bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–11–08
47 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Lactate accumulation triggered by RNA virus infection facilitates viral replication.
  2. Short-chain fatty acids and intestinal macrophage immunometabolism in metabolic syndrome: mechanisms and implications for chronic low-grade inflammation.
  3. Metabolic Reprogramming Regulates Neutrophil Plasticity: From Acute Infection to Tumour Immunosuppression.
  4. Immunometabolic crosstalk in intervertebral disc degeneration: a narrative review of neutrophil extracellular traps, macrophage polarization, and metabolic reprogramming.
  5. Itaconate alleviates sepsis-induced acute lung injury by suppressing Peroxiredoxin 1 dimerization through covalent alkylates at Cys173.
  6. IL-9 signaling requires ornithine decarboxylase-dependent polyamine metabolism in macrophages to promote allergic airway inflammation.
  7. Macrophages as orchestrators of gut-organ axis crosstalk: immunometabolic reprogramming and host-directed therapy in sepsis.
  8. Mitochondrial quality-control uncoupling in sepsis: a missing link to persistent immune hyporesponsiveness.
  9. Norepinephrine in septic shock: catecholamine burden, immunometabolic reprogramming, and precision vasopressor therapy.
  10. Targeting the FKBP5-ceramide axis driven mitochondrial reprogramming in cardiac macrophages attenuates post-infarct cardiac injury.
  11. Immunometabolic dysregulation of reactive microglia and astrocytes in neurodegenerative diseases: Mechanistic insights and therapeutic implications.
  12. ITGAM+ Extracellular Vesicles Trigger CD8+ T Cell Activation via S100a9-Mediated Metabolic Reprogramming in Acute Kidney Injury.
  13. Microglia: Metabolic Adaptation in Neurodegeneration.
  14. Lactylation of HSC70 Impairs Chaperone-Mediated Autophagy to Promote Pyrin Inflammasome-Dependent PANoptosis in Macrophages During Sepsis.
  15. Mitochondrial transfer enhances the metabolic fitness and antitumor activity of primary NK cells.
  16. Metabolic pathways as therapeutic target to improve allo-HSCT outcomes.
  17. Loss of T cell-intrinsic Keap1 alleviates colitis by suppressing Th17 differentiation and enhancing regulatory T cell functions.
  18. Fatty acid dysregulation in asthma: linking immunometabolic remodeling, phenotypic heterogeneity, and metabolic precision medicine.
  19. CISD1 suppresses COPD inflammation by recruiting ubiquitinated STING and altering macrophage metabolism.
  20. PD-1 deficiency impairs Treg differentiation in Trichinella-infected mice via inhibition of fatty acid oxidation.
  21. Targeting lactate-GPR81/TAZ/PPARα-induced ROS in Bregs overcomes immunosuppression and improves lung cancer outcomes.
  22. Impact of habitual physical activity and age on T cell metabolism and activation via β2-adrenergic receptor modulation.
  23. Succinate promotes multiple myeloma cell proliferation through TCA cycle oxidation.
  24. Lactylation in the regulation of macrophage polarization: Mechanisms pathophysiological significance (Review).
  25. The UCHL1-HIF-1α Axis Mediates Microglial Metabolic Reprogramming and Neuroinflammation in Parkinson's Disease.
  26. Taurine bolsters adoptive T cell therapy efficacy against hepatocellular carcinoma by reprogramming T cell function.
  27. Macrophage USF2 Lactylation-Mediated FABP4 Suppression Promotes Intracellular Proliferation of Brucella.
  28. A living enzymatic adenosine switch couples metabolic rescue to IL-12-driven antitumor immunity.
  29. From iron sequestration to immune paralysis: A biphasic model of Lipocalin-2 function in sepsis.
  30. Metabolic reprogramming of myeloid‑derived suppressor cells in colorectal cancer: Mechanistic insights and immunometabolic targeted rehabilitation (Review).
  31. Regulatory role of TIPE2 by inhibiting microglial pyroptosis and glycolysis in the treatment of sepsis-associated encephalopathy.
  32. β7-Integrin worsens diet-induced metabolic syndrome in mice by altering intestinal lipid handling and colonic inflammatory monocyte infiltration.
  33. The AMPK-ALDH7A1 axis drives metabolic reprogramming and anti-tumor immunity in hepatocellular carcinoma via KDM5C inhibition.
  34. Immunometabolic reprogramming: a working framework for disease development, endotype differentiation, and therapeutic considerations in pediatric asthma.
  35. DGAT1 regulates macrophage pyroptosis during Klebsiella pneumoniae infection.
  36. Diet-independent pregravid obesity drives premature but functionally dysregulated fetal immune maturation across multiple immune compartments in rhesus macaques.
  37. Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation.
  38. Therapy-induced methionine competition in bladder cancer: MAT2A-SAM axis remodeling as a metabolic immune checkpoint.
  39. Hypoxia Orchestrates the Natural History of Inflammatory Bowel Disease: Mechanisms and Therapeutic Opportunities.
  40. IL-33 modulates maternal-fetal macrophage immunometabolism and is associated with attenuation of MIA-associated behavioral abnormalities in adult offspring.
  41. Multi-omics profiling identifies a putative Akkermansia-HK3-lactate immunometabolic link associated with JPZS treatment in lupus nephritis.
  42. In vitro NAD+ supplementation increases CD4+ and CD8+ T cell function in people with HIV.
  43. Valuable Role of 18F-Fluorodeoxyglucose-PET/computed Tomography in Therapeutic Decision-Making of Infectious and Inflammatory Disorders.
  44. Mitochondrial RNA as a broad-spectrum DAMP coordinates antiviral and damage-related immune clearance and confers therapeutic potential.
  45. Mevalonate pathway regulates double-negative regulatory T cell stability in metabolic dysfunction-associated steatotic liver disease.
  46. Modulation of riboflavin biosynthesis enzymes in non-typhoidal Salmonella isolates differentially impacts human MAIT cell activation.
  47. Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy.
  1. Microbiol Spectr. 2026 Nov 02. e0216526
    Lactate accumulation triggered by RNA virus infection facilitates viral replication.
    Jiajia Zhang, Jing Wang, Yifan Sun, Juncheng Cai, Yuechi Hou, Wencan Zhang, Yuqiang Cheng, Libin Chen, Chan Ding, Tao Ren.
      As the terminal product of glycolysis, lactate has emerged as a crucial signaling molecule mediating metabolic reprogramming with immune regulation. Although RNA viruses are known to exploit host metabolism, the precise role of lactate accumulation in viral pathogenesis remains to be fully elucidated. Using Newcastle disease virus and influenza A virus as model pathogens, this study demonstrates that RNA virus infection rapidly activates host glycolysis and induces sustained lactate accumulation, thereby creating a microenvironment favorable for viral replication. Pharmacological inhibition of glycolysis markedly suppressed viral proliferation. In inhibition-rescue experiments, exogenous lactate supplementation reversed the antiviral immune gene and IRF3-phosphorylation changes induced by glycolytic inhibition. Adding exogenous sodium lactate without inhibiting glycolysis further repressed antiviral immune gene expression and IRF3 phosphorylation. Mechanistically, virus-induced lactate accumulation was associated with suppression of the retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway: excess lactate acted upstream of interferon regulatory factor 3 (IRF3), in a manner consistent with inhibition of the mitochondrial antiviral signaling protein (MAVS)-IRF3 axis, thereby attenuating type I interferon production. Together, these findings define a positive feedback loop in which RNA viruses exploit host metabolic reprogramming to accumulate lactate, which in turn restrains antiviral innate immunity and favors viral replication.IMPORTANCERNA viruses have no metabolism of their own and must rewire the host cell to replicate. Here, using two viruses from different families-Newcastle disease virus and influenza A virus-we show that infection rapidly drives host glucose uptake and glycolysis and causes lactate to accumulate. Lactate is not an inert by-product: blocking glycolysis lowers lactate, derepresses type I interferon and interferon-stimulated gene expression, and restricts viral replication, while adding lactate back reverses immune-signaling changes induced by glycolytic inhibition and further suppresses interferon regulatory factor 3 (IRF3) phosphorylation. Lactate therefore functions as an immunomodulatory effector linking virus-driven metabolic reprogramming to weakened innate immunity, consistent with inhibition of the mitochondrial antiviral signaling protein (MAVS)-IRF3 axis, forming a positive feedback loop that favoring replication. Since this loop was observed in two distinct RNA viruses, glycolysis and lactate handling may represent host-directed targets for antiviral intervention, while lactate's broader clinical relevance as an immune biomarker requires further investigation.
    Keywords:  RNA virus; glycolysis; innate immunity; lactate; metabolic reprogramming
    DOI:  https://doi.org/10.1128/spectrum.02165-26
  2. Front Immunol. 2026 ;17 2000672
    Short-chain fatty acids and intestinal macrophage immunometabolism in metabolic syndrome: mechanisms and implications for chronic low-grade inflammation.
    Jiaxin Ma, Chen Li, Hongjun Lou.
      Chronic low-grade inflammation (CLGI) is a major feature of metabolic syndrome (MetS), and the intestinal mucosa is an important site where microbial metabolites interact with host immunity. Intestinal lamina propria macrophages (LpMs) maintain mucosal tolerance, barrier homeostasis, and antimicrobial defense, and their phenotype and metabolism are altered in obesity and related metabolic disturbances. Short-chain fatty acids (SCFAs), generated mainly by microbial fermentation of dietary fiber, influence macrophage function through intracellular metabolism, G protein-coupled receptor signaling, and histone deacetylase inhibition. Butyrate is the best-characterized SCFA in this context and regulates glycolysis, mTOR-associated metabolism, antimicrobial responses, and HDAC-dependent inflammatory programs. Acetate and propionate also affect inflammasome activity, cytokine production, receptor signaling, and cellular metabolism. These mechanisms connect microbial metabolism with intestinal inflammation, epithelial barrier function, and systemic metabolic homeostasis. In obesity and insulin resistance, colonic macrophage recruitment and metabolic remodeling are closely associated with disease progression, whereas macrophage-related effects in metabolic dysfunction-associated steatotic liver disease and hypertension involve broader gut-liver, vascular, and renal pathways. Human studies of dietary fiber, microbiota-directed interventions, and SCFA delivery show variable cardiometabolic effects, with outcomes influenced by formulation, route, and baseline metabolic state. Given that most current mechanisms are derived from extraintestinal macrophages and in situ evidence from the human gut remains scarce, this narrative review summarizes the homeostatic biology of intestinal macrophages, the pathways through which SCFAs regulate their immunometabolism, the context-dependent relevance of this axis across MetS components, and the barriers to clinical translation.
    Keywords:  chronic low-grade inflammation; immunometabolism; intestinal macrophages; metabolic syndrome; short-chain fatty acids
    DOI:  https://doi.org/10.3389/fimmu.2026.2000672
  3. Immunology. 2026 Nov 03.
    Metabolic Reprogramming Regulates Neutrophil Plasticity: From Acute Infection to Tumour Immunosuppression.
    Meng-Yu Lu, Liang Zhang, Wan-Yi Feng, Qin Hu, Jin-Jun Bian, Jia-Feng Wang.
      Neutrophils are highly adaptable innate immune cells whose functions extend beyond antimicrobial defence to include regulation of chronic inflammation, tumour progression and tissue injury. Although traditionally considered glycolysis-dependent effector cells, emerging evidence reveals substantial metabolic plasticity that enables neutrophils to adapt to diverse microenvironmental pressures. Metabolic programmes involving carbohydrate utilisation, mitochondrial regulation, lipid metabolism, amino-acid-derived metabolites and redox control dynamically shape neutrophil migration, antimicrobial activity, survival, extracellular trap formation and immunoregulatory functions. However, the biological consequences of metabolic reprogramming are highly context dependent and the same pathway may support protective host defence in acute infection while promoting pathological inflammation or immunosuppression in chronic disease. Here, we develop a three-axis comparative framework based on temporal mode of metabolic reprogramming, granulocytic population identity and evidence level to examine neutrophil metabolism across acute infection, cancer and chronic inflammatory or metabolic disorders. This framework distinguishes transient metabolic adaptation in conventional neutrophils from sustained metabolic states associated with tumour-associated neutrophils and polymorphonuclear myeloid-derived suppressor cells, while separating direct human neutrophil evidence from broader myeloid or preclinical observations. We discuss how metabolic pathways, including glycolysis, mitochondrial signalling, lipid handling, itaconate biology and ferroptosis-related mechanisms, are differentially engaged according to cellular state and tissue context. Finally, we evaluate emerging therapeutic strategies targeting neutrophil metabolism and highlight key translational challenges, including target specificity, preservation of antimicrobial competence, delivery strategies and patient selection. By integrating metabolic mechanisms with cellular identity and evidence strength, this review provides a framework for understanding how neutrophil metabolic plasticity contributes to immune protection and disease progression and identifies principles for developing context-selective therapeutic approaches.
    Keywords:  NETosis; glycolysis; immunometabolism; immunotherapy; metabolic reprogramming; mitochondrial metabolism; neutrophil; tumour microenvironment
    DOI:  https://doi.org/10.1111/imm.70221
  4. Mol Biol Rep. 2026 Nov 06. pii: 1919. [Epub ahead of print]53(1):
    Immunometabolic crosstalk in intervertebral disc degeneration: a narrative review of neutrophil extracellular traps, macrophage polarization, and metabolic reprogramming.
    Fengjiang Li, Yong Peng, Haozhe Wu, Chao Song, Zhijiang Fu, Zongchao Liu.
      Intervertebral disc degeneration (IVDD) is a major pathological contributor to chronic low-back pain. Long viewed merely as a mechanical "wear-and-tear" condition, IVDD is now thought to be substantially driven by reciprocal immunometabolic interactions between infiltrating immune cells and disc-resident nucleus pulposus (NP) cells. This narrative review synthesizes and critically appraises available evidence for three core pathological components: neutrophil extracellular trap (NET) formation and its pro-inflammatory consequences, dysregulated macrophage plasticity within the degenerative microenvironment, and metabolic crisis triggered by mitochondrial impairment and maladaptive glycolytic reprogramming. We integrate these elements into a unified conceptual model of bidirectional immunometabolic crosstalk operating within the unique hypoxic, avascular, low-glucose intervertebral-disc niche. Importantly, many mechanistic links within this network remain hypothetical and are partly extrapolated from non-disc inflammatory models; we explicitly distinguish experimentally-supported observations from unvalidated causal hypotheses and summarize key unresolved mechanistic questions. We further outline molecular mediators mediating immune-metabolic communication and highlight stage-dependent therapeutic opportunities together with major translational bottlenecks. Finally, emerging intervention strategies targeting this immunometabolic network-including PAD4-directed NET inhibition, macrophage phenotype reprogramming, and restoration of mitochondrial and metabolic homeostasis - are discussed to inform future mechanism-oriented therapeutic research for IVDD.
    Keywords:  Glycolytic reprogramming; Immunometabolic dysregulation; Intervertebral disc degeneration; Macrophage polarization; Mitochondrial dysfunction; Neutrophil extracellular traps
    DOI:  https://doi.org/10.1007/s11033-026-13135-5
  5. Free Radic Biol Med. 2026 Nov 04. pii: S0891-5849(26)01250-5. [Epub ahead of print]
    Itaconate alleviates sepsis-induced acute lung injury by suppressing Peroxiredoxin 1 dimerization through covalent alkylates at Cys173.
    Jiamin Ma, Ying Chen, Yan Zhang, Yonghai Zhang, Zhiyuan Zhang, Gengjia Tu, Yi Liu, Yu Shen, Yanyan Deng, Jianjun Wu, Zhijie Deng, Caice Shen, Dali Zhan, Jinbao Li, Jianhua Li.
      Sepsis-associated acute lung injury (SALI) is characterized by overwhelming inflammation and oxidative stress, during which damage-associated molecular patterns (DAMPs) exacerbate tissue injury. Peroxiredoxin 1 (PRDX1), a canonical intracellular antioxidant enzyme, paradoxically functions as a pro-inflammatory DAMP after extracellular release. This pathogenic transition depends on PRDX1 dimerization through intermolecular disulfide bonds. However, the endogenous metabolic mechanisms that restrain PRDX1 release remain unclear. Here, we identify the ACOD1-itaconate axis as a critical suppressor of PRDX1-mediated hyperinflammation in SALI. Clinical dataset analysis revealed that elevated PRDX1 expression strongly correlates with sepsis mortality. In a murine cecal ligation and puncture (CLP) model, Acod1 deficiency exacerbated SALI and amplified PRDX1 secretion, whereas therapeutic administration of 4-octyl itaconate (4-OI) robustly alleviated lung injury and the accompanying cytokine storm. Mechanistically, chemical proteomics and mutagenesis showed that itaconate directly targets PRDX1. Acting as an electrophile, itaconate covalently alkylates the highly conserved cysteine 173 residue of PRDX1 via Michael addition. This redox modification sterically blocks intermolecular disulfide bond formation, thereby preventing PRDX1 dimerization and subsequent secretion from primary macrophages. Consequently, the loss of extracellular PRDX1 dimers reduces Toll-like receptor 4 (TLR4) engagement and suppresses downstream MAPK and NF-κB signaling cascades. Strikingly, the PRDX1-C173S loss-of-function mutation abolished the inhibitory efficacy of 4-OI, confirming Cys173 as an indispensable pharmacological target. Together, our study bridges immunometabolism and redox biology by demonstrating that itaconate restrains systemic inflammation through covalent trapping of PRDX1 in a monomeric state, providing a targeted redox-based therapeutic strategy for acute inflammatory diseases.
    Keywords:  ACOD1; Alkylation; Itaconate; Peroxiredoxin 1; Sepsis-induced acute lung injury
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.11.007
  6. Mucosal Immunol. 2026 Nov 04. pii: S1933-0219(26)00126-1. [Epub ahead of print] 100424
    IL-9 signaling requires ornithine decarboxylase-dependent polyamine metabolism in macrophages to promote allergic airway inflammation.
    Ahmed M Abdelaal, Jilu Zhang, Wenwu Zhang, Anthony M Cannon, Cherry C L Cheung, Maya S Krishnan, Kendra B Edgett, Raeleen H Sobetski, Emily Bromley, Gyoyeon Hwang, Isaac S Wilson, Kirsten M Kloepfer, Homer L Twigg, Benjamin Gaston, Basar Bilgicer, Teresa L Mastracci, Daniella M Schwartz, Mark H Kaplan.
      Lung macrophages play a key role in shaping immune responses during pulmonary diseases. Understanding molecular and environmental mechanisms that modulate macrophage functions is critical for developing effective therapies for these diseases. We have previously shown that IL-9 induced the expression of arginase1 (Arg1) in macrophages in the context of chronic allergic inflammation and that in the absence of IL-9R signaling, mice have reduced cellular infiltration. However, a mechanistic understanding of how IL-9R+ macrophages contribute to allergic airway inflammation is still lacking. Here, we found that IL-9R-deficiency reduced arginine-dependent polyamine metabolism. Polyamines were required effectors as myeloid cell deficiency of ornithine decarboxylase (ODC1), the gateway enzyme to polyamine synthesis, decreased the expansion of interstitial macrophages and attenuated allergic airway inflammation. Pulmonary supplementation of polyamines rescued allergic inflammation in IL-9R-deficient mice. Expression of CCL24 that augments eosinophil recruitment into the lung environment required both IL-9R signaling on, or ODC1 activity in, lung macrophages. Moreover, targeting of macrophage CCL24 using nanoparticles loaded with a Ccl24 siRNA inhibited allergic airway inflammation. Thus, our study reveals an IL-9R/macrophage/polyamine/CCL24 axis in lung macrophage populations and identifies polyamine biosynthesis as a potential therapeutic target for allergic airway inflammation.
    Keywords:  Allergic inflammation; Arginine metabolism; IL-9; Lung; Macrophages
    DOI:  https://doi.org/10.1016/j.mucimm.2026.100424
  7. Front Cell Infect Microbiol. 2026 ;16 1921762
    Macrophages as orchestrators of gut-organ axis crosstalk: immunometabolic reprogramming and host-directed therapy in sepsis.
    Wenqing Zeng, Ye Zhang, Liping Fan, Ying Xun, Zhaoqing Jiang, Feifei Dai.
      Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection. Among the numerous contributory factors, the gut microbiota and its metabolites are increasingly recognized as potential modulators of systemic inflammation, acting through multiple gut-organ axes. Within this network, macrophages serve as central integrators that transduce microbial signals into organ-specific inflammatory or reparative outcomes. Disease evolution is critically determined by immune-metabolic reprogramming of macrophages. This reprogramming comprises tricarboxylic acid cycle truncation, lipid remodeling, mitochondrial dysfunction, and inflammasome activation. These processes are closely intertwined with NFκB, cGAS-STING, TLR/MyD88, and aryl hydrocarbon receptor signaling. Gut-derived metabolites, particularly short-chain fatty acids and indole derivatives, shape macrophage functions in distal organs. These mechanisms predominantly operate during the acute phase of sepsis, driving early organ injury. In contrast, sepsis survivors often enter a distinct chronic phase, characterized by persistent immune dysregulation. Trained immunity, through metabolic-epigenetic rewiring, may underlie this long-term dysfunction in survivors. Preclinical promise has been demonstrated by host-directed therapies that target macrophage metabolism. Nevertheless, major challenges impede clinical translation. These include inadequate preclinical models, the absence of validated real-time biomarkers for immune-metabolic phenotyping, and marked heterogeneity among patients. This review positions macrophages as actionable sentinels in gut-organ crosstalk during acute sepsis, and further explores their role in chronic sequelae, underscoring the need for biomarker-guided stratification and precision immune-metabolic editing to overcome barriers in both settings.
    Keywords:  gut-organ axis; host-directed therapy; immune-metabolism; macrophages; sepsis
    DOI:  https://doi.org/10.3389/fcimb.2026.1921762
  8. Front Immunol. 2026 ;17 1982407
    Mitochondrial quality-control uncoupling in sepsis: a missing link to persistent immune hyporesponsiveness.
    Yu Zhang, Xin Ping Xia, Ling Zhao.
      Sepsis imposes competing demands for antimicrobial activity and organelle maintenance. Mitochondrial recovery requires coordinated damage containment, selective removal, lysosomal degradation and recycling, and functional replacement. We define mitochondrial quality-control uncoupling as a mismatch among these processes. When damage outpaces completed clearance, dysfunctional mitochondria retain redox and danger-signaling activity. When removal outpaces replacement, mitochondrial mass and spare respiratory capacity decline. Incomplete lysosomal processing can combine both phenotypes by removing mitochondria from the functional network while retaining undegraded cargo. Immune cells may therefore remain viable yet fail to increase metabolic and biosynthetic output during renewed challenge. Inhibitory immune signaling can further restrict substrate use and mitochondrial rebuilding, reinforcing mitochondrial and immune dysfunction. This framework reconciles divergent observations on mitophagy and explains how inflammation can coexist with ineffective host defense. We define state-matched longitudinal phenotyping as repeated, cell-type-specific assessment of damage burden, clearance completion, respiratory reserve and immune function over time. Such phenotyping could guide interventions toward the dominant defect rather than indiscriminately activating a single pathway.
    Keywords:  immune hyporesponsiveness; immunometabolism; lysosome; mitochondrial biogenesis; mitochondrial quality control; mitophagy; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1982407
  9. Front Immunol. 2026 ;17 1935801
    Norepinephrine in septic shock: catecholamine burden, immunometabolic reprogramming, and precision vasopressor therapy.
    Xiaoxi Yan, Miaobo Li, Caifen Yan, Yihan Dang, Yating Lv, Tongqin Li, Jing Zhang, Yuge Wu, Li Ma.
      Septic shock is a life-threatening syndrome characterized by circulatory failure, immune dysregulation, neuroendocrine activation, and cellular metabolic dysfunction. Norepinephrine (NE) remains the first-line vasopressor for early resuscitation because it restores vascular tone, increases mean arterial pressure, and maintains vital organ perfusion. However, emerging evidence from neuroimmunology and immunometabolism suggests that NE also acts beyond hemodynamic support. This review reexamines the dual role of NE in septic shock from the perspective of high catecholamine burden, which integrates endogenous sympathetic activation, exogenous NE exposure, receptor signaling, and downstream immune-metabolic effects. Prolonged or high-dose NE exposure may regulate NF-κB activation, cytokine release, IL-10 production, phagocytic killing, antigen presentation, and lymphocyte effector function through adrenergic receptor-dependent pathways, particularly β2-adrenergic receptor/cAMP/PKA signaling. These effects may limit excessive inflammation during early disease but may also aggravate immunoparalysis in selected patients. NE may further influence glycolysis, mitochondrial oxidative phosphorylation, reactive oxygen species generation, and metabolic signaling pathways involving HIF-1α, AMPK, and mTOR, thereby reshaping immune-cell activation thresholds and antimicrobial capacity. Catecholamine signaling may also affect host-pathogen interactions by modulating bacterial growth, iron acquisition, and biofilm formation in specific experimental settings. Importantly, associations between NE exposure and adverse outcomes are strongly confounded by shock severity, infection burden, vascular hyporesponsiveness, and organ dysfunction. Future studies should integrate NE dose trajectories, cumulative exposure, immune phenotypes, metabolic states, and infection outcomes to clarify when catecholamine burden shifts from adaptive circulatory support to a potential driver of immune-metabolic dysfunction. This framework may support precision vasopressor strategies that balance hemodynamic load, immune function, and metabolic adaptability while preserving effective tissue perfusion.
    Keywords:  high catecholamine burden; immunometabolism; immunoparalysis; neuroimmune regulation; norepinephrine; precision vasopressor therapy; septic shock; β2-adrenergic receptor
    DOI:  https://doi.org/10.3389/fimmu.2026.1935801
  10. Pharmacol Res. 2026 Nov 06. pii: S1043-6618(26)01652-X. [Epub ahead of print] 109737
    Targeting the FKBP5-ceramide axis driven mitochondrial reprogramming in cardiac macrophages attenuates post-infarct cardiac injury.
    Zekun Li, Xue Yang, Shengyuan Xu, Anzhuo Zhao, Bowen Zheng, Ning Sheng, Jinlan Zhang.
      Plasma ceramide levels are elevated in cardiovascular disease and predict recurrent adverse events and mortality after myocardial infarction (MI). However, mechanisms driving post-MI ceramide accumulation and pharmacologically actionable targets to counteract ceramide-driven myocardial damage are still lacking. Here, we identify FK506-binding protein 5 (FKBP5) as a druggable immunometabolic regulator of ceramide metabolism in cardiac macrophages, linking FKBP5 suppression to interrupted pathological crosstalk among sphingolipid remodeling, mitochondrial impairment and post-MI inflammatory injury. Using murine MI models and FKBP5-deficient cells, we examined FKBP5 inhibition or deficiency reduced infarct size and fibrosis, improved cardiac function, and protected against adverse remodeling. Mechanistically, FKBP5 was associated with the sphingomyelin phosphodiesterase 3 (Smpd3) promoter region and contributed to the regulation of its transcriptional activity after MI, thereby promoting ceramide accumulation. Specifically, FKBP5-mediated ceramide 24:1 (Cer24:1) upregulation impaired mitochondrial redox homeostasis by disrupting electron transport chain integrity, thereby reinforcing M1 polarization and exacerbating myocardial injury. Elevated Cer24:1 directly bound the mitochondrial TU translation elongation factor (TUFM), disrupting electron transport chain integrity and mitochondrial respiration, providing a defined link between ceramide species and mitochondrial dysfunction. Notably, in vivo treatment with Cer24:1 attenuated the cardioprotective effects of FKBP5 inhibition after MI. Collectively, we describe a previously unrecognized FKBP5-Smpd3-Cer24:1-TUFM signaling axis in cardiac macrophages. FKBP5-governed ceramide metabolism drives macrophage immunometabolic reprogramming, marking FKBP5 as a promising pharmacological target for ischemic heart disease. Our findings support the role of the FKBP5-ceramide axis in mediating post-infarct myocardial dysfunction and highlight pharmacological FKBP5 inhibition as a therapeutic strategy against post-MI cardiac injury.
    Keywords:  Cardiac macrophage; Ceramide; FK506 binding protein 5; Mitochondrial reprogramming; Myocardial infarction; SAFit2
    DOI:  https://doi.org/10.1016/j.phrs.2026.109737
  11. J Neurol Sci. 2026 Oct 28. pii: S0022-510X(26)00519-8. [Epub ahead of print]491 126237
    Immunometabolic dysregulation of reactive microglia and astrocytes in neurodegenerative diseases: Mechanistic insights and therapeutic implications.
    Cheng Gao, Ran Shi, Xianliang Jiang, Hui Chai, Xiao He.
      Neurodegenerative diseases (NDDs) are increasingly understood as multifactorial disorders characterized by intertwined pathological processes, in which metabolic dysfunction may act as a critical and potentially disease-amplifying contributor to the proteinopathy-driven pathological cascade. Despite growing recognition that microglial and astrocytic metabolism governs central nervous system tissue damage-repair homeostasis, intercellular metabolic crosstalk between glia and neurons remains insufficiently synthesized across major NDDs. This review delineates how core metabolic pathways, including glycolysis, mitochondrial respiration, lipid processing, and amino acid transport, shape glial reactivity in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We highlight glial metabolic reprogramming, a proposed theoretical framework arising from severe glial metabolic dysregulation. Within this framework, persistent pathological stress may drive reactive glia to sequester local energy substrates in excess, which is hypothesized to trigger bioenergetic failure in neighboring neurons. Broad-spectrum anti-inflammatory agents show poor clinical performance because they only block cytokine outputs rather than reverse glial metabolic exhaustion. Therapeutic efforts should therefore shift toward restoring glial metabolic flexibility. Cell-type-specific metabolic reprogramming, instead of pan-metabolic suppression, may circumvent systemic adverse effects. Precision strategies targeting such intercellular metabolic imbalance could provide promising cell-resolved metabolic avenues to retard NDD progression.
    Keywords:  Glial cells; Immunometabolism; Metabolic reprogramming; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.jns.2026.126237
  12. J Extracell Vesicles. 2026 Nov;pii: e70404. [Epub ahead of print]15(11):
    ITGAM+ Extracellular Vesicles Trigger CD8+ T Cell Activation via S100a9-Mediated Metabolic Reprogramming in Acute Kidney Injury.
    Yu-Qi Fu, Yi-Lin Zhang, An-Ran Shen, Ning Li, Jing Song, Yan Bao, Si-Meng Wang, Ding-Ding Xue, Min Wu, Bin Wang, Yi Wen, Tao-Tao Tang, Lin-Li Lv, Bi-Cheng Liu.
      Acute kidney injury (AKI) is a prevalent condition with limited therapeutic options, in which sustained renal injury driven by inflammation remains a central pathological challenge. Here, we identify a specific subset of extracellular vesicles (EVs) as the critical link translating early myeloid inflammation into metabolically fuelled CD8+ T cell pathogenicity. Using single-EV surface proteomics via a proximity barcoding assay in a murine ischemia-reperfusion injury model, we mapped the renal EV landscape and discovered a myeloid-derived ITGAM+ EV subset with markedly increased abundance after injury. Using a CD63-PAGFPITGAM-KI reporter mouse that genetically enhances ITGAM+ EV release, we further validated that these EVs interact with CD8+ T cells in the renal lymphatic niche, driving their pro-inflammatory activation. Proteomic profiling pinpointed S100a9 as the functional cargo on these ITGAM+ EVs. Mechanistically, EV-delivered S100a9 stabilized the mitochondrial aspartate-glutamate carrier Slc25a12 in recipient CD8+ T cells, thereby enhancing glutamate metabolism to fuel a pathogenic transcriptional program. Pharmacological inhibition of S100a9 with tasquinimod, combined with genetic loss of S100a9 in bone marrow-derived myeloid cells, established the necessity of EV-associated S100a9 in driving CD8+ T cell activation. Our findings establish ITGAM+ EVs as essential mediators of pro-metabolic and pro-inflammatory signal in AKI and highlight the S100a9-Slc25a12 axis as a promising therapeutic target for intercepting sterile inflammation.
    Keywords:  CD8+ T cell; ITGAM+ EVs; acute kidney injury; metabolic reprogramming
    DOI:  https://doi.org/10.1002/jev2.70404
  13. Neuroscientist. 2026 Nov 02. 10738584261498171
    Microglia: Metabolic Adaptation in Neurodegeneration.
    Leen Aljayousi, Noelle Gentile, Pinar Ayata.
      Microglia, the brain's primary innate immune cells, are metabolically dynamic cells whose functional states, from homeostatic surveillance to disease-associated phagocytosis, lipid droplet accumulation, and stress-induced neurotoxicity, are governed by distinct metabolic programs. Neurodegenerative stressors, including misfolded protein accumulation, oxidative stress, mitochondrial dysfunction, and sustained inflammation, initially trigger adaptive metabolic reprogramming of glycolysis, the tricarboxylic acid cycle, and amino acid and lipid pathways. Under chronic stimuli, these same shifts become maladaptive, impairing microglial phagocytosis, promoting lipid accumulation, and driving the secretion of neurotoxic lipid species. A unifying theme emerging across metabolic pathways is that the intermediates produced under stress, lactate, succinate, ceramide, acetyl-CoA, and α-ketoglutarate, do not merely reflect cellular state but actively reshape it through epigenetic modification of histones and DNA. In this review, we examine how each major metabolic pathway responds to acute and chronic neurodegeneration-associated stress in microglia, highlight where epigenetic mechanisms convert transient metabolic shifts into durable changes in microglial identity, and identify genetic risk factors that encode metabolic vulnerability in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; lipid metabolism; metabolic-epigenetic axis; microglia
    DOI:  https://doi.org/10.1177/10738584261498171
  14. Adv Sci (Weinh). 2026 Nov 03. pii: e78586. [Epub ahead of print]
    Lactylation of HSC70 Impairs Chaperone-Mediated Autophagy to Promote Pyrin Inflammasome-Dependent PANoptosis in Macrophages During Sepsis.
    Ying Chen, Yan Zhang, Pei Wang, Jiamin Ma, Xinru Zhao, Yi Li, Zhenghao Deng, Xueqing Meng, Jiali Zhu, Liangfang Yao, Jinbao Li.
      Sepsis-related cytokine storm is associated with poor prognosis in septic patients. IFNγ/LPS can synergistically trigger a sepsis-associated proinflammatory cytokine storm and induce macrophage death in the form of PANoptosis. The ensuing release of proinflammatory cytokines further amplifies macrophage death, leading to subsequent multiple organ damage. Concurrently, the IFNγ/LPS induced inflammatory cascade also downregulates chaperone-mediated autophagy (CMA) activity, and this dysregulation further exacerbates the inflammatory response in macrophages and in vivo. Thus, a positive feedback loop between dysfunctional CMA and the inflammatory cascade is established. Enhancing CMA activation reduces macrophage death and organ damage, whereas inhibiting CMA exacerbates macrophage PANoptosis and organ injury. Mechanistically, impaired CMA leads to accumulation of the transcription factor CUX1, which subsequently upregulates Pyrin expression and promotes Pyrin-mediated PANoptosome assembly, thereby driving macrophage PANoptosis. In addition to the cytokine storm, the lacylation at lysine 561 (K561) of HSC70, a core component of the CMA machinery, is associated with reduced CMA activity. Blocking lactylation can similarly attenuate macrophage death and multiple organ injury in sepsis. Taken together, this "Kla-CMA-CUX1/Pyrin-PANoptosis" signaling axis, linking metabolic reprogramming to immune dysregulation in sepsis, suggests that targeting key nodes of this axis may represent a promising therapeutic strategy to reduce sepsis-associated mortality.
    Keywords:  CMA; PANoptosis; lysine lactylation; macrophage; sepsis
    DOI:  https://doi.org/10.1002/advs.78586
  15. Exp Mol Pathol. 2026 Oct 31. pii: S0014-4800(26)00072-9. [Epub ahead of print]148 105093
    Mitochondrial transfer enhances the metabolic fitness and antitumor activity of primary NK cells.
    Min-Jeong Park, Mi Jin Kim, Mina Lim, Eun-Seo Back, Young June Jeon, Da-Yoon Kim, Chang-Koo Yun, Young Jik Kwon, Junho Park, Yong-Soo Choi.
      Natural killer (NK) cell therapy has emerged as a promising approach for cancer treatment. However, its efficacy is often limited by metabolic dysfunction, poor persistence, and reduced activity within the tumor microenvironment. Here, we investigated whether mitochondrial transfer could improve the metabolic fitness and antitumor activity of peripheral blood-derived primary NK cells. Using a simple centrifugation-based approach, mitochondria isolated from NK cells or umbilical cord-derived mesenchymal stem cells (UC-MSCs) were transferred into primary NK cells. Mitochondrial transfer significantly enhanced oxidative phosphorylation, glycolysis, and ATP production, leading to improved cytokine secretion and cytotoxicity against both hematologic and solid tumor targets. In xenograft models, mitochondrial transfer significantly suppressed tumor growth, with UC-MSCs-derived mitochondria producing the greatest therapeutic benefit. Proteomic analysis further revealed enrichment of pathways associated with immune activation, cellular migration, and cytoskeletal remodeling. Collectively, these findings demonstrate that mitochondrial transfer enhances NK-cell metabolic fitness and antitumor activity, highlighting its potential as a practical non-genetic strategy for improving NK cell-based cancer immunotherapy.
    Keywords:  Cell therapy; Immunometabolism; Metabolic reprogramming; Mitochondrial transfer; Natural killer cells; cancer immunotherapy
    DOI:  https://doi.org/10.1016/j.yexmp.2026.105093
  16. Bone Marrow Transplant. 2026 Nov 03.
    Metabolic pathways as therapeutic target to improve allo-HSCT outcomes.
    Angimar Uriepero-Palma, Marie Krielle Tasha Pantino, Ratika Dogra, Katia Beider, Arnon Nagler, Gabor Varadi.
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for many high-risk hematologic malignancies, yet its efficacy is limited by graft-versus-host disease (GVHD), relapse, and immune dysregulation. Emerging evidence identifies cellular metabolism as a central, underexplored determinant of transplant outcomes. Across transplant-relevant malignancies, including myelodysplastic neoplasms, acute myeloid and lymphoblastic leukemia, and high-risk lymphoma, disease-specific metabolic programs encompassing mitochondrial dysfunction, oxidative stress, lipid and fatty acid remodeling, and oncometabolite accumulation cooperate to sustain clonal persistence, suppress antitumor immunity, and confer resistance to cytotoxic and targeted therapies. Within the transplant itself, donor T-cell metabolic reprogramming fuels the dichotomy between GVHD and graft-versus-leukemia (GVL) activity, with alloreactive effector T cells depending on glycolysis and fatty acid oxidation in ways that are mechanistically separable from GVL-mediating responses. This review synthesizes current evidence on disease-specific and transplant-specific metabolic programs and evaluates pharmacological strategies that may be deployed peri-transplant to simultaneously reduce GVHD, prevent relapse, and preserve GVL.
    DOI:  https://doi.org/10.1038/s41409-026-03071-0
  17. Redox Biol. 2026 Oct 27. pii: S2213-2317(26)00460-X. [Epub ahead of print]98 104461
    Loss of T cell-intrinsic Keap1 alleviates colitis by suppressing Th17 differentiation and enhancing regulatory T cell functions.
    Debolina Dasgupta, Aprajita Tripathi, Rachel Griffard-Smith, Michael S Dahabieh, Md Saiful Islam Saif, Badal C Roy, Emily Burt, Abigail Ellis, Ryan D Sheldon, Poojaben Dhorajiya, Shahid Umar, Devin Koestler, Russell G Jones, Kalyani Pyaram.
      Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) characterized by chronic inflammation in the colon. In this study, we elucidate the roles of antioxidation proteins Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in modulating CD4+ T cell differentiation and intestinal inflammation in UC. Using mice with T cell-specific deletion of Keap1 or Nrf2, we demonstrate that T cell-intrinsic Nrf2 levels influence T helper (Th) cell differentiation, intestinal inflammation and colitis disease outcome. Loss of Keap1 in T cells suppressed proinflammatory Th1 and Th17 subset differentiation, while promoting induced regulatory T-cell (iTreg) generation in an Nrf2-dependent manner, thereby alleviating intestinal inflammation and protecting against colitis. Mechanistic analyses revealed that Keap1 deletion was associated with metabolic reprogramming in iTregs, characterized by increased glutamine utilization and enhanced mitochondrial respiration, suggesting that these metabolic changes may contribute to enhanced iTreg generation. Further, analyses of UC patient tissues and omics datasets revealed increased Nrf2 gene expression and enrichment of Nrf2-associated transcriptional signatures in colonic Tregs, correlating with Foxp3 expression. In summary, our findings identify Keap1-Nrf2 axis as an important regulator of iTreg generation and function, suggesting that targeting this pathway may represent a potential therapeutic strategy for IBD.
    Keywords:  Antioxidation; CD4(+)T cells; Inflammatory bowel disease (IBD); Metabolism; Nrf2; Tregs
    DOI:  https://doi.org/10.1016/j.redox.2026.104461
  18. Front Immunol. 2026 ;17 1974223
    Fatty acid dysregulation in asthma: linking immunometabolic remodeling, phenotypic heterogeneity, and metabolic precision medicine.
    Yuan Yuan, Yunhao Peng.
      Asthma is a highly heterogeneous chronic airway disease characterized by diverse inflammatory endotypes, variable airway remodeling patterns, and differential therapeutic responses. Although current classifications mainly rely on immune phenotypes, they do not fully explain severe steroid resistance, obesity-associated asthma, and inflammation-independent structural remodeling. Immunometabolic dysregulation, particularly fatty acid metabolic imbalance, has emerged as an additional dimension associated with asthma heterogeneity and the interplay among systemic metabolic status with airway inflammation and remodeling. In this review, we summarize major features of fatty acid dysregulation in asthma, including altered circulating and airway lipid profiles, PUFA-derived mediator imbalance, SFA-associated metabolic stress, and cell-type-specific alterations in fatty acid uptake, synthesis, oxidation, and storage. These alterations may affect airway epithelial cells, macrophages, lymphocytes, airway smooth muscle cells, and fibroblasts, thereby influencing epithelial barrier integrity, inflammatory programming, smooth muscle remodeling, and extracellular matrix deposition. Human studies have identified phenotype-associated lipid signatures, including AA-derived inflammatory mediators such as cysteinyl leukotrienes and PGD2 metabolites in T2-high asthma and alterations in linoleic acid and glycerophospholipid metabolism across granulocytic phenotypes, whereas obesity-associated asthma additionally reflects systemic metabolic disturbances arising from the adipose-lung axis. Much of the current human evidence remains associative, whereas functional support for specific fatty acids, lipid mediators, and metabolic pathways is derived largely from experimental and ex vivo studies. We further present a conceptual framework in which metabolic, inflammatory, and structural alterations may interact to contribute to persistent airway remodeling. Finally, we discuss the emerging translational potential of lipidomic-guided phenotyping and metabolism-directed interventions, while emphasizing that these approaches remain investigational and require prospective clinical validation.
    Keywords:  airway remodeling; asthma; fatty acid metabolism; immunometabolism; lipid dysregulation; precision medicine
    DOI:  https://doi.org/10.3389/fimmu.2026.1974223
  19. Respir Res. 2026 Oct 12. pii: 431. [Epub ahead of print]27(1):
    CISD1 suppresses COPD inflammation by recruiting ubiquitinated STING and altering macrophage metabolism.
    Jiameng Gao, Fengfeng Han, Lili Chen, Zhilong Jiang, Fang Wang, Zhihui Min, Yuhao Qian, Yao Shen, Zhihong Chen.
       BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disorder characterized by persistent oxidative stress and macrophage-driven airway injury. However, the molecular mechanisms linking mitochondrial dysfunction to innate immune activation in COPD remain unclear.
    METHODS: Using a combination of in vitro and in vivo models, we investigated the role of CDGSH iron-sulfur domain-containing protein 1 (CISD1) in regulating macrophage inflammation and its crosstalk with epithelial cells. Transcriptomic, proteomic, and metabolomic analyses were performed to elucidate the molecular networks downstream of CISD1. Co-immunoprecipitation, ubiquitination assays, and confocal imaging were used to characterize the interaction between CISD1, STING, and the E3 ligase Ubr5.
    RESULTS: Our previous study demonstrated that CSE downregulated CISD1 expression in macrophages. Based on this finding, we hypothesized that CISD1 might modulate STING activation and its downstream signaling pathways. Experimental validation confirmed that CISD1 downregulation indeed enhanced STING phosphorylation and activated the TBK1-IRF3-NF-KB pathway. Overexpression of CISD1 suppressed STING activation, type I interferon (IFN-b) production, and pro-inflammatory cytokine expression. Mechanistically, CISD1 directly interacted with STING and recruited Ubr5 to promote K48-linked ubiquitination and proteasomal degradation of STING, thereby restraining excessive innate immune signaling. Metabolomic profiling further revealed that CISD1 deficiency reduced intracellular daidzein, a key anti-inflammatory metabolite. Supplementation with daidzein attenuated NF-KB activation, restored antioxidant signaling, and alleviated epithelial apoptosis both in vitro and in COPD mouse models.
    CONCLUSION: Our results support a model in which CISD1 restrains STING-dependent innate immune activation by recruiting Ubr5 to catalyze ubiquitination and proteasomal turnover of STING, thereby dampening macrophage inflammation and preserving epithelial integrity under cigarette smoke exposure. This CISD1-dependent innate immune checkpoint mechanistically links macrophage metabolic regulation to macrophage-epithelial crosstalk in COPD and identifies the CISD1-Ubr5-STING pathway-and daidzein restoration-as testable therapeutic hypotheses.
    Keywords:  CISD1; COPD; Daidzein; Macrophage polarization; Mitochondrial regulation; STING; Ubiquitination; Ubr5
    DOI:  https://doi.org/10.1186/s12931-026-03917-7
  20. PLoS Negl Trop Dis. 2026 Nov 05. 20(11): e0014856
    PD-1 deficiency impairs Treg differentiation in Trichinella-infected mice via inhibition of fatty acid oxidation.
    Yao Zhang, Yuwan Hao, Chen Wu, Caiyuan Li, Jingjing Huang, Xinping Zhu, Yuli Cheng.
      Helminth infections establish long-term host persistence by inducing regulatory immune responses that limit pathology while promoting parasite survival. Programmed death 1 (PD-1), an inhibitory receptor expressed on activated T cells, plays an essential role in maintaining immune homeostasis during chronic infections. Regulatory T cells (Tregs) expand during helminth infection and are critical for controlling excessive inflammation; however, the metabolic mechanisms linking PD-1 signaling to Treg differentiation during helminth infection remain poorly defined. Here, we investigated the role of PD-1 in regulating Treg differentiation during Trichinella spiralis infection, focusing on metabolic reprogramming in CD4⁺ T cells. Using a murine infection model, we compared wild-type and PD-1-deficient (PD-1⁻/⁻) mice and evaluated Treg differentiation in vivo and in a bone marrow-derived dendritic cell (BMDC)-CD4⁺ T-cell co-culture system stimulated with muscle larval excretory-secretory products (MES). PD-1 deficiency significantly reduced splenic FoxP3⁺ Treg frequencies following infection and impaired MES-induced Treg differentiation and Treg-associated cytokine production in vitro. Metabolic profiling revealed that CD4⁺ T cells from infected PD-1⁻/⁻ mice exhibited markedly reduced fatty acid oxidation (FAO), accompanied by decreased expression of Carnitine Palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme in FAO. PD-1 deficiency was associated with enhanced PI3K-Akt-mTOR signaling and suppressed AMPK activation. Importantly, pharmacological inhibition of PI3K partially restored FAO activity and rescued Treg differentiation in PD-1⁻/⁻ CD4⁺ T cells. These findings suggest that PD-1 supports Treg development during T. spiralis infection, at least in part, through a CPT1A-associated FAO pathway, highlighting a PD-1-associated metabolic pathway that may contribute to helminth-induced immune regulation.
    DOI:  https://doi.org/10.1371/journal.pntd.0014856
  21. J Adv Res. 2026 Nov 03. pii: S2090-1232(26)00858-1. [Epub ahead of print]
    Targeting lactate-GPR81/TAZ/PPARα-induced ROS in Bregs overcomes immunosuppression and improves lung cancer outcomes.
    Zhanchuan Ma, Shan Lin, Wenji Xiong, Yu Zhen, Chaoying Liu, Ming Li, Yu Sun, Huanfa Yi.
       INTRODUCTION: Tumor-derived lactic acid (LA) plays a dual role in shaping the immunosuppressive tumor microenvironment by directly modulating immune cell function.
    OBJECTIVES: Tumor-infiltrating B cells enhance antitumor immunity by promoting T-cell proliferation, whereas immunosuppressive subsets such as regulatory B cells (Bregs) counteract these effects via IL-10 sretion. However, the metabolic impact of lactate on B-cell functionality remains unclear.
    METHODS: Using flow cytometry, we analyzed LA-induced phenotypic alterations in B cells and assessed Breg immunosuppressive activity via suppression assays. The tumor-inhibitory effects of blocking lactate receptor signaling were examined in animal models.
    RESULTS: Here, we reveal a previously unrecognized immunosuppressive mechanism mediated by CD25+CD81+ B cells (Bregs) in lung cancer. In murine models, LA induced ROS production in splenic and intratumoral Bregs through G protein-coupled receptor 81 (GPR81) signaling, thereby suppressing T-cell responses. Mechanistically, LA binding to GPR81 activates the cAMP/TAZ/PPARα axis, which orchestrates ROS generation in Bregs. Genetic ablation of lactate dehydrogenase A (LDHA) in tumor cells disrupted this signaling cascade in vivo, resulting in reduced ROS levels and restored T-cell activity. Pharmacological inhibition of GPR81 or PPARα similarly attenuated Breg-mediated immunosuppression and delayed tumor progression. Clinically, we identified ROS+ Breg populations in lung cancer patients, and elevated tumor LDHA expression correlated with poor prognosis.
    CONCLUSION: Our findings establish the LA-GPR81/TAZ/PPARα/ROS axis in Bregs as a redox-dependent checkpoint for tumor immune evasion, and highlighting novel therapeutic targets for lung cancer immunotherapy.
    Keywords:  GPR81; Lactic acid; Lung cancer; PPARα; Regulatory B cells
    DOI:  https://doi.org/10.1016/j.jare.2026.11.001
  22. Front Aging. 2026 ;7 1869552
    Impact of habitual physical activity and age on T cell metabolism and activation via β2-adrenergic receptor modulation.
    Amanda V Sardeli, Ana Ramkrapes, Jakob Boyes-Jensen, Jon Hazeldine, Helena Batatinha, Niharika A Duggal, Davide Calebiro, James E Turner.
       Background: Ageing impairs T cell function and responses to vaccines and infections. Effective T cell function requires rapid metabolic switching towards glycolysis, which becomes dysregulated with age. We have shown that physically active older adults have T cells that are more functional and metabolically fit. As exercise acutely elevates adrenaline and mobilises T cells via β2-adrenergic receptors (β2-AR), we hypothesise that habitual physical activity (PA) preserves β2-AR-mediated metabolic stimulation in T cells from older adults.
    Methods: Older adults (≥65 years) with habitually high PA (HPA, n = 6) or habitually moderate PA (MPA, n = 6) were compared with young controls (18-35 years, n = 6). T cells were exposed to the β-agonist isoproterenol for 30 min to mimic acute exercise-like adrenergic stimulation, with or without the β2-AR blocker ICI-118,551. Following 1 h of rest, T cells were stimulated for 4 h in vitro with PMA and ionomycin. T cell activation (CD69), glucose transporter-1 (Glut1), intracellular cAMP concentrations under isoproterenol stimulation, and β2-AR mRNA expression were assessed.
    Results: Older adults exhibited impaired CD8+ T cell activation and β2-AR blockade inhibited activation in all groups. Glut1 expression in CD8+ T cells was higher in older MPA than young, but did not differ from older HPA. In CD8+ T cells that were not stimulated with PMA and ionomycin, β2-AR blockade (with β-AR stimulation) increased Glut1 expression in all groups compared with β-AR stimulation alone, and this increase was greater in older HPA than MPA (p = 0.043). No group differences were observed in β2-AR mRNA expression or isoproterenol-induced β-AR cAMP responsiveness.
    Conclusion: These exploratory findings indicate that individuals with higher levels of habitual PA have lower age-associated impairments in CD8+ T cell activation and metabolic switching in response to β stimulation. Interestingly, β2-AR blockade did not fully abrogate β stimulation, therefore future studies should investigate a potential influence of β1-AR in this modulation, to generate definitive conclusions.
    Keywords:  T cell; adrenergic; aging; exercise; immunosenescence; lymphocyte; metabolism; physical activity
    DOI:  https://doi.org/10.3389/fragi.2026.1869552
  23. Cell Rep. 2026 Nov 06. pii: S2211-1247(26)01346-X. [Epub ahead of print]45(11): 118267
    Succinate promotes multiple myeloma cell proliferation through TCA cycle oxidation.
    Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Aidan Haslam, Graham McIlroy, Hannah Giles, Guy Pratt, Sarah Dimeloe.
      Multiple myeloma is a plasma cell malignancy that develops within the bone marrow. The bone marrow metabolome is altered in myeloma, with implications for malignant cell growth. Here, the impact of elevated bone marrow levels of the tricarboxylic acid (TCA) cycle metabolite, succinate, was interrogated. Succinate was found to promote proliferation of several myeloma cell lines. This was linked to its uptake and oxidation in the TCA cycle, as indicated by increased ATP-coupled mitochondrial respiration and incorporation of succinate-derived carbons into downstream TCA cycle intermediates, which also occurs in primary myeloma cells. Succinate-driven proliferation was dependent upon mitochondrial oxidative phosphorylation and abrogated by ATP synthase inhibition. Furthermore, interrogation of large-scale transcriptomic data identified that elevated expression of a mitochondrial succinate transporter associates with accelerated disease progression in myeloma, indicating this mechanism may promote plasma cell growth in vivo and highlighting a target for therapeutic intervention.
    Keywords:  CP: cancer; CP: metabolism; anti-tumour immunity; cancer; cancer metabolism; immunometabolism; metabolism; metabolites; mitochondria; multiple myeloma; succinate
    DOI:  https://doi.org/10.1016/j.celrep.2026.118267
  24. Mol Med Rep. 2027 Jan;pii: 5. [Epub ahead of print]35(1):
    Lactylation in the regulation of macrophage polarization: Mechanisms pathophysiological significance (Review).
    Xiao-Yu Wang, Dong-Xu Liao, Lin Yang, Qin Xie, Qing-Qing Huang, Yi Wen.
      Macrophage polarization is regulated by metabolic reprogramming epigenetic modifications. The discovery of histone lysine lactylation has revealed that lactate is not merely a glycolytic end product but also an important metabolic signal linking cellular metabolic status to gene expression programs. Lactylation modulates both histones (such as H3K18la) non‑histone proteins (such as nuclear factor‑κB p65 hypoxia‑inducible factor‑1α), thereby influencing macrophage polarization through transcriptional regulation signal transduction. Its functions are highly context‑dependent. In the tumor microenvironment, it predominantly promotes M2‑type immunosuppression; in certain neuroinflammatory conditions, it may be associated with M1‑like phenotypes; in metabolic diseases, it may exacerbate pro‑inflammatory damage. This modification involves extensive crosstalk with acetylation, methylation, other epigenetic modifications, constituting a complex regulatory network. However, current research faces critical bottlenecks: The intracellular source metabolic flux of lactyl‑CoA remain unclear; the substrate specificity physiological relevance of candidate writers, such as E1A‑binding protein p300 CREB‑binding protein, erasers, such as sirtuin 2, remain controversial; a bona fide reader domain that specifically recognizes lactylated lysine has not been identified; in vivo causal evidence remains limited. Future efforts should integrate multiomics technologies, genetic manipulation tools, precision delivery systems to decipher the spatiotemporal regulatory networks of lactylation, thereby facilitating the identification of new therapeutic targets strategies for inflammatory, neoplastic, metabolic diseases.
    Keywords:  epigenetic; lactylation modification; macrophage; metabolic reprogramming; polarization
    DOI:  https://doi.org/10.3892/mmr.2026.14063
  25. Free Radic Biol Med. 2026 Nov 06. pii: S0891-5849(26)01257-8. [Epub ahead of print]
    The UCHL1-HIF-1α Axis Mediates Microglial Metabolic Reprogramming and Neuroinflammation in Parkinson's Disease.
    Chunyan Jiang, Yaqing Li, Ying Qu, Yanuo Kong, Jiwen Ren, Qiqing He, Zhen Kong, Binghui Hou, Kaixin Dou, Anmu Xie.
      Microglial-mediated neuroinflammation is a key driver of Parkinson's disease (PD) progression. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a neuron-enriched deubiquitinating enzyme, yet its role in microglial immunometabolism and PD pathogenesis remains poorly understood. We investigated the role of UCHL1 using lipopolysaccharide (LPS)-stimulated BV2 microglial cells, and brain tissues from a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. UCHL1 expression, inflammatory responses, HIF-1α signaling, and glycolytic activity were assessed using Western blotting, RT-qPCR, immunofluorescence, and metabolic assays. The effects of UCHL1 modulation on neuronal survival were examined using conditioned medium transfer experiments. The neuroprotective effects of UCHL1 inhibition in an MPTP-induced mouse model were evaluated by behavioral assessments and immunofluorescence analysis. In BV2 microglia, LPS stimulation partially reduced endogenous UCHL1 expression, the remaining UCHL1 continued to microglial neuroinflammation. Pharmacological inhibition of UCHL1 attenuated inflammatory responses, whereas UCHL1 overexpression exacerbated microglial activation and bystander neuronal injury. UCHL1 promoted glycolytic reprogramming through upregulation of HK2, PKM2, and LDHA. Mechanistically, Inhibition of HIF-1α diminished the increases in pro-inflammatory mediators and glycolytic enzyme expression associated with UCHL1 overexpression. In vivo, immunofluorescence demonstrated UCHL1 expression in activated microglia within the substantia nigra, and UCHL1 inhibition attenuated microglial activation, preserved TH-positive dopaminergic (DA) neurons, and improved motor deficits in MPTP-treated mice. Collectively, our findings identify UCHL1 as a key regulator of microglial immunometabolism in PD. By promoting HIF-1α-dependent glycolytic reprogramming, UCHL1 amplifies neuroinflammation and contributes to DA neurodegeneration, highlighting the UCHL1/HIF-1α/glycolysis axis as a potential therapeutic target for PD.
    Keywords:  Glycolytic reprogramming; HIF-1α; Microglia; Neuroinflammation; Parkinson’s disease; UCHL1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.11.008
  26. Cancer Immunol Immunother. 2026 Aug 06. pii: 268. [Epub ahead of print]75(11):
    Taurine bolsters adoptive T cell therapy efficacy against hepatocellular carcinoma by reprogramming T cell function.
    Zhiming Zhang, Siwei Li, Mengjie Li, Li Gong, Xinyu Lu, Weikang Xu, An-An Chen, Yiyue Wang, Changsheng He, Guoheng Mo, Yuting Xie, Si-An Yue, Lei Huang, Chou Yang, Jinlin Hou, Wei Zhu.
      Adoptive T cell therapy for advanced hepatocellular carcinoma (HCC) is limited by the immunosuppressive tumor microenvironment, which impairs T-cell function. Overcoming this immunosuppression and restoring T-cell functionality are crucial for improving therapeutic efficacy. Here, we investigated the role of taurine in regulating alpha-fetoprotein (AFP)-specific T-cell receptor-engineered T cells (TCR-T) function. Metabolomic profiling revealed that intracellular taurine levels declined during the early phase of T-cell activation, while expression of the taurine transporter SLC6A6 increased over time. In addition, taurine abundance was lower in HCC tissues than in normal liver tissues in vivo, suggesting that taurine availability is reduced during both T-cell activation and tumor progression. Functionally, taurine supplementation enhanced the cytotoxic activity, persistence, and intratumoral infiltration of AFP-specific TCR-T, while reducing exhaustion and apoptosis after repetitive tumor stimulation. In contrast, taurine-limited conditions impaired T-cell proliferation and survival, attenuated antitumor activity in vitro and in vivo, and promoted an exhaustion-prone phenotype. Taurine supplementation also partially restored the function of β-alanine-preconditioned T cells. Mechanistically, transcriptomic and proteomic analyses identified PI3K-AKT signaling as a key pathway associated with taurine-mediated T-cell regulation. Taurine-limited T cells showed reduced AKT phosphorylation and developed a metabolically stressed state characterized by increased mitochondrial respiration, glycolytic activity, reactive oxygen species production and mitochondrial structural abnormalities during activation. Together, these findings identify taurine availability as an important metabolic regulator of engineered T-cell fitness and support taurine-based metabolic conditioning as a potential strategy to improve TCR-T therapy for HCC.
    Keywords:  Adoptive T cell; Hepatocellular carcinoma; SLC6A6; Taurine
    DOI:  https://doi.org/10.1007/s00262-026-04503-y
  27. Transbound Emerg Dis. 2026 ;pii: e3930677. [Epub ahead of print]2026(1):
    Macrophage USF2 Lactylation-Mediated FABP4 Suppression Promotes Intracellular Proliferation of Brucella.
    Yuanhao Yang, Yaping Zu, Xin Wang, Xiaofang Liu, Yunyi Zhai, Ye Yuan, Gaowa Wudong, Wei Liu, Yaping Jin, Dong Zhou, Aihua Wang.
      Brucella spp. are facultative intracellular bacteria that infect and induce brucellosis in a diverse range of mammalian hosts. Understanding the mechanisms underlying the intracellular survival of Brucella is of critical importance for the prevention and control of brucellosis. This study uncovers the mechanism by which Brucella abortus manipulates host lactate metabolism to facilitate its intracellular proliferation. Infection of macrophages by B. abortus enhanced L-lactate production by the host macrophages, which in turn promoted bacterial proliferation. Proteomic and functional analyses identified the host glucose transporter protein Slc2a1 as a positive regulator of both B. abortus proliferation and host cellular lactylation. The B. abortus effector protein SepA upregulated Slc2a1 expression and host cellular lactylation. Lactylation of the transcription factor USF2 at lysine residues 255 and 275 suppressed production of the host lipid metabolism-associated protein Fabp4, thereby enhancing bacterial survival. Moreover, Fabp4 inhibition attenuated B. abortus-induced M1 polarization and lipid metabolism in macrophages. These findings reveal a dual-axis regulatory network through which B. abortus exploits host L-lactate metabolic reprogramming via the SepA/Slc2a1 and L-lactate-USF2/Fabp4 axes to establish its intracellular niche, providing new insights into host-Brucella metabolic crosstalk.
    Keywords:  Brucella abortus A19; Fabp4; SepA; Slc2a1; USF2; lactylation
    DOI:  https://doi.org/10.1155/tbed/3930677
  28. Res Sq. 2026 Oct 29. pii: rs.3.rs-11368155. [Epub ahead of print]
    A living enzymatic adenosine switch couples metabolic rescue to IL-12-driven antitumor immunity.
    Rizwan Romee, Stephanie Sendker, Shaobo Yang, Eden Bobilev, Alice Chen, Fuguo Liu, Anna Bader, Xingyu Deng, Jenny Ho, Maily Nguyen, Michael James, Veronica Hui, Kate Marinchev, Andreia Maia, Castilleja Albert, Isabella Salinas, Ashley Hu, Alaa Kassim Ali, Jacqueline Garcia, Daniel DeAngelo, Mohammad Rashidian, Bartosz Grzywacz, Robert Soiffer, Jerome Ritz, Catherine Wu, John Koreth, Remy Dulery, Jose Cancelas, Roman Shapiro, Mounica Vallurupalli, Jiahe Li, Andrew Lane, Mubin Tarannum.
      Cancer cells remodel their metabolic environment to disable infiltrating immune cells. Adenosine is a principal mediator of this immunosuppression, impairing the metabolism and effector functions of T and natural killer (NK) cells. Blocking adenosine receptors or production within a redundant signaling network leaves the metabolite itself intact and has shown limited clinical efficacy. Adenosine deaminase (ADA) instead converts adenosine into inosine, a metabolite that can fuel T cell metabolism. We engineered non-pathogenic, tumor-tropic Escherichia coli K-12 DH5α to surface-display ADA, confining this metabolic switch to the tumor, and co-displayed interleukin-12 (IL-12) to couple metabolic rescue to local immune stimulation. Bacteria-displayed ADA alone restored metabolic and proliferative fitness in adenosine-suppressed lymphocytes to baseline, whereas incorporation of IL-12 coupled this rescue to enhanced effector function. Across multiple preclinical models of hematologic and solid malignancies, the dual-function bacteria were well tolerated, enhanced tumor control, prolonged survival, and induced durable protective immunity against melanoma rechallenge. The bacteria were enriched at tumor sites, reactivated quiescent immune compartments in leukemia, enhanced CAR-NK cell tumor trafficking and activity in pancreatic cancer, and outperformed recombinant proteins in breast cancer. These findings establish a modular living immunotherapeutic strategy that couples a local extracellular metabolic switch with localized cytokine delivery.
    DOI:  https://doi.org/10.21203/rs.3.rs-11368155/v1
  29. Innate Immun. 2026 Jan-Dec;32:32 17534259261506889
    From iron sequestration to immune paralysis: A biphasic model of Lipocalin-2 function in sepsis.
    David M Cauvi, Antonio De Maio.
      Sepsis is a life-threatening syndrome arising from a dysregulated host response to infection, characterized by a biphasic immune trajectory in which an early hyperinflammatory phase transitions into a prolonged state of immunosuppression. This late phase is dominated by massive apoptotic depletion of lymphocytes, functional exhaustion of monocytes and macrophages, and an inability to mount effective responses against secondary infections, collectively defining immune paralysis. Indeed, most sepsis-related deaths occur during this phase of immune paralysis. Throughout the sepsis response, various pro- and anti-inflammatory mediators are released, particularly cytokines. Among the factors released during sepsis, Lipocalin-2 (Lcn2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is a secreted innate immune glycoprotein induced during infection as a bacteriostatic mediator that sequesters iron-bound bacterial siderophores, thereby depriving pathogens of a nutrient essential for growth and dissemination. While this early protective function of Lcn2 is well established, accumulating experimental and clinical evidence points to a second, temporally distinct role during the immunosuppressive phase. In murine models of polymicrobial sepsis, Lcn2 expression at both the mRNA and protein levels is uniquely sustained throughout the late phase, in sharp contrast to other inflammatory mediators that rapidly resolve. This persistent expression may drive iron-dependent metabolic stress, activation of intrinsic apoptotic pathways in lymphocytes, and stabilization of macrophage tolerance. In human patients, circulating NGAL correlates with inflammatory cytokines, endothelial activation, and disease severity, and persistently elevated levels associate with adverse outcomes. We propose that Lcn2 may act as a phase-dependent regulator of the septic immune response, serving a protective and antimicrobial role during early infection while potentially contributing to immune dysfunction when its expression is sustained. This dual behavior positions Lcn2 as both a clinically informative biomarker and a candidate target for therapeutic intervention in sepsis.
    Keywords:  Antimicrobial Agent; Immune Paralysis; Immunosuppression; Infection; Inflammation; Lipocalin-2 (Lcn2); Sepsis
    DOI:  https://doi.org/10.1177/17534259261506889
  30. Mol Med Rep. 2027 Jan;pii: 3. [Epub ahead of print]35(1):
    Metabolic reprogramming of myeloid‑derived suppressor cells in colorectal cancer: Mechanistic insights and immunometabolic targeted rehabilitation (Review).
    Liang-Xiao Zhu, Guang-Jie Jiang, Feng-Hou Gao, Yi-Qiao Du.
      Metabolic reprogramming of myeloid‑derived suppressor cells (MDSCs) plays a role in immunotherapy resistance in colorectal cancer (CRC). This metabolic reprogramming appears to be coordinated by oncogenic mutations (such as adenomatous polyposis coli, KRAS and TP53) through a proposed self‑reinforcing 'mutation‑metabolism‑suppression' axis. In the present review, four core metabolic pillars sustaining MDSC pathogenicity and the epimetabolic regulation that durably locks them into a suppressive state were examined. Furthermore, two emerging dimensions were highlighted: The spatial metabolic antagonism through which MDSCs may construct a metabolically hostile zone to limit the functional activity of tertiary lymphoid structures, and the remote manipulation of MDSC function by gut and intratumoral microbiota‑derived metabolites. To transcend the limitations of non‑specific myeloid depletion, immunometabolic rehabilitation is proposed as a potentially transformative framework targeting intrinsic metabolic vulnerabilities to functionally reprogram MDSCs from an immunosuppressive to a homeostatic or immunostimulatory phenotype. By integrating emerging spatial omics for precise target validation, artificial intelligence‑guided rational drug design and microbiome modulation, this paradigm provides a strategic roadmap for next‑generation precision immunotherapy, aiming to achieve durable responses across both microsatellite stable and microsatellite instability‑high CRC.
    Keywords:  colorectal cancer; histone lactylation; immunometabolism; immunotherapy resistance; metabolic reprogramming; myeloid‑derived suppressor cells; spatial omics; tertiary lymphoid structures; tumor microenvironment
    DOI:  https://doi.org/10.3892/mmr.2026.14061
  31. Clin Transl Med. 2026 Nov;pii: e70881. [Epub ahead of print]16(11):
    Regulatory role of TIPE2 by inhibiting microglial pyroptosis and glycolysis in the treatment of sepsis-associated encephalopathy.
    Min Yuan, Yunzhao Yang, Huifan Liu, Qian Kong, Guoqing Jing, Hailong Gong, Yuxuan Wang, Zhengyu Zhang, Wanhong Liu, Xuemin Song, Zhongyuan Xia, Xiaojing Wu.
       BACKGROUND: Sepsis_associated encephalopathy (SAE) denotes acute cerebral dysfunction triggered by sepsis and is accompanied by high mortality. Our previous study showed that TIPE2 significantly ameliorated cognitive impairment in SAE mice by inhibiting neuroinflammation, but the specific mechanism was unknown.
    METHODS: TIPE2 expression and cell specificity were analysed by scRNA‑seq and immunofluorescence. To establish SAE, cecal ligation and puncture (CLP) was carried out in TIPE2 knockout (KO) and WT mice. Neuronal/synaptic damage was assessed by TUNEL and TEM; cognitive function by behavioural tests and EEG. Hippocampal scRNA‑seq compared WT and TIPE2 KO mice. In vitro, primary microglia and BV2 cells were stimulated with LPS/nigericin. Protein expression (Western blot/IF), RhoA activation (GST‑pulldown), glucose/lactate levels, ROS production, and TIPE2‑RhoA interaction (Co‑IP/confocal) were examined.
    RESULTS: scRNA‑seq confirmed that TIPE2 is predominantly expressed in microglia and downregulated in SAE; its deficiency promotes pro‑inflammatory microglia associated with pyroptosis and glycolysis. TIPE2 KO significantly aggravated cognitive impairment, promoted M1 polarisation, enhanced pyroptosis (GSDMD cleavage, caspase‑1 activation), and increased ROS production. Mechanistically, TIPE2 directly bound to RhoA and inhibited its activation, thereby suppressing NLRP3‑mediated pyroptosis and glycolysis in microglia. Treatment with the RhoA‑specific inhibitor Rhosin reversed TIPE2 deficiency‑induced microglial polarisation, pyroptosis, ROS production, and glycolytic reprogramming, and also ameliorated cognitive dysfunction in TIPE2 KO mice.
    CONCLUSIONS: TIPE2 protects against SAE by directly interacting with RhoA, inhibiting its activation, and subsequently suppressing NLRP3‑mediated microglial pyroptosis and glycolysis.
    Keywords:  TIPE2; glycolysis; microglia; pyroptosis; sepsis‑associated encephalopathy
    DOI:  https://doi.org/10.1002/ctm2.70881
  32. iScience. 2026 Nov 20. 29(11): 118042
    β7-Integrin worsens diet-induced metabolic syndrome in mice by altering intestinal lipid handling and colonic inflammatory monocyte infiltration.
    Sreepradha Eswaran, Agnes Seeger, Sabine Hamm, Kerstin Scheuer, Nicole Treichel, Juliane Hermann, Trong-Hieu Nguyen, Thomas Clavel, Joachim Jankowski, Norbert Wagner, Angela Schippers.
      Western diet (WD)-induced metabolic syndrome (MetS) involves obesity, insulin resistance, dyslipidemia, and low-grade inflammation. While β7 integrin-expressing adaptive immune cells contribute to WD-induced MetS, the role of β7 integrin in innate immunity remains unclear. To address this, the effect of antibody-mediated β7 integrin blockade or β7 integrin deficiency on WD-induced MetS was studied in recombination activating gene-2-deficient mice. Loss or inhibition of β7 integrin protected mice from WD-induced obesity, dyslipidemia, and glucose intolerance, partially via loss of β7 integrin-MAdCAM-1 interactions. β7 integrin deficiency altered intestinal lipid handling and monocyte infiltration into the colon and adipose tissue. Adoptive transfer confirmed that β7-expressing monocytes promote metabolic dysfunction in WD-fed recipients. Phospho-signaling analyses revealed attenuated PI3K-Akt pathway activation in β7 integrin-deficient colonic macrophages, and antibody treatments caused minor shifts in fecal microbiota profiles. Thus, β7 integrin-expressing innate immune cells drive WD-induced metabolic inflammation through monocyte recruitment, macrophage activation, and altered intestinal fat metabolism.
    Keywords:  innate immune cells; intestinal lipid metabolism; metabolic syndrome; monocytes/macrophages; β7 integrin
    DOI:  https://doi.org/10.1016/j.isci.2026.118042
  33. Dev Cell. 2026 Nov 03. pii: S1534-5807(26)00392-8. [Epub ahead of print]
    The AMPK-ALDH7A1 axis drives metabolic reprogramming and anti-tumor immunity in hepatocellular carcinoma via KDM5C inhibition.
    Yue Tong, Jiayu Wang, Rui Ma, Min Wang, Tong Zhang, Hanhua Dong, Feng Ge, Cunqi Ye, Tailang Yin, Xilan Yu, Shanshan Li.
      Mitochondrial dysfunction is a feature of hepatocellular carcinoma (HCC), yet how respiratory suppression arises remains unclear. Here, we identify an evolutionarily conserved metabolic-epigenetic axis integrating metabolic regulation with tumor suppression and anti-tumor immunity. Through comparative studies in yeast, HCC cell lines, and orthotopic/autochthonous HCC mouse models, we demonstrate that AMP-activated protein kinase (AMPK)/Snf1-mediated phosphorylation of aldehyde dehydrogenase ALDH7A1/Ald6 promotes its nuclear translocation and local acetate production, leading to inhibition of histone lysine demethylase KDM5C/Jhd2. This results in H3K4 trimethylation (H3K4me3) accumulation at respiratory genes, activating their transcription and maintaining mitochondrial function. During HCC pathogenesis, loss of AMPK signaling disrupts this pathway, impairing ALDH7A1 nuclear translocation and enabling KDM5C-mediated respiratory suppression. Notably, AMPK-ALDH7A1-acetate-mediated KDM5C inhibition also potentiates cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, driving CD8+ T cell infiltration and synergizing with immune checkpoint blockade. Our work defines the evolutionarily conserved AMPK-ALDH7A1-KDM5C axis and establishes acetate as a dual regulator of mitochondrial metabolism and anti-tumor immunity, offering therapeutic strategies for targeting metabolic vulnerabilities in HCC.
    Keywords:  acetate; cGAS-STING; epigenetic modifications; histone methylation; metabolic reprogramming; tumorigenesis; yeast
    DOI:  https://doi.org/10.1016/j.devcel.2026.10.006
  34. Front Immunol. 2026 ;17 1999531
    Immunometabolic reprogramming: a working framework for disease development, endotype differentiation, and therapeutic considerations in pediatric asthma.
    Kaiwen Zheng, Ran Ma, Yingqian Zhang.
       Background: Paediatric asthma exhibits marked clinical heterogeneity and cannot be simply considered the childhood counterpart of adult asthma. Early-life environmental exposures can reshape immune-cell metabolic programs and potentially drive long-lasting inflammatory phenotypes. Existing explanatory frameworks for paediatric asthma largely centre on Th2-related inflammation, epithelial-alarm signalling and neuro-immune crosstalk, while the contributions of immunometabolic processes to disease endotypes remain under-summarised.
    Objective: This review collates available evidence regarding metabolic reprogramming in the pathogenesis of paediatric asthma and provides an integrated immunometabolic perspective on this condition.
    Results: Summarized evidence covers immunometabolic changes across key airway-resident and infiltrating cell populations. Discussion addresses core paediatric-specific biological features, including early-life developmental windows, virus-related trained immunity, obese asthma, circadian-sleep interactions, neuro-metabolic-immune communication and metabolomics-based endotyping. The framework is organized around substrate competition rather than a glycolysis-versus-OXPHOS binary, because Tregs, M2-like macrophages and pathogenic ILC2s share lipid and amino-acid pools but exert opposing functions. From these observations emerges a testable "Metabolic Latching Model" of how early-life insults establish persistent inflammatory memory through metabolism-epigenetic coupling, with "latching" operationally defined by exposure removal and persistence beyond responding-cell turnover. Group 2 innate lymphoid cells (ILC2s) and the Treg-to-effector balance are placed at the centre of this framework. Three hypotheses are prioritised as feasible with current technology: H1 (monocyte glycolytic baseline predicting wheeze-to-asthma transition), H4 (metabolic intervention in obese asthma), and H6 (the HDAC2-GSH/butyrate axis in steroid sensitivity).
    Conclusion: Current evidence suggests that immunometabolic reprogramming serves as one plausible contributing factor for the heterogeneity of paediatric asthma. This conceptual framework may bridge molecular metabolic findings and paediatric clinical contexts, and inform future mechanistic and clinical studies in this research area.
    Keywords:  endotype; ferroptosis; glucocorticoid resistance; immunometabolism; metabolic reprogramming; obese asthma; pediatric asthma; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1999531
  35. Cell Death Discov. 2026 Aug 11. pii: 446. [Epub ahead of print]12(1):
    DGAT1 regulates macrophage pyroptosis during Klebsiella pneumoniae infection.
    Hui-Jung Jung, Seong Hun Jeong, Sang-Hee Lee, Hyowon Hong, Yong-Uk Lee, Miri Hyun, Ji Yeon Lee, Won-Ki Baek, Jin Kyung Kim, Hyun Ah Kim.
      Klebsiella pneumoniae (Kp) is a Gram-negative opportunistic pathogen that causes severe infections, including pneumonia and sepsis, yet the molecular mechanisms governing macrophage cell death during Kp infection are incompletely understood. Here, we identify diacylglycerol acyltransferase-1 (DGAT1) as a critical regulator of macrophage pyroptosis during infection with a classical Kp (cKp) isolate. cKp infection induced lipid droplet (LD) accumulation in murine macrophages, whereas pharmacological inhibition or genetic suppression of DGAT1 attenuated LD formation and pyroptotic cell death. Mechanistically, DGAT1-dependent LD accumulation was associated with lysosomal dysfunction and mitochondrial reactive oxygen species (ROS) production, which together facilitated NLRP3 inflammasome activation and pyroptosis. Furthermore, LD accumulation, ROS production, and mTOR signaling were mutually interconnected, as inhibition of any one component attenuated the others, collectively sustaining pyroptotic signaling during cKp infection. Small RNA sequencing further identified miR-155-5p as a ROS-dependent microRNA up-regulated during cKp infection, which promoted LD accumulation in a DGAT1-dependent manner and contributed to pyroptotic cell death. Collectively, these findings identify DGAT1 as a key immunometabolic regulator of macrophage pyroptosis and suggest that targeting DGAT1 may represent a potential therapeutic strategy to mitigate Kp infection-induced macrophage pyroptosis.
    DOI:  https://doi.org/10.1038/s41420-026-03272-y
  36. Mucosal Immunol. 2026 Nov 04. pii: S1933-0219(26)00125-X. [Epub ahead of print] 100423
    Diet-independent pregravid obesity drives premature but functionally dysregulated fetal immune maturation across multiple immune compartments in rhesus macaques.
    Brianna M Doratt, Sheridan Wagner, Uriel Avila, Travis Hodge, Lauren D Martin, Oleg Varlamov, Ilhem Messaoudi.
      Pregravid obesity is associated with long-term immune alterations in offspring, but the mechanisms linking maternal metabolic state to fetal immune development remain poorly defined. To address this gap, we used a rhesus macaque model of spontaneous, diet-independent pregravid obesity to examine impact of pregravid obesity on fetal immune maturation and function. We profiled immune cell frequency, function, transcriptional programs, and inferred intercellular communication in umbilical cord blood, fetal spleen, and fetal lung using spectral flow cytometry, multiplex cytokine profiling, functional stimulation assays, and single-cell RNA sequencing. Pregravid obesity was associated with altered fetal organ growth, elevated inflammatory mediators, altered immune cell frequencies, and hyperresponsive splenic leukocyte responses to in vitro stimulation. Single-cell transcriptomic analyses revealed a conserved program of innate immune reprogramming across all three compartments, characterized by heightened inflammatory, migratory, and metabolic signatures together with reduced antigen-presentation potential. We also observed impaired T cell maturation with premature effector differentiation and evidence of B cell dysfunction. Computationally inferred cell-cell communication predicted loss of tolerogenic signaling and enhanced proinflammatory pathways across splenic and lung myeloid cells. Together, these findings indicate that diet-independent pregravid obesity drives premature but functionally dysregulated maturation of fetal circulating and tissue-resident immune cells, providing a candidate mechanism for the increased susceptibility to infection, respiratory disease, and immune dysregulation reported in offspring of mothers with obesity. This connection should be tested directly in postnatal studies.
    Keywords:  Fetal immune development; Maternal programming; Nonhuman primate; Spontaneous obesity
    DOI:  https://doi.org/10.1016/j.mucimm.2026.100423
  37. Cell Host Microbe. 2026 Nov 05. pii: S1931-3128(26)00439-7. [Epub ahead of print]
    Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation.
    Juyeong Cho, Rebecca Danner, Woo Sung Kim, Luiz Lopez, Jonathan Williams, Anshit Singh, Jiyoung A Han, Jonathan G Van Vranken, Allison S Walker, Timothy W Rhoads, Snehal N Chaudhari.
      Methotrexate (MTX) is a gold standard therapy for inflammatory diseases but has mixed therapeutic success in inflammatory bowel disease (IBD). The gut microbiota impact MTX efficacy and toxicity by metabolizing MTX and altering its bioavailability, yet how inflammation alters this metabolism, and how the resulting metabolites act on the host, remain poorly understood. Here, we find that gut microbes, notably Clostridium asparagiforme, metabolize MTX via carboxypeptidase G2 (CPDG2) to produce deoxyaminopteroic acid (DAMPA). In intestinal epithelial cells, DAMPA preserves mitochondrial health through mitochondrial signal transducer and activator of transcription 3 (STAT3) signaling and enhances mitophagy. DAMPA administration attenuates intestinal inflammation in vivo, and remodels colonic mitochondrial pathways. IBD mouse models show reduced microbial CPDG2 and DAMPA, while patients with IBD show reduced CPDG2 gene abundance and suppressed DAMPA-enriched mitochondrial pathways, potentially explaining MTX outcomes in IBD. Together, these findings reframe microbial MTX metabolism from passive drug detoxification to active regulation of host mitochondrial and inflammatory homeostasis.
    Keywords:  DAMPA; inflammatory bowel disease; methotrexate; microbiome; mitophagy
    DOI:  https://doi.org/10.1016/j.chom.2026.10.005
  38. Front Immunol. 2026 ;17 1965813
    Therapy-induced methionine competition in bladder cancer: MAT2A-SAM axis remodeling as a metabolic immune checkpoint.
    Chengyuan Zhang, Zhe Zhang, Jianbin Bi.
      Bladder cancer is increasingly treated with platinum chemotherapy, immune checkpoint blockade, and antibody-drug conjugates, but treatment resistance remains common. Methionine connects nutrient availability with S-adenosylmethionine (SAM) production, methylation, redox homeostasis, and lymphocyte function. In cisplatin-resistant tumor cells, MAT2A stabilization sustains a SAM-dependent program of stem-like renewal and drug resistance. Concurrently, increased SLC7A6-associated methionine uptake can create a tumor methionine sink that lowers methionine and SAM in CD8+ T cells, weakens H3K79me2-STAT5 signaling, and impairs effector function. Separately, methionine-sensitive YTHDF1 signaling suppresses RIG-I-dependent innate sensing and increases PD-L1 translation. A layered metabolic immune checkpoint is proposed to explain how these convergent but non-equivalent mechanisms link treatment-selected tumor fitness, nutrient competition, and reduced immune visibility. The framework exposes a context-dependent therapeutic paradox: methionine restriction may weaken tumor adaptation but compromise T-cell fitness, whereas SAM restoration may support antitumor immunity while also fueling malignant cells. Therefore, treatment-state biomarkers should guide compartment-selective targeting and intervention timing.
    Keywords:  CD8+ T cells; MAT2A; SLC7A6; YTHDF1; bladder cancer; cisplatin resistance; immunotherapy; methionine metabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1965813
  39. Pharmacol Res. 2026 Nov 05. pii: S1043-6618(26)01651-8. [Epub ahead of print] 109736
    Hypoxia Orchestrates the Natural History of Inflammatory Bowel Disease: Mechanisms and Therapeutic Opportunities.
    M Victoria Sánchez Luque, Abel Santiago Amador Moreno, María Elena Angarita-Planchez, Ana M Múnera-Rodríguez, Soledad López-Enríquez, David Casado-Jurado, Manuel de Miguel, Francisca Palomares.
      Inflammatory bowel disease (IBD) arises from a dynamic interplay between epithelial dysfunction, immune activation, microbial dysbiosis and tissue remodelling. Although hypoxia was initially regarded as a consequence of intestinal inflammation, it is now recognized as an active regulator of epithelial, immune and stromal responses that coordinate disease progression. Here, we propose that hypoxia acts as a biological organizer linking oxygen sensing to the transition from intestinal homeostasis to chronic inflammation and structural tissue damage. We use this term in a mechanistic rather than a hierarchical sense: oxygen availability is a shared upstream constraint on epithelial, immune, microbial and stromal programmes, not a single initiating event. This review integrates evidence connecting oxygen sensing with epithelial barrier integrity, immunometabolism, microbial ecology and stromal remodelling, with emphasis on advances in single-cell transcriptomics, spatial biology and microbiome research. Physiological low-oxygen gradients support epithelial metabolism, barrier integrity and immune tolerance, whereas persistent inflammatory hypoxia drives oxidative stress, metabolic reprogramming and maladaptive epithelial-immune-microbial interactions. Hypoxia also contributes to spatially distinct epithelial, immune and stromal niches that may sustain chronic inflammation and fibrotic progression. Microbial metabolites, including short-chain fatty acids and succinate, together with iron metabolism and ferroptosis, further link oxygen sensing to tissue injury, adaptation and repair. These findings position hypoxia-responsive signalling as a pharmacologically actionable network rather than a downstream consequence of inflammation. Targeting selected components may promote mucosal healing and limit structural disease progression, although successful translation will require cell- and isoform-selective modulation, adequate tissue exposure and careful assessment of long-term safety.
    Keywords:  Hypoxia; Immunometabolism; Inflammatory bowel disease; Intestinal fibrosis; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.phrs.2026.109736
  40. J Biomed Res. 2026 Oct 25. 1-18
    IL-33 modulates maternal-fetal macrophage immunometabolism and is associated with attenuation of MIA-associated behavioral abnormalities in adult offspring.
    Xinyi Zhu, Chunxiang Shen, Kaiyue He, Hao Chang, Jingfan Qiu, Lu Chen, Lin Chen, Min Hou, Minjun Ji, Zhipeng Xu.
      Maternal immune activation (MIA) is a pivotal risk factor for neurodevelopmental disorders, including autism spectrum disorder. However, the mechanisms of MIA at the maternal-fetal interface remain elusive. Here, we used soluble tachyzoite antigen (STAg) from Toxoplasma gondii to induce MIA in pregnant mice at E14.5, followed by maternal administration of interleukin-33 (IL-33) from E15.5 to E17.5. Proteomic profiling coupled with protein-protein interaction network analysis nominated IL-33 as a candidate immunoregulatory factor. In exploratory analyses, maternal IL-33 administration was associated with shifts in macrophage-associated immune profiles, reduced placental inflammation, and attenuated MIA-associated behavioral abnormalities in adult offspring. Given that suppression of tumorigenicity 2 (ST2) is the cognate receptor for IL-33, we next interrogated this pathway in ST2-deficient mice. ST2 deficiency abolished the effects of IL-33 on macrophage repolarization and inflammatory homeostasis, and the behavioral improvements were not evident in ST2-deficient offspring. Mechanistically, IL-33 administration was associated with reduced glycolytic features and improved mitochondrial function in macrophages, consistent with partial restoration of immunometabolic homeostasis at the maternal-fetal interface. Collectively, our findings highlight an immunometabolic axis in STAg-induced MIA pathogenesis, revealing IL-33/ST2 signaling as a potential experimental target for mitigating MIA-associated immune and behavioral abnormalities.
    Keywords:  IL-33; Toxoplasma gondii; macrophage; maternal immune activation; metabolism
    DOI:  https://doi.org/10.7555/JBR.40.20260347
  41. Front Immunol. 2026 ;17 1873518
    Multi-omics profiling identifies a putative Akkermansia-HK3-lactate immunometabolic link associated with JPZS treatment in lupus nephritis.
    Ming Li, Lijun Pang, Yunfei Li, Shuangshuang Shang, Chuanbing Huang.
       Background: Lupus nephritis (LN) is associated with aberrant glycolytic reprogramming in renal immune cells, yet its relationship with gut microbial alterations remains poorly defined. Hexokinase 3 (HK3) has emerged as a candidate metabolic node in myeloid activation, while the relationship between gut Akkermansia abundance and renal HK3-associated metabolic changes in LN remains unclear. We used Qihuang Jianpi Zishen decoction (JPZS), an herbal formula used as an adjunct in clinical practice, as an experimental probe to investigate this putative gut-immunometabolic connection through integrated multi-omics.
    Methods: Female MRL/lpr mice (n = 6 per group) received JPZS (6.305, 12.61, or 25.22 g/kg/day) or vehicle for 8 weeks, with C57BL/6 mice serving as a healthy reference group. Renal function, autoantibodies, histopathology, and glomerular IgG deposition were assessed across treatment groups. Integrated multi-omics profiling-fecal 16S rRNA sequencing, untargeted plasma metabolomics, and renal RNA sequencing-was performed in the matched control, model, and high-dose JPZS groups. Renal lactate and pyruvate were quantified, and HK3 and Ldhal6b mRNA and their corresponding proteins were evaluated by qPCR and western blotting. HK3/F4/80 dual immunofluorescence was additionally performed to examine the spatial localization of HK3 relative to renal macrophages.
    Results: JPZS reduced proteinuria, serum creatinine, glomerular IgG deposition, and renal histopathological injury in MRL/lpr mice. Gut microbiome profiling showed marked enrichment of Akkermansia and altered community composition, without significant recovery of Chao1 or Shannon diversity, accompanied by reductions in Klebsiella and Enterococcus. Plasma metabolomics revealed remodeling of amino-acid and central carbon metabolism, while renal transcriptomics identified immune-related differences and an exploratory glycolysis/gluconeogenesis enrichment signal. JPZS reduced renal lactate accumulation and the lactate/pyruvate ratio and decreased renal HK3 expression at both the mRNA and protein levels. Dual immunofluorescence showed increased HK3 and F4/80 fluorescence in model kidneys, with overlapping signals evident in merged images; both signals were lower following JPZS-H treatment. Cross-layer correlation analyses linked gut genera, circulating metabolites, and renal gene expression; targeted assays separately characterized renal lactate/pyruvate status.
    Conclusion: JPZS ameliorated renal injury while inducing coordinated changes in the gut microbiome, circulating metabolome, and renal immunometabolic profile in MRL/lpr mice. Integrated multi-omics and targeted validation identified a putative Akkermansia-HK3-lactate immunometabolic link associated with JPZS treatment. These findings provide a hypothesis-generating framework for gut-kidney immunometabolic crosstalk in LN and warrant future causal validation through microbiota- and HK3-targeted approaches.
    Keywords:  akkermansia; gut microbiota; gut–kidney axis; herbal medicine; hexokinase 3; immunometabolism; lupus nephritis; multi-omics
    DOI:  https://doi.org/10.3389/fimmu.2026.1873518
  42. HIV Med. 2026 Nov 02.
    In vitro NAD+ supplementation increases CD4+ and CD8+ T cell function in people with HIV.
    Guangming Li, Salma Sharaf, Yaoxian Lou, Lishan Su, Shyam Kottilil, Poonam Mathur.
       OBJECTIVES: HIV perturbs T cell homeostasis and disrupts immune function, increasing the risk of age-associated comorbidities. Ageing people with HIV (PWH) have exacerbated expression of CD38 on T cells, which depletes intracellular nicotinamide adenine dinucleotide (NAD+). We investigated whether boosting intracellular NAD+ could restore T cell homeostasis and function.
    METHODS: We collected blood samples from virally suppressed PWH to determine the effects of in vitro NAD+ on CD38 expression and T cell function in response to anti-CD3/CD28 antibodies stimulation in PBMCs culture supplemented with IL-2 and IL-7.
    RESULTS: We observed that NAD+ supplementation not only reduced expression of CD38 but also improved T cell function with an alleviated exhaustion phenotype in response to anti-CD3/CD28 antibodies stimulation.
    CONCLUSIONS: If confirmed in clinical trials, NAD+ supplementation has the potential to restore T cell homeostasis and immune function in PWH and ameliorate age-associated comorbidities.
    Keywords:  CD38; HIV; NAD +; T cell homeostasis and function
    DOI:  https://doi.org/10.1111/hiv.70342
  43. PET Clin. 2026 Nov 06. pii: S1556-8598(26)00131-8. [Epub ahead of print]
    Valuable Role of 18F-Fluorodeoxyglucose-PET/computed Tomography in Therapeutic Decision-Making of Infectious and Inflammatory Disorders.
    Srinivas Ananth Kumar, Harish Goyal, Dhanapathi Halanaik.
      18F-FDG (18F-Fluorodeoxyglucose)-PET/computed tomography (CT) has emerged as a pivotal molecular imaging modality that extends beyond diagnosis to influence therapeutic decision-making in infectious and inflammatory diseases. By detecting increased glucose metabolism in activated inflammatory cells, it enables whole-body visualization of active disease before structural abnormalities become apparent on conventional imaging. Quantitative parameters support reproducible longitudinal monitoring. Its incorporation into international guidelines highlights its growing role in precision-guided management. Emerging technologies, including digital and long axial field-of-view PET/CT, artificial intelligence, radiomics, PET/MR imaging, and pathogen-specific or immune cell-specific tracers, may further enhance diagnostic accuracy and personalized treatment.
    Keywords:  (18)F-FDG PET/CT; Image-guided diagnosis; Immunometabolism; Infection; Inflammation; Metabolic biopsy; Precision medicine; Treatment response
    DOI:  https://doi.org/10.1016/j.cpet.2026.09.022
  44. Cell Death Dis. 2026 Aug 04. pii: 928. [Epub ahead of print]17(1):
    Mitochondrial RNA as a broad-spectrum DAMP coordinates antiviral and damage-related immune clearance and confers therapeutic potential.
    Mingfu Tian, Guangli Li, Zelin Chai, Siyu Liu, Zhiqiang Li, Dehua Zhang, Chengliang Zhu, Kailang Wu, Xinghui Liu.
      During viral infection and tissue injury, efficient immune clearance of infected or damaged cells is crucial for host defense and homeostasis. Here, we identify mitochondrial RNA (mtRNA) as a broad-spectrum damage-associated molecular pattern (DAMP) that coordinates antiviral and damage-related immune clearance. Through an integrative approach combining in vitro cellular assays and multi-strain murine models, we demonstrate that viral infection and cellular stress promote POLRMT-dependent mtRNA synthesis and its release into the cytosol through BAX/mPTP-mediated mitochondrial pores. Once released, mtRNA activates the MAVS signaling pathway, triggering a robust type I interferon response that operates independently of the cGAS-STING axis. Notably, viruses exploit a negative feedback loop for immune evasion: type I interferon upregulates the exoribonuclease PNPT1, which degrades cytosolic mtRNA and thereby dampens the mtRNA-MAVS axis. Critically, pharmacological inhibition of PNPT1 with lanthanum chloride (LanC), combined with BH3 mimetics that relieve the BCL-2-mediated blockade of BAX/BAK pores, synergistically reactivates mtRNA release and restores antiviral immunity. This dual strategy demonstrates potent antiviral and anti-fibrotic efficacy in preclinical models without significant toxicity. Our findings establish the mtRNA-MAVS axis as a central, broadly applicable immune surveillance pathway and provide a mechanistic framework for developing therapies that overcome both viral immune evasion and the limitations of current STING-targeted agonists.
    DOI:  https://doi.org/10.1038/s41419-026-09153-7
  45. Sci Adv. 2026 Nov 06. 12(45): eaeb8568
    Mevalonate pathway regulates double-negative regulatory T cell stability in metabolic dysfunction-associated steatotic liver disease.
    Hua Jin, Xiyu Wang, Longyang Zhou, Xinjie Zhong, Yunxiong Wei, Xiaotong Han, Nan Xu, Peiyang Fang, Zihan Zhang, Xiaonan Du, Mengyi Li, Songlin Wang, Zhongtao Zhang, Guangyong Sun, Dong Zhang.
      Lipid metabolism dysfunction and immune imbalance are critical pathogenic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD). Double-negative regulatory T cells (DNTreg) are important immune regulatory cells that maintain liver immune homeostasis. However, their survival and function are compromised in MASLD. Herein, we found that mevalonate pathway and its rate-limiting enzyme HMG-CoA reductase (HMGCR) were significantly down-regulated in DNTreg from both mice and patients with MASLD, correlating with impaired DNTreg viability and immunosuppressive function. Arachidonic acid is enriched in MASLD liver and inhibits DNTreg HMGCR expression. Geranylgeranyl pyrophosphate (GGPP), a downstream product of HMGCR, mediates RAC1 geranylgeranylation, which facilitates its interaction with mitochondrial CLPX protease, thereby enhancing mitochondrial function and immunoregulatory activity of DNTreg. Adoptive transfer of Pggt1b+/- DNTreg into MASLD mice demonstrated significantly diminished therapeutic efficacy compared with wild-type DNTreg. In conclusion, mevalonate metabolism-mediated geranylgeranylation is essential for the suppressive activity and immune homeostasis of DNTreg in MASLD.
    DOI:  https://doi.org/10.1126/sciadv.aeb8568
  46. PLoS Pathog. 2026 Nov;22(11): e1014715
    Modulation of riboflavin biosynthesis enzymes in non-typhoidal Salmonella isolates differentially impacts human MAIT cell activation.
    Leia Vainman, Corinna A Kulicke, Nurudeen Oketade, Noa Bossel Ben-Moshe, Camilla Ciolli-Mattioli, Aryeh Solomon, Jay C D Hinton, Karen M Dobos, David M Lewinsohn, Shelly Hen-Avivi, Roi Avraham.
      Invasive non-typhoidal Salmonella (iNTS) sequence type 313 (ST313) isolates have emerged in sub-Saharan Africa, with a high incidence of multidrug resistance, enhanced intracellular persistence, increased dissemination and immune evasion. ST313 isolate D23580 was shown to avoid activation of mucosal-associated invariant T (MAIT) cells compared with a genetically similar, non-invasive Salmonella Typhimurium (S.Tm) 4/74 strain, but the mechanism remains unclear. Here, we studied immune responses to infection with typhoidal strains and ST313 isolates using comparative transcriptomic profiling of human peripheral blood mononuclear cells (PBMCs). MAIT cells responded to typhoidal strains but not to D23580. To uncover underlying mechanisms, we engineered an inducible CRISPRi system targeting riboflavin biosynthesis enzymes (rib), which process MAIT ligands, in D23580 and 4/74 strains. Several rib hypomorphs exhibited prolonged lag time in minimal media, which was more pronounced in D23580 than in 4/74. In PBMC infection, knockdown of lumazine synthase (RibH) and riboflavin synthase (RibE) resulted in contrasting MAIT cell activation phenotypes. RibH knockdown restored MAIT cell activation in D23580 but did not affect activation in 4/74. Conversely, RibE knockdown diminished MAIT cell activation by 4/74 but had no impact on MAIT cell activation by D23580. Metabolomic analysis revealed accumulation of the biosynthetic intermediate DMRL in RibE knockdown and a differential impact on riboflavin biosynthesis end products between D23580 and 4/74 RibH knockdown, suggesting altered pathway flux between the strains. Our results indicate RibH and RibE as pivotal nodes for strain-specific MAIT-activation during Salmonella infection of human PBMCs, illustrating teir central role in the complex interplay between bacterial metabolism and host immunity.
    DOI:  https://doi.org/10.1371/journal.ppat.1014715
  47. bioRxiv. 2026 Oct 27. pii: 2026.10.24.761570. [Epub ahead of print]
    Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy.
    Katarina Benejova, Kristina Travis, Deepti Mathur, No Joon Song, Zihai Li, Mitch A Phelps, Elaine Mardis, Liza Makowski, David P Carbone, Dwight H Owen, Martin Benej.
      Given its status as the leading cause of global cancer mortality, there is a critical need to enhance immunotherapy strategies for lung cancer to overcome widespread resistance to current treatments. Immunotherapy recruits the patient's immune system to attack and destroy cancer cells. While highly effective in a subset of patients, chronic exposure of immune cells to cancer cells leads to a progressive loss of effector T cell function and progression of T cell exhaustion; now considered two well-established hallmarks of immunotherapy resistance. The tumor-immune microenvironment (TIME)-driven differentiation into the exhausted T cell phenotype is marked by a loss of metabolic plasticity and epigenome-wide changes in distribution of repressive histone marks such as histone H3 subunit methylation at lysine 27 (H3K27me 3 ). Here, we studied how these processes are connected to metabolite availability within the TIME. In vitro , chronic antigen stimulation and hypoxia led to rapid loss of effector function, associated with a suppression of alpha-ketoglutarate (aKG) intracellular concentrations in T cells. Supplementation of cell-permeable aKG led to a rescue of effector cytokine production and to improved cytotoxic capacity despite chronic antigen stimulation and hypoxia. Increased intracellular aKG levels restored the activity of H3K27 demethylases UTX and JMJD3, consistent with epigenome-wide decreased H3K27me 3 . In vivo , dietary supplementation with commercially available calcium-aKG (Ca-aKG) supplements led to an elevation of serum and intratumoral aKG levels associated with a significant increase of immunotherapy effectiveness in mouse models of NSCLC. Clinical samples from patients with NSCLC contained significantly decreased serum aKG levels in older NSCLC patients (>65 years of age). Analysis identified a novel association between serum aKG levels and poor immunotherapy response. Thus, our work demonstrates that intratumoral metabolite "starvation" can be therapeutically exploited to improve immunotherapy outcomes in non-small cell lung cancer (NSCLC).
    DOI:  https://doi.org/10.64898/2026.10.24.761570
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