bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–06–28
63 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Gut microbiome metabolites meet immunometabolism in inflammatory bowel disease.
  2. Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.
  3. Immuno-cell metabolic changes in HIV-1 infection.
  4. Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
  5. Oral Barrier Immunometabolism in Chronic Low-Grade Inflammation: Molecular Mechanisms and Systemic Implications.
  6. Foot-and-mouth disease virus regulates glycolysis through autophagy to drive viral replication in vivo and in vitro.
  7. Decoding the immunometabolic landscape identifies SLC7A5 as a vulnerability in chemo-immunotherapy resistant TNBC.
  8. Metformin as an Innate Immune Modulator: Metabolic and Epigenetic Reprogramming of Innate Immune Cells and Therapeutic Implications.
  9. Metabolic alterations in the tumor microenvironment influence the anti-tumor immune function of CD8+ T cells via epigenetic modifications.
  10. Pathogenic Rewiring of IL6 Signaling Fuels Macrophage Immunometabolic reprogramming in COPD.
  11. Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
  12. Macrophage-Orchestrated Metabolic Sensing Drives IBD Pathogenesis: A Framework for Targeted Therapy.
  13. Fatty acid-binding protein 5 deficiency impairs alveolar macrophage function and metabolism.
  14. New insights into the ACLY-mediated metabolic and epigenetic interplay in macrophages.
  15. Immune metabolic remodeling during exercise rehabilitation: Linking skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation.
  16. Diet-Microbiota-Immune Interactions in Hepatocellular Carcinoma: An Immunometabolic and Spatial Perspective.
  17. De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity.
  18. Metabolic Reprogramming-Driven Cardiovascular Immune Damage: From Glyco-Lipotoxicity and Epigenetic Memory to Multidimensional Cross-Organ Communication Networks.
  19. Lipid droplet-mitochondria tethering releases MAVS inhibition to potentiate antiviral immunity.
  20. Disturbed metabolic adaptation drives natural killer cell dysfunction in association with nosocomial infection during human sepsis.
  21. H3K18 lactylation promotes allergic airway inflammation in asthma via a CSF1/CSF1R/MAPK autocrine axis.
  22. Metabolic reprogramming regulates macrophage polarization to impact ovarian cancer progression.
  23. Copper Metabolism in Isolated Macrophages: Regulator of Immunity and Inflammation.
  24. O-GlcNAcylation-mediated glycolytic reprogramming of CD4+ T cells contributes to type H vessel impairment in diabetic osteoporosis.
  25. Lactylation: a novel post-translational modification for cGAS-STING pathway.
  26. AFF3 maintains metabolic quiescence in naïve CD8 T cells and prevents premature immune aging.
  27. Offense and defense: itaconate mediates bidirectional immune regulation of host-bacteria interaction.
  28. Diacylglycerol kinase ζ in B lymphocytes supports CD40-mediated immune synapse formation, mTORC1 signaling, and plasma cell fate.
  29. NAD+ metabolism at the host-virus interface.
  30. PFKFB3 Mediated Glycolytic Reprogramming Drives Vascular Endothelial Injury Under Chronic Intermittent Hypoxia.
  31. Hexokinase 2 deficiency protects against sepsis-associated lung injury via suppressing the NF-κB signaling pathway.
  32. Severity-dependent metabolic rewiring in COVID-19 based on untargeted metabolomic profiling of patient plasma.
  33. Differential regulation of hepatic macrophage fate by Chi3l1 in metabolic dysfunction-associated steatotic liver disease.
  34. Immune cell-intrinsic STING activation drives tumor ferroptosis via AA-mediated suppression of ACSL4 lactylation in colorectal cancer.
  35. Crosstalk between CD8+ T cells and systemic bile acid metabolism shapes antiviral immunity and immunopathology.
  36. Beyond a waste product: lactate as a master metabolite dictating anti-tumor T-cell fate.
  37. Immune Cell Mitochondrial Respiration and Inflammatory Profiles Are Partially Modulated by Cardiorespiratory Fitness in Male Adults.
  38. NFAT5 in alveolar macrophages exacerbates seawater-induced acute lung injury via PFKP-driven glycolysis.
  39. Immunometabolic Reprogramming in Hepatocellular Carcinoma Mechanisms, Biomarkers, and Therapeutic Implications.
  40. Activation-induced SLC7A1 expression enhances T cell sensitivity to cGAMP-mediated STING signaling.
  41. Impaired BCAA Catabolism in Macrophages Exacerbates Sepsis-Induced Lung Injury by Modulating Mitochondrial AGE-RAGE and mtDNA Release.
  42. Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
  43. Dietary fructose promotes MASH/HCC progression through enhanced intestinal HIF-2α-dependent iron absorption.
  44. PCK2-Mediated PQBP1 Lactylation Promotes Asthmatic Inflammation through PRMT5 Inhibition.
  45. Lactate-Primed NETosis Modulates Hepatic Regeneration During Acute Liver Failure via the TLR9/KLF15/AJUBA Axis.
  46. Zinc Inhibits BTK Phosphorylation in Macrophages to Ameliorate Encephalitis in Neurotropic Virus-Infected Mice.
  47. Melatonin Modulates Macrophage Polarization and Immunometabolic Responses in the Colostrum of Obese Mothers.
  48. Circulating acidic α-glucosidase as a potential biomarker for lactate-related immunometabolism in ischemic stroke.
  49. Methylmalonic acid as a ferroptosis-derived danger signal: activation of the PI3K-NF-κB pathway drives M1 macrophage polarization in renal ischemia-reperfusion injury.
  50. The gut-joint axis in gout: microbial outer membrane vesicles and m6A-mediated metabolic-epigenetic coupling from acute flare to chronicity.
  51. Lactylation-driven microglial GCH1-BH4 axis suppresses neuroinflammation and underlies the preventive effects of treadmill running against CSDS-induced depression-like behaviors in mice.
  52. Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation.
  53. Adenosine deaminase co-immunization reverses age-associated immunosenescence by restoring germinal center T follicular helper cell function.
  54. Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
  55. Amino Acid Metabolic Reprogramming in Immunotherapy for Hepatocellular Carcinoma: Adaptive Resistance, Patient Stratification, and Longitudinal Monitoring.
  56. The metabolic basis of regulated cell death.
  57. Gut microbiota-dependent metabolism of 6-shogaol generates bioactive metabolites that mediate its anti-inflammatory effects.
  58. The immunomodulatory role of vitamins in tumor: mechanisms and therapeutic implications.
  59. Mitochondria: from powerhouses of cells to hubs in antitumor immunity.
  60. Immunometabolic Stratification of Autism Spectrum Disorder by CD4+ T-Cell Phenotype Reveals Subtype-Specific Energetic Deficit and Coordinated Suppression of Micronutrient Acquisition Pathways.
  61. Engineering the "pro-healing niche": Hydrogel-driven immunometabolic reprogramming for diabetic foot ulcers.
  62. Adipose tissue as a site of immune activation and dysfunction in individuals with obesity and asthma.
  63. Mitochondrial stress response drives microglial senescence.
  1. Trends Immunol. 2026 Jun 23. pii: S1471-4906(26)00138-9. [Epub ahead of print]
    Gut microbiome metabolites meet immunometabolism in inflammatory bowel disease.
    Qing Li, Rodrigo de Oliveira Formiga, Harry Sokol.
      Growing evidence indicates that gut microbiota-derived metabolites are key regulators of immunometabolism in inflammatory bowel disease (IBD). Intestinal epithelial cells and immune cells exhibit profound metabolic alterations in IBD. Microbial metabolites act as intermediates in host-microbe communication, reshaping mitochondrial functions and cellular metabolic pathways, thereby impacting immune functions. Dysbiosis may, therefore, perturb immune homeostasis by rewiring host metabolic circuits. Understanding how microbial metabolites orchestrate immunometabolic crosstalk in the gut and leveraging it to recalibrate host immunometabolic circuits represents promising, underexplored therapeutic avenues. In this review, we highlight emerging concepts on how gut microbiota-derived metabolites shape immune cell immunometabolism and discuss the therapeutic potential of targeting the microbiota-metabolite-immunometabolism axis in IBD.
    Keywords:  endosymbiosis; gut microbiota; immunometabolism; inflammatory bowel disease; mitochondria
    DOI:  https://doi.org/10.1016/j.it.2026.06.001
  2. Trends Immunol. 2026 Jun 25. pii: S1471-4906(26)00137-7. [Epub ahead of print]
    Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.
    Amélie E Bura, Andrea Rolong, Christophe Paget, Maxime Guéguinou.
      Mitochondrial calcium (mtCa2+) has long been framed as a bioenergetic regulator, yet evidence redefines it as a relevant immunometabolic switch. Within the tumor microenvironment, the mitochondrial calcium uniporter (MCU) complex and the NCLX-TMEM65 efflux axis maintain a 'Goldilocks zone' of Ca2+ homeostasis. This can be exploited by cancer cells to sustain oxidative phosphorylation and tricarboxylic acid-derived oncometabolite production, including succinate, fumarate, and 2-hydroxyglutarate, while imposing ionic and nutrient constraints on infiltrating immune cells. Chronic mtCa2+ overload in effector T cells drives mitochondrial dysfunction and exhaustion, while oxidative phosphorylation-dependent Ca2+ flux enforces the acquisition of an immunosuppressive profile in macrophages. Disrupting these tumor-immune ionic imbalances through selective MCU modulation or efflux pathway targeting offers a strategy to restore immune surveillance and/or enhance immune checkpoint inhibitor therapies.
    Keywords:  T cells; cancer; immune checkpoint blockade; immunometabolism; mitochondrial calcium signaling; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.it.2026.05.012
  3. Infect Dis Immun. 2025 Jul;5(3): 177-189
    Immuno-cell metabolic changes in HIV-1 infection.
    Linle Xu, Yufen Jiang, Xuexing Zheng, Hongbo Shi.
      Recent research has shown that metabolic processes within immune cells are essential for both human immunodeficiency virus 1 (HIV-1) infection and the immune response. Throughout HIV-1 infection-from acute stages to chronic infection and viral latency-immune cells experience shifts in energy demands and metabolic pathways, paralleling T-cell exhaustion. Dysregulated immune metabolism compromises immune cell function, leading to immune dysfunction and persistent inflammation. Therefore, metabolic alterations in immune cells constitute a critical mechanism in HIV-1 progression and chronic inflammation. This review specifically explores the metabolic profiles and roles of T cells, monocytes-macrophages, dendritic cells, natural killer cells, and B cells at different stages of HIV-1 infection, emphasizing the effects of HIV-1 on the metabolic pathways of diverse immune cell types. These insights offer valuable therapeutic strategies aimed at inhibiting viral replication, restoring immune function, and controlling disease progression.
    Keywords:  DCs; Glycolysis; HIV-1; Metabolism; Monocyte–macrophages; T cells
    DOI:  https://doi.org/10.1097/ID9.0000000000000159
  4. Antioxidants (Basel). 2026 Jun 19. pii: 768. [Epub ahead of print]15(6):
    Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
    Shikha Yadav, Rajagopal Kamarajan, Varadarajan Sudhahar, Sheela Nagarkoti, Archita Das, Stephanie Kelley Spears, Rajalakshmi Veeranan Karmegam, Tohru Fukai, Masuko Ushio-Fukai.
      Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated "redox-dead" DRP1-C631A knock-in mutant (Drp1C/A) BM exhibited markedly reduced limb perfusion recovery and CD31+ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G+ neutrophil accumulation, pro-inflammatory F4/80+CD80+ M1-like macrophages and reduced anti-inflammatory F4/80+CD206+ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD.
    Keywords:  DRP1; hindlimb ischemia; inflammation; macrophage; metabolic reprogramming; mitochondrial fission; peripheral arterial disease; post-translational modification; sulfenylation
    DOI:  https://doi.org/10.3390/antiox15060768
  5. Int J Mol Sci. 2026 Jun 13. pii: 5356. [Epub ahead of print]27(12):
    Oral Barrier Immunometabolism in Chronic Low-Grade Inflammation: Molecular Mechanisms and Systemic Implications.
    Aferdita Ademi, Skender Topi, Mitilda Gugu, Alessia Ciafarone, Maria Grazia Cifone, Davide Pietropaoli, Serena Altamura.
      Chronic low-grade inflammation is a hallmark of aging and a major driver of metabolic and degenerative diseases. While systemic immune dysfunction has been widely investigated, the contribution of barrier tissues to persistent inflammatory signaling remains incompletely defined. The oral mucosa represents a uniquely exposed barrier, continuously challenged by microbial, mechanical, and metabolic stressors and characterized by a specialized immune architecture. Here, we synthesize current evidence supporting the oral barrier as an active immunometabolic interface linking local immune activation to systemic inflammatory tone. Spatially organized epithelial, neutrophil, and antigen-presenting cell (APC) compartments coordinate immune responses tightly coupled to metabolic reprogramming, including hypoxia-inducible factor-1α (HIF-1α)-dependent glycolysis and mitochondrial reactive oxygen species (mtROS) production. In parallel, the oral microbiota provides ligands and metabolites such as lipopolysaccharide (LPS), short-chain fatty acids (SCFAs), and succinate, which activate pattern-recognition receptors (PRRs), including toll-like receptors (TLRs) and the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, thereby sustaining nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-mediated inflammatory signaling. Barrier disruption and dysbiosis promote microbial translocation and persistent innate immune activation, while saliva and gingival crevicular fluid facilitate systemic dissemination of inflammatory mediators. Overall, sustained immunometabolic engagement at the oral barrier emerges as a key driver of chronic low-grade systemic inflammation and a potential therapeutic target in inflammaging.
    Keywords:  NLRP3 inflammasome; barrier tissues; chronic inflammation; immunometabolism; inflammaging; mtROS; oral microbiota; oral mucosa; oral–systemic axis
    DOI:  https://doi.org/10.3390/ijms27125356
  6. Autophagy. 2026 Jun 23.
    Foot-and-mouth disease virus regulates glycolysis through autophagy to drive viral replication in vivo and in vitro.
    Qiao Xue, Huisheng Liu, Zhihua Dong, Yingming Zhu, Fan Yang, Weijun Cao, Zixiang Zhu, Haixue Zheng.
      Viruses, lacking an intrinsic metabolic network, exploit host cell metabolism in order to hijack resources for their own replication. However, the regulatory relationship between foot-and-mouth disease virus (FMDV) and energy metabolism remains incompletely elucidated. Here, metabolomic analysis was performed on PK-15 cells and tonsils infected with FMDV. Metabolites involved in glycolysis were significantly upregulated, whereas metabolites associated with the tricarboxylic acid (TCA) cycle were markedly downregulated in vivo and in vitro, which indicated that FMDV induced reprogramming of host cell energy metabolism, shifting it from oxidative phosphorylation (OXPHOS) to glycolysis. Furthermore, FMDV infection promoted glucose uptake and its subsequent utilization in FMDV-infected PK-15 cells, facilitating viral replication. Mechanistically, on the one hand, FMDV infection activated the AKT-MTOR-dependent macroautophagy/autophagy pathway to suppress the expression of OTUD4 (OTU deubiquitinase 4), upregulating HK2 (hexokinase 2) to facilitate glycolysis. On the other hand, FMDV infection decreased the level of mitochondrial SIRT3 (sirtuin 3) through PINK1-PRKN-dependent mitophagy, leading to the increase of HIF1A (hypoxia inducible factor 1 subunit alpha), HK2, phosphofructokinase 1 (PFK1), and PKM/PKM2 (pyruvate kinases M1/2), promoting glycolysis. Overall, this study elucidates how FMDV modulates glycolysis through two different autophagic pathways, which would contribute to our understanding of how the autophagy-glycolysis axis regulates viral replication, providing new avenues for developing antiviral strategies targeting metabolism.
    Keywords:  Autophagy; FMDV; OTUD4; SIRT3; glycolysis
    DOI:  https://doi.org/10.1080/15548627.2026.2693780
  7. Clin Exp Med. 2026 Jun 25.
    Decoding the immunometabolic landscape identifies SLC7A5 as a vulnerability in chemo-immunotherapy resistant TNBC.
    Sen Zhong, Bolin Yu, Shengyi Zhou, Wenlong Chen, Fanglong Liu, Huanhuan Zhu, Fang Min, Fengyuan Qian.
      Metabolic reprogramming within the tumor microenvironment (TME) limits the efficacy of chemo-immunotherapy in triple-negative breast cancer (TNBC). Despite advances in high-resolution profiling, the specific intercellular metabolic crosstalk driving immune evasion remains incompletely understood. Here, we present a comprehensive single-cell metabolic atlas of the TNBC ecosystem to decode spatial and cell-type-specific metabolic vulnerabilities. Our multidimensional analysis reveals a distinct paracrine metabolic communication axis: CXCL9+ macrophages upregulate rate-limiting enzymes (IDO1/2) to become a potential source of local kynurenine, which is subsequently imported by cytotoxic T cells. Through in vitro co-culture and in vivo models, we demonstrate that this kynurenine uptake triggers impaired effector function and phenotypic exhaustion. Crucially, pharmacological blockade of SLC7A5 with the specific inhibitor JPH203 abrogates this metabolic toxicity, restores T cell effector function, and enhances the anti-tumor efficacy of combined cisplatin and anti-PD-1 therapy. Collectively, our findings delineate the Kynurenine-SLC7A5 metabolic axis as a critical driver of immunosuppression, providing a compelling rationale for integrating amino acid transport blockade to overcome resistance to chemo-immunotherapy.
    Keywords:  Chemo-immunotherapy resistance; Immunometabolism; Kynurenine; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10238-026-02231-2
  8. Curr Issues Mol Biol. 2026 Jun 22. pii: 642. [Epub ahead of print]48(6):
    Metformin as an Innate Immune Modulator: Metabolic and Epigenetic Reprogramming of Innate Immune Cells and Therapeutic Implications.
    Yunfeng Shi, Sheng Xia.
      Metformin, widely prescribed for type 2 diabetes mellitus (T2D), has emerged as a systemic immunomodulator with effects that extend far beyond glycemic control. Recent advances in immunometabolism reveal that metformin modulates innate immune responses through coordinated cellular metabolic reprogramming and epigenetic modification, which collectively modulate the functional phenotype of innate immune cells. This narrative review summarizes current evidence regarding the immunomodulatory effects of metformin on the innate immune system, with a focus on immunometabolism and epigenetic regulation. It explores how metformin modulates innate immunity by altering cellular energy sensing, mitochondrial function, and nutrient utilization. Such metabolic changes and alterations further reshape chromatin structure and architecture, as well as transcriptional profiles and programs. Through the regulation of glycolysis, fatty acid oxidation, and histone modification landscapes, metformin regulates the phenotypes of innate immune cells, which can be pro-inflammatory, tolerogenic, or homeostatic. This conceptual framework presents a new understanding of metformin. As well as acting as an anti-inflammatory agent, it may regulate immune memory.
    Keywords:  AMP-activated protein kinase; epigenetic regulation; immunometabolism; innate immunity; macrophage; metformin
    DOI:  https://doi.org/10.3390/cimb48060642
  9. Int Rev Immunol. 2026 Jun 27. 1-18
    Metabolic alterations in the tumor microenvironment influence the anti-tumor immune function of CD8+ T cells via epigenetic modifications.
    Yaru Liu, Wei Du, Weimin Deng.
      Metabolic reprogramming within the tumor microenvironment (TME) is a pivotal driver of CD8+ T cell dysfunction in cancer. Tumor cells outcompete T cells for essential nutrients, including glucose and amino acids, while accumulating immunosuppressive metabolites such as lactate and 2-hydroxyglutarate. Beyond direct functional impairment, emerging research reveals that these metabolic alterations orchestrate CD8+ T cell transcriptional programs by remodeling their epigenome-via histone modifications, DNA methylation, and non-coding RNA networks-thereby dictating their differentiation, cytotoxic potential, and memory formation. A deeper understanding of how TME-derived metabolic signals shape the epigenetic landscape of CD8+ T cells is crucial for improving current cancer immunotherapeutic strategies. This review systematically delineates how key TME metabolic features, including nutrient deprivation and oncometabolite accumulation, regulate CD8+ T cell fate through epigenetic pathways. Furthermore, we discuss promising therapeutic strategies that target the metabolism-epigenetics axis to reinvigorate CD8+ T cell anti-tumor immunity, offering novel perspectives for enhancing adoptive cell therapy and immune checkpoint blockade.
    Keywords:  CD8+ T cells; Cancer immunotherapy; epigenetics; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1080/08830185.2026.2687543
  10. Am J Respir Cell Mol Biol. 2026 Jun 23. pii: aanag113. [Epub ahead of print]
    Pathogenic Rewiring of IL6 Signaling Fuels Macrophage Immunometabolic reprogramming in COPD.
    Xiaoli Zou, Qiqing Huang, Chenxi Cao, Shaoran Shen, Pinping Shao, Xuening Zhang, Yibo Bian, Wei Xu, Jianqing Wu.
      While human genetics implicate the interleukin-6 (IL6) signaling pathway as a potential therapeutic target in chronic obstructive pulmonary disease (COPD), its functional role in pulmonary macrophages remains paradoxical given its established role in promoting cholesterol efflux. Here, integrating single-cell transcriptomics of human COPD lungs with mechanistic studies, we resolve this paradox by identifying a pathogenic rewiring of the IL6/STAT3 pathway. We discovered a disease-enriched macrophage subpopulation exhibiting co-activation of IL6/STAT3 signaling, cholesterol biosynthesis, and inflammatory pathways. In a murine COPD model, chronic cigarette smoke (CS) exposure recapitulated this immunometabolic phenotype. We defined a linear pathway wherein CS-induced IL6 activates STAT3, which directly transactivates the sterol regulatory element-binding protein 2 (SREBP2) to drive de novo cholesterol synthesis. This SREBP2-dependent cholesterol accumulation was essential for NLRP3 inflammasome activation and pro-inflammatory cytokine release. In vitro, pharmacological inhibition of STAT3 or SREBP2, as well as IL6 silencing, disrupted this cascade, suppressing cholesterol-driven inflammation. Critically, in vivo macrophage-specific Il6 knockdown attenuated pulmonary inflammation, cholesterol accumulation, and emphysema development by disrupting the entire IL6/STAT3/SREBP2 axis. Thus, we define the IL6/STAT3/SREBP2 axis as a core immunometabolic driver of COPD pathogenesis, which directly couples CS exposure to sustained macrophage inflammation via pathological cholesterol synthesis, thereby providing a mechanistic basis for targeting this druggable pathway.
    Keywords:  Cigarette Smoke; Metabolic Reprogramming; NLRP3 inflammasome; SREBP2
    DOI:  https://doi.org/10.1093/ajrcmb/aanag113
  11. Nat Commun. 2026 Jun 25.
    Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
    Zhongkun Liu, Lang Chen, Tong Zhang, Yuliang Wang, Panpan Ma, Xiangwei Zhang, Ronghui Liu, Ruiying Zhang, Xuanhao Zhang, Qingqing Su, Jinyan Huang, Da Wang, Qi Zhang, Cunqi Ye, Yun-Hua Liu.
      Lipid accumulation is a hallmark of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment, yet effective strategies to reprogram this lipid-rich niche and restore anti-tumor immunity remain limited. Here, we show that diacylglycerol O-acyltransferase 1 (DGAT1) as a tumor-intrinsic metabolic checkpoint that promotes immune evasion. DGAT1 inhibition rewires tumor lipid metabolism by promoting increased fatty acid uptake and redistribution, thereby depleting extracellular free fatty acids that impair CD8⁺ T cell function. Mechanistically, decreased palmitate availability alleviates endoplasmic reticulum stress, preserves FOXO1 activity, and supports stem-like CD8⁺ T cell differentiation. This competitive lipid remodeling enhances memory potential, restrains terminal exhaustion, and sensitizes PDAC tumors to PD-1 checkpoint blockade in vivo. Together, our findings identify tumor-immune lipid crosstalk as a key barrier to effective immunity in PDAC and establish DGAT1 as a promising therapeutic target to restore T cell function and improve immunotherapy response.
    DOI:  https://doi.org/10.1038/s41467-026-74315-2
  12. Int J Biol Sci. 2026 ;22(11): 5754-5779
    Macrophage-Orchestrated Metabolic Sensing Drives IBD Pathogenesis: A Framework for Targeted Therapy.
    Guangqi Guan, Xuelin Sun, Yaoxing Chen, Qingyun Guo, Yulan Dong.
      Inflammatory bowel disease (IBD) arises from dysregulated interactions among the gut microbiota, immune system, and intestinal epithelium. Intestinal macrophages are central to these processes, yet are often viewed primarily as downstream inflammatory effectors. Here, we present a conceptual review that reframes intestinal macrophages as metabolic sensors and regulatory hubs that orchestrate inflammatory persistence or resolution. We propose a Macrophage-Orchestrated Metabolic Sensor (MOMS) framework organized into three coordinated layers: Sense, in which macrophages detect microbial- and host-derived metabolites; Switch, in which metabolic and epigenetic reprogramming stabilizes intracellular inflammatory or reparative states; and Command, in which these stabilized states drive epithelial repair, immune-cell recruitment, or fibrotic remodeling. Integrating evidence from immunometabolism, microbiome research, and single-cell biology, we identify key molecular nodes-including METTL3 and NLRP3-as programmable regulators of macrophage fate. The MOMS framework generates testable predictions linking macrophage metabolic states to disease severity and treatment responsiveness, and provides a conceptual foundation for precision macrophage-directed therapies in IBD and related immune-metabolic disorders.
    Keywords:  conceptual framework; immunometabolism; inflammatory bowel disease; intestinal macrophages; microbiota-derived metabolites
    DOI:  https://doi.org/10.7150/ijbs.131531
  13. J Lipid Res. 2026 Jun 23. pii: S0022-2275(26)00095-7. [Epub ahead of print]67(7): 101069
    Fatty acid-binding protein 5 deficiency impairs alveolar macrophage function and metabolism.
    Jack H Ratliff, Katja Aviszus, Sophia Addi, Manale El Kharbili, Steven Fujaros, Sarah K Sasse, Brian E Vestal, Anthony N Gerber, Evgenia Dobrinskikh, Fabienne Gally.
      Macrophages are large mononuclear immune cells that participate in host protection, not only by phagocytosing foreign or infected cells and initiating inflammatory responses, but also by contributing to the resolution of inflammation. Chronic Obstructive Pulmonary Disease (COPD) is characterized by increased numbers of macrophages in lung tissue, with altered engulfment capabilities. However, the molecular pathways leading to macrophage dysfunction in COPD remain unclear. Using integrated genetics and genomics approaches, we previously identified Fatty Acid Binding Protein 5 (FABP5) as a key target in the resolution of airway inflammation that exhibits decreased expression in COPD patients. The objective is to define the significance of alveolar macrophage FABP5 by comparing the resolution of inflammation in WT and Fabp5-/- mice following nontypeable Haemophilus influenzae (NTHi) infection or LPS sterile inflammation. Immune and metabolic responses were analyzed using functional assays, flow cytometry, ELISA, cell metabolic profiling and tracing, as well as ATAC-seq. Fabp5-/- mice exhibited impaired efferocytosis, reflected by a reduction of apoptotic cell engulfment by alveolar macrophages. This was accompanied by a reduction in fatty acid uptake and fatty acid β-oxidation, a reduction in mitochondrial respiration, an accumulation of TCA cycle and glycolysis metabolites, and an increased chromatin accessibility for AP-1 family members. Fabp5-deficient alveolar macrophages failed to initiate reparative metabolic programming, which is critical for the resolution of inflammation. Our data suggest that increasing FABP5 expression could provide a metabolic switch that facilitates macrophage conversion to a pro-resolving phenotype and restores alveolar macrophage efferocytic functions in the lungs of COPD patients.
    Keywords:  COPD; resolution of inflammation
    DOI:  https://doi.org/10.1016/j.jlr.2026.101069
  14. J Enzyme Inhib Med Chem. 2026 Dec;41(1): 2689852
    New insights into the ACLY-mediated metabolic and epigenetic interplay in macrophages.
    Leyi Yuan, Tong Wang, Yajuan Song, Peng Guo, Yifu Zhu, Yuye Cao, Baoqiang Song, Zhou Yu.
      Macrophages are plastic innate immune cells that polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes in response to microenvironmental signals, with their dynamic balance governing inflammation resolution and tissue homeostasis. This polarization entails profound metabolic reprogramming, wherein ATP-citrate lyase (ACLY) acts as a key regulator. By controlling intracellular acetyl-CoA production, ACLY modulates histone acetylation and chromatin remodeling, thereby influencing the expression of inflammation-related genes. This review systematically outlines ACLY's structural features and elucidates its core mechanisms that integrate metabolic and epigenetic cues to orchestrate macrophage polarization and inflammatory responses. In addition, it summarizes the pharmacological properties and clinical translational potential of ACLY inhibitors, highlighting their promise as therapeutic agents. Collectively, this work aims to offer novel theoretical insights and intervention strategies for targeting macrophage immunometabolism in chronic inflammation and associated metabolic disorders.
    Keywords:  ACLY; acetyl-CoA; inflammatory; macrophages
    DOI:  https://doi.org/10.1080/14756366.2026.2689852
  15. Tissue Cell. 2026 Jun 13. pii: S0040-8166(26)00381-2. [Epub ahead of print]103 103687
    Immune metabolic remodeling during exercise rehabilitation: Linking skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation.
    Fei Wang, Wenjie Qin.
      Exercise rehabilitation harnesses immune metabolic remodeling to drive coordinated skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation. Physical activity functions as a controlled metabolic stressor that reprograms immune cell metabolism-shifting macrophages from glycolytic M1 to oxidative M2 phenotypes, expanding regulatory T cells through fatty acid oxidation and ketone body signaling, and modulating neutrophils, NK cells, and B cells via lactate, succinate, itaconate, ROS, NAD⁺, and gut-derived SCFAs. These metabolic shifts regulate immune cell polarization, efferocytosis, cytokine profiles, and growth factor release (IGF-1, amphiregulin, GDF-15), creating an optimal regenerative niche for satellite cell activation, proliferation, and differentiation in muscle while supporting bone remodeling through mechanosensory osteocyte signaling and osteokine secretion (osteocalcin, sclerostin, RANKL/OPG). Distinct exercise modalities generate characteristic immune-metabolic signatures: aerobic training promotes sustained oxidative phosphorylation and anti-inflammatory tolerance beneficial for both muscle and bone; resistance training induces controlled glycolytic bursts followed by anabolic M2 polarization, muscle hypertrophy, and improved bone microarchitecture; HIIT generates oscillatory stress that trains innate immune memory and enhances muscle-bone resilience. Energy-sensing pathways (AMPK, mTOR, HIF-1α, SIRT1/3, PGC-1α) and metabolite checkpoints integrate mechanical loading with immune and endocrine signals to balance pro-regenerative inflammation with timely resolution across the musculoskeletal system. Clinically, this framework enables precision rehabilitation protocols based on immune metabolic phenotyping, lactate kinetics, and skeletal imaging (BMD, microarchitecture) to optimize outcomes in sarcopenia, osteosarcopenia, postoperative recovery, chronic inflammatory diseases, cancer cachexia, and post-viral syndromes. Exercise-induced immune metabolic remodeling thus serves as a master regulator of muscle-bone-immune coupling, offering a mechanism-driven foundation for next-generation rehabilitation medicine that enhances tissue repair, bone quality, and systemic homeostasis.
    Keywords:  Exercise rehabilitation; Immune metabolic remodeling; Macrophage polarization; Muscle–bone crosstalk; Osteokines; Satellite cells
    DOI:  https://doi.org/10.1016/j.tice.2026.103687
  16. Nutrients. 2026 Jun 12. pii: 1911. [Epub ahead of print]18(12):
    Diet-Microbiota-Immune Interactions in Hepatocellular Carcinoma: An Immunometabolic and Spatial Perspective.
    Asmaa E Salem, Nourhan Nassar, Shimaa M Emam, Shaimaa H Negm, Wamidh H Talib, Bence Raposa.
      Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and one of the leading causes of cancer-related mortality globally, with its incidence increasingly driven not only by viral hepatitis and alcohol-related etiologies but also by metabolic dysfunction-associated steatotic liver disease. Dietary intake can modify gut microbial activity and the production of microbial metabolites, which in turn may regulate hepatic immune signaling and metabolic pathways along the gut-liver axis. Microbiota-derived metabolites have emerged as important immunometabolic mediators linking dietary factors to hepatic immune responses and metabolic reprogramming. These metabolites, which have been shown to influence hepatic immune cell function and inflammatory signaling, include short-chain fatty acids, secondary bile acids, and tryptophan-derived indoles. Changes in the production and composition of these metabolites have been associated with immune dysregulation, chronic inflammation, and metabolic reprogramming that promote hepatocellular carcinoma development. This review highlights how diet-microbiota interactions reshape hepatic immunometabolism and discusses their potential translational relevance for prevention and therapeutic strategies in hepatocellular carcinoma.
    Keywords:  gut microbiota; gut–liver axis; hepatocellular carcinoma; immunometabolism; microbial metabolites
    DOI:  https://doi.org/10.3390/nu18121911
  17. Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00665-0. [Epub ahead of print]45(7): 117587
    De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity.
    Julia L Weber, Tien Bui, Keomonyroth Nuon, Adam J Fike, Sophia M Crocker, Kristen N Bricker, Anju Maharjan, Wujuan Zhang, Aaron R Goldman, Sathi Babu Chodisetti, Ziaur S M Rahman.
      Whether and how pyrimidine metabolites promote systemic autoimmunity is unknown. Here, metabolomics and 15N-amide glutamine tracing show enhanced flux through de novo pyrimidine synthesis in systemic lupus erythematosus (SLE)-prone B cells. Temporal inhibition of pyrimidine synthesis dampens SLE-prone but not foreign antigen-specific germinal center (GC), plasma cell (PC), and antibody responses. Uridine monophosphate synthase (UMPS) conditional deletion, however, reveals a B cell-intrinsic requirement of de novo pyrimidine synthesis in foreign antigen-driven and SLE-prone GC, PC, and antibody responses and kidney immune complex deposition. Metabolomics, mitochondrial stress test, metabolic flow cytometry, glycolytic rate assay, and RNA sequencing highlight the importance of pyrimidine synthesis in promoting aerobic glycolysis and oxidative phosphorylation in SLE-prone B cells. De novo pyrimidine synthesis helps SLE-prone B cells maintain heightened metabolic state and expression of metabolic regulator, cMYC. Mechanistically, mTORC1 and S6K1 downstream of TLR7 and CD40 signaling in B cells promote pyrimidine synthesis by activating CAD, a rate-limiting enzyme of this pathway.
    Keywords:  CAD; CP: Immunology; UMPS; autoantibody; autoimmunity; germinal center; mTORC1; plasma cell; pyrimidine metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117587
  18. Int J Mol Sci. 2026 Jun 18. pii: 5526. [Epub ahead of print]27(12):
    Metabolic Reprogramming-Driven Cardiovascular Immune Damage: From Glyco-Lipotoxicity and Epigenetic Memory to Multidimensional Cross-Organ Communication Networks.
    Zijin Sun, Yongchao Liu, Kai Wang, Haojia Zhang, Rui Zhou, Wei Shao.
      Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, and residual inflammatory risk persists despite optimal lipid and glucose control. Emerging evidence indicates that metabolic reprogramming within immune cells constitutes a central driver of cardiovascular immune injury. In this review, we propose a unifying framework in which glyco-lipotoxicity acts as a primary metabolic trigger, inducing mitochondrial dysfunction, oxidative stress, and activation of the NLRP3 inflammasome and cGAS-STING pathways. Hyperglycaemia and dyslipidaemia reshape intracellular metabolic circuits, enhancing glycolysis and disrupting oxidative phosphorylation, thereby promoting sustained pro-inflammatory phenotypes. Crucially, metabolic intermediates function as cofactors for epigenetic remodelling. This establishes trained immunity in both circulating innate immune cells and haematopoietic stem/progenitor cells, which serves as the cellular basis for persistent metabolic memory. This persistent immunometabolic imprint amplifies sterile inflammation and accelerates vascular and myocardial remodelling. Furthermore, these processes are systemically propagated through cross-organ communication networks, including the heart-adipose, gut-heart, and cardio-hematopoietic axes, forming a multidimensional inflammatory amplification loop. We also summarise emerging therapeutic strategies targeting the metabolic-epigenetic axis, aiming to reverse maladaptive trained immunity and mitigate residual CVD risk. By integrating immunometabolism, epigenetic regulation, and organ crosstalk, this review highlights metabolic reprogramming as a pivotal mechanistic nexus and potential precision target for cardiovascular protection.
    Keywords:  NLRP3 inflammasome; cross-organ communication; epigenetic remodelling; glyco-lipotoxicity; metabolic reprogramming; trained immunity
    DOI:  https://doi.org/10.3390/ijms27125526
  19. Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00679-0. [Epub ahead of print]45(7): 117601
    Lipid droplet-mitochondria tethering releases MAVS inhibition to potentiate antiviral immunity.
    Qianwen Peng, Wenbo Liang, Wei Wang, Jie Wang, Qi Wang, Chunyuan Zhao, Mutian Jia, Yue Fu, Chengjiang Gao, Hui Song, Ying Qin, Li Tong, Wei Zhao.
      Mitochondrial antiviral signaling protein (MAVS) forms prion-like aggregates to activate innate immunity against RNA viruses, but the metabolic regulation of MAVS remains poorly understood. Here, we show that viral infection induces the formation of lipid droplets (LDs), which physically interact with mitochondria to promote the assembly of MAVS prion-like aggregates. Mechanistically, the LD-resident protein PLIN3 binds to the mitochondrial fusion protein MFN2, thereby relieving MFN2-mediated inhibition of MAVS and enabling its oligomerization. Furthermore, LD-mitochondria contact sites facilitate fatty acid transfer, sustaining mitochondrial membrane potential required for MAVS signaling. Oleic acid (OA)-enriched diets enhance LD formation and boost antiviral immunity in vivo, while myeloid-specific Seipin (an LD biogenesis regulator) deficiency attenuates MAVS activation and exacerbates viral susceptibility. These findings establish LDs as metabolic platforms that bridge cellular lipid metabolism with innate antiviral defense through organelle crosstalk, suggesting LD induction as a novel therapeutic strategy against viruses.
    Keywords:  CP: immunology; MAVS; Seipin; antiviral immunity; innate immunity; lipid droplet; type I interferon
    DOI:  https://doi.org/10.1016/j.celrep.2026.117601
  20. EBioMedicine. 2026 Jun 26. pii: S2352-3964(26)00228-8. [Epub ahead of print]129 106345
    Disturbed metabolic adaptation drives natural killer cell dysfunction in association with nosocomial infection during human sepsis.
    André van der Wurff, Monika Gambusz, Bettina Budeus, Maren Claus, Carsten Watzl, Dani Miteva, Brendon P Scicluna, Ignacio Rubio, Elena Siakaeva, Frederic Zinsmeister, Sonja Vonderhagen, Nadja Klenke, Frank Herbstreit, Karsten Schmidt, Marc M Berger, Thorsten Brenner, Marcel Dudda, Stefanie B Flohé.
       BACKGROUND: Patients with sepsis are highly susceptible to detrimental nosocomial infections. During bacterial infection, natural killer (NK) cells release Interferon (IFN) γ that drives the elimination of invading pathogens. Interleukin (IL) 12 in synergy with other cytokines increases sensing and uptake of nutrients by NK cells for metabolic adaptation required for induction of IFN-γ production. We hypothesised that inappropriate function of NK cells was associated with nosocomial infections during human sepsis and linked to altered metabolic adaptation.
    METHODS: We performed a longitudinal exploratory study on circulating human NK cells during sepsis and evaluated adaptation of nutrient sensing, activation of the metabolic hub mammalian target of rapamycin (mTOR) C1, and IFN-γ production upon exposure to Staphylococcus aureus as a model for an opportunistic pathogen in vitro. The involvement of cell-intrinsic and extrinsic pathways in NK cell function was addressed.
    FINDINGS: Expression of the IL-12 receptor (p < 0.001) and downstream production of IFN-γ (p < 0.01) after exposure to S. aureus were suppressed in NK cells for at least 14 days after sepsis diagnosis, particularly in patients who developed secondary infections (p < 0.01). Mechanistically, suppression of NK cells was independent from environmental cues but was cell-intrinsic and associated with impaired activation of mTORC1 and with reduced expression of nutrient transporters required for anabolic metabolism. Inhibition of AMP kinase (AMPK) restored mTORC1 activity (p < 0.01) and increased the production of IFN-γ (p < 0.01) in NK cells from septic patients.
    INTERPRETATION: Defective metabolic regulation is associated with persistent NK cell dysfunction during human sepsis and might represent a potential therapeutic target to improve immune competence and decrease the risk for nosocomial infections.
    FUNDING: The study was supported by the "Research and Training" program "ELAN" for medical students of the medical faculty of the University Duisburg-Essen.
    Keywords:  Immunosuppression; Interferon γ; Mammalian target of rapamycin C1; Metabolism; Natural killer cells; Sepsis
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106345
  21. Respir Res. 2026 Jun 23.
    H3K18 lactylation promotes allergic airway inflammation in asthma via a CSF1/CSF1R/MAPK autocrine axis.
    Minxuan Hu, Yixin Chen, Haohua Huang, Jinzhong Zhuo, Haishan Zhong, Dongyu Liu, Qi Yu, Yuhan Du, Jinming Zhang, Shaoxi Cai, Hangming Dong.
       BACKGROUND: Metabolic reprogramming of airway epithelial cells is a hallmark of asthma, yet the mechanisms by which altered metabolism drives inflammation remain largely unknown. Histone lactylation, a recently identified metabolism-derived epigenetic modification, may provide a mechanistic link.
    METHODS: Clinical specimens and single-cell RNA sequencing (scRNA-seq) were analyzed to map the metabolic landscape of asthma. Histone lactylation in airway epithelial cells was assessed by western blotting and immunofluorescence. Functional roles of histone lactylation were evaluated via modulation of glycolysis, lactate availability, or P300 expression. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) were performed to identify transcriptional targets of H3K18 lactylation (H3K18la).
    RESULTS: Glycolysis and histone lactylation, particularly H3K18la, were significantly elevated in the airway epithelial cells of asthma. Inhibition of glycolysis or P300 knockdown attenuated the inflammatory response by suppressing histone lactylation; whereas lactate supplementation exacerbated inflammation by promoting histone lactylation. H3K18la accumulated at the CSF1R promoter, directly enhancing its transcription and establishing a CSF1/CSF1R/MAPK autocrine positive feedback axis that positions airway epithelial cells as an upstream driver and inflammatory amplifier in allergic airway inflammation.
    CONCLUSION: This study defines a glycolysis-histone lactylation-CSF1R signaling axis that links epithelial metabolic reprogramming to sustained inflammatory gene activation in asthma, highlighting histone lactylation as a potential therapeutic target for allergic airway inflammation.
    Keywords:  Allergic airway inflammation; Asthma; CSF1R; Glycolysis; Histone lactylation; MAPK signaling
    DOI:  https://doi.org/10.1186/s12931-026-03781-5
  22. Discov Oncol. 2026 Jun 27.
    Metabolic reprogramming regulates macrophage polarization to impact ovarian cancer progression.
    Meng Zhang, Haizhou Fang, Shuangshuang Yang, Jinxi Yue, Lianlin Zeng, Hong Zhang.
      Metabolic reprogramming and macrophage polarization exhibit a tightly regulated reciprocal interplay, wherein the modulation of energy metabolic pathways and signaling networks directly dictates the functional phenotype and immune responses of macrophages, thereby exerting a critical influence on ovarian cancer progression and therapeutic outcomes. This manuscript elucidates the regulatory mechanisms by which diverse metabolic pathways-including glycolysis, oxidative phosphorylation, and glutamine metabolic reprogramming-orchestrate macrophage polarization. Special emphasis is placed on the functional role of tumor-associated macrophages (TAMs) within the ovarian cancer immune microenvironment, as well as the molecular mechanisms underlying their metabolic regulation. Based on the latest research advances, this study analyzes how metabolic reprogramming modulates the M1/M2 polarization balance to influence tumor immune escape and treatment resistance. Additionally, it summarizes emerging nanoscale strategies for the precise treatment of ovarian cancer via metabolic modulation of macrophage polarization. The overarching aim of this research is to clarify the pivotal role of metabolic regulation in macrophage polarization, thereby providing novel insights and therapeutic strategies for the management of ovarian cancer.
    Keywords:  Macrophage polarization; Metabolic pathways; Metabolic reprogramming; Nanotherapy; Ovarian cancer
    DOI:  https://doi.org/10.1007/s12672-026-05495-y
  23. Vet Sci. 2026 May 24. pii: 511. [Epub ahead of print]13(6):
    Copper Metabolism in Isolated Macrophages: Regulator of Immunity and Inflammation.
    Xinao Leng, Ping Yu, Zhidi Xu, Chenglong Xia, Rui Du, Qiwen Luo, Yanqiu Zhu, Hongrui Guo.
      Copper is essential for the proper functioning of immune cells and participates in diverse biochemical processes. The maintenance of copper ion homeostasis is critical for normal host physiology, while dysregulation of copper metabolism is closely linked to various diseases. Emerging evidence indicates that disease-associated elevations in copper levels significantly enhance macrophage functions, including the expression of inflammatory cytokines, phagocytosis, and bactericidal activity. As key innate immune cells, macrophages not only eliminate invading pathogens but also contribute to immune regulation, tissue repair, and angiogenesis. In this review, we summarize current knowledge of copper transport and homeostatic mechanisms in macrophages and highlight how copper regulates their antimicrobial activity, inflammatory responses, and reparative functions. A deeper understanding of these mechanisms may provide new insights into therapeutic strategies targeting macrophage regulation through copper metabolism in the context of infectious and inflammatory diseases.
    Keywords:  antimicrobial activity; copper; inflammatory response; macrophages; tissue repair
    DOI:  https://doi.org/10.3390/vetsci13060511
  24. Cell Signal. 2026 Jun 26. pii: S0898-6568(26)00349-9. [Epub ahead of print] 112694
    O-GlcNAcylation-mediated glycolytic reprogramming of CD4+ T cells contributes to type H vessel impairment in diabetic osteoporosis.
    Yujun Jiang, Yaling Dai, Xiaolin Li, Yajun Cui, Hongrui Liu, Tomoka Hasegawa, Minqi Li.
      Diabetic osteoporosis (DOP) is a metabolic bone disease characterized by skeletal fragility and impaired angiogenesis-osteogenesis coupling, in which type H vessel impairment has emerged as an important pathological feature. While adaptive immunity is known to regulate bone homeostasis, the immunometabolic mechanisms driving vascular dysfunction in DOP remain elusive. Here, we investigated whether pathological metabolic reprogramming of CD4+ T cells is linked to type H vessel impairment in DOP. CD4+ T cells from DOP mice exhibited enhanced glycolytic activation accompanied by increased hexokinase 2 (HK2) expression and elevated O-GlcNAcylation. In vitro, high glucose and palmitic acid (HGPA) treatment was associated with increased HK2 O-GlcNAcylation, HK2 stabilization, mitochondrial localization, and enhanced glycolytic activity in CD4+ T cells. These metabolic alterations were accompanied by senescence-associated and pro-inflammatory phenotypes, including upregulation of P53, P16, PD-1, IL-6, and IL-17 A, as well as enhanced T helper 17 (Th17) polarization. Co-culture experiments showed that HGPA-treated CD4+ T cells were associated with impaired endothelial viability, migration, tube formation, and reduced VEGFA/VEGFR2 expression. Pharmacological inhibition of O-GlcNAcylation or glycolysis partially attenuated CD4+ T cell dysfunction and improved endothelial angiogenic function. Collectively, these findings suggest that O-GlcNAcylation-associated HK2 glycolytic activation may contribute to CD4+ T cell dysfunction and type H vessel impairment in DOP. Targeting this immunometabolic pathway may represent a potential therapeutic strategy for diabetic skeletal complications.
    Keywords:  Diabetic osteoporosis; Glycolysis; O-GlcNAcylation; T cell senescence; Th17; Type H vessels
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112694
  25. Inflamm Res. 2026 Jun 20. pii: 149. [Epub ahead of print]75(1):
    Lactylation: a novel post-translational modification for cGAS-STING pathway.
    Hongquan Wang, Zhiji Wang, Fanyu Meng, Ying Gao, Ming Zhang, Wei Zhang, Erdan Wang, Kerui Shi, Yuzi Jin.
       BACKGROUND: Lysine lactylation (Kla) is a lactate-derived post-translational modification that has emerged as a critical metabolic-epigenetic regulator linking cellular metabolic states to innate immune signaling. The cGAS-STING pathway, a central cytosolic DNA-sensing mechanism essential for antiviral defense, antitumor immunity, and inflammatory regulation, is profoundly influenced by the metabolic milieu. However, the precise role of lactylation in modulating this pathway remains to be systematically synthesized.
    OBJECTIVE: This review aims to comprehensively analyze the molecular mechanisms by which lysine lactylation regulates the cGAS-STING signaling axis, and to discuss the pathophysiological implications and therapeutic potential of targeting this modification in diseases ranging from autoimmunity and neuroinflammation to cancer.
    METHODS: A comprehensive review of the relevant literature was conducted to summarize the biochemical basis of lactylation (including writers, erasers, and readers) and to systematically examine emerging evidence demonstrating direct and indirect regulation of cGAS-STING components by lactylation. Studies involving site-specific modifications, disease models, and therapeutic interventions were collated and analyzed.
    RESULTS: Lactylation directly targets core pathway components-cGAS at residues such as K21, K131, K156, K162, K275, and K409, and STING-altering their stability, enzymatic activity, DNA-binding capacity, phase separation, and downstream signaling outputs. Depending on context, lactylation exerts dual effects: it stabilizes cGAS and amplifies type I interferon responses in autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis) and hypoxic-ischemic encephalopathy, but promotes cGAS degradation or suppresses STING activity in cancer (lung adenocarcinoma, glioblastoma) and neuropathic pain, thereby facilitating immune evasion or pain sensitization. Indirectly, lactylation modulates cytosolic DNA ligand availability by influencing mitochondrial DNA release (via HMGB1, VDAC1, Arg1, DRP1) or DNA repair (via KU70). The discovery of specific lactyltransferases (AARS1/2, p300) and delactylases (SIRT1-3, HDAC1-3) establishes lactylation as a dynamic, enzymatically controlled process.
    CONCLUSION: Lactylation functions as a pivotal metabolic-immune checkpoint that fine-tunes cGAS-STING signaling in a cell-type- and disease-specific manner. Targeting the lactylation regulatory axis-by inhibiting pathogenic lactylation to restore anti-tumor immunity or enhancing it to dampen deleterious inflammation-offers a novel immunometabolic therapeutic strategy for autoimmune disorders, chronic infections, neurodegeneration, and cancer.
    Keywords:  Lactylation; Post-translational modification; STING; cGAS
    DOI:  https://doi.org/10.1007/s00011-026-02306-6
  26. JCI Insight. 2026 Jun 23. pii: e207387. [Epub ahead of print]
    AFF3 maintains metabolic quiescence in naïve CD8 T cells and prevents premature immune aging.
    Molly E Lumnitzer, Stefanie F Valbon, Stephanie A Condotta, Allison E Norlander, Sheng Liu, Jun Wan, Martin J Richer.
      It is necessary for naïve CD8 T cells to be actively maintained in a quiescent metabolic state in order to respond robustly to infection while avoiding inappropriate activation during homeostasis. With age this quiescent state is lost and the CD8 T cell response to infection decreases. The factors regulating metabolic quiescence of CD8 T cells and how this regulation is lost during aging are not completely understood. Herein, we identify the transcription factor AFF3 as a regulator of metabolic quiescence in naïve CD8 T cells. While naïve AFF3 deficient CD8 T cells are more metabolically active prior to infection, they have reduced accumulation in response to viral infection, and this is correlated with a poor capacity to engage glycolysis. During aging in both murine and human CD8 T cells, AFF3 expression is decreased. In mice, this is associated with a loss of metabolic quiescence and reduced capacity to accumulate following infection. Our data highlight the role of metabolic regulation in CD8 T cell quiescence and identifies a transcription factor that may be a target to reinvigorate CD8 T cell responses during aging.
    Keywords:  Aging; Glucose metabolism; Immunology; Metabolism; Metabolomics; T cells
    DOI:  https://doi.org/10.1172/jci.insight.207387
  27. J Biomed Sci. 2026 Jun 26. pii: 68. [Epub ahead of print]33(1):
    Offense and defense: itaconate mediates bidirectional immune regulation of host-bacteria interaction.
    Zhaoyue Men, Zishen Lin, Zhe Wang, Peng Tan, Shuyang Yu, Xi Ma.
      Itaconate has garnered significant attention in recent years due to its immunomodulatory and antimicrobial functions. During inflammation and pathogenic infections, itaconate is formed through the decarboxylation of cis-aconitate in the mitochondrial tricarboxylic acid cycle and accumulates in large quantities to counteract excessive inflammation and pathogenic infections. However, many pathogenic bacteria have also evolved pathways to directly degrade itaconate or indirectly resist its stimulatory effects. We first review the research history and metabolic pathways of itaconate. Then we focus on exploring its direct mechanism of inhibiting pathogenic bacteria growth and reproduction by post-translational modification of metabolic enzymes such as isocitrate lyase, aldolase, and IMP dehydrogenase. Additionally, we examine its indirect mechanism of coordinating immune cell functions to eliminate pathogenic bacteria. Pathogenic bacteria counteract this by directly degrading itaconate through the IcT-IcH-CcL cascade reaction or by adapting through metabolic reprogramming to enable chronic infection. Subsequently, we discuss the spatiotemporal specificity of itaconate during the early and late stages of pathogenic bacteria infection, highlighting its role in regulating immune defense strategies at different phases. Finally, we discuss the potential and limitations of itaconate-related interventions as adjunctive strategies for bacterial disease control, particularly in the context of drug-resistant infections. This review elucidates the mechanism of itaconate in host-microbial crosstalk from the perspective of bidirectional resistance between host and bacteria, emphasizing its crucial role as a metabolic messenger in mediating co-evolutionary, co-developmental, and co-metabolic interactions between the host and bacteria. Current evidence of itaconate-mediated bidirectional interactions may help guide future mechanistic studies and the development of itaconate-related adjunctive strategies for bacterial disease control. Further in vivo, clinical, and field validation is still required before these findings can be translated into therapeutic or agricultural applications.
    Keywords:  Bacterial disease; Host-bacteria interaction; Immune modulation; Immunity; Itaconate; Pathogenic bacteria
    DOI:  https://doi.org/10.1186/s12929-026-01266-7
  28. Sci Signal. 2026 Jun 23. 19(943): eadw1017
    Diacylglycerol kinase ζ in B lymphocytes supports CD40-mediated immune synapse formation, mTORC1 signaling, and plasma cell fate.
    Ana Fernández-Barrecheguren, Adrián Fernández-Rego, Lucía Fuentes-Cantos, Tirso Pons, Belén S Estrada, Marta Iborra-Pernichi, María Velasco de la Esperanza, Tahmineh Ebrahimi, Ana Sagrega-Aparisi, Sara Cogliati, Nuria Martínez-Martín, Rodrigo Jiménez-Saiz, Yolanda R Carrasco.
      To mount a robust T cell-dependent immune response, antigen-specific B lymphocytes require the stimulation of the transmembrane receptor CD40 through immune synapse formation with CD4+ T follicular helper cells. CD40 stimulates the activation of mammalian target of rapamycin complex 1 (mTORC1) and remodels mitochondria to meet the increased bioenergetic and anabolic demands of activated B cells. Here, we found that diacylglycerol kinase ζ (DGKζ) supported mTORC1 activation downstream of CD40 stimulation in mouse B cells. We showed that DGKζ was required for organellar translocation to the CD40-mediated immune synapse and for the recruitment of mTORC1 to lysosomes, the latter of which was necessary for mTORC1 activation and function. The production of phosphatidic acid by DGKζ was crucial for these processes. DGKζ-/- B cells exhibited defects in protein biosynthesis, metabolite transporter expression, and cell cycle progression, together with dysregulation of the transcriptional network that determines B cell fate. To sustain their bioenergetic and metabolic demands, DGKζ-/- B cells enhanced their mitochondrial function. Together, these effects of DGKζ loss led to decreases in germinal center responses and in the generation of long-lived plasma cells and memory B cells in mice. Thus, our data identify DGKζ as an essential mediator of CD40 functions in the B cell immune response.
    DOI:  https://doi.org/10.1126/scisignal.adw1017
  29. J Gen Virol. 2026 Jun;107(6):
    NAD+ metabolism at the host-virus interface.
    Prince Jhandai, Kishore Vaddadi, Lin Liu.
      Nicotinamide adenine dinucleotide (NAD+) is one of the most important metabolic coenzymes that not only drives redox reactions and energy production but also acts as a critical substrate for several enzymes involved in immune signalling, DNA repair and epigenetic regulation. Viral infections are known as potent modulators of NAD+ metabolism, with pathogens such as SARS-CoV-2, influenza A virus, Zika virus, herpes simplex virus and human immunodeficiency virus altering NAD+ biosynthesis and consumption to benefit their persistence and replication. In this review, we summarize the current understanding of NAD+ metabolism and its regulatory enzymes: sirtuins, poly (ADP-ribose) polymerases and CD38/CD157. We then discuss the interplay between NAD+ homeostasis and virus infection. Understanding how diverse viruses manipulate NAD+ metabolism could lead to broad-spectrum antiviral strategies grounded in metabolic resilience.
    Keywords:  CD38; coronavirus; influenza A virus; nicotinamide adenine dinucleotide (NAD+) metabolism; poly (ADP-ribose) polymerases (PARPs); sirtuins
    DOI:  https://doi.org/10.1099/jgv.0.002285
  30. Int J Biol Sci. 2026 ;22(11): 5735-5753
    PFKFB3 Mediated Glycolytic Reprogramming Drives Vascular Endothelial Injury Under Chronic Intermittent Hypoxia.
    Shi Qi Li, Yi Wang, Liu Zhang, Ya Ru Yan, Fang Ying Lu, Xi Xi Chen, Ying Ni Lin, Jun Qi Lin, Jian Ping Zhou, Li Ming Lu, Qing Yun Li.
      Metabolic-inflammatory crosstalk is a hallmark of cardiovascular pathogenesis. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for cardiovascular diseases. While endothelial inflammation driven by CIH is pivotal in disease progression, the underlying metabolic mechanisms remain poorly defined. Our research shows that phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic activator, is markedly upregulated in endothelial cells (ECs) exposed to CIH, correlating with enhanced glycolysis, suppressed mitochondrial respiration, and amplified inflammatory responses. Endothelial-specific PFKFB3 deficiency or pharmacological suppression of PFKFB3 restores the glycolytic balance and alleviates vascular endothelial injury. Mechanistically, CIH enhances the expression of hypoxia-inducible factor 1α (HIF-1α), which regulates PFKFB3 expression. PFKFB3-induced production of lactate further promotes H3K18 lactylation (H3K18la), which in turn binds the PFKFB3 promoter, forming a positive-feedback loop. Disruption of the HIF-1α/PFKFB3 axis alleviates the inflammatory and glycolytic signatures of ECs. In conclusion, our findings identify PFKFB3 as a critical metabolic driver of endothelial inflammation under CIH, orchestrated through a HIF-1α-PFKFB3-H3K18la loop. These findings reveal novel pathogenic insights and potential therapeutic targets for OSA-associated cardiovascular diseases.
    Keywords:  PFKFB3; chronic intermittent hypoxia; endothelial inflammation; glycolysis; obstructive sleep apnea
    DOI:  https://doi.org/10.7150/ijbs.129280
  31. Int Immunopharmacol. 2026 Jun 20. pii: S1567-5769(26)00869-6. [Epub ahead of print]185 117023
    Hexokinase 2 deficiency protects against sepsis-associated lung injury via suppressing the NF-κB signaling pathway.
    Jianmin Ling, Jun Lu, Guangyang Bai, Minghao Fang, Shusheng Li, Cuihong Xie.
       BACKGROUND: Inflammation plays a pivotal role in the pathogenesis and treatment of sepsis-associated lung injury (S-ALI). Although hexokinase 2 (HK2) is known to be involved in regulating inflammation, metabolism, and mitochondrial homeostasis, its mechanism in S-ALI remains unclear.
    METHODS: In the cecal ligation and puncture (CLP)-induced S-ALI mouse model, haploinsufficiency of HK2 or pharmacological inhibition of HK2 by Lonidamine (LND) was administered. The effects of gene silencing or pharmacological inhibition of HK2 on pulmonary inflammation, lipid metabolism and mitochondrial damage were evaluated using qRT-PCR, immunofluorescence, Western blotting and transmission electron microscopy. Furthermore, siRNA and LND were used to further investigate the impact of gene silencing or pharmacological inhibition of HK2 on the NF-κB signaling pathway in MH-S cells.
    RESULTS: HK2 expression was elevated in lung tissues of CLP-induced septic mice. HK2 haploinsufficiency attenuated CLP-induced lung injury by suppressing M1 polarization of pulmonary macrophages, thereby exerting a lung-protective effect. HK2 haploinsufficiency also improved lipid metabolism, mitigated mitochondrial damage, and reduced endoplasmic reticulum stress in S-ALI. Genetic silencing or pharmacological inhibition of HK2 in LPS-stimulated MH-S alveolar macrophages modulated IκBα expression and suppressed nuclear NF-κB.
    CONCLUSION: HK2 partial antagonism ameliorated CLP-induced pulmonary inflammation, lipid metabolic dysfunction, and mitochondrial damage, potentially through modulation of the NF-κB signaling pathway.
    Keywords:  Hexokinase 2; Inflammation; Lung injury; Metabolism; Sepsis
    DOI:  https://doi.org/10.1016/j.intimp.2026.117023
  32. PLoS One. 2026 ;21(6): e0352437
    Severity-dependent metabolic rewiring in COVID-19 based on untargeted metabolomic profiling of patient plasma.
    Marta Majewska, Mateusz A Maździarz, Ewa Lepiarczyk, Aleksandra Lipka, Marta Wiszpolska, Beata Moczulska, Elżbieta Łopieńska-Biernat, Piotr Iwanowicz, Piotr Kocbach, Hilde Galtung, Leszek Gromadziński.
      Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a major global health challenge, characterised by a heterogeneous clinical spectrum. While metabolomic studies have identified disruptions in amino acid, lipid, nucleotide, and energy metabolism during COVID-19, these investigations often lack fine-grained clinical stratification. In this study, we performed untargeted metabolomic profiling of plasma from 25 participants, including five healthy controls and twenty COVID-19 patients classified into four severity groups (COV1-COV4) based on pulmonary involvement and the need for respiratory support. Using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS), 541 metabolites were detected and analysed across all samples. Principal component analysis revealed a progressive metabolic divergence corresponding to disease severity. Monocarboxylic acid dysregulation was predominant in early to moderate cases (COV1-COV3), whereas severe disease (COV4) demonstrated a shift toward pyrimidine metabolism enrichment, consistent with heightened nucleotide turnover driven by viral replication and immune cell proliferation. Phenylalanine metabolism emerged as a consistently enriched pathway in COV1-COV3, suggesting aromatic amino acid perturbations as early markers of metabolic stress and immune activation. In contrast, pyrimidine pathway activation in COV4 could reflect profound systemic metabolic reprogramming associated with critical illness. These findings provide novel insights into COVID-19 pathophysiology, highlighting stage-specific metabolic signatures and potential biomarkers for disease monitoring. Our results support the concept of metabolomics-guided precision medicine, offering a rationale for targeted therapeutic interventions based on disease stage and metabolic phenotype.
    DOI:  https://doi.org/10.1371/journal.pone.0352437
  33. Elife. 2026 Jun 26. pii: RP107023. [Epub ahead of print]14
    Differential regulation of hepatic macrophage fate by Chi3l1 in metabolic dysfunction-associated steatotic liver disease.
    Jia He, Bo Chen, Weiju Lu, Xiong Wang, Ruoxue Yang, Chengxiang Deng, Xiane Zhu, Keqin Wang, Lang Wang, Cheng Xie, Rui Li, Xiaokang Lu, Ruizhi Yang, Cheng Peng, Canpeng Li, Zhao Shan.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) progression involves the replacement of protective embryo-derived Kupffer cells (KCs) by inflammatory monocyte-derived macrophages (MoMFs), yet the regulatory mechanisms remain unclear. Here, we identify chitinase 3-like 1 (Chi3l1/YKL-40) as a critical metabolic regulator of hepatic macrophage fate. We observed high expression of Chi3l1 in both KCs and MoMFs during MASLD development. Genetic deletion of Chi3l1 specifically in KCs significantly exacerbated MASLD severity and metabolic dysfunction, whereas MoMF-specific Chi3l1 deletion showed minimal metabolic effects. Mechanistic studies revealed that this cell type-specific regulation arises from differential metabolic requirements: KCs display elevated glucose metabolism compared to MoMFs. Chi3l1 directly interacts with glucose to inhibit its cellular uptake, thereby selectively protecting glucose-dependent KCs from metabolic stress-induced cell death while having negligible effects on less glucose-dependent MoMFs. These findings uncover a novel Chi3l1-mediated metabolic checkpoint that preferentially maintains KCs populations through glucose metabolism modulation, providing important new insights into the pathogenesis of MASLD and potential therapeutic strategies targeting macrophage-specific metabolic pathways.
    Keywords:  Chi3l1; MASLD; kupffer cells; medicine; monocytes-derived macrophages; mouse
    DOI:  https://doi.org/10.7554/eLife.107023
  34. Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2524594123
    Immune cell-intrinsic STING activation drives tumor ferroptosis via AA-mediated suppression of ACSL4 lactylation in colorectal cancer.
    Lina Ding, Wenqi Du, Jing Zhu, Yuxiang Zhang, Xingyue Wang, Linfeng Li, Buhui Liu, Xiaohong Wang, Qingling Wang, Dongsheng Pei.
      Ferroptosis has emerged as a key effector mechanism in antitumor immunity, yet the transcellular metabolic cross talk that modulates ferroptotic sensitivity in colorectal cancer (CRC) remains incompletely understood. Here, we describe an integrative regulatory axis linking immune cell-intrinsic Stimulator of Interferon Genes (STING) signaling to tumor ferroptosis through coordinated lipid metabolism and posttranslational modifications (PTMs). Mechanistically, STING activation in immune cells triggers TANK-binding kinase 1 (TBK1)-dependent phosphorylation of cytosolic phospholipase A2 (cPLA2) at Ser505, thereby releasing arachidonic acid (AA) into the tumor microenvironment (TME). This immune-derived AA is taken up by adjacent CRC cells, where it promotes ACSL4-dependent ferroptosis by inhibiting EP300-mediated lactylation of ACSL4 at lysine 426 (K426). In vivo, pharmacological activation of STING enhances AA release and facilitates ferroptosis-mediated tumor suppression. Notably, STING agonist synergizes with PD-1 checkpoint blockade to inhibit tumor progression, which is reversed by the ferroptosis inhibitor. Collectively, our findings establish an integrative and transcellular immunometabolic framework linking innate immune sensing to tumor ferroptosis, providing a strong rationale for combinatorial therapeutic strategies in CRC.
    Keywords:  STING signaling pathway; arachidonic acid; ferroptosis; lactylation
    DOI:  https://doi.org/10.1073/pnas.2524594123
  35. JCI Insight. 2026 Jun 22. pii: e189882. [Epub ahead of print]11(12):
    Crosstalk between CD8+ T cells and systemic bile acid metabolism shapes antiviral immunity and immunopathology.
    Felix Clemens Richter, Zsofia Keszei, Csilla Viczenczova, Maximilian Baumgartner, Henrique G Colaço, Magdalena Siller, Lisa Holnsteiner, Hatoon Baazim, Anna Hofmann, Aubrey Burrett, Anna Schönbichler, Lukas Endler, Joel Xu En Wong, Laura Antonio-Herrera, Oleksandr Petrenko, Fabian Amman, Jakob-Wendelin Genger, Claudia D Fuchs, Hubert Scharnagl, Hanns-Ulrich Marschall, Thomas Reiberger, Karl S Lang, Clarissa Campbell, Michael Trauner, Andreas Bergthaler.
      Antiviral immunity profoundly impacts host metabolism, which can, in turn, modulate immune responses and influence disease pathology. The liver orchestrates systemic bile acid (BA) metabolism, a pathway disrupted in chronic liver diseases such as viral hepatitis. BAs are increasingly recognized for their immunomodulatory properties. Thus, improved understanding of the interplay between immunity and BA metabolism may reveal novel therapeutic avenues. Using lymphocytic choriomeningitis virus (LCMV) as a model, we investigated the interplay between chronic virus infection, BA metabolism, and immunity. Chronic LCMV infection increased BA levels and shifted circulating and liver BA composition toward host-derived, conjugated BAs. Hepatic BA transport and synthesis genes were broadly downregulated, in part depending on CD8+ T cells. Pharmacological inhibition of the main hepatic transporter of conjugated BAs, NTCP (Slc10a1), increased hepatic damage, while combined genetic disruption of the BA transporters Slco1a1, Slco1a4, and Slco1b2, responsible for the hepatic reuptake of unconjugated BA, reduced liver pathology and impaired antiviral CD8+ T cell responses. These findings reveal a reciprocal interplay between BA metabolism and CD8+ T cells, expanding our understanding of adaptive immunity in viral hepatitis. They also highlight how immunometabolic changes in liver disease may affect adaptive immune responses against infections.
    Keywords:  Hepatitis; Hepatology; Immunology; Metabolism; T cells
    DOI:  https://doi.org/10.1172/jci.insight.189882
  36. Cell Death Dis. 2026 Jun 23.
    Beyond a waste product: lactate as a master metabolite dictating anti-tumor T-cell fate.
    Xiangyu Dai, Jingjia Chang, Siyue Wang, Lutterodt Bentum-Ennin, Jian Zhou, Xiaomin Zuo, Wanglai Hu.
      Lactate, a key byproduct of tumor metabolic reprogramming, accumulates in the tumor microenvironment (TME) and profoundly shapes T cell-mediated anti-tumor immunity. As research into TME metabolism advances, lactate has emerged as a critical regulator with broad effects on immune function. In many cancers-including gastric cancer, hepatocellular carcinoma, lung cancer, melanoma, and pancreatic cancer-lactate suppresses or remodels anti-tumor immunity by acting on CD8⁺ T cells, regulatory T cells (Tregs), dendritic cells (DCs), and immune checkpoint molecules. The underlying mechanisms are becoming increasingly well-defined. However, major knowledge gaps remain, especially regarding how lactate-associated enzymes (e.g., LDHA), lactate transporters (e.g., MCT4), and signaling pathways impact T cell function. This review summarizes how lactate regulates anti-tumor immune responses and explores emerging immunotherapies targeting lactate metabolism, with a focus on metabolic enzymes and transporters. We cover preclinical and clinical progress on LDHA inhibitors and lactate transporter inhibitors. By comprehensively analyzing lactate's function in the TME, we aim to build a theoretical framework for precision tumor immunotherapy and propose future directions centered on modulating the immune microenvironment through lactate-targeted strategies.
    DOI:  https://doi.org/10.1038/s41419-026-08976-8
  37. Appl Physiol Nutr Metab. 2026 Jun 24.
    Immune Cell Mitochondrial Respiration and Inflammatory Profiles Are Partially Modulated by Cardiorespiratory Fitness in Male Adults.
    Caique Figueiredo, José Gerosa-Neto, Priscila Almeida Queiroz Rossi, Pedro Enrico Martin de Oliveira, Rayana Loch Gomes, Miquéias de Lima Portugal, Pedro Costa Monteiro Pizzol, Gabriel Masiero da Silva, Marcos F S Teixeira, Ricardo Ribeiro Agostinete, Jonathan P Little, José Cesar Rosa-Neto, Fábio S Lira.
      Cardiorespiratory fitness (CRF) appears to be related to the metabolic and inflammatory profile of immune cells, though this association is still uncertain. This study presents two main objectives: 1) To determine whether individuals with low-CRF, compared to high-CRF, would have lower peripheral blood mononuclear cells (PBMCs) mitochondrial respiration and higher inflammatory profile, and 2) To analyze the association between PBMCs mitochondrial respiration and cytokine release at rest and upon stimulation. Adults self-reporting male sex were classified as Low- (n = 9) or High-CRF (n = 7) based on established thresholds. To control for confounders, variables related to metabolism, inflammation, body composition, physical activity, and diet were assessed. PBMCs were isolated to evaluate mitochondrial respiration and cytokine release under basal and stimulated conditions (LPS or PMA+ionomycin - in vitro culture during 24h). As main results, PBMCs from individuals with high CRF exhibited higher mitochondrial oxygen consumption than those from the Low-CRF group; however, this difference did not remain after controlling for visceral fat. At rest, PBMCs from low-CRF individuals released more pro-inflammatory cytokines, which correlated negatively with mitochondrial oxygen consumption. Moreover, PBMCs from low-CRF individuals showed strong responsiveness to LPS (higher TNF-α release), while PBMCs from high-CRF individuals showed strong responsiveness to PMA plus ionomycin (higher IFN-γ release), without correlation to mitochondrial respiration. These findings indicate that low CRF is associated with lower mitochondrial respiration and greater basal and LPS-induced cytokine release in PBMCs. Differences in visceral fat appear to be an additional factor associated with PBMCs metabolism and function when comparing individuals with low and high CRF.
    DOI:  https://doi.org/10.1139/apnm-2025-0448
  38. Cell Signal. 2026 Jun 21. pii: S0898-6568(26)00340-2. [Epub ahead of print]146 112685
    NFAT5 in alveolar macrophages exacerbates seawater-induced acute lung injury via PFKP-driven glycolysis.
    Xinxin Wang, Xian Guo, Yifeng Wang, Yongheng Gao, Lin Wang, Yanfeng Fang, Fuguo Gao, Fangrun Yuan, Boyang Gao, Yan Li, Le Yang, Faguang Jin.
      Seawater-induced acute lung injury (ALI) shares pathological features with other forms of ALI, characterised by high mortality; however, it presents unique traits, particularly persistent hypoxemia. Nuclear Factor of Activated T cells 5 (NFAT5), initially recognised as a tonicity-responsive enhancer-binding protein, has emerged as acritical regulator of inflammation. Nonetheless, its specific function in alveolar macrophages (AMs) during hyperosmolar seawater-induced ALI remains unclear. This study establishes a murine model of seawater-induced ALI, revealing significantly elevated NFAT5 expression in lung macrophages. Siglec1-specific NFAT5 knockout effectively mitigated seawater-induced lung injury. Mechanistically, NFAT5 was found to directly bind the promoter region of Phosphofructokinase, Platelet type (PFKP) in AMs, enhancing its transcriptional activity. NFAT5 knockdown resulted in downregulation of PFKP expression and suppression of glycolysis, which inhibited M1 macrophage polarisation while promoting M2 macrophage polarisation, thereby reducing the release of inflammatory cytokines. Additional in vitro and in vivo experiments demonstrated that PFKP overexpression counteracts the protective effects of Siglec1-specific NFAT5 knockout in seawater-induced ALI by restoring glycolytic activity. Collectively, these findings illustrate that the NFAT5-PFKP signaling axis in AMs regulates macrophage polarisation and inflammatory responses through glycolytic reprogramming, playing a critical pathogenic role in seawater-induced ALI. These insights enhance understanding of the energy metabolism in AMs, previously regarded as less relevant in inflammation, and identify the NFAT5-PFKP axis as a promising therapeutic target for seawater-induced ALI.
    Keywords:  Acute lung injury; Alveolar macrophage; Glycolysis; Inflammation; NFAT5; Seawater
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112685
  39. Oncol Res. 2026 ;34(7): 13
    Immunometabolic Reprogramming in Hepatocellular Carcinoma Mechanisms, Biomarkers, and Therapeutic Implications.
    Guodong Yu, Weiying Ge, Hongliang Yao, Xuefeng Bai, Jianfei Wu, Yuan Wang, Jiangtao Bai, Yong Cui, Jijing Han.
      Hepatocellular carcinoma (HCC) develops in a chronically inflamed and dysregulated liver metabolism, in which tumor progression and resistance to treatment are orchestrated by the changes in cellular metabolism and immune control. Growing evidence recognizes immunometabolic reprogramming as the two-way interaction of metabolic processes and immune cell capabilities as one of the major determinants of immune evasion and heterogeneity of treatment response in HCC. The review aims to comprehensively evaluate immunometabolic reprogramming in hepatocellular carcinoma, with a focus on its role in tumor progression, immune regulation, and its potential for biomarker identification and therapeutic targeting. Dysregulated glycolysis, lipid metabolism, amino acid utilization, and mitochondrial dysfunction contribute to remodeling of the tumor microenvironment and defects in antitumor immunity. Immunometabolic biomarkers derived from tumor tissue, immune cell states, circulating and liquid biopsy platforms, and metabolic imaging are critically examined for their clinical relevance and associations with disease outcomes and treatment responses. Besides, the role of different immunometabolic conditions on therapeutic efficacy, specifically within the frames of immune checkpoint-inhibitor-based and combination regimens, is addressed. Altogether, immunometabolic reprogramming is identified as a common framework of biomarker-based stratification and precision therapeutic techniques in hepatocellular carcinoma.
    Keywords:  Metabolic reprogramming; biomarkers; hepatocellular carcinoma; immune checkpoint; tumor microenvironment
    DOI:  https://doi.org/10.32604/or.2026.080746
  40. Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00658-3. [Epub ahead of print]45(7): 117580
    Activation-induced SLC7A1 expression enhances T cell sensitivity to cGAMP-mediated STING signaling.
    Valentino Sudaryo, Dayanne R Carvalho, Jacqueline A Carozza, Xujun Cao, Courtney Kernick, Anthony F Cordova, J Michelle Lee, Theodore L Roth, Lingyin Li.
      STING (stimulator of interferon genes) agonists are promising innate immune therapies and can be synergized with adaptive immune checkpoint blockade therapies for cancer treatment, but their effectiveness is limited by the toxicity to activated T cells. How STING agonists such as cGAMP and its analogs enter and induce STING activation and toxicity in T cells is unclear despite known transporters for other cell types. Here, we identify the cationic amino acid transporter SLC7A1 as a cGAMP transporter in activated primary mouse and human T cells. T cells upregulate this transporter upon activation to meet their high metabolic demand, but this comes at the cost of enabling increased transport and toxicity of cGAMP. We identified distinct residues in SLC7A1 that mediate cGAMP and arginine activity, suggesting that cGAMP transport may be separable from arginine uptake. These findings suggest that modulation of SLC7A1 may influence T cell susceptibility to cGAMP and its analogs.
    Keywords:  ADU-S100; CP: immunology; CP: molecular biology; LRRC8A; LRRC8C; SLC7A1; STING; T cells; VRAC; arginine; cGAMP; extracellular cGAMP; toxicity
    DOI:  https://doi.org/10.1016/j.celrep.2026.117580
  41. Free Radic Biol Med. 2026 Jun 22. pii: S0891-5849(26)00896-8. [Epub ahead of print]
    Impaired BCAA Catabolism in Macrophages Exacerbates Sepsis-Induced Lung Injury by Modulating Mitochondrial AGE-RAGE and mtDNA Release.
    Ying Hong, Yan Xu, Kaiteng Luo, Hanbing Wang, Yunlu Li, Junzhu Liu, Ye Mao, Li Zhou, Guochang Hu, Chunling Jiang.
      Although macrophage immunometabolism is a key contributor to the progression of sepsis-induced acute lung injury, the specific role of branched-chain amino acid (BCAA) catabolism in this process remains unclear. Here, we hypothesized that defective BCAA catabolism in macrophages exacerbates lung injury through activation of the advanced glycation end products (AGEs)-RAGE axis and mitochondrial DNA (mtDNA)-mediated inflammation. We employed a myeloid-specific Pp2cm knockout mouse model to examine the impact of impaired BCAA catabolism on lung injury during sepsis. We found that Pp2cm deficiency upregulated AGEs and their receptor RAGE in macrophages, leading to mitochondrial damage and structural damage. This mitochondrial impairment increased mitochondrial reactive oxygen species production and promoted exosomal mtDNA release, ultimately resulting in aggravated lung injury and higher mortality in myeloid Pp2cm deficient mice subjected to polymicrobial sepsis. Therapeutically, adoptive transfer of bone marrow-derived macrophages from wild-type donors into myeloid Pp2cm deficient mice, restoration of BCAA catabolism using the branched-chain ketoacid dehydrogenase kinase inhibitor BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), inhibition of the AGE-RAGE axis with aminoguanidine, or blockade of exosome release with GW4869 all significantly attenuated lung injury and improved survival. Importantly, in septic patients, PP2Cm expression in peripheral blood mononuclear cells was inversely correlated with radiographic lung injury severity and oxygenation index. Together, these findings identify impaired macrophage BCAA catabolism as a critical driver of sepsis-induced lung injury and highlight the AGE-RAGE axis and mtDNA release as potential therapeutic targets.
    Keywords:  AGEs-RAGE; BCAA catabolism; Macrophage; Mitochondria; Sepsis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.041
  42. bioRxiv. 2026 Jun 12. pii: 2026.06.11.731694. [Epub ahead of print]
    Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
    Andrea L Cote, Claire L McIntyre, Joshua A Acklin, Lillian R Delacruz, Yunping Qiu, Irwin J Kurland, Alison E Ringel.
      Cytokine production is a core function of effector T cells, yet the mechanisms that regulate cytokine output during an immune response remain incompletely understood. Here, we identify citrate compartmentalization as a cellular mechanism by which CD8 + T cells couple cytokine production to glucose availability. Under glucose-replete conditions, citrate transport from the mitochondria to the cytosol by the citrate carrier SLC25A1 suppresses calcium-dependent transcription factor activity in effector T cells. Either reducing glucose availability or blocking the exchange of citrate across the mitochondrial membrane raises free cytosolic calcium, thereby driving nuclear localization of Nuclear Factor of Activated T cells (NFAT)-family transcription factors and sustaining cytokine production. As a calcium-chelating metabolite, we show that citrate buffers free cytosolic calcium, thereby linking calcium-dependent signaling to mitochondrial fuel oxidation. We also identify signatures of this regulatory mechanism across hundreds of human cancer cell lines, where there are negative associations between citrate-derived metabolites and calcium-dependent transcriptional programs, and within the spatial organization of human tumors. These findings identify cytosolic citrate as a broadly conserved metabolic rheostat coupling glucose availability to calcium signaling. By adding calcium signaling to the known functions regulated by SLC25A1, our work reveals a mechanism by which mitochondria adaptively tune cytokine expression and other calcium-dependent programs in response to local metabolic conditions, such as nutrients that are available within a tissue or tumor.
    DOI:  https://doi.org/10.64898/2026.06.11.731694
  43. bioRxiv. 2026 Jun 11. pii: 2026.06.07.729655. [Epub ahead of print]
    Dietary fructose promotes MASH/HCC progression through enhanced intestinal HIF-2α-dependent iron absorption.
    Robert A Mitchell, Manman Xu, Elizabeth Hudson, Madison S Teer, Bradford G Hill, Craig J McClain, Ming Song.
      Dietary fructose is a major risk factor driving the progression of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, the underlying fructose-induced nutrient-sensing pathway remains unclear. Here, we report that fructose facilitates iron absorption through the (Ketohexokinase) KHK/PKM2/HIF-2α axis, driving MASH and HCC development. Fructose aberrantly stabilizes intestinal HIF-α; this effect is abrogated by a KHK inhibitor and genetic Khk deletion. Mechanistically, fructose-induced metabolic reprogramming drives glutamine-dependent oxidative phosphorylation, leading to HIF-α stabilization, which is mediated by pyruvate kinase M2 (PKM2). A selective PKM2 inhibitor rescues reduced intestinal HIF-α stability in Khk -deficient mice. Furthermore, dietary fructose increases plasma iron levels. Conversely, Khk -deficient mice exhibit spontaneous systemic iron deficiency, characterized by hypochromic anemia. Moreover, Khk deficiency inhibits iron absorption in a HIF-2α-dependent manner. Finally, fructose promotes MASH and HCC progression in an iron-dependent manner. This study reveals a unique, therapeutically targetable nutrient-sensing pathway utilized by dietary fructose.
    In brief: Mitchell et al. demonstrate that fructose consumption increases plasma iron levels, while KHK deficiency inhibits iron absorption in a HIF-2α-dependent manner. Mechanistically, dietary fructose-induced metabolic reprogramming aberrantly stabilizes intestinal HIF-α, which is mediated by PKM2. Fructose promotes MASH and HCC progression in an iron-dependent manner.
    Highlights: Fructose aberrantly stabilizes intestinal HIF-αKHK is required for intestinal HIF-α stabilityKHK deficiency inhibits iron absorption in a HIF-2α-dependent mannerDietary fructose promotes MASH and HCC progression in an iron-dependent manner.
    DOI:  https://doi.org/10.64898/2026.06.07.729655
  44. Research (Wash D C). 2026 ;9 1321
    PCK2-Mediated PQBP1 Lactylation Promotes Asthmatic Inflammation through PRMT5 Inhibition.
    Qiaoyun Bai, Ningpo Ding, Rixin Feng, Fengxiang Shang, Zongqi Wang, Liangchang Li, Zhiguang Wang, Yihua Piao, Chongyang Wang, Yilan Song, Guanghai Yan.
      Background: Asthma involves chronic inflammation linked to metabolic reprogramming, but how metabolites reshape epigenetics through posttranslational modifications remains unclear. Methods: We used house dust mite (HDM)-induced asthmatic mice with multiomics analyses (metabolomics, posttranslational modification-proteomics, and chromatin immunoprecipitation sequencing) and validated findings through gene editing and adeno-associated virus interventions. Results: Asthmatic airways showed lactate-driven glutaminolysis, causing lactate/succinate accumulation. Phosphoenolpyruvate carboxykinase 2 (PCK2) succinylation at K100 enhanced stability by antagonizing ubiquitination, creating a lactate-generating feedback loop. Accumulated lactate triggered polyglutamine-binding protein 1 (PQBP1) lactylation at K223, enabling protein arginine methyltransferase 5 (PRMT5)/WD repeat domain 77 complex inhibition. This erased H4R3me2s repressive marks from proinflammatory gene promoters, particularly mitogen-activated protein kinase pathway genes, causing transcriptional derepression. Airway epithelium-specific Pqbp1 knockout reduced inflammation, goblet cell hyperplasia, and T helper 2 responses. Pck2-short hairpin RNA or oxamate treatment ameliorated asthmatic pathology. Conclusion: We identified a PCK2-lactate-PQBP1-PRMT5 axis linking metabolic reprogramming to epigenetic dysregulation in asthma. PCK2-K100 succinylation drives lactate accumulation, inducing PQBP1-K223 lactylation that inhibits PRMT5 and activates inflammatory genes, representing a therapeutic target for asthma.
    DOI:  https://doi.org/10.34133/research.1321
  45. Cell Prolif. 2026 Jun 22. e70251
    Lactate-Primed NETosis Modulates Hepatic Regeneration During Acute Liver Failure via the TLR9/KLF15/AJUBA Axis.
    Jin Guo, Xiaoya Zhang, Danmei Zhang, Chunxia Shi, Luwen Wang, Zuojiong Gong.
      Acute liver failure (ALF) is characterised by massive hepatocyte death and compromised regenerative capacity, yet the metabolic-immune crosstalk underlying these pathological processes remains poorly understood. Here, we demonstrate that lactate acts as a pivotal signal that triggers neutrophil extracellular traps (NETs) formation and release. Integrated RNA-seq and scRNA-seq analyses revealed profound glycolytic reprogramming in Kupffer cells (KCs) during ALF, leading to lactate accumulation within the hepatic microenvironment. Mechanistically, neutrophils import exogenous lactate into mitochondria via monocarboxylate transporter 1 (MCT1), which subsequently activates NETosis. Macrophage depletion or administration of an MCT1 inhibitor reduced NETs formation and ameliorated liver injury. Furthermore, we demonstrate that hepatocytes internalise NETs DNA, which is sensed by endosomal Toll-like receptor 9 (TLR9). Activation of the TLR9 signalling pathway suppresses the expression of Krüppel-like factor 15 (KLF15). This downregulation diminishes AJUBA and disrupts the KLF15-AJUBA interaction, thereby increasing the phosphorylation of YAP1 and impeding hepatocyte proliferation. Notably, KLF15 overexpression bypassed TLR9-mediated inhibitory signals and rescued the NETs-induced regenerative failure in vitro. In conclusion, our study elucidates a novel KCs-neutrophil-hepatocyte crosstalk wherein lactate-driven NETosis thwarts liver regeneration via the TLR9/KLF15/AJUBA axis, thereby identifying potential therapeutic targets for the clinical management of ALF.
    Keywords:  ALF; KLF15; NETosis; TLR9; lactate; liver regeneration
    DOI:  https://doi.org/10.1111/cpr.70251
  46. FASEB J. 2026 Jun 30. 40(12): e71991
    Zinc Inhibits BTK Phosphorylation in Macrophages to Ameliorate Encephalitis in Neurotropic Virus-Infected Mice.
    Xiaochen Sun, Baokai Zhang, Shengli Zhao, Hongyang Liu, Rong Wang, Dan Yang, Taikun Tian, Linlin Qi, Bin Wei.
      Zinc is an essential micronutrient with well-characterized immunomodulatory properties and has been widely investigated in viral infectious diseases, yet its specific functional role in neurotropic viral encephalitis remains poorly elucidated. In this study, we demonstrate that a zinc-supplemented (ZnS) dietary intervention confers protection against Japanese encephalitis virus (JEV) infection by suppressing macrophage-mediated inflammatory pathology in the central nervous system (CNS). Besides, zinc inhibited the phosphorylation of Bruton's tyrosine kinase (BTK) and NF-κB p65 in macrophages, thereby effectively curbing excessive neuroinflammation and alleviating JEV-induced neuronal damage in the murine brain. Our findings have identified a previously unrecognized mechanism by which zinc regulates immune responses in the central nervous system, and suggest zinc supplementation as a potential intervention for neurological complications arising from central nervous system infections.
    Keywords:  JEV; btk; encephalitis; macrophage; zinc
    DOI:  https://doi.org/10.1096/fj.202504616RRRR
  47. Metabolites. 2026 Jun 15. pii: 420. [Epub ahead of print]16(6):
    Melatonin Modulates Macrophage Polarization and Immunometabolic Responses in the Colostrum of Obese Mothers.
    Silvia Hannah Bilotti Ratto Gomes da Silva, Danielle Cristina Honorio França, Kênia Maria Resende Silva, Emanuelle Carolina Honorio França, Viviane Francelina Luz, Arce Dos Santos Sfredo, Tassiane Cristina Morais, Eduardo Luzía França, Adenilda Cristina Honorio-França.
      Background/Objectives: Obesity is a major public health problem associated with chronic inflammation and functional alterations in multiple organs and systems. Few studies have examined colostrum from obese mothers, particularly with respect to macrophage function, enzyme and cytokine concentrations, and the role of melatonin in immune modulation. This study aimed to evaluate melatonin levels and their effects on macrophage polarization, cytokine concentrations, nitric oxide synthase [iNOS], and arginase in colostrum from obese mothers. Colostrum samples were collected from eutrophic mothers [BMI: 18.5-24.9 kg/m2] and obese mothers [BMI: ≥30 kg/m2]. Methods: Macrophages were isolated by density gradient and treated with melatonin. The expression of M1 and M2 macrophages and cytokine concentrations were assessed by flow cytometry, while melatonin levels in colostrum supernatants, iNOS, and arginase in cell lysates were determined by ELISA. Results: An endogenous increase in melatonin was also observed in the colostrum of obese mothers. Maternal obesity has been shown to reduce M1 and M2 macrophage expression, increase nitric oxide synthase [NOS] activity, and elevate interleukin-6 [IL-6] and interleukin-17 [IL-17] levels. However, melatonin treatment restored M1 and M2 macrophage levels and reduced inducible nitric oxide synthase [iNOS] and arginase production to levels similar to those observed in mothers of healthy weight. Conclusions: these findings suggest that maternal obesity creates a pro-inflammatory environment in colostrum, characterized by altered macrophage polarization, altered cytokine secretion, and an imbalance in the enzymatic activities of iNOS and arginase within the L-arginine metabolic pathway. Both natural and supplemental melatonin exhibited immunomodulatory, antioxidant, and anti-inflammatory effects, helping to restore immune balance in colostrum. These results emphasize the potential benefits of melatonin as an immunometabolic modulator and its contribution to understanding immunometabolic regulation in obese mothers.
    Keywords:  colostrum; cytokines; macrophages; melatonin; nitric oxide synthase; obesity
    DOI:  https://doi.org/10.3390/metabo16060420
  48. Brain Res. 2026 Jun 20. pii: S0006-8993(26)00299-4. [Epub ahead of print]1888 150439
    Circulating acidic α-glucosidase as a potential biomarker for lactate-related immunometabolism in ischemic stroke.
    Dan Liao, Tian Zeng, Min Zhang, Qiuzi Yang, Chunqing Gao, Zhezhe Gao, Jing Bai, Leilei Jin, Haifeng Wang, Peng Luo, Shuhui Dai, Xin Li.
       BACKGROUND: The role of lactate metabolism in ischemic stroke (IS) remains incompletely understood. This study aimed to characterize lactate-related transcriptomic profiles in IS to identify novel diagnostic biomarkers.
    METHODS: Gene co-expression network analysis and machine learning were used to identify core lactate metabolism-related genes from public transcriptomic datasets and validate them in an independent clinical cohort. Single-cell mouse brain transcriptomic data further characterized GAA expression across brain cell types. An in vitro OGD/R model was established in GAA-high-expressing cells to assess its expression under ischemic/hypoxic conditions. GAA expression in immune cells and its association with macrophage polarization were also evaluated.
    RESULTS: GAA emerged as a core gene, exhibiting significant upregulation in the whole blood of IS patients with robust diagnostic performance (area under the curve = 0.873). This upregulation was confirmed in validation models. After stroke, GAA exhibited a cell-type-specific expression pattern: it was elevated in macrophages and microglia. Notably, GAA expression positively correlated with the anti-inflammatory M2 macrophage marker MRC1 (r = 0.43) and negatively correlated with the pro-inflammatory cytokine interleukin-1β (IL-1β) (r = -0.48), indicating that high GAA levels favor M2-biased polarization.
    CONCLUSION: GAA acts as a potential upstream regulator of lactate metabolism in IS. By linking lysosomal glycogen metabolism to lactate production, GAA may modulate macrophage polarization via a "lactate timer" mechanism. These findings highlight GAA as a promising blood-based biomarker for the auxiliary diagnosis of IS.
    Keywords:  Biomarker; GAA; Immunometabolism; Ischemic stroke; Lactate metabolism; Macrophage polarization
    DOI:  https://doi.org/10.1016/j.brainres.2026.150439
  49. Inflamm Res. 2026 Jun 22. pii: 153. [Epub ahead of print]75(1):
    Methylmalonic acid as a ferroptosis-derived danger signal: activation of the PI3K-NF-κB pathway drives M1 macrophage polarization in renal ischemia-reperfusion injury.
    Huimeng Wang, Jiajia Sun, Xiaohu Li, Hongxuan Ma, Yongsheng Luo, Minghui Qin, Hao Zhang, Haodong Bian, Jinfeng Li.
       BACKGROUND: Ferroptosis and macrophage activation are key contributors to the development of acute kidney injury (AKI). Ferroptosis is accompanied by metabolic reprogramming and the release of soluble mediators, including metabolites, cytokines, and extracellular signals, which can propagate tissue damage and modulate immune responses. However, the metabolic profile of ferroptotic tubular epithelial cells and its impact on the immune microenvironment during ischemia-reperfusion injury (IRI) remains largely unexplored.
    METHODS: Using untargeted metabolomics, we found that ferroptotic cells secreted abnormally elevated levels of methylmalonic acid (MMA), and investigated the physiological role of MMA in acute kidney injury in mice. Furthermore, through transcriptomics and Western blotting, we explored the mechanism by which the ferroptosis-associated metabolite MMA promotes macrophage polarization.
    RESULTS: Here, untargeted metabolomics revealed a distinct metabolic secretome of ferroptotic tubular epithelial cells, with the level of MMA markedly elevated after IRI. Mechanistic studies demonstrated that MMA activated the PI3K/ Akt /NF-κB pathway in macrophages, driving M1 polarization and increasing the secretion of proinflammatory cytokines such as IL-6 and TNF-α, ultimately exacerbating acute kidney injury.
    CONCLUSION: These findings reveal the mechanism of metabolite-immune crosstalk in AKI, and suggest that targeting the ferroptosis-macrophage axis may represent a therapeutic strategy to disrupt the vicious cycle of inflammation and tissue injury.
    Keywords:  Ferroptosis; Ischemia–reperfusion injury; Macrophage; Methylmalonic acid
    DOI:  https://doi.org/10.1007/s00011-026-02300-y
  50. Front Immunol. 2026 ;17 1854522
    The gut-joint axis in gout: microbial outer membrane vesicles and m6A-mediated metabolic-epigenetic coupling from acute flare to chronicity.
    Yiyang Qi, Jixiang Bai, Dewei Liu, Shuhui Wang.
      Gout is increasingly recognized as a systemic metabolic disorder driven by the "gut-joint axis" rather than a purely localized joint disease. However, the exact mechanisms by which intestinal dysfunction causes persistent joint inflammation remain unclear. This review proposes a novel "Two-Hit" theoretical framework mediated by bacterial outer membrane vesicles (OMVs) and N6-methyladenosine (m6A) epigenetic modifications. We hypothesize that the high uric acid environment in the gut exerts a metabolic stress on specific bacteria, driving the release of highly pathogenic OMVs. Following intestinal barrier damage, these OMVs, working synergistically with intestinal-derived lipopolysaccharide (LPS), act as cross-organ messengers to deliver a "two-hit" strike to the joint. First, they prime synovial macrophages (SMs) by upregulating m6A methylation (via the methyltransferase-like 3 enzyme, METTL3), creating a pro-inflammatory epigenetic memory. Second, they induce metabolic reprogramming, characterized by enhanced glycolysis and local acidification in synovial fibroblasts, which physically forces the crystallization of uric acid. Based on this theoretical model, we evaluate emerging therapeutic strategies. These include stabilizing bacterial membranes to block OMV release, using biomimetic nanotechnology to intercept circulating vesicles, and targeting m6A enzymes to erase inflammatory memory. Ultimately, this hypothesis suggests a potential framework to conceptually shift gout management from symptom relief toward source-to-epigenetic precision interventions, while highlighting the necessary directions for future experimental validation.
    Keywords:  epigenetic memory; gout; gut-joint axis; histone lactylation; immunometabolism; m6A methylation; outer membrane vesicles (OMVs); systemic intervention
    DOI:  https://doi.org/10.3389/fimmu.2026.1854522
  51. Prog Neuropsychopharmacol Biol Psychiatry. 2026 Jun 26. pii: S0278-5846(26)00211-3. [Epub ahead of print] 111813
    Lactylation-driven microglial GCH1-BH4 axis suppresses neuroinflammation and underlies the preventive effects of treadmill running against CSDS-induced depression-like behaviors in mice.
    Nan Wang, Shuyang Chen, Chenglang Li, Ju Zou, Sijie Tan.
      Exercise is a novel non-pharmacological intervention for depression, yet the molecular mechanisms linking exercise-induced metabolic signals to epigenetic regulation of neuroinflammation remain largely undefined. We hypothesized that treadmill running ameliorates depressive-like behaviors via suppressing neuroinflammation by lactate-mediated histone lactylation and activation of the GCH1-BH4 axis in the microglia. A chronic social defeat stress (CSDS) mouse model, combined with treadmill running, BH4 treatment, and C646 infusion, along with BV2 microglial cell experiments, were used to assess role and mechanism of GCH1-BH4 axis in the antidepressive effects of running exercise. Treadmill running significantly reduces susceptibility to CSDS-induced depressive-like behaviors in mice, inhibited hippocampal microglial activation and pro-inflammatory cytokine expression. Additionally, running elevated systemic lactate levels, increased H3K18la lactylation, and upregulated microglial GCH1 expression with restored BH4 levels in the hippocampus. In BV2 cells, sodium lactate directly upregulated H3K18la and GCH1 in a concentration- and time-dependent manner, effects that were blocked by the glycolysis inhibitor 2-DG and the P300 inhibitor C646. Exogenous BH4 attenuated LPS-induced microglial inflammation in vitro and reversed CSDS-induced behavioral deficits in vivo. Conversely, intraperitoneal C646 infusion reversed the antidepressant effects of running by downregulating GCH1. These findings establish the lactate-GCH1-BH4 axis as a novel epigenetic mechanism by which treadmill exercise suppresses neuroinflammation and ameliorates depressive-like behaviors, offering a potential therapeutic target for stress-related mood disorders.
    Keywords:  Depression; GCH1-BH4 axis; Histone lactylation; Neuroinflammation; Treadmill running
    DOI:  https://doi.org/10.1016/j.pnpbp.2026.111813
  52. Elife. 2026 Jun 25. pii: RP107596. [Epub ahead of print]14
    Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation.
    Agnese Serafini, Acely Garza-Garcia, Davide Sorze, Luiz Pedro Sorio de Carvalho, Riccardo Manganelli.
      In this study, we investigated how iron limitation alters central metabolism in Mycobacterium tuberculosis using metabolomics and stable isotope tracing. Our findings reveal a well-orchestrated metabolic programme to enable Krebs cycle activity despite the inefficient action of its iron-dependent enzymes. Under such conditions, carbon flux through the oxidative branch of the Krebs cycle is stalled, resulting in the accumulation of metabolites that are partially secreted. As a result, carbon flux from glycolysis is partially diverted to the reductive branch of the Krebs cycle to support the production of oxaloacetate and malate through the activity of phosphoenolpyruvate carboxykinase and pyruvate carboxylase. Both branches terminate with the synthesis of malate, which is secreted. This unprecedented split of the Krebs cycle and malate secretion in a bacterial pathogen facilitates the continuous flow of carbon through the core of carbon metabolism, overcoming the metabolic stalling triggered by iron starvation.
    Keywords:  Mycobacterium tuberculosis; central carbon metabolism; infectious disease; iron starvation; isotope tracing; microbiology; nutritional immunity
    DOI:  https://doi.org/10.7554/eLife.107596
  53. bioRxiv. 2026 Jun 09. pii: 2026.06.04.730208. [Epub ahead of print]
    Adenosine deaminase co-immunization reverses age-associated immunosenescence by restoring germinal center T follicular helper cell function.
    Emily N Bitsko, David R Joyner, Jeffrey R Maslanka, Kyra Woloszczuk, Arden O Edgerton, Matthew R Bell, Christian Sell, Mohamad-Gabriel Alameh, Joris Beld, Elias K Haddad, Michael C Abt, Michele A Kutzler.
      Older adults experience disproportionate morbidity and mortality from Clostridioides difficile infection (CDI); however, existing toxoid- and receptor binding domain (RBD)-based vaccines elicit suboptimal protection in aged hosts due to the age-associated defects in CD4 + T cell function, T follicular helper (T FH ) cell activation, and antibody quality. We evaluated whether adenosine deaminase (ADA), an enzymatic immune modulator that degrades immunosuppressive adenosine, and improves GC T FH differentiation and survival, could reverse these age-related impairments when co-delivered with DNA vaccine plasmids targeting toxin A and B RBDs (pRBD). In aged mice, pRBD vaccination alone produced markedly reduced toxin-specific effector/memory CD4 + T cells, diminished T FH activation, and poor toxin A neutralization compared to vaccinated young mice. Co-immunization with plasmid-encoded adenosine deaminase-1 (pADA) restored toxin-specific CD4 + T cell generation and cytokine production, activation-induced marker (AIM) T FH responses, and antibody-mediate toxin neutralization to levels comparable to young adults. Mechanistically, pADA co-immunization was associated with the reduction of CXCR4 on germinal center (GC) T FH cells-an age-related defect linked to impaired GC positioning and diminished B cell help-suggesting that ADA improves humoral quality by correcting GC T FH mislocalization. These immune enhancements corresponded with improved clinical outcomes in morbidity, mortality, and weight-loss following C. difficile spore challenge of aged mice. Finally, pADA significantly reduced adenosine levels in aged lymph nodes, implicating a potential enzymatic-based regulation of GC immunosenescence. Together, these findings identify ADA as a metabolic adjuvant capable of reversing key features of vaccine immunosenescence and highlight adenosine dependent CXCR4 regulation as a tractable axis for improving vaccine efficacy in older populations.
    DOI:  https://doi.org/10.64898/2026.06.04.730208
  54. Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00685-6. [Epub ahead of print]45(7): 117607
    Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
    Tatsuki Yasuda, Aoi Ichikawa, Kenta Onoue, Emi Ogasawara, Takaya Ishihara, Hidetaka Kosako, Naotada Ishihara.
      Mitochondria are dynamic organelles that continuously remodel their morphology through fusion and fission in response to cellular cues. While this dynamic behavior is essential for diverse cellular functions, how mitochondrial dynamics influence innate immune responses remains incompletely understood. Here, we show that mitochondrial hyperfusion-induced by loss of the fission factor DRP1 or by cellular stress, including cycloheximide or doxorubicin treatment-is associated with activation of a RIG-I-MAVS-dependent innate immune response and BAX-dependent cytosolic release of mitochondrial RNA. Functionally, our data suggest that this pathway contributes to enhanced susceptibility to NK cell-mediated cytotoxicity in vitro and reduced tumor growth in a xenograft model. Collectively, our findings identify mitochondrial hyperfusion-induced mtRNA release as a mechanism that engages innate immune signaling downstream of impaired mitochondrial dynamics.
    Keywords:  CP: immunology; DRP1; RIG-I; innate immunity; mitochondrial RNA; mitochondrial dynamics; mitochondrial hyperfusion; molecular biology
    DOI:  https://doi.org/10.1016/j.celrep.2026.117607
  55. Crit Rev Oncol Hematol. 2026 Jun 26. pii: S1040-8428(26)00344-6. [Epub ahead of print] 105457
    Amino Acid Metabolic Reprogramming in Immunotherapy for Hepatocellular Carcinoma: Adaptive Resistance, Patient Stratification, and Longitudinal Monitoring.
    Hongyang He, Zhiheng Qiao, Xiaocan Gai, Guoliang Ji, Shumin Liu.
       BACKGROUND: Immunotherapy has become an important component of systemic treatment for advanced hepatocellular carcinoma (HCC), yet durable benefit remains limited to a subset of patients because of marked response heterogeneity and acquired resistance.
    PROBLEM: Current biomarkers are often static, single-time-point indicators that incompletely capture evolving tumor-immune metabolic interactions before and during therapy. In HCC, amino acid availability, nitrogen handling, and suppressive metabolite production are shaped by tumor-intrinsic programs, immune-cell competition, and liver-specific metabolic physiology.
    MAIN BODY: This review frames amino acid metabolic reprogramming as a mechanistically and translationally informative axis for HCC immunotherapy. We discuss three clinically relevant domains. First, pretreatment amino acid states may inform patient stratification by reflecting nutrient competition, immune readiness, and transcriptomic signatures linked to glutamine, tryptophan-kynurenine, lysine, and arginine/nitrogen metabolism. Second, adaptive resistance is highlighted as the domain with the strongest mechanistic support, in which therapy pressure rewires amino acid transport, catabolism, and cross-compartment metabolic exchange to create immunosuppressive niches, reinforce suppressive myeloid and regulatory T-cell states, and impair effector T-cell function. Third, longitudinal monitoring through circulating metabolites, paired tissue profiling, spatial multi-omics, and computational integration is evaluated according to mechanistic resolution and clinical scalability.
    CONCLUSION: Amino acid metabolism should be viewed not merely as a descriptive hallmark, but as a clinically organizing and potentially actionable framework for organizing patient stratification, adaptive resistance, and longitudinal monitoring in HCC immunotherapy. Prioritizing reproducible, actionable on-treatment resistance states may help move the field beyond static biomarkers toward earlier therapeutic adaptation.
    Keywords:  Adaptive resistance; Amino acid metabolism; Hepatocellular carcinoma; Immunotherapy; Longitudinal monitoring
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105457
  56. Cell Metab. 2026 Jun 25. pii: S1550-4131(26)00227-5. [Epub ahead of print]
    The metabolic basis of regulated cell death.
    Jiao Liu, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.
      Regulated cell death (RCD) has long been conceptualized as a genetically encoded signaling process, yet its outcome is ultimately dictated by cellular metabolism. Here, we propose that cellular metabolism functions as a gatekeeper of RCD, establishing permissive or restrictive states that determine cell fate. Bioenergetic capacity, redox balance, lipid composition, and metal availability impose metabolic constraints that bias cells toward survival or distinct death modalities. At the systems level, organelle-resolved metabolism and inter-organelle communication coordinate the spatial control of death processes. We further position RCD pathways along a metabolic continuum, ranging from energy-dependent apoptosis to chemistry-driven ferroptosis. This framework explains the plasticity of death responses and suggests that metabolic reprogramming can redirect cell fate. Targeting metabolic dependencies thus offers a strategy to control cell death in disease.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.001
  57. Food Funct. 2026 Jun 23.
    Gut microbiota-dependent metabolism of 6-shogaol generates bioactive metabolites that mediate its anti-inflammatory effects.
    Shuwei Zhang, Yantao Zhao, Rachel C Newsome, Yingdong Zhu, Christian Jobin, Shengmin Sang.
      6-Shogaol (6S), a major bioactive constituent of ginger, exhibits anti-inflammatory activity, but the contribution of gut microbiota to its metabolism and biological effects remains unclear. Using germ-free (GF) and specific pathogen-free (SPF) mice, we demonstrate that gut microbiota plays an essential role in the in vivo metabolism of 6S and the generation of bioactive metabolites. Two previously unreported metabolites were isolated from fecal samples, structurally characterized using high-resolution LC-MS/MS and NMR spectra, and confirmed by chemical synthesis. The most potent fecal fraction (fraction 4), enriched in microbial metabolites of 6S, significantly suppressed nitric oxide production by 75%, reduced inducible nitric oxide synthase (iNOS) expression by 22% and cyclooxygenase-2 (COX-2) expression by 64%, and inhibited NF-κB p65 activation by 67% in lipopolysaccharide-stimulated RAW 264.7 macrophages. Moreover, intrarectal administration of microbial metabolites of 6S markedly attenuated LPS-induced inflammatory responses in mice by inhibiting TNF-α and IL-6 levels, with effects comparable to or exceeding those of 6S. Collectively, these findings demonstrate that gut microbiota extensively metabolizes 6S and its microbial metabolites still exhibit anti-inflammatory activity.
    DOI:  https://doi.org/10.1039/d6fo01722c
  58. Pharmacol Res. 2026 Jun 23. pii: S1043-6618(26)00224-0. [Epub ahead of print] 108309
    The immunomodulatory role of vitamins in tumor: mechanisms and therapeutic implications.
    Jingwen Jiang, Linlu Wen, Huan Liu, Xun Liao, Yanting Liu, Yinghua Ji, Ping Lu, Sujun Chen, Luoqiang Zhang, Wenyong Yang.
      The tumor microenvironment (TME)-marked by hypoxia, acidosis, and nutrient scarcity-creates a metabolically restrictive niche that undermines sustained antitumor immunity. Within this niche, infiltrating immune cells could become functionally exhausted to limit the efficacy of existing immunotherapies. Recently, metabolic competition between tumor cells and immune cells for nutrients has attracted great attention in immunometabolism to explain the immune dysfunction. Notably, micronutrients, particularly vitamins, have been increasingly revealed to serve as active immunoregulatory agents rather than working solely as metabolic precursors or intermediates. In this review, we highlight the role of vitamins as immune-metabolic modulators that coordinate metabolic reprogramming, epigenetic remodeling, and signal transduction in tumor-infiltrating immune cells. We further discuss how vitamin activity is shaped by tumor-specific metabolic states, molecular forms, microbiome-dependent regulation and microenvironmental conditions, resulting in context-dependent immunological outcomes. By integrating preclinical mechanistic insights with the current landscape of clinical trials, the translational challenges arising from the pleiotropic effects of vitamins have also been evaluated. Finally, we also summarize emerging biomarker-guided and tumor-targeted intervention strategies that may help improve the therapeutic utility of vitamins and overcome immunotherapy resistance.
    Keywords:  Cancer immunotherapy; Immunometabolism; Nutritional immunology; Tumor microenvironment; Vitamins
    DOI:  https://doi.org/10.1016/j.phrs.2026.108309
  59. Front Immunol. 2026 ;17 1852236
    Mitochondria: from powerhouses of cells to hubs in antitumor immunity.
    Xiaofeng Li, Yanfeng Shi, Yan Zhao, Gengjun Zhu, Lifang Jin.
      While immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies constitute the cornerstone of current immunotherapy, their efficacy is often limited by, most notably, the immunosuppressive tumor microenvironment. Recently, mitochondria are recognized as pivotal metabolic-immune hubs that critically support tumor progression, metastasis, and immune evasion. However, this insight has not yet translated into a clear understanding of the underlying mechanisms or their therapeutic potential. This review summarizes the role of mitochondria in cellular metabolic regulation, with a focus on mitochondrial-mediated metabolic reprogramming in cancer and immune cells within the tumor microenvironment. We then discuss therapeutic opportunities to potentiate antitumor immunity by targeting mitochondrial reprogramming in cancer and CAR-T cells. Finally, we offer a forward-looking perspective on emerging mitochondria-targeted strategies, such as mitochondrial vaccines, precise mtDNA editing, and engineered mitochondrial transplantation.
    Keywords:  CAR-T; antitumor immunity; metabolic reprogramming; mitochondria; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1852236
  60. Metabolites. 2026 Jun 15. pii: 416. [Epub ahead of print]16(6):
    Immunometabolic Stratification of Autism Spectrum Disorder by CD4+ T-Cell Phenotype Reveals Subtype-Specific Energetic Deficit and Coordinated Suppression of Micronutrient Acquisition Pathways.
    Albion Dervishi.
       BACKGROUND: Autism spectrum disorder (ASD) is associated with immune dysregulation in a subset of individuals, though findings remain heterogeneous and poorly defined, particularly regarding immune subtypes and metabolic context.
    METHODS: We analyzed whole-blood microarray data from GSE18123 (GPL570: ASD n = 46, controls n = 19; GPL6244: ASD n = 68, controls n = 21) using an integrated immunometabolic framework. CD4+ T-cell transcriptional programs were used to assign dominant immune phenotypes (TH1, TH2, TH17, Tfh, FOXP3+ Treg, Tr1-like). Metabolic demand was quantified via the τ-axis; execution capacity was assessed using cytosolic and mitochondrial energy compensation ratios (CECR, MECR). Induction-execution mismatch was captured by three Gap metrics (Cytosolic, Warburg, Global). Functional validation correlated these metrics with transcriptional signatures of folate transport, one-carbon metabolism, receptor-mediated micronutrient uptake (LRP2-CUBN-AMN), cobalamin processing, and vitamin D activation across both platforms.
    RESULTS: Six immunometabolic CD4+ subtypes were identified within ASD. τ-axis discrimination was strongest for Tr1-like (AUC = 0.811) and Tfh (AUC = 0.825) states, while TH17 profiles were indistinguishable from controls. Despite variation in metabolic demand, CECR and MECR remained relatively preserved, indicating decoupling between induction and execution capacity. Global Gap values were most negative in Tfh and TH1 states and positive in TH17 and controls. Negative Gap states showed coordinated suppression of ATP-intensive micronutrient acquisition pathways, including folate transport (FOLR1/2, SLC19A1), megalin-cubilin-mediated uptake (r ≈ 0.77-0.79), and vitamin D activation (CYP27B1). Intracellular cobalamin processing was upregulated in proportion to metabolic demand (r > 0.9). Findings were directionally replicated across both datasets.
    CONCLUSIONS: These data demonstrate that ASD exhibits structured immunometabolic heterogeneity characterized by subtype-specific demand-capacity imbalance. The Global Gap framework provides transcriptomic evidence of energetic deficit in Tfh- and Tr1-like-dominant states. Future clinical studies should incorporate subtype-stratified assessment of micronutrient status and metabolic execution capacity.
    Keywords:  CD4+ T-cell subtypes; GPL570; GPL6244; Global Gap; Warburg effect; autism spectrum disorder; folate transport; immunometabolic stratification; luxury pathway suppression; micronutrient triage; vitamin B12; vitamin D; τ-axis
    DOI:  https://doi.org/10.3390/metabo16060416
  61. Biomater Adv. 2026 Jun 19. pii: S2772-9508(26)00331-6. [Epub ahead of print]188 215033
    Engineering the "pro-healing niche": Hydrogel-driven immunometabolic reprogramming for diabetic foot ulcers.
    Ziming Xu, Zongtong Yang, Rui Liu, Yutao Wang, Yufei Li, Qing Sun.
      The refractory nature of diabetic foot ulcers (DFUs) stems from persistent immunometabolic dysregulation. Although a myriad of reviews have extensively categorized hydrogel dressings, most remain confined to passive material classifications and isolated phenotypic targets. To bridge this gap, this review delineates an integrated "hydrogel engineering-immunometabolic regulation-tissue regeneration" framework. We redefine hydrogels as "intelligent bioreactors" that actively construct a "pro-healing niche," dissecting the underlying mechano-metabolic crosstalk (e.g., VASP/HIF-1α and mTOR signaling). Furthermore, we elucidate the interventional mechanisms of diverse hydrogel strategies-including externally triggered, dynamically responsive, nanocomposite, and mechanically programmed platforms-across four critical pathways: glycolysis, lipid metabolism, amino acid metabolism, and oxidative stress. Crucially, by extracting raw healing data to calculate relative improvement rates and daily relative improvement rates, we quantitatively benchmark the discrepancies in healing kinetics among distinct strategies. Building upon this, we propose scenario-oriented clinical selection pathways: prioritizing near-infrared (NIR)-responsive or photocatalytic hydrogels for severely hypoxic DFUs, and recommending ultrasound-driven sequential "sterilization-then-antioxidation" hydrogels for neuropathic ulcers complicated by multidrug-resistant bacterial infections. Additionally, via precise metabolic reprogramming, these tailored hydrogels actively drive macrophage repolarization, restore T cell subset balance, and enhance dendritic cell efferocytosis. Finally, by integrating biomarker-driven standardized evaluations, GMP-compliant scale-up engineering, and AI-assisted modular production platforms, this review outlines a step-by-step clinical translational roadmap. This strategic roadmap aims to bridge the gap between laboratory prototypes and personalized precision medicine, ultimately providing a comprehensive blueprint for next-generation metabolic therapeutics in chronic wound management.
    Keywords:  Diabetic foot ulcers; Dynamic metabolic buffering; Immunometabolic reprogramming; Intelligent hydrogels; Macrophage polarization; Pro-healing niche
    DOI:  https://doi.org/10.1016/j.bioadv.2026.215033
  62. bioRxiv. 2026 Jun 10. pii: 2026.06.08.730463. [Epub ahead of print]
    Adipose tissue as a site of immune activation and dysfunction in individuals with obesity and asthma.
    Dawn C Newcomb, Alessandra Tomasello, Jean-Philippe Cartailler, Bilgunay Ilkin Safa, LaToya Hannah, Shristi Shrestha, Shahar Hartman, Melissa H Bloodworth, Kevin Niswender, John R Koethe, Samuel Bailin, James Matthew Luther, Nancy J Brown, Mona Mashayekhi, Katherine N Cahill.
      Obesity increases local inflammatory responses in adipose tissue. Individuals with obesity have increased asthma incidence and severity and reduced responses to asthma therapeutics through unknown mechanisms. To identify mechanisms by which increased fat mass augments asthma pathogenesis, single cell RNA sequencing of the immune-rich stromovascular fraction of subcutaneous adipose tissue was conducted from well-characterized adults with obesity-associated asthma matched to adults without asthma. Individuals with asthma had increased abundance of perivascular macrophages and lymphoid-associated macrophages (LAMs) and reduced abundance of classical monocytes and CD4+ and CD8+ naïve T cells. Pseudo-bulk differential expression (DE) identified upregulation of cellular metabolism, specifically oxidative phosphorylation, and decreased immune homeostatic pathways in asthma across immune cell subsets. Cell type specific DE analysis of effector cell subtypes identified significant induction of metallothionein gene expression in asthma, a signature of immune cell dysfunction characterized by both an activation and exhaustion phenotype. Gene co-expression analysis identified gene modules associated with asthma diagnosis, lung function, and biomarkers of type 2 inflammation were enriched in effector cells. These data identify adipose tissue dysfunction occurs in obesity-associated asthma and support adipose tissue as therapeutic target to address the enhanced asthma risk among those with obesity.
    Grant Support: NIH U01AI155299, P30DK020593, R01AI182159, K23HL159351, UL1RR024975-03, P30CA68485, P30EY08126, G20RR030956, 5UL1TR002243, KL2TR002245, P30AI110527, DK020593, American Heart Association 17SFRN33520017.
    DOI:  https://doi.org/10.64898/2026.06.08.730463
  63. Nat Neurosci. 2026 Jun 26.
    Mitochondrial stress response drives microglial senescence.
    Luca Peruzzotti-Jametti, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s41593-026-02264-6
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