bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–05–17
48 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Rewiring macrophage immunometabolism in gouty arthritis: from metabolic checkpoints to intelligent nano-delivery.
  2. A two-membrane gateway for monocarboxylates couples host glycolysis to Toxoplasma mitochondrial fitness and virulence.
  3. Metabolic Reprogramming of Microglia in Neuroinflammation and Depression.
  4. Beyond ATP: Lipid-Driven Plasticity and the Immunometabolism of ILC2s.
  5. Autofluorescence imaging reveals the impact of cryopreservation on T cell metabolism and activation response.
  6. The natural β-glucan polysaccharide laminarin ameliorates microglial inflammation by metabolic reprogramming through the sirtuin 1/AMP-activated protein kinase axis.
  7. Metabolic pattern changes of macrophages during cancer development and progression.
  8. CD8+ T cells turn resilient under stress.
  9. Pentagalloyl glucose suppresses MSU crystal-induced gout inflammation and arachidonic acid production in vitro and in vivo.
  10. Metabolic Reprogramming and Immune Metabolism in Sepsis: Targeting the PPAR Pathway for Personalized Therapeutic Approaches.
  11. Nucleotide metabolism reprogramming in obesity-associated cardiovascular inflammation: a new perspective.
  12. Targeting NLRP3 palmitoylation: Celastrol alleviates inflammasome activation induced by immunometabolism dysregulation in Kupffer cells.
  13. CARM1 drives sepsis-induced lung injury by coupling PKM2-governed metabolic rewiring to macrophage ferroptosis.
  14. Metabolite-neuro-immune relay in chronic pain: spatial-temporal lactate, succinate and itaconate signalling as drivers of glial reprogramming and neuronal sensitisation.
  15. SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.
  16. 1-deoxysphinganine promoted microglial glycolytic reprogramming and neuroinflammation in alzheimer's disease.
  17. Zika Virus-Induced Metabolic Reprogramming Drives Lipid Droplet Biogenesis, Promoting Viral Replication and Ocular Pathogenesis.
  18. Albiflorin contributes to Xuebijing-mediated protection against sepsis-associated acute kidney injury by modulating the succinate-PFKFB3 immunometabolic axis.
  19. Immunometabolomics Applied to Physical Exercise: Accomplishments and New Directions for Health Improvement.
  20. The alkylation of AIM2 by itaconate mediates macrophage PANoptosis during sepsis.
  21. Lactate Enhances CD8+ T Cell Cytotoxicity Through H3K9la Upregulation to Drive Vitiligo Pathogenesis.
  22. PRC1 impairs sepsis host defense by suppressing NF-κB/JAK-STAT signaling and macrophage glycolytic reprogramming.
  23. ORFV-induced glycolysis facilitates virus replication by increasing lactate production to promote the association between HK2 and STING.
  24. Soluble Uric Acid Drives CD8⁺ T-cell Exhaustion by Inducing KSR1-Mediated MAPK Hyperactivation.
  25. Immunometabolism in Cardiac Remodeling: Mechanisms and Therapeutic Perspectives.
  26. Amino Acid-Driven Mitochondrial Metabolic Rewiring Controls Antitumor Immunity.
  27. PD-1 deficiency exacerbates Mycobacteroides abscessus lung infection via metabolic rewiring and dysregulated neutrophil/T cell responses.
  28. Targeting macrophage metabolic checkpoints: a host-directed strategy to overcome drug tolerance in tuberculosis.
  29. PFOA induced metabolic and immune perturbations in a SARS-2 infection model.
  30. Metabolic reprogramming as a driver of immune escape in melanoma: implications for immunotherapy.
  31. β-oxidation-mediated differentiation of effector CD4+ T cells in the lung enhances neuroinflammation.
  32. Epigenetic reprogramming of T cell metabolism restores function and enhances anti-tumor immunity in lung cancer.
  33. The PI3K-Akt-CCND2 axis couples metabolic reprogramming with macrophage M1 polarization.
  34. The ATP-adenosine axis as a driver of tumor-associated macrophage reprogramming in colorectal cancer: mechanistic insights into immune evasion and therapeutic vulnerabilities.
  35. Indole-3-carboxaldehyde from Limosilactobacillus reuteri targets the DUSP1/ERK/NOX2/ROS axis to enhance the bactericidal activity of macrophages and protects against sepsis.
  36. FAS-controlled T cells drive lymphoproliferation through glycolysis without effector differentiation.
  37. CD4+ T cells promote fibrosis during metabolic dysfunction-associated steatohepatitis.
  38. An Implantable Optogenetics-Engineered Hydrogel for Amelioration of Rheumatoid Arthritis through Light-Controlled Metabolic Reprogramming of Synovial Macrophages.
  39. Metabolic-epigenetic rewiring in rheumatoid arthritis: from pathogenic memory to precision restoration.
  40. A neutrophil-intrinsic CKLF1-PKM2 axis drives glycolytic flux for de novo DAG synthesis and pro-inflammatory ROS production.
  41. Ambient temperature regulates CD4+ T cell tonic T cell receptor signaling and responsiveness.
  42. Persistent Adipose Inflammation Despite Metabolic Recovery Reveals Tissue-Specific Immunomodulation by Tirzepatide.
  43. Dietary tryptophan enhances aryl hydrocarbon receptor activation and reduces colitis through microbial metabolism.
  44. Inhibition of RGS1 ameliorates obesity-associated macrophage dysfunction and metaflammation through restoration of PINK1/Parkin-mediated mitophagy.
  45. Macrophage Phenotypic Plasticity and Inflammatory Mechanisms in Hyperoxia-Induced Lung Injury.
  46. Microbial phosphoketolase promotes histone lactylation to improve anti-TNF therapy efficacy in inflammatory bowel disease.
  47. Metabolic dysfunction-associated steatohepatitis exacerbated by Clostridium perfringens-derived ammonia is attenuated by tripeptide DT-109.
  48. Human MAITregs possess diverse TCR repertoires and are functionally supported by glycolysis.
  1. Front Pharmacol. 2026 ;17 1794487
    Rewiring macrophage immunometabolism in gouty arthritis: from metabolic checkpoints to intelligent nano-delivery.
    Feng Xiao, Xin Zhou, Jie Liu, Kaijun Huang, Qixiang Qin, Chengxue Li, Yifan Lu, Hui Xiong, Xiaobin Luo, Zhiqiang Luo, Aitian Zhang, Wenjie Su.
      Gouty arthritis (GA) is driven by NLRP3 inflammasome activation, yet its underlying metabolic mechanisms remain poorly explored. Current therapies focus on uric acid reduction and anti-inflammation, often overlooking the plasticity of macrophages controlled by metabolic reprogramming. This review systematically dissects the metabolic shifts in GA, particularly the transition from oxidative phosphorylation (OXPHOS) to glycolysis (Warburg effect) and the unique role of lipid/amino acid metabolism. We describe macrophage immunometabolism, tricarboxylic acid (TCA)cycle breakpoints, and metabolite functions, with particular emphasis on the "metabolic-epigenetic" axis (e.g., lactate conversion). We summarize emerging nanotherapeutic strategies (e.g., nanoenzymes, biomimetic carriers) precisely targeting these metabolic checkpoints. Current reviews on GA primarily focus on conventional anti-inflammatory and uric acid-lowering strategies. However, although macrophages are central drivers of the GA disease process, the mechanisms underlying the coupling of their metabolic reprogramming and polarization have not yet been fully elucidated. In particular, metabolite-mediated "metabolic-epigenetic" crosstalk, as well as how to precisely regulate these metabolic targets using emerging nanotargeting technologies, remain blind spots in current research. This paper is the first to systematically integrate these dimensions, aiming to fill this gap by exploring novel nanostrategies and future prospects for treating GA through the remodeling of macrophage immunometabolism. Targeting macrophage metabolism offers a paradigm shift for GA-from conventional symptom management to targeted disease resolution by directly inhibiting glycolytic flux and succinate accumulation, thereby repolarizing pro-inflammatory M1 macrophages into the tissue-repairing M2 phenotype.
    Keywords:  OXPHOS; glycolysis; gouty arthritis; immunometabolism; intelligent nano-delivery; lactylation; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fphar.2026.1794487
  2. bioRxiv. 2026 Feb 24. pii: 2026.02.23.707530. [Epub ahead of print]
    A two-membrane gateway for monocarboxylates couples host glycolysis to Toxoplasma mitochondrial fitness and virulence.
    Melanie Key, Steven Joseph, Zhicheng Dou.
      Intracellular pathogens must coordinate their metabolism with nutrient supplies from the host cell, yet the specific metabolites and transport pathways that sustain parasite bioenergetics remain incompletely defined. In the apicomplexan parasite Toxoplasma gondii , infection increases host glycolytic flux and elevates cytosolic lactate and pyruvate, suggesting that these intermediates are co-opted as carbon and energy sources. Here, we show that T. gondii imports host-derived lactate and pyruvate across both the parasitophorous vacuole membrane and the parasite plasma membrane to maintain mitochondrial function, extracellular survival, and acute virulence. Using a hexokinase knockout (Δ hk ) to abolish endogenous pyruvate production, we find that parasites preserve basal oxygen consumption but become strictly dependent on exogenous monocarboxylates to stimulate mitochondrial respiration. By disrupting the parasite formate-nitrite transporters TgFNT1-3, we identify TgFNT1 and TgFNT2 as the principal monocarboxylate transporters required for lactate- and pyruvate-driven respiratory responses. Furthermore, genetic ablation of TgGRA17, a parasitophorous vacuole pore protein, compromises the growth advantage conferred by elevated exogenous lactate, implicating this pore as the entry route for host-derived monocarboxylates into the vacuole. Conversely, host cells lacking the monocarboxylate exporter MCT1 accumulate cytosolic lactate/pyruvate and enhance parasite growth, linking host monocarboxylate export to parasite fitness. When both endogenous pyruvate production and exogenous uptake are disrupted, parasites display severely reduced mitochondrial basal respiratory capacity, membrane potential, ATP levels, extracellular survival, and virulence in mice. Collectively, these findings define a dual-step pyruvate acquisition pathway in T. gondii and reveal host monocarboxylates as critical fuels that buffer parasite bioenergetic stress during infection.
    Significance Statement: Intracellular parasites rely on host nutrients to power their metabolism, yet the routes by which these metabolites cross the membranes between host cytosol and parasite mitochondria are not well defined. Here, we show that Toxoplasma gondii exploits host glycolysis by importing lactate and pyruvate to sustain mitochondrial function and virulence. We identify a two-step pathway in which these monocarboxylates cross the parasitophorous vacuole via the pore GRA17 and then enter the parasite through the formate-nitrite transporters TgFNT1/2. Blocking both endogenous glycolysis and this exogenous pyruvate supply disables parasite mitochondrial fitness, extracellular survival, and virulence. These findings reveal a fundamental strategy of metabolic plasticity in apicomplexan parasites using a multi-membrane nutrient gateway that couples host glycolysis to parasite bioenergetics.
    DOI:  https://doi.org/10.64898/2026.02.23.707530
  3. Int J Mol Sci. 2026 Apr 29. pii: 3984. [Epub ahead of print]27(9):
    Metabolic Reprogramming of Microglia in Neuroinflammation and Depression.
    Qingru Wu, Jing Tian, Yan Gu, Xiaoying Bi, Hailing Zhang.
      Depression is a highly heterogeneous psychiatric disorder with its pathogenesis increasingly linked to dysregulated neuroinflammation. Microglia, as the resident immune cells of the central nervous system (CNS), play a pivotal role in the initiation and progression of the neuroinflammation and the pathophysiology of depression. These cells exhibit a dual role in pro- and anti-inflammatory processes, dynamically regulating immune responses through immunometabolic reprogramming in response to environmental cues. This review elaborates how metabolic remodeling in microglia, particularly within glucose, lipid, and amino acid pathways, drives their polarization toward a pro-inflammatory phenotype. This shift promotes depression pathogenesis via the release of inflammatory factors, disruption of synaptic plasticity, and mediation of neurotoxicity. We further discuss the impact of existing antidepressants on cellular metabolism and highlight the promise and challenges of targeting specific microglial metabolic pathways as a novel therapeutic strategy. This synthesis provides new insights into the immunometabolic mechanisms of depression and outlines directions for developing targeted treatments.
    Keywords:  depression; glutamate; glycolysis; immunometabolism; lipid metabolism; metabolic reprogramming; microglia; mitochondria; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms27093984
  4. Cells. 2026 May 03. pii: 838. [Epub ahead of print]15(9):
    Beyond ATP: Lipid-Driven Plasticity and the Immunometabolism of ILC2s.
    Vanessa-Vivien Pesold, Jafar Cain, Steven J Bensinger, Omid Akbari.
      Group 2 innate lymphoid cells (ILC2s) are tissue-resident immune cells that play a central role in type 2 immunity. Beyond cytokine signaling, they integrate inputs from lipids, nutrients, neuroendocrine mediators, and local metabolic cues, establishing cellular metabolism as a key regulator of their function. Immunometabolism provides a framework to understand how ILC2s adapt to diverse tissue environments such as the lung, adipose tissue, gut, skin, and brain, each defined by distinct nutrient availability, oxygen tension, and inflammatory conditions. Unlike many immune cells that primarily rely on glycolysis, ILC2s dynamically balance glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) depending on activation state and tissue context. Lipids not only serve as energy substrates but also regulate membrane organization, lipid raft-dependent signaling, and the generation of bioactive mediators, including eicosanoids, oxysterols, and sphingolipids. Emerging evidence linking cholesterol biosynthesis, steroid metabolism, and sphingolipid signaling to ILC2 function underscores the importance of lipid-dependent immune regulation. Dysregulation of these pathways contributes to chronic inflammatory diseases such as asthma, metabolic disorders, and fibrosis. Targeting metabolic pathways and checkpoints may therefore offer new strategies to modulate ILC2-driven pathology. This review summarizes current insights into metabolic programs governing ILC2 activation, survival, and plasticity and highlights emerging therapeutic opportunities.
    Keywords:  IL-33; ILC2; fatty acid oxidation; immunometabolism; lipid metabolism
    DOI:  https://doi.org/10.3390/cells15090838
  5. Mol Ther Adv. 2026 Jun 11. 34(2): 201704
    Autofluorescence imaging reveals the impact of cryopreservation on T cell metabolism and activation response.
    Dan L Pham, Meghana Kalluri, Cole Weaver, Angela Hsu, Amani Gillette, Wenxuan Zhao, Tyce Kearl, Peiman Hematti, Nirav N Shah, Melissa C Skala.
      Cryopreservation or the process of freezing cells is a cornerstone of most cell therapy protocols. Optimization of cryopreservation protocols and cryoprotectant agents to improve cell viability and functionality is under further investigation. However, the impact of cryopreservation on cellular metabolism and function immediately post-thaw is not fully understood. Here, we used label-free, non-invasive optical metabolic imaging (OMI) of NAD(P)H and FAD to characterize the activation response of frozen T cells from healthy donors and lymphoma patients post-thaw. Using OMI, we identified significant metabolic shift, along with delayed and diminished activation response, in healthy donor T cells throughout the first 4.5 h upon thawing. In cryopreserved peripheral T cells from lymphoma patients in our bispecific CD20/CD19 CAR T clinical trial, OMI could identify early metabolic stress and allowed gating of metabolically fit cells associated with post-thaw viability. Notably, in our pilot study involving four patients, metabolically fit T cells from complete responders exhibited metabolic responses to activating stimuli within the first 4.5 h post-thaw. Overall, our findings suggest that 4-5 h post-thaw is a critical time window to assess the impact of cryopreservation and thawing, supporting the potential of OMI to optimize cryopreservation protocols and evaluate patient T cell quality for cell therapy.
    Keywords:  autofluorescence imaging; chimeric antigen receptor T cell manufacturing; cryopreservation; fluorescence lifetime imaging; immunometabolism
    DOI:  https://doi.org/10.1016/j.omta.2026.201704
  6. Int J Biol Macromol. 2026 May 12. pii: S0141-8130(26)02415-3. [Epub ahead of print] 152488
    The natural β-glucan polysaccharide laminarin ameliorates microglial inflammation by metabolic reprogramming through the sirtuin 1/AMP-activated protein kinase axis.
    Chae Young Moon, Subin Shin, Jinho Lee, Suji Kim, Sooyeun Lee, Hyunju Kang.
      Neuroinflammation, driven by the activation of immune cells such as microglia, is tightly linked to metabolic reprogramming, thereby emerging as a key therapeutic target. This study investigated the potential of laminarin, a natural β-glucan polysaccharide, to ameliorate immunometabolic dysfunction in lipopolysaccharide (LPS)-stimulated microglia. Laminarin potently suppressed the production of pro-inflammatory cytokines, reduced oxidative stress, and ameliorated metabolic dysfunction through the activation of sirtuin 1 (SIRT1), which was identified as a key molecular target. Molecular docking simulations predicted a high-affinity binding of its representative unit, laminarihexaose, to the SIRT1 allosteric activation site, leading to its effective activation. In LPS-challenged microglia, laminarin's ability to enhance cellular NAD+ levels via the NAD+ salvage pathway also contributed to SIRT1 activation. Furthermore, the promotion of SIRT1 activation was linked to laminarin's capacity to promote the phosphorylation of AMP-activated protein kinase (AMPK), suggesting a potential positive feedback loop that reinforces the integrity of the SIRT1-AMPK axis. Laminarin prevented LPS-induced abnormal flux of the TCA cycle by regulating the related genes and the concentration of intermediates like aconitic acid and 2-hydroxyglutaric acid. Laminarin's efficacy also extended to suppressing the compensatory glycolytic switch and to ameliorating mitochondrial dysfunction by restoring the mitochondrial membrane potential and regulating genes involved in mitochondrial respiration. Collectively, these results suggest that laminarin ameliorates microglial inflammation and metabolic dysregulation by activating the SIRT1-AMPK axis to restore metabolic homeostasis. These findings position laminarin as a promising therapeutic candidate for neuroinflammatory disorders by targeting the crucial link between immunity and metabolism.
    Keywords:  Immunometabolism; Laminarin; Microglia; Neuroinflammation; Sirtuin 1
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152488
  7. J Transl Med. 2026 May 12.
    Metabolic pattern changes of macrophages during cancer development and progression.
    Guanfu Liu, Binxue Wang, Shaojie Wang, Shi Li, Hua Han, Tai An.
       BACKGROUND: Tumor-associated macrophages (TAMs) are critical components of the immune cell population within the tumor microenvironment (TME), where they play dynamic and multifaceted roles throughout the progression of tumorigenesis. Recent evidence suggests that shifts in macrophage metabolic programs-including glycolysis, oxidative phosphorylation, fatty acid utilization, glutamine metabolism, and the pentose phosphate pathway, are closely associated with diverse and context-dependent functional states rather than fixed polarization phenotypes. During tumor progression toward invasion and metastasis, macrophage metabolic programs dynamically adapt to spatial and temporal variations within the TME, often contributing to immunoregulatory or tumor-supportive niches that facilitate angiogenesis, tumor dissemination, immune evasion, and metabolic crosstalk with tumor cells. However, the precise mechanisms underlying these context-dependent adaptations remain incompletely understood.
    MAIN BODY: This article reviews current evidence regarding TAM activation states and metabolic reprogramming by various signals in the TME during tumorigenesis and tumor progression, as well as dynamic alterations in TAM metabolic patterns. Furthermore, we explore how secondary metabolites present in the TME influence macrophage metabolic reprogramming and summarize current research on potential therapeutic agents targeting macrophage metabolism.
    CONCLUSIONS: We propose that modulating key metabolic regulators in TAMs or intervening in metabolic-immune crosstalk pathways may offer novel strategies for precision medicine in cancer therapy, providing a theoretical foundation for metabolic intervention-based immunotherapeutic approaches.
    Keywords:  Cancer immunotherapy; Immunometabolism; Metabolic intermediates; Metabolic reprogramming; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s12967-026-08210-1
  8. Immunity. 2026 May 12. pii: S1074-7613(26)00168-8. [Epub ahead of print]59(5): 1171-1173
    CD8+ T cells turn resilient under stress.
    Daniele C Nascimento, Luciana Berod.
      Tumors present metabolic challenges for T cells. In this issue of Immunity, Scaglione et al. show that CD8+ T cells adapt to nutrient stress through biosynthetic plasticity, coupling translational reprioritization to metabolic reprogramming, preserving effector function and supporting antitumor immunity.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.006
  9. Front Pharmacol. 2026 ;17 1812913
    Pentagalloyl glucose suppresses MSU crystal-induced gout inflammation and arachidonic acid production in vitro and in vivo.
    Sadiq Umar, Yu Lu, Sugasini Dhavamani, Poorna C R Yalagala, Mateusz S Wietecha, Sriram Ravindran.
       Background: Gout is an acute inflammatory arthritis triggered by monosodium urate (MSU) crystal deposition and activation of innate immune responses. In addition to inflammasome signaling, emerging evidence suggests that metabolic reprogramming of arachidonic acid (AA) pathways amplifies inflammatory responses during gout flares. However, the contribution of upstream fatty acid desaturation processes that regulate endogenous AA availability remains poorly defined. 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (PGG) is a naturally occurring polyphenol with reported anti-inflammatory activity, but its effects on MSU-induced fatty acid metabolism and gouty inflammation have not been well established.
    Methods: Publicly available bulk and single-cell transcriptomic datasets from human and mouse gout studies were analyzed to assess dysregulation of AA-associated pathways. MSU-induced inflammatory responses were examined in mouse bone marrow-derived macrophages and in a murine MSU-induced gout model. Macrophages were treated with PGG prior to MSU stimulation, and inflammatory cytokine production, phagocytosis, and expression of fatty acid desaturases were assessed. Lipidomic analysis of macrophages and plasma was performed using gas chromatography-mass spectrometry (GC-MS) to quantify arachidonic acid and related fatty acids. In vivo disease severity, cytokine expression, and anti-inflammatory markers were evaluated following PGG treatment.
    Results: Analysis of public datasets revealed consistent dysregulation of arachidonic acid-associated inflammatory pathways during gout flares. In macrophages, MSU stimulation increased expression of fatty acid desaturases FADS1 and FADS2 and promoted accumulation of arachidonic acid, concomitant with robust production of pro-inflammatory cytokines. PGG treatment significantly suppressed MSU-induced FADS1, FADS2 and arachidonic acid levels, and attenuated pro-inflammatory cytokine production. PGG also markedly impaired macrophage phagocytosis of MSU crystals. In vivo, PGG treatment significantly reduced clinical disease severity in an MSU-induced gout model, suppressed fatty acid desaturation and arachidonic acid accumulation in plasma, decreased pro-inflammatory cytokine expression, and enhanced anti-inflammatory markers.
    Conclusion: These findings identify fatty acid desaturation as an important metabolic contributor to gouty inflammation and demonstrate that PGG suppresses MSU-induced inflammation by limiting endogenous arachidonic acid availability, reducing inflammatory amplification, and impairing MSU crystal phagocytosis. Targeting upstream fatty acid metabolism represents a potential therapeutic strategy for modulating acute gout flares beyond conventional anti-inflammatory approaches.
    Keywords:  MSU-gout model; arachidonic acid pathway; inflammation; macrophages; pentagalloyl glucose
    DOI:  https://doi.org/10.3389/fphar.2026.1812913
  10. PPAR Res. 2026 ;2026 2166122
    Metabolic Reprogramming and Immune Metabolism in Sepsis: Targeting the PPAR Pathway for Personalized Therapeutic Approaches.
    Zheqian Wu, Yisheng Chen, Lili Yin, Liming Zhu, Fei Ding, Lihua Dai.
      Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, in which metabolic reprogramming plays a critical role in disease progression and organ failure. Metabolic reprogramming involves alterations in glucose, lipid, and protein metabolism, leading to imbalanced energy production, immune dysregulation, and tissue damage. Immune cells, under septic stress, switch to aerobic glycolysis, enhancing energy production but causing lactate accumulation and mitochondrial dysfunction, which exacerbates inflammation and organ injury. This metabolic shift emphasizes the need for personalized therapeutic strategies that address the metabolic heterogeneity between pathogens and hosts. The peroxisome proliferator-activated receptor (PPAR) pathway serves as a central regulator of both metabolic and immune responses, offering protective effects through the promotion of fatty acid oxidation and suppression of inflammation. However, the translational application of PPAR-directed therapies is constrained by limited drug specificity and significant interpatient heterogeneity. Advances in multiomics technologies provide promising opportunities for identifying metabolic biomarkers and tailoring PPAR-targeted treatments. Future research should focus on integrating metabolic pathways, developing precise diagnostic tools, and refining personalized interventions to improve sepsis management and patient prognosis. Unlike previous reviews that primarily focus on general immunometabolic alterations in sepsis, this review is the first to systematically integrate PPAR isoform-specific regulatory mechanisms, multiomics-based patient stratification, and phenotype-driven therapeutic targeting, thereby offering a novel framework for precision medicine in sepsis management. We critically evaluate the controversies on the efficacy of PPAR agonists, highlight cross talk with HIF-1α/NF-κB/Nrf2, and propose a phenotype-based stratification for sepsis therapy, a perspective that has not been explored in the literature.
    Keywords:  PPAR pathway; immune regulation; metabolic intervention; metabolic reprogramming; personalized therapy; sepsis
    DOI:  https://doi.org/10.1155/ppar/2166122
  11. Front Immunol. 2026 ;17 1829718
    Nucleotide metabolism reprogramming in obesity-associated cardiovascular inflammation: a new perspective.
    Taoming Qian, Meijun Zhang, Yuhan Liu, Donghao Guo, Juan Jin.
      Obesity drives cardiovascular disease primarily through chronic meta-inflammation, yet the precise molecular convergence linking nutrient excess to sustained NLRP3 inflammasome activation in macrophages has remained unclear. Obesity induces inhibitory phosphorylation of SAMHD1, resulting in cytosolic dNTP accumulation, mitochondrial import through SLC25 transporters, uncontrolled mtDNA synthesis and oxidation, and consequent NLRP3 hyperactivation. This SAMHD1-dNTP-mtDNA-NLRP3 axis is supported by emerging evidence as a potential upstream checkpoint that may set macrophage inflammatory tone and may contribute to three major manifestations of obesity-associated cardiovascular pathology: accelerated atherosclerosis, diastolic dysfunction in obesity cardiomyopathy, and exaggerated ischemia-reperfusion injury. Integration of human macrophage data, atherosclerotic plaque biology, and mitochondrial transport mechanisms reveals actionable therapeutic nodes at selective SLC25 inhibition, SAMHD1-preserving kinase modulation, and mitochondria-targeted antioxidants that act at the metabolic initiation phase rather than downstream effector cascades. Nucleotide metabolism reprogramming thereby provides a plausible framework that may help address a long-standing mechanistic gap in immunometabolism and opens a new class of precision interventions that could address the root cause of obesity-driven cardiovascular risk.
    Keywords:  NLRP3 inflammasome; atherosclerosis; cardiovascular inflammation; dNTP pools; immunometabolism; macrophage reprogramming; mitochondrial DNA; nucleotide metabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1829718
  12. Free Radic Biol Med. 2026 May 10. pii: S0891-5849(26)00467-3. [Epub ahead of print]
    Targeting NLRP3 palmitoylation: Celastrol alleviates inflammasome activation induced by immunometabolism dysregulation in Kupffer cells.
    Limei Tao, Zheng Fang, Wanshan Gu, Yanfei Li, Guoqiang Fan, Xiaojing Yang.
      Protein palmitoylation, the only reversible lipid-linked post-translational modification, acts as a critical regulatory mechanism for modulating protein function and subcellular localization. However, its specific roles and underlying mechanisms in the inflammatory response of liver macrophages (Kupffer cells) remain largely undefined. This study aimed to elucidate the precise mechanism by which palmitoylation regulates inflammation in Kupffer cells and to explore potential therapeutic interventions targeting this modification. Through metabolomic and membrane proteomic analyses, we demonstrated that LPS induces metabolic reprogramming, disrupts lipid homeostasis, and elicits palmitic acid accumulation in Kupffer cells. This lipid overload promotes NLRP3 palmitoylation at conserved cysteines Cys126 and Cys898, which in turn facilitates its translocation to the trans-Golgi network membrane and subsequent inflammasome activation. Targeting this palmitoylation switch thus represents a promising therapeutic strategy for inflammatory liver diseases. We further identified the natural compound celastrol as an effective inhibitor of NLRP3 palmitoylation. Mechanistically, this effect may be cooperatively mediated by the regulation of intracellular lipid metabolism and the covalent binding of celastrol to NLRP3. Our results uncover a novel mechanistic link between metabolic dysregulation and inflammasome activation in Kupffer cells mediated by palmitoylation. Importantly, we highlight celastrol as a promising therapeutic agent that targets immunometabolic crosstalk in the pathogenesis of inflammatory liver diseases.
    Keywords:  Celastrol; Immunometabolism; Kupffer cells; NLRP3; Palmitoylation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.003
  13. Int Immunopharmacol. 2026 May 12. pii: S1567-5769(26)00681-8. [Epub ahead of print]182 116835
    CARM1 drives sepsis-induced lung injury by coupling PKM2-governed metabolic rewiring to macrophage ferroptosis.
    Yao Wang, Jiayue Qian, Yinna Tan, Rui Peng, Dan Wang.
      Ferroptosis has been linked to impaired macrophage function and acute lung injury (ALI), a condition associated with high mortality. Nevertheless, the regulatory mechanisms underlying ferroptosis remain to be fully elucidated. In pro-inflammatory macrophages, glycolysis is preferentially upregulated, with pyruvate kinase M2 (PKM2) acting as a key regulatory enzyme. Here, we elucidate a distinct functional role of ferroptosis in this context. We identified CARM1, an arginine methyltransferase, as a crucial metabolic mediator that promotes ferroptosis by activating PKM2-dependent glycolysis. CARM1 is ubiquitously expressed and hyperactivated in sepsis models, leading to elevated levels of glycolysis-related enzymes, including LDHA and PKM2. Therapeutic intervention with the CARM1 inhibitor TP-064 significantly attenuated inflammatory responses in macrophages and ameliorated ALI in septic models. Furthermore, TP-064 suppressed ferroptosis and PKM2-dependent glycolysis both in vitro and in vivo. Notably, genetic ablation of CARM1 phenocopied the inhibitory effects of TP-064. Pharmacological inhibition of PKM2 by shikonin also effectively suppressed ferroptosis-associated markers and alleviated ALI. Taken together, these findings establish CARM1 as an integrative node that couples metabolic reprogramming with PKM2 activity to regulate ferroptosis. Therefore, pharmacological targeting CARM1 may represent a promising therapeutic strategy for mitigating dysregulated ferroptosis and cytokine storm syndromes driven by hyper-glycolytic states.
    Keywords:  ALI; CARM1; Ferroptosis; Glycolysis; PKM2; Sepsis
    DOI:  https://doi.org/10.1016/j.intimp.2026.116835
  14. Front Pharmacol. 2026 ;17 1786751
    Metabolite-neuro-immune relay in chronic pain: spatial-temporal lactate, succinate and itaconate signalling as drivers of glial reprogramming and neuronal sensitisation.
    Zhen Hu, Quan Ji, Qianqi Xiong, Youzhi Ning, Yong Rao, Jia Fu, Lu Wang, Xia Xiong, Cehua Ou, Yue Zhang.
      Chronic pain is sustained by coupled neuronal hyperexcitability and neuroinflammation, yet prevailing frameworks incompletely explain why similar injuries diverge toward recovery or persistent sensitisation. Growing evidence indicates that lactate, succinate and itaconate act as signalling metabolites that shape glial state transitions and nociceptive circuit gain. Here, we synthesise preclinical and emerging clinical findings and propose a metabolite-neuro-immune relay model in which metabolic perturbations in astrocytes, microglia and peripheral immune cells generate characteristic lactate-succinate-itaconate patterns; glia decode these cues into pro-inflammatory or pro-resolving programs; and the resulting cytokines and physicochemical changes remodel dorsal root ganglion and spinal dorsal horn circuits. We highlight how spatially restricted metabolic microdomains and temporally phased shifts from transient bursts to stable immunometabolic reprogramming can sustain self-reinforcing neuroimmune loops. We then outline mechanism-guided therapeutic opportunities, including modulation of pathological glycolysis, lactate and acidosis-targeted microenvironment remodelling, succinate receptor 1 blockade and augmentation of the IRG1-itaconate-NRF2 axis using precision delivery approaches. This framework links molecular immunometabolism with circuit plasticity and offers testable targets for stage-aware analgesic development.
    Keywords:  biomarkers; chronic pain; microglia; patient stratification; signaling metabolites
    DOI:  https://doi.org/10.3389/fphar.2026.1786751
  15. J Neuroinflammation. 2026 May 13.
    SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.
    Hui-Wen Zhang, Xue-Jie Wang, Mao-Mao Chu, Guang-Yuan Xing, Kai Qiu, Yu-Ge Zhang, Wen-Feng Zhang, Yu-Tong Zhang, Xue Liu, Lei Li, Xiao-Wei Lu, Xin-Xin Huang, Lei-Yang Zhang, Zhi-Yuan Zhang.
      Peri-lesional microglia are particularly sensitive to traumatic brain injury (TBI)-induced disruption of brain lipid homeostasis. This disruption is characterized by elevated levels of acylcarnitines and phospholipids in acute lipidomic profiling, reflecting global lipid alterations. Under physiological conditions, microglial lipid processing involves fatty acid uptake, storage, and mitochondrial oxidation. However, following TBI, excessive fatty acid uptake promotes lipid droplet accumulation, mitochondrial stress, and pro-inflammatory activation. In this study, we investigated whether modulating this process confers therapeutic benefits. Trilobatin (Tri), a natural flavonoid glycoside with potent immunometabolic modulatory activity, markedly reduced neuroinflammation and neuropathological damage while improving motor and cognitive performance in a mouse model of TBI. Integrated transcriptomic and metabolomic analyses revealed that Tri reduced excessive mitochondrial lipid accumulation, alleviated mitochondrial damage, and inhibited mitochondrial DNA release, thereby blocking the TLR9/MyD88/P-P65 pro-inflammatory pathway. Further screening and validation identified that Tri downregulates the lipid transporter SLC27A3, limits excessive lipid uptake, and consequently alleviates microglial pro-inflammatory responses driven by lipid overload. Collectively, these findings establish a link between microglial lipid metabolism and inflammatory activation and support trilobatin as a promising therapeutic agent targeting metabolic-inflammatory crosstalk in acute neural injury.
    Keywords:  Lipid reprogramming; Microglial immunometabolism; Mitochondrial lipotoxicity; Neuroprotection; SLC27A3; Trilobatin
    DOI:  https://doi.org/10.1186/s12974-026-03826-y
  16. Transl Psychiatry. 2026 May 14.
    1-deoxysphinganine promoted microglial glycolytic reprogramming and neuroinflammation in alzheimer's disease.
    Tao Ye, Xinhuang Lv, Zheyu Fang, Qiyao Li, Feichi Chen, Yiyao Dong, Kun Xiang, Yao Yang, Conghui Dai, Quang Le Do, Jing Sun, Kuan-Pin Su, Jiaming Liu.
      Recent evidence suggests that microglial activation, driven by a metabolic shift towards glycolysis, was involved in the pathogenesis of Alzheimer's disease (AD). Although sphingolipid (SL) dysregulation has been linked to AD, the role of 1-deoxysphinganine (deoxySO), an atypical and neurotoxic SL, on microglial glycolytic reprogramming remains unclear. We measured serum deoxySO levels in AD patients and evaluated their association with cognitive performance. In APP/PS1 mice, we examined cerebral deoxySO level and the effects of deoxySO supplementation on cognitive function, neuropathology, and microglial activation. In vitro, BV2 microglia were used to assess inflammatory and metabolic changes via qPCR, western blot, ELISA, and RNA-seq analyses. The serum deoxySO levels were significantly elevated in AD patients, which was positively correlated with cognitive impairment. APP/PS1 mice exhibited increased cerebral deoxySO level, and supplementation with deoxySO could exacerbate cognitive deficits and Aβ plaque accumulation. Moreover, deoxySO supplementation increased microglial activation and enhanced inflammation in vivo and in vitro AD models. qPCR analysis identified disease-associated microglia (DAM) as a key deoxySO-responsive subpopulation, while RNA-seq revealed significant enrichment of genes related to glycolytic metabolism and inflammatory responses. Subsequently, qPCR confirmed that deoxySO promoted glycolytic metabolic reprogramming, which promoted DAM activation, thereby aggravating AD pathology. These findings identify deoxySO as a critical metabolic driver that links to microglial glycolytic activation and neuroinflammation, suggesting that targeting deoxySO-mediated metabolic pathways may offer a novel therapeutic strategy for AD.
    DOI:  https://doi.org/10.1038/s41398-026-04093-4
  17. Cells. 2026 Apr 30. pii: 817. [Epub ahead of print]15(9):
    Zika Virus-Induced Metabolic Reprogramming Drives Lipid Droplet Biogenesis, Promoting Viral Replication and Ocular Pathogenesis.
    Prince Kumar, Jieon Kim, Nikhil Deshmukh, Pawan Kumar Singh.
      Zika virus (ZIKV) remains a significant global public health threat due to its association with severe neurological and ocular abnormalities, including microcephaly and congenital glaucoma in infants. Viruses often exploit host metabolic programs, such as energy and lipid metabolism, to support their replication. However, how ZIKV-driven metabolic reprogramming affects the anterior segment of the eye, especially trabecular meshwork (TM) cells, remains poorly defined. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) signaling, fatty acid (FA) metabolism, and lipid droplet (LD) biogenesis in ZIKV-induced ocular pathogenesis using primary human TM cells and an IFNAR1-deficient mouse model. ZIKV infection triggered time-dependent activation of the LKB1-AMPK-ACC signaling axis and significantly increased LD accumulation. Pharmacological activation of AMPK suppressed viral replication, whereas its inhibition enhanced infection, highlighting an antiviral role for AMPK signaling. In contrast, ZIKV promoted LD biogenesis, and inhibition of DGAT1 reduced both LD formation and viral replication, indicating a proviral role for LDs. Modulation of FA metabolism further revealed differential effects on ZIKV infection: saturated FA (palmitate) enhanced viral replication, whereas inhibition of FA oxidation with etomoxir reduced infection. Conversely, unsaturated FAs (oleate and linoleate) suppressed viral replication, in part by impairing viral binding and entry. Collectively, these findings show that ZIKV reshapes host metabolic pathways in TM by differentially engaging AMPK signaling, FA metabolism, and LD biogenesis to promote viral replication and spread in ocular tissue. Targeting these metabolic pathways may offer promising therapeutic avenues for preventing and/or treating ZIKV-associated ocular complications.
    Keywords:  AMPK; Zika virus; energy metabolism; fatty acids; glaucoma; lipid droplet; lipid metabolism; trabecular meshwork; β-oxidation
    DOI:  https://doi.org/10.3390/cells15090817
  18. Int Immunopharmacol. 2026 May 14. pii: S1567-5769(26)00687-9. [Epub ahead of print]182 116841
    Albiflorin contributes to Xuebijing-mediated protection against sepsis-associated acute kidney injury by modulating the succinate-PFKFB3 immunometabolic axis.
    Yang Xu, Jian Wei, Mengting Chen, Jingge Pang, Wei Shi, Siying Liu, Tianfeng Hua, Min Yang.
       BACKGROUND: Xuebijing injection (XBJ) is widely used in China as an adjunctive therapy for sepsis and sepsis-associated acute kidney injury (SAKI). Here, we evaluated its immunometabolic and inflammatory effects in macrophages and identified candidate bioactive monomers to define the underlying mechanisms.
    METHODS: An inflammatory model was established in RAW264.7 macrophages using lipopolysaccharide, and targeted energy metabolomics identified succinate (SA) as a key responsive metabolite. XBJ-derived monomer screening prioritized Albiflorin for mechanistic investigation. Exogenous SA replenishment, pharmacological inhibition, and siRNA-mediated knockdown were used to investigate key glycolytic nodes and examine causal relationships. Key findings were validated in bone marrow-derived macrophages (BMDMs) and in a cecal ligation and puncture (CLP)-induced SAKI rat model.
    RESULTS: In RAW264.7 macrophages, XBJ markedly reduced SA, and phenotype-guided screening prioritized Albiflorin as a representative monomer for mechanistic investigation. Albiflorin improved mitochondrial respiration, attenuated oxidative stress, and restored succinate dehydrogenase activity, consistent with reduced SA accumulation. Exogenous SA replenishment partially reversed Albiflorin's anti-glycolytic and anti-inflammatory effects and restored PFKFB3 expression, whereas HIF-1α inhibition or knockdown did not block SA-induced PFKFB3 upregulation. PFKFB3 inhibition or knockdown reduced inflammatory outputs and lactate production and constrained SA-driven glycolytic enhancement. These findings were further supported in BMDMs and in a CLP-induced SAKI rat model.
    CONCLUSION: This study identified SA as an XBJ-responsive metabolite linked to macrophage inflammation and prioritized Albiflorin as a representative effector monomer for mechanistic investigation. Albiflorin lowered SA burden and suppressed PFKFB3-associated glycolytic and inflammatory activation in macrophages, supporting its contribution to SAKI protection.
    Keywords:  Albiflorin; PFKFB3; Sepsis-associated acute kidney injury; Succinate; Xuebijing injection
    DOI:  https://doi.org/10.1016/j.intimp.2026.116841
  19. Annu Rev Anal Chem (Palo Alto Calif). 2026 May;19(1): 307-330
    Immunometabolomics Applied to Physical Exercise: Accomplishments and New Directions for Health Improvement.
    Luciele Guerra Minuzzi, Alex Castro, Claudia Regina Cavaglieri, Ana Valéria Colnaghi Simionato.
      Immunometabolomics is a multidisciplinary field that explores how metabolic pathways regulate immune cell function, using metabolomics-the large-scale analysis of small molecules (metabolites)-to map these interactions in health and disease. Emerging evidence highlights that metabolic shifts are not merely by-products but key drivers of exercise-induced immune adaptations, with significant implications for performance, recovery, and disease prevention. This narrative review summarizes the latest findings on how exercise shapes immune responses through metabolic pathways. We discuss how key metabolites, such as succinate, itaconate, lactate, short-chain fatty acids, and kynurenine, act as molecular links between energy metabolism and immune regulation during and after exercise. We also investigate the effects of physical exercise on immunometabolic profiles within distinct tissues, elucidating their roles in promoting either proinflammatory or anti-inflammatory adaptations. Methodological advances in metabolomics and multi-omics are also addressed. Our review highlights robust evidence from human trials that physical exercise reprograms immunometabolic pathways in a time-, tissue-, and modality-specific manner, supporting its role in both health maintenance and clinical interventions.
    Keywords:  biomarkers; immunometabolomics; metabolic adaptation; metabolites; metabolomics; physical exercise
    DOI:  https://doi.org/10.1146/annurev-anchem-091024-095826
  20. Cell Mol Immunol. 2026 May 12.
    The alkylation of AIM2 by itaconate mediates macrophage PANoptosis during sepsis.
    Jiamin Ma, Ying Chen, Pei Wang, Yan Zhang, Yi Li, Qing Tu, Xinru Zhao, Xuanqi Yao, Fang Li, Yuan Yuan, Chenwei Wu, Lin Wang, Yuwei Chen, Chenchen Liu, Rui Kang, Daolin Tang, Liangfang Yao, Feng Chen, Jinbao Li.
      Although the immunometabolite itaconate has long been considered an anti-inflammatory, we found that its profound accumulation paradoxically drives macrophage cell death and pro-inflammatory responses. However, the exact molecular mechanisms underlying itaconate-induced macrophage toxicity remain unclear. Here, we demonstrate that pathophysiologically relevant high concentrations of itaconate covalently alkylate the absent in melanoma 2 (AIM2) protein at the cysteine 113 (C113) residue. Itaconate-mediated C113 alkylation structurally stabilizes the AIM2 protein and triggers a conformational change, enabling it to drive ASC oligomerization, PANoptosome assembly, and subsequent macrophage PANoptosis. Utilizing in vitro lentiviral reconstitution in primary macrophages alongside plasmid-mediated expression in cell lines, we rigorously confirmed that the AIM2 C113A mutation completely abolishes itaconate-induced AIM2 stabilization and PANoptosis. In vivo models further corroborated the pathogenic contribution of this axis to systemic sepsis. Taken together, our findings reveal a novel pro-inflammatory mechanism of itaconate via the post-translational modification of AIM2. The itaconate-AIM2 alkylation axis provides crucial mechanistic insights into macrophage depletion and systemic inflammation, highlighting a potential therapeutic target for severe sepsis.
    Keywords:  AIM2; Itaconate; Macrophages; PANoptosis; Sepsis
    DOI:  https://doi.org/10.1038/s41423-026-01414-x
  21. Int J Mol Sci. 2026 Apr 24. pii: 3795. [Epub ahead of print]27(9):
    Lactate Enhances CD8+ T Cell Cytotoxicity Through H3K9la Upregulation to Drive Vitiligo Pathogenesis.
    Hang Yin, Yufei Xu, Luling Huang, Yuxuan Qian, Qing Zhu, Jianru Chen.
      Vitiligo is characterized by epidermal melanocyte destruction, with autoreactive CD8+ T cells playing a central pathogenic role, yet the mechanisms driving their hyperactivation remain unclear. Lactate has emerged as a key immunometabolite that functions as both a signaling molecule and an epigenetic modulator via protein lactylation. Nevertheless, the role of lactate in vitiligo pathogenesis has not been explored. Here, we report that serum lactate levels are significantly elevated in vitiligo patients and correlate positively with disease activity. In a mouse model, lactate administration accelerated vitiligo progression, accompanied by increased CD8+ T cell infiltration and melanocyte destruction in lesional skin. In vitro, lactate enhanced CD8+ T cell effector molecule expression (granzyme B, perforin, IFN-γ, CD107a) and cytotoxic function. Mechanistically, lactate increased global protein lactylation in CD8+ T cells, with marked enrichment at histone H3 lysine 9 (H3K9). H3K9 lactylation (H3K9la) was associated with enhanced chromatin accessibility and transcriptional activation of effector genes, as revealed by RNA sequencing and CUT&Tag analyses. Pharmacological inhibition of lactate production or lactylation abrogated these effects. Collectively, our findings identify lactate as a critical driver of CD8+ T cell pathogenicity in vitiligo through H3K9la-mediated epigenetic reprogramming, highlighting lactate metabolism and lactylation as potential therapeutic targets.
    Keywords:  CD8+ T cells; autoimmunity; lactylation; vitiligo
    DOI:  https://doi.org/10.3390/ijms27093795
  22. Int Immunopharmacol. 2026 May 11. pii: S1567-5769(26)00662-4. [Epub ahead of print]182 116816
    PRC1 impairs sepsis host defense by suppressing NF-κB/JAK-STAT signaling and macrophage glycolytic reprogramming.
    Huawei Wei, Xiaoyan Meng, Haoyu Fan, Tianhao Xia, Haowei Wang, Yutong Yang, Yiman Han, Dashuang Chen, Honghao Song, Lei Peng, Yan Chu, Shaowei Li, Yi Liu, Hongbin Yuan.
      Sepsis is a life-threatening syndrome characterized by immune paralysis and impaired host defense. Effective macrophage-mediated bacterial clearance depends on tightly coordinated inflammatory signal transduction and infection-driven metabolic reprogramming toward glycolysis, yet the key molecular checkpoints governing this immunometabolic network remain poorly defined. Here, integrative transcriptomic analyses were performed to identify prognostic biomarkers in sepsis, leading to the recognition of Protein Regulator of Cytokinesis 1 (PRC1) as a core candidate associated with poor survival and an immunosuppressive phenotype. Functional and mechanistic studies using Escherichia coli-infected macrophages and a cecal ligation and puncture (CLP) murine model demonstrated that PRC1 acts as a negative regulator of macrophage innate immunity. PRC1 overexpression was associated with dampened NF-κB and JAK-STAT signaling, reduced phagocytic and bactericidal capacity, and attenuation of infection-induced glycolytic reprogramming together with relative preservation of mitochondrial metabolic features, whereas PRC1 silencing showed the opposite pattern. Consistently, PRC1 expression was elevated in septic mice, and PRC1 silencing reduced organ injury and bacterial burden and significantly improved survival. Collectively, these results support the interpretation that PRC1 is associated with altered macrophage immune-metabolic responses and may contribute to sepsis-associated immune dysfunction. PRC1 may therefore represent a potential target for future investigation aimed at restoring host defense in sepsis.
    Keywords:  Glycolysis; Inflammation; Macrophage; PRC1; Sepsis
    DOI:  https://doi.org/10.1016/j.intimp.2026.116816
  23. Vet Microbiol. 2026 May 05. pii: S0378-1135(26)00184-7. [Epub ahead of print]319 111052
    ORFV-induced glycolysis facilitates virus replication by increasing lactate production to promote the association between HK2 and STING.
    Huizi Li, Xijiao Chen, Shishi Wang, Zhenzhen Sun, Ming Chen, Siyu Chen, Zhangyong Ning.
      Orf virus (ORFV), a zoonotic DNA virus, has developed the unique tactics to repeatedly infect previously exposed hosts. Metabolism of the host plays an irreplaceable role in the replication of the virus. Whether ORFV reprograms the metabolism of host cells in its proliferation and the possible mechanism involved is still unknown. Here, we report that ORFV-induced glycolysis-associated metabolic changes facilitates virus replication by promoting lactate production that promotes the association between hexokinase 2 (HK2) and STING. ORFV infection induces glycolysis-associated changes in ovine fetal turbinate (OFTu) cells with increased lactate content, and overexpressing of pyruvate kinase M (PKM), HK2, phosphoglycerate kinase 1 (PGK1), and pyruvate dehydrogenase kinase 1 (PDK1) promotes ORFV replication, and glycolysis inhibitors have opposite results. ORFV induced lactate inhibits expression of STING and the pathway downstream genes including interferon regulatory factor 3 (IRF3), TANK-binding kinase 1 (TBK1), interferon-α (IFN-α), and IFN-β. Co-immunoprecipitation (Co-IP) showed HK2 binds with STING and ORFV inhibits the expression of STING by promoting the expression of HK2. In the mice infection experiments, the viral load in lactate treated mice was significantly increased compared to the control, and the expression of STING, IRF3, and interleukin 6 (IL6) increased in oxamate treated group compared to the control. The results depict the relationship between reprogrammed metabolism and attenuated innate immune in ORFV infection and provide new insights on the relationship between ORFV and the host.
    Keywords:  Glycolysis; HK2; Orf virus; STING
    DOI:  https://doi.org/10.1016/j.vetmic.2026.111052
  24. Cancer Res. 2026 May 12.
    Soluble Uric Acid Drives CD8⁺ T-cell Exhaustion by Inducing KSR1-Mediated MAPK Hyperactivation.
    Anyi Liu, Fan Zuo, Mao Li, Lanlan Yin, Dongjing Zhang, Lang Liu, Chengxin Yu, Changsheng Huang, Yaqi Chen, Qi Wu, Li Sun, Guihua Wang, Junbo Hu.
      T-cell exhaustion in the tumor microenvironment undermines anti-tumor immunity and limits immunotherapy efficacy. Further defining the metabolic triggers of this dysfunctional state could provide therapeutic targets for circumventing immunosuppression. Here we identified soluble uric acid (UA)-an abundant purine metabolite frequently elevated in cancer patients-as a metabolic checkpoint that drives exhaustion of CD8⁺ T cells and immune evasion in colorectal cancer (CRC). In hyperuricemic mouse models, elevated UA accelerated tumor progression in immunocompetent hosts, but not T-cell-deficient ones, by functionally exhausting tumor-infiltrating CD8⁺ T cells. Mechanistically, UA directly bound the kinase scaffold KSR1 and hyperactivated MEK-ERK signaling, leading to chronic MAPK stimulation that upregulated inhibitory receptors, including PD-1, Tim-3, on CD8⁺ T cells and blunted their cytotoxic function. Genetic disruption of this UA-KSR1-MAPK axis via Tim-3 knockout or Ksr1 knockdown restored T-cell effector activity and tumor control. Notably, pharmacological UA depletion with the clinical xanthine oxidase inhibitor febuxostat reinvigorated CD8⁺ T cells, slowing tumor growth and markedly enhancing the efficacy of both chemotherapy and adoptive T cell therapy in vivo. These findings establish soluble UA as a metabolic immune checkpoint that subverts anti-tumor T-cell immunity. Targeting UA metabolism may offer a strategy to overcome immune resistance and improve the efficacy of cancer immunotherapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3911
  25. Int J Mol Sci. 2026 Apr 28. pii: 3906. [Epub ahead of print]27(9):
    Immunometabolism in Cardiac Remodeling: Mechanisms and Therapeutic Perspectives.
    Julia Nazaruk, Barbara Bilnik, Maciej Niewiadomski, Wojciech Pawlak, Piotr Gajewski.
      Cardiovascular diseases remain the leading cause of mortality worldwide, and one of the key mechanisms driving the development of heart failure is pathological remodeling of the myocardium. This process involves complex structural, cellular, and metabolic alterations in which the immune system and its interactions with cardiomyocytes and fibroblasts play a central role. The aim of this work was to present the current state of knowledge on immunometabolism in cardiac remodeling and to discuss its pathophysiological relevance and therapeutic potential. This review focuses on the metabolism of cardiac macrophages, highlighting the differences between the pro-inflammatory (M1) and reparative (M2) phenotypes and their impact on inflammation, fibrosis, and myocardial regeneration. The roles of major metabolic pathways, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, are discussed, as well as the importance of the NLRP3 inflammasome and efferocytosis in regulating the inflammatory response. Furthermore, the review briefly incorporates recent insights into neutrophil, T cell, and regulatory T cell (Treg) metabolism and their contributions to inflammation, repair, and fibrotic remodeling. Particular attention is also given to cardiac fibroblasts and their metabolic reprogramming during fibrosis, with emphasis on the pivotal role of transforming growth factor-β (TGF-β) signaling. The review further discusses the role of microRNAs as mediators of intercellular communication integrating immunological and metabolic signals. The work is complemented by a discussion of therapeutic perspectives, including modulation of macrophage metabolism, fibrogenic signaling pathways, mitochondrial function, and miRNA-based therapies. Immunometabolism emerges as a promising research field whose further exploration may contribute to the development of novel, more precise strategies for the treatment of cardiovascular diseases.
    Keywords:  cardiac fibrosis; cardiac remodeling; immunometabolism; inflammation; molecular mechanisms
    DOI:  https://doi.org/10.3390/ijms27093906
  26. Cancers (Basel). 2026 May 03. pii: 1474. [Epub ahead of print]18(9):
    Amino Acid-Driven Mitochondrial Metabolic Rewiring Controls Antitumor Immunity.
    Suji Ham, Min-Jeong Jo, Kwon-Ho Song, Bo-Hyun Choi.
      Amino acids are essential nutrients for both tumor growth and immune cell function. Cancer cells actively deplete intracellular and extracellular amino acid pools, and limited amino acid availability in the tumor microenvironment (TME) reinforces immunosuppression. Mitochondria are not merely adenosine triphosphate-producing organelles. Amino acid metabolism within mitochondria contributes to tumor progression and influences immune cell fate and effector function. These effects are mediated through biosynthetic precursor generation for lipid, nucleotide, and polyamine synthesis, maintenance redox homeostasis through glutathione and NAD+ metabolism, and regulation of gene expression through aryl hydrocarbon receptor signaling. In this review, we discuss four major mitochondrial amino acid metabolic pathways: glutamine-driven anaplerosis, serine/glycine-dependent one-carbon metabolism, arginine-ornithine metabolism, and tryptophan-kynurenine metabolism. We examine how these pathways are rewired in cancer cells, how they influence immune cell function through direct or mitochondria-associated mechanisms, and how such metabolic reprogramming promotes tumor progression while impairing antitumor immunity. Finally, we consider therapeutic strategies to improve cancer immunotherapy by targeting amino acid metabolism, including mitochondrial metabolic enzymes. This review may help guide the development of more effective metabolic biomarkers and mitochondria-based therapeutic strategies for cancer immunotherapy.
    Keywords:  amino acid metabolism; antitumor immunity; immunotherapy resistance; mitochondrial metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18091474
  27. Front Immunol. 2026 ;17 1803806
    PD-1 deficiency exacerbates Mycobacteroides abscessus lung infection via metabolic rewiring and dysregulated neutrophil/T cell responses.
    Xiaowen Yu, Lu Huang, Jianping Xie.
       Background: Pulmonary Mycobacteroides abscessus (MAB) infection presents a therapeutic challenge, and while anti-programmed cell death protein 1(PD-1) therapy is clinically associated with increased MAB risk, yet the underlying immunomodulatory mechanisms remain elusive.
    Methods: We established a PD-1-deficient mouse model of MAB infection and assessed bacterial clearance, immune responses, and metabolic alterations using colony counting, histopathology, flow cytometry, multiplex immunofluorescence, transcriptomics, and metabolic assays.
    Results: PD-1-/- mice showed increased susceptibility to MAB. Early infection was marked by elevated lung CD4+ T cells (Th17/Treg), diminished Th1 cells and neutrophils, and increased blood cytokines (IFN-γ, IL-21, IL-6, IL-27). Late infection featured further Th1 reduction, neutrophil accumulation, and NETs activation (H3cit, NE-DNA, MPO), along with reduced CXCL9 but elevated IL-6, IL-21, IL-27, CXCL10, and S100A8 in blood. Metabolic changes included decreased blood glucose, elevated lung ATP, and upregulation of HIF-1 pathway proteins (e.g., HK2, iNOS). In vitro, PD-1 deficiency suppressed glycolysis in T cells yet augmented it in neutrophils upon MAB infection.
    Conclusion: PD-1 deficiency disrupts T cell-neutrophil crosstalk via metabolic reprogramming, resulting in immune dysregulation and exacerbated infection. These findings underscore infection risks linked to PD-1/PD-L1 blockade, informing clinical safety and therapeutic strategies.
    Keywords:  CD4+ T cell; Mycobacteroides abscessus; PD-1; metabolic reprogramming; neutrophil
    DOI:  https://doi.org/10.3389/fimmu.2026.1803806
  28. Ther Adv Infect Dis. 2026 Jan-Dec;13:13 20499361261445295
    Targeting macrophage metabolic checkpoints: a host-directed strategy to overcome drug tolerance in tuberculosis.
    Tarun Kumar Suvvari, Sridhar V N S Kocharlakota, Venkataramana Kandi.
      
    Keywords:  host-directed therapy; macrophage metabolism; tuberculosis
    DOI:  https://doi.org/10.1177/20499361261445295
  29. bioRxiv. 2026 Feb 23. pii: 2026.02.21.707085. [Epub ahead of print]
    PFOA induced metabolic and immune perturbations in a SARS-2 infection model.
    Deanna N Lanier, Dawne Rowe Haas, Mario Uchimiya, Cheryl Jones, Scott Johnson, Kaori Sakamoto, Jessie R Chappel, Allison N Fry, Franklin E Leach, Jamie DeWitt, Tracey Woodlief, David A Gaul, Erin S Baker, Facundo M Fernández, Stephen M Tompkins, Arthur S Edison.
      This study evaluates the impact of PFOA exposure on the metabolome and immune response to SARS-2 using a ferret model. Ferrets were separated into control or PFOA-exposed groups (10/mg/kg/day) and challenged with SARS-2. Longitudinal analyses encompassing clinical assessments, serological profiling, histopathology, and untargeted nuclear magnetic resonance (NMR) metabolomics revealed significant metabolic and immunological perturbations. We found prominent effects of PFOA exposure on metabolism, which resulted in altered metabolic responses to SARS-2 infection. PFOA exposure was also associated with impaired immune function, as evidenced by decreased serum IgG levels, increased viral loads, and prolonged peak infectivity. These findings underscore the consequences of PFOA exposure on host metabolism and immunity during infectious diseases.
    DOI:  https://doi.org/10.64898/2026.02.21.707085
  30. Front Immunol. 2026 ;17 1805144
    Metabolic reprogramming as a driver of immune escape in melanoma: implications for immunotherapy.
    Hong Liang, Lina Han, Xiao Feng, Lian Zhang.
      Melanoma has long served as a paradigm for cancer immunotherapy due to its high immunogenicity and the transformative impact of immune checkpoint blockade. However, durable clinical benefit remains confined to a subset of patients, with primary and acquired resistance remaining common. This plateau highlights a central unresolved question: how melanoma evades immune-mediated elimination despite reinvigorated antitumor immunity. Immune escape in melanoma cannot be fully explained by defects in antigen presentation, interferon signaling, or checkpoint regulation alone. Increasing evidence identifies tumor-intrinsic metabolic reprogramming as a dominant driver of immune dysfunction. By rewiring glucose, amino acid, lipid, and mitochondrial metabolism, melanoma cells create a metabolically restrictive microenvironment that suppresses effector T and NK cell function while favoring regulatory and myeloid immunosuppressive states through nutrient competition, inhibitory metabolite accumulation, and metabolite-driven signaling. In this Review, we synthesize recent advances establishing metabolic reprogramming as an organizing principle of immune escape in melanoma. We integrate how tumor metabolic programs shape immune cell fate, function, and spatial organization, and how metabolic crosstalk between tumor and immune compartments generates immune-resistant niches that persist despite checkpoint blockade. We further discuss emerging therapeutic strategies that target metabolic vulnerabilities, alone or in rational combination with immunotherapy, to overcome resistance by reconditioning the metabolic context of antitumor immunity. By reframing metabolism as a governing axis rather than a secondary hallmark of melanoma, this Review provides a conceptual and translational framework for the development of mechanism-guided immunotherapies with durable clinical impact.
    Keywords:  immune escape; immunotherapy resistance; melanoma; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1805144
  31. J Neuroinflammation. 2026 May 09.
    β-oxidation-mediated differentiation of effector CD4+ T cells in the lung enhances neuroinflammation.
    Qianling Jiang, Gaochen Zhu, Xin Ma, Wen Si, Guan Yang.
      Although the lung-brain axis has emerged as a potential regulator of central nervous system (CNS) autoimmunity, the cellular and molecular mechanisms by which the lung microenvironment influences pathogenesis of multiple sclerosis (MS) remain unclear. Here, using experimental autoimmune encephalomyelitis (EAE), a murine model of MS, we found a marked expansion of effector CD4⁺ T cells in the lungs of EAE mice. The EAE lung microenvironment promoted metabolic reprogramming in CD4⁺ T cells, characterized by enhanced fatty acid uptake and upregulation of carnitine transporters. Metabolomic profiling further demonstrated enrichment of carnitine-related metabolites in the EAE lungs, with a strong correlation between metabolic profiles in the lungs and brains, suggesting coordinated metabolic remodeling along the lung-brain axis. Mechanistically, the EAE lung microenvironment significantly enhanced effector CD4⁺ T cell differentiation in vitro through a β-oxidation-dependent pathway. Importantly, pharmacological inhibition of β-oxidation in the lungs significantly attenuated EAE severity, reduced CD4⁺ T cell infiltration into the CNS, and impaired effector CD4⁺ T cell differentiation in the lungs. Collectively, these findings demonstrate that β-oxidation-mediated differentiation of effector CD4⁺ T cells in the lung exacerbates neuroinflammation, highlighting the lung-brain axis as a potential therapeutic target for MS.
    Keywords:  Effector CD4+ T cells; Experimental autoimmune encephalomyelitis; Lipid metabolism; Lung-brain axis; Multiple sclerosis
    DOI:  https://doi.org/10.1186/s12974-026-03865-5
  32. Nat Immunol. 2026 May 12.
    Epigenetic reprogramming of T cell metabolism restores function and enhances anti-tumor immunity in lung cancer.
    Yi-Chieh Wu, Shih-Feng Yang, Yu-Ting Lee, Meng-Wei Chou, Shu-Yung Lin, Yu-Ching Wang, Sheng-Yao Su, Chia-Lang Hsu, Nai-Wen Chang, Yi-Jhen Huang, Yi-Hsiu Juan, Hsuan-Hsuan Lu, Chien-Yin Chen, Yi-Fu Wang, Po-Ju Lee, Hsiao-Jung Kao, Pei-Shan Wu, Miao-Hsia Lin, Li-Chung Hsu, Yen-Ling Chiu, Shih-Yu Chen, Chong-Jen Yu, Hsing-Chen Tsai.
      T cell exhaustion represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally exhausted state. Here we used an epigenetic drug screen and identified bromodomain and extra-terminal motif inhibitors (BETis) as enhancers of effector functions in primary exhausted T cells (TEX) from malignant pleural effusions in patients with lung cancer. Transcriptomics, metabolomics and ATAC-seq analyses revealed that BETis reinvigorate TEX cells by activating the polyamine biosynthesis pathway, expanding intracellular polyamine pools and altering chromatin accessibility. Genetic and pharmacological inhibition of ornithine decarboxylase (ODC1), a key enzyme in this pathway, abolished BETi-mediated immunopotentiation. Single-cell RNA-seq demonstrated that BETis reduced terminal TEX while promoting progenitor TEX through activation of the MYC-ODC axis. BETi treatment or adoptive transfer of BETi-treated T cells suppressed malignant pleural effusion formation in a syngeneic lung cancer model. These findings highlight an epigenetic-metabolic approach to enhance TEX plasticity and offer insights for novel cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-026-02515-5
  33. Sci Rep. 2026 May 13.
    The PI3K-Akt-CCND2 axis couples metabolic reprogramming with macrophage M1 polarization.
    Xiaoyu Liu, Wei Shi, Lin Chai, Jianyuan Liu, Yanqian Su, Shuxing Wei, Chunkai Jia, Xiaomei Zhu, Shubin Guo.
      Dysregulated macrophage M1 polarization is a core pathological feature of inflammatory disorders. However, the crosstalk between metabolic reprogramming and cell-cycle regulator Ccnd2 during macrophage polarization remains largely unclear. This study explored the role of the PI3K-Akt-Ccnd2 axis in LPS-induced macrophage inflammation and verified its therapeutic potential in sepsis-associated acute kidney injury (SA-AKI). In vitro experiments were performed using RAW264.7 macrophages (Sham, LPS, PI3K inhibitor + LPS, M-CSF alone, M-CSF + LPS, Ccnd2 inhibitor, Ccnd2 inhibitor + Akt activator). In vivo studies were conducted using a cecal ligation and puncture (CLP)-induced SA-AKI mouse model with M-CSF intervention. Transcriptomic/metabolomic profiling, Western blotting, qRT-PCR, flow cytometry, and histopathological analysis were applied. Renal function, systemic inflammation, and signaling pathway activation were evaluated. LPS triggered transcriptional reprogramming enriched in PI3K-Akt, cell-cycle, and inflammatory pathways, and downregulated Ccnd2 expression; M-CSF restored Ccnd2 via PI3K-Akt signaling, which was abolished by PI3K inhibition. Metabolomic analysis identified marked alterations in purine, glycerophospholipid, and amino acid metabolism in LPS-stimulated macrophages. LPS enhanced M1 polarization, whereas M-CSF or PI3K inhibition suppressed this effect. In CLP mice, M-CSF significantly reduced serum Cre/BUN levels, alleviated systemic inflammation and renal histopathological damage, and activated the renal PI3K-Akt-Ccnd2 axis; these renoprotective effects were reversed by PI3K inhibition. LPS-induced metabolic reprogramming cooperates with PI3K-Akt signaling to regulate Ccnd2, thereby coupling macrophage cell-cycle progression and M1 polarization. The PI3K-Akt-Ccnd2 axis modulates macrophage inflammation in vitro and ameliorates CLP-induced SA-AKI in vivo, representing a promising therapeutic target for sepsis and related inflammatory organ injury. The PI3K-Akt-Ccnd2 axis may represent a candidate for further investigation for sepsis and other inflammatory disorders.
    Keywords:  Ccnd2; Inflammation; LPS; Macrophage polarization; Metabolic reprogramming; Metabolomics; PI3K-Akt signaling; Sepsis; Transcriptomics
    DOI:  https://doi.org/10.1038/s41598-026-51817-z
  34. Purinergic Signal. 2026 May 15. pii: 50. [Epub ahead of print]22(3):
    The ATP-adenosine axis as a driver of tumor-associated macrophage reprogramming in colorectal cancer: mechanistic insights into immune evasion and therapeutic vulnerabilities.
    Abdullah Faisal Albukhari.
      Colorectal cancer progression is increasingly recognized as a process shaped not only by tumor-intrinsic genetic alterations but also by dynamic interactions within the tumor microenvironment. Tumor-associated macrophages represent a dominant immune population in colorectal tumors and exhibit remarkable functional plasticity in response to metabolic and immunological cues. Among these cues, extracellular nucleotide signaling has emerged as a critical regulator of macrophage behavior. Metabolic stress, hypoxia, and cell death within colorectal tumors promote the release of extracellular ATP, which is rapidly hydrolyzed by ectonucleotidases into adenosine. This ATP-adenosine axis functions as a molecular switch that transforms pro-inflammatory immune activation into sustained immunosuppression. This mechanistic review synthesizes current evidence delineating how dysregulated extracellular ATP metabolism and adenosine signaling reprogram tumor-associated macrophages toward immunosuppressive, tumor-supportive phenotypes in colorectal cancer. This review discusses the coordinated roles of ectonucleotidases, purinergic receptors, and hypoxia-driven signaling in shaping macrophage immunometabolic states. Particular emphasis is placed on adenosine receptor-mediated pathways that impair antigen presentation, suppress cytotoxic immune responses, and contribute to resistance against immunotherapy and chemotherapy. By integrating immunometabolism, purinergic signaling, and macrophage plasticity, this review highlights the ATP-adenosine axis as a central mechanism of immune evasion in colorectal cancer. This review further explores therapeutic strategies targeting this pathway as a means to reprogram macrophages and overcome tumor-induced immune suppression. Understanding these mechanisms may support the rational development of macrophage-centered interventions aimed at restoring effective antitumor immunity.
    Keywords:  ATP–adenosine axis; Adenosine receptors; Colorectal cancer; Immune evasion; Immunometabolism; Purinergic signaling; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s11302-026-10156-4
  35. Gut Microbes. 2026 Dec 31. 18(1): 2671382
    Indole-3-carboxaldehyde from Limosilactobacillus reuteri targets the DUSP1/ERK/NOX2/ROS axis to enhance the bactericidal activity of macrophages and protects against sepsis.
    Zhiwang Li, Peiyu Li, Tian Peng, Xing Zhou, Yihong Liu, Chenmu Ai, Neng Xiao, Shunxin Song, Xiaomei Lei, Junyong Liu, Wenlei Wang, Pan Zhou, Zhangyong Li, Zhanhong Liu, Xingui Dai, Zhiming Zhang, Tao Li.
      The gut microbiota plays a critical regulatory role in the pathogenesis of sepsis, yet the immunomodulatory mechanisms of Limosilactobacillus reuteri (L. reuteri) and its metabolites in sepsis remain to be fully elucidated. This study found that the abundance of intestinal L. reuteri was significantly reduced in patients with bacterial sepsis and showed a negative correlation with disease severity. In a mouse model of sepsis induced by cecal ligation and puncture, fecal microbiota transplantation and live bacterial supplementation further confirmed that live L. reuteri effectively attenuated sepsis progression. Integrated metabolomic and network pharmacological analysis identified indole-3-carboxaldehyde (IAld), a metabolite derived from L. reuteri, which enhances macrophage bactericidal function and alleviates sepsis-associated organ damage. Mechanistically, IAld directly targets DUSP1 in macrophages, inhibits its phosphatase activity, thereby promoting ERK phosphorylation, upregulating NOX2 expression, stimulating reactive oxygen species production, and ultimately enhancing bacterial clearance. Notably, circulating IAld levels in septic patients were significantly inversely correlated with SOFA score, APACHE II score, and arterial lactate levels, and IAld safely enhanced the bactericidal function of human macrophages in vitro. This study is the first to systematically demonstrate that L. reuteri and its metabolite IAld exert a protective effect against sepsis through the DUSP1/ERK/NOX2/ROS axis, providing novel mechanistic insights and potential therapeutic targets for immunometabolic intervention in sepsis.
    Keywords:  DUSP1; Limosilactobacillus reuteri; ROS; Sepsis; indole-3-carboxaldehyde; macrophage; phagocytosis
    DOI:  https://doi.org/10.1080/19490976.2026.2671382
  36. J Hum Immun. 2026 Jul 06. 2(4): e20250233
    FAS-controlled T cells drive lymphoproliferation through glycolysis without effector differentiation.
    Maria Elena Maccari, Christoph König, Geoffroy Andrieux, Patrick Kury, Sarah A Berger, Jasmin Mann, Beth Kelly, Simon Völkl, Chenglong Huang, Martin Helmstädter, Simon Lagies, Marco Fischer, Francesc Baixauli, Oliver Gorka, Olaf Groß, Markus Hufnagel, Sarah Salou, Susan Farmand, Sabine Heine, Volker Schuster, Wolfgang Willenbacher, Gregor Dückers, Bodo Grimbacher, Klaus Warnatz, Friedrich G Kapp, Myriam Lorenz, Miriam Groß, Jens Wittner, Roland Elling, Luca Scorrano, Iwona A Koenig, Bertram Bengsch, Carsten Speckmann, Bernd Kammerer, Melanie Börries, Klaus Schwarz, Johannes Hertel, Erika L Pearce, Stephan Ehl, Ramon I Klein Geltink, Anne Rensing-Ehl.
      Lymphoproliferation in autoimmune lymphoproliferative syndrome (ALPS) due to FAS deficiency is driven by highly proliferative FAS-controlled T cells (FCT) with a distinct molecular signature. Activating signals and metabolic fuels of their proliferation are poorly understood. Lymphoproliferation caused by proliferative T cells is also a hallmark of acute EBV infection. In these antiviral T cells, a metabolic switch to glycolysis underpins effector differentiation and IFNγ translation. Here, we used EBV-induced CD8 effector T cells as a benchmark to characterize FCT metabolism. Metabolic assays, RNA sequencing, and in silico computational analysis revealed that FCT are as highly glycolytic as EBV-induced effector T cells, but this metabolic program is uncoupled from T-BET expression and IFNγ production. In contrast to virus-activated T cells, FCT showed mitochondrial hyperpolarization and elevated reactive oxygen species production. These findings support a model of FCT lymphoproliferation, in which activating signals strongly enhance glycolysis but do not induce classical effector differentiation.
    DOI:  https://doi.org/10.70962/jhi.20250233
  37. Hepatology. 2026 Apr 30.
    CD4+ T cells promote fibrosis during metabolic dysfunction-associated steatohepatitis.
    Lucía Valenzuela-Pérez, Hyun Se Kim Lee, Rachel L Bayer, Dina F Manna, Shravan K Mishra, Alexander M Washington, Adna A Hassan, Malaz M Sidahmed, Edward Ssali, Ece Janet Dinc, Benie K Manwana, Ahmed Ibrahim, Qianqian Guo, Adam Herman, Rondell P Graham, Kevin D Pavelko, Gregory J Gores, Patrick Starlinger, Xavier S Revelo, Samar H Ibrahim, Enis Kostallari, Adebowale O Bamidele, Petra Hirsova.
       BACKGROUND AND AIMS: Unresolved inflammation and fibrosis are defining features of metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of steatotic liver disease that can advance to cirrhosis and hepatocellular carcinoma. While innate immune mechanisms in MASH have been extensively characterized, the role of CD4+ T cells remains poorly understood despite their central function in orchestrating immune responses through effector and regulatory mechanisms.
    APPROACH AND RESULTS: Integrated single-cell proteomic, transcriptomic, and functional analyses were used to investigate the CD4+ T-cell landscape in murine and human MASH. We delineated a profound shift in the differentiation of intrahepatic and peripheral CD4+ T cells toward Th1, regulatory, and cytotoxic phenotypes in murine and human MASH. Notably, hepatic CD4+ T cells exhibited heightened effector activity and elevated secretion of proinflammatory cytokines, thus amplifying inflammatory signaling cascades. The CD4+ T-cell reprogramming in MASH also included the induction of the co-stimulatory receptor OX40. In parallel, OX40 ligand (OX40L)-expressing monocyte-derived macrophages and dendritic cells accumulated in MASH livers, establishing a feed-forward CD4+ T cell-myeloid activation loop. Therapeutic blockade of the OX40-OX40L axis, in turn, reversed liver pathology in mice with established MASH and reduced disease markers in an ex vivo human liver model. Furthermore, genetic depletion or functional inhibition of CD4+ T cells attenuated fibrosis, accompanied by decreased infiltration of monocyte-derived macrophages.
    CONCLUSIONS: These studies provide a comprehensive single-cell proteogenomic atlas of CD4+ T cells in MASH and identify an OX40-dependent CD4+ T cell-macrophage axis as a promising therapeutic target for the treatment of MASH and liver fibrosis.
    Keywords:  MASH; MASLD; fibrosis
    DOI:  https://doi.org/10.1097/HEP.0000000000001772
  38. Adv Sci (Weinh). 2026 May 12. e23949
    An Implantable Optogenetics-Engineered Hydrogel for Amelioration of Rheumatoid Arthritis through Light-Controlled Metabolic Reprogramming of Synovial Macrophages.
    Dahai Hu, Yaru Sun, Qi Lu, Yi Zhang, Jieruo Li, Huige Hou, Huajun Wang, Hui Tang, Yunsong Zhang, Xiaofei Zheng, Qingsong Mei.
      Rheumatoid arthritis (RA) has always been a therapeutic challenge in clinical due to the lack of effective drug treatments. Inspired by the impact of daily diet on RA, herein we proposed an innovative energy metabolism modulation strategy to reprogram synovial macrophages for RA treatment. An implantable hydrogel, encapsulating with optogenetics-engineered cells, was designed to enable in-situ and on-demand secretion of glucagon-like peptide-1 (GLP-1) through blue light irradiation. GLP-1 in synovium was found to activate GLP-1R/HK2/VDAC1 pathway to upregulate the tricarboxylic acid cycle and oxidative phosphorylation in macrophages. This metabolic reprogramming elicited a phenotypic transition in macrophage polarization, shifting from M0/M1 state to M2 state. Significantly, the GLP-1-mediated approach reduced synovial inflammatory cytokine levels and facilitated tissue repair and bone erosion recovery. These findings reveal the therapeutic potential of GLP-1R/HK2/VDAC1 pathway as a novel target for RA.
    Keywords:  cartilage damage; joint inflammation; macrophage polarization; metabolic reprogramming
    DOI:  https://doi.org/10.1002/advs.202523949
  39. Front Immunol. 2026 ;17 1836618
    Metabolic-epigenetic rewiring in rheumatoid arthritis: from pathogenic memory to precision restoration.
    Shu Li, Lei Wan, Kun Wang, Xiaojun Zhang.
      Rheumatoid arthritis (RA) is a systemic autoimmune disorder wherein sustained, drug-free remission remains an elusive clinical goal. Frequent disease flares upon treatment withdrawal indicate that conventional immunosuppression fails to eradicate a deeply ingrained "pathogenic memory." In this Review, we provide a comprehensive framework illustrating how the hostile, nutrient-deprived synovial microenvironment acts as a metabolically restrictive microenvironment. Driven by "metabolic parasitism" and mitochondrial collapse, the massive accumulation of intermediate metabolites-most notably lactate, acetyl-CoA, and succinyl-CoA-transcends their traditional roles as bioenergetic waste to function as potent epigenetic regulators. We decode the emerging "PTM multiverse," highlighting how aberrant lactylation, acetylation, and RNA modifications (ac4C) persistently rewire chromatin architecture and critical non-histone sensors (e.g., cGAS). Amplified by hyperactive acetyltransferases and the hypoxia-induced collapse of Sirtuin deacetylases, these modifications engrave resilient "epigenetic scars" that lock innate immune and stromal cells into highly destructive phenotypes via trained immunity. We further integrate this localized articular inflammation into a holistic meta-organ model, tracing disease origins to mucosal gene-environment interactions and detailing systemic regulation via the gut-microbiota-joint axis and chronobiological rhythms. Ultimately, we explore how deciphering these integrated networks translates into next-generation prognostic biomarkers (e.g., AMPAs and GlycA) and heralds a critical therapeutic paradigm shift-from transient immune blockade to precise metabolic-epigenetic restoration.
    Keywords:  epigenetic reprogramming; immunometabolism; lactylation; rheumatoid arthritis; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1836618
  40. Cell Death Differ. 2026 May 12.
    A neutrophil-intrinsic CKLF1-PKM2 axis drives glycolytic flux for de novo DAG synthesis and pro-inflammatory ROS production.
    Yuan Ruan, Pinglong Fan, Ruifang Zheng, Xiaolei Wu, Shanhe Qu, Kaichao Hu, Tianyi Zhang, Wen Bin He, Hongshuo Sun, Zhongping Feng, Shifeng Chu, Zhao Zhang, Naihong Chen.
      Reactive oxygen species (ROS) burst and subsequent recruitment to the ischemic brain characterize neutrophil activation in the hyperacute phase of ischemic stroke, yet the underlying metabolic drivers remain elusive. Here, we report that neutrophil-intrinsic chemokine-like factor 1 (CKLF1) acts as a key immunometabolic regulator following stroke. CKLF1 was rapidly upregulated in neutrophils within 6 h post-ischemia in both humans and mice. Mechanistically, CKLF1 bound directly to the tetrameric form of pyruvate kinase M2 (PKM2), enhancing glycolytic flux and diverting intermediates toward de novo diacylglycerol (DAG) synthesis. This rewiring promoted protein kinase C-dependent phosphorylation of p47‑phox and assembly of NADPH oxidase, driving ROS production that reinforced neutrophil recruitment and adhesion via αMβ2 integrin. Genetic deletion of neutrophil CKLF1 attenuated neutrophil recruitment and improved functional recovery. Leveraging this mechanism, we developed a neutrophil-targeted nanotherapeutic using engineered outer membrane vesicles from E. coli W3110 to deliver a stapled CKLF1-derived peptide (C19) that disrupts CKLF1-PKM2 binding. This intervention suppressed glycolysis-driven ROS, reduced neutrophil recruitment and αMβ2 expression, and provided robust neuroprotection. Our findings reveal a CKLF1-PKM2-DAG axis that directs metabolic reprogramming and neutrophil pathogenicity in stroke, offering a novel target for immunometabolic therapy.
    DOI:  https://doi.org/10.1038/s41418-026-01754-1
  41. iScience. 2026 May 15. 29(5): 115801
    Ambient temperature regulates CD4+ T cell tonic T cell receptor signaling and responsiveness.
    Keisuke Sawada, John Eom, Bree A Mahoney-Sutherland, Traci E Stankiewicz, Jarren R Oates, Daniel A Giles, Pablo C Alarcon, Michelle S M A Damen, Angela Cannata, Julie Hargis, Jaclyn W McAlees, Cassidy J Ulanowicz, Jennifer L Wayland, David A Hildeman, Ian P Lewkowich, Simon P Hogan, Nathan Salomonis, Maria E Moreno-Fernandez, Senad Divanovic.
      Mice (Mus musculus) used in biomedical research are commonly housed at 19°C-23°C, below their thermoneutral zone (29°C-34°C), where metabolic homeostasis occurs. Although traditional housing exposes mice to chronic cold stress and modulates their immune response, the cellular mechanisms by which thermoneutrality shapes immune responses remain underdefined. CD4+ T cells are major contributors to host immunity through T cell receptor (TCR) signaling activated via recognition of peptide-major histocompatibility complex class II (pMHCII). We demonstrate that thermoneutral housing, compared to traditional housing, enhances tonic TCR signaling, upregulates genes associated with endogenous TCR stimulation, and increases TCR-driven TNF expression in CD4+ T cells. Mechanistically, these effects are in part dependent on tonic TCR engagement with self-pMHCII. In inflammatory disease models, thermoneutrality-driven increased CD4+ T cell TNF production correlates with amplified tissue inflammation. Together, these findings reveal how housing temperature may shape inflammatory responses through self-pMHCII-dependent TCR signaling in CD4+ T cells.
    Keywords:  immunology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115801
  42. Endocrinol Metab (Seoul). 2026 May 15.
    Persistent Adipose Inflammation Despite Metabolic Recovery Reveals Tissue-Specific Immunomodulation by Tirzepatide.
    Mihye Seo, Maria Averia, Vivi Julietta, Shindy Soedono, Esther Jin Joo, Ellen Budiono, Minjoon Lee, Min-Kyu Kim, Yongsung Hwang, Hyeong Kyu Park, Kyoil Suh, Kae Won Cho.
       Background: Obesity is characterized by chronic inflammation and fibrosis of adipose tissue; however, the extent to which these pathological features persist during pharmacologically induced weight loss remains poorly understood. This study investigated the effects of tirzepatide, a dual agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, on adipose tissue inflammation and fibrosis in obese mice.
    Methods: Diet-induced obesity was treated with tirzepatide or vehicle for 25 days. Metabolic parameters, tissue inflammation, fibrosis, and macrophage activation were assessed using histology, flow cytometry, gene expression analyses, and immunoblotting. In vitro experiments were conducted to compare the effects of tirzepatide on classically activated and metabolically activated macrophages.
    Results: Tirzepatide significantly reduced body weight and adiposity, increased energy expenditure, and upregulated thermogenic and mitochondrial proteins in brown adipose tissue. Hyperglycemia and glucose intolerance were normalized. However, adipose tissue inflammation and fibrosis persisted despite weight loss, as evidenced by sustained immune cell infiltration, collagen deposition, and activation of Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling. In contrast, hepatic inflammation and fibrosis were substantially improved. Mechanistically, tirzepatide suppressed inflammatory gene expression in classically activated macrophages but not in metabolically activated macrophages, suggesting that the local metabolic context determines tissue responsiveness to its anti-inflammatory actions.
    Conclusion: Tirzepatide exerts distinct tissue-specific effects on inflammation and fibrosis during weight loss, ameliorating hepatic pathology while sparing adipose tissue inflammation. These findings identify metabolically activated macrophages as potential determinants of tissue-specific inflammatory persistence and underscore the need for therapeutic strategies that target macrophage activation and fibrotic remodeling to achieve durable metabolic benefits during pharmacological weight loss.
    Keywords:  Adipose tissue; Fibrosis; Inflammation; Macrophages; Tirzepatide; Weight loss
    DOI:  https://doi.org/10.3803/EnM.2025.2766
  43. Cell Mol Gastroenterol Hepatol. 2026 May 12. pii: S2352-345X(26)00089-5. [Epub ahead of print] 101811
    Dietary tryptophan enhances aryl hydrocarbon receptor activation and reduces colitis through microbial metabolism.
    Liam E Rondeau, Bruna B Da Luz, Dominic Haas, Pranshu Muppidi, Xuanyu Wang, Rebecca Dang, Gaston Rueda, Andrea Nardelli, Giada De Palma, Harry Sokol, Premysl Bercik, Alberto Caminero.
       BACKGROUND & AIM: Disrupted microbial tryptophan metabolism and impaired aryl hydrocarbon receptor (AhR) activation are implicated in inflammatory bowel disease (IBD) pathogenesis. However, strategies to restore this pathway through diet or microbial modulation remain poorly defined. This study investigates how dietary tryptophan and human and mouse microbiota modulate metabolism, AhR activation, and intestinal inflammation in preclinical models.
    METHODS: Gnotobiotic mice colonized with microbiota of varying complexity or human fecal microbiota from ulcerative colitis (UC) patients and healthy controls were used to assess the impact of microbiota and dietary tryptophan supplementation on AhR activation and colitis severity. Chemically induced and spontaneous colitis models were investigated.
    RESULTS: IBD fecal samples showed reduced AhR activation compared to healthy controls, and fecal microbiota transplantation into germ-free mice demonstrated that impaired AhR is microbiota-dependent. Mice colonized with minimal microbiota had impaired microbial tryptophan metabolism, lower AhR activation, and worsened colitis severity compared to those colonized with complex microbiota. Dietary tryptophan supplementation in conventional and UC-humanized mice enhanced microbial production of AhR agonists, restored AhR activation, and reduced colitis severity in an AhR-dependent manner. Co-colonization with a tryptophan-metabolizing bacterium, Clostridium sporogenes, further improved tryptophan metabolism and colitis severity in mice with impaired microbial tryptophan metabolism.
    CONCLUSIONS: Microbial tryptophan metabolism is critical for determining intestinal inflammation. Dietary tryptophan supplementation restores microbial metabolic pathways, mitigates colitis severity in preclinical models, and may address key metabolic deficiencies in IBD patients with impaired tryptophan metabolism. This study demonstrates the therapeutic potential of targeting microbial metabolism with diet in IBD management.
    Keywords:  Tryptophan metabolism; aryl hydrocarbon receptor; inflammatory bowel disease; microbiota
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101811
  44. Mol Cell Endocrinol. 2026 May 13. pii: S0303-7207(26)00106-1. [Epub ahead of print] 112829
    Inhibition of RGS1 ameliorates obesity-associated macrophage dysfunction and metaflammation through restoration of PINK1/Parkin-mediated mitophagy.
    Yunmeng Li, Xuan Fu, Baolong Yin, Mahbuba Nasrin, Rui Huo.
       BACKGROUND: Obesity-associated metabolic inflammation is characterized by the infiltration and pro-inflammatory polarization of adipose tissue macrophages (ATMs). Mitochondrial dysfunction represents a central pathogenic mechanism; however, the upstream molecular mechanisms that link metabolic stress to impaired mitochondrial quality control in macrophages remain inadequately defined. Regulator of G protein signaling 1 (RGS1) is significantly upregulated in ATMs under obese conditions; nevertheless, its functional role and mechanistic relevance have not been fully elucidated.
    METHODS: Integrated transcriptomic analyses identified RGS1 as a pivotal gene associated with obesity, and its expression profiles in adipose tissue macrophages were analyzed by integrating single-cell RNA sequencing data from humans and mice. In vivo, immunohistochemistry and immunofluorescence assessed RGS1 localization in adipose tissue from high-fat diet-fed obese mice. In vitro, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were treated with palmitic acid (PA) or PA plus interleukin-6 (IL-6), combined with lentivirus-mediated RGS1 knockdown. The effects of RGS1 on mitochondrial integrity, mitophagic flux, lipid metabolism, and macrophage polarization were assessed by Western blot, quantitative real-time PCR, transmission electron microscopy, TMRE staining, reactive oxygen species (ROS) production, ATP levels, and oxidative phosphorylation (OXPHOS). Furthermore, bafilomycin A1 (Baf-A1) was used to assess mitophagic flux, and Mdivi-1 was utilized to inhibit mitophagy for mechanistic validation.
    RESULTS: Bioinformatic analyses revealed a significant upregulation of RGS1 in ATMs under obese conditions. In vivo studies demonstrated elevated levels of RGS1 in the epididymal adipose tissue of obese mice, where it co-localized with CD86+ M1 macrophages. In vitro, PA treatment induced RGS1 expression and caused lipid accumulation and M1 macrophage polarization; co-stimulation with PA and interleukin-6 (IL-6) further upregulated RGS1 and exacerbated pro-inflammatory responses. Conversely, RGS1 knockdown markedly attenuated both lipid accumulation and M1 polarization. Furthermore, PA treatment induced severe mitochondrial dysfunction, characterized by cristae disruption, loss of membrane potential, ROS accumulation, ATP depletion, and decreased expression of OXPHOS complexes, and inhibited PINK1/Parkin-mediated mitophagy. In contrast, RGS1 knockdown restored mitochondrial function. Baf-A1 treatment assays confirmed that RGS1 knockdown augmented mitophagic flux, while treatment with Mdivi-1 significantly diminished this protective effect, indicating that these protective effects were likely mediated in a mitophagy-dependent manner.
    CONCLUSION: RGS1 acts as a critical switch linking metabolic stress to macrophage dysfunction. Targeting RGS1 may represent a promising therapeutic strategy for alleviating obesity-induced inflammation.
    Keywords:  Macrophage Polarization; Mitochondrial Dysfunction; Mitophagy; Obesity; PINK1/Parkin; RGS1
    DOI:  https://doi.org/10.1016/j.mce.2026.112829
  45. J Inflamm Res. 2026 ;19 591994
    Macrophage Phenotypic Plasticity and Inflammatory Mechanisms in Hyperoxia-Induced Lung Injury.
    Wei Fu, Yawei Yao, Tingyang Meng, Yulan Li.
      Hyperoxia-induced lung injury is a prominent inflammatory complication encountered in neonatal and adult critical care, contributing to acute lung injury and bronchopulmonary dysplasia. Although oxidative stress is a primary initiating factor, accumulating evidence suggests that dysregulated immune responses, particularly those mediated by macrophages, critically influence disease progression and resolution. Macrophages exhibit remarkable phenotypic plasticity in response to hyperoxic stress, extending beyond the conventional pro-inflammatory and anti-inflammatory polarization framework. Recent advances, including single-cell transcriptomic analyses, have revealed substantial heterogeneity among macrophage subsets, highlighting inflammatory, metabolically reprogrammed, senescent, and pyroptotic phenotypes in hyperoxic lung injury. These phenotypic shifts are tightly regulated by inflammatory signaling pathways, immunometabolic alterations, and cellular stress responses. In this review, we summarize current evidence regarding macrophage phenotypic plasticity in hyperoxia-induced lung injury, with a focus on key inflammatory pathways, metabolic reprogramming, inflammasome activation, and emerging cell fate programs such as pyroptosis and cellular senescence. We further discuss macrophage-mediated intercellular communication with epithelial and endothelial cells and its contribution to persistent inflammation and impaired lung repair. By integrating these findings, this review aims to provide updated insights into macrophage-driven inflammatory mechanisms and to highlight potential avenues for therapeutic modulation in hyperoxic lung injury.
    Keywords:  acute lung injury; cellular crosstalk; immunometabolism; macrophage plasticity; single-cell transcriptomics
    DOI:  https://doi.org/10.2147/JIR.S591994
  46. Cell Metab. 2026 May 13. pii: S1550-4131(26)00150-6. [Epub ahead of print]
    Microbial phosphoketolase promotes histone lactylation to improve anti-TNF therapy efficacy in inflammatory bowel disease.
    Yi Jiang, Yanru Ma, Lijun Ning, Hao Wu, Hongli Huang, Nan Shen, Xia Xie, Xiaoqiang Zhu, Jinmei Ding, Zhenyu Wang, Ying Sun, Ying Zhao, Yilu Zhou, Yue Zhang, Yuqi Shao, Xi Xu, Muni Hu, Lingxi Li, Jing-Yuan Fang, Haoyan Chen, Zhijun Cao, Baoqin Xuan, Xitao Xu, Jie Hong.
      Anti-tumor necrosis factor (TNF) therapy is widely used for inflammatory bowel disease, yet primary non-response and secondary loss of response remain challenges in clinical practice. In this study, we demonstrate that bacterial phosphoketolase improves the primary response to anti-TNF antibodies during induction therapy by enhancing Treg-mediated immunosuppression and maintaining higher serum drug concentrations. Mechanistically, phosphoketolase acts as a microbial host enzyme in macrophages, increasing phosphoketolase pathway flux and lactate production. Elevated lactate induces histone H4K12 lactylation, leading to the upregulation of the serotonin transporter, which mediates serotonin uptake for subsequent conversion to 5-hydroxyindoleacetic acid, a potential inhibitor of TNF-α-converting enzyme. This increases surface transmembrane TNF levels, thereby enhancing TNFR2 signaling in Tregs and promoting their proliferation and differentiation. In a prospective clinical trial, phosphoketolase-producing Bifidobacterium enhanced anti-TNF antibody efficacy during induction therapy. These findings support phosphoketolase-producing probiotics as an effective adjunct to anti-TNF therapy in inflammatory bowel disease.
    Keywords:  5-hydroxyindoleacetic acid; Bifidobacterium; anti-TNF biologics; inflammatory bowel disease; lactylation; macrophage; microbial-host isozyme; phosphoketolase; regulatory T cells
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.012
  47. J Clin Invest. 2026 May 12. pii: e200522. [Epub ahead of print]
    Metabolic dysfunction-associated steatohepatitis exacerbated by Clostridium perfringens-derived ammonia is attenuated by tripeptide DT-109.
    Pengxiang Qu, Shusi Ding, Yanru Zhang, Yang Zhao, Erfei Song, Liangshuo Hu, Ruike Ding, Wenbin Cao, Yiting Hou, Jia Qi, Juan Zhao, Chenjing Duan, Shuangqing Liu, Chong Shen, Ying Zhao, Yanhong Guo, Zuowen Zheng, Shiwei Luo, Huizhong Hu, Liang Bai, Sihai Zhao, Bo Wang, Shuixiang He, Yi Wu, Xuelian Xiong, Qiutong Wu, Weiwang Gu, Oren Rom, Aimin Xu, Lemin Zheng, Jifeng Zhang, Enqi Liu, Y Eugene Chen.
      The global prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is rising, driven by a complex interplay of metabolic disturbances, inflammation, and fibrosis, yet effective treatment options remain limited. This study examined the relationships among intestinal microbial dysbiosis, ammonia production, and hepatic CD8+ T cell activity in MASH, and assessed the therapeutic potential of DT-109, a glycine-based tripeptide. We investigated the gut-liver axis across human cohorts and both non-human primate and mouse MASH models. Multi-omics approaches were used to characterize ileal microbiota, ammonia levels, and hepatic immune and metabolic pathways. Causality was verified through microbiota transplantation, C. perfringens NirA-knockout mutants, and functional validation in vitro and in vivo. The efficacy of DT-109 was evaluated in non-human primates and mice. Our results revealed a significant increase in the ammonia-producing gut bacterium C. perfringens, which led to elevated intestinal ammonia and disruption of the intestinal barrier in MASH. Elevated ammonia levels triggered FosB-mediated upregulation of chemokine C-C motif ligand 5 (CCL5) in CD8+ T cells, which in turn drove T cell cytotoxicity in the liver. Notably, DT-109 effectively lowered C. perfringens abundance, reduced intestinal ammonia, restored intestinal barrier integrity, and alleviated CD8+ T cell dysregulation in MASH. These results identify a distinct mechanism in which gut-derived ammonia drives CD8+ T cell-mediated MASH and demonstrate that DT-109 effectively targets this axis by inhibiting C. perfringens and reducing ammonia, ultimately ameliorating MASH.
    Keywords:  Gastroenterology; Hepatology; Microbiome; T cells
    DOI:  https://doi.org/10.1172/JCI200522
  48. Sci China Life Sci. 2026 Apr 30.
    Human MAITregs possess diverse TCR repertoires and are functionally supported by glycolysis.
    Maoyu Tang, Xinying Li, Xudong Yang, Changfeng Zhao, Yuwei Zhang, Sanwei Chen, Zhenghui Ye, Liujin Hou, Yusheng Chen, Rong Lv, Hongchuan Zhao, Xiaowen Cheng, Hua Wang, Li Bai, Sicheng Fu.
      Mucosal-associated invariant T (MAIT) regulatory cells (MAITregs) represent a specialized subset with immunosuppressive functions, yet their properties and molecular basis are largely unknown. We demonstrate that MAITregs, while sharing T cell receptor (TCR) repertoires with conventional MAIT cells, undergo selective clonal expansion during in vitro generation, leading to biased V(D)J profiles and restricted CDR3 diversity. Moreover, integrated transcriptomics revealed that MAITregs preferred glycolysis, which was supported by chromatin remodeling at glycolytic gene loci. Functionally, glycolysis in MAITregs favored their IL-10 production but inhibited Th1 cytokines, whereas oxidative phosphorylation (OXPHOS) promoted their Th1/Th17 cytokines. Our study defines MAITregs as a clonally expanded population whose regulatory potency is strictly governed by cellular metabolism.
    Keywords:  diverse TCR repertoires; glycolysis; human MAITregs
    DOI:  https://doi.org/10.1007/s11427-025-3259-0
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