bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–10–18
47 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Metabolic gatekeepers shape immune cell function in rheumatoid arthritis.
  2. Itaconate: a dual-edged sword in immunometabolism and host-pathogen interactions.
  3. Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation.
  4. Itaconate as an immunometabolic hub in host-pathogen interactions: Mechanisms, resistance, and therapeutic opportunities.
  5. Host-secreted lactate during respiratory viral infection diminishes macrophage antibacterial activity through metabolic reprogramming.
  6. ApoE lipidation state directs immunometabolic reprogramming of human microglia.
  7. Macrophage immunometabolism in osteoporosis: an emerging regulatory axis linking metabolic-polarization coupling to therapeutic targets.
  8. Glycolysis-Dependent Fatty Acid Metabolism Supports Human Tfh Cell Function.
  9. Research Progress of T Cell Metabolism in Graft-Versus-Host Disease.
  10. Targeting Cannabinoid 1 Receptor in Macrophages Alleviates Psoriatic Skin Inflammation Through the AUF1-NLRP3 Axis.
  11. The role of metabolic crosstalk between Intestinal epithelial cells and immune cells in inflammatory bowel disease and targeting strategies.
  12. Liraglutide ameliorates obese type 2 diabetes by regulating macrophage cholesterol metabolism and H3K27ac modification to promote M2 polarization and adipocyte thermogenic activation.
  13. Nucleotide Metabolic Reprogramming in Sepsis: From Immune-Cell Fate to Organ Injury and Precision Therapeutics.
  14. Deoxythymidylate Kinase (DTYMK)-Driven Pyrimidine Hypermetabolism Is Associated with a Folate-Dependent Macrophage Programme in Triple-Negative Breast Cancer.
  15. The immune hub of metabolism: how adipose tissue macrophage infiltration redefined obesity.
  16. Inducible cAMP Early Repressor Limits Glycolytic Programming in Regulatory T Cells and Supports Control of Inflammatory Colitis.
  17. Dopamine-induced mitochondrial dysfunction activates cGAS-sTING to drive IL-6 secretion in macrophages.
  18. Editorial: Targeting dysregulation in metabolic diseases: potential therapeutic intervention.
  19. SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast- like State to Drive Metabolic Disease.
  20. Macrophage Polarization and Metabolic Reprogramming in Endometriosis: Mechanisms and Therapeutic Implications.
  21. Activation of KCa3.1 K+ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M2-like Macrophages.
  22. The Lag3 KIEELE motif couples HPK1 to metabolic and functional regulation of Foxp3+ regulatory T cells.
  23. Lysine lactylation in neutrophil functional remodeling across diverse disease contexts.
  24. CTR1-mediated copper uptake orchestrates metabolic-epigenetic regulation of pathogenic T H 17 cells in autoimmune disease.
  25. Glucose-6-Phosphate Dehydrogenase Deficiency Reprograms Macrophage Metabolism in Hyperlipidemia.
  26. Macrophage states and immunometabolic adaptation in peritoneal metastases from colorectal cancer.
  27. ARID2 Loss Reprograms the Kynurenine-AhR Pathway to Restore Antitumor Immunity in CTNNB1-Mutant Hepatocellular Carcinoma.
  28. Lactate dehydrogenase A-dependent redox control of selective mRNA translation directs monocyte fate commitment.
  29. Glutamate attenuates the ILC2 response and allergic airway inflammation via the kainate receptor GluK2.
  30. Metabolic basis of post-infectious sequelae after Ebola virus disease.
  31. A helminth-microbiota metabolic relay promotes disease tolerance.
  32. Mitochondria strike two hits to drive the SASP.
  33. Convergent Microglial and Astrocytic Responses across Diverse Stress Paradigms: Integrating Inflammation, Metabolism, and Behavior.
  34. Acetate modulates host physiology and bacterial energetics to improve antibiotic efficacy during obesity-associated infection.
  35. WSSV355 enhances IDH1 enzymatic activity and promotes efficient WSSV replication.
  36. Viral deISGylation holds the key to the metabolic kingdom.
  37. Loss of Acid Ceramidase in Myeloid Cells Protects From Chronic Colitis in IL10-Deficient Mice.
  38. Sdhd hypermethylation promotes succinate accumulation and NLRP3-related pyroptosis in septic lung injury.
  39. The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.
  40. Lactate metabolism and lactylation in uveal melanoma: from metabolic adaptation to immune regulation.
  41. Hyocholic acid: a primary bile acid regulating lifespan immunometabolism.
  42. Macrophage- or neutrophil-expressed UPP1 drives tumor growth and immune suppression in the tumor microenvironment.
  43. UBE2C-TRIM21-driven NOS2 degradation stabilizes Tregs and suppresses pyroptotic signaling in thyrocytes in Hashimoto's thyroiditis.
  44. UDP-glucose ceramide glucosyltransferase (UGCG) is a novel positive regulator of MyD88-driven inflammation in sepsis.
  45. NAD+ Attenuates Neuroinflammation in Ischemic Stroke by Suppressing the cGAS- STING Pathway via Mitochondrial Homeostasis Restoration.
  46. Lactobacillus reuteri attenuates chronic diarrhea by modulating microbiota homeostasis and macrophage polarization through the cGAS/STING pathway dependent on D-lactate-mediated mitochondrial function.
  47. Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.
  1. Clin Sci (Lond). 2026 Nov 11. 140(11): 2363-2385
    Metabolic gatekeepers shape immune cell function in rheumatoid arthritis.
    Li Jia, Murari N Kothagundla, Jörg J Goronzy, Cornelia M Weyand.
      Immune cell function is tightly coupled to cellular metabolism, with glycolysis, oxidative phosphorylation, and amino acid and lipid metabolism governing activation, differentiation, survival, and effector responses. In rheumatoid arthritis (RA), an autoimmune disease characterized by destructive joint inflammation, metabolic checkpoints have emerged as critical regulators of immune-cell behavior and drivers of tissue pathology. RA CD4+ T cells undergo profound metabolic reprogramming: glycolysis is suppressed, and glucose is redirected into the pentose phosphate pathway, resulting in NADPH accumulation, reduced ROS levels, and a highly reductive intracellular environment. Concurrent defects in mitochondrial DNA repair and electron transport chain function compromise mitochondrial fitness, leading to NAD+ depletion, altered tricarboxylic acid cycle activity, and metabolic exhaustion. The resulting accumulation of citrate and acetyl-CoA promotes lipogenesis and protein acetylation, driving membrane remodeling, tissue invasiveness, and proinflammatory effector functions. Depletion of oxaloacetate and aspartate limits NAD+ regeneration, inducing endoplasmic reticulum expansion and enhanced tumor necrosis factor production. Defective lysosomal coordination of AMPK and mTORC1 signaling uncouples energy sensing from anabolic programs, enabling cellular activation and proliferation despite metabolic insufficiency. Macrophage fate and function are similarly shaped by metabolic state. In synovial macrophages, GLUD1-dependent glutamine oxidation sustains mitochondrial respiration and ATP production, enabling survival under nutrient-deprived conditions while promoting antigen presentation. Conversely, metabolic stress in MerTK+ macrophages activates the NAD+ hydrolase SARM1, triggering NAD+ depletion, mitochondrial collapse, and PANoptotic cell death. Together, these findings identify NAD+ availability, mitochondrial fitness, and organelle-based signaling as central metabolic gatekeepers linking bioenergetic stress to immune-cell dysfunction and chronic inflammation in RA.
    Keywords:  T-cells; glycolysis; lysosomes; mitochondria; oxidative phosphorylation; rheumatoid arthritis
    DOI:  https://doi.org/10.1042/CS20250834
  2. Arch Microbiol. 2026 Oct 15. pii: 26. [Epub ahead of print]209(1):
    Itaconate: a dual-edged sword in immunometabolism and host-pathogen interactions.
    Yani Li, Haojie Zhang, Zhiwei Shen, Kunning Wang, Jie Luo, Junhan Zhou, Ruizhi Zhu, Yuting Jiang, Yan Zhang.
      Itaconate (ITA), a tricarboxylic acid (TCA) cycle-derived immunometabolite produced mainly by activated macrophages and other myeloid cells (e.g., neutrophils) through immune-responsive gene 1 (IRG1)/aconitate decarboxylase 1 (ACOD1), links host metabolism with immune regulation and antimicrobial defense. Initially recognized as an anti-inflammatory metabolite, ITA regulates immune responses through antioxidant signaling, lysosomal activation, inflammasome modulation, and metabolic remodeling. However, emerging evidence reveals context-dependent immunomodulatory effects across different cellular and tissue environments. ITA plays a dual role in host-pathogen interactions by regulating host immune responses while simultaneously serving as a metabolic interface between host defense and bacterial survival. Host-derived ITA restricts pathogens by targeting conserved metabolic enzymes, biosynthetic pathways, and redox homeostasis, whereas bacteria counteract ITA stress through enzymatic degradation, metabolic rewiring, stress adaptation, biofilm formation, and interference with ITA availability. This review summarizes recent advances in ITA-mediated immunometabolic regulation and highlights the reciprocal metabolic competition shaping host-pathogen interactions.
    Keywords:  Host-pathogen interactions; IRG1/ACOD1; Immunometabolism; Inflammatory response; Itaconate
    DOI:  https://doi.org/10.1007/s00203-026-05258-x
  3. J Physiol. 2026 Oct 16.
    Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation.
    Yukun Min, Órlaith C Henry, Luke A J O'Neill.
      Nearly 100 years ago, Otto Warburg observed that cancer cells preferentially use glycolysis even in the presence of oxygen, supporting rapid cell growth. Since then, the concept of the Warburg effect has expanded far beyond tumour bioenergetics and is now recognised as a key feature of immune cell activation. A notable example is in macrophages, which, following pro-inflammatory stimulation, undergo Warburg-like metabolic reprogramming, characterised by increased glycolysis. Recent studies have shown that accumulated metabolites such as lactate have a range of immunoregulatory functions that shape macrophage inflammatory responses. In addition, glycolytic enzymes have been found to exert non-canonical functions that directly regulate macrophage immune signalling. Mitochondria, once considered suppressed during Warburg reprogramming, also undergo profound changes, with the electron transport chain generating reactive oxygen species and metabolites such as succinate, fumarate and itaconate playing complex immunoregulatory roles, and mitochondrial dynamics actively shaping metabolism and immune responses. Together, these findings redefine the Warburg effect in macrophages as a coordinated metabolic and signalling process that integrates glycolysis, mitochondrial function and immunometabolite signalling to optimise context-dependent immune responses.
    Keywords:  ETC; TCA cycle; Warburg metabolism; glycolysis; itaconate; lactate; macrophage; mitochondria
    DOI:  https://doi.org/10.1113/JP291073
  4. Virulence. 2026 Dec;17(1): 2749933
    Itaconate as an immunometabolic hub in host-pathogen interactions: Mechanisms, resistance, and therapeutic opportunities.
    Wei Zuo, Xinhui Wang, Jiaxiang Sun, Weiqi Guo, Beibei Zhang, Xinyu Wang, Jiangang Hu, Jingjing Qi, Mingxing Tian, Lei Deng, Shaohui Wang, Yanqing Bao.
      Produced by IRG1 in macrophages, itaconate has emerged as an immunometabolic hub at the host-pathogen interface. This review integrates itaconate's roles in antimicrobial defense. We first examine how itaconate inhibits pathogen metabolism by targeting key enzymes including isocitrate lyase, fructose-bisphosphate aldolase, and inosine monophosphate dehydrogenase. Beyond direct inhibition, itaconate reprograms host immunity through SDH suppression, Nrf2 activation, ATF3 induction, and context-dependent NLRP3 regulation, and promotes lysosomal biogenesis via TFEB. Conversely, pathogens have evolved counter strategies including enzymatic degradation, biofilm formation, and immune microenvironment remodeling. We also summarize preclinical evidence supporting itaconate and derivatives' therapeutic potential for infection-associated conditions. Finally, we appraise theoretical gaps and methodological challenges, offering guidance for future investigation in this rapidly advancing field.
    Keywords:  Itaconate; antimicrobial defense; host-pathogen interactions; immunometabolism; innate immunity
    DOI:  https://doi.org/10.1080/21505594.2026.2749933
  5. Infect Immun. 2026 Oct 12. e0040926
    Host-secreted lactate during respiratory viral infection diminishes macrophage antibacterial activity through metabolic reprogramming.
    Sadia Sultana, Erin Walsh, Jennifer M Bomberger.
      In polymicrobial infections, how the host recognizes and responds to pathogens influences which species will persist to cause chronic infections. The human respiratory tract is a common anatomical site for viral-bacterial co-infections, where primary viral infections predispose to secondary bacterial infections, leading to increased morbidity and mortality. Additionally, co-infections are disproportionately prevalent in people with chronic lung diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. We previously reported that primary viral infections and antiviral interferon (IFN) signaling stimulate Pseudomonas aeruginosa biofilm formation on airway epithelial cells (AECs). IFN signaling induces aerobic glycolysis in AECs and generates lactate as a cellular byproduct. Given that innate immune systems play an integral role in co-infection dynamics, we investigated the role of host-secreted metabolites (i.e., lactate) on innate immune cell activity during respiratory co-infections. We found that exposure to the apical secretions from IFNβ-treated AECs significantly compromised macrophage antibacterial activity, with the soluble metabolite lactate playing an important role. Macrophages used monocarboxylate transporters (MCTs) and G-protein receptors to transport and/or sense lactate, respectively, and this exposure to lactate diminished their bacterial-killing activity in a time exposure-dependent manner. Lactate exposure particularly reprogrammed macrophage cellular metabolism toward a metabolically uncoupled state by increasing oxidative phosphorylation, fatty acid oxidation, and downregulating the proinflammatory antimicrobial functions. Collectively, these findings provide insights into metabolites as complex regulators of trans-kingdom interactions and epithelial-macrophage crosstalk during respiratory co-infections.
    Keywords:  Pseudomonas aeruginosa; co-infections; immunometabolism; innate immunity; lactate; macrophages
    DOI:  https://doi.org/10.1128/iai.00409-26
  6. Alzheimers Dement. 2026 Oct;22(10): e71882
    ApoE lipidation state directs immunometabolic reprogramming of human microglia.
    Tsion G Shiferaw, Snigdha Sarkar, Katelyn M Baker, Rowan S Wooldridge, Hannah M Binfet, Victoria N Prozapas, Chinemerem P Ogbu, Athena A Schepmoes, Isaac K Attah, Christy S Niemeyer, Kayla G Sprenger, James E Hassell, Robert H Eckel, John T Melchior, Kimberley D Bruce.
       INTRODUCTION: ApoE ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.
    METHODS: Human microglia were treated with lipid-free (LF) or lipid-bound ApoE3 or ApoE4. Label-free, live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet (LD) dynamics, mitochondrial morphology, and microglial phenotype.
    RESULTS: ApoE4 treatment resulted in fewer but enlarged LDs and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to LF-ApoE, which was exacerbated by LF-ApoE4.
    DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas LF-ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.
    Keywords:  APOE ε4; Alzheimer's disease; apolipoprotein E; holotomography; lipid metabolism; microglia
    DOI:  https://doi.org/10.1002/alz.71882
  7. Front Immunol. 2026 ;17 1953599
    Macrophage immunometabolism in osteoporosis: an emerging regulatory axis linking metabolic-polarization coupling to therapeutic targets.
    Lian Weng, Qianli Yuan, Taizhou Mo, Taiming Yuan, Zhongwei Xiong, Liao Ding.
      Osteoporosis has long been understood, and treated, as an imbalance between osteoblastic bone formation and osteoclastic resorption. Yet many patients continue to lose bone, pointing to upstream regulators of the remodeling unit that remain poorly defined. Macrophages are developmentally continuous with osteoclasts and functionally coupled to bone-forming cells, and are now recognized as central immune regulators of skeletal homeostasis. What sets their polarization state, however, has been comparatively neglected in bone. This review adopts metabolic-polarization coupling as a unifying framework for macrophage function in osteoporosis. We argue that the metabolic program a macrophage selects acts as an upstream regulator that biases its phenotype and, in turn, the balance of bone resorption and formation, and we examine how this switch is reinforced epigenetically, amplified by comorbidity, and rendered therapeutically actionable. Aerobic glycolysis via the HIF-1α axis, versus oxidative phosphorylation and fatty-acid oxidation, sets M1 versus M2 phenotype and thereby the balance of resorption and osteogenic-vascular support. Lactate-derived post-translational modifications, notably histone lactylation, make this metabolic state durable at the epigenetic level, while metabolic comorbidities, including ageing, diabetes and obesity, amplify the axis to accelerate bone loss. We emphasize at the outset that direct intra-osseous evidence for this axis remains scarce: the skeletal phenotypes conferred by macrophage-specific deletion of HIF-1α or CPT1A are unreported, histone lactylation has yet to be quantified in bone-resident macrophages, and much of the mechanistic support stems from non-skeletal tissues, inflammatory bone-loss, or periodontal models rather than from primary postmenopausal or age-related osteoporosis. Accordingly, throughout this review we explicitly distinguish evidence established within bone from evidence merely extrapolated to bone. Repositioning macrophage metabolism from a passive correlate to an upstream causal node yields an emerging regulatory axis yields a testable sequence, metabolic node to polarization to remodeling imbalance to bone loss, that identifies metabolic enzymes such as HIF-1α and CPT1A as candidate druggable targets and polarization and lactylation signatures as candidate readouts for stratification. This perspective reframes osteoporosis therapy from suppressing mature osteoclasts toward reprogramming macrophage metabolism itself.
    Keywords:  bone remodeling; histone lactylation; immunometabolism; macrophage polarization; metabolic reprogramming; osteoporosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1953599
  8. Immunol Cell Biol. 2026 Oct 16.
    Glycolysis-Dependent Fatty Acid Metabolism Supports Human Tfh Cell Function.
    Someshwar Nath Jha, Bhushan Nikam, Vivekananda Barik, Anuska Khatua, Deepak Jena, Shilpa Sachan, Mamuni Swain, Poonam Coshic, Sunil K Raghav, Nimesh Gupta.
      Follicular helper T (Tfh) cells orchestrate germinal center (GC) derived humoral immunity by providing essential help to B cells. Despite their key role in humoral immunity, the metabolic cues that shape Tfh cell differentiation and functions in humans remain poorly understood. Here, using a human ex vivo Tfh cell differentiation model, we investigated the metabolic requirements of Tfh cell development and function through targeted metabolic perturbation of glycolysis and fatty acid metabolism, transcriptomic analyses, and metabolic rescue experiments. Unexpectedly, early glycolytic inhibition enhanced Tfh cell differentiation but markedly impaired function, including reduced IL-21 production and diminished B-cell help. Transcriptomic and metabolic analyses revealed that glycolytic inhibition was accompanied by suppression of fatty acid metabolism. Consistently, independent inhibition of fatty acid synthesis or oxidation suppressed Tfh cell help functions, including IL-21 and IFN-γ production, as well as B-cell help potential. Interestingly, acetate supplementation partially restored IFN-γ secretion in glycolysis-inhibited conditions, but not IL-21, indicating limited metabolic compensation. Together, these findings reveal distinct metabolic requirements for Tfh cell differentiation and function and identify glycolysis-dependent fatty acid metabolism as an important determinant of human Tfh cell functional competence. This metabolic crosstalk provides new insight into the regulation of Tfh cells and Tfh-driven humoral immunity in vaccination and autoimmunity.
    DOI:  https://doi.org/10.1111/imcb.70166
  9. Transplant Cell Ther. 2026 Oct 14. pii: S2666-6367(26)00798-0. [Epub ahead of print]
    Research Progress of T Cell Metabolism in Graft-Versus-Host Disease.
    Yihan Ding, Bo Hu, Chengwan Zhang.
      Graft-versus-host disease (GVHD) is a common and severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is caused by activated alloreactive T cells that attack recipient target organs and represents a major cause of non-relapse mortality, thereby limiting the efficacy of allo-HSCT. Persistent alloantigen stimulation can induce metabolic dysregulation in T cells, involving pathways such as glycolysis, lipid metabolism, amino acid metabolism, nucleotide metabolism, and mitochondrial oxidative phosphorylation. Given the close relationship between T cell metabolism and T cell activation, differentiation, and effector functions, targeted modulation of T cell metabolism may emerge as a novel strategy for the prevention and treatment of GVHD. This review summarizes the roles of major T cell metabolic pathways in the pathogenesis and progression of GVHD with the aim of informing future mechanistic studies and therapeutic strategies.
    Keywords:  Graft-versus-host disease; T cell metabolism; allo-HSCT
    DOI:  https://doi.org/10.1016/j.jtct.2026.10.010
  10. Adv Sci (Weinh). 2026 Oct 14. e78313
    Targeting Cannabinoid 1 Receptor in Macrophages Alleviates Psoriatic Skin Inflammation Through the AUF1-NLRP3 Axis.
    Hongseo Choi, Sukyoung Han, Jinho Kim, Ji Hye Han, Eunsu Kim, Yeonjeong Heo, Minju Lee, Jooyoung Lee, Heerim You, Soyoun Lee, Su-Hee Han, Ilrok Yoon, Sung Anjeon, Hyerim Kang, Seungyeon Ryu, Hyun-Ji Park, Eunha Kim, Chul Hwan Bang, Ji Hyun Lee, Josephine M Egan, Jung-Woong Kim, Eun Kyung Lee, Wook Kim.
      Psoriasis is a chronic inflammatory skin disease associated with systemic metabolic dysregulation; however, the molecular pathways linking metabolic signaling to skin inflammation remain poorly understood. Here, we identify cannabinoid 1 receptor (CB1R) in macrophages as a key immunometabolic regulator of psoriatic inflammation and a potential therapeutic target. CB1R expression was increased in macrophages infiltrating psoriatic lesional skin in both humans and mice, and both pharmacological inhibition and genetic deletion of CB1R markedly attenuated psoriasis-like pathology in mouse models by reducing epidermal hyperplasia, inflammation, and barrier dysfunction in a macrophage-dependent manner. Mechanistically, CB1R signaling in macrophages suppressed expression of the RNA-binding protein AUF1, leading to stabilization of Nlrp3 mRNA and enhanced NLRP3 inflammasome activation. AUF1 directly bound an AU-rich region within the Nlrp3 3' untranslated region and promoted mRNA destabilization, thereby limiting inflammasome activation and IL-1β production. Restoration of AUF1 expression, either by CB1R inhibition or overexpression, reduced NLRP3 levels and alleviated psoriasis-like pathology, whereas Nlrp3 deficiency abrogated these effects. Collectively, these findings define a CB1R-AUF1-NLRP3 signaling axis that links metabolic signaling to inflammasome-driven skin inflammation in macrophages. Targeting macrophage CB1R may therefore represent a promising therapeutic strategy for psoriasis and other immunometabolic inflammatory diseases.
    Keywords:  AUF1; NLRP3; cannabinoid 1 receptor (CB1R); immunometabolism; macrophage; psoriasis; skin inflammation
    DOI:  https://doi.org/10.1002/advs.78313
  11. Front Immunol. 2026 ;17 1854880
    The role of metabolic crosstalk between Intestinal epithelial cells and immune cells in inflammatory bowel disease and targeting strategies.
    Heng Li, Beibei Wang, Xianhong Shi, Lulu Tian, Bin Li, Tianqi Zhou, Mingcan Qiu, Jiwei Yuan, Kai Yin.
      Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disorder characterized by disruption of the intestinal epithelial barrier and dysregulated immune responses. IBD pathogenesis is intricately linked to the metabolic reprogramming of the intestinal epithelial cells (IECs), which are central to both barrier maintenance and immune crosstalk. Mitochondrial dysfunction in the IECs leads to energy deficit, oxidative stress, and barrier failure, which activates the adjacent immune cells and establishes a vicious cycle of inflammation. This review focuses on the key role of the mitochondrial metabolism in IBD with a specific focus on the remodeling of the glucose, lipid, and amino acid metabolic pathways in epithelial and immune cells. We elaborate on the specific regulatory mechanisms underlying these metabolic processes and the functions of metabolic products as signaling molecules in cell-cell communication. In addition to causing energy crises and barrier defects in epithelial cells, metabolic remodeling directly controls the activation of immune cells and their polarization toward a pro-inflammatory phenotype. Thus, a deeper understanding of mitochondrial metabolism underlying IBD would provide a crucial theoretical foundation for developing novel precision therapies targeting metabolism. Additionally, elucidating these metabolic networks would provide new therapeutic opportunities for restoring homeostasis in IBD.
    Keywords:  immune cells; immunometabolism; intestinal epithelial cells; metabolic reprogramming; mitochondrial dysfunction; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2026.1854880
  12. J Mol Histol. 2026 Oct 14. pii: 333. [Epub ahead of print]57(6):
    Liraglutide ameliorates obese type 2 diabetes by regulating macrophage cholesterol metabolism and H3K27ac modification to promote M2 polarization and adipocyte thermogenic activation.
    Ping Wang, Jie Zhang, Weifeng Zhou, Nan Zhang, Yiqing Chen.
      Obesity-related type 2 diabetes mellitus (O&T2DM) has become a major global public health issue. Chronic low-grade inflammation in adipose tissue is one of its core pathological features, among which excessive infiltration of M1-type macrophages and impaired function of M2-type macrophages are key drivers of inflammation. Liraglutide, a glucagon-like peptide-1 receptor agonist, exhibits significant glucose-lowering, weight-reducing, and anti-inflammatory effects. However, the molecular mechanisms by which liraglutide regulates cholesterol metabolism and epigenetic modifications in adipose tissue macrophages remain to be fully elucidated. A high-fat diet combined with streptozotocin was used to establish an O&T2DM model in male C57BL/6 mice. After 8 weeks of intervention, metabolic phenotypes, adipose tissue macrophage polarization, and cholesterol metabolism-related indicators were assessed. Raw264.7 macrophages were cultured in vitro and stimulated with IFN-γ + LPS to induce M1 polarization. Following liraglutide pretreatment, cell polarization phenotypes, the expression of genes involved in cholesterol metabolic pathways, and histone modification levels were examined. Using shRNA gene silencing, p300 inhibitor intervention, and Acetyl-CoA supplementation experiments in combination with ChIP-qPCR, the central role of the cholesterol metabolism-epigenetic axis in macrophage polarization was elucidated. Finally, a Transwell co-culture system was employed to verify the regulatory effects of liraglutide-reprogrammed macrophages on adipocyte lipid accumulation and energy metabolism. Liraglutide significantly reduced body weight, fasting blood glucose, and HOMA-IR in O&T2DM mice, decreased visceral fat accumulation, and promoted adipose tissue browning. It also increased the proportion of M2 macrophages within adipose tissue and significantly activated the key cholesterol efflux pathway LXRα/ABCA1. In vitro experiments confirmed that liraglutide pretreatment suppressed IFN-γ + LPS-induced M1 polarization and promoted the expression of M2-type markers, upregulated the expression of ABCA1, ABCG1, PPARγ, and LXRα, and increased levels of histone H3K27ac. Mechanistic studies revealed that silencing ABCA1 or LXRα reversed the liraglutide-induced increase in H3K27ac and M2 polarization. Acetyl-CoA supplementation partially restored the macrophage polarization phenotype following ABCA1 silencing. ChIP-qPCR results showed that liraglutide significantly enhanced the enrichment of H3K27ac in the promoter regions of M2 polarization genes and cholesterol metabolism genes. Co-culture experiments demonstrated that liraglutide-reprogrammed macrophages significantly promoted adipocyte thermogenic gene expression, increased mitochondrial membrane potential-dependent staining intensity, and enhanced ATPase activity via paracrine signaling, an effect that was blocked by silencing ABCA1 or LXRα. This study demonstrates that liraglutide activates the ABCA1/LXRα-mediated cholesterol metabolism pathway, upregulates histone H3K27ac modification, and drives macrophage M2 polarization, which in turn induces adipocyte lipid accumulation and mitochondrial metabolic activation via paracrine signaling. These findings provide a new molecular mechanism for the anti-inflammatory and metabolic-improving effects of liraglutide, and also offers a potential epigenetic target for the treatment of O&T2DM.
    Keywords:  Cholesterol metabolism; Liraglutide; Obesity-related type 2 diabetes mellitus; mMacrophage
    DOI:  https://doi.org/10.1007/s10735-026-10993-y
  13. J Inflamm Res. 2026 ;19 654590
    Nucleotide Metabolic Reprogramming in Sepsis: From Immune-Cell Fate to Organ Injury and Precision Therapeutics.
    Chun Wang, Fu Shuying, Jin Jing, Fang Fuquan, Jie Huang.
      Sepsis is a life-threatening syndrome characterized by concurrent inflammation, immunosuppression, endothelial dysfunction and metabolic failure. Although current immunometabolic research primarily focuses on glycolysis, mitochondrial respiration and lipid metabolism, nucleotide metabolism links biosynthesis, redox homeostasis, epigenetic regulation and extracellular danger signalling. This Review synthesizes evidence for altered purine and pyrimidine synthesis, ribonucleotide reduction, nucleoside salvage and purinergic signalling across immune-cell populations in sepsis. We distinguish clinical observations from mechanistic evidence in experimental sepsis and hypotheses extrapolated from cancer or immune-mediated disease. Human observational studies support involvement of the extracellular ATP-CD39/CD73-adenosine axis in sepsis, while experimental studies provide complementary mechanistic evidence. By contrast, the roles of DHODH, RRM2 and the uridine-UPP1 salvage pathway remain predominantly preclinical, particularly in ferroptosis and acute organ injury. We propose that nucleotide metabolism functions as a time-, cell- and compartment-dependent regulatory network rather than a uniformly activated pathway. Clinical translation will require longitudinal metabolite-enzyme-receptor profiling, isotope-resolved flux analysis, spatial and single-cell approaches, and biomarker-defined therapeutic windows. Such strategies may enable nucleotide-directed interventions to complement antimicrobial treatment and organ support without compromising protective immunity.
    Keywords:  immunometabolism; nucleotide metabolism; purine; purinergic signalling; pyrimidine; sepsis; uridine
    DOI:  https://doi.org/10.2147/JIR.S654590
  14. Int J Mol Sci. 2026 Sep 26. pii: 8626. [Epub ahead of print]27(19):
    Deoxythymidylate Kinase (DTYMK)-Driven Pyrimidine Hypermetabolism Is Associated with a Folate-Dependent Macrophage Programme in Triple-Negative Breast Cancer.
    Gaoge Peng, Dequan Liu, Wucheng Zhu, Beibei Xin, Yi Wu, Yifeng Hou, Hefen Sun, Wei Jin.
      Immune checkpoint blockade benefits only a minority of patients with triple-negative breast cancer (TNBC), and the tumour-intrinsic programmes that establish its immunosuppressive microenvironment remain poorly defined. Pyrimidine metabolism supplies nucleotides and one-carbon units in malignant cells, but whether it shapes the immune microenvironment is unknown. Integrating single-cell, bulk breast cancer transcriptomics with Xenium spatial transcriptomics, DTYMK knockdown, tumour-conditioned-medium co-culture and folate rescue, we found that pyrimidine pathway activity was elevated in the malignant epithelium of TNBC, within which we identified Epi4, a high-potency subpopulation coupling pyrimidine and folate metabolism and predicted to export folate. Furthermore, this folate was predicted to be taken up by FOLR2+ tumour-associated macrophages (TAMs) and was associated with S-adenosylmethionine(SAM)-dependent methylation signatures and MAFB activity. Spatially, Epi4 and FOLR2+ TAMs co-localised at the tumour-stroma margin, a region of reduced T-cell density. DTYMK depletion reduced tumour fitness and attenuated folate-mediated macrophage reprogramming, which was largely restored by exogenous folate. Here, we therefore identify a DTYMK-folate-MAFB axis in which tumour metabolic rewiring is associated with epigenetic reprogramming of macrophages.
    Keywords:  DTYMK; FOLR2+ macrophages; metabolic crosstalk; multi-omics; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/ijms27198626
  15. Nat Rev Endocrinol. 2026 Oct 14.
    The immune hub of metabolism: how adipose tissue macrophage infiltration redefined obesity.
    Olivia Horrigan.
      
    DOI:  https://doi.org/10.1038/s41574-026-01317-x
  16. Eur J Immunol. 2026 Oct;56(10): e70297
    Inducible cAMP Early Repressor Limits Glycolytic Programming in Regulatory T Cells and Supports Control of Inflammatory Colitis.
    Aleksandra Lopez Krol, Luana Silva, Daniele C Nascimento, Sophie M Oberwalder, Hitikk Chawla, Gabriel Alberto Barbosa de Carvalho, Fatima Boukhallouk, Monica Romero, Anne Hausen, Matthias M Gaida, Luciana Berod, José Carlos Alves-Filho, Tim Sparwasser.
      Regulatory T cells (Tregs) are essential for immune tolerance, with cAMP metabolism central to their suppressive function. Inducible cAMP early repressor (ICER) is a negative regulator of cAMP signalling. However, its role in Treg biology is not fully understood. Here we generated Foxp3-specific ICER knockout mice to assess ICER's function in Tregs. We found that ICER deficiency does not impair Treg development or suppression of effector T cell proliferation under homeostatic conditions. However, ICER-deficient Tregs display enhanced Foxp3 stability, increased glycolysis and proliferation but exhibit impaired suppression of IFN-γ production by effector T cells. In a dextran sodium sulphate-induced colitis model, loss of ICER in Tregs led to aggravated intestinal inflammation and tissue damage, without, however, a marked effect on gross disease parameters. These results identify ICER as a context-dependent modulator of Treg metabolism and inflammatory cytokine control, highlighting its potential role in regulating immune responses during inflammation.
    Keywords:  DSS colitis; ICER/CREM; cAMP metabolism; glycolysis; regulatory T cells
    DOI:  https://doi.org/10.1002/eji.70297
  17. Cell Rep. 2026 Oct 10. pii: S2211-1247(26)01197-6. [Epub ahead of print]45(10): 118118
    Dopamine-induced mitochondrial dysfunction activates cGAS-sTING to drive IL-6 secretion in macrophages.
    Marzieh Daniali, Breana Channer, Erin O Curley, Amirali Amirfallah, Taylor Kist, John Montilla Luna, Stephanie Kosashvili, Lexi Sheldon, Kelly Stauch, Joshua G Jackson, Anneliese M Faustino, Thomas Beer, Hsin-Yao Tang, Stephanie M Matt, Will Dampier, Howard Fox, Peter J Gaskill.
      Despite growing evidence that dopamine acts as an innate immune inflammatory mediator, the molecular mechanisms by which dopamine modulates human immune function are incompletely defined. Here, we define the pathway in which dopamine induces robust IL-6 secretion in primary human monocyte-derived macrophages (hMDMs) through mitochondrial stress. Dopamine initiates a transient mitochondrial membrane depolarization that leads to sustained alterations in mitochondrial dynamics, including morphology and metabolism. These events promote the release of mtDNA into the cytoplasm, triggering the cGAS-STING pathway and NF-κB signaling. Pharmacological inhibition at multiple nodes of this pathway attenuates IL-6 secretion, establishing mitochondrial dysfunction and cGAS-STING signaling as central mediators of dopamine-driven IL-6 secretion. Variability in dopamine receptor expression across donors correlates with the magnitude of IL-6 responses. These findings highlight a potential link between dopamine signaling and systemic inflammation and suggest that differences in dopamine receptor expression may contribute to inter-individual variation in innate immune responses.
    Keywords:  CP: immunology; IL-6; cGAS-STING; dopamine; immunopharmacology; immunoregulation; inflammation; macrophages; mitochondria; mitochondrial DNA; mtDNA
    DOI:  https://doi.org/10.1016/j.celrep.2026.118118
  18. Front Pharmacol. 2026 ;17 1995384
    Editorial: Targeting dysregulation in metabolic diseases: potential therapeutic intervention.
    Vítor S Fernandes, Yoshinori Moriyama.
      
    Keywords:  immunometabolism; inflammation; metabolic diseases; metabolic dysregulation; precision medicine; therapeutic targets
    DOI:  https://doi.org/10.3389/fphar.2026.1995384
  19. bioRxiv. 2026 Sep 28. pii: 2026.09.24.754142. [Epub ahead of print]
    SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast- like State to Drive Metabolic Disease.
    Karima Drareni, Ryan P Calhoun, Lan Cheng, Camille E M Piguet, Lin Liu, Sarah Traynor, Josephine M Tan, Marco Angelozzi, David M Merrick, Veronique Lefebvre, Patrick Seale.
      Pathogenic adipose tissue remodeling promotes metabolic disease in obesity, but the mechanisms that establish this unhealthy tissue state remain poorly understood. Here, we show that obesity drives SOX4-dependent reprogramming of mesenchymal stromal cells (MSCs) into cancer-associated fibroblast-like (CAF-like) cells that promote adipose tissue dysfunction. TGFβ signaling is elevated in obesity and activates SOX4 in mouse and human MSCs, inducing their conversion to a CAF-like state. In mice, MSC-specific SOX4 activation induces the CAF-like program and exacerbates adipose tissue inflammation and glucose intolerance, whereas Sox4 deletion attenuates inflammation and improves glucose homeostasis during obesity. We further identify the growth factor Midkine (MDK) as a SOX4-regulated paracrine effector produced by CAF-like cells. MDK inhibition in obese mice reduces adipose tissue inflammation and improves metabolic function. Together, these findings define a TGFβ-SOX4-MDK stromal signaling axis that drives pathological adipose tissue remodeling in obesity and highlight this pathway as a potential therapeutic target for improving metabolic health.
    DOI:  https://doi.org/10.64898/2026.09.24.754142
  20. Am J Reprod Immunol. 2026 Oct;96(4): e70331
    Macrophage Polarization and Metabolic Reprogramming in Endometriosis: Mechanisms and Therapeutic Implications.
    Leila Adamyan, Igor Malyshev, Laura Pivazyan, Maria Yurkanova, Kristina Kurbatova, Karina Mailova, Assia Stepanian.
      This review synthesizes evidence on macrophage roles, polarization (M1/M2), and immunometabolic/signaling pathways in endometriosis, outlining therapeutic implications. We searched PubMed, Cochrane Library, ClinicalTrials.gov, Scopus, Embase, and Google Scholar. Available evidence demonstrates increased macrophage accumulation and substantial heterogeneity across the eutopic endometrium, peritoneal fluid, and established endometriotic lesions. Rather than undergoing a uniform shift from an M1 to an M2 phenotype, endometriosis-associated macrophages acquire overlapping inflammatory, immunoregulatory, angiogenic, phagocytic, metabolic, and profibrotic programs. Endometriotic epithelial and stromal cells regulate macrophage recruitment and activation through estrogen receptor β-NF-κB-CCL2 signaling, IL-17A- and TNF-α-dependent cytokine production, extracellular-vesicle-mediated microRNA transfer, and lactate-driven METTL3-Trib1-ERK/STAT3 signaling. The CCL2/MCP-1-CCR2 axis further links monocyte recruitment with inflammatory signaling and the invasive behavior of endometriotic cells, whereas TET3-mediated suppression of let-7 microRNAs sustains disease-associated macrophage activation. Functionally, macrophages contribute to defective clearance of displaced endometrial tissue, ectopic cell survival, angiogenesis, fibrosis, neuroimmune sensitization, pain, and impaired reproductive function. These findings support an immunometabolic model in which macrophage plasticity drives lesion establishment, progression, neuroangiogenesis, pain, and infertility. Therapeutically, targeting macrophage polarization and metabolism-via glycolytic and mitochondrial pathways, lactate signaling, or epitranscriptomic regulators-may restore immune homeostasis and limit disease progression. Further translational studies are needed to validate biomarkers and develop macrophage-directed interventions.
    Keywords:  endometriosis; immunometabolism; macrophage polarization; macrophages; metabolic reprogramming
    DOI:  https://doi.org/10.1111/aji.70331
  21. Int J Mol Sci. 2026 Sep 23. pii: 8477. [Epub ahead of print]27(19):
    Activation of KCa3.1 K+ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M2-like Macrophages.
    Junko Kajikuri, Ayano Kitahara, Miki Matsui, Yasuhiro Maeda, Hiroaki Kito, Yohei Yamaguchi, Ryo Otsuka, Susumu Ohya.
      M2-like macrophages contribute to the establishment of immunosuppressive microenvironments through coordinated activation of inflammatory and metabolic programs. Cyclooxygenase-2 (COX2) catalyzes prostaglandin E2 (PGE2) production, whereas arginase-1 (ARG1) hydrolyzes L-arginine (ARG) to ornithine (ORN) and urea. However, the ion channel-dependent mechanisms governing these immunometabolic pathways remain poorly defined. Here, we examined the role of the Ca2+-activated K+ channel KCa3.1 in regulating COX2 and ARG1 in THP-1-derived M2-like macrophages. COX2 and ARG1 were markedly upregulated during M2-like differentiation, whereas pharmacological activation of KCa3.1 with SKA-121 significantly reduced their mRNA and protein expression. KCa3.1 activation also decreased PGE2 production, increased extracellular ARG, and reduced ORN accumulation. Exposure to elevated extracellular K+ concentration ([K+]e) further enhanced COX2 and ARG1 expression, increased PGE2 production, and shifted ARG metabolism toward ORN formation; each of these responses was attenuated by KCa3.1 activation. Pharmacological inhibition of ERK or CREB signaling suppressed both COX2 and ARG1 expression, whereas inhibition of JNK, AP-1, NOX2, or NRF2 had limited effects. CREB2 knockdown similarly reduced COX2 and ARG1 under both basal and elevated [K+]e conditions. These findings demonstrate that KCa3.1 activation negatively regulates COX2- and ARG1-associated immunometabolic programs in THP-1-derived M2-like macrophages and suggest a potential role for KCa3.1 in modulating macrophage-associated inflammatory and metabolic responses.
    Keywords:  ARG1; COX2; K+ channel; KCa3.1; M2-like macrophage; PGE2; arginine; elevated extracellular K+ concentration; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27198477
  22. bioRxiv. 2026 Oct 03. pii: 2026.09.28.755064. [Epub ahead of print]
    The Lag3 KIEELE motif couples HPK1 to metabolic and functional regulation of Foxp3+ regulatory T cells.
    Giha Kim, Dongkyun Kim, Sohee Kim, Booki Min.
      Lymphocyte activation gene-3 (Lag3) is an inhibitory receptor that limits effector T cell activation and function. We previously demonstrated that Lag3 supports regulatory T (Treg) cell function through Myc-dependent metabolic reprogramming. However, the intracellular mechanisms underlying this regulation remain incompletely understood. Here, we generated mice with Treg-specific deletion of the Lag3 KIEELE motif and demonstrated that this motif is required for Treg-mediated suppression of autoimmune inflammation. Loss of the Lag3 KIEELE motif led to enhanced TCR/PI3K-Akt/MEK-ERK signaling and Myc expression, accompanied by increased glycolytic activity and acquisition of effector T cell-like features. We also identified that hematopoietic progenitor kinase 1 (HPK1) and Cbl-interacting protein of 85 kDa (CIN85) associate with Lag3 through the KIEELE motif. HPK1 depletion partially recapitulated the phenotypic changes and impaired Treg suppressive function in vivo. Together, these findings identify the KIEELE motif as a critical link between Lag3-associated signaling machinery and metabolic regulation that sustains Treg suppressive function during autoimmune inflammation.
    DOI:  https://doi.org/10.64898/2026.09.28.755064
  23. Front Immunol. 2026 ;17 1892562
    Lysine lactylation in neutrophil functional remodeling across diverse disease contexts.
    Yushu Wang, Xiaotong Liu, Chao Wang.
      Lactate, traditionally regarded as a product of glycolytic metabolism, is increasingly recognized as a metabolite that can influence cellular signaling and protein post-translational modification, including lysine lactylation (Kla). Neutrophils rely on glycolytic metabolism to support rapid effector functions and encounter substantial metabolic changes during inflammation, infection, ischemic injury, and tumor progression. Emerging studies have implicated histone and non-histone lactylation in the regulation of neutrophil-associated processes, including migration, inflammatory activation, neutrophil extracellular trap (NET) formation, and functional phenotypic remodeling. However, the extent to which these effects are mediated directly by lactylation within neutrophils remains incompletely defined, as some available evidence derives from other cell types, tissue compartments, or indirect associations with neutrophil responses. In this review, we summarize current knowledge of the molecular mechanisms regulating lysine lactylation, with a focus on lactyltransferases, delactylases, and lactylation-associated reader proteins. We further examine evidence linking lactylation-associated signaling to neutrophil migration, NET formation, and functional heterogeneity across inflammatory, ischemic, and tumor-associated settings, with consideration of distinct neutrophil populations. We also discuss the potential interplay between lactylation and other lysine acylation modifications, as well as current methodological challenges in accurately detecting and quantifying Kla and distinguishing enzymatic from non-enzymatic lactylation. Finally, we evaluate emerging pharmacological and biomarker-based approaches targeting lactate metabolism and lactylation-associated pathways. Although these studies provide a growing framework for understanding how metabolic alterations may influence neutrophil function, most evidence remains preclinical or indirect, and the relative contribution of lactylation to neutrophil responses across different pathological contexts remains to be established. Further studies using site-specific quantitative approaches, primary human neutrophils, and neutrophil-specific genetic or mechanistic models will be required to define the causal and context-dependent roles of lysine lactylation in neutrophil biology.
    Keywords:  immunometabolism; lysine lactylation; neutrophil extracellular traps (NETs); neutrophils; post-translational modifications
    DOI:  https://doi.org/10.3389/fimmu.2026.1892562
  24. bioRxiv. 2026 Sep 28. pii: 2026.09.22.747582. [Epub ahead of print]
    CTR1-mediated copper uptake orchestrates metabolic-epigenetic regulation of pathogenic T H 17 cells in autoimmune disease.
    Lucile Noyer, Liwei Wang, Miki Jishage, Maxwell McDermott, Aidan T Pezacki, Anthony Y Tao, Ravichandran Ramasamy, Matthias Stadtfeld, Christopher J Chang, Stefan Feske.
      Pathogenic T helper 17 (pT H 17) cells are a subset of CD4 + T cells driving autoimmune diseases including multiple sclerosis (MS). Compared to homeostatic T H 17 cells and other T H subsets, pT H 17 have enhanced mitochondrial function and oxidative phosphorylation (OXPHOS) that supports their differentiation and pathogenic function. Here we identify Copper Transporter 1 (CTR1), encoded by Slc31a1, as essential for copper uptake in CD4 + T cells, OXPHOS and pT H 17 cell differentiation and function. While copper levels are known to be higher in the cerebrospinal fluid of patients with MS compared to healthy individuals, and excess copper contributes to oligodendrocyte loss in murine models of MS, the effect of copper on T cell function and pathogenicity in MS are unclear. We demonstrate that deletion of Slc31a1 in CD4 + T cells decreased intracellular copper levels, disrupting mitochondrial respiration and rewiring metabolism. These changes altered the epigenetic landscape of pT H 17 cells by impairing DNA demethylation capacity, leading to hypermethylated DNA and altered chromatin accessibility at key binding sites for AP-1 transcription factors essential for pT H 17 differentiation. As a result, CTR1-deficient T cells showed defective differentiation into pT H 17 cells, with decreased production of IL-17A and expression of T H 17 signature genes, while the differentiation of other CD4 + T cell subsets remained largely unaffected. Moreover, T cell-specific deletion of Slc31a1 protected mice from central nervous system (CNS) inflammation in the experimental autoimmune encephalomyelitis (EAE) model of MS by suppressing clonal expansion of autoreactive CD4 + T cells. These findings establish copper as a critical regulator of pT H 17 differentiation and function, revealing a previously unknown molecular link between copper homeostasis, metabolism and epigenetic regulation governing pT H 17-mediated autoimmunity.
    DOI:  https://doi.org/10.64898/2026.09.22.747582
  25. Blood Red Cells Iron. 2026 Dec;pii: 100119. [Epub ahead of print]2(4):
    Glucose-6-Phosphate Dehydrogenase Deficiency Reprograms Macrophage Metabolism in Hyperlipidemia.
    Christopher M Clements, Megan Mazzei, Sydney Blimbaum, Ariel M Hay, Francesca I Cendali, Monika Dzieciatkowska, Sotirios P Fortis, Julie A Reisz, Brett P Ransegnola, Coleen A McNamara, James C Zimring, Angelo D'Alessandro.
      Macrophages regulate inflammatory responses in hyperlipidemia and dysmetabolic states while performing a critical homeostatic function by clearing damaged or senescent red blood cells (RBCs) through erythrophagocytosis. This process delivers heme and iron that must be detoxified and recycled through NADPH-dependent pathways. Glucose-6-phosphate dehydrogenase deficiency (G6PDd), affecting ~6% of the global population, limits NADPH generation and predisposes RBCs to oxidative damage and hemolysis. Whether G6PD deficiency alters macrophage metabolic responses to RBC clearance in hyperlipidemic environments remains unknown. Humanized mouse models expressing canonical (hG6PDND), African (hG6PDA-), or Mediterranean (hG6PDMed-) G6PD variants were exposed to Western diet-induced hyperlipidemia. RBCs, plasma, and splenic macrophages were analyzed using metabolomics, lipidomics/oxylipin profiling, and quantitative proteomics. Hyperlipidemia increased circulating lipid species and altered RBC metabolism, while G6PD deficiency selectively reduced pentose phosphate pathway intermediates. Plasma metabolomics revealed signatures consistent with increased hemolysis in hyperlipidemic G6PD-deficient mice. Splenic macrophages from G6PDd animals showed biochemical evidence of erythrophagocytosis, glutathione depletion, and remodeling of central carbon metabolism. Variant-specific alterations included increased glycolytic flux, disrupted TCA cycle activity, and elevated succinate/fumarate ratios consistent with mitochondrial dysfunction. Proteomics revealed extensive mitochondrial and proteasomal remodeling. G6PD deficiency and hyperlipidemia converge to reprogram macrophage metabolism through NADPH limitation, redox imbalance, and impaired handling of RBC-derived metabolites. These findings identify an NADPH-dependent metabolic vulnerability linking RBC fragility, erythrophagocytosis, and inflammatory macrophage reprogramming.
    Keywords:  Erythrophagocytosis; G6PD; Hemolysis; Lipid; Multi-Omics analysis
    DOI:  https://doi.org/10.1016/j.brci.2026.100119
  26. Front Immunol. 2026 ;17 1974770
    Macrophage states and immunometabolic adaptation in peritoneal metastases from colorectal cancer.
    Weihao Chen, Jiali Wei, Yi Wang, Long Sun, Yang Ye, Kang Sun.
      Immunotherapy responses in colorectal cancer peritoneal metastases (CRCPM) are not determined by mismatch repair (MMR) status alone. Most MMR-proficient/microsatellite-stable (pMMR/MSS) tumors have low baseline sensitivity, while MMR-deficient/microsatellite instability-high (dMMR/MSI-H) tumors do not respond uniformly, particularly in patients with ascites. This Mini Review compares evidence across compartments and disease stages: human associations, macrophage-resolved functional studies and interventions altering immunotherapy efficacy in mice. Human ascites and tissue studies identify resident-like and monocyte-associated macrophages, including C1Q+ and SPP1+ states, but shared markers do not establish equivalent functions or origins. During niche conditioning and early seeding, ABCA9-dependent cholesterol handling, tumor-derived lysophosphatidic acid signaling and TLR4-CXCL10 activation can support local T-cell-mediated tumor control, although these studies did not test immune checkpoint blockade (ICB) or adoptive cell therapy (ACT). In established disease, SPP1-associated macrophage-intrinsic peroxisome proliferator-activated receptor-γ (PPARγ) programming and extracellular SPP1-CD44 signaling restrain CD8+ T cells, and SPP1 perturbation improves anti-PD-1 and ACT responses in mice. The relative contributions of these routes to treatment rescue remain unresolved. TIM-4 and MerTK provide distinct non-metabolic constraints. Human evidence for the resistance-associated SPP1 state remains cross-sectional. Lipid-related pathways in CRCPM models thus have opposing immune effects rather than acting as a single metabolic switch.
    Keywords:  adoptive cell therapy; colorectal cancer; immune checkpoint blockade; immunometabolism; macrophage states; peritoneal metastasis
    DOI:  https://doi.org/10.3389/fimmu.2026.1974770
  27. Cancer Res. 2026 Oct 14.
    ARID2 Loss Reprograms the Kynurenine-AhR Pathway to Restore Antitumor Immunity in CTNNB1-Mutant Hepatocellular Carcinoma.
    Qianyu Li, Yunfeng Yuan, Ning Liu, Linfeng Li, Yifei Qian, Fan Wang, Songling Li, Wenli Qin, Quankun Lin, Hongmin Lu, Yuliang Rao, Qiang Xia, Yanan Wang, Yanfeng Liu.
      Hepatocellular carcinoma (HCC) driven by gain-of-function mutations in CTNNB1 (CTNNB1GOF) that stabilize β-catenin exhibits a profoundly immunosuppressive tumor microenvironment (TME), rendering it resistant to immune checkpoint blockade (ICB). Metabolic reprogramming is increasingly recognized as a crucial mediator of immune activity, highlighting the need to elucidate the specific metabolic mechanisms underlying immune exclusion in CTNNB1GOF HCC. Here, we identified a critical metabolic-immune network orchestrated by co-mutations of CTNNB1 and ARID2. Integrative analysis of HCC patient cohorts and a de novo MYC/CTNNB1GOF HCC mouse model revealed that tumors harboring concurrent CTNNB1 and ARID2 mutations exhibited a more immune-active TME and improved survival compared to tumors with CTNNB1 mutations alone. Mechanistically, β-catenin and ARID2 cooperatively enhanced the transcription of tryptophan 2,3-dioxygenase (TDO2), leading to accelerated kynurenine production and activation of the aryl hydrocarbon receptor (AhR) in myeloid-derived suppressor cells (MDSCs). This metabolic axis established an immunosuppressive milieu characterized by MDSC accumulation and impaired T cell function. Genetic ablation of Arid2 in CTNNB1GOF HCC attenuated TDO2-dependent kynurenine synthesis, reduced MDSC infiltration, and enhanced CD8⁺ T cell cytotoxicity, thereby sensitizing tumors to anti-PD-1 therapy. Clinically, co-mutations of CTNNB1 and ARID2 correlated with elevated immune infiltration and favorable ICB responses across multiple human cancers, including HCC. Importantly, pharmacological inhibition of AhR phenocopied the immunomodulatory effect of ARID2 loss and, when combined with anti-PD-1, robustly reversed the immune-cold phenotype of CTNNB1GOF HCC. These findings reveal TDO2-kynurenine-AhR signaling as a pivotal metabolic pathway enforcing immune evasion in CTNNB1-mutant HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0860
  28. Immunity. 2026 Oct 15. pii: S1074-7613(26)00397-3. [Epub ahead of print]
    Lactate dehydrogenase A-dependent redox control of selective mRNA translation directs monocyte fate commitment.
    Ning Yang, Huixia He, Xin Liu.
      Monocyte-to-macrophage differentiation is a central process that shapes immune responses across diverse contexts, yet how inflammatory cues engage metabolism to instruct monocyte fate commitment remains unclear. Here, using a CRISPR-based metabolic screen combined with monocyte-specific perturbations in bacterial lung infection, we identified lactate dehydrogenase A (LDHA) as a key metabolic regulator of monocyte commitment to the nitric oxide synthase 2 (NOS2)+ macrophage fate in vivo. LDHA-dependent cytosolic nicotinamide adenine dinucleotide (NAD+) regeneration enabled selective hypoxia-inducible factor 1-alpha (HIF1α) translation through its 5' untranslated region (UTR) and is associated with structural remodeling of this region. HIF1α then functioned as a downstream effector that promoted the NOS2+ macrophage fate. Granulocyte-macrophage colony-stimulating factor (GM-CSF) further acted as an upstream metabolic priming signal that enhanced LDHA-dependent HIF1α regulation and supported this differentiation process. Together, these findings suggest that metabolic redox state regulates monocyte fate commitment through selective mRNA translation coupled to RNA structural remodeling.
    Keywords:  GM-CSF; HIF1α; LDHA; RNA structural remodeling; cytosolic NAD(+) regeneration; monocyte fate commitment; redox metabolism; selective mRNA translation
    DOI:  https://doi.org/10.1016/j.immuni.2026.09.022
  29. Cell Mol Immunol. 2026 Oct 16.
    Glutamate attenuates the ILC2 response and allergic airway inflammation via the kainate receptor GluK2.
    Bo Peng, Siying Sun, Lin Zhu, Shufen Zhong, Xixi Chen, Yaguang Zhang, Huacheng Yan, Yidan Sun, Jiajia Lv, Yuying Huang, Jianye Zhang, Bing Sun, Guochao Shi, Wei Tang.
      Group 2 innate lymphoid cells (ILC2s) play a critical role in initiating the type 2 immune response, particularly in allergic airway diseases. Although the effects of glutamate on the immune system have been reported previously, its role in modulating the function of ILC2s and lung inflammation remains unclear.In this study, we report that the glutamate levels increased in lung tissue following exposure to allergens. Consequently, glutamate was found to restrain ILC2 responses during lung inflammation in mice. Using Rag1-/- mice, we demonstrated that the inhibitory effect of glutamate on type 2 inflammation was independent of T and B cells. Further ILC2 adoptive transfer experiments in Rag-/-Il2rg-/- mice confirmed that glutamate likely exerted its effects by directly targeting ILC2s. In vitro experiments revealed that glutamate suppressed ILC2 function through ionic kainate receptor signaling. Genetic deletion of the kainate receptor subunit GluK2 enhanced ILC2 responses and exacerbated type 2 lung inflammation. Mechanistically, transcriptome and metabolic analyses revealed that glutamate reduced oxidative metabolism in ILC2s, thereby limiting their activation. Consistently, in vivo administration of BPAM344-a positive allosteric modulator that potentiates GluK2 signaling-effectively suppressed allergen-induced type 2 inflammation. Notably, ILC2-specific GluK2 deletion markedly attenuated the anti-inflammatory effects of BPAM344, indicating that its protective effects depend on ILC2-intrinsic GluK2 signaling.These findings demonstrate a novel role for glutamate in restraining ILC2 function, as it plays a protective role in alleviating airway inflammation. We propose that GluK2 activation may offer a promising therapeutic strategy for treating ILC2-driven allergic asthma.
    Keywords:  GluK2; Glutamate; ILC2; Type 2 lung inflammation
    DOI:  https://doi.org/10.1038/s41423-026-01461-4
  30. Metabolomics. 2026 Oct 10. pii: 170. [Epub ahead of print]22(6):
    Metabolic basis of post-infectious sequelae after Ebola virus disease.
    Anna C Sanford, Nell G Bond, Samuel Ficenec, Charlotte Osterman, Payton Farkas, Emily Engel, Bronwyn Gunn, Donald S Grant, Robert Samuels, Kevin J Zwezdaryk, John S Schieffelin.
       INTRODUCTION: Ebola virus disease (EVD) survivors often present with clinical sequelae after acute disease resolution, called post-Ebola syndrome (PES). Why some survivors develop these sequelae and others do not is poorly defined. Altered metabolism has been noted in acute EVD but has not been studied in PES. Here, we identified distinct metabolic pathways in EVD survivors with PES compared to asymptomatic survivors and potential biomarkers of PES.
    OBJECTIVES: The purpose of this study was to determine if EVD survivors with PES demonstrated differential metabolism compared to asymptomatic EVD survivors.
    METHODS: Plasma was collected from EVD survivors in Sierra Leone as part of an ongoing cohort study. Untargeted metabolomics (LC-MS/MS) was performed on survivors with and without sequelae as well as household contacts. Univariate, multivariate, biomarker and pathway analyses were performed in MetaboAnalyst. Spearman's R correlation was performed using JMP.
    RESULTS: We identified differential expression of metabolites involved in multiple metabolic pathways in EVD survivors with PES compared to asymptomatic survivors. These pathways include the tricarboxylic acid cycle as well as amino acid, nucleotide, and short chain fatty acid metabolism. Several of these pathways are associated with immune dysfunction. The identified metabolites have potential use as biomarkers of PES.
    CONCLUSION: EVD survivors with PES exhibit differing metabolism compared to asymptomatic EVD survivors in several pathways. Other studies have linked these pathways to immune dysfunction and chronic viral infection, however further immunometabolic studies of EVD survivors with PES are needed.
    DOI:  https://doi.org/10.1007/s11306-026-02544-z
  31. Gut Microbes. 2026 Dec 31. 18(1): 2748132
    A helminth-microbiota metabolic relay promotes disease tolerance.
    Ruohang Sun, Yi Liu, Yang Wang, Nuo Xu, Xiaoxiao Ma, Qingbo Lv, Xiufeng Zhao, Pascal Boireau, Zeming Wu, Mingyuan Liu, Xiaolei Liu, Xuemin Jin.
      Persistent infection by helminths requires limiting inflammatory damage despite incomplete pathogen clearance, yet how helminths mobilize resident microbiota to establish this state remains unclear. Here we identify a cross-kingdom metabolic relay through which Trichinella spiralis promotes systemic disease tolerance. Infection selectively expanded Ligilactobacillus murinus and redirected microbial tryptophan metabolism toward indole-3-lactic acid (ILA), a direct ligand of the aryl hydrocarbon receptor (AhR). Antibiotic perturbation abrogated ILA production, AhR activation and Treg-Th17 remodeling, whereas transfer of helminth-conditioned fecal preparations or supplementation with L. murinus or ILA restored these responses. Pharmacological inhibition or genetic deletion of AhR eliminated the protection conferred by T. spiralis, L. murinus and ILA against endotoxin-induced lung injury. In lethal SARS-CoV-2 infection, oral ILA improved survival and limited pulmonary immunopathology without reducing viral burden, thereby uncoupling host protection from pathogen control. In a human COVID-19 cohort, ILA relative abundance remained inversely associated with IFN-γ after adjustment for available clinical covariates. These findings reveal that helminths can reprogram commensal metabolism to govern systemic immune tolerance and identify microbial ILA production as a tractable postbiotic strategy for limiting inflammatory tissue damage.
    Keywords:  AhR; ILA; Treg/Th17; Trichinella spiralis; gut microbiota
    DOI:  https://doi.org/10.1080/19490976.2026.2748132
  32. Dev Cell. 2026 Oct 14. pii: S1534-5807(26)00358-8. [Epub ahead of print]61(10): 1945-1946
    Mitochondria strike two hits to drive the SASP.
    Jun Bum Park, Zhixun Dou.
      Senescent cells develop a persistent inflammatory signature with broad consequences for tissue function and disease. Martini et al.1 show that mitochondrial citrate metabolism drives inflammation through a pathway that acts independently of mitochondrial DNA-driven immune signaling yet cooperates with it to amplify the inflammatory response.
    DOI:  https://doi.org/10.1016/j.devcel.2026.09.010
  33. Neurosci Biobehav Rev. 2026 Oct 14. pii: S0149-7634(26)00497-5. [Epub ahead of print] 107039
    Convergent Microglial and Astrocytic Responses across Diverse Stress Paradigms: Integrating Inflammation, Metabolism, and Behavior.
    Kyoungho Suk.
      The central nervous system responds to diverse challenges through convergent glial mechanisms, yet most reviews examine single stressor paradigms in isolation. This review uniquely integrates current knowledge across five major stress categories (psychosocial, immune/inflammatory, infectious, injury/damage, and metabolic), revealing both shared pathways and stimulus-specific glial responses that have not been systematically compared. Because microglia and astrocytes are the principal immune-metabolic sensors mediating these responses, this review is centered on these two cell types, while acknowledging that oligodendrocytes, oligodendrocyte precursor cells, and ependymal cells also participate in stress-related glial pathology, particularly with respect to white matter and cerebrospinal fluid homeostasis. While all stressors activate common inflammatory cascades including NF-κB signaling, complement activation, and inflammasome assembly, they elicit distinguishable molecular signatures. For instance, psychosocial stress uniquely engages type I interferon responses driving microglial synapse elimination. Viral infections produce severe metabolic reprogramming, hijacking host metabolism to support viral replication while depleting cellular NAD+ and ATP. Autoimmune inflammation generates lipid-laden disease-associated microglia with upregulated cholesterol metabolism genes. Unlike previous reviews focusing solely on inflammation or metabolism, we emphasize their bidirectional integration as a unifying principle. Inflammatory signals trigger metabolic shifts toward aerobic glycolysis, generating lactate serving dual functions as neuronal fuel and inflammatory mediator. This metabolic reprogramming, orchestrated by pyruvate dehydrogenase kinase, hypoxia-inducible factor-1α, and mTOR, creates feedback loops linking glial dysfunction to neuronal alterations. Complement-mediated synaptic pruning, disrupted neuron-glia metabolic coupling, and impaired neurotrophic support converge to produce depression, cognitive impairment, and sickness behaviors. Individual variability reflects interactions among genetic factors, sex, age, and blood-brain barrier integrity. This cross-paradigm comparative approach identifies high-value therapeutic targets applicable across multiple conditions rather than single diseases. We propose integrated intervention strategies simultaneously targeting inflammatory and metabolic pathways, guided by single-cell profiling for personalized medicine tailored to individual patient molecular signatures. We further discuss the conceptual overlaps inherent to the five-category classification scheme adopted here and outline the limitations of extrapolating across heterogeneous stress paradigms, glial cell types, and species.
    Keywords:  Astrocytes; Depression; Glia; Metabolic reprogramming; Microglia; Neuroinflammation; Precision medicine; Stress; Synaptic pruning
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.107039
  34. mBio. 2026 Oct 16. e0163026
    Acetate modulates host physiology and bacterial energetics to improve antibiotic efficacy during obesity-associated infection.
    Arsalan Hussain, Prateek Bhardwaj, Ashish Kumar Ray, Aakash Singh, Abhiroop Sett, Ranjana Pathania.
      Antibiotic efficacy is conventionally attributed to the susceptibility of the infecting pathogen. However, obese patients experience disproportionately poor infection outcomes despite receiving antibiotics to which pathogens remain genetically susceptible. These observations suggest that host-associated factors can influence treatment outcomes independently of the bacterial genotype, although the underlying mechanisms remain poorly understood. Using a mechanistic comparison of diet-induced obese and healthy mice infected with Acinetobacter baumannii, we demonstrate that the effect of antibiotics is not solely a property of the pathogen but can be governed by a gut microbiota-derived metabolite acting on both host immunity and bacterial physiology. We identify obesity-associated acetate depletion as a key driver of antibiotic treatment failure, linking gut microbial metabolism to antibiotic activity during infection. We observed that this depletion impaired innate immune activation, reducing cytokine responses and neutrophil-mediated bacterial clearance. Under these conditions, A. baumannii displayed enhanced tolerance to bactericidal antibiotics, particularly tobramycin. Given these findings, we investigated whether acetate could be leveraged therapeutically to restore antibiotic efficacy. We observed that oral acetate supplementation remodeled the dysbiotic microbiome, whereas systemic acetate restored innate immune competence and neutrophil-mediated bacterial clearance. Most importantly, acetate reversed antibiotic tolerance and restored aminoglycoside killing by directly sensitizing host-induced tolerant bacterial populations. Mechanistically, acetate directly reprogrammed bacterial physiology to enhance aminoglycoside-mediated killing. Combined acetate-tobramycin treatment resulted in eradication of tolerant populations and markedly improved bacterial clearance in vivo. Our findings establish a mechanistic link between host metabolic state and antibiotic efficacy and identify acetate as a therapeutic intervention for obesity-associated gram-negative infections.
    IMPORTANCE: Antibiotic treatment failure in obese patients remains poorly understood and therapeutically unaddressed. This study reveals that host metabolic state can control antibiotic response through a gut microbiota-derived metabolite that acts on both host defense and bacterial physiology. We identify obesity-driven depletion of microbiota-derived acetate as a previously unrecognized determinant of antibiotic failure, operating independently of bacterial resistance. By simultaneously restoring gut microbial balance, rescuing impaired innate immunity, and directly sensitizing pathogens to aminoglycoside killing through bacterial membrane alteration, acetate supplementation addresses the host-pathogen-microbiome axis through a single intervention. Given its established clinical safety, acetate represents a compelling combination therapy alongside aminoglycosides in obesity-associated gram-negative infections in a population for which host-directed treatment strategies are currently limited.
    Keywords:  aminoglycosides; gram-negative infections; host-directed therapy; short-chain fatty acids; treatment failure
    DOI:  https://doi.org/10.1128/mbio.01630-26
  35. Int J Biol Macromol. 2026 Oct 13. pii: S0141-8130(26)04796-3. [Epub ahead of print] 154846
    WSSV355 enhances IDH1 enzymatic activity and promotes efficient WSSV replication.
    Cong-Yan Chen, Yen-Cheng Liang, Shu-Wen Cheng, Leonilo Endoma, Yi-Ting Tseng, Shu-Ting He, Ramya Kumar, Shih-Shun Lin, Chien-Kang Huang, Saengchan Senapin, Pakkakul Sangsuriya, Han-Ching Wang.
      White spot syndrome virus (WSSV) drives extensive metabolic reprogramming to support viral replication, including activation of reductive carboxylation, a pathway in which host isocitrate dehydrogenase 1 (IDH1) has a central role. However, the mechanisms by which viral factors regulate IDH1 and associated metabolic networks remain unclear. Here, we identified WSSV355 as a key viral regulator that contributed to IDH1 binding and activation during infection. Using yeast two-hybrid screening, WSSV355 was identified as an LvIDH1-interacting protein and further validated by co-immunoprecipitation and co-localization analyses. Functional assays demonstrated that WSSV355 enhanced IDH1 enzymatic activity, whereas truncation mapping revealed that distinct regions of WSSV355 contributed to IDH1 binding and activation. In vivo silencing of WSSV355 suppressed viral gene expression, and decreased viral genome copy number, establishing its role in promoting efficient WSSV replication. Affinity purification-mass spectrometry (AP-MS) further revealed that WSSV355 identified a set/network of WSSV355-associated proteins enriched in cytoskeletal, RNA-processing, and metabolic pathways. Integration with infection-responsive proteomic datasets identified candidate modules linking the WSSV355-associated protein network to host infection responses, suggesting broader potential involvement of WSSV355 in host cellular processes during infection. Collectively, these findings identify WSSV355 as an LvIDH1-interacting viral protein that enhances IDH1 enzymatic activity and is required for efficient WSSV replication. To our knowledge, WSSV355 is the first reported virus-encoded protein shown to enhance IDH1 enzymatic activity, providing new insights into how aquatic viruses exploit host metabolic machinery to promote infection.
    Keywords:  Isocitrate dehydrogenase 1 (IDH1); Litopenaeus vannamei; Metabolic reprogramming; Reductive carboxylation; Virus-host protein interaction; WSSV355; White spot syndrome virus (WSSV)
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154846
  36. Immunity. 2026 Oct 13. pii: S1074-7613(26)00392-4. [Epub ahead of print]59(10): 2605-2607
    Viral deISGylation holds the key to the metabolic kingdom.
    Byron Shue, Sonja M Best.
      The interferon-induced modification of cellular and viral proteins by ISG15 inhibits viral infection and is reversed by virus-encoded deISGylases, but the broad physiological impacts of this host-pathogen clash remain unclear. In this issue of Immunity, Zhu et al. reveal that ISG15 modification broadly restricts key metabolic pathways that deISGylation relieves to promote viral replication.
    DOI:  https://doi.org/10.1016/j.immuni.2026.09.017
  37. FASEB J. 2026 Oct 31. 40(20): e72368
    Loss of Acid Ceramidase in Myeloid Cells Protects From Chronic Colitis in IL10-Deficient Mice.
    Keila S Espinoza, Brandon K Dahl, Ella M Ryan, Mary R Gordon, Chelsea L Doll, Marilyn T Marron, Cameron A Beard, Pujarini D Dey, David G Besselsen, Richard J Simpson, Justin M Snider, Justin E Wilson, Pawel R Kiela, Ashley J Snider.
      Patients with inflammatory bowel disease exhibit elevated expression of acid ceramidase (AC), an enzyme in sphingolipid metabolism. Recent studies have shown that myeloid cells contribute to the elevated expression of AC, such that the conditional loss in these cell types protects from acute colitis. We crossed conditional ASAH1 LyzMCRE knockout mice with IL10 knockout mice to determine the role of AC in a model of spontaneous, chronic colitis. Colon tissues were analyzed for lipids, mRNA, and protein. We performed flow cytometry to determine the role of myeloid AC in recruiting immune cells in disease. In this study, the conditional loss of AC in myeloid cells protected from chronic colitis, reduced markers of inflammation, increased ceramides in the colon, and reduced the inflammatory metabolite sphingosine-1-phosphate (S1P). Recruitment of immune cells into intestinal tissue was significantly impaired, specifically recruitment of neutrophils and effector Th1/Th17 T cells. The findings from this study indicate that AC may be a promising therapeutic target for patients with inflammatory bowel disease by modulating sphingolipid metabolism in immune cells.
    Keywords:  acid ceramidase; colitis; inflammatory bowel disease; macrophage; sphingolipid
    DOI:  https://doi.org/10.1096/fj.202602342RRR
  38. Free Radic Biol Med. 2026 Oct 15. pii: S0891-5849(26)01213-X. [Epub ahead of print]
    Sdhd hypermethylation promotes succinate accumulation and NLRP3-related pyroptosis in septic lung injury.
    Yan Fan, Haiyan Zhang, Shuqi Meng, Shuang Li, Lintao Lou, Keliang Xie, Jiang Xie.
      Sepsis-induced acute lung injury (Si-ALI) involves metabolic and inflammatory dysregulation; however, its underlying mechanisms remain unclear. Here, we investigated the role of succinate accumulation and epigenetic silencing of succinate dehydrogenase subunit D (SDHD) in Si-ALI using septic mice, macrophages, and a publicly available transcriptomic dataset from patients with sepsis. Succinate supplementation increased lung inflammation, macrophage pyroptosis, and mortality in septic mice. Analysis of the GSE54514 dataset showed reduced SDHD expression in patients with sepsis. In septic mice, Sdhd overexpression reduced succinate accumulation, pyroptosis, lung injury, and mortality. In macrophages, Sdhd overexpression reduced oxidative mitochondrial DNA (ox-mtDNA) release and NLRP3-related pyroptosis. Mechanistically, sepsis-induced upregulation of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) was associated with Sdhd promoter hypermethylation and reduced Sdhd expression. Pharmacological DNMT inhibition with SGI-1027 reversed Sdhd promoter hypermethylation, restored Sdhd expression, reduced succinate accumulation and pyroptosis, and ameliorated lung injury. These findings support a DNMT-SDHD-succinate axis in sepsis-induced lung injury and suggest that targeting this pathway may represent a potential therapeutic target for Si-ALI.
    Keywords:  DNA methylation; NLRP3-related pyroptosis; SGI-1027; Sdhd; Succinate; acute lung injury
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.10.022
  39. Cell Rep. 2026 Oct 16. pii: S2211-1247(26)01233-7. [Epub ahead of print]45(10): 118154
    The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.
    Pham Thuy Tien Vo, Julien Cicero, Zichen Wang, Hiroyuki Hakozaki, Thomas S Hoang, Sendi Rafael Adame-Garcia, Dana J Ramms, Kuniaki Sato, Erica Stevenson, Yuan Zhou, Katie Fan, Juliette A Bokor, Vasiliya Kril, Cara Schiavon, Scott B Biering, Danielle L Swaney, Nevan J Krogan, Johannes Schöneberg, Uri Manor, J Silvio Gutkind.
      The stimulator of interferon genes (STING) pathway is essential for mounting robust innate immunity, yet its chronic activation can drive detrimental inflammation. Although multiple cell-autonomous mechanisms that restrain STING signaling have been reported, whether inflammatory mediators within the tissue microenvironment regulate STING activation remains elusive. Using herpes simplex virus type 1 infection as a model of STING activation, we revealed that the COX2-PGE2-PKA axis functions as a critical negative regulator of STING-mediated antiviral innate immunity. Mechanistically, PGE2 acts through the EP4-PKA cascade to induce PTEN-induced kinase 1 (PINK1)-mediated mitophagy by phosphorylating STOML2 at Ser29. This pathway facilitates the clearance of damaged mitochondria that serve as a source of immunostimulatory cytosolic mitochondrial DNA, thereby attenuating downstream STING activation and type I interferons while promoting viral replication. Together, these findings establish mitochondrial quality control as the mechanistic link between PGE2 signaling and mtDNA-dependent STING activation and identify the COX2-PGE2-PKA pathway as a druggable therapeutic target to enhance STING-mediated innate immunity.
    Keywords:  CP: immunology; EP4; STING signaling; antiviral innate immunity; cyclooxygenase-2; herpes simplex virus type 1; mitochondrial DNA; mitophagy; prostaglandin E2; protein kinase A; type I interferons
    DOI:  https://doi.org/10.1016/j.celrep.2026.118154
  40. Front Immunol. 2026 ;17 1965851
    Lactate metabolism and lactylation in uveal melanoma: from metabolic adaptation to immune regulation.
    Yingluan Wang, Zhan Cao, Dawei Sun, Lijun Qu.
      Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The liver is its most common site of metastasis, and in some patients, distant metastases may become clinically apparent years after treatment of the primary tumor. Metastatic UM generally shows limited responsiveness to immune checkpoint blockade. Although genetic alterations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX are important for the molecular classification and prognostic stratification of UM, these factors do not fully explain late metastatic recurrence, persistence of low-proliferative tumor cell states, immune escape, or adaptation to the hepatic metastatic microenvironment. Lactate is not only a major product of glycolysis but also an immunometabolic regulator. Through monocarboxylate transporter-mediated transport, HCAR1/GPR81 signaling, extracellular vesicle-associated transfer, and lysine lactylation, lactate influences tumor cell states, tumor-immune metabolic communication, chromatin regulation, and post-transcriptional control. In UM cell studies, exogenous lactate induces a quiescence-like phenotype characterized by reduced proliferation and migration, increased oxidative metabolism, changes in chromatin organization, and elevated H3K18la levels. Tumor-derived lactate increases the stability of PD-L1 and HLA-E proteins through GPR81-related signaling, enhancing the resistance of UM cells to T cell- and NK cell-mediated killing. Under hypoxic conditions, extracellular vesicle-associated lactate participates in metabolic communication between tumor cells and immune cells, alters macrophage states, and impairs CD8+ T-cell effector function. Lactylation further links lactate metabolism with chromatin regulation and RNA modification-related post-transcriptional control. Studies in related ocular melanoma models indicate that H3K18la regulates YTHDF2 and ALKBH3 and thereby affects m6A- and m¹A-associated RNA regulation. This review summarizes current studies on lactate production, transport, receptor signaling, extracellular vesicle-associated lactate transfer, and lactylation in UM and related ocular melanoma models, and discusses their roles in low-proliferative adaptation, tumor-immune metabolic communication, hepatic metastatic microenvironment adaptation, and therapeutic resistance.
    Keywords:  RNA modification; immune escape; lactate; lactylation; metabolic adaptation; quiescence-like state; tumor–immune metabolic communication; uveal melanoma
    DOI:  https://doi.org/10.3389/fimmu.2026.1965851
  41. Trends Endocrinol Metab. 2026 Oct 14. pii: S1043-2760(26)00268-7. [Epub ahead of print]
    Hyocholic acid: a primary bile acid regulating lifespan immunometabolism.
    Wei Jia, Xiaojiao Zheng.
      Hyocholic acid (HCA), a newly identified human primary bile acid, regulates glucose and lipid metabolism and maintains immunometabolic homeostasis. This forum article highlights HCA and its derivatives as key mediators of inter-organ crosstalk across the lifespan, underscoring their potential to advance diagnostics and therapeutics for immunometabolic disorders.
    Keywords:  bile acid; developmental programming; hyocholic acid; immunity; lifespan; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2026.09.016
  42. Sci Adv. 2026 Oct 16. 12(42): eaea8798
    Macrophage- or neutrophil-expressed UPP1 drives tumor growth and immune suppression in the tumor microenvironment.
    Yin Li, Qin Ran, Anying Xiong, Manling Jiang, Fengkai Xu, Yongqi Wei, Jie Gu, Guoping Li, Di Ge, Chunlai Lu.
      Uridine phosphorylase 1 (UPP1) has recently emerged as a metabolic regulator with critical roles in tumor cell biology. However, its expression pattern and functional significance in nonmalignant components of the tumor microenvironment (TME) remain largely unexplored. Here, we performed a comprehensive pan-cancer single-cell transcriptomic analysis revealing that UPP1 is highly expressed not only in tumor cells but also in tumor-associated macrophages (TAMs) and neutrophils (TANs). Clinically, UPP1 expression in TAMs and TANs correlates with poor prognosis and diminished response to immunotherapy across multiple cancer types. Mechanistically, UPP1 up-regulation could be driven by NF-κB signaling. Functionally, UPP1 reprograms macrophages toward a tumor-promoting phenotype, characterized by enhanced glycolysis, ATP-adenosine signaling activation, and increased production of immunosuppressive cytokines such as granulocyte colony-stimulating factor. In neutrophils, UPP1 also supports TAN polarization, influences neutrophil extracellular trap release, and contributes to broad immunosuppressive remodeling. In vivo, targeting UPP1 in macrophages or neutrophils reprograms the immune landscape and restrains tumor progression. Together, our findings uncover a previously underappreciated role of UPP1 in nonmalignant immune populations and establish it as a key immune mediator within the TME, offering a potentially promising therapeutic target for enhancing antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.aea8798
  43. Inflamm Res. 2026 Oct 12. pii: 238. [Epub ahead of print]75(1):
    UBE2C-TRIM21-driven NOS2 degradation stabilizes Tregs and suppresses pyroptotic signaling in thyrocytes in Hashimoto's thyroiditis.
    Xinyuan Cui, Yanting Mao, Bojin Xu, Mengru Yuan, Haiping Zhou, Shan Huang, Wenfang Peng.
       BACKGROUND: Hashimoto's thyroiditis (HT) features persistent immune intolerance and progressive thyrocyte injury, yet the mechanistic linkage between regulatory T cell (Treg) instability and inflammasome-driven inflammatory damage in thyroid follicular cells remains unclear. We hypothesized that a Treg-intrinsic proteostasis module restrains inflammatory effectors to preserve immune tolerance and limit thyrocyte pyroptotic signaling.
    METHODS: We integrated peripheral-blood Treg transcriptomics from HT patients and healthy controls with functional perturbation, proteomic interaction screening, ubiquitination reconstitution, immunometabolic profiling, and in vivo validation. Candidate regulators were prioritized using differential expression and network analyses, then interrogated in Tregs using gain/loss-of-function approaches and Transwell co-culture with primary thyroid cells. Protein-protein interactions were identified by Flag immunoprecipitation-mass spectrometry and validated by co-immunoprecipitation and BiFC. NOS2 ubiquitination and degradation were assessed by CHX chase, ubiquitination assays, linkage profiling, and in vitro reconstitution. Mitochondrial and metabolic consequences were evaluated by JC-1 staining and Seahorse OCR/ECAR assays. Translational relevance was tested in an experimental autoimmune thyroiditis (EAT) model with adoptive transfer of engineered Tregs and assessment of thyroid pathology, cytokines, autoantibodies, and pyroptosis-associated markers.
    RESULTS: Ubiquitin-conjugating enzyme E2C (UBE2C) emerged as a consistently downregulated hub gene in HT-associated Tregs and was linked to ubiquitin-proteasome and inflammatory programs. UBE2C preserved the Treg suppressive program (FOXP3/CD25, IL-10/TGF-β), improved protection of thyroid cells, and reduced thyrocyte inflammasome/pyroptosis-associated signaling (NLRP3/ASC induction, caspase-1 processing, and GSDMD-N generation). TRIM21 was identified as a UBE2C-interacting E3 ligase partner that cooperated with UBE2C to drive predominantly K48-linked polyubiquitination and proteasomal degradation of NOS2 (with K516 as a key acceptor site). NOS2 accumulation impaired Treg mitochondrial membrane potential and shifted bioenergetics toward glycolysis, undermining Treg stability and restoring thyrocyte inflammasome activation. In EAT, adoptive transfer of UBE2C-enhanced Tregs mitigated thyroid inflammation, reduced TgAb/TPOAb, increased IL-10/TGF-β, and suppressed tissue pyroptosis-associated markers, whereas NOS2 reconstitution counteracted these benefits.
    CONCLUSIONS: The UBE2C-TRIM21-NOS2 axis defines a proteostasis checkpoint that stabilizes Tregs and disrupts a Treg-thyrocyte inflammasome-GSDMD injury loop, highlighting potentially actionable nodes for future tolerance-restoring strategies in HT.
    Keywords:  Adoptive Treg transfer; Hashimoto’s thyroiditis; NLRP3 inflammasome; NOS2; Pyroptosis; Regulatory T cells; TRIM21; UBE2C; Ubiquitin-proteasome system
    DOI:  https://doi.org/10.1007/s00011-026-02375-7
  44. Life Sci. 2026 Oct 12. pii: S0024-3205(26)00547-3. [Epub ahead of print]406 124738
    UDP-glucose ceramide glucosyltransferase (UGCG) is a novel positive regulator of MyD88-driven inflammation in sepsis.
    Yidi Ding, Xuan Zhong, Fangfang Li, Lina Yan, Wen Tian, Xiaofei Yang, Huanjun Shen, Xuyang Zheng, Jianqi Lian.
      Excessive activation of MyD88 in sepsis drives uncontrolled cytokine production, leading to multi-organ injury and high mortality. However, the mechanisms that regulate MyD88 activation and link it to glycosphingolipid metabolism remain incompletely understood. Here, we identify UDP-glucose ceramide glucosyltransferase (UGCG) as a novel positive regulator of MyD88-mediated signaling and a potential biomarker for sepsis. UGCG expression was elevated in septic patients and LPS-stimulated cells. Transcriptomic analysis showed that UGCG knockdown broadly suppresses inflammatory pathways. Functionally, UGCG deficiency selectively impaired MyD88- but not TRIF-dependent signaling and reduced cytokine production. Pharmacological inhibition of UGCG using the FDA-approved drug N-butyl-deoxynojirimycin (NB-DNJ) suppressed inflammatory gene expression, immune cell infiltration, and lung injury in an LPS-induced murine sepsis model. Mechanistically, UGCG interacts with the MyD88 TIR domain to promote MyD88 protein stability, while UGCG deficiency is associated with impaired ligand-triggered MyD88 oligomerization. Together, these findings uncover a previously unrecognized UGCG-MyD88 axis that directly links UGCG to innate immune signaling independently of its enzymatic activity, and highlight UGCG as a promising therapeutic target for sepsis.
    Keywords:  Inflammatory response; MyD88; Oligomerization; Sepsis; Stability; UGCG
    DOI:  https://doi.org/10.1016/j.lfs.2026.124738
  45. Mol Neurobiol. 2026 Oct 14. pii: 964. [Epub ahead of print]63(1):
    NAD+ Attenuates Neuroinflammation in Ischemic Stroke by Suppressing the cGAS- STING Pathway via Mitochondrial Homeostasis Restoration.
    Sijia Jiang, Bo Liao, Guiping Wang, Rui Sheng, Chong Han, Zhi Jiang, ShanYao Pan, Chu Wu, Guoqiang Liang, Yongming Zhu, Ming Cheng, Feiyan Zhao, Zhiyin Jiang, Xuyi Yao, Zhenghong Qin, Yaping Huai, Yiqing Lu, Weiwei Yang, Jie Bao, Qing Zhang, Gang Zhao, Jiao Deng, Zhi Gang Lv, Junchao Wu, Li Luo, Yuanyuan Qin.
      Stroke remains one of the leading causes of death and disability worldwide, with neuroinflammation playing a critical role in its pathogenesis. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a major driver of innate immune responses activated by endogenous DNA, including mitochondrial DNA (mtDNA), and contributes significantly to post-ischemic neuroinflammation. Nicotinamide adenine dinucleotide (NAD+), a vital metabolic coenzyme, has demonstrated anti-inflammatory potential in various diseases, including stroke; however, its specific role in regulation of neuroinflammation following stroke remains unclear. In this study, we examined the protective effects of NAD+ against ischemic stroke and explored its role in modulating cGAS-STING-mediated neuroinflammatory responses. Utilizing a transient middle cerebral artery occlusion/reperfusion mouse model and an oxygen-glucose deprivation/reoxygenation BV2 microglia model, we observed that NAD+ treatment significantly reduced infarct volume and brain edema, and improved neurological outcomes. NAD+ reduced the levels of pro-inflammatory cytokines and facilitated the polarization of microglia from pro-inflammatory M1 to the anti-inflammatory M2 phenotype. This effect was associated with the inhibition of cGAS-STING-TBK1 signaling pathway activation. Pharmacological inhibition or genetic knockdown of STING largely abrogated the anti-inflammatory effects of NAD+ in BV2 microglia, indicating a STING-dependent mechanism. Furthermore, NAD+ restored mitochondrial respiratory function and reduced cytoplasmic mtDNA leakage, suggesting that the improvement of mitochondrial homeostasis may underlie the suppression of cGAS-STING-TBK1 signaling pathway by NAD+. Our findings indicate that NAD+ alleviates neuroinflammation following brain ischemia/reperfusion injury by regulating mitochondrial homeostasis and attenuates the cGAS-STING-TBK1 signaling pathway activation in microglia, thereby providing new therapeutic insights for ischemic stroke.
    Keywords:  CGAS-STING pathway; Ischemic stroke; Microglia; Mitochondrial homeostasis; NAD+ ; Neuroinflammation
    DOI:  https://doi.org/10.1007/s12035-026-06257-1
  46. Microbiol Res. 2026 Oct 04. pii: S0944-5013(26)00314-9. [Epub ahead of print]315 128750
    Lactobacillus reuteri attenuates chronic diarrhea by modulating microbiota homeostasis and macrophage polarization through the cGAS/STING pathway dependent on D-lactate-mediated mitochondrial function.
    Xukai Cheng, Yining Zhang, Chao Li, Mi Jiang, Jia Song, Feifei Fang, Ke Chang, Xinyue Zhu, Chenxing Jian, Jinhuang Chen, Xiaogang Shu.
      Chronic diarrhea (CD) severely affects patients' quality of life and is linked to ulcerative colitis, inflammatory bowel disease, and colorectal cancer. Gut microbiota dysbiosis plays a crucial role in intestinal health, with Lactobacillus reuteri emerging as a key regulator. However, its role in chronic diarrhea remains unclear. In this study, we observed macaques with spontaneous diarrhea and investigated microbial and metabolic changes. We also developed a chronic diarrhea mouse model using dextran sulfate sodium. CD group of both models revealed a significant reduction of L. reuteri. L. reuteri transplantation alleviates intestinal injury in CD by secreting D-lactate and modulates macrophage polarization. L. reuteri-derived D-lactate binds to IARS2 in intestinal epithelial macrophages, reducing mitochondrial IARS2 activation and suppressing cGAS-STING pathway activation. This preserves mitochondrial function while decreasing M1 macrophage polarization. Our research revealed the significance of microbiota dysbiosis in CD with both non-human primate and murine model, and highlighted the critical role of L. reuteri, which is conducted with D-lactate-mediated modulation of macrophage function and offered new insights into probiotic therapy for CD.
    Keywords:  Chronic diarrhea; D-Lactate; IARS2; L. reuteri; Macrophage polarization
    DOI:  https://doi.org/10.1016/j.micres.2026.128750
  47. Aging Cell. 2026 Oct;25(10): e70771
    Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.
    McKenna M Somerville, Sydney S Lin, Scott W Ballinger, Alecia K Gross.
      Mitochondria are central regulators of retinal bioenergetics and innate immune signaling, yet how mitochondrial genetic background and aging jointly influence immunometabolic responses in the retina remains poorly defined. Here, we investigated the effects of mitochondrial DNA (mtDNA) variation on retinal function and the combined effects of mtDNA variation and age on bioenergetic composition, mtDNA damage, and the microglial expression and intracellular localization of stimulator of interferon genes (STING) protein. Using mitochondrial-nuclear eXchange (MNX) mice harboring identical C57BL/6J nuclear genomes but distinct C57 or C3H mtDNA haplotypes, we assessed oxidative phosphorylation complex composition, electrophysiological function, mtDNA damage, and microglial STING dynamics across the lifespan and following acute intraocular pressure (IOP) elevation. Aging was associated with increased mtDNA damage and remodeling of oxidative phosphorylation complex composition, characterized by reduced Complex III and V abundance and increased Complex IV. Despite these age-associated changes, photoreceptor- and retinal ganglion cell-associated retinal responses were preserved at early ages, whereas bipolar cell-associated responses differed by mtDNA background. Microglial STING expression increased with age. Acute IOP elevation was associated with differential microglial STING dynamics and STING association with lysosomal compartments decreased with age. Together, these findings demonstrate that mitochondrial genetic background and aging influence retinal bioenergetics and neuroimmune protein expression and identify mtDNA variation as a modifier of age-associated microglial STING expression in the retina.
    Keywords:  metabolism; microglia; neuroinflammation; retina
    DOI:  https://doi.org/10.1111/acel.70771
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