bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–06–14
forty-nine papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Pro- and Anti-Inflammatory Macrophages Adjust UCP2 Protein Levels Based on Their Intrinsic Metabolism and Available Metabolites.
  2. Sleeve Gastrectomy Is Associated with Improved Systemic Redox Homeostasis in T2DM Through Ghrelin-GHSR Attenuation, POMC Neuronal Modulation, and CD4+ T Cell Metabolic Reprogramming.
  3. Cysteine's metabolic fork: Sulfur partitioning shapes T cell function.
  4. STING-associated metabolic changes engage AMPK to amplify interferon signaling in Listeria-infected macrophages.
  5. Cholesterol metabolism in immune cells: From mechanisms to therapeutic opportunities.
  6. Met-Vision reveals coexisting energetic states in tissue macrophages redistributed by inflammation.
  7. Macrophage immunometabolism in stroke: a view from single-cell and nano technologies.
  8. Neutrophil immunometabolism in ACLF and sepsis: mechanisms, dysfunction, and therapeutic opportunities.
  9. Immune regulation and cell metabolism in B cell subsets in patients with systemic lupus erythematosus.
  10. m6A-Mediated Glycolysis by IL-37 Drives T Cell Metabolic Reprogramming to Regulate Colitis.
  11. Lactate acts as a metabolic brake on inflammation by repressing NLRP3 transcription via NF-κB inhibition.
  12. β-Hydroxybutyric acid impairs host antimicrobial defense by targeting the CEACAM1-NADPH-ROS axis to disrupt macrophage bactericidal activity.
  13. Metabolic Reprogramming of T Cells by MSCs Rebalances Th17/Treg Axis to Attenuate Collagen-Induced Arthritis.
  14. DNA sensing and regulation of lipid metabolism.
  15. The immune-cardiovascular metabolic circuitry in myocardial ischemia-reperfusion injury: from metabolic signal release to spatiotemporal reprogramming.
  16. Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
  17. Metabolic Regulation of Immune Responses: Molecular Mechanisms, Diseases, and Therapeutic Targets.
  18. In vitro generation of RORγt+ regulatory T cells reveals enhanced immunosuppressive function and OXPHOS-dependent metabolism.
  19. Harnessing the glycolysis-TCA cycle axis to boost host defense against neonatal infection.
  20. Dietary tryptophan supplementation prevents sepsis by enhancing macrophage bacterial defense through GPR37 activation.
  21. Lactic Acid Promotes TNBC Lung Metastasis via TGF-β/Smad-Driven Lipid Metabolic Toxicity and NK Cell Dysfunction.
  22. Intermittent fasting alleviates ulcerative colitis via lithocholic acid-mediated macrophage reprogramming.
  23. The circadian clock component BMAL1 enhances macrophage inflammation by nuclear translocation of peroxisomal β-oxidation enzyme MFP2.
  24. FABP4 Disrupts Redox Homeostasis Through GOT2 Interaction to Drive Macrophage Mitochondrial Lipid Metabolic Reprogramming in Atherosclerosis.
  25. Quercetin targets BCAT1 to potentiate CD8+ T cell immunity by rewiring branched-chain amino acid metabolism against colorectal cancer metastasis.
  26. Cholera-toxin-induced disease generates epithelial-cell-derived L-lactate that promotes Vibrio cholerae growth in the small intestine.
  27. Mitochondrial remodeling by lithium drives CD4+ naïve T cell fate and immune homeostasis in bipolar disorder.
  28. Targeting TMED4 enhances CD8+ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis.
  29. VSIG4 suppresses antitumor T cell immunity via the SLC3A2-dependent metabolic-ionic checkpoint.
  30. Aerobic Exercise attenuates airway inflammation in allergic asthma by regulating M2 macrophage polarization via drp1-mediated mitophagy.
  31. Bilirubin mitigates ischemic white matter injury by targeting transferrin-receptor-mediated B cell immunometabolism.
  32. Erucic acid aggravates cardiac fibrosis after myocardial infarction by CD36-mediated metabolic reprogramming with impaired mitochondrial aerobic oxidation.
  33. The McbR transcription factor links the intracellular folate pool to virulence in enterohemorrhagic Escherichia coli.
  34. The kynurenine pathway: an immunometabolic bridge linking systemic inflammation to neuroaxonal vulnerability in multiple sclerosis.
  35. Curcumin Inhibits Renal Fibrosis by Suppressing S100A8/A9-TLR4 Signaling via Gut Microbiota-Derived Short-Chain Fatty Acid in Macrophages.
  36. Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation.
  37. Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet-induced obesity.
  38. Metabolic Mechanisms of Neutrophil Phagocytic Activity in Patients with Widespread Purulent Peritonitis Bacterial Peritonitis Before and After Surgery.
  39. Critical illness expands a transcriptionally distinct hypometabolic CD8 + T effector program associated with respiratory failure and mortality.
  40. Bioelectric signaling as an emerging layer of macrophage communication.
  41. Elemental selenium activates GPX1 to reprogram NK cell lipid metabolism and restores antitumor immunity.
  42. GPR84 blockade in macrophages mitigates sepsis-induced liver injury via PPARα-driven metabolic reprogramming and M2 polarization.
  43. Infection-induced glucose starvation triggers NINJ1-dependent macrophage lysis and Candida escape.
  44. The Glutamate-Glutamine Axis in Pediatric Septic Shock: Immunometabolic Mechanisms, Biomarker Potential, and Clinical Implications.
  45. Carboxylesterase 1 contributes to the human macrophage alternative activation response to Th2 cytokine interleukin-4.
  46. LDL receptor-mediated lipoprotein uptake fuels human CD4+ T cell polarization toward a c-MAF/IL-10- and FOXP3-driven phenotype.
  47. Single-plate Runs of Mito Stress And Glycolysis Stress Tests using Adherent or Non-Adherent Cells.
  48. Natural killer cell-mediated immunosurveillance modulates liver cancer evolution through cancer stemness enhancement and lipid metabolism reprogramming.
  49. The Legionella pneumophila type IVb secretion system effector BinA subverts amino acid transport to sensitize TORC1 signaling in macrophages.
  1. Eur J Immunol. 2026 Jun;56(6): e70218
    Pro- and Anti-Inflammatory Macrophages Adjust UCP2 Protein Levels Based on Their Intrinsic Metabolism and Available Metabolites.
    Jila Nasirzade, Felix Sternberg, Andrea Vogel, Roko Sango, Taraneh Beikbaghban, Thomas Kolbe, Thomas Rattei, Thomas Weichhart, Elena E Pohl.
      The immune and metabolic responses of macrophages are closely linked. Mitochondrial uncoupling protein 2 (UCP2), proposed to facilitate metabolite transport, is involved in regulating inflammation and glucose metabolism in macrophages. However, its significance and regulatory mechanism in subsets of macrophages with distinct metabolic profiles remain unclear. In this study, we demonstrate that under physiological nutrient conditions, inflammatory stimuli in classically activated macrophages (via LPS) reduce UCP2 expression in line with decreased oxygen consumption rates, indicating mitochondrial suppression. In contrast, alternatively activated macrophages (via IL4) displayed higher UCP2 levels and enhanced respiration. Under glucose deprivation, LPS-stimulated macrophages retained mitochondrial activity despite lower UCP2 levels. Blocking pyruvate entry into the mitochondria reduced UCP2 expression, highlighting the connection between glycolysis and mitochondrial metabolism. Mimicking the hypoxic milieu characteristic of LPS-activated macrophages through CoCl2 treatment of IL-4-activated macrophages resulted in decreased UCP2 expression, suggesting that hypoxia broadly mediates UCP2 suppression in macrophages. Overall, our findings suggest that UCP2 protein levels are modulated by metabolic alterations in macrophages, with pyruvate acting as a key regulator of UCP2 abundance. This emphasizes the importance of UCP2 in linking glycolysis with mitochondrial metabolism, providing insights for developing therapeutic strategies for diseases involving immunometabolic dysregulation.
    Keywords:  RAW 264.7 cells; SLC25A8; UK5099; cobalt chloride; extracellular acidification rate; glycolysis; oxygen consumption rate; tissue‐resident macrophages
    DOI:  https://doi.org/10.1002/eji.70218
  2. Antioxid Redox Signal. 2026 Jun 08. 15230864261455465
    Sleeve Gastrectomy Is Associated with Improved Systemic Redox Homeostasis in T2DM Through Ghrelin-GHSR Attenuation, POMC Neuronal Modulation, and CD4+ T Cell Metabolic Reprogramming.
    Xin Li, Ren-Yi Zhang, Wei-Hui Liu.
       OBJECTIVE: Sleeve gastrectomy (SG) improves obesity-associated type 2 diabetes mellitus (T2DM) beyond mere weight loss. We investigated whether SG enhances systemic metabolic homeostasis by suppressing the Ghrelin-growth hormone secretagogue receptor (GHSR) axis, remodeling hypothalamic pro-opiomelanocortin (POMC) neuronal activity, and reprogramming CD4+ T cell immunometabolism.
    METHODS: Using a diet-induced T2DM mouse model undergoing SG or Sham surgery, we integrated bulk/single-cell RNA sequencing and metabolomics to evaluate systemic neuro-immune-metabolic alterations. Functional assays validated Ghrelin's effects on CD4+ T cell metabolism and differentiation, alongside assessments of hepatic/pancreatic function and hypothalamic neuronal activity.
    RESULTS: SG globally remodeled peripheral immunity, expanding Tregs while reducing pro-inflammatory Th17 cells. scRNA-seq and metabolomic profiling revealed that CD4+ T cells shifted metabolically from glycolysis toward oxidative phosphorylation, matching increased tricarboxylic acid cycle intermediates. Functionally, Ghrelin-GHSR signaling promoted CD4+ T cell glycolysis, mitochondrial damage, and Th17 skewing; GHSR antagonism successfully reversed these detrimental effects. Systemically, SG reduced hyperglycemia and hepatic lipidosis, restored islet α/β-cell balance, activated anorexigenic POMC neurons, and suppressed AgRP neurons.
    CONCLUSION: SG alleviates T2DM through coordinated suppression of the Ghrelin-GHSR axis, bridging central appetite regulation with peripheral immunometabolic reprogramming. By shifting CD4+ T cells toward oxidative metabolism and restoring the Treg/Th17 balance, SG drives systemic metabolic recovery, providing critical molecular insights into the neuro-immune mechanisms of metabolic surgery. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  CD4+ T cells; Ghrelin–GHSR signaling axis; POMC neurons; immune homeostasis; multiomics integration; sleeve gastrectomy
    DOI:  https://doi.org/10.1177/15230864261455465
  3. Cell. 2026 Jun 11. pii: S0092-8674(26)00570-2. [Epub ahead of print]189(12): 3506-3508
    Cysteine's metabolic fork: Sulfur partitioning shapes T cell function.
    Melanie Grusdat, Dirk Brenner.
      T cells live or die by their metabolism, yet one nutrient can serve very different ends. In this issue of Cell, Kelly et al. show that cysteine's sulfur is partitioned between glutathione and iron-sulfur cluster synthesis. This routing drives CD8+ T cell proliferation, effector function, and anti-tumor immunity.
    DOI:  https://doi.org/10.1016/j.cell.2026.05.011
  4. Biochim Biophys Acta Mol Cell Res. 2026 Jun 11. pii: S0167-4889(26)00070-4. [Epub ahead of print] 120172
    STING-associated metabolic changes engage AMPK to amplify interferon signaling in Listeria-infected macrophages.
    Shukun Chen, Xiao Wang, Zhuoyu Duan, Min Wang, Xiaoya Qu, Jiayue Li, Jinglei Xia, Yang Xu, Lei Xu.
      Innate immune activation is tightly coupled to metabolic remodeling, yet how STING-associated signaling intersects with macrophage metabolism during bacterial infection remains incompletely understood. Here, using Listeria monocytogenes infection models, we show that infection is accompanied by increased glycolytic gene expression, glucose consumption, and lactate production in macrophages, and that STING deficiency attenuates these metabolic changes, whereas cGAS deficiency has a comparatively limited effect under our experimental conditions. Reduced glucose availability, 2-deoxy-d-glucose, and metformin enhanced AMPK activation, TBK1 phosphorylation, and IFN/ISG transcription, whereas Compound C treatment or Prkaa1 knockdown attenuated this enhancement. STING deficiency or acute STING inhibition reduced infection-associated glucose metabolic responses and limited the amplification of type I interferon-response gene expression under metabolic stress. Although the upstream mechanism by which STING regulates glucose metabolism remains to be fully defined, our findings support a model in which STING-associated metabolic changes and AMPK activity cooperate to enhance infection-induced interferon signaling during Listeria monocytogenes infection.
    Keywords:  AMPK; Glycolysis; Listeria monocytogenes; STING; Type I interferon
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120172
  5. Immunity. 2026 Jun 09. pii: S1074-7613(26)00218-9. [Epub ahead of print]59(6): 1493-1511
    Cholesterol metabolism in immune cells: From mechanisms to therapeutic opportunities.
    Mingyang Yin, Tao Liang, Yumeng Zhang, Guangchuan Wang, Wei Yang, Chenqi Xu.
      All immune cells engage in cholesterol metabolism, which generates a spectrum of bioactive metabolites that mainly include cholesterol itself, its biosynthetic intermediates, and oxidized or sulfated derivatives. These metabolites regulate not only cellular metabolism but also immune signaling. In addition, several functional proteins within cholesterol metabolic pathways exert non-canonical signaling functions that shape immune cell responses. Distinct immune cell types adopt specialized cholesterol metabolic programs tailored to their functional demands, and these programs are further influenced by physiological factors such as diet and aging. In human disease, immune cell cholesterol metabolism is frequently dysregulated, which highlights metabolic intervention as a promising therapeutic strategy. Accordingly, the repurposing of established metabolic drugs such as statins and PCSK9 inhibitors is gaining momentum, alongside the identification of additional therapeutic targets. A deeper understanding of how cholesterol metabolism governs immune responses will advance fundamental immunology and accelerate the development of next-generation immunotherapies.
    Keywords:  cholesterol metabolism; human diseases; immune cells; metabolic reprograming; therapeutic strategies
    DOI:  https://doi.org/10.1016/j.immuni.2026.05.007
  6. J Cell Biol. 2026 Aug 03. pii: e202603170. [Epub ahead of print]225(8):
    Met-Vision reveals coexisting energetic states in tissue macrophages redistributed by inflammation.
    Adriana Lecourieux, Margot Bardou, Zacarias Garcia, Philippe Bousso.
      The function of tissue-associated macrophages is tightly linked to their energy metabolism. Yet, the diversity of macrophage metabolic profiles coexisting in tissues at homeostasis or during immune challenges is incompletely understood. Here, we introduce Met-Vision, an imaging-based pipeline for single-cell functional profiling and classification of energy metabolism. Across multiple tissue contexts, we identified that macrophages do not adopt a uniform metabolic profile but typically coexist in four discrete metabolic states with distinct dependence on OXPHOS and metabolic plasticity. Inflammation reconfigured the distribution of macrophage metabolic profiles that remained heterogeneous. Notably, inflammation-derived nitric oxide finely tuned the distribution of macrophage energetic states. These findings challenge the view of homogeneous metabolic activation and reveal a layer of metabolic diversity in tissue at steady state and during inflammation. The ability to stratify macrophage energy metabolic profiles with Met-Vision should help guide the development of metabolism-targeted therapies for inflammatory diseases, cancer, and metabolic disorders.
    DOI:  https://doi.org/10.1083/jcb.202603170
  7. J Transl Med. 2026 Jun 13.
    Macrophage immunometabolism in stroke: a view from single-cell and nano technologies.
    Yajun Zhu, Zichao Huang, Xiaoguo Li, Jiru Zhou, Xingwei Lei, Fuming Liang, Jin Yan, Hongji Deng, Xiaochuan Sun, Zongduo Guo.
       BACKGROUND: Stroke induces profound neuroinflammation in which macrophages play a complex dual role, contributing to both injury and repair. The traditional M1/M2 classification is increasingly recognized as oversimplified. Advances in single-cell RNA sequencing (scRNA-seq) have revealed a spectrum of dynamic macrophage subpopulations with distinct functional and metabolic states, fundamentally reshaping our understanding of post-stroke immunity.
    MAIN BODY: This review synthesizes recent insights into macrophage heterogeneity from a single-cell perspective, highlighting novel subsets such as an LCP1⁺ population defined by coupled glycolipid metabolism. We discuss how metabolic reprogramming, including glycolysis, oxidative phosphorylation, cholesterol metabolism, hypoxia‑driven gradients, and mitochondrial dynamics, critically underpins macrophage polarization. Glycolysis fuels pro-inflammatory (M1-like) responses, whereas oxidative phosphorylation and fatty acid oxidation support anti-inflammatory and reparative (M2-like) functions. We further explore innovative nano‑therapeutic strategies, including engineered liposomes, exosomes, and responsive polymeric nanoparticles, that enable spatiotemporally precise modulation of macrophage activity. Based on these advances, we propose an integrative framework that directly links scRNA‑seq‑defined macrophage subsets to their metabolic pathways, druggable targets, and tailored nano‑interventions. We also critically examine clinical translation barriers and prioritize actionable targets (e.g., CCR2, PPARγ, Nrf2) for future stroke therapy.
    CONCLUSIONS: The convergence of single‑cell genomics, immunometabolism, and nanotechnology offers a transformative path toward precision immunomodulation in stroke. Moving beyond the static M1/M2 dichotomy to target macrophage subpopulations and their metabolic drivers guided by an integrated framework holds significant promise for developing more effective therapies.
    DOI:  https://doi.org/10.1186/s12967-026-08412-7
  8. Front Immunol. 2026 ;17 1828801
    Neutrophil immunometabolism in ACLF and sepsis: mechanisms, dysfunction, and therapeutic opportunities.
    Sonali Mukherjee, Takhellambam Malemnganba, Pragyan Acharya.
      Innate immune cells, undergo profound metabolic changes in critical illnesses. In both, acute-on-chronic liver failure (ACLF) and sepsis, these alterations underpin the paradoxical coexistence of hyperinflammation and immune dysfunction. Here, we present a comparative framework to examine how immune metabolic circuits are reshaped across these two syndromes. We focus primarily on neutrophil function while also considering contributions from other immune cell types, highlighting shared pathways, divergent mechanisms, and their clinical implications. We first delineate shared features of neutrophil activation in critical illness, including glycolysis-driven metabolic reprogramming, excessive reactive oxygen species (ROS) generation, and neutrophil extracellular trap (NET) formation, all processes that amplify tissue injury and propagate systemic inflammation. However, fundamental differences emerge in the baseline immune state, trajectory, and underlying immunometabolic programming of the two diseases. Sepsis arises as an acute insult in a previously homeostatic immune system, triggering a rapid transition from hyperactivation to mitochondrial dysfunction and eventual metabolic exhaustion. In contrast, ACLF develops on a background of chronic liver disease, where immune cells are already primed and metabolically stressed, resulting in a constrained and dysfunctional response from the outset. By placing ACLF and sepsis side by side, this review highlights the metabolic regulation of innate immunity, particularly neutrophils, as both a unifying principle and a disease-specific vulnerability. This comparative perspective deepens mechanistic understanding and provides a framework for precision immunometabolic interventions in critical illness.
    Keywords:  NEtosis; acute on chronic liver failure (ACLF); immune dysfunction; immune reprogramming; immunometabolism; inflammation; metabolic exhaustion; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1828801
  9. Front Immunol. 2026 ;17 1755589
    Immune regulation and cell metabolism in B cell subsets in patients with systemic lupus erythematosus.
    Masanobu Ueno, Satoshi Kubo, Yasuyuki Todoroki, Shingo Nakayamada, Yoshiya Tanaka.
      Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects young women and involves multiple organs, including the skin, joints, kidneys, and nervous system. In the pathogenesis of SLE, autoreactive B cells play a pivotal role through mediating antibody production, antigen presentation, and cytokine secretion. Recent studies have highlighted immunometabolism as a pivotal regulatory axis operating at both intracellular and extracellular levels during immune dysregulation. In SLE, plasma cells produce large quantities of autoantibodies, playing an important role in disease progression. This process demands a substantial energy supply, along with protein and nucleic acid synthesis, and is accompanied by dynamic reconstitution of intracellular metabolism. Furthermore, alterations in metabolic pathways not only facilitate efficient energy production but also directly modulate immune responses, including cytokine production and cell differentiation. Differences in cellular metabolism can shape B cell differentiation trajectories. Elucidating the immunometabolic mechanisms governing B cell activation and fate decisions may reveal novel drivers of lupus pathogenesis and identify new opportunities for therapeutic intervention.
    Keywords:  B cell; OXPHOS; glycolysis; immunometabolism; systemic lupus eryhematosus
    DOI:  https://doi.org/10.3389/fimmu.2026.1755589
  10. Adv Sci (Weinh). 2026 Jun 09. e20472
    m6A-Mediated Glycolysis by IL-37 Drives T Cell Metabolic Reprogramming to Regulate Colitis.
    Xiaoyan Wang, Jiadong Yu, Guolin Li, Ya Li, Fanlian Zeng, Jing Hu, Yifan Zhou, Chengcheng Yue, Qixiang Zhao, Chen Zhang, Hong Zhou, Fulei Zhao, Yawen Hu, Pei Zhou, Linna Gu, Yuting Feng, Mingxiang He, Shishi Huang, Xiaochi Sun, Xinmeng Wang, Jie Tang, Xinyu Zeng, Wenling Wu, Nongyu Huang, Xinai Cui, Kaijun Cui, Jiong Li.
      N6-methyladenosine (m6A) modification and T-cell metabolic reprogramming are increasingly recognized as critical drivers of inflammatory bowel disease (IBD). However, how the anti-inflammatory cytokine interleukin-37 intersects with m6A-mediated metabolic regulation remains unclear. Here, we show that IL-37 alleviates colitis by reducing global m6A levels and reshaping CD4+ T-cell metabolism. Mechanistically, IL-37 signals through its receptor SIGIRR to inhibit IRAK4 and JNK phosphorylation, suppress NF-κB p65 activation, and downregulate METTL14, thereby decreasing m6A deposition. The IL-37/METTL14 axis notably reduces m6A enrichment at the A2445 site in the 3'UTR of SLC2A1, destabilizing its mRNA and suppressing glycolysis. In vitro T-cell polarization and adoptive transfer of METTL14-overexpressing CD4+ T cells confirmed that this metabolic shift restrains Th1/Th17 differentiation while promoting Th2 expansion. Together, these findings reveal the IL-37/SIGIRR-METTL14-m6A axis as a novel regulator of T-cell metabolism and highlight SLC2A1 as a potential therapeutic target in IBD.
    Keywords:  IL‐37; T cell metabolism; colitis; glycolysis; m6A methylation
    DOI:  https://doi.org/10.1002/advs.202520472
  11. Inflamm Res. 2026 Jun 11. pii: 137. [Epub ahead of print]75(1):
    Lactate acts as a metabolic brake on inflammation by repressing NLRP3 transcription via NF-κB inhibition.
    Hsin-An Lin, Hsin-Chung Lin, Chih-Yung Chiou, Hao-Hsuan Peng, Yu-Jen Chen, Bo-Ying Bao, Kuen-Jou Tsai, Chao-Feng Lin, Chieh-Tien Shih, Sheng-I Hu, Kuo-Yang Huang, Lih-Chyang Chen.
       OBJECTIVE: Activation of the NLRP3 inflammasomes couples glycolytic metabolism to IL-1β-driven inflammation, but how pathologically elevated lactate feeds back on this pathway is unclear.
    METHODS: Using real-time bioenergetic Seahorse XF analysis, epigenetic profiling, and molecular signaling assays, we investigated the regulatory role of lactate in mouse bone marrow-derived macrophages (BMDMs) and human THP-1-derived macrophages.
    RESULTS: Pathophysiological concentrations of lactate suppressed ASC speck formation, caspase-1 activation, and IL-1β secretion induced by ATP, nigericin, or monosodium urate crystals. This inhibition was associated with a reversible downregulation of NLRP3 expression, whereas ASC, pro-caspase-1, and pro-IL-1β levels remained unaffected. Mechanistically, this suppressive effect was independent of the GPR81 receptor and reactive oxygen species (ROS). Instead, lactate utilized the monocarboxylate transporter (MCT) axis to fundamentally reprogram cellular metabolism, leading to the coordinated suppression of aerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). The resulting decline in cellular ATP levels impaired ATP-dependent NF-κB p65 phosphorylation and subsequent NLRP3 promoter activity. Notably, while lactate globally increased histone lactylation and acetylation-including localized enrichment at the NLRP3 promoter-these epigenetic shifts were insufficient to overcome the metabolic-driven repression of NF-κB-dependent transcription.
    CONCLUSION: Our findings identify lactate as a metabolic negative-feedback signal that restrains NLRP3 transcriptional priming by disrupting metabolic fitness. This study clarifies how the lactate-MCT-ATP- NF-κB axis serves as a critical metabolic checkpoint to limit inflammasome-driven inflammation in metabolically stressed microenvironments.
    Keywords:  GPR81; Lactate; Lactylation; NF-κB; NLRP3 inflammasome
    DOI:  https://doi.org/10.1007/s00011-026-02290-x
  12. Biochem Pharmacol. 2026 Jun 09. pii: S0006-2952(26)00488-0. [Epub ahead of print] 118152
    β-Hydroxybutyric acid impairs host antimicrobial defense by targeting the CEACAM1-NADPH-ROS axis to disrupt macrophage bactericidal activity.
    Tao Zhong, Ke Deng, Zishan Peng, Jiamin Li, Shuntian Lei, Mingxia Li, Sainan Chen, Jing Cai, Jianbin Guan, Ping Chang, Jingjing Yang, Dongping Li, Xingxing Liu, Zhanguo Liu.
      During bacterial infections, the immune function of macrophages in the host is crucial for eliminating bacteria. Metabolic disturbances can directly interfere with the normal function of host immune cells. However, it is unknown whether β-hydroxybutyric acid (BHBA), an important nutrient metabolite in humans, affects the bactericidal capacity of macrophages and the overall bacterial load in the infected host. Our clinical data show that circulating BHBA levels are higher in septic patients upon admission and positively correlate with increased infection-related parameters, such as procalcitonin (PCT) and high-sensitivity C-reactive protein (hsCRP). A similar clinical phenomenon was observed in mice suffering from bacterial peritonitis. Further, animal and cell experiments confirmed that BHBA stimulation could impair the antibacterial defense response of hosts by disrupting the bactericidal activity of macrophages. Interestingly, BHBA could disrupt the nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species (ROS)-mediated bactericidal activity of macrophages by binding to the membrane protein carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1), ultimately affecting the bacterial load in the host. In conclusion, we identify BHBA as an endogenous negative pharmacological ligand that directly targets CEACAM1 as a macrophage druggable receptor, thereby disrupting the NADPH-ROS bactericidal axis. This BHBA-CEACAM1-NADPH-ROS pharmacological cascade impairs host antimicrobial defense, providing a biochemically tractable target for the development of novel anti‑infective therapies.
    Keywords:  Bacterial infection; Bactericidal activity; CEACAM1; Macrophage; Reactive oxygen species; β-Hydroxybutyric acid
    DOI:  https://doi.org/10.1016/j.bcp.2026.118152
  13. J Immunol Res. 2026 ;2026(1): e1862250
    Metabolic Reprogramming of T Cells by MSCs Rebalances Th17/Treg Axis to Attenuate Collagen-Induced Arthritis.
    Xiaoping Wang, Jingjing He, Qun Wang, Xue Liu, Haoming Yuan, Lu Jin, Meng Ding, Lin Yang, Shaoxin Cui, Fei Chang, Tong Xin, Hongtao Jin, Min Shi, Yongzhou Song, Wensen Pan, Aijing Liu.
       BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by dysregulated T cell responses and metabolic disturbances. Mesenchymal stromal cells (MSCs) have shown therapeutic promise, but their mechanisms, particularly concerning T cell metabolism, remain incompletely defined. This study investigated whether human umbilical cord-derived MSCs (hUC-MSCs) ameliorate collagen-induced arthritis (CIA) by modulating T cell metabolism and differentiation.
    METHODS: CIA was induced in DBA/1 mice. Animals received PBS or hUC-MSCs on day 28. Arthritis index (AI), joint histology, serum cytokines (TNF-α, IL-6, IL-17, and TGF-β), and metabolites (lactate and pyruvate) were assessed. Splenic T cell transcription factors (FOXP3, RORγt, and PU.1) and glycolytic genes (GLUT1, G6PD, and PFKFB3) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. In vitro, human CD4+ T cells were cocultured with hUC-MSCs under T-helper 17 (Th17)-polarizing conditions. T cell subsets, glycolytic metabolites, and gene/protein expression were evaluated by flow cytometry, colorimetric assays, RT-qPCR, and western blot.
    RESULTS: MSC treatment significantly attenuated arthritis severity, joint destruction, and splenomegaly in CIA mice. It reduced serum pro-inflammatory cytokines and normalized elevated lactate and pyruvate levels. In the spleen, MSCs suppressed RORγt and PU.1 while enhancing FOXP3 expression, and downregulated GLUT1 and G6PD mRNA. Positive correlations were found between glycolytic markers (GLUT1 and G6PD) and pro-inflammatory transcription factors (RORγt and PU.1), and between serum lactate and inflammatory cytokines. In vitro, hUC-MSCs directly inhibited Th17 differentiation and promoted Treg generation in human CD4+ T cells. This metabolic reprogramming was functionally coupled to a shift in T cell differentiation: a suppression of pro-inflammatory Th17 cells and a promotion of regulatory T (Treg) generation in human CD4+ T cells. This was accompanied by reduced lactate production and significant downregulation of GLUT1, G6PD, and PFKFB3 at both mRNA and protein levels.
    CONCLUSIONS: hUC-MSCs ameliorate CIA by restoring the Th17/Treg balance through metabolic reprogramming of T cells, specifically by suppressing glycolysis. This immunometabolic mechanism highlights the therapeutic potential of MSCs in RA.
    Keywords:  T cell metabolism; Th17/Treg balance; collagen-induced arthritis; glycolysis; mesenchymal stromal cells; rheumatoid arthritis
    DOI:  https://doi.org/10.1155/jimr/1862250
  14. Trends Immunol. 2026 Jun 09. pii: S1471-4906(26)00131-6. [Epub ahead of print]
    DNA sensing and regulation of lipid metabolism.
    Soumyabrata Guha, Yasmine Messaoud-Nacer, Nadine Laguette.
      Immunity and metabolism are deeply intertwined in maintaining homeostasis. With the recognition of cytosolic dsDNA sensing as an initiator of immune responses, its interface with metabolic rewiring has emerged as a key area of investigation. Focusing on the stimulator of interferon genes adaptor protein, critical for dsDNA-mediated inflammation, we examine the link between lipid metabolism and innate immunity. Adopting an evolutionary perspective and through comparisons with the inflammasome pathway, also specialized in innate immune activation, we explore the conservation of this interface across innate immune systems. We propose that the connection between dsDNA sensing and metabolism could unlock innovative precision medicine strategies for inflammatory diseases.
    Keywords:  cGAS-STING; immunometabolism; inflammasome; inflammation; lipid metabolism; nucleic acid sensing
    DOI:  https://doi.org/10.1016/j.it.2026.05.006
  15. Front Immunol. 2026 ;17 1848067
    The immune-cardiovascular metabolic circuitry in myocardial ischemia-reperfusion injury: from metabolic signal release to spatiotemporal reprogramming.
    Conghao Tan, Junjie Zhou, Jiawen Li, Xinyi Zhang, Wei Yuan.
      Myocardial ischemia-reperfusion injury (MIRI) remains a major driver of infarct expansion, adverse remodeling, and poor outcomes after reperfusion therapy, yet mechanism-based treatments remain limited. Emerging evidence suggests that MIRI is not simply the additive result of oxidative stress and sterile inflammation. Rather, it reflects a spatiotemporally organized imbalance in immune-cardiac metabolic communication. In this framework, cardiomyocytes, coronary microvascular endothelial cells, fibroblasts, and resident cardiac macrophages act as both injury targets and signal-emitting units. They release succinate, lactate, ATP, lipid mediators, and mitochondrial danger signals. Infiltrating neutrophils, monocytes/macrophages, and lymphocyte subsets decode these cues through reprogramming of glycolysis, oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism. These responses shape inflammatory amplification, resolution, and tissue repair. This review summarizes key connecting mechanisms, including hypoxia sensing, mitochondrial dysfunction, and the axis linking adenosine monophosphate-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). It also discusses immunometabolites such as succinate, lactate, itaconate, and ATP/adenosine as links between tissue injury and immune cell-state transitions. Finally, we highlight temporal windows, spatial niches, and cell-state specificity, and evaluate how single-cell omics, spatial transcriptomics, spatial metabolomics, and metabolic flux analysis may guide time-sensitive, subpopulation-specific, and spatially precise therapies.
    Keywords:  immune cells; immunometabolism; metabolic reprogramming; myocardial ischemia-reperfusion injury; spatiotemporal heterogeneity
    DOI:  https://doi.org/10.3389/fimmu.2026.1848067
  16. Neuron. 2026 Jun 09. pii: S0896-6273(26)00386-7. [Epub ahead of print]
    Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
    Yongqing Liu, Yingzhi Ye, Minghua Fan, Henry Yi Cheng, Shuying Sun, Zhaozhu Qiu.
      Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of cytidine/uridine monophosphate kinase 2 (Cmpk2), a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease β-amyloid burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a potential therapeutic target for AD.
    Keywords:  Alzheimer’s disease; CMPK2; KAT7; cGAS-STING; microglia; mitochondrial DNA; neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuron.2026.05.015
  17. MedComm (2020). 2026 Jun;7(6): e70801
    Metabolic Regulation of Immune Responses: Molecular Mechanisms, Diseases, and Therapeutic Targets.
    Chunwei Li, Ziqiang Liu, Dezheng Kong, Zhengze Li, Yiming Yan, Yanyu Dong, Lili Zhu, JiaNing Cao, Zhirui Fan, Gautam Sethi, Lifeng Li.
      Cancer-associated metabolic reprogramming profoundly reshapes the tumor microenvironment (TME), emerging as a central driver of immune evasion and therapeutic resistance. Increasing evidence indicates that metabolic enzymes function not only as bioenergetic regulators but also as active modulators of immune signaling, immune cell fate, and immune checkpoint expression. To elucidate these complex immunometabolic networks, this review utilizes fructose-1,6-bisphosphatase 1 (FBP1)-a key gluconeogenic enzyme-as a paradigmatic metabolic gatekeeper to illustrate how metabolic dysregulation drives tumor progression. By examining both the canonical metabolic effects and noncanonical signaling mechanisms of such enzymes, we synthesize recent advances demonstrating how metabolic rewiring promotes glycolytic reprogramming, immune suppression, and resistance to immunotherapy. Specifically, we explore broad mechanisms of immune evasion, including STAT3-PD-L1 regulation, modulation of innate immune surveillance, T cell exhaustion, and remodeling of stromal and fibrotic tumor niches. Furthermore, we discuss emerging therapeutic strategies targeting these immunometabolic pathways, encompassing small-molecule modulators, vitamin- and gene-based interventions, nanotechnology-enabled delivery systems, and metabolism-informed combination immunotherapy. Finally, we highlight key challenges, including metabolic heterogeneity and context-dependent enzyme function, emphasizing the need for biomarker-guided precision strategies to translate fundamental immunometabolic insights into durable and safe cancer therapies.
    Keywords:  FBP1; cancer immunotherapy; immunometabolism; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.70801
  18. Front Immunol. 2026 ;17 1742866
    In vitro generation of RORγt+ regulatory T cells reveals enhanced immunosuppressive function and OXPHOS-dependent metabolism.
    Marcella Cipelli, Eloísa Martins da Silva, Lais Cavalieri Paredes, Mariana Abrantes do Amaral, Barbara Nunes Padovani, Luísa Menezes-Silva, Vinicius Andrade-Oliveira, Niels Olsen Saraiva Camara.
       Background: RORγt+ regulatory T cells (Treg) play a crucial role in immune regulation, particularly in the gut. However, most current knowledge about this subset derives from in vivo studies, as in vitro investigation has been limited by the lack of protocols capable of preserving their phenotype.
    Methods: Here, we developed and optimized an in vitro differentiation protocol to efficiently generate RORγt+ Treg cells. The protocol was evaluated based on the frequency of RORγt+ Treg cells generated, their suppressive function compared to conventional induced Treg (iTreg), and their metabolic profile.
    Results: The optimized protocol increased the frequency of RORγt+ Treg cells in vitro by up to 70%, providing a robust system for their study. Functionally, in vitro-differentiated RORγt+ Treg cells displayed enhanced immunosuppressive activity compared to conventional iTreg, effectively inhibiting effector CD4⁺ T cell proliferation. Metabolic analyses further revealed a reliance on oxidative phosphorylation (OXPHOS) in this subset.
    Conclusion: This protocol enables the efficient in vitro generation of RORγt+ Treg cells, facilitating functional and metabolic studies of this population and opening new avenues for potential therapeutic applications in immune-mediated diseases.
    Keywords:  RORγt; T cell differentiation; T cell function; Treg; immunometabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1742866
  19. EMBO Mol Med. 2026 Jun 08.
    Harnessing the glycolysis-TCA cycle axis to boost host defense against neonatal infection.
    Ziyuan Wu, Nguyen Tran Nam Tien, Björn Klabunde, Karoline Aasmul-Olsen, Simone Margaard Offersen, Nguyen Thi Hai Yen, Tik Muk, Anna Hammerich Thysen, Susanne Brix, Nicklas Brustad, Tingting Wang, Jakob Stokholm, Klaus Bønnelykke, Anders Brunse, Nguyen Phuoc Long, Bo Chawes, Ole Bæk, Duc Ninh Nguyen.
      Preterm infants are highly susceptible to infections that can lead to sepsis, yet therapies beyond antibiotics are limited. Nutrition and host energy metabolism are known as immune modulators, but how they interact to mediate newborn host infection defense remains poorly understood. Here, we identify tricarboxylic acid (TCA) cycle metabolites as key modulators of early life infection outcomes. First, in a birth cohort of 700 children, elevated plasma TCA metabolite levels were associated with reduced infection burdens and systemic inflammation. Next, in a piglet neonatal sepsis model, sustained hepatic TCA cycle activity was associated with survival. These led us to explore clinically relevant nutritional strategies boosting TCA cycle activity. Substituting glucose in parenteral nutrition for galactose or glucogenic amino acids improved both pathogen clearance and preserved glucose homeostasis and prevented lethal sepsis. Mechanistically, these interventions promoted hepatic metabolic rewiring from glycolysis toward TCA-cycle-based oxidative phosphorylation, while mitigating excessive inflammation and organ injury. Our findings establish a clear connection between systemic energy metabolism and neonatal infection defense, suggesting clinically relevant strategies to improve outcomes in vulnerable newborns.
    DOI:  https://doi.org/10.1038/s44321-026-00463-z
  20. Chin Med J (Engl). 2026 Jun 08.
    Dietary tryptophan supplementation prevents sepsis by enhancing macrophage bacterial defense through GPR37 activation.
    Shihao Xie, Fengyuan Lyu, Kai Gao, Qi Chen, Meiling Chen, Xiaofei Yan, Ting Li, Hongbin Li, Yuechu Zhao, Lingying Qu, Peng Chen, Xin Li, Yuelin Zhang, Bei Hu.
       BACKGROUND: Sepsis, a critical and life-threatening condition, is one of the most common causes of death among inpatients. Emerging evidence suggests that active metabolites derived from gut microbe-associated metabolism of dietary essential amino acid L-tryptophan (Trp) help the host in combating infectious diseases. This study aims to investigate the mechanisms through which these active metabolites regulate sepsis progression.
    METHODS: The effects of dietary Trp and indole-3-pyruvate (IPyA) on the mouse septic model were evaluated by 72-hour survival rate monitoring, organ pathological injury score, bacterial load, and inflammatory factor expression. The changes in gut microbiota composition caused by dietary Trp were detected by 16S rRNA gene sequencing. The changes in Trp bacterial metabolites were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The effects of IPyA on macrophage phagocytosis were evaluated by flow cytometry and plate colony formation assay. The interaction between IPyA and G protein-coupled receptor 37 (GPR37) was evaluated by Western blot and surface plasmon resonance. Gpr37 knockout mice, small interfering RNA transfection in macrophages, and macrophage adoptive transfer assay were used to explore the detailed mechanism of IPyA in protecting sepsis.
    RESULTS: It is revealed that dietary Trp supplementation alleviated septic organ injury by modulating the abundance of key commensal microbes and their metabolic function. Furthermore, we found that GPR37 activation in macrophages by a key microbial metabolite, IPyA, raised after dietary Trp supplementation, protected the host against sepsis. Mechanistically, IPyA bound directly to GPR37 in macrophages, causing activation of small GTPases Ras-related C3 botulinum toxin substrate 1/Cell division cycle 42 (RAC1/CDC42) and increased expression of actin-related protein (Arp) 2/3, ultimately enhancing bacterial phagocytosis in macrophages. In addition, IPyA exhibited the potential to promote bacterial phagocytosis in macrophages obtained from patients.
    CONCLUSION: Targeting GPR37 through dietary Trp supplementation may be a potential prophylactic strategy to optimize gut microbiota metabolic functioning and ameliorate septic bacterial infections.
    Keywords:  Dietary tryptophan; GPR37; GTPases; Gut microbiota; Indole-3-pyruvate; Macrophage; Phagocytosis; Sepsis
    DOI:  https://doi.org/10.1097/CM9.0000000000004108
  21. J Biochem Mol Toxicol. 2026 Jun;40(6): e70938
    Lactic Acid Promotes TNBC Lung Metastasis via TGF-β/Smad-Driven Lipid Metabolic Toxicity and NK Cell Dysfunction.
    Peiling Zhu, Zhisheng Tian, Ying Wang, Haiying Liao, Zehui Mi.
      Lactic acid in the tumor microenvironment (TME) drives triple-negative breast cancer (TNBC) progression by coordinately reprogramming lipid metabolism and suppressing immune function. RNA-Seq analysis of lactate-treated MDA-MB-231 and NK-92 cells revealed simultaneous activation of the TGF-β/Smad pathway and upregulation of lipid metabolism genes (FASN, ACSL1). Functionally, lactate treatment increased TGF-β protein levels by approximately 3.5-fold, significantly enhancing TNBC cell invasion (~3-fold) and colony formation (~2.4-fold), while concurrently impairing NK cell cytotoxicity through upregulated PD-1 expression (~3-fold) and suppressed IFN-γ secretion (>60% reduction). These pro-metastatic and immunosuppressive effects were effectively reversed by TGF-β receptor inhibition (SB-431542) or Smad2 knockdown. In mouse xenograft models, lactic acid accelerated tumor growth and increased lung metastatic nodules by ~4-fold, whereas blocking TGF-β signaling reduced tumor burden by approximately 60% and restored NK cell activity. Our findings establish lactic acid as a metabolic-immune regulator that synergistically fuels TNBC metastasis through TGF-β/Smad-mediated lipid reprogramming and immune suppression, offering novel therapeutic targets.
    Keywords:  TGF‐β/Smad signaling pathway; immune escape; lactic acid; lipid metabolism reprogramming; natural killer cells; triple‐negative breast cancer metastasis
    DOI:  https://doi.org/10.1002/jbt.70938
  22. Front Nutr. 2026 ;13 1841890
    Intermittent fasting alleviates ulcerative colitis via lithocholic acid-mediated macrophage reprogramming.
    Yujen Tseng, Lingxi Lin, Feng Ji, Huan Song, Lin Chen, Maolin Ye, Suhan Zhao, Qi Zhou, Shaocong Mo, Xiangxi Ye, Jie Liu, Wanwei Zheng, Feifei Luo.
       Background: Ulcerative colitis (UC) is a relapsing inflammatory disorder, in which nutritional intervention has emerged as a modifiable factor for influencing disease onset and severity. This study aimed to investigate whether intermittent fasting (IF) alleviates UC and identify the underlying mechanisms, focusing on bile acid metabolism-immune system crosstalk.
    Methods: The study employed a 5:2 IF intervention (5 days ad libitum eating, 2 days low-calorie intake) in a chronic colitis model. Bile acid metabolic flux and lithocholic acid (LCA) levels were measured via metabolomics profiling, while gut microbiota composition was analyzed via 16S rRNA sequencing. Mechanistic studies explored the effect of LCA on macrophage polarization and metabolic reprogramming. UC patient samples were integrated to validate correlations between LCA levels, disease severity, erythrocyte sedimentation rate (ESR) and calprotectin.
    Results: 5:2 IF promoted remission of chronic colitis. Mechanistically, IF reshaped gut microbiota composition, enhanced bile acid metabolic flux and elevated LCA levels. LCA directly inhibited pro-inflammatory macrophage polarization via inducing metabolic reprogramming and enhancing mitochondrial oxidative respiration. Analysis of human UC samples revealed that higher LCA levels correlated with milder UC, lower ESR, and reduced calprotectin.
    Conclusions: IF alleviated chronic experimental colitis by enhancing bile acid metabolism and elevating LCA, which exerted anti-inflammatory effects via regulating macrophage mitochondrial oxidative respiration. This identifies LCA as a key mediating metabolite and provides a mechanistic basis for understanding how IF may affect intestinal inflammation in preclinical models.
    Keywords:  intermittent fasting; lithocholic acid; macrophage; metabolic reprogramming; ulcerative colitis
    DOI:  https://doi.org/10.3389/fnut.2026.1841890
  23. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00558-9. [Epub ahead of print]45(6): 117480
    The circadian clock component BMAL1 enhances macrophage inflammation by nuclear translocation of peroxisomal β-oxidation enzyme MFP2.
    Akito Tsuruta, Nodoka Hirao, Megumi Shibata, Yuya Yoshida, Yoshihiro Izumi, Naoya Shindo, Yuki Shiiba, Kazuhiro Higashi, Takuto Inoki, Yuichiro Kai, Yasuha Hiraoka, Tomoaki Yamauchi, Akio Ojida, Takeshi Bamba, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo.
      The circadian clock regulates diverse immune functions, yet the role of clock components in macrophage inflammation remains controversial, with both pro- and anti-inflammatory effects reported. Here, we identify a previously unrecognized mechanism by which the core circadian clock component BMAL1 enhances the inflammatory response of macrophages through the nuclear translocation of the peroxisomal β-oxidation enzyme multi-functional protein 2 (MFP2). BMAL1 drives MFP2 accumulation in the nucleus, where MFP2 contributes to acetyl-CoA production and acetylation of the NF-κB subunit p65, thereby facilitating M1 polarization and inflammatory chemokine expression. Nuclear MFP2 levels oscillate in a diurnal manner in the liver, but this rhythmicity is abolished in Bmal1-deficient mice. Macrophage-specific deletion of BMAL1 alleviates diethylnitrosamine-induced hepatic inflammation and tumorigenesis, concomitant with reduced inflammatory gene expression. These findings uncover a BMAL1-dependent nuclear metabolic pathway that links circadian regulation of macrophage inflammation and suggest that targeting nuclear MFP2 may offer a therapeutic approach for inflammatory diseases and tumorigenesis.
    Keywords:  BMAL1; CP: immunology; CP: metabolism; Intranuclear acetyl-CoA; MFP2; circadian rhythm; inflammation; peroxisomal β-oxidation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117480
  24. FASEB J. 2026 Jun 30. 40(12): e72035
    FABP4 Disrupts Redox Homeostasis Through GOT2 Interaction to Drive Macrophage Mitochondrial Lipid Metabolic Reprogramming in Atherosclerosis.
    Xin Zhang, Qiong Yi, Hao Liang, Jinxia Li, Yidi Zeng, Chunhui Li.
      This study aims to investigate the role of fatty acid-binding protein 4 (FABP4) in macrophage lipid metabolism and inflammatory responses during atherosclerosis development, and to determine whether its function is mediated through interaction with glutamate oxaloacetate transaminase 2 (GOT2). Herein, macrophage-specific FABP4 knockout mice and RAW 264.7 macrophages were subjected to high-fat diet (HFD) or oxidized LDL (ox-LDL) treatment, respectively. Co-immunoprecipitation (Co-IP), qPCR, western blot, flow cytometry, ELISA, enzymatic assays, and histological staining (hematoxylin and eosin (H&E), Oil Red O) were used to assess protein interaction, expression, cytokine secretion, lipid accumulation, pro-inflammatory activation, and redox state. Macrophage-specific FABP4 deletion markedly reduced atherosclerotic plaque formation, lipid accumulation, pro-inflammatory cytokine levels, and the proportion of CD86+ pro-inflammatory macrophages, while improving systemic lipid profiles. Mechanistically, FABP4 directly bound to mitochondrial GOT2 without altering its expression, leading to disruption of mitochondrial NADH/NAD+ redox homeostasis and subsequent metabolic dysfunction. Importantly, concurrent knockdown of GOT2 fully reversed the beneficial effects of FABP4 deficiency on lipid metabolism and inflammation, confirming GOT2 as a critical downstream mediator. FABP4 promotes atherosclerosis by binding to GOT2 and disrupting mitochondrial redox balance, thereby driving macrophage lipid metabolic reprogramming and inflammatory activation. Targeting the FABP4-GOT2 axis may offer a novel therapeutic strategy for atherosclerosis and related metabolic diseases.
    Keywords:  FABP4; GOT2; atherosclerosis; inflammation; lipid metabolism; macrophage; mitochondrial redox
    DOI:  https://doi.org/10.1096/fj.202600611R
  25. Phytomedicine. 2026 Jun 05. pii: S0944-7113(26)00614-8. [Epub ahead of print]158 158382
    Quercetin targets BCAT1 to potentiate CD8+ T cell immunity by rewiring branched-chain amino acid metabolism against colorectal cancer metastasis.
    Chuyi Wang, Yunxing Xu, Pengcheng Ding, Yunhai Ding, Liangfeng Zheng, Tianyi Li, Shouliang Cheng, Chen Zhang, Feiyue Ji, Xiaojiang Liu, Kai Chen, Guiyuan Gu, Xiaomin Lu.
      Colorectal cancer (CRC) metastasis is a major cause of cancer‑related death, highlighting the need for therapies that target immune‑metabolic pathways. Here, we show that quercetin inhibits CRC progression via dual actions: directly suppressing tumor cell growth and migration, while systemically reinvigorating CD8+ T cell mediated immunity. In vitro, quercetin potently inhibited CRC cell proliferation, migration, and survival. In an experimental lung metastasis mouse model, quercetin enhanced the effector function of CD8+ T cells, as evidenced by increased production of Granzyme B, Perforin, and IFN-γ in metastases, blood, and tumor-draining lymph nodes. Metabolomic profiling uncovered a pronounced remodeling of branched-chain amino acid (BCAA) metabolism following quercetin intervention. Screening via the HERB database identified BCAA transaminase 1 (BCAT1) as a candidate target, confirmed by molecular docking and surface plasmon resonance (SPR). Importantly, the combination of oral leucine and quercetin produced a synergistic effect, significantly boosting CD8+ T cell cytotoxicity and dramatically reducing the lung metastatic burden. Taken together, these data identify BCAT1 as a direct target of quercetin and elucidate a resultant immunometabolic circuit that bolsters CD8+ T cell function, providing a rationale for targeting this pathway in advanced CRC.
    Keywords:  BCAT1; Branched-chain amino acid; Colorectal cancer metastasis; Quercetin
    DOI:  https://doi.org/10.1016/j.phymed.2026.158382
  26. Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00587-5. [Epub ahead of print]45(6): 117509
    Cholera-toxin-induced disease generates epithelial-cell-derived L-lactate that promotes Vibrio cholerae growth in the small intestine.
    Maria de la Paz Gutierrez, Jenna L Hall, Hugo L P Masson, Maria G Winter, Sebastian E Winter, Fabian Rivera-Chávez.
      Cholera toxin (CT) promotes Vibrio cholerae colonization by altering gut metabolism to favor pathogen growth. Here, we show that CT-induced disease leads to the upregulation of mammalian lactate dehydrogenase A (LDHA), an enzyme that catalyzes the conversion of pyruvate to L-lactate, in small intestinal epithelial cells. In a suckling mouse model, the bacterial L-lactate dehydrogenase (LldD) confers a fitness advantage to V. cholerae but not to the ΔctxAB mutant incapable of producing CT. Finally, mice lacking epithelial-cell-specific LDHA have reduced luminal L-lactate concentrations, and the fitness advantage conferred by LldD is significantly reduced in these mice, demonstrating that epithelial-derived L-lactate is a major contributor to CT-dependent pathogen expansion. These findings identify epithelial-derived L-lactate as a host-derived metabolite generated in the small intestine during cholera disease that directly fuels V. cholerae growth during infection, uncovering a mechanism by which CT confers a fitness advantage to the pathogen during disease.
    Keywords:  CP: Microbiology; L-lactate; Vibrio cholerae; bacterial pathogenesis; cholera toxin; host-pathogen interactions; metabolic remodeling; small intestine
    DOI:  https://doi.org/10.1016/j.celrep.2026.117509
  27. Brain Behav Immun. 2026 Jun 09. pii: S0889-1591(26)00611-2. [Epub ahead of print] 106863
    Mitochondrial remodeling by lithium drives CD4+ naïve T cell fate and immune homeostasis in bipolar disorder.
    Zhenni Chen, Yingrui Lin, Bingqi Wang, Min Wang.
       BACKGROUND: Immune signaling and mitochondrial redox biology have been implicated in bipolar disorder (BD), but the relationship between the clinical efficacy of lithium (Li) and immune dysfunction remains unclear.
    METHODS: We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from BD patients during the manic phase before and after Li treatment, and conducted Li intervention experiments in a mouse model exhibiting BD manic-like behaviors (BD-manic). At the cellular level, we assessed mitochondrial metabolic and bioenergetic parameters in CD4⁺ naïve T cells, along with the distribution of T cell subsets. We further measured peripheral cytokines and central nervous system inflammatory markers to characterize peripheral and central inflammatory changes.
    RESULTS: Transcriptomic analysis of PBMCs from BD patients before and after Li treatment revealed significant alterations in metabolic pathways. In BD-manic mice, CD4⁺ naïve T cells exhibited metabolic alterations characterized by reduced mitochondrial membrane potential, decreased ATP production, impaired glucose uptake, increased ROS accumulation, and mitochondrial fragmentation compared with Control. These abnormalities were accompanied by increased total Drp1 expression, enhanced Drp1 Ser616 phosphorylation, and reduced Mfn2/Opa1 expression. Relative to BD-manic mice, Li treatment improved behavioral abnormalities, partially restored mitochondrial structure and bioenergetic function, and was associated with T cell subsets distribution. Li also reduced peripheral pro-inflammatory cytokines and attenuated hippocampal IL-6 expression, accompanied by amelioration of neuronal and microglial abnormalities.
    CONCLUSION: These findings indicate that Li treatment is accompanied by mitochondrial remodeling in CD4⁺ naïve T cells together with peripheral immune and central inflammatory changes in BD.
    Keywords:  Bipolar disorder; CD4⁺ naïve T; Immune Homeostasis; Lithium; Mitochondria
    DOI:  https://doi.org/10.1016/j.bbi.2026.106863
  28. Sci Adv. 2026 Jun 12. 12(24): eaee0517
    Targeting TMED4 enhances CD8+ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis.
    Huizi Wang, Licai Shi, Ke Jiang, Shuyao Wu, Zhenyan Jiang, Yuexiao Tao, Jia Li, Xin Li, Jiamin Liu, Jun Ni, Emily Jiatong Wu, Sophia Jiaxin Wu, Guang Chen, Ming Qin, Lin Xu, Chu-Hu Lai, Alexandra Aicher, Youqiong Ye, Christopher Heeschen, Yu J Cao, Xuefeng Wu.
      Endoplasmic reticulum stress (ERS) and autophagy regulate tumor-infiltrating T cell function and exhaustion, but the underlying mechanisms remain unclear. Here, we identified the ERS-related transmembrane protein TMED4 (transmembrane emp24 domain-containing 4) as a critical regulator of CD8+ T cell antitumor immunity. Tmed4 deletion in T cells enhanced antitumor responses by promoting CD8+ T proliferation, infiltration, and killing capacity, while reducing terminal exhaustion. Mechanistically, Tmed4 deficiency hyperactivated the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis and induced autophagy flux in an IRE1α-dependent manner. Genetic deletion of Ern1 (IRE1α) or Becn1 (Beclin1) impaired the antitumor effects of Tmed4 deficiency, underscoring the role of ERS and autophagy in CD8+ T cell function. Moreover, Tmed4-deficient chimeric antigen receptor T cells (CAR T cells) displayed improved antitumor immunity. Pharmacological inhibition of Tmed4 using antisense oligonucleotide also enhanced CD8+ T cell-mediated tumor control. In summary, our study reveals that TMED4 governs CD8+ T cell effector function and limits terminal exhaustion through IRE1α-driven autophagy, establishing TMED4 as a promising immunotherapeutic target for improving CAR T cell efficacy.
    DOI:  https://doi.org/10.1126/sciadv.aee0517
  29. J Immunother Cancer. 2026 Jun 08. pii: e013562. [Epub ahead of print]14(6):
    VSIG4 suppresses antitumor T cell immunity via the SLC3A2-dependent metabolic-ionic checkpoint.
    Guoling Huang, Ruirui He, Wei Wang, Heping Wang, Yangyang Li, Bo Zeng, Panyin Shu, Ting Pan, Ming Yi, Lingyun Feng, Zhihui Cui, Xi Li, Yanyun Du, Hong Jiang, Xue Xiao, Yuan Wang, Chenhui Wang.
      BackgroundImmune checkpoint blockade therapy aims to restore T-cell function within the tumor microenvironment (TME), eliciting durable antitumor responses. However, clinical response rates to PD-1/PD-L1 inhibitors remain limited, particularly in immunologically "cold" tumors such as pancreatic cancer, underscoring the need for alternative immunotherapeutic strategies. V-set and immunoglobulin domain-containing 4 (VSIG4) has been implicated in tumor progression, but its functional role in T-cell regulation and mechanisms of tumor immune evasion remain unclear.
    METHODS: Syngeneic tumor models and human VSIG4 knock-in mice were employed to investigate the therapeutic effect of VSIG4 blockade. Mouse-specific and human-specific neutralizing antibodies against VSIG4 were administered across multiple tumor types, including pancreatic cancer. Tumor-infiltrating immune cells were analyzed by flow cytometry and functional assays. Mechanistic studies examined the interaction between VSIG4 and solute carrier family 3 member 2 (SLC3A2) and its impact on amino acid transport, ion flux, and T-cell activation.
    RESULTS: Therapeutic blockade of VSIG4 significantly suppressed tumor growth and prolonged survival in several cancer models, with particular efficacy in pancreatic cancer. VSIG4 expression correlated with tumor aggressiveness, and its blockade reactivated CD8+ T cells within the TME, enhancing intratumoral infiltration and effector function. Mechanistically, VSIG4 directly bound to SLC3A2, a chaperone for amino acid transporters, thereby impairing glutamine uptake, disrupting sodium and calcium flux, and ultimately suppressing T-cell activation. VSIG4 blockade restored nutrient and ion availability to CD8+ T cells, thereby reinvigorating antitumor immunity.
    CONCLUSIONS: These findings define a previously unrecognized metabolic-ionic checkpoint axis by which VSIG4 restricts T-cell activation through SLC3A2. Blockade of VSIG4 reprograms the TME and enhances antitumor immunity, highlighting VSIG4 as a promising therapeutic target, particularly in metabolically repressive tumors such as pancreatic cancer.
    Keywords:  Antibody; Immune Checkpoint Inhibitor; Immunotherapy; Macrophage; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-013562
  30. Immunol Lett. 2026 Jun 06. pii: S0165-2478(26)00071-4. [Epub ahead of print] 107198
    Aerobic Exercise attenuates airway inflammation in allergic asthma by regulating M2 macrophage polarization via drp1-mediated mitophagy.
    Linfang Ding, Nannan Wu, Jie Lin.
       BACKGROUND: Allergic asthma is a chronic respiratory condition characterized by persistent airway inflammation and dysregulated macrophage activation. Although aerobic exercise is known to exert anti-inflammatory effects, its influence on macrophage polarization and mitochondrial dynamics in asthma remains poorly defined METHODS: : Using a rat model of ovalbumen (OVA)-induced allergic asthma, we investigated the impact of aerobic exercise on macrophage polarization and mitophagy regulation. Animals were divided into four experimental groups: control, OVA-induced asthma, OVA with aerobic exercise intervention, and OVA with Drp1 inhibitor (Mdivi-1) treatment. We evaluated airway inflammation, macrophage phenotypes, mitochondrial function, and key mitophagy-related proteins RESULTS: : Aerobic exercise significantly attenuated allergic airway inflammation, as evidenced by reduced inflammatory cell infiltration, decreased mucus production, and a shift in macrophage polarization from the M2 towards the M1 phenotype. At the molecular level, exercise suppressed mitophagy activation, reduced Drp1 phosphorylation, and downregulated the expression of mitophagy-related proteins. These effects were mirrored by Drp1 inhibition with Mdivi-1, confirming the crucial role of Drp1-mediated mitophagy in exercise-induced modulation of macrophage polarization CONCLUSION: : Our findings indicate that aerobic exercise alleviates allergic airway inflammation by inhibiting Drp1-dependent mitophagy and rebalancing macrophage polarization. These results provide novel mechanistic insights into the therapeutic potential of exercise in asthma and highlight mitophagy as a promising target for inflammatory respiratory diseases.
    Keywords:  Drp1; aerobic exercise; airway inflammation; allergic asthma; macrophage polarization; mitophagy
    DOI:  https://doi.org/10.1016/j.imlet.2026.107198
  31. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00476-6. [Epub ahead of print]45(6): 117398
    Bilirubin mitigates ischemic white matter injury by targeting transferrin-receptor-mediated B cell immunometabolism.
    Lian Chen, Xiao-Wei Pang, Zhi-Cheng Mei, Lan Zhang, Yun-Hui Chu, Meng-Lu Tian, Li-Fang Zhu, Luo-Qi Zhou, Sheng Yang, Ming-Hao Dong, Ke Shang, Jun Xiao, Jian-Ke Gong, Wei Wang, Dai-Shi Tian, Chuan Qin.
      Physiological bilirubin exerts protective effects against ischemic stroke, but its role in post-stroke white matter injury (WMI) remains unclear. Here, through integrated epidemiological, genetic, and mechanistic studies, we demonstrate that mild elevation of serum bilirubin mitigates ischemic WMI by modulating B cell immunometabolism. Prospective cohort and Mendelian randomization analyses revealed an inverse association between bilirubin levels and WMI severity. In experimental models, bilirubin suppressed B cell activation and neuroinflammation by targeting transferrin receptor (TFRC), thereby reducing iron overload, restoring glucose metabolism, and improving mitochondrial homeostasis. Single-cell profiling further linked bilirubin-mediated B cell modulation to attenuated microglial activation via Fcγ receptor signaling. The existence of a bilirubin-B cell immunometabolism axis bridges preclinical findings with clinical relevance. Our findings establish bilirubin as a key immunometabolic checkpoint in B cells and propose TFRC blocking as a therapeutic strategy for ischemic WMI.
    Keywords:  B cells; CP: immunology; CP: metabolism; CP: neuroscience; bilirubin; immunometabolism; ischemic stroke; white matter injury
    DOI:  https://doi.org/10.1016/j.celrep.2026.117398
  32. Cell Signal. 2026 Jun 06. pii: S0898-6568(26)00289-5. [Epub ahead of print] 112636
    Erucic acid aggravates cardiac fibrosis after myocardial infarction by CD36-mediated metabolic reprogramming with impaired mitochondrial aerobic oxidation.
    Meng Zhang, Qiongfang Wang, Xiaoyu Wang, Shengyao Zhang, Yutong Chen, Shihao Li, Ling Zhang, Letai Li, Guoli Li, Dilong Chen, Jiajie Leng, Jianhua Ran.
       BACKGROUND: Post-myocardial infarction (MI) cardiac fibrosis is a key driver of heart failure, with dysregulated cardiac metabolism playing a central role. The specific impact of circulating fatty acid metabolites on mitochondrial function and fibrotic remodeling remains unclear. Erucic acid, a very-long-chain fatty acid found in certain edible oils, has a historical association with cardiac lipidosis, yet its causal role and mechanism in post-MI fibrosis are unknown.
    METHODS: We employed an integrative, two-stage strategy. First, a hypothesis-free two-sample Mendelian Randomization (MR) analysis was performed using genome-wide association study (GWAS) data for 1400 serum metabolites and MI (FinnGen consortium) to identify causal risk metabolites. Second, the top-ranked metabolite, erucic acid, was functionally validated in vivo and in vitro. A murine MI model with graded dietary erucic acid supplementation was used to assess cardiac function, fibrosis, oxidative stress, mitochondrial ultrastructure, and energy metabolism. RNA-seq was performed to elucidate global pathway alterations. Complementary in vitro studies in TGF-β-stimulated HL-1 cardiomyocytes and in vivo AAV9-mediated cardiomyocyte-specific CD36 overexpression rescue experiments were conducted to dissect the molecular mechanism involving the CD36 lipid metabolism axis.
    RESULTS: MR analysis identified erucic acid as a putative causal risk metabolite for MI. In mice, erucic acid levels increased post-MI, and dietary supplementation dose-dependently exacerbated cardiac dysfunction, fibrosis, oxidative stress, and mitochondrial damage. High-dose erucic acid induced a severe metabolic shift, characterized by suppressed mitochondrial oxidative phosphorylation and enhanced glycolysis. In vitro, erucic acid suppressed the CD36 pathway and downstream lipid-handling enzymes, leading to aggravated lipid peroxidation (increased 4-HNE/rH2X, decreased SOD2). Crucially, in vitro CD36 overexpression rescued these detrimental metabolic and lipotoxic effects. Furthermore, in vivo cardiomyocyte-specific CD36 overexpression via AAV9-cTNT significantly attenuated erucic acid-induced cardiac fibrosis, mitochondrial damage, lipid peroxidation, and the glycolytic shift, firmly establishing CD36 as the central mediator.
    CONCLUSION: This study establishes erucic acid as a causal dietary metabolite that aggravates post-MI cardiac fibrosis. Its pathogenic mechanism involves the disruption of the cardioprotective CD36 lipid metabolism pathway, leading to mitochondrial dysfunction, lipotoxicity, and a detrimental bioenergetic shift. These findings highlight erucic acid and the CD36 axis as potential targets for risk stratification and dietary intervention following MI.
    Keywords:  CD36; Cardiac fibrosis; Erucic acid; Lipid metabolism; Mitochondrial dysfunction; Myocardial infarction
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112636
  33. mBio. 2026 Jun 09. e0101626
    The McbR transcription factor links the intracellular folate pool to virulence in enterohemorrhagic Escherichia coli.
    Quentin Perraud, Vanessa Sperandio.
      Bacterial pathogens coordinate the expression of metabolically expensive virulence programs during host colonization. While the impact of environmental cues on virulence has been extensively studied, direct sensing of metabolic intermediates to inform virulence expression is less understood. Competition with the resident microbiota in the case of an infection has a massive impact on the bacteria's central metabolism, which can be used as a cue for the timely expression of virulence factors. Here, we identify how fluctuations in the intracellular folate pool can affect the expression of virulence factors in the enteric pathogen enterohemorrhagic E. coli (EHEC). Using transcriptomics, mutagenesis, and ligand-binding assays, we demonstrate that the EHEC's type III secretion system, which is a syringe-like apparatus employed by multiple pathogens to infect and manipulate host cell function, is repressed when the bacteria's folate biosynthetic pathway is pharmacologically disrupted, and that this effect is mediated by two regulatory proteins: PurR and McbR. Additionally, we identify dihydrofolate as a ligand of the previously orphaned McbR transcription regulator. It is notable that folate (vitamin B9) is an essential building block for DNA synthesis, cell formation, and division throughout the tree of life.
    IMPORTANCE: Host colonization requires enteric pathogens to tightly regulate their virulence program in response to a multitude of factors. In this work, we show that the bacterial physiological state directly informs pathogenic behavior in enterohemorrhagic E. coli (EHEC). Through the study of folate-starved bacterial cultures, we identified dihydrofolate as the endogenous ligand of the McbR transcription factor and demonstrated that McbR is directly linking one-carbon metabolism to virulence gene expression. These findings reveal how metabolites can act as regulatory signals controlling horizontally acquired pathogenicity islands.
    Keywords:  enterohemorrhagic E. coli (EHEC); folate metabolism; type III secretion; virulence regulation
    DOI:  https://doi.org/10.1128/mbio.01016-26
  34. Front Cell Neurosci. 2026 ;20 1831349
    The kynurenine pathway: an immunometabolic bridge linking systemic inflammation to neuroaxonal vulnerability in multiple sclerosis.
    José Luis Maldonado-García, Lissette Haydee García-Mena, Eduardo Alberto Ferat-Peláez, Gilberto Pérez-Sánchez, Enrique Becerril-Villanueva, Argelia Esperanza Rojas-Mayorquín, Manuel Iván Girón-Pérez, Daniel Ortuño-Sahagún, Lenin Pavón.
      Multiple sclerosis (MS) extends beyond focal autoimmune demyelination, with progressive neurodegeneration and cognitive impairment arising from mechanisms not fully explained by inflammatory lesions alone. We propose the kynurenine pathway (KP) as a unifying immunometabolic interface that translates peripheral inflammation into central neuroaxonal vulnerability. Cytokine-driven induction of indoleamine 2,3-dioxygenase accelerates systemic tryptophan catabolism, increasing circulating kynurenine that crosses the blood-brain barrier via L-type amino acid transporter 1 (LAT1). Within the CNS, microglial kynurenine 3-monooxygenase generates the excitotoxic and pro-oxidant metabolites quinolinic acid and 3-hydroxykynurenine, while astrocytic kynurenine aminotransferases produce the neuroprotective antagonist kynurenic acid. This enzymatic dichotomy creates a dynamic amplification loop that intensifies excitotoxicity, oxidative stress, oligodendrocyte injury, and axonal loss. Clinical evidence shows that kynurenine metabolite ratios correlate with plasma neurofilament light chain, cognitive deficits, obesity-related inflammation, and phenotype-specific exercise responsiveness, underscoring KP plasticity as a potential determinant of disease trajectory. By reframing MS through this immunometabolic lens, the KP emerges as both a mechanistic bridge between inflammation and neurodegeneration and a tractable biomarker system with therapeutic potential.
    Keywords:  inflammation; kynurenic acid; kynurenines pathway; multiple sclerosis; pro-inflammatory cytokines; quinolinic acid
    DOI:  https://doi.org/10.3389/fncel.2026.1831349
  35. Mol Nutr Food Res. 2026 Jun;70(11): e70521
    Curcumin Inhibits Renal Fibrosis by Suppressing S100A8/A9-TLR4 Signaling via Gut Microbiota-Derived Short-Chain Fatty Acid in Macrophages.
    Cheng Li, Xulong Chen, Weiwei Zha, Jiangwen Shen, Jun Lai, Bingxuan Zheng, Lin Li, Hongli Jiang, PuXun Tian.
      Renal fibrosis, a pivotal pathological process in chronic kidney disease (CKD), is closely associated with inflammatory responses and gut microbiota dysbiosis. Curcumin (CUR), a natural polyphenol derived from turmeric, shows anti-inflammatory and microbiota-modulating properties. However, its potential to attenuate renal fibrosis via gut microbiota-derived metabolites remains unclear. In this study, we investigated the mechanisms underlying the renoprotective effects of CUR, using a murine model of unilateral ureteral obstruction and LPS-stimulated bone marrow-derived macrophages (BMDMs). CUR treatment significantly alleviated renal interstitial fibrosis, reduced collagen deposition, and downregulated the pro-inflammatory mediators S100 calcium-binding proteins A8 (S100A8)/A9. Additionally, CUR modified the gut microbiota composition by enriching short-chain fatty acid (SCFA)-producing bacteria, leading to elevated systemic SCFA levels, particularly acetate, whose supplementation also ameliorated renal fibrosis, suppressed the S100A8/A9-toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF‑κB) signaling axis, and inhibited macrophage-myofibroblast transition (MMT). Acetate in vitro treatment attenuated the LPS-induced co-expression of S100A8/A9 and TLR4 in BMDMs, reduced pro-inflammatory cytokine release, and suppressed M1 polarization. These findings highlight that acetate, a key microbiota-derived metabolite increased by CUR treatment, mediates renal protection by targeting the S100A8/A9-TLR4 signaling pathway in macrophages, suggesting a novel gut-kidney axis-based therapeutic strategy for CKD.
    Keywords:  acetate; chronic kidney disease; curcumin; fibrosis; macrophage
    DOI:  https://doi.org/10.1002/mnfr.70521
  36. Front Immunol. 2026 ;17 1776555
    Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation.
    Alexia Tasoula, Shehbeel Arif, Ethan Waisberg, Lucas Bauer, Elizabeth Aslinger, Joseph W Guarnieri.
       Introduction: Post-COVID Syndrome (PCS), or long-COVID, is a major public health burden, but its underlying mechanisms remain poorly understood. Because acute SARS-CoV-2 infection induces marked suppression of mitochondrial oxidative phosphorylation (OXPHOS), we investigated whether persistent immunometabolic remodeling is a recurring transcriptional, metabolic, and proteomic feature of PCS.
    Methods: We performed an integrated multi-omics analysis of transcriptomic, proteomic, and metabolomic datasets across multiple tissues from Syrian hamster models and human cohorts spanning acute infection through post-acute and PCS stages extending up to 12 months post-infection.
    Results: Across species and tissues, we observed overlapping signatures of mitochondrial dysfunction, including sustained suppression of OXPHOS, activation of mitochondrial stress responses, and enrichment of inflammatory pathways. Skeletal muscle exhibited the most pronounced and persistent mitochondrial repression in both hamsters and PCS patient biopsies, consistent with fatigue-associated phenotypes. Hamster heart and kidney tissues also showed persistent OXPHOS suppression, while lung tissue demonstrated prolonged inflammatory signaling despite partial metabolic recovery. In the nervous system, transcriptional profiles revealed region-specific patterns, including persistent cortical mitochondrial repression and partial recovery in sensory-associated regions. Peripheral blood mononuclear cells (PBMCs) transcriptomics and serum metabolic datasets suggested prolonged downregulation of OXPHOS-associated programs up to 12 months post-infection, potentially contributing to persistent immune dysregulation in susceptible individuals with underlying conditions. Longitudinal serum proteomics in PCS patients revealed sustained mitochondrial stress responses, increased oxidative stress signatures, and persistent immune activation at 1 and 6 months post-infection compared to recovered controls.
    Discussion: Together, these multi-omics results identify persistent mitochondrial repression and immune dysregulation as recurring features across PCS-associated datasets, providing a framework linking bioenergetic dysfunction with chronic immune activation and supporting future mechanistic and therapeutic investigation.
    Keywords:  SARS-CoV-2 infection; bioenergetic dysfunction; metabolic remodeling; mitochondrial stress response; post-acute sequelae of COVID-19 (PASC); systemic inflammation; transcriptomic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1776555
  37. Clin Transl Immunology. 2026 ;15(6): e70100
    Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet-induced obesity.
    Yizhuo Wang, Divya Ramnath, Kaustav Das Gupta, P Prakrithi, Kavita Bisht, Gregory C Miller, Zherui Xiong, Yujun Wan, Ellen N Tejo, James Eb Curson, Rishika Abrol, Sahar Keshvari, Kimberley S Gunther, Jordan D Atkinson, Zhixuan Loh, Jessica A Engel, Christian R Engwerda, Sabrina Sofia Burgener, Kate Schroder, David P Fairlie, Andrew D Clouston, Elizabeth E Powell, Katharine M Irvine, Mitchell A Sullivan, Jean-Pierre Lévesque, Quan Nguyen, Matthew J Sweet, Denuja Karunakaran.
       Objectives: Histone deacetylase 7 (HDAC7), a classical HDAC family member, promotes LPS-inducible glycolysis and inflammatory mediator production in macrophages, innate immune cells that contribute to pathology in metabolic diseases. Here, we investigated myeloid HDAC7 functions in obesity-driven metabolic disease.
    Methods: We used gain- and loss-of-function genetic approaches in mice to investigate myeloid HDAC7 functions in hepatic inflammation and metabolic disease, as well as associations with hepatic gene signatures characteristic of advanced chronic liver disease (CLD).
    Results: Transgenic expression of Hdac7 in myeloid cells increased liver inflammation and liver mRNA levels of Ccl2 and Il1b, key inflammatory mediators linked to CLD. Liver glycogen levels were also decreased, another feature of CLD. Transgenic expression of Hdac7 in myeloid cells mimicked the hepatic inflammatory phenotype that was observed in mice fed a high fat, high cholesterol and high sucrose (HFHCHS) diet, an obesity model that mimics some features of metabolic dysfunction-associated steatotic liver disease. In myeloid Hdac7 transgenic mice fed a HFHCHS diet, relative weight gain was increased, fasted glucose levels were elevated, and glucose tolerance was dysregulated by comparison to control mice. Conversely, fasted blood glucose levels were reduced and glucose tolerance was improved in myeloid Hdac7-deleted mice on a HFHCHS diet. HDAC7 mRNA levels were also elevated in the livers of people with advanced CLD and spatial transcriptomics revealed that myeloid HDAC7 directs hepatic gene signatures characteristic of advanced CLD.
    Conclusion: Myeloid HDAC7 contributes to hepatic inflammation and systemic glucose dysregulation in a mouse model of obesity and liver inflammation.
    Keywords:  glucose metabolism; histone deacetylase 7; inflammation; macrophages; metabolic dysfunction‐associated steatotic liver disease; obesity
    DOI:  https://doi.org/10.1002/cti2.70100
  38. Int J Mol Sci. 2026 Jun 05. pii: 5128. [Epub ahead of print]27(11):
    Metabolic Mechanisms of Neutrophil Phagocytic Activity in Patients with Widespread Purulent Peritonitis Bacterial Peritonitis Before and After Surgery.
    Andrey A Savchenko, Dmitry Kudlay, Ivan I Gvozdev, Elena N Anisimova, Dmitry V Cherdantsev, Igor Kudryavtsev, Artem Rubinstein, Anna An Starshinova, Alexandr Borisov.
      Bacterial peritonitis (BP) remains a significant clinical challenge due to its high risk of multiple organ failure and associated mortality. Neutrophils are central effectors of innate immunity, and their functional activity and metabolism may influence the progression and outcomes of immunoinflammatory diseases. To investigate the phagocytic activity and intracellular metabolic profiles of neutrophils in patients with BP and to evaluate their relationship with postoperative clinical outcomes, 51 patients with BP (23 men, 28 women; mean age 49.6 ± 9.4 years) were examined. Blood samples were collected preoperatively and on postoperative day 7. Phagocytic activity of total, actively, and weakly phagocytic neutrophils was assessed using flow cytometry. Intracellular activity of NAD(P)- and NAD(P)H-dependent oxidoreductases and dehydrogenases was measured by bioluminescence. Patients were stratified according to postoperative outcome: favorable (n = 32) or unfavorable (n = 19). Seventy healthy individuals served as controls. Preoperatively, the proportion and phagocytic activity of neutrophils were markedly elevated in all patients. Postoperatively, the proportion of phagocytosing neutrophils remained high; however, phagocytic activity increased in patients with favorable outcomes but decreased to control levels in those with unfavorable outcomes. Neutrophil metabolism before surgery exhibited activation of both anaerobic and aerobic pathways, accompanied by reduced glucose-6-phosphate dehydrogenase activity. Postoperative metabolic adaptations differed according to outcome: patients with favorable outcomes demonstrated normalization of energy metabolism, whereas patients with unfavorable outcomes exhibited enhanced anaerobic metabolism, persistent aerobic activity, increased substrate flux towards glutamate/glutamine synthesis, and intensified lipid peroxidation. Phagocytic activity and metabolic profiles of neutrophils in BP are outcome-dependent. Effective postoperative anti-inflammatory responses, including reverse migration of activated neutrophils, are associated with favorable outcomes, whereas persistent metabolic activation and oxidative stress correlate with unfavorable prognosis. Neutrophil functional and metabolic parameters may serve as prognostic biomarkers and potential targets for therapeutic modulation in BP.
    Keywords:  anaerobic and aerobic metabolism; bacterial peritonitis; glucose-6-phosphate dehydrogenases; immunometabolism; neutrophils; oxidative stress; phagocytic activity; postoperative outcome; prognostic biomarkers; reverse neutrophil migration; synthetic processes
    DOI:  https://doi.org/10.3390/ijms27115128
  39. bioRxiv. 2026 Jun 02. pii: 2026.05.28.728555. [Epub ahead of print]
    Critical illness expands a transcriptionally distinct hypometabolic CD8 + T effector program associated with respiratory failure and mortality.
    Casey M Nichols, Erin L Mwizerwa, Chooi Ying Sim, Sarah N Obeidalla, Jacqueline-Yvonne Cephus, Caroline E Roe, Jonathon M Irish, Dawn C Newcomb, V Eric Kerchberger, Julie A Bastarache, Jeffrey C Rathmell, Lorraine B Ware, Matthew T Stier.
      Immune dysfunction is a major driver of morbidity and mortality in critical illness syndromes including sepsis. Specifically, CD8 + T cell dysfunction has been linked to organ failure and death. To characterize the immune substructure of circulating CD8 + T cells in critical illness at high dimension, we used single-cell RNA sequencing of peripheral blood CD8 + T cells from 38 critically ill patients and 9 healthy controls. We annotated seven CD8 + T cell clusters, which included a CD8 + effector subset, termed T effector state 2 (T Eff-2 ), that was only present in critically ill patients and associated with more severe respiratory failure and higher mortality. T Eff-2 showed effector activation and inflammatory stress conditioning yet had markedly reduced metabolic transcripts without canonical features of exhaustion. Trajectory analyses positioned T Eff-2 as a terminal CD8 + T effector cell fate driven in part by DDIT4 and DUSP1 , which negatively regulate mTOR and MAPK signaling, respectively. Interestingly, this transcriptional program was indistinguishable by classical protein cytometry methods. These results, including the mortality association, were validated in a larger (n=91) independent external cohort of critically ill patients with sepsis. In summary, T Eff-2 represents a latent transcriptional program that delineates a clinically high-risk CD8 + T cell state in critical illness.
    DOI:  https://doi.org/10.64898/2026.05.28.728555
  40. Trends Immunol. 2026 Jun 10. pii: S1471-4906(26)00130-4. [Epub ahead of print]
    Bioelectric signaling as an emerging layer of macrophage communication.
    Weijia Zheng, Yitao Li, Wei Jia.
      Bioelectric signaling may represent an emerging layer of macrophage communication. This forum discusses how membrane-potential dynamics, ion fluxes, and context-dependent intercellular coupling may coordinate macrophage responses within tissues, highlighting a potential new dimension of immune regulation with broad implications for tissue-level immunity.
    Keywords:  bioelectric signaling; ion channels; macrophage polarization; metabolic syndrome; tissue-resident macrophages
    DOI:  https://doi.org/10.1016/j.it.2026.05.005
  41. Biomaterials. 2026 Jun 01. pii: S0142-9612(26)00378-9. [Epub ahead of print]335 124354
    Elemental selenium activates GPX1 to reprogram NK cell lipid metabolism and restores antitumor immunity.
    Haoqiang Lai, Guizhen Li, Kexin Guo, Haimei Zhang, Shuoshan Li, Fang Yang, Tianfeng Chen.
      Metabolic rewiring-induced immune dysfunction limits the efficacy of NK cell-based immunotherapy for solid tumors, underscoring the need for targeted metabolic interventions. In this study, we found that NK cells within tumor tissues exhibited lipid accumulation and decreased infiltration across multiple tumor models, including B16F10 melanoma, MC38 colon carcinoma, 4T1 breast cancer, and LLC lung carcinoma. Among the selected common selenium species, including Selenocystine (SeCys2), selenomethionine (SeMet) and selenium nanoparticles (SeNPs), SeNPs were found to effectively reverse abnormal lipid metabolism-mediated NK cell immune exhaustion induced by palmitic acid, oleic acid, or tumor-conditioned media. Additionally, SeNPs also effectively reverse palmitic acid-induced diminished antitumor activities in NK cells in vivo. Mechanistically, SeNPs inhibited palmitoylation of the fatty acid transporter CD36, restricting membrane localization and excessive lipid uptake, thereby preventing PPARδ-mediated mTOR inactivation and mitochondrial dysfunction. Importantly, SeNPs maintained glutathione peroxidase 1 (GPX1) protein abundance by counteracting palmitoylation-dependent downregulation, preserving redox homeostasis and sustaining mTOR signaling to enhance NK cell immunity. Furthermore, we also found that there is a positive correlation between high GPX1 expression and tumor-infiltrating NK cells in human breast tumor tissues, which further highlights the importance of elevated GPX1 expression in NK cell-mediated antitumor activity. Taken together, this study identifies SeNPs as a metabolic regulator that reprograms dysregulated lipid metabolism to restore NK cell antitumor immunity, which provides a mechanistic framework for developing selenium-based metabolic strategies to enhance cancer immunotherapy.
    Keywords:  GPX1; Lipid metabolism; Natural killer cell; Palmitoylation; Selenium
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124354
  42. Metabolism. 2026 Jun 09. pii: S0026-0495(26)00183-6. [Epub ahead of print] 156673
    GPR84 blockade in macrophages mitigates sepsis-induced liver injury via PPARα-driven metabolic reprogramming and M2 polarization.
    Yixin Chen, Yanying Zhou, Shuai Guo, Kaiyin Zhang, Juexian Wei, Ping Zhang, Yuting Zhang, Zaixia Bai, Han Lin, Wutong Shi, Fangwei Han, Xiaohui Chen, Huichang Bi, Yiming Xu.
       BACKGROUND & AIMS: Sepsis-associated liver injury (SLI) is a severe complication that substantially worsens clinical outcomes and increases mortality in patients with sepsis, yet its molecular drivers remain poorly defined. Recent meta-analyses identified GPR84, a G protein-coupled receptor activated by saturated medium-chain fatty acids, as markedly upregulated in sepsis, particularly in patients with acute liver injury. This study investigated the functional role of GPR84 in SLI pathogenesis and the mechanisms through which it contributes to disease progression.
    APPROACH & RESULTS: In murine models of SLI, single-cell RNA sequencing and immunohistochemistry revealed that Gpr84 expression is enriched in hepatic macrophages. Both genetic knockdown and pharmacological inhibition of Gpr84 significantly reduced acute liver inflammation. In vitro, Gpr84 blockade suppressed macrophage pro-inflammatory responses and promoted a shift from the M1 phenotype toward the anti-inflammatory M2 phenotype. Transcriptomic profiling linked these protective effects to enhanced lipid metabolic pathways and activation of peroxisome proliferator-activated receptor-α (PPARα). Mechanistically, Gpr84 suppression restored Pparα activity by reactivating the cAMP-PKA-CREB signaling axis. PKA-mediated phosphorylation of Pparα at Ser179 and Thr200 was essential for its activation, while CREB directly bound to and upregulated the Pparα promoter. These coordinated mechanisms improved mitochondrial fatty acid oxidation in macrophages and strengthened their anti-inflammatory capacity. In Pparα-deficient mice, the hepatoprotective effects of Gpr84 inhibition were largely abolished, confirming that Pparα activation is required for therapeutic benefit.
    CONCLUSIONS: This study identifies a previously unrecognized GPR84-PPARα regulatory axis as a central driver of SLI and establishes GPR84 as a compelling therapeutic target for mitigating hepatic inflammation in sepsis.
    Keywords:  GPR84; Macrophage; PBI-4050; PPARα; Sepsis-associated liver injury
    DOI:  https://doi.org/10.1016/j.metabol.2026.156673
  43. Nat Commun. 2026 Jun 10.
    Infection-induced glucose starvation triggers NINJ1-dependent macrophage lysis and Candida escape.
    Harshini Weerasinghe, Orawan Tulyaprawat, Helen Stölting, Johannes Sonnberger, Byron Mobbs, Joshua Nickson, Theresa Lange, Bryce van Denderen, Tricia L Lo, Tim Bastian Schille, Françios A B Olivier, Natasha Kapoor-Kaushik, Timothy A Gottschalk, Cathrine Hall, John Silke, James E Vince, Kate E Lawlor, Stefan Bröer, Kate Schroder, Sabrina Sofia Burgener, Bernhard Hube, Thomas Naderer, Adam J Rose, Ana Traven.
      Pathogens compete for glucose with macrophages, which disrupts host glycolysis, modulates antimicrobial responses and causes macrophage death. We show that glucose starvation induced by major fungal pathogens Candida albicans and Candida auris causes macrophage lysis by activating NINJ1, the executioner of membrane rupture during cell death. In glucose-starved macrophages, NINJ1 ruptures membranes independently of known cell death programs. Consistently, NINJ1 is the dominant effector of fungal-induced macrophage damage amongst host cell death factors. Supplementation of the amino acid alanine rescues glucose-starved macrophages better than glucose, and it does so by inhibiting NINJ1 oligomerization. Moreover, C. albicans infection disrupts amino acid metabolism in mice and reduces serum alanine. Finally, NINJ1-mediated membrane rupture enables C. albicans egress from macrophages together with the toxin candidalysin. We establish the mechanism of glucose starvation-induced macrophage damage by NINJ1, and demonstrate the roles of NINJ1 and alanine in immune responses to Candida and fungal escape.
    DOI:  https://doi.org/10.1038/s41467-026-74195-6
  44. Int J Mol Sci. 2026 May 23. pii: 4708. [Epub ahead of print]27(11):
    The Glutamate-Glutamine Axis in Pediatric Septic Shock: Immunometabolic Mechanisms, Biomarker Potential, and Clinical Implications.
    Yaru Cui, Juan Wang, Yiyao Bao.
      Pediatric septic shock remains a major cause of morbidity and mortality in critically ill children and is increasingly recognized as a syndrome of profound immunometabolic dysregulation. This narrative review synthesizes current clinical, translational, and mechanistic evidence on the glutamate-glutamine axis in pediatric septic shock. The review focuses on how glutamine and glutamate metabolism may interact with immune-cell function, mitochondrial substrate handling, redox defense, and intestinal barrier integrity, while distinguishing biological plausibility from validated clinical utility. Current evidence supports the glutamate-glutamine axis as a mechanistically relevant pathway and a source of candidate biomarkers, but pediatric-specific data remain limited and do not yet justify routine biomarker use or glutamine-based intervention in unselected children with septic shock. Future studies should use standardized sampling, reproducible analytical methods, pediatric validation cohorts, and phenotype-guided trial designs before this axis can be translated into clinical decision making.
    Keywords:  biomarkers; critical care; glutamate–glutamine axis; immunometabolism; metabolic reprogramming; pediatric septic shock; prognosis
    DOI:  https://doi.org/10.3390/ijms27114708
  45. J Leukoc Biol. 2026 Jun 10. pii: qiag073. [Epub ahead of print]
    Carboxylesterase 1 contributes to the human macrophage alternative activation response to Th2 cytokine interleukin-4.
    Matthew K Ross, Abdolsamad Borazjani, Hannah L Thrash, Oluwabori Adekanye, J Allen Crow.
      Carboxylesterase 1 (CES1) is a hydrolytic enzyme with roles in xenobiotic and lipid metabolism. Our previous studies suggested a novel role for CES1 in the regulation of macrophage gene expression following exposure to inflammatory molecules. The nuclear receptor PPARγ has an important role in the M(IL-4) polarization response. Here we investigated CES1 in human primary macrophages and THP-1 macrophages during M(IL-4) polarization. We hypothesized that ablating CES1's activity would decrease ligand signaling through PPARγ, thereby reducing the M2 polarization response. Inhibition of CES1's activity by small-molecule inhibitors (WWL113 or WWL229) attenuated the mRNA expression of several IL-4-induced M2 markers, including ALOX15. Similar results were found in macrophages in which CES1 or PPARg expression was silenced. Immunoblot and mass spectrometric analyses indicated that IL-4-induced ALOX15 and its enzymatic product, 15-hydroxyeicosatetraenoic acid, were both reduced by CES1 inhibition. Further, a PPARγ antagonist (GW9662) also altered the profile of IL-4-induced M2 markers. The M(IL-4)-induced increase in endogenous PPARγ ligands was augmented by WWL113. Surprisingly, PPARγ agonist 'add-back' strengthened the WWL113-mediated repression of IL-4-induced ALOX15 expression, whereas IL-4-induced FABP4 mRNA levels were augmented. Collectively, these results suggest that CES1 has a complex role in driving the alternative activation phenotype in response to IL-4, possibly through an ability to influence PPARγ. These findings are consistent with previous work in which CES1 appeared to hold in check the inflammatory response of innate immune cells. The significance of our findings is that CES1 appears to contribute to the integration of extracellular signals that shape macrophage phenotypes.
    Keywords:  ALOX15; IL-4; PPARγ; alternative macrophage activation; carboxylesterase
    DOI:  https://doi.org/10.1093/jleuko/qiag073
  46. JCI Insight. 2026 Jun 08. pii: e198505. [Epub ahead of print]11(11):
    LDL receptor-mediated lipoprotein uptake fuels human CD4+ T cell polarization toward a c-MAF/IL-10- and FOXP3-driven phenotype.
    Angela Markovska, Niels S van Heusden, Dagmar Duijzer, Alejandra Bodelón, Greta Rogani, Enric Mocholi, Edwin Ca Stigter, Can Gulersonmez, Sander Kooijman, Leonie Van der Zee, Monique T Mulder, Jeanine E Roeters van Lennep, Patrick Cn Rensen, Jorg van Loosdregt, Sebastiaan J Vastert, Noam Zelcer, Marianne Boes, Henk S Schipper.
      Human CD4+ T cells utilize nutrients, including lipids, to support their activation and polarization. Considering the pivotal role of lipoproteins in lipid transport, we reasoned that lipoprotein uptake and processing could effect CD4+ T cell function. Here, we demonstrate that activation of human CD4+ T cells induced expression of LDL receptor (LDLR) to facilitate LDLR-mediated endocytosis of LDL. Degradation of surface LDLR on CD4+ T cells with PCSK9 hampered activation and proliferation of the cells. Lipoprotein deprivation or blocking of lysosomal cholesterol egress impaired activation of mechanistic target of rapamycin complex 1 (mTORC1), affecting CD4+ T cell activation and proliferation. Furthermore, lipoprotein deprivation of cultured primary CD4+ T cells lead to reduced expression of c-MAF and FOXP3, key transcription factors for IL-10, accompanied by reduced IL-10 secretion. The pivotal role of LDLR-mediated lipoprotein uptake for mTORC1 activity, c-MAF and FOXP3 expression, and IL-10 secretion was confirmed using LDLR-dysfunctional CD4+ T cells from patients with homozygous familial hypercholesterolemia. Our study offers valuable insights into the lipoprotein metabolism of human CD4+ T cells and their reliance on the LDLR pathway for activation and polarization, a feature that may be leveraged to modulate CD4+ T cell function.
    Keywords:  Cell biology; Immunology; Lipoproteins; T cells
    DOI:  https://doi.org/10.1172/jci.insight.198505
  47. J Vis Exp. 2026 May 22.
    Single-plate Runs of Mito Stress And Glycolysis Stress Tests using Adherent or Non-Adherent Cells.
    Jane Tonello, Salvador Gonzalez Ochoa, Thanigaivelan Kanagasabai, Muna Mohammed, Anil Shanker, Alla V Ivanova.
      Real-time metabolic analysis provides label-free measurements of mitochondrial respiration and glycolysis, allowing researchers to link cellular energy metabolism with disease mechanisms and therapeutic responses across diverse fields. When comparing energy metabolism across different mice, other animals, humans, or cells under varying treatments, it is crucial to perform measurements within a single run to ensure accurate and reliable results. Moreover, experimental design must consider the cell type being analyzed, for example, whether they are adherent, like bone marrow-derived macrophages (BMDMs), or non-adherent, like lymphocytes. Therefore, a protocol was developed that enables the simultaneous performance of Mito Stress and Glycolysis Stress tests on the same plate, despite the assays requiring distinct drug injections and analytical programs. Separate handling protocols were optimized for analysis of both highly adherent cells (e.g., BMDMs) and non-adherent "floating" cells (e.g., T cells and other lymphocytes). Here, detailed protocols for conducting these assays efficiently and reproducibly are presented.
    DOI:  https://doi.org/10.3791/69504
  48. Nat Commun. 2026 Jun 11.
    Natural killer cell-mediated immunosurveillance modulates liver cancer evolution through cancer stemness enhancement and lipid metabolism reprogramming.
    Liang Shi, Boqiang Liu, Ruya Sun, Jing He, Hao Shen, Weiqi Li, Yi Wang, Weijun Zhao, Chenqi Jin, Binghan Jin, Yuanshi Tian, Lingfeng Ma, Lidan Hou, Mingyu Chen, Jiaying Shen, Bo Shen, Xiao Liang, Hong Yu, Yifan Wang, Di Wang, Xiujun Cai.
      Tumor evolution enables liver cancer cells to acquire survival advantages and evade therapy-induced cell death. However, the role of natural killer (NK) cells in liver cancer evolution remains unclear. Here, we establish immune-humanized spatiotemporal liver cancer models and integrate single-cell, spatial transcriptomic, and CRISPR/Cas9 screening analyses to investigate this process. We demonstrate that early NK cell-mediated immunosurveillance promotes tumor cell state transition and impairs subsequent adaptive immune responses. Mechanistically, NK cells induce lipid metabolic reprogramming, particularly cholesterol accumulation, and enhance tumor stemness, both of which promote liver cancer evolution. Furthermore, combined anti-LAG-3 treatment and liver X receptor activation suppress tumor evolution and improve the efficacy and durability of immune checkpoint blockade in advanced liver cancer. Collectively, our findings identify that NK cell-mediated early immunosurveillance promotes liver cancer evolution and suggest immunometabolic therapy as a potential strategy for advanced liver cancer.
    DOI:  https://doi.org/10.1038/s41467-026-74360-x
  49. PLoS Pathog. 2026 Jun;22(6): e1012998
    The Legionella pneumophila type IVb secretion system effector BinA subverts amino acid transport to sensitize TORC1 signaling in macrophages.
    Magdalena Circu, Reneau Castore, Brian Latimer, Stephanie Shames, Craig R Roy, Ana-Maria Dragoi, Stanimir S Ivanov.
      Legionella pneumophila is an environmental Gram-negative bacterium that parasitizes unicellular protozoa and can cause severe pulmonary infections when aerosolized bacteria are inhaled by humans. One critical aspect of Legionella pathogenesis is the establishment in the cytosol of infected macrophages of a unique ER-derived vacuole, that requires a sustained supply of host lipids during expansion. Subversion of pro-lipogenic pathways downstream of the metabolic checkpoint kinase mTOR (Mechanistic Target of Rapamycin) are critical for niche expansion. In eukaryotic cells, amino acids sufficiency and growth factor sensory signals converge on mTOR to ensure metabolic processes are coupled to nutrients/energy availability. Legionella can trigger mTOR signaling in infected cells by increasing the intracellular abundance of amino acids through inhibition of host translation. Here, we describe a novel mechanism by which Legionella sensitizes mTOR in infected macrophages. A forward genetic screen identified Lpg0393 protein as a putative bacterial mTOR regulator that contains a VPS9-domain typically found in eukaryotic GEFs (Guanine nucleotide exchange factors) for Rab5 GTPase family members (Rab5/Rab21/Rab22). We uncovered that Lpg0393 lowers the activation threshold for mTOR signaling upon stimulation with arginine or leucine by promoting anterograde trafficking of amino acid permeases through subversion of the small GTPases Rab21 and Rab22. Data from cells expressing either a bacterial or a eukaryotic mTOR sensitizing factor uncovered two distinct non-cytosolic Arg/Leu pools that fuel mTOR activation in parallel - one regulated by Rab21/22 and the other by Rab5. Consistent with the role of mTOR in expansion of the Legionella-occupied organelle, deletion of Lpg0393 also resulted in premature vacuolar rupture in a mTOR-dependent manner. All together, we have identified a novel bacterial mTOR regulator and consistent with its reported functions we propose Lpg0393 is named as BinA (Bacterial initiator of TORC1 signaling and an activator of Rab5 family GTPases).
    DOI:  https://doi.org/10.1371/journal.ppat.1012998
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