bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–03–15
fifty-six papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Immunometabolism of IRF4 in Adipose, Muscle, and Immune Cells Influences Obesity and MASLD.
  2. MALAT1 regulates human macrophage metabolism by interacting with HADHB.
  3. Mitochondrial Electron Transport Chain Modulation Orchestrates Divergent TLR3 and TLR7 Responses.
  4. Large neutral amino acid uptake and mTOR activation within CD4 T cells coordinate type 2 immunity and host resistance to Trichuris muris.
  5. Immunometabolism in lung cancer - The link between metabolism and immune response.
  6. Crosstalk of mitochondrial dysfunction and macrophage polarization in sepsis.
  7. Effect of Oral Ketone Body Intake on Human CD8+ T-Cell Immunometabolism.
  8. Acod1/itaconate axis controls anxiety-like behaviors induced by chronic infection of Toxoplasma gondii in mice.
  9. Bioenergetic Profiling of Lymphocytes in Patients With Visceral Leishmaniasis (VL) and Post Kala-Azar Dermal Leishmaniasis (PKDL).
  10. Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense.
  11. Sex Differences in Metabolite-Immune Circuits of Neuroinflammation.
  12. DPEP2 suppresses hyperinflammation via metabolic reprogramming of macrophages in sepsis.
  13. Itaconate Modulates Neutrophil Homeostasis to Ameliorate Airway Inflammation in Diesel Exhaust Particles-exacerbated Asthma via Inhibiting NETs Formation.
  14. Lipophagy fuels phosphatidylcholine synthesis for Newcastle disease virus replication.
  15. Heme as a metabolic cell-fate switch.
  16. FYN/LCK kinase balance as a metabolic switch orchestrates progenitor exhausted T Cell differentiation in hepatocellular carcinoma.
  17. ODC1 restricts meningeal B cell age-associated-like phenotype and function in multiple sclerosis: A human and experimental study.
  18. LDHB K156 lactylation links cGAS-STING-mediated metabolic reprogramming to NLRP3 inflammasome activation in sepsis-associated acute kidney injury.
  19. Macrophage metabolic exhaustion and PANoptotic cell death drive chronic tissue inflammation in rheumatoid arthritis.
  20. CD79A/CD40 intracellular domain uses a 4-1BB-like metabolic pathway driven by cholesterol biosynthesis.
  21. Mitochondrial transfer to granulocytic myeloid-derived suppressor cells augments immunosuppressive activity.
  22. NIPAL1 Drives a Metabolic-Epigenetic Feedback Loop to Promote Lactate-Mediated Immune Evasion in Esophageal Cancer.
  23. MHC-I upregulation and increased glucose dependence define innate antifungal immune responses to Cryptococcus neoformans.
  24. Untargeted LC-MS-based metabolic fingerprinting of Escherichia coli-associated urinary tract infections and urosepsis: Insights into the urine, serum, and bacterial interactomes.
  25. Pharmacological elevation of lactate alleviates sepsis via histone lactylation-induced IL-10 production.
  26. Dietary Saturated Fatty Acids as Evolutionarily Conserved Signals of Immune Activation.
  27. DRP1/DMNL-1-mediated mitochondrial fission augments Rickettsia parkeri replication in macrophages.
  28. Lactylation-Driven Macrophage Polarisation Regulates Pulp Inflammation.
  29. Metabolically reprogrammed eosinophils impair T cell immunity and cause chronic skin infection.
  30. Cross-species hepatic transcriptomics identify conserved immune-metabolic reprogramming in acute-on-chronic liver failure progression.
  31. Regulatory T cells in hypoxic environments.
  32. African swine fever virus hijacks lipolysis induced by chaperone-mediated autophagy to upregulate fatty acid β-oxidation and promote viral replication.
  33. Inhibition of T cell polyamine metabolism promotes transplant acceptance by modulating cytotoxic CD8+ T cell differentiation.
  34. Microglia Dld-K127 lactylation promotes Parkinson's disease via regulating the metabolism of lactate-pyruvate transformation.
  35. Growth differentiation factor 11 reprograms M2-like macrophages: Targeting immunometabolism for cancer therapy.
  36. Cortistatin antagonizes Piezo1-STING axis and facilitates mitochondrial homeostasis of keratinocytes by attenuating AGEs accumulation in diabetic ulcers.
  37. Blockade of KCa3.1 ameliorates rheumatoid arthritis by suppressing macrophage M1 polarization via the NLRP3 inflammasome signaling pathway.
  38. Proteomics and tracer metabolomics link GAPDH ISGylation to glycolytic control.
  39. STING-mediated metabolic reprogramming drives lipid peroxidation during Staphylococcus aureus infection.
  40. MCT1 inhibition reprograms Treg metabolism via ABC transporters: implications for tumor immunity and the prognosis of acute myeloid leukemia patients.
  41. Macrophage anti-bacterial activity is controlled by adenylate kinase 4-mediated mitochondrial DNA synthesis.
  42. Ammonia: a metabolic checkpoint for Treg potency.
  43. Gut-derived hyodeoxycholate reprograms the spleen-eye immunometabolic axis to suppress autoimmune uveitis.
  44. Exploring the metabolic mysteries: Mechanistic insights into lactylation-mediated regulation of autoimmune diseases.
  45. Metabolic Adaptation of CD8⁺ T Cells Limits the Efficacy of Fatty Acid Oxidation Inhibition in Type 1 Diabetes.
  46. Porcine epidemic diarrhea virus infection activates SREBP2 and induces RORγ expression to enhance cholesterol biosynthesis and virus replication.
  47. Trimethylamine-N-oxide: the microbial cue in immune-mediated disorders.
  48. Oncometabolites and Hypoxia-Regulated Exosomes Shape HIF-Driven Macrophage Programs Across Type 2 Diabetes, Atherosclerosis, and Cancer.
  49. Immunometabolic Reprogramming in Experimental Sepsis: A Driver of Multiple Organ Dysfunction Syndrome.
  50. Targeting tumor-infiltrating regulatory T cells based on immunometabolism.
  51. Glycosomal Phosphoenolpyruvate Carboxykinase CRISPR/Cas9-Deletion and Its Role in Trypanosoma cruzi Metacyclogenesis and Infectivity in Mammalian Host.
  52. Integrated Genome-wide Association and Single-cell Transcriptomic Analysis Identifies OAT as Therapeutic Targets for Periodontitis.
  53. L-2-aminoadipic acid inhibits porcine epidemic diarrhea virus replication by targeting and reducing cellular autophagy.
  54. Sex-Dependent Metabolic Alterations in Red Blood Cells During COVID-19.
  55. β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
  56. γδTreg/γδTh17 Cell Imbalance Drives Xanthine-Mediated Metabolic Dysfunction in Restraint Stress-Induced Anxiety-Like Behavior.
  1. Am J Physiol Endocrinol Metab. 2026 Mar 09.
    Immunometabolism of IRF4 in Adipose, Muscle, and Immune Cells Influences Obesity and MASLD.
    Daniel M Marko, Jonathan D Schertzer.
      Interferon regulatory factor 4 (IRF4) connects immunity and metabolism in immune cells and parenchymal cells of metabolic tissues. In immune cells, IRF4 is a metabolic rheostat that promotes glycolysis to support macrophage polarization and increase oxidative phosphorylation to enable T cell proliferation and memory, while limiting transcription of pro-inflammatory programs. IRF4 also dictates cell-autonomous responses in adipocytes and muscle cells, including transcriptional regulation of lipolysis in white adipocytes, thermogenesis in brown adipocytes, and glucose and amino acid metabolism in muscle cells. IRF4 responds to nutritional status and hormonal signals involved in obesity pathogenesis and mediates inter-organ communication involved in liver steatosis during metabolic dysfunction-associated steatotic liver disease (MASLD). This review summarizes how IRF4 participates in metabolic and immune responses in adipose tissue, skeletal muscle, liver, and tissue resident immune cells during obesity. IRF4 immunometabolism is relevant to obesity and MASLD because of its bidirectional role in immune cells and metabolic cells. Obesity alters inflammatory and nutritional activators of IRF4 which modify immune and parenchymal cell metabolism to produce local and systemic metabolic inflammation, which can alter endocrine control of metabolism. Therefore, the cell-specific functions of IRF4 in immune cells and metabolic cells positions IRF4 as a transcriptional node connecting changes in immunity and metabolism during metabolic disease.
    Keywords:  IRF4; Immunometabolism; Metabolic Disease; Tissue Crosstalk
    DOI:  https://doi.org/10.1152/ajpendo.00554.2025
  2. iScience. 2026 Mar 20. 29(3): 115107
    MALAT1 regulates human macrophage metabolism by interacting with HADHB.
    Yuxiang Liu, Yukiteru Nakayama, Junichi Sugita, Tsukasa Oshima, Kunihito Kani, Atsushi Kobayashi, Naoto Setoguchi, Yoshiko Iwai, Ichiro Manabe, Katsuhito Fujiu.
      Long noncoding RNAs (lncRNAs) are critical regulators of immune responses and cellular metabolism. Here, we report a previously unrecognized interaction between MALAT1 and HADHB, which reveals additional regulatory roles for MALAT1 in human macrophages. Our findings demonstrate that MALAT1-HADHB interaction significantly enhances HADHB thiolase activity during the late phase of inflammation via HuR-MTCH2-mediated mitochondrial targeting of MALAT1. MALAT1 also negatively regulates the pro-inflammatory macrophage activation via HADHB. Knockdown of MALAT1 induces metabolic reprogramming, characterized by enhanced glycolysis, increased fatty acid synthesis, and reduced fatty acid oxidation, suggesting that MALAT1 suppresses inflammatory metabolic pathways. This study uncovers the MALAT1-HADHB interaction and demonstrates that MALAT1 regulates macrophage metabolic reprogramming, offering new insights into the metabolic control of inflammation and highlighting MALAT1 as a potential therapeutic target for inflammatory diseases.
    Keywords:  cell biology; metabolic flux analysis; molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2026.115107
  3. J Leukoc Biol. 2026 Mar 11. pii: qiag034. [Epub ahead of print]
    Mitochondrial Electron Transport Chain Modulation Orchestrates Divergent TLR3 and TLR7 Responses.
    Mary-Elizabeth Sheridan, Duale Ahmed, Malak Al Daraawi, Nikki Kovac, Edana Cassol.
      Macrophages are on the front lines against viral infections and play a central role in initiating antiviral immune responses. They do this by sensing viral ligands through their arsenal of pattern recognition receptors, which fine-tune and determine the specificity of the immune response. Cellular metabolism has emerged as a central regulator of this specificity, driven in part by alterations in mitochondrial function. Yet, we are only starting to elucidate the specific mitochondrial dynamics that contribute to this differential modulation. Here, we report that TLR3 vs. TLR7 engagement results in divergent metabolic reprogramming that regulates their specific responses and that PKM2 dimerization and nuclear translocation serve as regulators of the balance in type I IFN, pro-inflammatory and anti-inflammatory programming. Furthermore, we found chemical modulation of ETC complexes I and II activity can selectively alter PKM2-dependent signalling, enabling a fine-tuning of macrophage effector response. Given that TLR3 and TLR7 ligands are utilized as vaccine adjuvants and have demonstrated potential as cancer immunotherapies, our findings suggest that specific targeting of mitochondrial function can be used to manipulate macrophage responses and to improve the efficacy and limit the off-target effects of these therapeutics.
    Keywords:  Antiviral Responses; Immunometabolism; Macrophage; Mitochondria; Toll-like receptors
    DOI:  https://doi.org/10.1093/jleuko/qiag034
  4. Discov Immunol. 2026 ;5(1): kyag003
    Large neutral amino acid uptake and mTOR activation within CD4 T cells coordinate type 2 immunity and host resistance to Trichuris muris.
    Maria Z Krauss, Kelly S Hayes, Suzanne H Hodge, Ana Villegas-Mendez, Matthew R Hepworth, Linda V Sinclair, Kevin N Couper, Richard K Grencis.
       Introduction: Trichuris trichiura (whipworm) is a gastrointestinal nematode that infects approximately 465 million people worldwide. Trichuris muris is used as a tractable model for the human whipworm. In wild-type mice, infection with a high dose of T. muris eggs leads to worm expulsion, which is dependent on a CD4Th2 response and interleukin (IL-)13 production. T cells up-regulate glycolysis and uptake of substrates following activation. The amino acid transporter SLC7A5 has been shown to be necessary for activation of mTORC1, a nutrient/energy/redox sensor critical for T cell differentiation into effector cells.
    Methods and Results: We found that mice lacking SLC7A5 in CD4T cells have significantly delayed worm expulsion, associated with reduced IL-13, reduced pmTOR, and reduced glycolytic rates. However, as infection progressed, IL-13 levels recovered in T cell-specific SLC7A5-deficient mice, alongside resistance. The critical role of CD4T cell metabolism per se and downstream mTOR in CD4T cells in host resistance was shown in mice lacking mTOR in CD4T cells that failed to expel their parasites and developed chronic infection.
    Conclusion: Our study shows that mTOR is essential for optimal functioning of T cells during whipworm infection and that deletion of Slc7a5 significantly delays worm clearance indicating a key role for amino acid acquisition by CD4T cells in resistance to helminth infection.
    Keywords:  helminths; host resistance; metabolism; parasites; type 2 immunity
    DOI:  https://doi.org/10.1093/discim/kyag003
  5. iScience. 2026 Mar 20. 29(3): 115041
    Immunometabolism in lung cancer - The link between metabolism and immune response.
    Yasamin Eivazzadeh, Niloufar Orooji, Tamana Eskandari, Mahdieh Tarahomi, Fatemeh Tavassoli Razavi, Dariush Haghmorad.
      Lung cancer remains a leading cause of cancer-related mortality worldwide, characterized by complex interactions between tumor metabolism and immune evasion mechanisms. This review explores the emerging field of immunometabolism, highlighting how metabolic reprogramming within lung tumors not only fuels cancer progression but also shapes the tumor immune microenvironment (TME). Key metabolic pathways, such as glycolysis, glutaminolysis, and lipid metabolism, are extensively altered in lung cancer cells, facilitating immune suppression through mechanisms such as nutrient competition, lactate accumulation, and modulation of immune checkpoints. Immune cells, including tumor-associated macrophages (TAMs), T cells, NK cells, and dendritic cells, undergo functional impairment due to these metabolic constraints. The review further discusses therapeutic strategies targeting immunometabolic pathways, including inhibitors of glucose and amino acid transporters, lipid biosynthesis enzymes, and immune-metabolic checkpoints such as IDO and CD73. Despite promising preclinical outcomes, challenges such as metabolic plasticity, systemic toxicity, and limited biomarker availability hinder clinical translation. Future directions emphasize the integration of multi-omics, metabolic profiling, and combinatory immunotherapy to personalize treatment and overcome resistance. A deeper understanding of immunometabolic crosstalk is pivotal for advancing precision medicine in lung cancer.
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.115041
  6. Front Immunol. 2026 ;17 1692597
    Crosstalk of mitochondrial dysfunction and macrophage polarization in sepsis.
    Fuxi Ji, Li Zhang, Lili Ning, Min Zhang, Jingxiao Zhang.
      Sepsis is a complex condition marked by significant dysregulation of immune and metabolic processes, leading to multi-organ failure. Macrophages, key mediators of immune activity, demonstrate functional flexibility by switching between pro- and anti-inflammatory phenotypes in response to inflammatory and metabolic signals in their local environment. During sepsis, pathogen-derived signals activate host defense responses that impair intercellular oxygen transport, increase oxygen consumption by immune cells within inflamed tissues, and promote a metabolic transition toward aerobic glycolysis. This metabolic transition supports immune defense mechanisms, and the metabolic by-products further regulate immune activation through feedback in key signaling cascades, promoting a transition toward tolerance during the resolution phase. Since mitochondria are central hubs for cellular energy homeostasis, they play a crucial role in this process. Mitochondrial dysfunction and metabolic changes are now recognized as major contributors to the progression of sepsis. The accumulation of mitochondria-derived metabolites can further modulate immune signaling pathways, actively influencing macrophage function. Therefore, this review emphasizes the crosstalk between macrophage polarization and mitochondrial changes, with a focus on new molecular insights and the potential of mitochondrial pathways as biomarkers or therapeutic targets. These concepts provide a foundation for advancing both experimental research and clinical applications, potentially guiding future interventions to better manage sepsis and its associated mortalities.
    Keywords:  crosstalk; macrophage polarization; metabolic adaptation; mitochondrial dysfunction; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1692597
  7. Nutrients. 2026 Feb 27. pii: 778. [Epub ahead of print]18(5):
    Effect of Oral Ketone Body Intake on Human CD8+ T-Cell Immunometabolism.
    David Effinger, Simon Hirschberger, Thore Arntjen, Michaela Zell, Lesca Miriam Holdt, Simone Kreth.
      Background/Objectives: The ketogenic diet (KD) has been shown to exert beneficial effects on human immunity by enhancing cytotoxic T lymphocyte function through metabolic reprogramming. However, strict dietary restrictions limit adherence and complicate its use in clinical practice. Exogenous ketone supplements have therefore been promoted as a more feasible alternative to elevate ketone body levels without the need for dietary changes. The objective of this study was to assess whether ketone salt or ketone ester supplementation can reproduce KD-mediated immunometabolic effects on CD8+ T cells in healthy individuals. Methods: In a prospective interventional study, healthy volunteers received either ketone salts (KS) or ketone esters (KE) for three weeks. Plasma β-hydroxybutyrate (BHB) concentrations were determined, and CD8+ T-cell cytokine secretion, functional responses, and mitochondrial energy metabolism were analyzed. In a subgroup, KS supplementation was combined with a carbohydrate-restricted, non-ketogenic diet. Results: While KS supplementation resulted in a short-lived increase in plasma BHB concentrations followed by increased BHB uptake in immune cells, KE supplementation led to more sustained plasma BHB levels, however, without detectable intracellular BHB accumulation. Neither intervention affected CD8+ T-cell cytokine production, functional capacity, or mitochondrial energy metabolism, and KS intake combined with a carbohydrate-restricted, non-ketogenic diet likewise did not alter CD8+ T-cell immunometabolic parameters. Conclusions: Transient elevation of circulating ketone body levels through supplementation seems insufficient to reproduce the immunometabolic effects of a KD, which likely require broader metabolic adaptations. Thus, the impact of exogenous ketones on adaptive immunity in healthy individuals appears limited.
    Keywords:  T-cell function; cytotoxic T cells; exogenous ketones; immunometabolism; ketogenic diet; ketone esters; ketone salts
    DOI:  https://doi.org/10.3390/nu18050778
  8. PLoS Negl Trop Dis. 2026 Mar;20(3): e0014077
    Acod1/itaconate axis controls anxiety-like behaviors induced by chronic infection of Toxoplasma gondii in mice.
    Ziyi Yan, Yumeng Zhou, Yingting Huang, Huiling Lv, Siyu Li, Yifan Zhang, Yan He, Xinde Jiang, Heng Deng, Yujuan Shen, Yumei Zhang, Wei Pan, Fenfen Sun.
       BACKGROUND: Chronic infection of Toxoplasma gondii (T. gondii) induces the anxiety-like behavior in hosts, which is closely linked to neuroinflammatory processes. Cis-aconite decarboxylase 1 (Acod1) is an enzyme that is responsible for itaconate production in Krebs Cycle. Emerging evidence highlights the Acod1/itaconate axis as a key regulatory node in macrophage immune-metabolic reprogramming. However, its role in infection-induced neurobehavioral alterations remains unclear. Here, we investigated the role of Acod1/itaconate axis in the anxiety induced by T. gondii chronic infection in mice.
    METHODS: To assess anxiety-like behaviors, we performed open field test and elevated plus maze test. Transcriptomic alterations and neuroinflammatory responses in the mouse amygdala were profiled via RNA sequencing, immunofluorescence staining, quantitative PCR (qPCR), and western blot. The functional role of the Acod1/itaconate axis was further investigated using Acod1-/- mice. Additionally, the therapeutic potential of dimethyl itaconate (DI), a cell-permeable itaconate derivative, was evaluated in chronically T. gondii-infected mice. The levels of indoleamine 2,3-dioxygenase (IDO), and serotonin (5-hydroxytryptamine, 5-HT) in serum were measured by enzyme-linked immunosorbent assay. Finally, DI's anti-inflammatory mechanism was identified in the microglial cell line BV-2 cells.
    RESULTS: Chronic T. gondii infection induced anxiety-like behaviors in mice and triggered the activation of Acod1/itaconate axis in the amygdala. Transcriptomic and histological analyses revealed upregulation of neuroinflammation-related genes, along with microglia activation. Genetic knockout of Acod1 induced the anxiety-like phenotypes, which were rescued by DI administration. Notably, DI treatment conferred both prophylactic and therapeutic benefits, effectively mitigating anxiety induced by infection. Mechanistically, DI suppressed T. gondii-induced M1 polarization in microglia to mitigate neuroinflammation via activating Nrf2 signaling. These events further reduced indoleamine IDO expression, leading to increased 5-HT levels and subsequent amelioration of anxiety-like behavior.
    CONCLUSIONS: Our findings demonstrate that the Acod1/itaconate axis plays an important role in regulating anxiety-like behavior by modulating neuroinflammation during chronic T. gondii infection. These results reveal a promising immune-metabolic drug target for treating T. gondii-associated neuropsychiatric conditions.
    DOI:  https://doi.org/10.1371/journal.pntd.0014077
  9. Parasite Immunol. 2026 Mar;48(3): e70069
    Bioenergetic Profiling of Lymphocytes in Patients With Visceral Leishmaniasis (VL) and Post Kala-Azar Dermal Leishmaniasis (PKDL).
    Shilpa Sengupta, Mitali Chatterjee.
      Studies pertaining to Visceral leishmaniasis (VL) and its dermal sequel, Post Kala-azar Dermal Leishmaniasis (PKDL) are usually restricted to their immunopathogenesis, but the role, if any, regarding metabolic dysfunction of lymphocytes remains unanswered, and was the focus of this study. To delineate and correlate the functional and bioenergetic status of lymphocytes in patients with VL and PKDL. In Peripheral blood of patients with VL (n = 11) or PKDL (n = 18), along with healthy controls (n = 10), the T lymphocyte subsets (CD4+ and CD8+), their activation (CD69) and exhaustion (CD279) status were determined by flow cytometry. Oxidative phosphorylation (OXPHOS) and glycolysis were measured concomitantly in an extracellular flux analyser, whilst the status of mitochondrial respiration and glycolysis related genes was measured by qPCR. In comparison to healthy controls, the activation status remained unchanged in VL and PKDL cases but the frequency of exhausted T cells was significantly raised. These exhausted T cells showed an increased expression of OXPHOS in terms of signalling markers (SMAD3 and CPT1A) and oxygen consumption rate (OCR), along with an increased expression of mitochondrial respiration genes, which correlated positively with CD279+ T cells, whereas glycolysis remained unchanged. Patients with VL and PKDL demonstrated increased expression of CD279/Programmed cell death protein 1 (PD-1). This PD-1 signalling possibly activated SMAD3 and mitochondrial CPT1A, which led to increased mitochondrial respiration. This metabolic adaptation possibly facilitated sustenance of the exhausted T cell phenotype and contributed to disease progression. Targeting immunometabolism could well be a therapeutic approach worthy of future pharmacological consideration.
    Keywords:  T cells; glycolysis; oxidative phosphorylation (OXPHOS); post kala‐azar dermal leishmaniasis PKDL; programmed cell death protein 1 (PD‐1 or CD279)
    DOI:  https://doi.org/10.1111/pim.70069
  10. JCI Insight. 2026 Mar 09. pii: e198342. [Epub ahead of print]11(5):
    Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense.
    Adam S Krebs, Tomi Lazarov, Anthony T Reynolds, Kimberly A Dill-McFarland, Abigail Xie, James M Bean, Muxue Du, Olivier Levy, John A Buglino, Aaron Zhong, Anna-Lena Neehus, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Elouise E Kroon, Marlo Möller, Thomas R Hawn, Ting Zhou, Lydia Ws Finley, Marc Antoine Jean Juste, Dan W Fitzgerald, Frederic Geissmann, Michael S Glickman.
      Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.
    Keywords:  Cytokines; Immunology; Infectious disease; Macrophages; Pulmonology; Tuberculosis
    DOI:  https://doi.org/10.1172/jci.insight.198342
  11. Immunol Rev. 2026 Mar;338(1): e70114
    Sex Differences in Metabolite-Immune Circuits of Neuroinflammation.
    Priyanka Saminathan, Maija Corey, Alicia Gibbons, Mahati Rayadurgam, Neha Reddy, Pavithra Ramesh, Sonia Sharma.
      Sex is a fundamental yet underexplored determinant of human neuroinflammation. Across autoimmune, neurodegenerative, and post-infectious neurological syndromes, males and females exhibit consistent differences in disease vulnerability, progression, and immune tone. While sex hormones and chromosomes strongly shape immune development and function in health and disease, they do not fully explain the magnitude or disease-specific patterns of these disparities, nor do they provide sufficient mechanistic information for developing novel therapeutics. Emerging evidence suggests that sex-defining factors interact with age and environment to shape downstream metabolite-immune circuits, networks in which metabolic enzymes, metabolites, and immune cells tune inflammatory set points. Pathways spanning purine metabolism, glycolytic remodeling, lipid sensing, mitochondrial stress, and nucleic-acid sensing can recalibrate microglial activation thresholds, T-cell cytokine programs, innate type I interferon antiviral responses, and shape overall CNS resilience in a sex-dependent manner. Here, we synthesize mechanistic and human systems-level studies to propose an integrated framework in which sex-biased immunometabolism serves as a mechanistic bridge between biological sex and neuroimmune disease risk, progression, and responses to injury. We highlight key knowledge gaps and discuss how targeting metabolite-immune pathways may enable sex-informed biomarkers and therapeutic strategies in neuroinflammatory disease.
    Keywords:  bio‐active lipids; immunometabolism; microglia; neuroinflammation; purine metabolism; sex differences
    DOI:  https://doi.org/10.1111/imr.70114
  12. Nat Commun. 2026 Mar 09.
    DPEP2 suppresses hyperinflammation via metabolic reprogramming of macrophages in sepsis.
    Wenchen Luo, Wei Xu, Qimeng Yin, Jieqiong Song, Jie Wang, Yian Guan, Jian Huang, Jian Yu, Kefeng Zou, Danfeng Jin, Chao Xu, Min Qiu, Zhixin Qiu, Jing Zhong.
      Sepsis-induced excessive inflammation contributes to mortality, but restricting hyperinflammation in sepsis remains challenging. Here, we identify dipeptidase 2 (DPEP2) as an immunotherapeutic target in sepsis by integrating single-cell and bulk RNA sequencing data from septic patients. In patients with sepsis, peripheral monocytes/macrophages have reduced DPEP2 expression, with DPEP2 levels negatively correlating with inflammation severity, disease progression, and clinical outcomes. In vitro, Dpep2 knockdown enhances macrophage-mediated inflammation, while in septic mice in vivo, macrophage-specific Dpep2 loss decreases survival by exacerbating inflammation and organ damage. Mechanistically, sepsis-induced EGR1 represses Dpep2 transcription, leading to reduced DPEP2-mediated enzymatic cleavage of leukotriene D4 (LTD4). Increased LTD4 redirects the metabolic flux toward prostaglandin E2 overproduction, amplifying NF-κB activation and lipopolysaccharide-induced inflammatory cytokine production. Lastly, lipid nanoparticle (LNP)-mediated delivery of Dpep2 mRNA expression to monocytes/macrophages mitigates inflammation and organ damage in septic mice. Our findings thus suggest a protective function for DPEP2 in sepsis-induced hyperinflammation via immunometabolic regulation, and also present LNP-mediated Dpep2 mRNA delivery as a potential therapy for septic hyperinflammation.
    DOI:  https://doi.org/10.1038/s41467-026-70466-4
  13. Int J Biol Sci. 2026 ;22(5): 2603-2621
    Itaconate Modulates Neutrophil Homeostasis to Ameliorate Airway Inflammation in Diesel Exhaust Particles-exacerbated Asthma via Inhibiting NETs Formation.
    Guiping Zhu, Ling Ye, Yansha Song, Yu Chen, Hui Cai, Zilinuer Abuduxukuer, Liping Zhu, Yingying Zeng, Wenjiao Zhu, Dan Ye, Yuanlin Song, Pu Wang, Meiling Jin, Jian Wang.
      Particulate matter exposure, especially diesel exhaust particles (DEP), can exacerbate neutrophilic airway inflammation which presents corticosteroid insensitivity, resulting in the loss of asthma control. The underlying biological mechanisms remain poorly understood, thereby impeding the development of innovative therapeutic strategies. Itaconate (ITA) is an anti-inflammatory metabolite that suppresses excessive immune activation in multiple pathological conditions. In this study, we identified that neutrophil acted as an essential regulator in DEP-induced corticosteroid-resistant asthma mouse models. Multi-omics and single-cell sequencing analysis found that aconitate decarboxylase 1 (ACOD1)/ITA was significantly elevated in neutrophils via the NF-κB signaling pathway in DEP-exacerbated asthma. Knockout of Acod1 exacerbated asthma pathogenesis, while treatment with exogenous ITA or 4-octyl itaconate (4-OI) conferred protection against airway inflammation and reversed corticosteroid resistance in asthma mouse models. Mechanistically, neutrophil-derived ITA helped maintain immune homeostasis by reducing the formation of neutrophil extracellular traps (NETs), which further inhibited Th17 cell differentiation in DEP-exacerbated asthma. Our results delineate the dual immunoregulatory function of neutrophils in DEP-induced corticosteroid-resistant asthma, wherein they simultaneously propagate inflammation through NETosis and Th17 activation while restraining immune hyperactivation via ITA-mediated metabolic regulation. ITA serves as a negative regulator of airway inflammation and corticosteroid resistance, highlighting its promising therapeutic potential in asthma.
    Keywords:  Corticosteroid-resistant asthma; Diesel exhaust particles; Itaconate; Neutrophil extracellular traps; Neutrophils
    DOI:  https://doi.org/10.7150/ijbs.124927
  14. Autophagy. 2026 Mar 11. 1-18
    Lipophagy fuels phosphatidylcholine synthesis for Newcastle disease virus replication.
    Mengqing Yang, Juan Chen, Xiang Su, Xianjin Kan, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Shengqing Yu, Chan Ding, Yingjie Sun.
      Lipid droplets (LDs) are dynamic organelles that store neutral lipids and maintain lipid homeostasis. Many viruses exploit LDs as replication platforms or lipid sources, but their role in supplying membrane lipids for viral assembly remains unclear. Newcastle disease virus (NDV), an enveloped RNA virus with oncolytic potential, extensively remodels host metabolism, yet its impact on LD lipid mobilization is unknown. Here, we show that NDV reprograms host lipid metabolism via SQSTM1/p62-dependent lipophagy, selectively degrading triglycerides (TAGs) enriched in unsaturated fatty acids (UFAs). Lipidomics revealed concurrent depletion of UFA-containing triglycerides (UFA-TAGs) and UFA-containing phosphatidylcholines (UFA-PCs) during infection. Inhibition of lipophagy blocked LD degradation, reduced viral replication, and suppressed UFA-PC formation. Isotope tracing demonstrated that lipophagy-derived UFAs are incorporated into phosphatidylcholines (PCs) via the Kennedy pathway, whereas β-oxidation was dispensable. UFA supplementation rescued viral replication under lipophagy blockade and promoted virus-like particle (VLP) release, indicating that UFA-PCs facilitate viral budding. These findings uncover a distinct NDV strategy linking lipophagy-driven UFA release to phospholipid synthesis and membrane remodeling, revealing a lipid-based metabolic vulnerability for antiviral and oncolytic interventions.Abbreviations: AP: autophagosome; ATG: autophagy related; ATP: adenosine triphosphate; CQ: chloroquine; EGFP: enhance green fluorescent protein; FFA: free fatty acid; HN: Hemagglutinin-Neuraminidase; LA: linoleic acid; LD: lipid droplet; LIPA: lipase A, lysosomal acid type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NDV: newcastle disease virus; NP: nucleoprotein; OA: oleic acid; PA: palmitic acid; PC: phosphatidylcholine; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; POA: palmitoleic acid; SFA: saturated fatty acid; TAG: triglyceride; UFA: unsaturated fatty acid; UFA-PC: UFA-containing phosphatidylcholine; VLP: virus-like particle.
    Keywords:  Newcastle disease virus; SQSTM1/p62; lipid droplets; lipophagy; phosphatidylcholine; unsaturated fatty acids
    DOI:  https://doi.org/10.1080/15548627.2026.2642980
  15. Trends Endocrinol Metab. 2026 Mar 10. pii: S1043-2760(26)00033-0. [Epub ahead of print]
    Heme as a metabolic cell-fate switch.
    Jia Liu, Rui Kang, Daolin Tang.
      Heme availability shapes mitochondrial function, redox balance, and innate immune signaling. Recent studies reveal threshold-dependent heme states that predispose cells to cuproptosis, ferroptosis, apoptosis, pyroptosis, or PANoptosis. Viewing heme as a metabolic rheostat provides a unifying framework for interpreting regulated cell death across cancer, infection, and metabolic disease.
    Keywords:  damage-associated molecular pattern signaling; heme metabolism; immunometabolism; mitochondrial stress; regulated cell death
    DOI:  https://doi.org/10.1016/j.tem.2026.01.017
  16. Hepatology. 2026 Mar 11.
    FYN/LCK kinase balance as a metabolic switch orchestrates progenitor exhausted T Cell differentiation in hepatocellular carcinoma.
    Junyu Wu, Zhuofeng Jiang, Qiucheng Li, Chien-Shan Cheng, Yau-Tuen Chan, Ranna Yeerken, Junbang Chen, Pengde Lu, Zixin Feng, Hongchao Yuan, Lin Xu, Zhiqiang Meng, Yibin Feng, Hor-Yue Tan, Ning Wang.
       BACKGROUND AND AIMS: Immune checkpoint blockade (ICB) shows therapeutic promise in hepatocellular carcinoma (HCC) but is associated with suboptimal responses in patients. Progenitor exhausted T (Tpex) cells are key responders to ICB, but the regulatory mechanisms regarding Tpex maintenance in HCC remain elusive.
    APPROACH AND RESULTS: Through an integrated analysis of HCC single-cell RNA-sequencing datasets, we constructed an exhausted CD8+ T cell atlas and identified FYN as a marker of Tpex cells in ICB responders. FYN deficiency in CD8+ T cells induced LCK hyperactivation, which drove terminal exhaustion under high-affinity antigen stimulation. Mechanistically, LCK hyperactivation disrupted metabolic homeostasis by triggering excessive glycolysis and impairing mitochondrial function in Tpex cells. Conversely, LCK inhibition elevated compensatory FYN activity, restored mitochondrial fitness and preserved Tpex cell stemness. In preclinical HCC models, transient LCK inhibition during T cell expansion enhanced adoptive cell therapy efficacy by increasing Tpex cell persistence and stemness. Besides, preemptive low-dose LCK inhibition prior to anti-PD1 therapy expanded the Tpex cell pool, reduced terminal exhaustion, and improved therapeutic outcomes.
    CONCLUSIONS: This study establishes the balance between SRC kinases FYN and LCK as a critical regulator of the terminal exhaustion of Tpex cell through metabolic reprogramming. The finding suggests that modulating the FYN/LCK kinase balance is a promising strategy to overcome immunotherapy resistance in HCC.
    Keywords:  Adoptive cell transfer; CD8 T cells; SRC kinases; T cell exhaustion; immune checkpoint blockade; metabolic reprogramming
    DOI:  https://doi.org/10.1097/HEP.0000000000001740
  17. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2526147123
    ODC1 restricts meningeal B cell age-associated-like phenotype and function in multiple sclerosis: A human and experimental study.
    Jonathan Zurawski, Alara Tuncer, Martin R Profant, Jianuo Wang, Miranda Green, Yoobhin Park, Ke Cao, Simon Paris, Shahamat Tauhid, Youmna Jalkh, Molly Quattrucci, Renxin Chu, Xingshan Cao, Alex Kiss, Tanuja Chitnis, Howard Weiner, Clary B Clish, Rohit Bakshi, Chao Wang.
      Meningeal inflammation, as a clinical feature of multiple sclerosis (MS), is associated with worse clinical disease outcomes. In both relapsing and secondary progressive MS and the experimental autoimmune encephalomyelitis (EAE) MS model, the meninges have been found to contain ectopic lymphoid follicles enriched with B cells. The metabolic requirement of meningeal B cell function in MS or EAE is not well elucidated. Using 7-Tesla MRI brain scans of MS patients and leptomeningeal enhancement as a marker, we found a correlation between meningeal inflammation and metabolites of the arginine/polyamine pathway, a finding recapitulated in EAE. Ornithine Decarboxylase (ODC1), the rate limiting enzyme for polyamine biosynthesis, as well as polyamine metabolism was diminished in the dura meningeal B cells from mice with MOG35-55 induced EAE mice as compared to naïve controls. Pharmacological inhibition of ODC1 restricted meningeal T cells but promoted meningeal B cell proliferation. B cell-specific deletion of ODC1 resulted in expansion of B cells with age-associated B cell-like phenotype (CD11c+CD21/35-CD23-IgD-), an increase in MOG-specific IgG in the brain, reduction of hippocampal synaptic density, and exacerbated disease in the MOG1-125 EAE model. Together, these findings demonstrate a divergent role of polyamines in regulating B and T cell responses in the meninges during autoimmunity.
    Keywords:  age associated B cells; autoimmunity; immunometabolism; multiple sclerosis; polyamines
    DOI:  https://doi.org/10.1073/pnas.2526147123
  18. Life Sci. 2026 Mar 06. pii: S0024-3205(26)00120-7. [Epub ahead of print]392 124311
    LDHB K156 lactylation links cGAS-STING-mediated metabolic reprogramming to NLRP3 inflammasome activation in sepsis-associated acute kidney injury.
    Mengyuan Luo, Zhihua Mi, Boyang Yu, Sujing Zhang, Pinwen Wu, Yi Shi, Hao Fang, Qiqing Shi.
       AIMS: Sepsis-associated acute kidney injury (SA-AKI) pathogenesis remains incompletely understood. This study aimed to elucidate the immunometabolic mechanisms driving SA-AKI, focusing on the role of metabolic reprogramming and non-histone protein lactylation in amplifying renal inflammation.
    MATERIALS AND METHODS: We utilized a cecal ligation and puncture (CLP) mouse model and lipopolysaccharide (LPS)-stimulated HK-2 cells. Evaluations included lactyl-proteomic screening, cellular metabolic/biochemical assays, and in vivo adeno-associated virus (AAV)-mediated renal tubule-specific expression of wild-type (WT) or lactylation-deficient mutant (K156R) lactate dehydrogenase B (LDHB).
    KEY FINDINGS: Sepsis induced pronounced glycolysis, lactate accumulation, and NLRP3 inflammasome activation. Lactyl-proteomics revealed significant upregulation of LDHB lysine 156 (K156) lactylation. Mechanistically, upstream cGAS-STING signaling promoted glycolytic reprogramming and lactate production, providing substrates for LDHB K156 lactylation, which was regulated by the EP300/HDAC2 axis. In vivo, compared with the K156R mutant, LDHB WT exacerbated renal dysfunction, histopathological injury, and inflammasome activation.
    SIGNIFICANCE: LDHB K156 lactylation represents a critical molecular nexus linking cGAS-STING-mediated metabolic dysregulation to inflammatory amplification. Targeting this lactylation regulatory axis offers a potential mechanism-oriented therapeutic strategy for SA-AKI.
    Keywords:  Glycolysis; LDHB K156; Lysine lactylation; NLRP3 inflammasome; Sepsis-associated acute kidney injury; cGAS–STING
    DOI:  https://doi.org/10.1016/j.lfs.2026.124311
  19. Immunity. 2026 Mar 06. pii: S1074-7613(26)00040-3. [Epub ahead of print]
    Macrophage metabolic exhaustion and PANoptotic cell death drive chronic tissue inflammation in rheumatoid arthritis.
    Tao Huang, Yoshinori Takashima, Jitendra Kumar, Jose Morales, Kevin Le, Zhensheng Hu, Selene Rubino, Robert T Trousdale, Gerald J Berry, Jorg J Goronzy, Cornelia M Weyand.
      In the autoimmune disease rheumatoid arthritis, the inflammatory response evolves from protective to pathogenic, causing tissue destruction. Rheumatoid synovitis persists despite the presence of pro-repair SELENOPhiMerTK+CD206+ macrophages, suggesting that these cells acquire pro-arthritogenic functions. Patient-derived synovial SELENOPhiMerTK+CD206+ macrophages produced high concentrations of the complement component C1q and concurrently expressed its receptor, C1QBP. Stimulation of these macrophages with C1q induced metabolic exhaustion, characterized by diminished ATP production, cleavage of mitochondrial nicotinamide adenine dinucleotide (NAD), and accumulation of cyclic ADP ribose (cADPR). This metabolic crisis was driven by the mitochondrial enzyme Sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), which catalyzed the conversion of NAD into cADPR, triggering PANoptotic and pro-inflammatory macrophage death. In vivo experiments demonstrated that C1q treatment exacerbated synovitis, whereas SARM1 inhibition conferred therapeutic benefit. These findings identify the NAD+ hydrolase SARM1 as a marker of metabolically stressed macrophages and an executor of pro-inflammatory macrophage death during autoimmune tissue inflammation.
    Keywords:  C1Q-binding protein; C1q; NAD; NAD(+) hydrolase; PANoptosis; SARM1; cADPR; metabolic exhaustion; rheumatoid arthritis; tissue macrophage
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.019
  20. J Immunother Cancer. 2026 Mar 11. pii: e012309. [Epub ahead of print]14(3):
    CD79A/CD40 intracellular domain uses a 4-1BB-like metabolic pathway driven by cholesterol biosynthesis.
    Yuki Takeuchi, Seitaro Terakura, Kohei Ishigiwa, Jakrawadee Julamanee, Shiho Hirano, Hirofumi Yokota, Shihomi Kuwano, Ryo Hanajiri, Hitoshi Kiyoi.
       BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has transformed the treatment of hematologic malignancies. The costimulatory domain (CSD) of CAR constructs plays a crucial role in determining T cell metabolism, persistence, and antitumor function. We previously developed a novel CSD combining CD79A and CD40, which conferred superior proliferation and antitumor efficacy compared with CD28-based or 4-1BB-based CAR-T cells. The metabolic mechanisms underlying these effects remain to be elucidated.
    METHODS: We compared CD28, 4-1BB, and CD79A/CD40 CAR-T cells using transcriptomic analysis, metabolic flux assays, and metabolomics. Patient samples treated with 4-1BB-based or CD28-based CAR-T therapies were analyzed to assess correlations between serum lipids and CAR-T expansion.
    RESULTS: Transcriptomic profiling revealed that CD79A/CD40 CAR-T cells shared gene expression patterns with 4-1BB CAR-T cells, particularly in pathways related to oxidative phosphorylation (OXPHOS) and T cell memory differentiation, but were distinct from CD28 CAR-T cells. Both 4-1BB and CD79A/CD40 CAR-T cells relied on OXPHOS and exhibited greater mitochondrial fitness, as evidenced by higher spare respiratory capacity and mitochondrial mass. Notably, CD79A/CD40 CAR-T cells displayed significantly enhanced glycolysis during the early phase following antigen stimulation, distinguishing them from 4-1BB CAR-T cells and supporting rapid initial expansion. Metabolomic profiling showed upregulation of cholesterol biosynthesis enzymes in both CD79A/CD40 and 4-1BB CAR-T cells, suggesting a shared reliance on cholesterol metabolism. Importantly, in patients treated with 4-1BB-based CAR-T therapy, higher serum low-density lipoprotein cholesterol levels positively correlated with CAR-T expansion in the late phase, particularly within CD4+T cell subsets. This relationship was not observed in patients receiving CD28-based CAR-T therapy. These findings indicate that cholesterol availability may influence CAR-T persistence in vivo, and that the metabolic phenotype of CD79A/CD40 CAR-T cells is optimized for both early proliferation and long-term survival.
    CONCLUSIONS: CD79A/CD40 CAR-T cells exhibit unique metabolic adaptations, including early glycolytic activation, sustained OXPHOS, and upregulated cholesterol metabolism, which together may underpin their enhanced proliferation and persistence. Targeting cholesterol metabolism may represent a novel strategy to optimize CAR-T cell function and improve therapeutic outcomes.
    Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Hematologic Malignancies; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-012309
  21. Cell Rep. 2026 Mar 10. pii: S2211-1247(26)00135-X. [Epub ahead of print]45(3): 117057
    Mitochondrial transfer to granulocytic myeloid-derived suppressor cells augments immunosuppressive activity.
    Prabhakar Arumugam, Cortney E Heim, Rachel W Fallet, Dhananjay D Shinde, Vinai C Thomas, Rafael J Argüello, Tammy Kielian.
      The anti-inflammatory properties of granulocytic myeloid-derived suppressor cells (G-MDSCs) promote Staphylococcus aureus (S. aureus) biofilm persistence. Evidence suggests that G-MDSC activity is shaped not only by S. aureus products but also by intrinsic metabolic programs. This study explores whether G-MDSC activity can be modulated by increasing mitochondrial abundance using a co-culture paradigm with macrophages as a mitochondrial donor. Macrophages transfer mitochondria directly to G-MDSCs via tunneling nanotubes, enhancing G-MDSC respiration, as reflected by increased basal, maximal, and spare respiratory capacity. Augmenting mitochondrial abundance in G-MDSCs enhances T cell-suppressive activity and reduces tumor necrosis factor (TNF) and interleukin 6 (IL-6) production. In a mouse model of S. aureus prosthetic joint infection, adoptively transferred macrophages deliver mitochondria to G-MDSCs, enhancing their suppressive activity and increasing bacterial burden, which is reversed when macrophages with non-functional mitochondria are introduced. These findings support the theory that G-MDSCs exploit mitochondria to augment their anti-inflammatory properties in response to S. aureus biofilm.
    Keywords:  CP: cell biology; CP: immunology; Staphylococcus aureus; biofilm; granulocytic myeloid-derived suppressor cells; immunometabolism; macrophages; mitochondria; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.celrep.2026.117057
  22. Adv Sci (Weinh). 2026 Mar 12. e20055
    NIPAL1 Drives a Metabolic-Epigenetic Feedback Loop to Promote Lactate-Mediated Immune Evasion in Esophageal Cancer.
    Ri-Xin Chen, Xiao-Dan Ma, Shui-Dan Xu, Ao-Tian Mo, Min-Hua Deng, Jun-Han Wu, Wei-Tao Zhuang, Jin-Ling Duan, Shu-Huan Xie, Jin-Long Lin, Peng Lin, Ji-Ming Tang, Hai-Yu Zhou, Xiao-Song Ben, Gui-Bin Qiao, Dan Xie.
      Metabolic reprogramming is a hallmark of cancer that promotes tumor progression and immune evasion. Here, we identify a NIPAL1-driven metabolic-epigenetic circuit in esophageal squamous cell carcinoma (ESCC) that facilitates tumor growth and suppresses antitumor immunity. Mechanistically, NIPAL1 recruits the tyrosine kinase HCK to phosphorylate LDHA at Y10, enhancing glycolysis and lactate production. Lactate accumulation promotes p300-mediated histone H3K18 lactylation (H3K18la), which transcriptionally activates NIPAL1 expression, establishing a self-sustaining NIPAL1-HCK-p-LDHA-lactate-p300-H3K18la loop. This axis functions independently of NIPAL1's canonical magnesium transporter activity and promotes immune escape by impairing CD8+ T cell function. Pharmacological inhibition of HCK or p300 disrupts this loop and restores antitumor immunity, sensitizing tumors to anti-PD-1 therapy. Clinically, expression of NIPAL1, p-LDHA (Y10), and H3K18la correlates with response to immune checkpoint blockade. Our findings reveal a previously unrecognized NIPAL1-HCK-H3K18la signaling loop that integrates tumor metabolism to immune regulation, offering promising targets to improve immunotherapy efficacy in ESCC.
    Keywords:  NIPAL1; esophageal squamous cell carcinoma; histone lactylation; immune evasion; lactate
    DOI:  https://doi.org/10.1002/advs.202520055
  23. J Infect Dis. 2026 Mar 07. pii: jiag144. [Epub ahead of print]
    MHC-I upregulation and increased glucose dependence define innate antifungal immune responses to Cryptococcus neoformans.
    Ayesha S Nair, Karen L Wozniak.
       BACKGROUND: Cryptococcus neoformans, the etiological agent of cryptococcosis, can survive and replicate within host immune cells, contributing to development of cryptococcal meningitis. Within the lung, C. neoformans interacts with innate immune subsets, including macrophages and dendritic cells (DCs). Our previous work demonstrated that Ly6c- monocyte-like macrophages restrict fungal proliferation, whereas CD11b+ DCs promote fungal growth. Transcriptomic profiling revealed differential expression of MHC class I gene H2-K1, Calreticulin (Calr), and metabolic genes. Therefore, we hypothesized that H2-K1 and metabolic pathways modulate the intracellular fungal fate within pulmonary macrophages and DCs.
    METHODS: H2-K1 expression was knocked down using siRNA in J774 macrophages and GM-CSF-induced bone marrow-derived DCs (BMDCs). Antifungal activity was determined by CFU enumeration. Phagocytic uptake, cathepsin B activity, Nos2 expression and reactive oxygen species (ROS) production were quantified by flow cytometry. Metabolic dependencies were evaluated using SCENITH assay.
    RESULTS: H2-K1 KD in J774 cells significantly reduced antifungal activity compared to controls. H2-K1 knockdown also decreased Calr gene expression, suggesting H2-k1 has downstream effects in the pathway. H2-K1 silencing did not significantly alter phagocytic uptake, cathepsin B activity, or Nos2 expression. However, ROS production was significantly reduced in H2-K1 KD J774 cells, indicating impaired responses. SCENITH analysis revealed that antifungal macrophages shift their metabolism toward glucose oxidation for ATP generation, which is important for antifungal activity.
    CONCLUSION: These findings indicate that metabolic reprogramming is critical for effective antifungal responses. Our data provide a foundation for future studies aimed at targeting host immune and metabolic pathways to enhance antifungal immunity.
    Keywords:  Cryptococcus; H2-K1; MHC-I; SCENITH; antifungal immunity; calreticulin; metabolic reprogramming; reactive oxygen species
    DOI:  https://doi.org/10.1093/infdis/jiag144
  24. J Pharm Biomed Anal. 2026 Mar 02. pii: S0731-7085(26)00113-5. [Epub ahead of print]275 117445
    Untargeted LC-MS-based metabolic fingerprinting of Escherichia coli-associated urinary tract infections and urosepsis: Insights into the urine, serum, and bacterial interactomes.
    Paweł Wityk, Joanna Raczak-Gutknecht, Margot Biesemans, Beata Krawczyk, Wiktoria Brzezińska, Michał J Markuszewski.
      Urinary tract infections (UTIs) and urosepsis necessitate a deeper understanding of host-pathogen interactions at the metabolic level. We use LC-MS and GC-MS techniques to characterize metabolic pathway alterations in patients and Escherichia coli isolates during UTI and urosepsis. Our findings reveal substantial metabolic adaptations in the human host, including increased porphyrin metabolism, suggesting oxidative stress response or tissue damage. Activation of the pentose phosphate pathway (PPP) and tricarboxylic acid cycle (TCA) highlights the host's heightened immune and energy demands during infection. Additionally, enhanced malate-aspartate shuttle activity suggests a greater reliance on glycolysis for energy production, while increased pyruvaldehyde degradation indicates active detoxification of harmful metabolic byproducts. In E. coli, distinct metabolic shifts depended on the extracellular/intracellular niche and infection stage. Intracellular metabolites of E. coli during urosepsis exhibited upregulated purine and biotin metabolism, reflecting a focus on replication and essential metabolic functions. Conversely, intracellular metabolites of E. coli during UTI displayed increased aspartate metabolism, TCA cycle activity, Warburg effect, fatty acid biosynthesis, and glycine/serine metabolism, indicative of urinary tract adaptation. Extracellular metabolites of E. coli during urosepsis exhibited a broad activation of sugar metabolism, highlighting its ability to exploit diverse nutrient sources in systemic infection. In contrast, extracellular metabolites of E. coli during UTI demonstrated specific metabolic changes, including propanoate metabolism activation and homocysteine dysregulation, reflecting unique urinary tract conditions. These findings provide insights into the metabolic pathways employed by host and pathogen during UTI and urosepsis, uncovering potential metabolic vulnerabilities in E. coli.
    Keywords:  E. coli; LC-MS; Metabolites; Metabolomics; UTI; Urosepsis
    DOI:  https://doi.org/10.1016/j.jpba.2026.117445
  25. Free Radic Biol Med. 2026 Mar 06. pii: S0891-5849(26)00200-5. [Epub ahead of print]249 27-42
    Pharmacological elevation of lactate alleviates sepsis via histone lactylation-induced IL-10 production.
    Lina Chen, Rongrong Ren, Shihao Zhang, Jinlei Zhu, Xiaoying Li, Xiaofang Zhang, Xiangmin Wu, Bangdong Liu, Qian Fang, Zhengshang Ruan.
      Despite that lactate accumulation is deemed to be a marker of severe sepsis, lactate-driven histone lactylation induces transcription of homeostatic genes. Thus, the biological roles of lactate in sepsis remain unknown. Here, we report that amlexanox, an anti-inflammatory drug, improves survival, mitigates multiorgan dysfunction, and suppresses inflammatory infiltrates in endotoxemia and sepsis. Mechanistically, amlexanox elevates intracellular lactate to enhance histone lactylation of IL10 gene promoter and IL-10 production to alleviate sepsis. Blocking IL-10 receptor nearly abrogates therapeutic effect of amlexanox, and inhibiting lactate production abrogates amlexanox-induced IL-10. Amlexanox treatment significantly downregulates gene expression of electron transport chain, inhibits OCR, while promotes ECAR, indicating it elevates lactate level by breaking aerobic respiration. Importantly, in vivo sodium lactate administration improves survival in endotoxemia. Our study clarifies that elevating lactate-mediated histone lactylation plays a protective role in sepsis, and amlexanox is a potential drug for sepsis.
    Keywords:  Amlexanox; IL-10; Inflammation; Lactate; Lactylation; Sepsis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.016
  26. DNA Cell Biol. 2026 Mar 10. 10445498261427141
    Dietary Saturated Fatty Acids as Evolutionarily Conserved Signals of Immune Activation.
    Sam J McCright, Olivia Harding, David A Hill.
      Dietary fat is comprised largely of fatty acids (FAs), which function not only as metabolic substrates but also as key intracellular signaling molecules. Saturated fatty acids (SFAs) have long been linked to metabolic and inflammatory disease, yet the mechanisms by which they regulate immune function remain incompletely defined. In this review, we synthesize evidence that dietary SFAs directly modulate innate and adaptive immune responses through conserved inflammatory pathways. We highlight mechanisms of myeloid cell activation, including endoplasmic reticulum stress, inflammasome engagement, and NF-κB-dependent cytokine production, and discuss findings implicating SFAs in T cell activation and differentiation. We integrate recent work from our group demonstrating that dietary SFAs promote lung innate immune activation, linking lipid exposure to neutrophilic inflammation and impaired pulmonary function. Finally, we propose an evolutionary framework in which SFA-induced immune activation was adaptive during intermittent exposure but becomes maladaptive with chronic consumption, such as in modern diets.
    Keywords:  adaptive immunity; diet-immune interactions; evolutionary immunology; immune regulation; immunometabolism; inflammasome; inflammation; innate immunity; saturated fatty acids
    DOI:  https://doi.org/10.1177/10445498261427141
  27. Infect Immun. 2026 Mar 09. e0008626
    DRP1/DMNL-1-mediated mitochondrial fission augments Rickettsia parkeri replication in macrophages.
    Elliott Collins, Natasha Kelly, Heather Green, William Beavers, Basel Abuaita, Juan J Martinez.
      Pathogenic Spotted Fever Group (SFG) Rickettsia species, including Rickettsia parkeri, replicate in endothelial cells and macrophages in vitro and during infections in murine models of disease. We demonstrated that infection of human macrophage-like cells with a related SFG Rickettsia, R. conorii, resulted in a significant increase in mitochondria-associated proteins. However, the role of mitochondrial functions in Rickettsia pathogenesis is unknown. Here, we found that R. parkeri exploits mitochondrial dynamics to promote intracellular replication in mouse and human macrophages by activating the mitochondrial fission regulator, the dynamin-related protein 1 (DRP1). R. parkeri proliferated in macrophages, which coincided with a significant increase in mitochondria fission, mitochondria content, and host cell ATP production, primarily due to mitochondrial respiration compared to uninfected cells. In addition, R. parkeri infection also led to a temporal increase in DRP1 serine phosphorylation that was dependent on rickettsial de novo protein synthesis. Importantly, R. parkeri growth was significantly impacted in DRP1-deficient macrophages. These results suggest that the modulation of mitochondrial fission, content, and function is important for replication and survival of pathogenic SFG Rickettsia species in macrophages. Our data highlight that hijacking mitochondrial dynamics and function is essential for intracellular replication of Rickettsia species and may be a shared mechanism utilized by related obligate intracellular pathogens for growth.
    Keywords:  DRP1; Rickettsia; mitochondria
    DOI:  https://doi.org/10.1128/iai.00086-26
  28. Int Endod J. 2026 Mar 08.
    Lactylation-Driven Macrophage Polarisation Regulates Pulp Inflammation.
    Ziting Wang, Wanli Xu, Tingyun Xu, Hang Zhao, Xiaolin Lyu, Leyi Chen, Wenjing Yi, Buling Wu, Wenan Xu.
       AIM: This study investigated the effects of lactate-induced lactylation in the inflammatory microenvironment of pulpitis and further explored the mechanism.
    METHODOLOGY: Lactate levels in pulpitis samples were quantified using a high-sensitivity assay. Histological, immunohistochemical, and immunofluorescence staining were conducted to evaluate lactylation, macrophage marker, pro-inflammatory, and anti-inflammatory markers. A time-course murine experimental pulpitis model (0-72 h) was established to characterise lactylation dynamics during inflammatory progression in pulpitis. An in vitro inflammatory dental pulp microenvironment model of THP-1 macrophages cocultured with LPS-pretreated dental pulp cells derived conditioned media (iCM) was developed to investigate lactate production and macrophage phenotypes. Transcriptomic profiling identified differentially expressed genes, with gene set enrichment analysis (GSEA) employed to assess the functions of differentially expressed genes. Transmission electron microscopy, quantitative real-time PCR (qRT-PCR), concurrent oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were measured to evaluate the mitochondrial activity of iCM-pretreated macrophages. Mouse experimental pulpitis models treated with iCM were conducted to evaluate anti-inflammation and pro-healing properties by histological, immunohistochemical, and immunofluorescence staining.
    RESULTS: Histological staining revealed that elevated lactate levels, increased Pan Kla expression, and upregulated extent of M2 phenotype macrophage infiltration in clinical pulpitis specimens. Notably, we identified a positive correlation between Pan Kla levels and M2 macrophage markers. In vitro inflammatory dental pulp microenvironment model, we demonstrated that M1 macrophages actively uptake lactate from iCM, leading to increased lactylation and subsequent M2-like polarisation. Importantly, we found that iCM could regulate polarisation of M1 macrophages via metabolic reprogramming, as evidenced by RNA sequencing. Our integrated analyses revealed significant mitochondrial structural remodelling, while metabolic flux assays demonstrated a characteristic shift from glycolytic metabolism to oxidative phosphorylation. This metabolic reprogramming was functionally linked to M2 polarisation, as evidenced by phenotypic marker analysis. Moreover, iCM treatment significantly downregulated pro-inflammatory cytokine (IL-6) while upregulating anti-inflammatory marker (CD206) in experimental pulpitis models.
    CONCLUSION: This study revealed that elevated lactate production in the inflammatory microenvironment roles as a mediator of immunometabolic crosstalk, bridging dental pulp cells-macrophage communication. And the mechanism involved in lactylation induced metabolic reprogramming. This helps to better understand the repair potential of inflamed dental pulp, supporting biologically-based preservation approaches.
    Keywords:  immunotherapy; inflammation; innate immunity; posttranslational modification; pulp biology; pulpitis
    DOI:  https://doi.org/10.1111/iej.70136
  29. EMBO Mol Med. 2026 Mar 11.
    Metabolically reprogrammed eosinophils impair T cell immunity and cause chronic skin infection.
    David Barinberg, Heidi Sebald, Tobias Gold, Baplu Rai, Daniel Radtke, Dominik Lerm, David Voehringer, Jonathan Jantsch, Stefan Wirtz, Alina Ulezko Antonova, Marco Colonna, Christian Bogdan, Ulrike Schleicher.
      Eosinophils exhibit antimicrobial, cytotoxic and immunoregulatory effects, but our knowledge of their transcriptional and functional heterogeneity is still limited, especially in non-intestinal tissues. Here, we used a mouse model of chronic cutaneous inflammation elicited by the protozoan pathogen Leishmania mexicana to investigate the function and transcriptional dynamics of skin eosinophils. Infection of C57BL/6 mice triggered local and systemic eosinophilia that was driven by type 2 innate lymphoid cells and interleukin-5. Genetic and pharmacological eosinophil depletion led to an enhanced Th1 response, polarization towards M1-like macrophages and resolution of clinical disease, despite an unexpected simultaneous upregulation of IL-4. Single-cell transcriptomics revealed a skin-imprinted trajectory of inflammatory eosinophils that strongly expressed the glucose transporter Slc2a3 (GLUT3) These eosinophils impeded the function of Th1 cells by forming a competitive metabolic niche through preferential glucose uptake. Our findings uncover an inflammatory, metabolically reprogrammed eosinophil population that promotes chronic skin inflammation by limiting protective T cell responses.
    Keywords:  Chronic Skin Inflammation; Cutaneous Leishmaniasis; Eosinophils; Interleukin-5; scRNA-seq
    DOI:  https://doi.org/10.1038/s44321-026-00392-x
  30. Front Immunol. 2026 ;17 1702689
    Cross-species hepatic transcriptomics identify conserved immune-metabolic reprogramming in acute-on-chronic liver failure progression.
    Panyu Chen, Yun Song, Xiao Lin, Zhaokai Zeng, Wenxi Su, Yunyun Ren, Chen Wang, Kang He, Min Shi, Yugang Wang.
       Background: Acute-on-chronic liver failure is a fatal syndrome involving sudden hepatic deterioration in patients with chronic liver disease, resulting in high short-term mortality. The intrahepatic molecular mechanisms that drive disease progression are poorly understood, partly due to limited access to human liver tissues.
    Method: Transcriptomic profiling of liver tissues from patients with hepatitis B virus-related acute-on-chronic liver failure and a corresponding murine model was performed. Comparative analyses were conducted across disease stages to delineate the dynamic immune and metabolic trajectories.
    Result: The analysis uncovered a conserved immune-metabolic dysregulation during disease progression. In both patients and mice, immune activation-characterized by monocyte and macrophage infiltration and altered cytokine signaling-coincided with progressive metabolic failure, including the suppression of mitochondrial functions. The murine model further demonstrated a transition from an early stage of hyperinflammation to a later stage of immune exhaustion. Moreover, several monocyte and macrophage-associated genes were identified as conserved markers that correlate with disease severity, highlighting their potential as biomarkers or therapeutic targets.
    Conclusion: This study defines a conserved immune-metabolic interplay during the progression of hepatitis B virus-related acute-on-chronic liver failure and validates the murine model's accuracy for studying the disease's terminal stage. The identified dysregulation of immune cells and metabolic pathways presents actionable targets for developing stage-specific therapies intended to disrupt the disease's vicious immune-metabolic cycle.
    Keywords:  acute-on-chronic liver failure; immune dysfunction; liver cirrhosis; metabolic disorder; monocyte/macrophage; transcriptional profiles
    DOI:  https://doi.org/10.3389/fimmu.2026.1702689
  31. Front Immunol. 2026 ;17 1755928
    Regulatory T cells in hypoxic environments.
    Lourdes González-Rivera, Rodrigo Luna-Gutiérrez, Stephanie Cárdenas, Consuelo Merino-González, Alex Handy, Inés Pepper, Mercedes Natalia López.
      Oxygen availability is considered as an important determinant of immune regulation, yet its impact on regulatory T cells remains incompletely understood. In this review, we synthesize current evidence on how chronic and intermittent hypoxia influence the differentiation, stability and function of regulatory T cells across diverse physiological and pathological settings. We describe the main cellular pathways engaged during hypoxic adaptation, with emphasis on the role of hypoxia-inducible factors in shaping regulatory T cell metabolism and lineage integrity. We then evaluate findings from clinical contexts characterized by sustained or cyclical oxygen deprivation, including chronic lung disease, sleep-disordered breathing and severe viral infection. Across these conditions, hypoxia is associated with alterations in regulatory T cell phenotype and its suppressive function, although patterns vary according to microenvironment and disease stage. A clearer understanding of how distinct hypoxic patterns modulate regulatory T cell biology will be essential for identifying therapeutic strategies aimed at restoring immune balance in hypoxia-associated disease.
    Keywords:  COVID-19; chronic obstructive pulmonary disease; hypoxia; hypoxia-Inducible factor 1, alpha Subunit; inflammatory mediators; metabolic reprogramming; obstructive sleep apnea; regulatory T (Treg) cell
    DOI:  https://doi.org/10.3389/fimmu.2026.1755928
  32. mBio. 2026 Mar 09. e0336825
    African swine fever virus hijacks lipolysis induced by chaperone-mediated autophagy to upregulate fatty acid β-oxidation and promote viral replication.
    Xing Yang, Xin Xiong, Huanan Liu, Xiaodan Wen, Xijuan Shi, Han Ma, Renpo Wang, Weijun Cao, Fan Yang, Yi Ru, Hong Tian, Jijun He, Jianhong Guo, Shichong Han, Zixiang Zhu, Haixue Zheng.
      Lipid metabolism plays a crucial role in cellular signal transduction, affects the structural integrity of cell membranes, and regulates energy metabolism. However, various viruses, including African swine fever virus (ASFV), usurp lipid metabolism to enhance their replication. The mechanism for the positive role of lipid metabolism in ASFV infection is unclear. Here, we present data that ASFV infection concurrently upregulates both fatty acid synthesis (FAS) and fatty acid β-oxidation (FAO) to enhance viral replication. Pharmacological inhibition of FAS significantly suppresses ASFV replication, an effect that can be markedly reversed by exogenous palmitate (the end product of FAS). Similarly, inhibition of FAO also impairs viral replication. Lipidomic profiling revealed that ASFV infection dramatically alters lipid droplet (LD) lipid composition, particularly triglycerides (TG) and diacylglycerols (DAG). ASFV infection triggers the accumulation of LDs, which in turn promote viral replication. Mechanistically, we discovered that ASFV exploits chaperone-mediated autophagy (CMA) to degrade perilipin 2 (PLIN2), a protein on the LD surface, thereby stimulating lipolysis. Furthermore, ASFV infection induces LD-mitochondrion contacts, facilitating the transfer of LD-derived fatty acids to mitochondria. These data indicate that LDs provide lipids to fuel ASFV-induced FAO upregulation. Collectively, our study reveals that ASFV orchestrates a complex metabolic network involving FAS, LD biogenesis, lipolysis, and FAO to optimize viral replication. These findings elucidate the pivotal role of lipid metabolism in ASFV replication, revealing a mechanism through which the virus manipulates cellular lipid pathways to facilitate its replication. This insight not only advances our understanding of ASFV pathogenesis but also presents potential therapeutic avenues for inhibiting viral production by modulating lipid metabolic processes.IMPORTANCEAfrican swine fever (ASF), caused by African swine fever virus (ASFV), represents a catastrophic threat to the global swine industry, with no safe and effective vaccines or antiviral therapies currently available except in Vietnam. Understanding how ASFV reprograms host lipid metabolism is critical for developing targeted interventions. Our study reveals a novel metabolic hijacking strategy employed by ASFV to reprogram lipid metabolism pathways, including fatty acid synthesis (FAS), lipid droplet (LD) biogenesis, chaperone-mediated autophagy (CMA)-mediated lipolysis, and mitochondrial β-oxidation (FAO), to support viral replication. Notably, we provide evidence that ASFV exploits CMA to degrade perilipin 2 (PLIN2), a key protein stabilizing lipid droplets, thereby promoting lipolysis. This mechanism resolves the paradox of concurrent upregulation of FAS and FAO by facilitating lipid shuttling through LD-mitochondrion contacts. Our findings offer new insights into how ASFV exploits host lipid networks and may pave the way for designing vaccines or targeted drugs to control ASF.
    Keywords:  African swine fever virus; chaperone-mediated autophagy; fatty acid synthesis; fatty acid β-oxidation; lipid droplets; lipolysis
    DOI:  https://doi.org/10.1128/mbio.03368-25
  33. Am J Transplant. 2026 Mar 09. pii: S1600-6135(26)00124-3. [Epub ahead of print]
    Inhibition of T cell polyamine metabolism promotes transplant acceptance by modulating cytotoxic CD8+ T cell differentiation.
    Renjie Tang, Yuan Chang, Yuqi An, Dan Shan, Shen Song, Kai Xing, Peiyuan Li, Hang Zhang, Xiumeng Hua, Xiao Chen, Ningning Zhang, Shengshou Hu, Jiangping Song.
      Polyamines, particularly spermidine, are well-documented for their cardiovascular protective, antitumor, and longevity-promoting properties. However, their role in heart transplantation, and specifically the contribution of T-cell polyamine metabolism to transplant acceptance, remains undefined. In this study, we integrated preclinical and clinical studies to address this gap. We found that polyamine metabolism was significantly upregulated in T cells during acute rejection (AR) in both murine allografts and human AR samples. Critically, conditional inhibition of polyamine metabolism in T cells completely prevents AR and promotes long-term graft survival. Mechanistically, we found that polyamine metabolism is crucial for the differentiation of cytotoxic CD8+ T cells. Further, this regulatory effect was mediated by polyamine-dependent hypusination of eukaryotic initiation factor 5A (eIF5A), with inhibition of T cell eIF5A hypusination recapitulating the anti-AR effects of polyamine blockade. Our study identifies T cell polyamine metabolism as a critical regulator of cytotoxic CD8+ T cell differentiation and AR in heart transplantation. Targeting this pathway holds promise as a novel therapeutic strategy for treating AR.
    Keywords:  Acute rejection; Heart transplantation; Odc1; Polyamine metabolism; T cell; eIF5A hypusination
    DOI:  https://doi.org/10.1016/j.ajt.2026.02.038
  34. J Adv Res. 2026 Mar 09. pii: S2090-1232(26)00235-3. [Epub ahead of print]
    Microglia Dld-K127 lactylation promotes Parkinson's disease via regulating the metabolism of lactate-pyruvate transformation.
    Guoqing Wang, Guichun Gong, Xinxing Yang, Yanran Qian, Yujia Zhao, Daidi Li, Mei Liu, Zucai Xu, Feng Zhang.
       INTRODUCTION: Microglial activation represents a central pathological hallmark of Parkinson's disease (PD), characterized by a distinct metabolic reprogramming from oxidative phosphorylation toward glycolysis during pro-inflammatory activation. This metabolic shift drives lactate accumulation and subsequent protein lactylation, which has been increasingly implicated in PD development. However, the molecular mechanisms through which protein lactylation exerts its pathological effects remain largely unknown.
    OBJECTIVES: This study aimed to elucidate the mechanism by which lactate-derived protein lactylation contributes to PD pathogenesis. We sought to identify key protein targets of lactylation in PD models, elucidate the functional consequences of these modifications on cellular metabolism, and ultimately establish a comprehensive mechanism linking lactylation to dopamine (DA) neuronal degeneration.
    METHODS: We employed an integrated approach including comprehensive lactylome screening to identify modified proteins, functional enzymatic assays to determine the influence of specific lactylation events, and clinical correlation studies in human PD specimens to validate the pathological relevance of our findings across species.
    RESULTS: Following our initial observation of elevated lactate in PD mice, a subsequent finding revealed that up-regulation of lactylation was paralleled by enhanced microglial activation. Furthermore, endogenous lactate-derived lactylation was ultimately involved in the pathological process of PD. In addition, global lactylome revealed significant hyperlactylation of dihydrolipoyl dehydrogenase (Dld) at residues Lys127, Lys277, and Lys410. Mechanistically, Dld-K127 hyperlactylation inhibited pyruvate dehydrogenase (PDH) enzyme activity and promoted the metabolism of lactate-pyruvate transition, thereby accelerating DA neuronal degeneration. Meanwhile, Dld-K127 lactylation participate PD progression in p300 (lactylation writer)-dependent manner. Notably, clinical human specimens reveled that Dld-K127 lactylation, lactate and pyruvate production were increased in PD patients, accompanied with reduced PDH activity.
    CONCLUSION: Our finding defined a lactate-Dld-K127-pyruvate positive feedback loop that drove DA neuronal loss in "metabolism-epigenetic" level, positioning the disruption of this self-amplifying cycle as a viable therapeutic strategy for PD.
    Keywords:  Dihydrolipoyl dehydrogenase; Lactylation; Microglia; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.jare.2026.03.016
  35. World J Gastroenterol. 2026 Mar 14. 32(10): 115371
    Growth differentiation factor 11 reprograms M2-like macrophages: Targeting immunometabolism for cancer therapy.
    Saeed Mohammadi, Mahmoud Darweesh, Ahmed Al-Harrasi.
      This editorial comments on recent research by Escobedo-Calvario et al. Their study revealed that growth differentiation factor 11 (GDF11) functions as a potent, non-cytotoxic immunometabolic modulator within the tumor microenvironment. GDF11 treatment initiates an intense reprogramming in pro-tumoral M2-like macrophages by activating the Smad2/3 pathway and driving a fundamental shift in cellular identity. This reversal is highlighted by the significant downregulation of the M2 marker cluster of differentiation 206 and critical metabolic restructuring, including enhanced mitochondrial function (increased oxygen consumption rate), decreased total cellular cholesterol content, and a necessary increase in reactive oxygen species production. This work uniquely positions GDF11 as a dual-axis therapeutic agent, capable of both direct tumor inhibition and immunometabolic reprogramming of M2-like macrophages, yielding a re-educated secretome that effectively suppresses the pro-proliferative and migratory capacity of hepatocellular carcinoma cells. It suggests GDF11 may be a promising, mechanism-based therapeutic strategy for simultaneously managing the progression of a subset of malignancies and resolving the underlying chronic inflammatory and metabolic disorders associated with M2-like macrophage dysfunction.
    Keywords:  Cancer; Growth differentiation factor 11; Hepatocellular carcinoma; Immunometabolism; Macrophage polarization; Macrophages; Tumor microenvironment
    DOI:  https://doi.org/10.3748/wjg.v32.i10.115371
  36. Cell Death Differ. 2026 Mar 13.
    Cortistatin antagonizes Piezo1-STING axis and facilitates mitochondrial homeostasis of keratinocytes by attenuating AGEs accumulation in diabetic ulcers.
    Guoli Ma, Qinghao Yuan, Yonggang Li, Ben Liu, Jingwei Bi, Mengfei Lv, Hang Li, Tengxiao Huang, Kaitian Yin, Wenke Zhao, Gaoxin Jin, Chuanju Liu, Krasimir Vasilev, Xinyu Liu, Yunpeng Zhao, Zhijian Wei, Weiwei Li.
      Diabetic complications frequently arise in mechanically stressed regions, yet the molecular links between biomechanical forces and metabolic dysfunction remain unclear. Here, we demonstrate that mechanical stress induces glucose accumulation and downstream metabolic stress in keratinocytes. Mechanistically, Piezo1 activation led to intracellular glucose overload and advanced glycation end-products (AGEs) accumulation, which induced mitochondrial DNA (mtDNA) leakage into the cytosol and subsequently activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling cascade (cGAS-STING pathway). Keratinocyte-specific Piezo1 deletion markedly reduced AGEs accumulation and preserved mitochondrial integrity, and STING ablation exhibited similar downstream protective effects. Notably, we identify Cortistatin (CST), an endogenous neuropeptide, as a previously unrecognized inhibitory ligand of Piezo1. CST binding attenuates calcium influx and glucose accumulation under mechanical stress, conferring notable protection in vitro and in diabetic ulcers (DUs) models. These findings uncover a CST-Piezo1-STING regulatory axis that integrates mechanical and metabolic cues to drive keratinocyte dysfunction in diabetes.
    DOI:  https://doi.org/10.1038/s41418-026-01699-5
  37. Eur J Pharmacol. 2026 Mar 06. pii: S0014-2999(26)00220-7. [Epub ahead of print]1019 178738
    Blockade of KCa3.1 ameliorates rheumatoid arthritis by suppressing macrophage M1 polarization via the NLRP3 inflammasome signaling pathway.
    Jing Xing, Yong-Gang Li, Yu-Fan Zhang, Peng Yu, Nan Cheng, Ke Wang, Ze-Jun Pei, Yu-Cai Xu, Xing-Yu Liu, Shu-Fang Li, Feng Yao, Jie Ding, Ying-Jie Zhao, Wei Hu, Ren-Peng Zhou.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and joint destruction, yet current therapies often fail to fully restore immune balance. This study identifies the calcium-activated potassium channel KCa3.1 (KCNN4) as a critical regulator of M1 macrophage polarization and RA pathogenesis. In a collagen-induced arthritis (CIA) model established in male DBA/1J mice and a collagen antibody-induced arthritis (CAIA) model constructed using KCNN4 myeloid-specific knockout mice and their littermate controls, pharmacological inhibition of KCa3.1 using TRAM-34 or genetic ablation of KCNN4 significantly reduced clinical arthritis scores, attenuated joint swelling, synovial hyperplasia, inflammatory cell infiltration, cartilage damage, and bone erosion. In vitro, pharmacological blockade of KCa3.1 suppressed lipopolysaccharide (LPS) and interferon-γ (IFN-γ) induced M1 polarization in bone marrow-derived macrophages (BMDMs) and RAW264.7 cells, evidenced by reduced expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), as well as decreased production of inflammatory cytokines. Mechanistically, we reveal that KCa3.1 facilitates NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, a key driver of macrophage inflammatory responses, and that its inhibition attenuates NLRP3 expression, caspase-1 activation, and IL-1β secretion. These findings establish that KCa3.1 promotes RA progression by enhancing NLRP3-mediated M1 macrophage polarization. Moreover, transient receptor potential melastatin-subfamily member 7 (TRPM7) potentiates KCa3.1-mediated NLRP3 inflammasome activation. Thus, targeting KCa3.1 may represent a promising therapeutic strategy to rebalance macrophage phenotypes, suppress chronic inflammation, and halt RA progression.
    Keywords:  KCa3.1; M1 macrophage polarization; NLRP3 inflammasome; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178738
  38. Genome Biol. 2026 Mar 11.
    Proteomics and tracer metabolomics link GAPDH ISGylation to glycolytic control.
    Denzel Eggermont, Lissa Eggermont, Nagihan Aslantaş, Fabien Thery, Katie Boucher, Antje Beling, Bart Ghesquière, Francis Impens.
       BACKGROUND: Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) is implicated in the regulation of central carbon metabolism, but conflicting findings across experimental systems limit mechanistic insight. Here, we apply a multi-omics approach in cells ectopically expressing the ISGylation machinery independent of immune stimuli, to generate a systematic view of ISGylation in metabolic control.
    RESULTS: ISGylation preferentially targets metabolic enzymes, with marked enrichment among glycolytic proteins, suppressing the energy-yielding phase of glycolysis. Tracer metabolomics reveals a bottleneck at glyceraldehyde-3-phosphate dehydrogenase (GAPDH), reflected by accumulation of upstream intermediates and depletion of downstream metabolites. This arises from multisite ISGylation of lysines near its catalytic and regulatory regions, which reduces enzymatic activity without disrupting tetramer assembly.
    CONCLUSIONS: These findings identify GAPDH as a central metabolic checkpoint regulated by ISGylation and uncover a direct post-translational mechanism by which ISG15 controls energy metabolism.
    Keywords:  GAPDH; Glycolysis; ISG15; Mass spectrometry; Metabolomics; Proteomics
    DOI:  https://doi.org/10.1186/s13059-026-04034-w
  39. Int Immunopharmacol. 2026 Mar 12. pii: S1567-5769(26)00341-3. [Epub ahead of print]176 116497
    STING-mediated metabolic reprogramming drives lipid peroxidation during Staphylococcus aureus infection.
    Rui Yu, Naiyan Sun, Shaodong Fu, Yingzou Fang, Shiyuan Feng, Yawei Qiu, Huanhuan Wang, Yuanyuan Xu, Jinfeng Miao.
      Metabolism serves as the foundation for all physiological activities. In recent years, it has been demonstrated that the innate immune receptor STING influences pathogen infection by modulating metabolism. Notably, fatty acid metabolism plays a crucial role in regulating cellular immune function. In this study, we found STING was activated in S. aureus-infected mammary epithelial cells, reprogramming host lipid metabolism. This activation results in lipid accumulation, increased lipid peroxide production, and GSH depletion. These effects can be mitigated by genetic ablation or pharmacological inhibition of STING. Mechanistically, STING interacts with FASN to promote de novo fatty acid synthesis, providing a substrate for the production and subsequent peroxidation of unsaturated fatty acids. The process is mediated by SCD2 and ACSL4. In summary, our study provides a new insight into the role of immune-related molecules in metabolic regulation and host defense against pathogens. These findings could inform the development of novel anti-inflammatory therapies aimed at safely inhibiting STING.
    Keywords:  Lipid peroxidation; Mastitis; Metabolism reprogramming; STING; Staphylococcus aureus
    DOI:  https://doi.org/10.1016/j.intimp.2026.116497
  40. Eur J Med Res. 2026 Mar 09.
    MCT1 inhibition reprograms Treg metabolism via ABC transporters: implications for tumor immunity and the prognosis of acute myeloid leukemia patients.
    Ziyu Wang, Hongyang Wang, Qinghai Wang, Tao Huang, Chen Guo, Jianlei Ji, Zhen Dong, Yanwei Cao.
      Glycolysis plays a critical role in regulatory T cells (Tregs), which are frequently exploited by tumor cells, as Treg survival depends on glycolytic activity to suppress antitumor immunity. However, the precise effects of glycolysis on Treg proliferation and differentiation remain incompletely understood. Monocarboxylate transporters (MCTs) are pivotal regulators of glycolytic flux. In this study, we investigated how MCT1 inhibition modulates Treg metabolism and function, and the potential implications for tumor immunotherapy. Silencing MCT1 in human primary Tregs using siRNA disrupted glycolysis, leading to G0/G1 cell cycle arrest, increased apoptosis, and ATP depletion. Integrated metabolomic and transcriptomic analyses identified the ABC transporter pathway as the most significantly altered, with coordinated changes in key genes (ABCA1, ABCB10, ABCC9, etc.) and the metabolite adenosine. Validation using The Cancer Genome Atlas (TCGA) acute myeloid leukemia cohort demonstrated that high expression of the ABC transporter gene ABCC9 is associated with improved overall survival (hazard ratio = 0.45, p < 0.001). These findings indicate that MCT1 inhibition is associated with alterations in the ABC transporter pathway, which may correlate with changes in Treg metabolism and the tumor immune microenvironment. Collectively, this work highlights metabolic reprogramming of Tregs as a novel therapeutic target for cancer immunotherapy.
    Keywords:  Glycolysis; Metabonomic; Monocarboxylate transporter; Regulatory T cells; Transcriptomic
    DOI:  https://doi.org/10.1186/s40001-026-04187-1
  41. J Exp Med. 2026 Apr 06. pii: e20250978. [Epub ahead of print]223(4):
    Macrophage anti-bacterial activity is controlled by adenylate kinase 4-mediated mitochondrial DNA synthesis.
    Wei-Yao Chin, Ching-Tung Wu, Gunn-Guang Liou, Si-Tse Jiang, Yi-Sheng Cheng, Jr-Shiuan Lin, Betty A Wu-Hsieh, Shi-Chuen Miaw.
      Macrophage antibacterial activity requires mtROS production. The specific gene(s) that participates in the mtROS-mediated antibacterial process remains unclear. We showed that Listeria and Salmonella infections in human and mouse macrophages increased mtDNA copy number with which dictates antibacterial activity. Interestingly, adenylate kinase 4 (Ak4) expression was upregulated in macrophages after infection. Ak4 KO mice as well as macrophage-specific Ak4 KO mice became highly susceptible to bacterial infections. Ak4 is critical for the increase of mtDNA synthesis and mitochondrial mass in macrophages after bacterial infection. Biochemically, Ak4 transfers a phosphate group from ATP/GTP to (d)AMP for (d)ADP formation, and the K18A and G89S/A166D mutations abolished this function. Our results suggest that induction of Ak4 after infection produces more dADP, whose conversion to dATP in mitochondria supports mtDNA synthesis and the subsequent increase of mtROS production. Loss of this metabolic coupling in Ak4 KO macrophages diminishes antibacterial activity. Our findings highlight the vital role of Ak4 in macrophage defense against pathogenic bacteria.
    DOI:  https://doi.org/10.1084/jem.20250978
  42. Trends Cancer. 2026 Mar 07. pii: S2405-8033(26)00033-6. [Epub ahead of print]
    Ammonia: a metabolic checkpoint for Treg potency.
    Ali Valipour Motlagh, Eyad Elkord, Weiwei Dai.
      Ammonia acts as a metabolic checkpoint fueling regulatory T cells (Tregs). Gu et al. demonstrate that utilizing argininosuccinate lyase-linked survival buffering and a FOXP3-spermine-PPARγ axis for mitochondrial reinforcement allows Tregs to convert toxic waste into suppressive power, driving tumor immune evasion and immunotherapy resistance.
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.002
  43. Cell Death Differ. 2026 Mar 11.
    Gut-derived hyodeoxycholate reprograms the spleen-eye immunometabolic axis to suppress autoimmune uveitis.
    Yitao Li, Weijia Zheng, Jiao Ma, Lu Liu, Xintong Yang, Junliang Kuang, Nickie Chan, Chengqiang Wang, Yang Li, Aihua Zhao, Ruonan Wang, Xiaojiao Zheng, Gerry Melino, Aiping Lu, Xiaolu Yang, Wei Jia.
      Autoimmune uveitis (AU) lacks targeted therapies beyond immunosuppression. We identified hyodeoxycholate (HDCA), a gut-derived secondary bile acid, as a key immunometabolic regulator in AU. Metabolomics revealed systemic depletion of HDCA and oleic acid (C18:1n9) in AU patients and experimental AU (EAU) mice, correlating with disease severity. HDCA administration effectively attenuated EAU by reducing pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and elevating IL-10. Mechanistically, HDCA inhibits Farnesoid X Receptor in splenic red pulp macrophages, activating SREBP1c-dependent fatty acid synthase, which enhances oleic acid production. Systemic oleic acid suppresses ocular Th17 responses and promotes M2 macrophage polarization, enhancing anti-inflammatory immunity. These findings define a spleen-to-eye immunometabolic axis driven by HDCA-mediated macrophage reprogramming, positioning HDCA as a promising therapeutic for AU.
    DOI:  https://doi.org/10.1038/s41418-026-01696-8
  44. Autoimmun Rev. 2026 Mar 07. pii: S1568-9972(26)00038-8. [Epub ahead of print]25(4): 104024
    Exploring the metabolic mysteries: Mechanistic insights into lactylation-mediated regulation of autoimmune diseases.
    Nan Kang, Bo Wang, Yunjia Li, Ruixia Zhu.
      Autoimmune diseases are chronic disorders caused by the immune system's aberrant recognition and attack of self-tissues. Accumulating evidence has revealed that these diseases are closely related to metabolic reprogramming and epigenetic regulation. Lactylation, a recently identified post-translational modification driven by lactate, has emerged as a critical link connecting cellular metabolism to immune regulation. In this review, we provide a comprehensive overview of the regulatory mechanisms and functional roles of lactylation in autoimmune pathogenesis. Lactate, by regulating both histone and non-histone lactylation, affects immune responses in both innate immunity (e.g., macrophages and dendritic cells) and adaptive immunity (e.g., T cells and B cells). The article focuses on exploring the specific regulatory mechanisms of lactate metabolism and lactylation in various autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and Sjögren's syndrome (SS). We describe how lactylation drives disease initiation and progression by modulating inflammatory responses, immune cell infiltration, and tissue damage, offering fresh perspectives on the pathophysiology of autoimmunity. Furthermore, lactylation-associated genes and modification levels demonstrate potential as disease biomarkers, suggesting that targeting lactate metabolic pathways or the involved enzymes can provide new therapeutic strategies and targets for autoimmune diseases.
    Keywords:  Autoimmune diseases; Immune cells; Lactylation; Metabolic reprogramming; Warburg effect
    DOI:  https://doi.org/10.1016/j.autrev.2026.104024
  45. Int J Biol Sci. 2026 ;22(5): 2196-2214
    Metabolic Adaptation of CD8⁺ T Cells Limits the Efficacy of Fatty Acid Oxidation Inhibition in Type 1 Diabetes.
    Manuel Salzmann, Laura Boccuni, Patrizia Gibler, Mira Brekalo, Tamara S Trimmel, Elena T Pichler, Patrick Haider, Julia L Blesch, Christian Hengstenberg, Michael B Fischer, Bruno K Podesser, Remi J Creusot, Julia B Kral-Pointner, Philipp J Hohensinner.
      Type 1 Diabetes Mellitus (T1D) is an organ-specific autoimmune disease characterized by persistent hyperglycemia due to immune-mediated destruction of pancreatic islet β-cells. Targeting immune cell metabolism has emerged as a promising therapeutic strategy. We investigated whether the fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ), one of only three approved drugs directly targeting cellular metabolism, can restrain autoreactive immunity and delay T1D in non-obese diabetic mice (NOD). TMZ enhanced mitochondrial membrane potential, suppressed FAO, and curtailed activation and proliferation of human CD8+ T cells. In dysglycemic NOD mice, a clinically approved dose of TMZ delayed progression to T1D, reduced mean glycemia, and decreased islet CD4⁺/CD8⁺ infiltration. Single-cell RNA sequencing revealed depletion of FAO-high, stress-responsive cells and mitochondrially active stromal cells, indicating improved pancreatic health. Prolonged exposure induced compensatory upregulation of carnitine-palmitoyl-transferase-1A (CPT1A) in CD8⁺ subsets, counterbalancing early benefits. In summary, TMZ transiently restrains CD8⁺ T cell activity, reduces islet infiltration, and improves pancreatic health. The adaptive upregulation of CPT1A demonstrates a novel evasion mechanism to FAO inhibition and underscores the central role of FAO in sustaining pathogenic T cells. Our work highlights metabolic adaptation as a key determinant of autoimmune progression, validating FAO as a therapeutic target in T1D.
    Keywords:  CD8+ T cell; CPT1A; Trimetazidine; fatty acid oxidation; metabolic reprogramming; type 1 diabetes
    DOI:  https://doi.org/10.7150/ijbs.125649
  46. Antiviral Res. 2026 Mar 06. pii: S0166-3542(26)00050-1. [Epub ahead of print]249 106391
    Porcine epidemic diarrhea virus infection activates SREBP2 and induces RORγ expression to enhance cholesterol biosynthesis and virus replication.
    Jingting Zhang, Shihan Deng, Miao Zhang, Xingying Wu, Penggang Liu, Jing Sun, Xiulong Xu.
      Cholesterol is a main lipid component of host cell membranes and plays an essential role in virus infection and replication. Porcine epidemic diarrhea virus (PEDV), an enteric coronavirus that replicates efficiently in intestinal epithelial cells, requires abundant cholesterol to complete its replication cycle. However, the mechanisms by which PEDV modulates host cholesterol biosynthesis remain incompletely understood. Here, we report that PEDV infection activates the sterol regulatory element-binding protein 2 (SREBP2) and induces the expression of the retinoic acid receptor-related orphan receptor γ (RORγ). These two transcription factors cooperate to induce the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. Silencing RORγ or pharmacologic inhibition using XY018 or GSK805 suppresses HMGCR expression, reduces cholesterol synthesis, and impedes PEDV replication. Conversely, RORγ overexpression enhances cholesterol biosynthesis-related gene expression and viral replication. Co-inhibition of SREBP2 and RORγ by their specific inhibitors synergistically suppresses PEDV replication. Exogenous cholesterol supplementation antagonizes the inhibitory effects of RORγ inhibitors on virus replication. Mechanistically, PEDV-induced RORγ expression relies on TAK1 and its downstream kinases JNK and IKK, which activate AP-1 and NF-κB signaling, respectively. Our study provides evidence that PEDV infection activates the TAK1-JNK/IKK-RORγ axis to drive cholesterol biosynthesis and support viral replication.
    Keywords:  Cholesterol; PEDV; RORγ; RORγ inhibitors; SREBP2; TAK1
    DOI:  https://doi.org/10.1016/j.antiviral.2026.106391
  47. Trends Endocrinol Metab. 2026 Mar 11. pii: S1043-2760(26)00043-3. [Epub ahead of print]
    Trimethylamine-N-oxide: the microbial cue in immune-mediated disorders.
    Gauri Mirji, Sajad Ahmad Bhat, Rahul S Shinde.
      Trimethylamine-N-oxide (TMAO), a gut microbial metabolite derived from dietary choline and carnitine, has emerged as a pivotal link between diet, microbial metabolism, and host immunity. Beyond its historical role as a marine osmolyte, TMAO engages core immune pathways-driving oxidative stress, inflammasome activation, and type I interferon signaling-to shape macrophage polarization, T cell responses, and systemic immune tone. These actions place TMAO at the intersection of chronic diseases, exacerbating cardiovascular, metabolic, renal, and neurodegenerative pathology while paradoxically enhancing antitumor immunity in pancreatic and breast cancers. Such duality underscores its significance as both a biomarker and a therapeutic target. We discuss current advances in TMAO biology, immune mechanisms, and strategies to modulate its activity through diet, microbiome interventions, and enzymatic inhibition.
    Keywords:  immune response; immune-mediated disorders; immunotherapy; macrophage polarization; microbial metabolite; trimethylamine-N-oxide (TMAO)
    DOI:  https://doi.org/10.1016/j.tem.2026.02.008
  48. Int J Mol Sci. 2026 Feb 28. pii: 2291. [Epub ahead of print]27(5):
    Oncometabolites and Hypoxia-Regulated Exosomes Shape HIF-Driven Macrophage Programs Across Type 2 Diabetes, Atherosclerosis, and Cancer.
    Antonina Nowinka, Gabriela Krystek, Zuzanna Gontarek, Martyna Góralczyk, Antonina Waligórska, Marta Walenciak, Dorota Formanowicz.
      Oncometabolites and hypoxia-regulated exosomes orchestrate hypoxia-inducible factor (HIF)-driven macrophage reprogramming across chronic cardiometabolic and oncologic conditions. In type 2 diabetes (T2D) and obesity, regional hypoxia in expanding white adipose tissue (WAT) reconfigures macrophage immunometabolism and chemokine signaling, recruits C-C chemokine receptor 2 (CCR2+) monocytes, and skews adipose-tissue macrophages toward M1-like programs that sustain low-grade inflammation and blunt the physiological M1-to-M2 transition during wound repair. In atherosclerotic plaques, lipid-core hypoxia stabilizes HIF-1α, amplifies nuclear factor kappa-light-chain-enhancer of activated B cells/reactive oxygen species (NF-κB/ROS) signaling, increases matrix metalloproteinase-2/-9 (MMP-2/-9) release, and reduces ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux, weakening the fibrous cap. In tumors, poorly perfused niches accumulate lactate and succinate, which act as paracrine cues. Lactate activates PKA/cAMP pathways and promotes immunosuppressive tumor-associated macrophages (TAMs), whereas succinate signals through succinate receptor 1 (SUCNR1) to reinforce HIF-1α-dependent transcription and M2-like programming. In parallel, hypoxia-regulated exosomes deliver microRNAs such as miR-301a-3p, which suppress phosphatase and tensin homolog (PTEN) and activate PI3Kγ, thereby augmenting immunosuppression and programmed death-ligand 1 (PD-L1) expression. Clinically, this hypoxia-oncometabolite-exosome triad links oxygen debt with macrophage state, plaque destabilization, impaired wound repair, and tumor immune escape. Translational entry points include selective HIF-2α inhibition, phosphoinositide 3-kinase gamma (PI3Kγ) blockade, SUCNR1 targeting, and exosome-based miRNA modulation, while a biomarker panel comprising HIF-1α, vascular endothelial growth factor A (VEGF-A), and MMP-9 offers a pragmatic readout of hypoxia burden, macrophage programming, and therapeutic response. We conducted a focused narrative review (PubMed, Scopus, Web of Science; English; 2003-2025), prioritizing mechanistic and translational studies on hypoxia-HIF, lactate/succinate, and hypoxia-regulated exosomes across T2D, atherosclerosis, and cancer.
    Keywords:  HIF-1α; HIF-2α; PD-L1; PI3Kγ; TAMs; atherosclerosis; belzutifan; hypoxia; hypoxia-regulated exosomes; lactate; macrophage polarization; obesity; oncometabolites; succinate; tumor microenvironment; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms27052291
  49. J Inflamm Res. 2026 ;19 577143
    Immunometabolic Reprogramming in Experimental Sepsis: A Driver of Multiple Organ Dysfunction Syndrome.
    Fan Wu, Yantong Chen, Lihua Chen, Xiaolu Wei, Lin Zhang, Yi Shen.
      Sepsis is a life-threatening syndrome characterized by infection-induced systemic inflammation and immune dysregulation, commonly resulting in the development of multiple organ dysfunction syndrome (MODS), a leading cause of mortality in clinical practice. In decades, immunometabolic reprogramming has been identified as a critical mechanism that contributes to the progression of sepsis and the associated organ injuries. The review provides a systematic overview of the metabolic alterations in immune cells and organs in experimental models of sepsis. Key features include enhanced glycolysis, impaired mitochondrial function, and disturbed lipid metabolism, all of which are closely associated with organ damage. These metabolic adaptations influence immune responses and cell fate decisions, inter-organ crosstalk, and the development of MODS. A detailed examination is conducted on the temporal progression of pathological changes in established animal models, along with organ-specific metabolic dysfunctions and novel therapeutic targets. It emphasizes the importance of dynamic immunometabolic regulation, tissue-specific responses, and inter-organ interactions in the context of sepsis treatment. The integration of multi-omics technologies, identification of reliable biomarkers, and the development of personalized therapeutic strategies should be used to facilitate clinical translation of mechanistic insights.
    Keywords:  experimental sepsis; glycolysis; immunometabolic reprogramming; inter-organ crosstalk; multiple organ dysfunction syndrome
    DOI:  https://doi.org/10.2147/JIR.S577143
  50. Cancer Biol Med. 2026 Mar 10. pii: j.issn.2095-3941.2025.0645. [Epub ahead of print]23(2):
    Targeting tumor-infiltrating regulatory T cells based on immunometabolism.
    Na Li, Dexue Tian.
      The immune checkpoint blockade (ICB) approach in cancer therapy involves the disruption of immune checkpoint inhibitory signals on tumor-specific CD8+ T cells, thereby reinstating the immune activity of CD8+ T cells and yielding therapeutic efficacy. However, due to the co-expression of immune checkpoint molecules, such as CTLA-4 and PD-1 on tumor-infiltrating Tregs (TI-Tregs) and conventional T cells (Tconvs), immune checkpoint inhibitors (ICIs) inadvertently amplify the immunosuppressive activity of Tregs while targeting CD8+ T cells, which contributes to the failure of immune therapy. Conventional strategies targeting Tregs, including ICI/conventional kinase and chemokine/chemokine receptor blockade, generally induce systemic Treg depletion, which triggers autoimmune diseases. Thus, achieving high selectivity and specificity in targeting TI-Tregs is of paramount importance in mitigating adverse immunologic reactions. Targeting metabolism-based TI-Tregs has been shown to enhance target precision, providing potential for the development of adjunctive immunotherapeutic strategies. This article explores the reciprocal interaction between TI-Tregs and the tumor microenvironment (TME), elucidating metabolic reprogramming, while envisioning plausible high-selectivity targets for TI-Tregs without compromising systemic immune homeostasis and immune reactivity of effector T cells.
    Keywords:  CD8+ T cells; Tumor-infiltrating regulatory T cells; immune checkpoint inhibitors; immunometabolism; tumor microenvironment
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0645
  51. FASEB J. 2026 Mar 31. 40(6): e71672
    Glycosomal Phosphoenolpyruvate Carboxykinase CRISPR/Cas9-Deletion and Its Role in Trypanosoma cruzi Metacyclogenesis and Infectivity in Mammalian Host.
    Carolina S D Vieira, Wei Wang, Fernando Sanchez-Valdez, Jihyun Lim, Brooke E White, Camilla G S Souza, Rick L Tarleton, Marcia C Paes, Natalia P A Nogueira.
      Trypanosoma cruzi, the causative agent of Chagas disease, possesses glycosomes-unique organelles that house key metabolic enzymes, several of which are promising therapeutic targets. Among them, phosphoenolpyruvate carboxykinase (PEPCK) plays a central role in succinic fermentation, the main pathway for NAD+ regeneration within the organelle. Using CRISPR/Cas9 editing, the PEPCK gene was disrupted in T. cruzi, producing single-allele knockout epimastigotes (TcPEPCK-sKO) with reduced PEPCK expression and enzyme activity. In a high glucose environment, PEPCK disruption impaired glucose consumption and mitochondrial respiration, particularly oxidative phosphorylation, reducing dependence on mitochondrial ATP production when glucose was supplied. To compensate, pyruvate phosphate dikinase was upregulated, increasing alanine production, possibly to maintain redox balance in glycosomes. Despite this metabolic adaptation, the growth of TcPEPCK-sKO epimastigotes was partially reduced compared with non-deleted parasites. In contrast, under low glucose conditions, PEPCK activity was not critical for mitochondrial bioenergetics, ATP production, or proliferation. Although TcPEPCK-sKO epimastigotes exhibited a minor reduction in growth in high glucose medium, their differentiation (metacyclogenesis) and invasion were severely compromised. However, once inside the host cell, TcPEPCK-sKO amastigotes increased their replication, leading to enhanced trypomastigote production. The same was observed in in vivo infection, where TcPEPCK-sKO infection in IFNγ-deficient mice caused uncontrolled parasitemia and severe pathology, highlighting the critical role of PEPCK in host-pathogen interactions. However, an intact immune system effectively contained TcPEPCK-sKO infection. Taken together, our findings demonstrate that glycosomal PEPCK is crucial for coupling glycolysis to mitochondrial bioenergetics, enabling the parasite differentiation within the insect vector and controlling the infection of mammalian host cells.
    Keywords:   Trypanosoma cruzi ; CRISPR/Cas9; bioenergetics; infection; metacyclogenesis; phosphoenolpyruvate carboxykinase
    DOI:  https://doi.org/10.1096/fj.202503541R
  52. Inflammation. 2026 Mar 11.
    Integrated Genome-wide Association and Single-cell Transcriptomic Analysis Identifies OAT as Therapeutic Targets for Periodontitis.
    Sixian Lou, Yecheng Shen, Sen Li.
      Periodontitis is a chronic inflammatory disease affecting tooth-supporting tissues. Beyond microbial dysbiosis, host metabolic regulation plays a critical role. This study identified ornithine aminotransferase (OAT), a mitochondrial enzyme in amino acid metabolism, as associated with altered fibroblast phenotypes and metabolic profiles in periodontitis. Integrative genetic analysis showed a putative causal relationship between increased OAT expression and disease risk. Single-cell RNA-Seq revealed OAT enrichment in fibroblasts, especially in subsets with inflammatory and matrix-remodeling characteristics. In diseased tissues, OAT-positive fibroblasts exhibited heightened metabolic activity and acted as central nodes in intercellular communication with immune and endothelial cells. Pseudotime analysis indicated progressive downregulation of OAT during fibroblast differentiation. OAT expression correlated with activation of arginine and proline metabolism, implicating a role in sustaining inflammation and matrix degradation. These results suggest that OAT contributes to periodontal tissue damage and may serve as a therapeutic target.
    Keywords:  Mendelian randomization; Ornithine aminotransferase; Periodontitis; Single-cell RNA-Seq
    DOI:  https://doi.org/10.1007/s10753-025-02392-4
  53. Vet Microbiol. 2026 Mar 03. pii: S0378-1135(26)00098-2. [Epub ahead of print]316 110967
    L-2-aminoadipic acid inhibits porcine epidemic diarrhea virus replication by targeting and reducing cellular autophagy.
    Xiao Ma, Hongbo Cui, Runze Song, Yanfei Huang, Yilei Li, Junxing Ma, Hongying Chen, Shijie Ma, Zhanyong Wei.
      Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus (PEDV) is an acute and highly contagious intestinal infectious disease. The metabolic alterations during PEDV infection remain largely unexplored. In this study, LLC-PK1 cells infected with PEDV were subjected to non-targeted metabolomics analysis. Notably, the amino acid metabolite L-2-aminoadipic acid (L-2AA) was significantly upregulated, while indole-3-acetic acid (3-IAA) exhibited a marked downregulation following PEDV infection. Subsequent investigations revealed that both L-2AA and 3-IAA significantly hindered the late stage of viral propagation. Mechanistically, aldehyde dehydrogenase 7A1 (ALDH7A1), a key enzyme involved in the biosynthesis of L-2AA, mediates the PEDV-induced upregulation of L-2AA and functions to negatively regulate viral replication. Detailed analysis indicated that L-2AA mitigates PEDV infection via reducing autophagic activity. These data support a novel mechanism used by L-2AA to downregulate autophagic activity to block viral replication and provide potential anti-PEDV drug targets.
    Keywords:  ALDH7A1; Amino acid metabolism; Autophagy; Metabolomics; Porcine epidemic diarrhea virus
    DOI:  https://doi.org/10.1016/j.vetmic.2026.110967
  54. Biology (Basel). 2026 Mar 05. pii: 422. [Epub ahead of print]15(5):
    Sex-Dependent Metabolic Alterations in Red Blood Cells During COVID-19.
    José Raul Herance, Idoia Álvarez-Ajuria, Carolina Aparicio-Gómez, Marina Giralt-Arnaiz, Celia Moya-Latorre, Rita Ortega-Vallbona, Martina Palomino-Schätzlein.
      COVID-19 is known to impair red blood cell (RBC) function, which may affect oxygen transport and disease progression. However, the metabolic consequences of SARS-CoV-2 infection on RBCs and how these changes relate to disease severity and sex differences, have not been systematically explored. Here, we compared RBC metabolomic profiles from healthy controls and individuals with COVID-19 using nuclear magnetic resonance (NMR) to gain insight into disease mechanisms and potential biomarkers. Multivariate and univariate analyses were performed within the men and women cohorts, and clinical factors, including body mass index, comorbidities, and critical clinical status were considered. We found that COVID-19 induces significant metabolic remodeling in RBCs of all patients, including reduced glycolytic and pentose phosphate pathway (PPP) intermediates, consistent with impaired energetic and antioxidant capacity. However, we also observed differences between men and women in the pattern and extent of these changes. Female patients showed changes in metabolites implicated in oxygen release and amino sugar metabolism, including 2,3-BPG, suggesting a distinct metabolic adaptation. By contrast, male patients exhibited a broader set of RBC-specific metabolic disruptions, most evident in severe disease, characterized by decreased amino acid levels, altered glycolytic activity, and weakened antioxidant responses. Overall, these findings identify RBC metabolism as a component of COVID-19 pathophysiology and support its potential as a source of biomarkers.
    Keywords:  COVID-19; NMR; antioxidant metabolism; cardiovascular diseases; diabetes; red blood cells; sex specific alteration
    DOI:  https://doi.org/10.3390/biology15050422
  55. Cell. 2026 Mar 06. pii: S0092-8674(26)00169-8. [Epub ahead of print]
    β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
    Shan Liu, Puneeth Guruprasad, Ranjani Ramasubramanian, Bhoomi Madhu, Luca Paruzzo, Kecheng Han, Andre Kelly, Alexander Shestov, He N Xu, Alberto Carturan, Chaoting Zhou, Kevin R Amses, Amichay Afriat, Lev Litichevskiy, Jason Lin, Ezra Dubowitz, Neil Tangal, Jing Zhang, Alana McSween, Melody Tan, Federico Stella, Andrew Lee, Siena Nason, Xianxin Hua, Michael Schneider, Madeleine Sleeman, Yunlin Zhang, Giulia Gabrielli, Ziqi Yang, Raymone Pajarillo, Ruchi Patel, Guido Ghilardi, Vrutti Patel, Akshita Joshi, Shunzhou Jiang, Yanqing Jiang, Patrizia Porazzi, Julia C Tchou, Brian Keith, Mingyao Li, Elise Chong, Stephen J Schuster, Michael Milone, Joshua Rabinowitz, Roddy S O'Connor, Christoph A Thaiss, Maayan Levy, Marco Ruella.
      The influence of lifestyle factors, such as diet, on the effectiveness of T cell-mediated cancer immunotherapies remains unclear. Here, we demonstrate that the ketogenic diet (KD)-induced ketone metabolite β-hydroxybutyrate (BHB) augments chimeric antigen receptor (CAR) T cell function across multiple preclinical cancer models. Mechanistically, BHB supports the tricarboxylic acid (TCA) cycle in CAR T cells, driving oxidative phosphorylation and energy generation. This metabolic enhancement is associated with CAR T cell proliferation and cytokine production, thereby leading to superior tumor control. Furthermore, BHB induces global transcriptional and epigenetic reprogramming in activated CAR T cells, which promotes an enhanced effector and metabolic profile. Lastly, in a prospective cohort of healthy volunteers, administration of BHB enhanced peripheral T cell oxygen consumption, mitochondrial membrane potential, and ATP production. Our results suggest that metabolite intervention via BHB supplementation is a promising, readily implementable strategy to improve adoptive T cell function against various cancers.
    Keywords:  CAR T cell; cancer therapy; ketogenic diet; metabolism; oxidative phosphorylation; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.cell.2026.02.004
  56. Cell Biol Int. 2026 Mar;50(3): e70149
    γδTreg/γδTh17 Cell Imbalance Drives Xanthine-Mediated Metabolic Dysfunction in Restraint Stress-Induced Anxiety-Like Behavior.
    Xiang Xue, Chong Tang, Na Yan, Xiaoling Lai, Qianqin Li, Enze Li.
      Anxiety disorder is a highly prevalent psychiatric disorder, yet the role of γδT17/γδTreg-mediated metabolism in its pathogenesis remains unclear. We employed chronic restraint stress (RS) to establish an anxiety-like behavior mouse model and assessed behavioral changes. LC-MS/MS was employed to analyze the serum metabolomics of mice. RS mice were intraperitoneally injected with xanthine and brain tissue was taken for immunofluorescence. Here, Nissl staining and behavioral experiments respectively confirmed the neuronal pathology and behavioral alterations in RS mice. Flow cytometry and immunofluorescence revealed a significant imbalance in γδT17 and γδTreg cell populations in RS mice, characterized by an increase in γδT17 cells accompanied by a decrease in γδTreg cells. Deprivation of γδT17 cells using an αIL-17 antibody significantly ameliorated anxiety-like behavior in RS mice, whereas γδTreg cells deprivation using an αFoxP3 antibody exacerbated anxiety in RS mice. Metabolomic profiling identified profound alterations in the serum metabolic landscape of RS mice, particularly in purine and nucleotide metabolism pathway. Among the differentially abundant metabolites, xanthine and hypoxanthine were significantly increased in RS mice, and γδT17 cell depletion reversed these elevations. Exogenous xanthine administration exacerbated neuronal damage in RS mice, while immunofluorescence confirmed that xanthine primarily affects neurons rather than astrocytes. ELISA demonstrated that xanthine crosses the blood-brain barrier and accumulates in the brains of RS mice. Collectively, this study identifies a novel γδT17/γδTreg-xanthine axis linking immune dysregulation and metabolic reprogramming to anxiety-like behavior, providing new mechanistic insights and potential therapeutic targets for anxiety disorders.
    Keywords:  anxiety‐like behavior; metabolome; xanthine; γδT17/γδTreg balance
    DOI:  https://doi.org/10.1002/cbin.70149
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