bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–07–27
forty-four papers selected by
Dylan Ryan, University of Cambridge
  1. Metabolic Reprogramming of NK Cells Drives Anti-Tumor Immunity.
  2. Decoding the metabolic dialogue in the tumor microenvironment: from immune suppression to precision cancer therapies.
  3. The Role of Lactate in Immune Regulation: A Metabolic Rheostat via Transporters, Receptors, and Epigenetic Modifiers.
  4. Metabolic pathways within cTfh subsets and glucose-dependent activation of cTfh17 in SLE and healthy individuals.
  5. Early methionine availability attenuates T cell exhaustion.
  6. Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis.
  7. Mitochondrial bioenergetic failure in SLE immunocytes: Targeting fitness for therapy.
  8. Itaconate: A key regulator of immune responses and potential therapeutic target for autoimmune and inflammatory diseases.
  9. Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells.
  10. The role of gut microbial metabolites in the T cell lifecycle.
  11. Effects of lactate concentration on T-cell phenotype and mitochondrial respiration.
  12. Macrophage fatty acid metabolism under chronic hypoxia shapes γδ T cell recruitment via CCL22.
  13. IL-1β-Mediated Immunometabolic Adaptation in Corneal Epithelial Cells.
  14. Sleep Deprivation Activates a Conserved Lactate-H3K18la-RORα Axis Driving Neutrophilic Inflammation Across Species.
  15. Dopamine as an endogenous regulator of innate immunity in sepsis.
  16. Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.
  17. Metabolic dysregulation of trained immunity in immune aging and the impact of dietary patterns.
  18. LARP4-mediated hypertranslation drives T cell dysfunction in tumors.
  19. DGAT2 reduction and lipid dysregulation drive psoriasis development in keratinocyte-specific SPRY1-deficient mice.
  20. Deletion of EP3 prostaglandin receptor in murine macrophages aggravates diet-induced obesity by suppressing SPARC.
  21. Gut microbiota-associated non-cholesterol sterol dysregulation modulates immune reconstitution during antiretroviral therapy in people living with HIV.
  22. Tumor-associated bacteria activate PRDX1-driven glycolysis to promote immune evasion and PD-1 antibody resistance in hepatocellular carcinoma.
  23. Regulation of dendritic cell biology by amino acids and their transporters.
  24. Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
  25. Exogenous arginine differentially regulates inflammatory cytokine and inducible nitric oxide synthase expression in macrophages.
  26. Small intestinal γδ T17 cells promote SAE through STING/C1q-induced microglial synaptic pruning in male mice.
  27. Myeloid TGF-β signaling shapes liver macrophage heterogeneity and metabolic liver disease pathogenesis.
  28. T cells require mitochondria to proliferate, function and generate memory.
  29. Involvement of the tryptophan-kynurenine pathway in the pathogenesis of autoimmune diseases.
  30. β-hydroxybutyrate restricts glycolytic metabolism in bovine neutrophils during toll-like receptor 2/1 stimulation.
  31. Inhibition of pyrimidine de novo synthesis fosters Treg cells and reduces diabetes development in models of Type 1 Diabetes.
  32. UBD-mediated glycolytic reprogramming promotes M2 macrophage polarization in ovarian cancer immune evasion.
  33. A gain-of-function PIK3CD variant, R512W, impairs T cell function through polyamine-dependent metabolic dysregulation.
  34. Gut microbiota-host post-translational modification axis in immunometabolic diseases.
  35. LPS mediates cuproptosis and inflammation in THP-1 macrophages through HKDC1.
  36. Vitamin D3 supplementation ameliorates adipose tissue inflammation and adipocyte hypertrophy in type 2 diabetic mice through downregulation of RAGE and SREBP-1c.
  37. Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans.
  38. JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation.
  39. Regulation of inflammatory responses by pH-dependent transcriptional condensates.
  40. Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma.
  41. Itaconate alleviates cholesterol burden via ABCA1 stabilization and cholesterol efflux.
  42. The essential host genome for Cryptosporidium survival exposes metabolic dependencies that can be leveraged for treatment.
  43. Postprandial Metabolism, Inflammation, and Plasma Bile Acid Kinetics in a Rat Model: Implications for Translational Research.
  44. Activating Mitochondrial Complex I by Polyphenol Nanoparticle to Inhibit Hypoxia-Inducible Factor-1 Subunit α for Immunotherapy.
  1. Crit Rev Oncol Hematol. 2025 Jul 21. pii: S1040-8428(25)00247-1. [Epub ahead of print] 104859
    Metabolic Reprogramming of NK Cells Drives Anti-Tumor Immunity.
    Pengcheng Yang, Wanrong Wang, Qiuyu Liu, Siqi Mu, Yue Zha, Weizhen Yan, Bin Yuan, Jing Yang.
      Cellular metabolism critically controls immune cell functionality, necessitating dynamic metabolic adaptation to sustain effector responses under microenvironmental fluctuations. Natural killer (NK) cells, innate lymphocytes essential for tumor immunosurveillance, exhibit functional plasticity intrinsically linked to metabolic reprogramming. While NK cell-based immunotherapy show promise due to MHC-independent cytotoxic, their clinical efficacy diverges markedly between hematological and solid tumor-a disparity rooted in tumor microenvironment (TME) driven immunosuppression. Cancer cells subvert NK cell elimination through metabolic competition, creating nutrient-depleted milieus that impair mitochondrial bioenergetics and glycolytic flux in tumor-infiltrating NK populations. These constraints induce functional exhaustion, characterized by diminished cytokine production and cytotoxic granule release, facilitating immune evasion. Emerging strategies targeting metabolic checkpoints-including glucose utilization, amino acid metabolism, and lipid signaling-demonstrate capacity to restore NK cell metabolic fitness. Preclinical models reveal enhanced anti-tumor activity when combining metabolic modulators with cytokine priming or checkpoint inhibitors, establishing metabolic optimization as a biochemical framework to overcome TME limitations. These advances position NK cell metabolic engineering as a promising approach for next-generation solid tumor immunotherapies, driving translational research toward precision metabolic reprogramming strategies.
    Keywords:  NK cells; anti-tumor immunity; immunotherapy; metabolic reprogramming; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104859
  2. Exp Hematol Oncol. 2025 Jul 22. 14(1): 99
    Decoding the metabolic dialogue in the tumor microenvironment: from immune suppression to precision cancer therapies.
    Ruoli Wang, Jincheng Zhuang, Qi Zhang, Wantao Wu, Xinrui Yu, Hao Zhang, Zongyi Xie.
      The tumor microenvironment (TME) represents a metabolic battleground where immune cells and cancer cells vie for essential nutrients, ultimately influencing antitumor immunity and treatment outcomes. Recent advancements have shed light on how the metabolic reprogramming of immune cells, including macrophages, T cells, and DCs, determines their functional polarization, survival, and interactions within the TME. Factors such as hypoxia, acidosis, and nutrient deprivation drive immune cells toward immunosuppressive phenotypes, while metabolic interactions between tumors and stromal cells further entrench therapeutic resistance. This review synthesizes new insights into the metabolic checkpoints that regulate immune cell behavior, focusing on processes like glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and amino acid dependencies. We emphasize how metabolic enzymes (e.g., IDO1, ACLY, CPT1A) and metabolites (e.g., lactate, kynurenine) facilitate immune evasion, and we propose strategies to reverse these pathways. Innovations such as single-cell metabolomics, spatial profiling, and AI-driven drug discovery are transforming our understanding of metabolic heterogeneity and its clinical implications. Furthermore, we discuss cutting-edge therapeutic approaches-from dual-targeting metabolic inhibitors to biomaterial-based delivery systems-that aim to reprogram immune cell metabolism and enhance the effectiveness of immunotherapy. Despite the promise in preclinical studies, challenges persist in translating these findings to clinical applications, including biomarker validation, metabolic plasticity, and interpatient variability. By connecting mechanistic discoveries with translational applications, this review highlights the potential of immunometabolic targeting to overcome resistance and redefine precision oncology.
    Keywords:  Immune cells metabolism; Immunotherapy resistance; Metabolic reprogramming; Therapeutic targeting; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-025-00689-6
  3. Cells. 2025 Jul 17. pii: 1096. [Epub ahead of print]14(14):
    The Role of Lactate in Immune Regulation: A Metabolic Rheostat via Transporters, Receptors, and Epigenetic Modifiers.
    Eun Jung Choi, Yoon Young Jang, Eun Joo Choi, Chang Joo Oh.
      Lactate, once regarded as a metabolic byproduct, is now recognized as a critical immunometabolic regulator that shapes immune responses in both physiological and pathological contexts. This review examines how lactate accumulation occurs across diverse disease settings, including cancer, sepsis, and diabetes, through mechanisms such as hypoxia, mitochondrial dysfunction, and pharmacologic intervention. We then explore how lactate modulates immunity via four integrated mechanisms: transporter-mediated flux, receptor signaling (e.g., GPR81), context-dependent metabolic rewiring, and histone/protein lactylation. Particular emphasis is placed on the dichotomous effects of endogenous versus exogenous lactate, with the former supporting glycolytic effector functions and the latter reprogramming immune cells toward regulatory phenotypes via redox shifts and epigenetic remodeling. The review also highlights how the directionality of lactate transport, and the metabolic readiness of the cell determine, whether lactate sustains inflammation or promotes resolution. After analyzing emerging data across immune cell subsets and disease contexts, we propose that lactate serves as a dynamic rheostat that integrates environmental cues with intracellular metabolic and epigenetic programming. Understanding these context-dependent mechanisms is essential for the rational design of lactate-targeted immunotherapies that aim to modulate immune responses without disrupting systemic homeostasis.
    Keywords:  anti-inflammation; immunometabolism; lactate
    DOI:  https://doi.org/10.3390/cells14141096
  4. JCI Insight. 2025 Jul 22. pii: e189858. [Epub ahead of print]10(14):
    Metabolic pathways within cTfh subsets and glucose-dependent activation of cTfh17 in SLE and healthy individuals.
    Vera Kim, Takaya Misao, Hong Tian, Meggan Mackay, Cynthia Aranow, Sun Jung Kim.
      Cellular metabolism plays a key role in T cell biology. Increased glycolysis and mitochondrial respiration have been identified in CD4+ helper T cells from both patients with systemic lupus erythematosus (SLE) and lupus mouse models. Inhibiting this metabolic activity can reduce T cell activation and ameliorate disease symptoms in lupus mice. However, the metabolic differences among circulating follicular helper T (cTfh) cell subsets in patients with SLE versus healthy controls (HCs) have not been thoroughly studied. While the frequencies of cTfh cells and their subsets were similar between patients with SLE and HCs, patients exhibited a higher proportion of activated ICOS+ programmed cell death 1-positive cells, which correlated with disease activity. cTfh17 cells from both patients with SLE and HCs demonstrated heightened glycolytic activity and expression of glycolysis-related genes compared with cTfh1 and cTfh2. Glucose deprivation significantly diminished costimulatory molecule expression and cytokine production, including IL-17A, IL-10, IL-2, and TNF-α. Glycolysis inhibition reduced the B cell activation capacity of cTfh17 cells. This glucose dependence was more pronounced in cTfh17 than cTfh2 from patients with SLE, but it similarly affected both cTfh2 and cTfh17 cells from HCs. These findings highlight distinct metabolic dependencies among cTfh subsets and the critical role of glycolysis in cTfh17-mediated B cell activation in SLE.
    Keywords:  Autoimmune diseases; Autoimmunity; Glucose metabolism; Metabolism; T cells
    DOI:  https://doi.org/10.1172/jci.insight.189858
  5. Nat Immunol. 2025 Jul 23.
    Early methionine availability attenuates T cell exhaustion.
    Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.
      T cell receptor (TCR) activation is regulated in many ways, including niche-specific nutrient availability. Here we investigated how methionine (Met) availability and TCR signaling interplay during the earliest events of T cell activation affect subsequent cell fate. Limiting Met during the initial 30 min of TCR engagement increased Ca2+ influx, NFAT1 (encoded by Nfatc2) activation and promoter occupancy, leading to T cell exhaustion. We identified changes in the protein arginine methylome during initial TCR engagement and identified an arginine methylation of the Ca2+-activated potassium transporter KCa3.1, which regulates Ca2+-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering T cells dysfunctional in mouse tumor and infection models. Furthermore, acute, early Met supplementation reduced nuclear NFAT1 in tumor-infiltrating T cells and augmented antitumor activity. These findings identify a metabolic event early after T cell activation that affects cell fate.
    DOI:  https://doi.org/10.1038/s41590-025-02223-6
  6. Adv Sci (Weinh). 2025 Jul 24. e02297
    Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis.
    Chuyi Tan, Han Ma, Jespar Chen, Gaifeng Ma, Alok Jha, Sipin Tan, Yaxi Zhu, Meidong Liu, Ke Liu, Xianzhong Xiao, Monowar Aziz, Huan Chen, Ping Wang, Huali Zhang.
      Immune cell metabolic reprogramming toward glycolysis is vital for sepsis defense. While interleukin 1 receptor 2 (IL1R2) acts as a decoy receptor for IL1α/β, its potential impact on cell metabolism and death during sepsis remains unclear. This study observed elevated plasma soluble IL1R2 (sIL1R2) levels in septic patients and mice. In pyroptotic macrophages, reduced intracellular IL1R2 expression led to its release extracellularly. Proteomic screening identified enolase 1 (ENO1), a key glycolysis enzyme, as the binding partner of IL1R2 in macrophages. IL1R2 suppresses ENO1 activity to inhibit glycolysis, gasdermin D (GSDMD)-mediated pyroptosis, and inflammation in macrophages. IL1R2-deficient mice exhibited heightened susceptibility to sepsis, with increased inflammation, organ injury, and mortality. Notably, ENO1 inhibition reduced inflammation, organ injury, and improved survival rates in septic mice. The study reveals that IL1R2 interacts with ENO1 to inhibit glycolysis-mediated pyroptosis and inflammation in sepsis, suggesting the IL1R2-ENO1 interaction as a promising therapeutic target of sepsis.
    Keywords:  IL1R2; enolase 1; glycolysis; macrophages; pyroptosis; sepsis
    DOI:  https://doi.org/10.1002/advs.202502297
  7. Clin Immunol. 2025 Jul 21. pii: S1521-6616(25)00146-9. [Epub ahead of print]280 110571
    Mitochondrial bioenergetic failure in SLE immunocytes: Targeting fitness for therapy.
    Anjali S Yennemadi, Natasha Jordan, Sophie Diong, Mark Little, Joseph Keane, Gina Leisching.
       BACKGROUND: Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses linked to immunometabolic perturbations. While mitochondrial dysfunction has been implicated in SLE, its cell-type-specific impact on immune subsets remains underexplored.
    METHODS: We repurposed existing RNA-seq data from SLE patient peripheral blood mononuclear cells, with a focus on nuclear-encoded mitochondrial (NEmt) genes, as well as mitochondrial genes themselves, to identify differentially expressed genes compared to healthy controls. Mitochondrial stress tests were performed on freshly isolated CD4+ T cells, CD8+ T cells, B cells, and monocytes from SLE patients and healthy donors to assess bioenergetic function.
    RESULTS: RNA-seq revealed that both NEmt genes and mitochondrial genes were downregulated in the PBMC population of SLE patients. In situ mitochondrial stress tests revealed significant reductions in oxygen consumption rate (OCR), indicating impaired oxidative phosphorylation (OXPHOS) across all immune subsets, while extracellular acidification rate (ECAR), a marker of glycolysis, remained unchanged. These findings highlight immune-cell-specific mitochondrial bioenergetic failure in SLE, without compensatory glycolytic adaptation.
    CONCLUSION: Our results position mitochondrial fitness as a novel therapeutic target in SLE. We propose leveraging high-throughput screening of mitochondria-targeted compounds, including FDA-approved agents, to enhance OXPHOS, regulate mitophagy, or mitigate oxidative stress. This precision-based approach offers a paradigm shift from conventional immunosuppression to metabolic recalibration, with the potential to restore immune homeostasis in SLE. Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses linked to immunometabolic perturbations. While mitochondrial dysfunction has been implicated in SLE, its cell-type-specific impact on immune subsets remains underexplored.Using existing RNA-seq data we focused on nuclear-encoded mitochondrial (NEmt) genes, as well as mitochondrial genes themselves. Mitochondrial stress tests were performed on freshly isolated CD4+ T cells, CD8+ T cells, B cells, and monocytes from SLE patients and healthy donors to assess bioenergetic function.RNA-seq revealed that both NEmt genes and mitochondrial genes were downregulated in the PBMC population of SLE patients. In situ mitochondrial stress tests revealed significant reductions in oxygen consumption rate, indicating impaired oxidative phosphorylation across all immune subsets, while glycolysis remained unchanged. These findings highlight immune-cell-specific bioenergetic failure in SLE and propose mitochondrial fitness as a novel therapeutic target in SLE. This precision-based approach offers a paradigm shift from conventional immunosuppression to metabolic recalibration.
    Keywords:  B cells; CD4+ T cells; CD8+ T cells; Metabolic therapy; Mitochondrial dysfunction; Oxidative phosphorylation; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.clim.2025.110571
  8. Autoimmun Rev. 2025 Jul 17. pii: S1568-9972(25)00145-4. [Epub ahead of print]24(10): 103885
    Itaconate: A key regulator of immune responses and potential therapeutic target for autoimmune and inflammatory diseases.
    Yutong Liu, Xueling Jiang, Songnian Zhuang, Lihua Zhu, Bo Zhu, Ke Rui, Jie Tian.
      Itaconate, a metabolite of the tricarboxylic acid cycle (TAC), has gained increasing attention in recent years due to its anti-inflammatory and immunomodulatory properties. It plays a crucial role in immune regulation by modulating signal transduction and posttranslational modification. Itaconate is derived from cis-aconitate decarboxylation and is produced by cis-aconitate decarboxylase (ACOD1) in the mitochondria. During cellular stress conditions, itaconate rapidly accumulates in myeloid cells. Recent studies have demonstrated that itaconate plays a pivotal role in modulating both innate and adaptive immune responses. Moreover, itaconate regulates the differentiation and function of innate immune and lymphoid cells, which is implicated in the pathogenesis of autoimmune diseases. In this review, we aim to explore the recent advancements in comprehending the functional regulation and mechanisms of itaconate in various populations of innate immune and lymphoid cells, as well as its immunomodulatory effects in the development of autoimmune diseases. In addition, we highlight the potential therapeutic applications of itaconate and its derivatives in autoimmune diseases.
    Keywords:  Autoimmune disease; Immune cell; Immunomodulation; Itaconate
    DOI:  https://doi.org/10.1016/j.autrev.2025.103885
  9. Cell Metab. 2025 Jul 14. pii: S1550-4131(25)00324-9. [Epub ahead of print]
    Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells.
    Tiezhu Shi, Jialiang Shao, Yufeng Ding, Hong Tang, Xiangyin Tan, Sisi Zhou, Shaoqing Yu, Xiang Wang, Guanzhen Yu, Ninghan Feng, Xiongjun Wang.
      Metabolic adaptations involved in tumor metastasis and immune evasion merit investigation. Here, using in vivo metabolic CRISPR/Cas9 knockout screening, we identified xylulokinase (XYLB) as a tumor suppressor that impairs lung colonialization by producing xylulose 5-phosphate (Xu5P), which promotes CD8+ T cell cytotoxicity. Mechanistically, CD8+ T cells express relatively high levels of solute carrier family 35 member E2 (SLC35E2), a homolog of the plant Xu5P transporter, to facilitate Xu5P uptake and subsequently intensify the pentose phosphate pathway and glycolysis for energy/redox balance. Furthermore, we revealed that Xu5P potentiates CD8+ T cell response by promoting Xu5P-responsive progenitor-like SLC35E2+ CD8+ exhausted T cells via tet methylcytosine dioxygenase 3 (TET3)-mediated DNA demethylation of the Tcf7 promoter. Clinically, elevated XYLB or blood Xu5P correlates with enhanced CD8+ T cell efficacy and reduced metastasis. In murine models, Xu5P supplementation or adopting Xu5P-rich diets synergizes with anti-PD-1 therapy to enhance antitumor immunity. These findings offer insights into the potentiality of dietary interventions for metastatic cancer.
    Keywords:  Xu5P; dietary metabolite; immunotherapy; progenitor-like CD8(+) T cells; tumor metastasis
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.011
  10. Nat Immunol. 2025 Jul 21.
    The role of gut microbial metabolites in the T cell lifecycle.
    Melissa Tran, Jun R Huh, A Sloan Devlin.
      T cells, a cornerstone of the adaptive immune system, have pivotal roles at the host-microorganism interface. The gut microbiome profoundly influences T cell biology by producing a diverse repertoire of small molecules that are sensed by host cells. These microbial metabolites regulate all aspects of the T cell lifecycle, from cell development to differentiation and activation to exhaustion. Recent studies have uncovered microbially derived molecules, including short-chain fatty acids, secondary bile acids and tryptophan metabolites, as potent regulators of T cell function. However, the full scope of microbial metabolite-T cell interactions remains largely unexplored. This Review presents a mechanistic framework linking gut microbial metabolites to discrete stages of T cell fate and function. Expanding our understanding of these intricate host-microbiome interactions will reveal new aspects of immune regulation and inspire microbiome-guided therapeutic strategies for infections, autoimmune diseases and cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-025-02227-2
  11. Physiol Rep. 2025 Jul;13(14): e70450
    Effects of lactate concentration on T-cell phenotype and mitochondrial respiration.
    Eunhan Cho, Guillaume Spielmann, Brian A Irving.
      Lactate is a critical regulator of cellular processes and immune signaling, and we hypothesize that exercise-induced elevations in lactate help activate immune cells in response to vigorous exercise. Despite its importance, the impact of lactate on T-cell mitochondrial respiration remains poorly understood. This study examines the impact of exposure to physiologically relevant lactate concentrations (0.5 and 4.0 mM) on the mitochondrial respiration of resting T-cells. Resting T-cells were isolated from 12 healthy participants (mean ± SD, 26.8 ± 3.5 years) and cultured in a plasma-like medium with either 0.5 mM (control) or 4 mM lactate for 1 h to mimic resting and vigorous exercise conditions. The composition of T-cell subsets was characterized using flow cytometry, and mitochondrial respiration was measured using high-resolution respirometry. Exposure to 4 mM lactate significantly increased mitochondrial oxygen flow (IO2, pmols∙s-1 million T-cells-1) across all respiratory states compared to the control condition (0.5 mM) (all p < 0.01), suggesting an enhanced capacity for oxidative phosphorylation compared to the control. This study demonstrates that lactate preconditions T-cells and leads to enhanced mitochondrial respiration, offering insights into immune cell metabolism under exercise-like conditions, independent of exercise-induced differential mobilization of immune cell subsets.
    Keywords:  L‐lactate; T‐cell bioenergetics; flow cytometry; high resolution respirometry; immunometabolism; preconditioning
    DOI:  https://doi.org/10.14814/phy2.70450
  12. iScience. 2025 Aug 15. 28(8): 113025
    Macrophage fatty acid metabolism under chronic hypoxia shapes γδ T cell recruitment via CCL22.
    Vanesa M Guerrero Ruiz, Aya Khabaza, Rebekka Bauer, Blerina Aliraj, Siavash Mansouri, Sofie P Meyer, Megan A Palmer, Hauke Winter, Laura V Klotz, Mohammed A F Elewa, Ivan M Kur, Carlo Angioni, Rahmat Mojaradfar, Lisa Hahnefeld, Rajkumar Savai, Dominik Fuhrmann, Andreas Weigert, Bernhard Brüne.
      Hypoxia in solid tumors is associated with poor outcomes because of metabolic adaptations that support tumor cell survival and alter immune cell function. However, the metabolic and phenotypic adaptations of macrophages (MФs) to chronic hypoxia (CH) remain unclear. This study identifies impaired activity of the oxygen-dependent enzyme stearoyl-CoA desaturase 1 (SCD1) as a driver of altered fatty acid (FA) metabolism in MФs under CH. SCD1 deletion enhanced pro-inflammatory gene expression while suppressing the production of the chemokine CCL22. We propose that attenuated SCD1 activity and an altered saturated fatty acids (SFA)/monounsaturated fatty acids (MUFA) ratio impair the function of the transcription factor HNF4α, thereby affecting the expression of inflammatory genes such as CCL22. Reduced CCL22 levels, in turn, impaired γδ T cell recruitment. Accordingly, CCL22 expression in non-small cell lung cancer patients correlated positively with γδ T cell frequency and patient survival. These findings highlight the immunometabolic role of SCD1 in the hypoxic tumor microenvironment.
    Keywords:  Cancer; Human metabolism; Immune response
    DOI:  https://doi.org/10.1016/j.isci.2025.113025
  13. J Inflamm Res. 2025 ;18 9537-9555
    IL-1β-Mediated Immunometabolic Adaptation in Corneal Epithelial Cells.
    Jose Marcos Sanches, Rajalakshmy Ayilam Ramachandran, Natalia Mussi, Hamid Reza Baniasadi, Danielle M Robertson.
       Purpose: As an external mucosal surface, the corneal epithelium is subject to a barrage of stressors that are known to trigger inflammation. IL-1β, a master regulator of inflammation, is secreted into the preocular tear film by ocular surface epithelial cells and infiltrating immune cells. While increased levels of IL-1β have been associated with corneal disease, the effects of IL-1β on mitochondrial function in corneal epithelial cells (CECs) is unknown.
    Methods: To investigate the effects of IL-1β on mitochondrial function, telomerase immortalized human CECs were cultured in either 50 ng/mL or 100 ng/mL IL-1β for short term (24 hours) or prolonged (72 hours) time periods. Cells were assessed for ROS, inflammatory cytokine production, mitochondrial polarization and ultrastructure, mitophagy, and changes in the metabolite composition. Lipid drops were examined using light and fluorescent microscopy.
    Results: Short term exposure to IL-1β triggered an increase in IL-8 and ROS levels that corresponded to a reduction in mitochondrial membrane potential. Long term exposure also showed increased levels of IL-8 and IL-6 and further increased ROS. After long term exposure however, there was a paradoxical increase in mitochondrial membrane potential that was associated an increase in spare respiratory capacity and mitochondrial hyperfusion. Metabolomics confirmed an upregulation of the pentose phosphate pathway and the TCA cycle. Fumarate was also increased, suggesting an increase in flux through complex II. Changes in lipid metabolism included an upregulation in cardiolipin and de novo triacylglyceride biosynthesis, along with increasing numbers of lipid droplets.
    Conclusion: Prolonged exposure to IL-1β induces metabolic rewiring in CECs that results in an increase in spare respiratory capacity. These findings suggest that the corneal epithelium is able to adapt to certain levels of chronic inflammation and may have important implications in our understanding of immune tone and cellular stress responses in ocular surface epithelia.
    Keywords:  IL-1β; cornea; epithelial cells; inflammation; metabolites; metabolome; mitochondria; mitophagy
    DOI:  https://doi.org/10.2147/JIR.S495323
  14. Adv Sci (Weinh). 2025 Jul 21. e04028
    Sleep Deprivation Activates a Conserved Lactate-H3K18la-RORα Axis Driving Neutrophilic Inflammation Across Species.
    Ren Zhou, Keyun Li, Xiezong Hu, Shuhao Fan, Yuxuan Gao, Xiaoshu Xue, Yu Bu, Haoyi Zhang, Yili Wang, Chunjiao Wei, Shangrong Zhang, Zhongwen Xie, Chao Liu, Peng Chen, Zongjun Yin, Dalong Ren.
      Sleep deprivation critically disrupts physiological homeostasis, impairing development, metabolic balance, and immune regulation, with excessive neutrophil activation being a hallmark consequence. However, the molecular mechanisms underlying sleep deprivation-induced neutrophilic inflammation remain elusive. Here, it is shown that acute sleep deprivation in mice triggers neutrophil hyperactivation, resulting in aberrant peripheral accumulation and a systemic cytokine storm. Mechanistically, this pathology is driven by metabolic dysregulation, specifically, increased glycolytic flux, which elevates tissue lactate levels and enhances histone H3K18 lactylation. Through H3K18 lactylation-specific CUT&Tag profiling, pronounced lactylation enrichment is identified at the promoter of the Rorα gene, directly activating its transcription. Genetic ablation of Rorα or pharmacological inhibition of glycolysis attenuate neutrophil recruitment and mitigated inflammation in sleep-deprived zebrafish. Strikingly, this metabolic‒epigenetic axis is evolutionarily conserved, as demonstrated by the recapitulation of key findings in diurnal zebrafish and pigs. The study reveals a lactate-H3K18 lactylation-Rorα signaling cascade that links sleep deprivation to immune dysregulation, suggesting actionable targets for combating sleep-related inflammatory disorders.
    Keywords:  Rorα; inflammation; lactylation; neutrophil; sleep deprivation
    DOI:  https://doi.org/10.1002/advs.202504028
  15. Front Immunol. 2025 ;16 1625368
    Dopamine as an endogenous regulator of innate immunity in sepsis.
    Haichao Wang, Rui Kang, Daolin Tang.
      Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, presents a major clinical challenge. While the complex interplay of inflammatory mediators and immune cells during sepsis is increasingly understood, the role of neurotransmitters, particularly dopamine, in modulating the innate immune response is emerging as a crucial area of investigation. Dopamine, traditionally recognized for its role in the central nervous system, acts as an endogenous regulator of innate immunity, significantly influencing the course and outcome of sepsis. In this mini-review, we highlight our recent finding of dopamine's critical role in regulating aconitate decarboxylase 1 (ACOD1) in sepsis.
    Keywords:  CD274; aconitate decarboxylase 1; dopamine; innate immunity; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2025.1625368
  16. Cell Rep. 2025 Jul 21. pii: S2211-1247(25)00803-4. [Epub ahead of print]44(8): 116032
    Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.
    Louise Nuyttens, Marah Heyerick, Geike Heremans, Elise Moens, Maxime Roes, Céline Van Dender, Liesbet De Bus, Johan Decruyenaere, Jan Dewaele, Jolien Vandewalle, Claude Libert.
      Sepsis, killing 11 million people yearly, is associated with increased production of lactate-a metabolite mechanistically linked to mortality-complicating glucose administration in sepsis. To understand the mechanism behind hyperlactatemia, we applied the cecal ligation and puncture (CLP) model and studied all pyruvate processing routes in liver mitochondria during acute sepsis. Our data suggest that mitochondrial pyruvate-driven respiration is nearly nonexistent in sepsis, not due to insufficient pyruvate uptake or carboxylation, but due to a dysfunctional pyruvate dehydrogenase complex (PDC). Septic mitochondria compensate via glutamate-mediated tricarboxylic acid (TCA) anaplerosis, simultaneously converting some pyruvate into alanine via enhanced mitochondrial glutamic pyruvate transaminase (GPT2) activity. PDC dysfunction is not caused by PDC inactivation per se but by a shortage of its cofactor, thiamine pyrophosphate (TPP). TPP supplementation restores pyruvate oxidation and protects mice from sepsis. TPP also allows safe glucose administration in mice, leading to a robust TPP-plus-glucose therapy.
    Keywords:  CP: Metabolism; CP: Microbiology; lactate; mitochondria; pyruvate; sepsis; thiamine
    DOI:  https://doi.org/10.1016/j.celrep.2025.116032
  17. Am J Physiol Cell Physiol. 2025 Aug 01. 329(2): C456-C470
    Metabolic dysregulation of trained immunity in immune aging and the impact of dietary patterns.
    Andra Grigorescu, Anca-Lelia Riza, Ioana Streata, Mihai G Netea.
      Trained immunity (TRIM) is the process through which the innate immune system undergoes memory-like epigenetic and metabolic reprogramming following an earlier infectious challenge. Trained immunity can be induced, in a similar fashion to microbial structures, by various endogenous compounds: oxidized low-density lipoproteins, lipoprotein(a), glucose and uric acid, and monosodium urate. Lipids, glucose, and protein metabolic dysfunction have the potential to perpetuate a proinflammatory feedback loop through the induction of maladaptive trained immunity programs, as shown in cardiovascular diseases, diabetes, and hyperuricemia. Molecular mechanisms leading to TRIM are susceptible to homeostatic disruptions of advanced age, and maladaptive TRIM may be the link between immune aging and age-associated pathologies. The present review discusses the current knowledge on metabolic pathways in adaptive and maladaptive trained immunity and its deleterious consequences of inappropriate activation during aging. Finally, we discuss how several dietary patterns modulate immunometabolism and influence trained immunity in aging.
    Keywords:  immune aging; inflammaging; nutrition; trained immunity
    DOI:  https://doi.org/10.1152/ajpcell.00153.2025
  18. Nat Immunol. 2025 Jul 22.
    LARP4-mediated hypertranslation drives T cell dysfunction in tumors.
    Yi Liu, Haochen Ni, Jie Li, Jing Yang, Ivann Sekielyk, Bryan E Snow, Zihao Zhang, Feifan Zhang, Michael St Paul, Jinyi Han, Meghan Kates, Shaofeng Liu, Yawei Zhang, Zurui Huang, Yin Xu, Samuel D Saibil, Tak W Mak, Dali Han, Meng Michelle Xu.
      Adoptive T cell therapies have therapeutic potential for treating solid tumors, but long-term efficacy is limited by reduced functional fitness and poor persistence within the tumor microenvironment. Here we show that intratumoral T cells undergo translatome remodeling, transitioning into a hypertranslational state as they acquire dysfunctional traits. The RNA-binding protein LARP4 is a translation regulator that drives hypertranslation and dysfunction by selectively enhancing the translation of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs in exhausted T cells, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion and enhances effector persistence, resulting in enhanced anti-tumor responses. Additionally, LARP4 knockdown in chimeric antigen receptor T cells prevents terminal exhaustion and improves the response to liquid and solid tumors. This study highlights translation dysregulation as a determinant of T cell dysfunction in tumors.
    DOI:  https://doi.org/10.1038/s41590-025-02232-5
  19. JCI Insight. 2025 Jul 22. pii: e192507. [Epub ahead of print]
    DGAT2 reduction and lipid dysregulation drive psoriasis development in keratinocyte-specific SPRY1-deficient mice.
    Ying-Ying Li, Li-Ran Ye, Ying-Zhe Cui, Fan Xu, Xi-Bei Chen, Feng-Fei Zhang, Yi Lu, Yu-Xin Zheng, Xiao-Yong Man.
      Psoriasis is a chronic autoimmune skin disease characterized by abnormal keratinocyte proliferation and immune dysregulation. Altered lipid metabolism has been implicated in its pathogenesis, but the underlying mechanisms remain unclear. In this study, we generated an keratinocyte-specific Sprouty RTK signaling antagonist 1 (SPRY1) knockout (Spry1ΔEpi) mouse model, which exhibits psoriasis-like symptoms. Using both psoriasis patient samples and Spry1ΔEpi mice, we investigated the role of diacylglycerol acyltransferase 2 (DGAT2) in psoriasis. Our results show that DGAT2 expression is reduced, and glycerides metabolism is disrupted in psoriatic lesions in both psoriasis patients and Spry1ΔEpi mice. Lipidomic analysis reveals significant alterations in glycerides, glycerophospholipids, sphingolipids, and fatty acids in Spry1ΔEpi mice. At the cellular level, DGAT2 downregulation and lipid dysregulation enhance Toll-like receptor 3 (TLR3)-mediated inflammatory signaling in keratinocytes. Furthermore, increased DGAT2 secretion from keratinocytes promotes CD8⁺ T cell activation, proliferation and survival, amplifying psoriatic inflammation. These findings highlight the role of DGAT2 and lipid metabolism in the pathogenesis of psoriasis and reveal their interaction with immune responses in psoriasis.
    Keywords:  Cellular immune response; Dermatology; Inflammation; Lipidomics; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.192507
  20. EMBO J. 2025 Jul 23.
    Deletion of EP3 prostaglandin receptor in murine macrophages aggravates diet-induced obesity by suppressing SPARC.
    Wenlong Shang, Yinxiu Li, Lu Wang, Jiao Liu, Huiwen Ren, Qian Liu, Shumin Guo, Yuhong Wang, Yubo Ma, Tianyi You, Yujun Shen, Yu Zhou, Danyang Tian, Ying Yu.
      Macrophages are primary immune cells involved in obesity-triggered chronic low-grade inflammation in adipose tissues. Prostaglandin E2 (PGE2), mainly generated from macrophages, can regulate adipose tissue remodeling, yet the underlying mechanisms are not fully understood. Here, we observed that PGE2 receptor subtype 3 (EP3) was remarkably downregulated in adipose tissue macrophages from high-fat diet (HFD)-fed mice and patients with obesity. Notably, macrophage-specific deletion of EP3 exacerbated HFD-induced fat expansion, whereas EP3α isoform overexpression in macrophages alleviated obesity phenotypes. Further, EP3 deficiency suppressed secretion of anti-adipogenic matricellular protein SPARC from macrophages. SPARC deletion in macrophages abrogated the protection of EP3-overexpression against diet-induced obesity. Mechanistically, EP3 activation promoted SPARC expression by suppressing DNA methylation in macrophages through a PKA-Sp1-Dnmt1/3a signaling cascade. Finally, EP3 agonist treatment ameliorated HFD-induced obesity in mice. Thus, EP3 inhibits adipogenesis through promoting release of SPARC from macrophages, suggesting a novel therapeutic target for diet-induced obesity.
    Keywords:  E-prostanoid 3 Receptor; Macrophage; Obesity; SPARC
    DOI:  https://doi.org/10.1038/s44318-025-00508-y
  21. Microbiol Spectr. 2025 Jul 24. e0140425
    Gut microbiota-associated non-cholesterol sterol dysregulation modulates immune reconstitution during antiretroviral therapy in people living with HIV.
    Jingying Pan, Xuebin Tian, Kai Wu, Jia Ji, Mingqing Dong, Ting Sun, Dan Lv, Peng Yao, Longxian Lv, Hangping Yao.
      Non-cholesterol sterol metabolism plays a crucial role in immune regulation. However, the non-cholesterol sterol profiles, its association with gut dysbiosis, and its impact on the CD4+ T cell recovery in people living with HIV (PLWH) are yet to be elucidated. In this study, we recruited 37 PLWH and 50 healthy controls to characterize non-cholesterol sterol profiles and gut microbiota composition using targeted liquid chromatography-mass spectrometry and metagenomic analysis. Correlations between sterol profiles and immune cell subsets were assessed. In vitro peripheral blood mononuclear cell (PBMC) model was used to validate key findings. We identified a distinct dysregulation of non-cholesterol sterol metabolism in PLWH, characterized by elevated levels of cholesterol precursors and metabolites and depleted levels of plant sterols, which were linked to gut dysbiosis. Our study results highlighted Oscillibacter spp. as the key regulator of sterol metabolism. Specifically, plant sterols (e.g., brassicasterol and campesterol) were found to be associated with impaired CD4+ T cell recovery during antiretroviral therapy (ART). These findings were validated using ex vivo PBMC models, which revealed that brassicasterol stimulates T cell abnormal activation and pro-inflammatory cytokine release, whereas lathosterol dampens immune activation and inflammation. In summary, our study highlights the interplay between gut dysbiosis and sterol dysregulation in PLWH, demonstrating that higher brassicasterol levels impair immune recovery post-ART by promoting CD4+ T cell hyperactivation. Hence, targeting microbial sterol metabolism-through Oscillibacter spp. enrichment or plant sterol modulation-may offer novel therapeutic strategies to optimize ART outcomes by balancing immune activation and resolution.IMPORTANCEThis study is the first to integrate non-cholesterol sterol profiling with gut microbiota analysis in people living with HIV (PLWH), uncovering a unique sterol dysregulation characterized by elevated cholesterol precursors and depleted plant sterols in this population. We demonstrate that Oscillibacter spp. were associated with these metabolic shifts and that specific sterols differentially affect immune recovery: plant sterols such as brassicasterol impede CD4+ T cell restoration by promoting hyperactivation, whereas the cholesterol derivative lathosterol mitigates inflammation and supports immune reconstitution. These insights reveal novel microbiome-sterol interactions that can be leveraged to develop targeted microbiome- and sterol-based interventions aimed at enhancing antiretroviral therapy efficacy and long-term immune health in PLWH.
    Keywords:  gut microbiota; human immunodeficiency virus; immunological non-responders; immunological responders; non-cholesterol sterols
    DOI:  https://doi.org/10.1128/spectrum.01404-25
  22. Front Microbiol. 2025 ;16 1599691
    Tumor-associated bacteria activate PRDX1-driven glycolysis to promote immune evasion and PD-1 antibody resistance in hepatocellular carcinoma.
    Heng Zhang, Xi Lan, Liquan Cai, Xunfeng Gao, Feng Gao, Dan Yu, Jinlong Zhang, Jinhui Zhang, Qinwen Tai.
       Background: Recent studies have highlighted the presence of intratumoral bacteria in hepatocellular carcinoma (HCC), yet their contribution to immunotherapy resistance remains largely unexplored. This study investigates the mechanisms by which bacterial infection reshapes tumor metabolism to undermine the efficacy of anti-PD-1 therapy.
    Methods: We conducted 16S rRNA gene sequencing on 29 HCC clinical samples and integrated the data with single-cell RNA sequencing of 12,487 cells to map microbial, metabolic, and immune interactions within the tumor microenvironment. Functional validation was performed using orthotopic HCC mouse models (n = 8 per group), coupled with flow cytometry-based immune profiling.
    Results: Enrichment of Streptococcaceae was strongly associated with upregulation of key glycolytic enzymes (LDHA, PKM2; p < 0.001) and dysfunction of natural killer cells (reduced CD56dim/CD16bright populations; hazard ratio = 2.15, 95% CI: 1.34-3.42). Mechanistically, bacterial colonization induced peroxiredoxin 1 (PRDX1) expression via the NF-κB pathway. This led to excessive lactate production, which suppressed CD8+ T cell cytotoxicity (p = 0.003) and increased the expression of immune checkpoint molecules (TIM-3: 2.7-fold; LAG-3: 1.9-fold). In vivo, bacterial infection decreased the antitumor efficacy of PD-1 blockade by 43% (tumor volume vs. control; p = 0.008), an effect that was reversed upon PRDX1 inhibition.
    Conclusion: Our findings identify PRDX1 as a central node in bacteria-driven metabolic reprogramming that facilitates immune evasion and resistance to PD-1 therapy in HCC. These findings provide the first evidence linking intratumoral bacteria to PD-1 resistance via redox-regulated metabolism, proposing dual targeting of PRDX1 and gut microbiota as a novel combinatorial immunotherapy strategy.
    Keywords:  PD-1 antibody resistance; PRDX1/NF-κB signaling; bacterial infection; evasion; hepatocellular carcinoma; single-cell multiomics
    DOI:  https://doi.org/10.3389/fmicb.2025.1599691
  23. Front Immunol. 2025 ;16 1626973
    Regulation of dendritic cell biology by amino acids and their transporters.
    Shanlin Chen, Gongwei Li, Zihao Jiang, Yuekang Xu, Adila Aipire, Jinyao Li.
      Dendritic cells (DCs) play a central role in inducing both immunity and tolerance as specialized antigen-presenting cells (APCs). The immunometabolic firestorm in recent years has focused our attention on how DCs use energy and respond to nutritional changes that affect immune functions. Like in every other cell, such metabolic events as the concentration of free amino acids, membrane-bound transporter proteins, key metabolic enzymes, and sensors (e.g., mTOR and GCN2), also profoundly affect the function and fate of DCs. Therefore, dysregulation of amino acid metabolism can cause metabolic reprogramming of DCs, leading to or accelerating the occurrence of various immunological disorders, like type 1 diabetes, rheumatoid arthritis, and cancer. Since amino acids cannot directly enter the cell to participate in metabolic activities, their transporters act as critical metabolic gatekeepers. To catch up with the rapid development in the immune metabolism field, this review summarized recent studies on the potential roles of different amino acids and their transporters in the regulation of DCs biology to offer new insights for immune-dysregulated diseases and explore new therapeutic targets.
    Keywords:  amino acids; amino acids transporters; dendritic cells; immune response; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2025.1626973
  24. Immunity. 2025 Jul 12. pii: S1074-7613(25)00286-9. [Epub ahead of print]
    Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
    Marco Di Gioia, Valentina Poli, Piao J Tan, Roberto Spreafico, Anne Chu, Alex G Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L S M Gordts, Joseph L Witztum, Talal A Chatila, Janet Chou, Xu Zhou, James R Springstead, Ivan Zanoni.
      Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.
    Keywords:  ARDS; DAMP; PAMP; PRR; damage-associated molecular pattern; epigenetic; macrophages; pathogen-associated molecular pattern; pattern recognition receptor; sepsis
    DOI:  https://doi.org/10.1016/j.immuni.2025.06.017
  25. Immunohorizons. 2025 Jul 14. pii: vlaf028. [Epub ahead of print]9(8):
    Exogenous arginine differentially regulates inflammatory cytokine and inducible nitric oxide synthase expression in macrophages.
    Kelsey Stayer, Saliha Pathan, Aalekhya Biswas, Huiqiao Li, Yi Zhu, Fong Wilson Lam, Juan Marini, Sundararajah Thevananther.
      Immune dysfunction and late mortality from multiorgan failure are hallmarks of severe sepsis. Arginine, a semi-essential amino acid important for protein synthesis, immune response, and circulatory regulation, is deficient in sepsis. However, arginine supplementation in sepsis remains controversial due to the potential to upregulate inducible nitric oxide synthase (iNOS)-mediated excessive nitric oxide (NO) generation in macrophages, leading to vasodilation and hemodynamic catastrophe. Citrulline supplementation has been considered an alternative to replenishing arginine via de novo synthesis, orchestrated by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). However, the functional relevance of the ASS1-ASL pathway in macrophages after endotoxin stimulation is unclear but it is crucial to consider amino acid restoration as a tool for treating sepsis. We demonstrate that lipopolysaccharide (LPS)-mediated iNOS, ASS1, and ASL protein expression and nitric oxide generation were dependent on exogenous arginine in RAW 264.7 macrophages. Exogenous citrulline was not sufficient to restore nitric oxide generation in arginine-free conditions. Despite the induction of iNOS and ASS1 mRNA in arginine-free conditions, exogenous arginine was necessary and citrulline was not sufficient to overcome eIF2-α (elongation initiation factor 2-α)-mediated translational repression of iNOS and ASS1 protein expression. Moreover, exogenous arginine, but not citrulline, selectively modified the inflammatory cytokine and chemokine expression profile of the LPS-activated RAW 264.7 and bone marrow-derived macrophages. Our study highlights the complex, differential regulation of proinflammatory cytokine expression, and NO generation by exogenous arginine in macrophages.
    Keywords:  cell activation; cytokines; endotoxin shock; monocytes/macrophages; nitric oxide
    DOI:  https://doi.org/10.1093/immhor/vlaf028
  26. Nat Commun. 2025 Jul 23. 16(1): 6779
    Small intestinal γδ T17 cells promote SAE through STING/C1q-induced microglial synaptic pruning in male mice.
    Yuming Wu, Yujing Zhang, Yuan Yu, Xin Wang, Zifan Zhen, Yin Yuan, Bing Xie, Mengqi Han, Mengyuan Wang, Xinyu Zhang, Xueqiang Sun, Xiaoyue Wen, Kenji Hashimoto, You Shang, Shiying Yuan, Jiancheng Zhang.
      Sepsis is a severe global health issue with high mortality rates, and sepsis-associated encephalopathy (SAE) further exacerbates this risk. While recent studies have shown the migration of gut immune cells to the lungs after sepsis, their impact on the central nervous system remains unclear. Our research demonstrates that sepsis could induce the migration of IL-7Rhigh CD8low γδ T17 cells from the small intestine to the meninges, where they secrete IL-17A, impairing mitochondrial function in microglia and activating the cGAS-STING-C1q pathway in male mice. This process is accompanied by inhibited ubiquitination of STING at the K150 site, resulting in STING accumulation and increased release of C1q-tagged hippocampal synapses, which are subsequently pruned by activated microglia. Importantly, 4-octyl itaconate mitigates the excessive synaptic pruning by inhibiting γδ T17 cell migration and promoting STING ubiquitination, thereby alleviating SAE. Our findings suggest a potential mechanism of synaptic pruning by microglia via the cGAS-STING-C1q pathway, emphasize the critical role of gut-derived γδ T17 cell migration to the meninges in SAE, and highlight the importance of STING ubiquitination in modulating C1q-mediated excessive synaptic pruning.
    DOI:  https://doi.org/10.1038/s41467-025-62181-3
  27. JHEP Rep. 2025 Aug;7(8): 101488
    Myeloid TGF-β signaling shapes liver macrophage heterogeneity and metabolic liver disease pathogenesis.
    Ziyi Meng, Xiaoxue Qiu, Zhimin Chen, Yu-Tung Lee, Linkang Zhou, You Lu, Tongyu Liu, Siming Li, Benjamin Levi, Katherine A Gallagher, Jiandie D Lin.
       Background & Aims: Cellular heterogeneity of innate immune cells, such as macrophages, in the liver is a hallmark of metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis. However, the mechanisms shaping liver macrophage heterogeneity and function during disease progression remain poorly understood.
    Methods: Control or myeloid-specific Tgfbr1 knockout mice (n = 9-12 per group) were fed a 12-week choline-deficient, amino acid-defined high-fat diet (CDA-HFD) or a 20-week GAN diet (40% fat, 22% fructose, 2% cholesterol). Liver tissue was analyzed using histopathology, quantitative PCR, immunoblotting, flow cytometry, and RNA sequencing (RNA-seq). Bulk RNA-seq (n = 3 per group) and single-nucleus RNA-seq were performed to investigate transcriptional reprogramming. Macrophage population dynamics were evaluated by flow cytometry and immunofluorescence.
    Results: We identified TGF-β signaling as a crucial regulator of disease-associated expansion of Trem2+ and Fcrl5+ macrophages in MASH livers. Myeloid-specific inactivation of Tgfbr1 in mice exacerbated diet-induced MASH, with increased hepatocyte injury, inflammation, and liver fibrosis. Mechanistically, loss of TGF-β signaling in myeloid cells altered macrophage composition, marked by a reduction in Trem2+ and expansion of Fcrl5+ macrophages. Additionally, macrophages lacking Tgfbr1 exhibited gene signatures associated with inflammasome activation, cytokine signaling, cellular senescence, and immunosuppression. These changes in macrophage composition and function promoted effector T cell exhaustion and the development of MASH-associated hepatocellular carcinoma in Tgfbr1-deficient mice.
    Conclusions: These findings identify myeloid TGF-β signaling as a key driver of liver macrophage heterogeneity and polarization within the microenvironment during the progression of MASH and MASH-associated liver cancer.
    Impact and implications: Our study reveals that myeloid TGF-β signaling plays a crucial role in shaping liver macrophage heterogeneity, which in turn influences the pathogenesis of metabolic liver disease. These findings are particularly important for researchers studying immune-metabolic interactions and for clinicians seeking new therapeutic strategies for liver disorders. By elucidating how TGF-β signaling regulates macrophage function, our work paves the way for targeted interventions that modulate immune responses to improve liver health. Future research should consider the potential translational applications of these findings while addressing limitations related to model systems and human variability.
    Keywords:  HCC; MASH; Macrophage; TGF-beta; TREM2
    DOI:  https://doi.org/10.1016/j.jhepr.2025.101488
  28. Nat Immunol. 2025 Jul 22.
    T cells require mitochondria to proliferate, function and generate memory.
      
    DOI:  https://doi.org/10.1038/s41590-025-02226-3
  29. Exp Gerontol. 2025 Jul 16. pii: S0531-5565(25)00166-4. [Epub ahead of print] 112837
    Involvement of the tryptophan-kynurenine pathway in the pathogenesis of autoimmune diseases.
    A-Yuan Chen, Ying-Jie Zhao, Yue-Ye Wang, Wei Wei, Wei Hu, Yan Chang.
      The kynurenine pathway (KP), a major metabolic pathway for L-tryptophan (Trp) in mammals, plays a multifaceted role in various physiological processes, including neural activity, immune system regulation, and the maintenance of intestinal homeostasis. The functional connection between the KP and immune system is supported by robust evidence, including disease-associated alterations in KP metabolite concentrations and enzyme activities that correlate with immune function changes. Imbalances in the KP can be detrimental, as excessive production of pro- or anti-inflammatory metabolites may promote autoimmunity or impair pathogen defense. To date, KP enzymes and metabolites have been extensively studied as both promoters and therapeutic targets in a wide array of autoimmune diseases (AID). Pharmacological modulation of the KP represents a promising therapeutic strategy, as it can regulate immune responses and attenuate disease progression in AID. However, the precise cellular and molecular mechanisms by which the KP contributes to AID pathogenesis remain incompletely understood. This review explores the complex mechanisms through which KP enzymes and metabolites regulate inflammatory immune responses in AID, and highlights potential therapeutic targets for drug development.
    Keywords:  Autoimmune disease; Indoleamine 2,3-dioxygenase; Kynurenine pathway; Metabolism; Tryptophan; Tryptophan 2,3- dioxygenase
    DOI:  https://doi.org/10.1016/j.exger.2025.112837
  30. Dev Comp Immunol. 2025 Jul 19. pii: S0145-305X(25)00116-8. [Epub ahead of print]170 105427
    β-hydroxybutyrate restricts glycolytic metabolism in bovine neutrophils during toll-like receptor 2/1 stimulation.
    John Quiroga, Rafael Agustín Burgos, Claudio Henríquez, María Daniella Carretta, Pablo Alarcón, Bayron Cortés, Gabriel Morán.
      Ketosis commonly affects high-producing dairy cows during the peripartum and peak lactation periods and is associated with immunosuppression. Elevated blood levels of β-hydroxybutyrate (β-OHB), the primary ketone body, have been linked to impaired neutrophil bactericidal activity, potentially explaining the increased susceptibility to mammary and uterine infections. Since neutrophils primarily rely on glycolysis for energy, this study investigated the effects of high β-OHB concentration on the energy metabolism of bovine neutrophils stimulated with the toll-like receptor 2/1 (TLR2/1) agonist Pam3CSK4. At both subclinical (2.5 mM) and clinical (5.0 mM) ketosis concentrations, β-OHB strongly narrowed glycolytic flux and glycolytic ATP production in unstimulated cells, accompanied by reduced extracellular glucose uptake without changes in glycogen content. TLR2/1 stimulation robustly enhanced glycolysis and ATP production, upregulated glycolytic enzyme expression, promoted the translocation of glucose transporters (GLUTs) 1 and 3, boosted extracellular glucose uptake, and decreased glycogen concentration. These changes were accompanied by increased glycogen phosphorylase (PYGL) phosphorylation over glycogen synthase (GYS1) and the activation of protein kinase B (Akt), glycogen synthase kinase 3 beta (GSK3β), and protein kinase A (PKA) pathways. However, preincubation with 2.5 and 5.0 mM β-OHB attenuated these metabolic responses, reducing glycolytic flux, ATP production, glycolytic enzyme expression, GLUTs translocation, and extracellular glucose uptake, while glycogen stores remained stable. Notably, β-OHB did not impact the phosphorylation of PYGL, GYS1, GSK3β, or PKA substrate, but it did decrease Akt phosphorylation at 5.0 mM. These results suggest that elevated β-OHB concentrations restrict glycolytic metabolism in bovine neutrophils, compromising their bioenergetics and potentially contributing to impaired immune competence in ketotic dairy cows.
    Keywords:  Bovine neutrophils; Glycogen metabolism; Glycolysis; Toll-like receptor 2/1 (TLR2/1); β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.dci.2025.105427
  31. Mol Metab. 2025 Jul 22. pii: S2212-8778(25)00125-5. [Epub ahead of print] 102218
    Inhibition of pyrimidine de novo synthesis fosters Treg cells and reduces diabetes development in models of Type 1 Diabetes.
    Hannah Hipp, Camilla Tondello, Hanna Gmehling, Lena K Scholz, Antigoni Stavridou, Maike Becker, Anne-Marie Bührer, Edith Hintermann, Sandra M Dirschl, Till M Johannsmann, Martin G Scherm, Hella Kohlhof, Isabelle Serr, Urs Christen, Carolin Daniel.
       BACKGROUND: In autoimmune Type 1 Diabetes (T1D), aberrant immune activation promotes regulatory T cell (Treg) impairments thereby boosting progression of islet autoimmunity. Consequently, there is a progressive destruction of the insulin-producing beta cells in the pancreas. Controlling overshooting immune activation represents a relevant approach to allow for efficient Treg-targeting by broadening the window of opportunity to induce Tregs.
    METHODS: We investigated the effect of restricting pyrimidine de novo synthesis during islet autoimmunity and T1D by Dihydroorotate dehydrogenase (DHODH) inhibition using the next-generation DHODH inhibitor Vidofludimus calcium. We assessed Treg-inducing features of DHODH inhibition in T cells from ongoing murine islet autoimmunity and human T1D in vitro. To dissect the functional relevance of these observations, we tested the impact of DHODH inhibition on interfering with autoimmune activation and disease progression in pre-clinical models of T1D in vivo.
    MAIN FINDINGS: We show that DHODH inhibition results in enhanced Treg induction in vitro especially during increased immune activation and reduced T cell proliferation. In addition, Vidofludimus calcium reduced T1D incidence in two mouse models. On the cellular level, treated mice showed reduced T cell activation accompanied by increased Treg frequencies.
    CONCLUSIONS: We demonstrate that restricting pyrimidine de novo synthesis by next-generation DHODH inhibition is a strategy to interfere with autoimmune activation while fostering Tregs.
    Keywords:  Autoimmunity; DHODH inhibition; Immunomodulation; Mouse model; Regulatory T cells; Type 1 diabetes; Vidofludimus calcium
    DOI:  https://doi.org/10.1016/j.molmet.2025.102218
  32. J Cell Commun Signal. 2025 Sep;19(3): e70034
    UBD-mediated glycolytic reprogramming promotes M2 macrophage polarization in ovarian cancer immune evasion.
    Nana Zhang, Fengming Zhao, Hailong Chen, Juli Wang, Haiyan Li.
      Ovarian cancer (OC) is one of the most common malignant tumors in women, with immunotherapy resistance (ITR) being a major challenge. Glycolytic metabolic reprogramming has been shown to play a crucial role in the tumor immune microenvironment and immune evasion, yet the underlying mechanisms remain unclear. This study aims to investigate the role of Ubiquitin D (UBD) in OC immunotherapy, particularly its regulation of macrophage polarization through glycolytic metabolism. Using data from the Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases, combined with proteomics techniques, we analyzed the expression of UBD in OC tissues and its correlation with key glycolytic enzymes. Through lentiviral-mediated gene manipulation and in vivo mouse models, we evaluated the effects of UBD on macrophage polarization, glycolytic metabolism, and immunotherapy. The results indicate that UBD promotes M2 macrophage polarization through glycolytic reprogramming, enhancing immune evasion and ITR in OC. Inhibiting UBD or targeting glycolytic pathways may provide new strategies for improving OC immunotherapy.
    Keywords:  glycolytic metabolism; immunotherapy resistance; macrophage polarization; ovarian cancer; tumor microenvironment; ubiquitin D
    DOI:  https://doi.org/10.1002/ccs3.70034
  33. Biochem Biophys Res Commun. 2025 Jul 17. pii: S0006-291X(25)01093-9. [Epub ahead of print]778 152378
    A gain-of-function PIK3CD variant, R512W, impairs T cell function through polyamine-dependent metabolic dysregulation.
    Kyoko Kiyota, Hiroshi Shiraishi, Shiho Ohno, Yasuhiro Soga, Nobuyuki Shimizu, Hiroyuki Yatsuka, Masanori Inoue, Takashi Takeno, Wang Hongxia, Adiana Mutamsari Witaningrum, Reiko Hanada, Yoshiki Yamaguchi, Kenji Ihara, Toshikatsu Hanada.
      We previously reported a patient harboring a novel heterozygous phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) missense variant (p.R512W) who presented with autoimmune features including Kawasaki disease, immune thrombocytopenic purpura, and systemic lupus erythematosus, without the classical signs of immunodeficiency typically associated with activated PI3Kδ syndrome (APDS). To elucidate the molecular mechanisms underlying this phenotype, we conducted functional and structural analyses of the R512W variant. Overexpression of mutant human p110δ (R512W) in a murine T cell line resulted in increased PIP3 accumulation and AKT phosphorylation, consistent with a gain-of-function effect. However, T cells expressing R512W exhibited paradoxical dysfunction, including reduced IL-2 production, impaired proliferation, increased PD-1 expression, and apoptosis, which are hallmarks of a T cell exhaustion-like state. A transcriptomic analysis revealed downregulation of polyamine biosynthesis genes, such as Odc1, Amd1, and Smox, along with reduced intracellular polyamine levels. Supplementation of the culture medium with spermidine partially rescued the proliferative defects, suggesting reversible metabolic insufficiency. Structural modeling indicated that R512W may alter the conformation of the helical domain of p110δ, potentially contributing to its hyperactivation. Unlike canonical APDS-associated mutations, the R512W variant appears to uncouple PI3K hyperactivation from effective T cell responses, resulting in immune dysregulation through both signaling and metabolic pathways. This autoimmune-dominant phenotype underscores mutation-specific clinical heterogeneity within the PIK3CD-associated disease spectrum. These findings reveal a novel link between aberrant PI3K signaling and polyamine metabolism, and suggest that targeting metabolic pathways may hold therapeutic potential in select cases of PI3K-driven autoimmunity.
    Keywords:  APDS; PIK3CD; Polyamines; T cell; p110δ
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152378
  34. Trends Immunol. 2025 Jul 21. pii: S1471-4906(25)00163-2. [Epub ahead of print]
    Gut microbiota-host post-translational modification axis in immunometabolic diseases.
    Shuo Li, Yan Guo, Sanqi An, Liangpeng Ge, Jinming You, Wenkai Ren.
      Communication between the gut microbiota and host post-translational modifications (PTMs) has been extensively characterized, and recent evidence delineates a functionally integrated gut microbiota-host PTM axis. This axis is not only essential for maintaining metabolism homeostasis but also plays diverse roles in regulating disease pathogenesis. In this review we discuss the emerging effects of microbial modulation of host PTMs by regulating substrate provisioning and enzyme activity. We also highlight the latest understanding of diverse microbiota-regulated PTMs in immune cell fate decision. Finally, we summarize the current understanding of how dysbiosis-induced PTM dysregulation drives pathologies in inflammatory bowel disease (IBD), obesity-related diseases, rheumatoid arthritis (RA), chronic kidney disease (CKD), and colorectal cancer (CRC). We also propose targeted strategies to restore homeostasis through the microbiota-PTM axis.
    Keywords:  gut microbiota; immune cells; immunometabolic diseases; microbial metabolites; post-translational modifications
    DOI:  https://doi.org/10.1016/j.it.2025.06.006
  35. Acta Biochim Biophys Sin (Shanghai). 2025 Jul 22.
    LPS mediates cuproptosis and inflammation in THP-1 macrophages through HKDC1.
    Langlin Ou, Zitong Meng, Jian Mei, Hao Yuan, Xiangrui Zhu, Xiaoying Wang, Ao Shen, Zhaosi Wang, Lixin Zhang, Song Wang, Yingli Chen, Xiangming Pang, Yuxiang Liu, Yadong Xu, Cui Ma.
      Cuproptosis is a recently identified form of copper-driven cell death characterized by the aggregation of acylated proteins and proteotoxic stress in the mitochondrial tricarboxylic acid cycle, which plays a role in inflammation. Recent studies suggest that hexokinase structural domain protein 1 (HKDC1), a fifth hexokinase, is involved in regulating mitochondrial function. However, the role of HKDC1 in cuproptosis and LPS-induced macrophage inflammation remains unclear. Here, we assess macrophage plasticity using CCK8 viability assays and phagocytosis activity experiments in an in vitro inflammatory model of THP-1 cells. We measure the levels of inflammatory factors and cuproptosis-related proteins using western blot analysis and RT-qPCR. Additionally, we examine the expression and localization of the HKDC1 protein using ChIP-qPCR and immunofluorescence staining. We find that LPS promotes the expressions of inflammatory factors and decreases cuproptosis levels in THP-1-derived macrophages while also activating glycolysis and inducing the expression of HKDC1 via the Toll-like receptor 4 (TLR4) receptor. We further demonstrate that HKDC1 knockdown inhibits glycolysis and induces cuproptosis. Mechanistically, we provide the first evidence that LPS promotes the binding of Yin Yang 1 (YY1) to the HKDC1 promoter, thereby regulating HKDC1 transcription. HKDC1 interacts with heat shock cognate B (HSCB) and ferredoxin 1 (FDX1), leading to increased intracellular copper levels and subsequent cuproptosis. HKDC1 knockdown in vivo alleviates acute sepsis by activating copper-dependent cell death pathways. Collectively, our findings suggest that LPS mitigates cuproptosis and promotes inflammation via HKDC1, suggesting a new cuproptosis-dependent anti-inflammatory strategy.
    Keywords:  HKDC1; LPS; cuproptosis; glycolysis; inflammation
    DOI:  https://doi.org/10.3724/abbs.2025089
  36. J Nutr Biochem. 2025 Jul 16. pii: S0955-2863(25)00200-1. [Epub ahead of print] 110037
    Vitamin D3 supplementation ameliorates adipose tissue inflammation and adipocyte hypertrophy in type 2 diabetic mice through downregulation of RAGE and SREBP-1c.
    Yoon-Ah Kim, Minha Oh, Sohee Jung, Deok Hoon Kwon, Ga Young Lee, Sung Nim Han.
      Type 2 diabetes is characterized by chronic low-grade inflammation and insulin resistance resulting from activation and infiltration of immune cells into adipose tissue. Vitamin D reportedly exerts an anti-inflammatory effect by regulating immune cell activity and inflammatory cytokine production. This study aimed to investigate the effects of vitamin D supplementation on lymphoid and myeloid immune cell distribution in the adipose tissue and explore the mechanisms by which vitamin D modulates adipose tissue inflammation in diabetes. Five-week-old, male C57BLKS/J-m+/m+ (CON) and C57BLKS/J-db/db (DB) mice were fed diets containing either 1,000 or 10,000 IU vitamin D/kg diet for 8 weeks. Vitamin D supplementation resulted in a smaller weight gain (33.8% lower), less adipocyte hypertrophy (16.9% lower), and a lower fasting blood glucose concentration (7.4% lower) in DB group. Vitamin D supplementation did not inhibit macrophage and dendritic cell infiltration into adipose tissue; nonetheless, it reduced the percentage of CD8+ T cells (18% lower). In DB group, vitamin D supplementation downregulated the gene expression of interleukin 6 (Il6) and C-C motif chemokine ligand 2 (Ccl2) in stromal vascular cells (28.2% and17.3% lower, respectively) as well as that of Il6, Ccl2, sterol regulatory element-binding transcription factor 1(Srebf1), and advanced glycosylation end product-specific receptor (Ager) in adipose tissue (42.8%, 24.9%, 33.1%, and 58.2% lower, respectively). In conclusion, vitamin D supplementation attenuated the inflammatory response and adipocyte hypertrophy in adipose tissue from diabetic mice. The inhibition of Ager and Srebf1 by vitamin D supplementation potentially contributes to vitamin D's inflammatory and anti-adiposity effects in diabetic mice.
    Keywords:  RAGE; Type 2 diabetes; adipocyte hypertrophy; adipose tissue; inflammatory responses; vitamin D
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.110037
  37. Commun Biol. 2025 Jul 23. 8(1): 1093
    Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans.
    Xianghong Zhang, Jianguo Lin, Baobo Zou, Jack R Killinger, Andrew C Sayce, Thiagarajan Meyyappan, Zeyu Xiong, Melanie J Scott, Janet S Lee, Matthew R Rosengart.
      Survivors of sepsis suffer from an elevated risk of premature death that is not explained by a higher burden of chronic diseases prior to the infection. Nearly 1 out of 4 survivors have persistent elevations of inflammation biomarkers, such as interleukin (IL) 6. These observations suggest that sepsis imparts durable changes to organismal biology. Eukaryotic life depends upon ATP and calcium (Ca2+). During sepsis, mitochondrial dysfunction, a failure of Ca2+ homeostasis, and sustained elevations in cytosolic [Ca2+] occur. These insults may serve as sufficient pressure to select for cells uniquely able to adapt. In this study of murine and human sepsis survivors, we observe that sepsis induces in lymphoid tissues a restructuring of the mitochondrial calcium uniporter (MCU) complex: the critical channel mediating the electrophoretic uptake of Ca2+ into the mitochondrion. We show these changes persist after clinical resolution of sepsis and lead to alterations in mitochondrial Ca2+ regulation, Ca2+ signaling, oxidative metabolism, and sensitivity to programmed cell death pathways. These biochemical changes manifest as fundamental alterations in phenotype: i.e., heightened systemic IL-6 concentration. Inhibiting lysosomal pathways partially restores the MCU complex stoichiometry, mitochondrial Ca2+ homeostasis, and lymphoid tissue phenotype to a sepsis naïve state.
    DOI:  https://doi.org/10.1038/s42003-025-08475-0
  38. EMBO Mol Med. 2025 Jul 23.
    JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation.
    Fran Prenen, Leen Vandermosten, Sofie Knoops, Emilie Pollenus, Hendrik Possemiers, Pauline Dagneau de Richecour, Giorgio Caratti, Christopher Cawthorne, Sabine Vettorazzi, Yevva Cranshoff, Dominique Schols, Sandra Claes, Christophe M Deroose, Uwe Himmelreich, Jan Tuckermann, Philippe E Van den Steen.
      Disease tolerance is a key defense mechanism that limits damage to the host without directly reducing pathogen levels. In malaria, these mechanisms are essential for preventing severe disease and death but remain poorly understood. In this study, we show that glucocorticoid receptor (GR)-mediated processes play a vital role in disease tolerance during Plasmodium chabaudi AS infection. GR deletion in infected mice resulted in lethal hypoglycemia and a cytokine storm. Hypoglycemia was driven by severe metabolic dysfunction in the liver and spleen, characterized by increased glucose uptake, glycogen depletion, a dominant glycolytic profile and reduced gluconeogenic gene expression. Importantly, this hypoglycemic state was strongly associated with overactivation of the JAK/STAT pathway and excessive cytokine expression. Treatment with the JAK1/2 inhibitor ruxolitinib significantly improved survival by preventing lethal hypoglycemia and suppressing hyperinflammation. Our findings reveal a novel link between GR signaling, STAT3 activation, cytokine expression and glucose metabolism during severe malaria. This underscores the critical role of GR-mediated processes in disease tolerance and highlights ruxolitinib as a promising adjuvant therapy for managing life-threatening metabolic complications in malaria.
    Keywords:  Glucocorticoid Receptor; Hypoglycemia; Malaria; Ruxolitinib; Tolerance
    DOI:  https://doi.org/10.1038/s44321-025-00264-w
  39. Cell. 2025 Jul 12. pii: S0092-8674(25)00735-4. [Epub ahead of print]
    Regulation of inflammatory responses by pH-dependent transcriptional condensates.
    Zhongyang Wu, Scott D Pope, Nasiha S Ahmed, Diana L Leung, Yu Hong, Stephanie Hajjar, Cathleen Krabak, Zhe Zhong, Krishnan Raghunathan, Qiuyu Yue, Diya M Anand, Elizabeth B Kopp, Daniel Okin, Weiyi Ma, Ivan Zanoni, Jonathan C Kagan, Jay R Thiagarajah, Diana C Hargreaves, Ruslan Medzhitov, Xu Zhou.
      Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here, we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as an intracellular pH sensor. Acidic pH disrupts transcription condensates containing BRD4 and MED1 via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.
    Keywords:  BRD4; IDR; acidosis; gene expression; histidine; inflammatory response; innate immunity; macrophage; pH; transcriptional condensates
    DOI:  https://doi.org/10.1016/j.cell.2025.06.033
  40. Nat Commun. 2025 Jul 23. 16(1): 6770
    Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma.
    Tianhao Chu, Guiqi Zhu, Zheng Tang, Weifeng Qu, Rui Yang, Haiting Pan, Yi Wang, Ruilin Tian, Leilei Chen, Zhiqi Guan, Yichao Bu, Qianfu Zhao, Jiafeng Chen, Shengwei Mao, Yuan Fang, Jun Gao, Xiaoling Wu, Jian Zhou, Weiren Liu, Dan Ye, Jia Fan, Yinghong Shi.
      The functional programs adopted by cancer cells and their impact on the tumor microenvironment are complex and remain unclear. Here, we identify three distinct single-cell archetypes (i.e. metabolism, stemness and inflammation) in hepatocellular carcinoma (HCC) cells, each exhibiting unique spatial distribution. Further analysis shows an immune-suppressive niche populated by metabolism archetype cancer cells and TREM2-positive tumor-associated macrophages (TREM2+ TAMs), which exacerbates immune exclusion and compromises patient outcomes. Mechanistically, we demonstrate that the upregulated squalene epoxidase (SQLE) expression in metabolism archetype cancer cells facilitates the generation of oxidized LDL (oxLDL). OxLDL induces TREM2+ TAM polarization through the TREM2-SYK-CEBPα axis, enabling these TAMs to promote cancer cell invasion, resistance to effector cytokines and CD8+ T cell dysfunction. Importantly, cancer cell-intrinsic SQLE and TREM2+ TAMs are associated with inferior immunotherapy response in human and mouse HCC. Our results highlight an oxLDL-mediated metabolic interplay between cancer cells and TREM2+ TAMs, offering a promising therapeutic avenue for HCC immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-025-62132-y
  41. Atherosclerosis. 2025 Jul 17. pii: S0021-9150(25)01343-7. [Epub ahead of print]408 120445
    Itaconate alleviates cholesterol burden via ABCA1 stabilization and cholesterol efflux.
    Natalie E Hong, Anastasia M Ravodina, Courteney Asase, Huiyun Gao, Olga A Cherepanova, Andrei Maiseyeu.
       BACKGROUND AND AIMS: Itaconate (ITA) is a metabolite produced from the tricarboxylic acid cycle (TCA) that has been shown to regulate atherosclerotic plaque growth and induce stability via immunomodulation. However, lipid metabolism regulation by ITA is currently underexplored in atherosclerosis. Here, we take advantage of plaque-targeting ITA-conjugated nanoparticles (ITA-LNPs) to investigate the effects of ITA on regulating lipid metabolism in foam cells/macrophages in atherosclerosis via ABCA1 stabilization and increased triglyceride metabolism.
    METHODS: Apoe-/- mice were fed a high-cholesterol/high-fat diet (HCHFD) for 12 weeks and injected once weekly with 50 mg/kg ITA-LNP or Ctrl-LNP. Aortas were tested for ITA-LNP biodistribution, followed by quantification of atherosclerotic plaque burden. Bone marrow-derived macrophages (BMDMs) or RAW 264.7 cells were treated with ITA-LNP or Ctrl-LNP in the presence of oxLDL, acLDL, or free cholesterol to investigate ITA's actions on lipid metabolism, Abca1 expression, and ABCA1 stability under a variety of conditions, including stable gene knockdown.
    RESULTS: ABCA1 was significantly upregulated with ITA-LNP treatment compared to Ctrl-LNP both in vivo and in vitro at the protein level, but not at the transcriptional level. ITA-LNPs were shown to prevent ABCA1 decay via the HO-1-calpain axis, resulting in significantly increased cholesterol efflux in macrophages. This was further confirmed in RAW 264.7 cells with a stable HO-1 knockdown. Additionally, ITA decreased lipid burden in conjunction with increased expression of Slc25a1 in ITA-LNP-treated BMDMs, suggesting enhanced fatty acid-derived citrate shuttling and increased fatty acid metabolism.
    CONCLUSIONS: ITA-LNPs regulate lipid metabolism in atherosclerosis by inducing triglyceride catabolism and cholesterol efflux.
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2025.120445
  42. Cell. 2025 Jul 17. pii: S0092-8674(25)00751-2. [Epub ahead of print]
    The essential host genome for Cryptosporidium survival exposes metabolic dependencies that can be leveraged for treatment.
    N Bishara Marzook, Ok-Ryul Song, Lotta Baumgärtel, Netanya Bernitz, Tapoka T Mkandawire, Lucy C Watson, Vanessa Nunes, Scott Warchal, James I MacRae, Michael Howell, Adam Sateriale.
      Cryptosporidium is a leading cause of diarrheal disease, yet little is known regarding the infection cell biology of this intracellular intestinal parasite. To this end, we implemented an arrayed genome-wide CRISPR-Cas9 knockout screen to microscopically analyze multiple phenotypic features of a Cryptosporidium infection following individual host gene ablation. We discovered parasite survival within the host epithelial cell hinges on squalene, an intermediate metabolite in the host cholesterol biosynthesis pathway. A buildup of squalene within intestinal epithelial cells creates a reducing environment, making more reduced glutathione available for parasite uptake. Remarkably, the Cryptosporidium parasite has lost the ability to synthesize glutathione and has become dependent on this host import. This dependency can be leveraged for treatment with the abandoned drug lapaquistat, an inhibitor of host squalene synthase that shifts the redox environment, blocking Cryptosporidium growth in vitro and in vivo.
    Keywords:  CRISPR-Cas9; Cryptosporidium; ROS; V-ATPase; actin; cholesterol; glutathione; host-pathogen; parasite; squalene
    DOI:  https://doi.org/10.1016/j.cell.2025.07.001
  43. Mol Nutr Food Res. 2025 Jul 22. e70174
    Postprandial Metabolism, Inflammation, and Plasma Bile Acid Kinetics in a Rat Model: Implications for Translational Research.
    Larissa Rodrigues, Carlos M Donado-Pestana, Tushar More, Mar Garcia-Aloy, Gustavo M Carneiro de Lima, Lucas X Martins de Oliveira, Urska Vrhovsek, Karsten Hiller, Jarlei Fiamoncini.
      The postprandial period is an opportunity window to assess metabolic phenotype, and its study is gaining popularity due to the wealth of information that can be uncovered when a dietary challenge is associated with the application of metabolomics approaches. Bile acids (BA) were recently identified as signaling molecules that display major changes in circulating levels following food intake. In this regard, a gap of information remains linking BA postprandial kinetics with their possible metabolic effects. This study aimed to characterizing a murine model for investigating postprandial metabolism and inflammation. Changes in plasma and hepatic markers of metabolism, inflammation and BA levels were assessed in male Sprague-Dawley rats before and after the ingestion of an energy-dense meal. Rats display postprandial alterations in circulating BA levels, with cholic acid constituting the predominant species (36%). These changes are accompanied by shifts in intermediates of energy metabolism and inflammatory markers, as demonstrated by a four-fold increase in hepatic NF-κB protein content, a key inflammatory transcription factor, two hours after food intake. Despite inherent species-specific differences, this murine model represents a promising tool for studying postprandial modulation energy metabolism, establishing a pioneering framework for future investigations into the role of BA in postprandial metabolic responses.
    Keywords:  bile acids; dietary challenge; inflammation; metabolomics; nutritional physiology; postprandial metabolism
    DOI:  https://doi.org/10.1002/mnfr.70174
  44. ACS Nano. 2025 Jul 21.
    Activating Mitochondrial Complex I by Polyphenol Nanoparticle to Inhibit Hypoxia-Inducible Factor-1 Subunit α for Immunotherapy.
    Ruiling Xu, Mingda Zhao, Yuedi Yang, Xiaowen Han, Xiang Ren, Gongbing Liu, Hailong Wang, Jie Liang, Aiping Tong, Xingchen Peng, Yujiang Fan, Yong Sun.
      Mitochondrial respiratory dysfunction accelerates the conversion of cellular oxidative phosphorylation into malignancy-dependent glycolysis to enhance tumor immune escape. Here, engineering PEGylated epigallocatechin gallate nanoparticles (PE-NPs) in injectable hyaluronan gels upregulated oxidative phosphorylation by activating mitochondrial complex I of B16F10 cells, which greatly increased NAD+ level, a NADH oxidation product catalyzed by complex I, to inhibit hypoxia-inducible factor-1 expression. The immunomodulatory effect of PE-NPs was confirmed by the simultaneous downregulation of the MAPK, PI3K-AKT/mTOR pathways, and PD-L1 protein expression. Surgical resection, paraneoplastic administration, and distal metastasis models confirmed that PE-NPs significantly suppressed tumor recurrence, growth, and metastasis. It also promoted a systemic immune response by increasing CD8+ T cell differentiation, reducing CD4+ regulatory T cells in melanoma, promoting splenic dendritic cell maturation, and improving memory T cell differentiation. A synergistic approach using PE-NPs with PD-1/PD-L1 inhibitors significantly enhanced immune efficacy, confirming the feasibility of activating mitochondrial complex I boosts oxidative phosphorylation to potentiate melanoma immunotherapy as an effective strategy.
    Keywords:  hypoxia-inducible factor-1; immunotherapy; mitochondrial complex I; oxidative phosphorylation; oxidized nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.1021/acsnano.5c03547
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