in sphingolipid, amino acid, redox, and nucleotide pathways. Integrated analyses identified sex-associated microbial communities and metabolomic profiles, highlighting distinct patterns of lipid and redox associations in females versus sphingolipid and short-chain fatty acid patterns in males. These results suggest that host sex influences how a commensal bacterium affects inflammatory lung injury and point to pathways for future research.
    Importance: ARDS is a fatal inflammatory response with high mortality and limited targeted therapies. Emerging evidence has pointed to the gut-lung axis as a source of inflammation that shapes pulmonary immune responses. Yet, how individual commensal bacteria influence this axis, and how biological sex alters both the microbiome and immune response remains poorly understood. Bacteroides acidifaciens , drives fundamentally different intestinal microbial and metabolic states in female and male mice during ARDS, and provides some evidence of how both can impact ARDS outcomes. Females develop an environment enriched in inflammatory lipid mediators, while males exhibit a metabolic profile associated with barrier support and reduced inflammation. These findings have implications for understanding sex-based differences in ARDS outcomes and for identifying microbiome-targeted therapeutic strategies.
    DOI:  https://doi.org/10.64898/2026.10.05.756742
  41. bioRxiv. 2026 Oct 07. pii: 2026.10.06.756889. [Epub ahead of print]
    One-carbon metabolism sustains effector T cell function through cell-surface glycosylation.
    Peng Wang, Amy Yu, Mohammed Mutaher, Almut S Eisele, Sarah Mouche, Kaitlyn Hung, Reece C Larson, Madeline Gish, Margaret Zimmer, Jeanette R Brook, Miriam McNerney, Lea Hammer, Arjun Garg, Efrat Ozeri, Alan Y L Wong, Boryana Petrova, Michal Weitman, Ramon C Sun, Jerome Tamburini, Mathias Wenes, Marc Schwartz, Nir Hacohen, Naama Kanarek.
      Folate is an essential driver of one-carbon metabolism. The cellular consequences of its deprivation in CD8 + T cell and impact on anti-tumor function are unknown. Single cell RNA-seq analysis of primary central nervous system lymphoma (PCNSL) patients' tumor samples revealed exhaustion in T cells with high folate metabolism gene expression signature. Functional genomics, metabolite profiling, and glycomics identified disrupted cell surface glycosylation as a major consequence of folate deprivation in CD8 + T cells. Mechanistically, folate deprivation reduced nucleotide sugar levels, perturbed glycosylation, and triggered the apoptotic unfolded protein response. Overexpressing folate transporters in adoptively transferred CD8 + T cells increased intratumoral T cell numbers and reduced exhaustion. Therefore, our data draw a mechanistic line between one-carbon metabolism, cell-surface glycosylation, and anti-tumor T cell function, and support a hypothesis that increased folate uptake can enhance CD8 + T cell function including ex vivo and in vivo CAR-T cells.
    Highlights: Although folate metabolism genes are highly expressed in both proliferating tumor and CD8 + T cells from primary central nervous system lymphoma patients, the T cells are exhausted while the tumor cells thrive Folate is depleted in the TME of MC38-OVA and B16-OVA tumors Folate deprivation impairs function and proliferation of CD8 + T cells Folate is essential for nucleotide sugar metabolism, and its depletion results in perturbation of cell surface glycosylationGenetic engineering to increase folate uptake by T cells increases intratumoral T cell numbers and reduces exhaustion.
    DOI:  https://doi.org/10.64898/2026.10.06.756889
  42. Cell Rep. 2026 Oct 29. pii: S2211-1247(26)01217-9. [Epub ahead of print]45(11): 118138
    Dopamine turns mitochondrial stress into inflammation.
    Rodrigo Pacheco.
      Daniali et al. show that dopamine drives mitochondrial stress, mtDNA release, and cGAS-STING-dependent IL-6 production in human macrophages. These findings suggest a mechanism linking dopaminergic signaling to mtDNA damage signatures increasingly detected in blood from patients with Parkinson's disease.
    DOI:  https://doi.org/10.1016/j.celrep.2026.118138
  43. bioRxiv. 2026 Oct 07. pii: 2026.10.06.757085. [Epub ahead of print]
    Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma.
    Navneesh Yadav, Olivia Pelcher, Raja G R Mooli, Robert B Cameron, Alberto Delaidelli, Kannan B N Rao, Bhagyalakshmi Manikandan, Senna Visser, Antonio C T Cobos, Vishal Parmar, Yuvraj Kayola, Siva K Natarajan, Yash Patel, Jiao Zhang, Hardik Shah, Subrahmanya D Vallabhapurapu, Saifur R Khan, Aaron Y Mochizuki, Kalil G Abdullah, Baoli Hu, Calixto-Hope G Lucas, Philipp Sievers, Felix Sahm, Andrew M Donson, Nicholas K Foreman, Martine F Roussel, Thomas M Pearce, Peter Dirks, Kristian W Pajtler, Stephen C Mack, Jeremy Rich, Richard J Gilbertson, Eric C Holland, Sadeesh K Ramakrishnan, Taylor J Abel, Srinivas Ramachandran, Sameer Agnihotri, Bokai Zhu, Sriram Venneti, Brandon Faubert, Michael D Taylor, Esther Hulleman, Ian F Pollack, Timothy Phoenix, Kulandaimanuvel Antony Michealraj.
      Supratentorial ependymomas (ST-EPNs) are aggressive pediatric brain tumors predominantly driven by the recurrent ZFTA-RELA fusion, an oncogenic chromatin regulator that establishes an aberrant transcriptional program. Although metabolic pathways modulate epigenetic regulation by controlling the availability of metabolic cofactors, how ZFTA-RELA coordinates metabolic reprogramming with epigenetic regulation is not well understood. Here, we show that ZFTA-RELA-positive ependymomas exhibit enhanced methionine dependency, elevated adenosyl homocysteinase (AHCY) expression, and epigenetically control aspartate metabolism for tumor growth. Mechanistically, ZFTA-RELA upregulates AHCY, increasing cellular methylation potential which promotes H3K4me3-dependent expression of CAD, the first enzyme complex of de novo pyrimidine biosynthesis, while simultaneously enforcing H3K27me3 mediated repression of ASNS, which encodes asparagine synthetase. Through this coordinated epigenetic program, aspartate utilization is directed toward pyrimidine biosynthesis while endogenous asparagine production is limited. Restricting S-adenosylmethionine availability or genetically or pharmacologically inhibiting AHCY reverses these epigenetic states, leading to CAD downregulation, ASNS upregulation, impaired nucleotide synthesis, and suppression of tumor growth in vitro and in vivo. Similarly, EZH2 inhibition also restores ASNS expression and suppresses tumor proliferation. These findings suggest that ZFTA-RELA EPN maintain ASNS-low phenotype which conditionally make them dependent on extracellular asparagine. We further show that enhanced de novo pyrimidine synthesis not only supports nucleotide production but also provides UDP-sugars required for N-glycosylation and stabilization of the asparagine transporter SLC1A5, thereby promoting extracellular asparagine uptake and tumor proliferation. Collectively, our findings identify AHCY as a critical metabolic regulator of epigenetic and metabolic reprogramming that drives pyrimidine synthesis and establishes extracellular asparagine dependency, revealing actionable metabolic vulnerabilities in ZFTA-RELA-positive ST-EPNs.
    Abstract Figure:
    Key Findings: ZFTA-RELA fusion drives aspartate metabolic reprogramming through chromatin regulationAdenosylhomocysteinase (AHCY) epigenetically enhance de novo pyrimidine synthesis and suppress endogenous asparagine synthesis ZFTA-RELA EPNs exhibit ASNS low phenotype and dependence on extracellular asparagine Enhanced de novo pyrimidine biosynthesis fuels nucleotide synthesis and SLC1A5-dependent asparagine uptakeTargeting de novo pyrimidine biosynthesis and depleting extracellular asparagine reveal actionable vulnerabilities in ZFTA-RELA ST-EPN.
    DOI:  https://doi.org/10.64898/2026.10.06.757085
  44. Int Immunol. 2026 Oct 30. pii: dxag057. [Epub ahead of print]
    Spermidine disrupts mitochondrial respiration and redox homeostasis in aged CD44+ CD49d- CD8+ T cells.
    Jun Wang, Yu Wang, Koki Ichimaru, Maharani Aprilia, Yasuharu Haku, Jiaxin Gu, Mai Kiyono, Keiko Yurimoto, Tomonori Yaguchi, Tasuku Honjo, Koji Kitaoka, Kenji Chamoto.
      Spermidine (SPD) is a polyamine metabolite with anti-aging and immunomodulatory properties. We previously reported that SPD enhances mitochondrial respiration in CD44- CD8+ naïve T cells through the upregulation of fatty acid oxidation (FAO). However, the effects of SPD on CD44+ CD8+ effector T cells remain unknown. We found that SPD suppressed mitochondrial oxygen consumption rate (OCR) in CD44+ CD8+ T cells from aged mice, in contrast to its effects on those from young mice. This FAO-dependent reduction in respiration was associated with mitochondrial oxidative stress and accompanied by reduced IFN-γ production and proliferative capacity. Notably, within the aged CD44+ CD8+ T cell compartment, senescence-like CD44+ CD49d- subset (CD49d- cells)-predominantly accumulated with age-exhibited a marked decrease in OCR following SPD treatment, whereas CD44+ CD49d+ CD8+ T cells (CD49d+ cells) were unaffected. In CD49d- cells, SPD treatment disrupted redox balance as evidenced by reduced intracellular reduced-thiol levels with unchanged mitochondrial reactive oxygen species (ROS) levels, suggesting consumption of antioxidant reserves. SPD also induced structural remodeling of mitochondria in CD49d- cells, characterized by a shift toward shorter, more fragmented mitochondria with wider cristae spacing than in CD49d+ cells. In summary, our findings reveal that SPD paradoxically compromises mitochondrial respiration in a specific subset of aged CD8+ T cells by perturbing fatty acid metabolism and redox homeostasis.
    Keywords:  fatty acid oxidation; mitochondrial damage; oxidative stress; polyamine
    DOI:  https://doi.org/10.1093/intimm/dxag057
  45. Mol Neurobiol. 2026 Oct 28. pii: 997. [Epub ahead of print]63(1):
    Mitochondrial Lactate Signaling and Protein Lactylation in Neurological Diseases.
    Yu Gu, Potao Zhang, Chunyan Lei, Wenyan Xu, Yunyu Cui.
      The brain, as a highly metabolically active organ, depends on mitochondrial oxidative phosphorylation (OXPHOS) to sustain energy demands. When mitochondrial function is impaired, cells undergo metabolic reprogramming toward aerobic glycolysis, leading to lactate accumulation. Beyond its traditional role as a metabolic byproduct, lactate is now recognized as a signaling molecule that links metabolism to epigenetic regulation through protein lactylation, a post-translational modification identified by Zhang et al. in 2019. Research on lactylation has progressed through three stages: initial discovery in histone lactylation as an epigenetic mark, expansion to non-histone proteins revealing roles in metabolic and structural regulation, and recent identification of mitochondrial protein lactylation influencing OXPHOS, the tricarboxylic acid (TCA) cycle, and reactive oxygen species (ROS) production. This review summarizes the mitochondrial-lactate-lactylation axis in the nervous system, including brain lactate metabolism, the astrocyte-neuron lactate shuttle, and regulatory mechanisms of lactylation (writers, erasers, and readers). We further discuss its roles in histone and non-histone modification, its bidirectional relationship with mitochondrial dysfunction, and its involvement in neurodegenerative, cerebrovascular, and neuropsychiatric disorders. Finally, we highlight the therapeutic potential of targeting lactylation pathways. Collectively, mitochondrial lactate signaling and protein lactylation emerge as a central link between metabolic reprogramming and epigenetic dysregulation in neurological diseases, providing new avenues for therapeutic intervention.
    Keywords:  Epigenetics; Lactylation; Metabolic reprogramming; Mitochondria; Neurological disorders; Oxidative phosphorylation
    DOI:  https://doi.org/10.1007/s12035-026-06291-z
  46. Front Immunol. 2026 ;17 1910050
    Single-cell transcriptomics uncovers persistent hepatic immunometabolic remodeling following SARS-CoV-2 infection in obese hosts.
    Wei Qian, Xiaoqin Wei, Soo-Jeung Park, Josefina Garcia Diaz, Tina Comlekoglu, Jane Yu, Jie Sun, Young S Hahn.
      SARS-CoV-2 infection affects multiple organs, and chronic post-viral tissue injury is often associated with persistent immune dysregulation. Obesity and related metabolic disorders are major risk factors for severe COVID-19 and post-acute sequelae of SARS-CoV-2 infection (PASC), including liver dysfunction. To define hepatic responses during post-acute infection, we studied lean and diet-induced obese mice at 7 and 28 days following infection with mouse-adapted SARS-CoV-2. Compared with lean mice, obese mice exhibited persistent lung inflammation and fibrosis, along with liver injury characterized by increased lipid accumulation, cellular apoptosis, and metabolic dysfunction. Single-cell RNA sequencing revealed obesity-associated alterations in hepatic immune and metabolic programs during post-acute infection. In particular, hepatic macrophages in obese mice showed sustained inflammatory and metabolic transcriptional alterations, while hepatocytes displayed altered programs associated with gluconeogenesis and lipid metabolism. Endothelial cells also exhibited persistent transcriptional changes linked to immune activation and prothrombotic pathways. These alterations remained evident at 28 days post-infection, suggesting incomplete restoration of immune and metabolic homeostasis in obese liver. Collectively, our findings reveal persistent obesity-associated hepatic immunometabolic remodeling following SARS-CoV-2 infection and identify cellular and molecular programs that may contribute to post-acute liver sequelae in metabolically compromised hosts.
    Keywords:  SARS-CoV-2; liver; macrophages; obesity; scRNA-seq
    DOI:  https://doi.org/10.3389/fimmu.2026.1910050
  47. Sci Transl Med. 2026 Oct 28. 18(873): eadz4081
    MIF-CD74 orchestrates synovial macrophage metabolic-inflammatory reprogramming by ENO2 interaction to drive osteoarthritis pathogenesis.
    Rui Peng, Bo Yu, Yulong Wei, Lutian Yao, Zhaowen Xue, Lei Zhang, Guihong Liang, Huajun Wang, Yongpeng Lin, Jianke Pan, Zhengang Zha, Xiaofei Zheng, Weiyi Yang, Bolai Chen, Tao Gui.
      Synovitis is a central driver of osteoarthritis (OA) progression, yet the cellular and molecular mechanisms sustaining inflammatory circuits in the synovium remain incompletely understood. Through integrative analysis of time-resolved single-cell RNA sequencing in murine synovium and spatial transcriptomics of human OA tissues, we identified a pathogenic CD74+ macrophage subset that expands in OA and localizes at the synovial-cartilage interface. This subset exhibits a proinflammatory, nonclassical polarization and displays a metabolic dependency on glycolysis. Multiomics and mechanistic studies revealed that CD74 interacts with the glycolytic enzyme enolase 2 (ENO2). This interaction orchestrates a feed-forward signaling axis wherein CD74/ENO2 facilitates the nuclear translocation of hypoxia-inducible factor 1-α (HIF-1α)/β-catenin dimers, which coactivate glycolytic and inflammatory gene programs, thereby sustaining a metabolically driven inflammatory state. Genetic ablation of CD74 in myeloid cells or its pharmacological blockade mitigated synovitis and cartilage degradation in murine OA models. To translate this axis therapeutically, we developed synovium-targeted cationic lipid nanoparticles decorated with MIF-mimetic peptides (PcLNPs) for the delivery of CD74 siRNA. Intra-articular administration of PcLNPs efficiently targeted CD74+ macrophages, attenuated their inflammatory and glycolytic phenotypes, and ameliorated murine OA progression in vivo. Our findings establish the CD74/ENO2/HIF-1α/β-catenin axis as a critical integrator of metabolic reprogramming and inflammation in OA synovitis and present a potential targeted nanotherapeutic strategy for disease modification.
    DOI:  https://doi.org/10.1126/scitranslmed.adz4081
  48. Eur J Immunol. 2026 Oct;pii: e70298. [Epub ahead of print]56(10):
    Prophylactic Soraphen A Treatment Attenuates Western Diet-Exacerbated IMQ-Induced Psoriasiform Inflammation.
    Yu-San Kao, Katharina S Kommoss, Tabea Bieler, Gloria Janet Godoy, Aleksandra Lopez Krol, Fatima Boukhallouk, Felix K F Kommoss, Danijela Heide, Susanne H Kirsch, Rolf Müller, Mathias Heikenwälder, Tim Sparwasser.
      Psoriasis is a T-cell-mediated inflammatory disease amplified by metabolic stress. Acetyl-CoA carboxylase 1 (ACC1)-dependent fatty acid synthesis is required for IL-17-producing T cells. Here, we asked whether short-term systemic administration of soraphen A (SorA), a dual ACC1/2 inhibitor, modulates imiquimod (IMQ)-induced psoriasiform inflammation under normal diet (ND) and Western diet (WD) conditions. Female C57BL/6J mice were fed ND or WD for 12 weeks prior to daily intraperitoneal injections of SorA or vehicle for 10 days, followed by 5 days of topical IMQ to induce psoriasiform dermatitis. Disease severity was assessed by macroscopic, histological, transcriptional, and flow cytometric readouts. Prophylactic SorA administration had no measurable effect in ND-fed mice. In WD-fed mice, prophylactic SorA reduced erythema, back skin thickening, and epidermal hyperplasia, whereas scaling remained unchanged. Selected histological skin readouts were numerically lower, whereas the qPCR panel showed no statistically significant differences. In skin-draining lymph nodes, IL-17A+ CD4+ and CD8+ T-cell frequencies and numbers were significantly reduced, whereas γδT17 cells did not differ significantly. Hepatic steatosis scores were unchanged, but hepatic neutrophil infiltration was reduced. Under the present prophylactic regimen, systemic SorA administration was associated with modest attenuation of WD-exacerbated IMQ-induced psoriasiform inflammation. These findings support further preclinical evaluation of ACC-targeted immunometabolic interventions in metabolically aggravated psoriasiform inflammation.
    Keywords:  acetyl‐CoA carboxylase (ACC) 1; fatty acid synthesis; metabolic inflammation; psoriasis
    DOI:  https://doi.org/10.1002/eji.70298
  49. J Immunother Cancer. 2026 Oct 30. pii: e015875. [Epub ahead of print]14(10):
    Gαi3 acts as a metabolic checkpoint orchestrating TAMs immunosuppression and lipid metabolism in glucose-deprived hepatocellular carcinoma.
    Meixi Lu, Yaoyao Li, Siyu Du, Senlin Lian, Jiajing Luo, Yi Fang, Yangyang Jin, Mingjun Gao, Xiaowei Wang, Minghui Zheng, Jie Wang, Yuanhong Xu, Chao Jiang, Runqiu Jiang.
      
    Keywords:  Hepatocellular Carcinoma; Macrophage; T cell
    DOI:  https://doi.org/10.1136/jitc-2026-015875
  50. iScience. 2026 Nov 20. 29(11): 117999
    Biotin-dependent metabolism controls germinal center fate and vaccine-induced antibody diversification.
    Chu-Han Hsieh, Wilson Aala, Ying-Chen Tsai, Ya-Fang Huang, Miao-Shan Lin, Daw-Yang Hwang, Dar-Bin Shieh, Hsiang-Hsuan Sung, Si-Tse Jiang, Ching-Wei Lin, Chih-An Chen, Michael Warren Hughes, Peng-Chieh Chen, Chi-Chang Shieh.
      Nutrient availability shapes antibody responses, yet its role in metabolic checkpoints governing germinal center (GC) B-cell differentiation remains incompletely defined. Using heterozygous (HZ) Slc5a6 M60K mice modeling human loss-of-function mutations in the multivitamin transporter SLC5A6, we found that deficient biotin imports impaired mitochondrial metabolism and restricted preGC-to-dark zone progression after vaccination. Single-cell transcriptomics and RNA velocity revealed disrupted GC trajectories, while B-cell receptor repertoire analysis showed impaired class-switch recombination, somatic hypermutation, and vaccine-induced clonal diversity. Spatial multiplexed imaging showed reduced GL7-high GC-associated B-cell regions. Flow cytometric analyses revealed reduced frequencies of RBD-specific B cells and RBD-specific GL7+CD95+ GC B cells in HZ mice, with higher frequencies after biotin supplementation. Pseudovirus assays demonstrated impaired neutralization of Wuhan-Hu-1 and Omicron BA.2. Dietary biotin supplementation restored GC-associated differentiation, antibody diversification, and vaccine-induced humoral responses. These findings identify biotin-dependent mitochondrial metabolism as an important checkpoint linking micronutrient availability to GC B-cell differentiation and vaccine responsiveness.
    Keywords:  B cell; biotin; germinal center; metabolic rewiring; vaccine response
    DOI:  https://doi.org/10.1016/j.isci.2026.117999
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