bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–04–19
fifty-five papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Immunometabolic reprogramming in sepsis: mechanisms, clinical endotypes, and therapeutic opportunities.
  2. Metabolic Programming of Tumor-Associated Macrophages in Head and Neck Squamous Cell Carcinoma: Implications for Innate Immunity and Therapeutic Response.
  3. Fatty acid metabolism-an emerging regulatory node in T-cell immunometabolism.
  4. Metabolic Control of Immunity and Inflammation: Mitochondrial Dynamics, Pharmacological Targets, and Therapeutic Opportunities.
  5. Multimodal profiling reveals Mycobacterium tuberculosis restricts lung mitochondrial immunometabolism to promote pathogenesis.
  6. Branched-chain amino acids and innate immunity in metabolic disease: Mechanisms, paradox, and therapeutic opportunities.
  7. Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
  8. Amino acid metabolism modulates macrophage polarization: implications for autoimmune-related diseases.
  9. Effects of CMV on T and NK Cells; With Emphasis on Immunometabolism.
  10. Human pneumovirus induces IFN-dependent expression of the immune-responsive gene 1 and is inhibited by 4-octyl itaconate in human macrophages.
  11. Monophosphoryl lipid A boosts macrophage antimicrobial immunity by metabolically regulating source-specific ROS generation.
  12. Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
  13. Roles of Oxidative Phosphorylation and Fatty Acid Oxidation in Neuroinflammation Induced by Lipopolysaccharide in Hypothalamic Neuronal Cells.
  14. Sensing succinate: SUCNR1 as a context-dependent metabolic and cellular signal integrator.
  15. Apolipophorin-III inhibits BmNPV replication by reprogramming sphingolipid metabolism to accumulate ceramide.
  16. SCD1 licenses STING signaling through fatty acid desaturation-mediated membrane remodeling.
  17. Therapeutic Regulation of Macrophage Polarization for Diabetic Kidney Disease by Targeted Metabolic Reprogramming.
  18. NAD+ precursor supplementation reverses CD36-mediated lipid accumulation and ferroptosis to restore antitumor function of NK cells in DLBCL.
  19. Immunometabolic dysregulation in autoimmune rheumatic diseases: the central role of glycolytic reprogramming in pathogenesis and traditional Chinese medicine therapy.
  20. Multiomics-guided discovery of protective microbiome signatures in lupus-prone mice treated with Faecalibacterium prausnitzii.
  21. Lipid metabolic regulation of pathogenic type 2 immunity in the airway.
  22. Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
  23. Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion.
  24. Early Effects of Poly(I:C)-induced Neuroinflammation on Hippocampal Astrocyte Function and Glycolytic Metabolism.
  25. Mitochondrial dysfunction in immune cells during the perioperative period: mechanisms, emerging therapeutic strategies, and implications for multi-organ protection.
  26. Extracellular ATP Functions as a Metabolic Lineage Selection Signal That Stabilizes Tc9 Cells During Adoptive T Cell Therapy.
  27. Targeting LRPPRC lactylation disrupts metabolic-immune crosstalk and restores antitumor immunity in hepatocellular carcinoma.
  28. Fumarate inhibits the formation of neutrophil extracellular traps (NETs) in a Nrf2-controlled and Annexin-A1-dependent manner associated with mitochondrial fusion.
  29. Purine salvage pathway protects CD8+ T cells from metabolic stress.
  30. Iron in Respiratory Immunity and Infection.
  31. Itaconate ameliorates cardiovascular inflammation in a mouse model of Kawasaki disease vasculitis - brief report.
  32. Adaptive metabolic strategies of intracellular bacterial pathogens.
  33. Targeting PKM2-dependent glycolysis reprogrammes monocytes into Cadm1+ macrophages to promote mucosal repair and attenuate colitis progression.
  34. Folate receptor beta drives NLRP3 inflammasome activation and pyroptosis in macrophages independent of folate binding.
  35. Targeting HIF-1α rescues microglial efferocytosis via the SLC7A11-TAM pathway to ameliorate Sepsis-associated encephalopathy.
  36. Association of Changes in Portal Insulin with Immunometabolism During and After Hepatitis C Virus Infection.
  37. Mitochondrial transfer as a driver of immune microenvironment remodeling.
  38. Stimulus-Driven Remodeling of Microglial Endocannabinoid Metabolism Illuminates ABHD12 Function in Immunity.
  39. Ailanthone ameliorates CCl4-induced liver fibrosis by targeting PKM2-mediated macrophage M1 polarization and glycolytic reprogramming.
  40. p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease.
  41. Kinsenoside Targets IDH1 to Restore Microglial Immune-Metabolic Homeostasis for Alzheimer's Disease Therapy.
  42. Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.
  43. β-hydroxybutyrate supplementation boosts the tumor-killing potential of CAR T cells.
  44. Heme oxygenase-1-enriched tolerogenic dendritic cell-derived exosomes attenuate lupus nephritis by restoring immune balance and iron homeostasis.
  45. Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
  46. Integrative multi-omics dissection identifies ACO2, KLF5, and IMP4 as central regulators of the mitochondrial-immune axis in ulcerative colitis.
  47. Japanese encephalitis virus orchestrates GLUT4-mediated glucose metabolism to potentiate viral replication via insulin receptor signaling.
  48. Characterising the urinary metabolome in HIV/TB coinfection and the impact of antiretroviral treatment.
  49. Cell-specific exosomes in sepsis-associated ARDS: from immunometabolic reprogramming to precision medicine.
  50. AI-guided discovery of the IRF4-PAICS-LDHA axis as a multitarget hub linking tumor metabolism to CD8+ T cell exhaustion in DLBCL.
  51. Kv1.3 regulates macrophage immune function through PI3K/AKT signaling pathway to alleviate metabolic dysfunction-associated steatohepatitis.
  52. Long-term bone metabolism outcomes in critically Ill patients with sepsis: a prospective series study.
  53. Phosphorothioate antisense oligonucleotide induced innate immune activation is attenuated by tryptophan oxidation products.
  54. A Microbial Lipid-ATP Synthase Axis Fuels NK Cell Antitumor Activity.
  55. PDK4 drives abdominal aortic aneurysm by promoting smooth muscle cell metabolic reprogramming and NLRP3-mediated pyroptosis.
  1. Front Immunol. 2026 ;17 1731995
    Immunometabolic reprogramming in sepsis: mechanisms, clinical endotypes, and therapeutic opportunities.
    Chibo Liu, Yanqun Cai, Qinfei Ma, Wei Sun.
      Sepsis, a systemic inflammatory syndrome triggered by infection, is tightly linked to dysregulated host immunometabolism. We review three hallmark metabolic alterations. First, a shift from oxidative phosphorylation (OXPHOS) to glycolysis provides rapid ATP early on; prolonged glycolytic engagement, however, drives excessive cytokine release through abnormal accumulation of metabolic intermediates. Second, impaired fatty acid oxidation (FAO) and disrupted cholesterol homeostasis not only compromise energy supply but also amplify pro-inflammatory signaling. Third, mitochondrial dysfunction unleashes reactive oxygen species (ROS) and derails metabolic homeostasis, promoting multi-organ injury. Notably, short-chain fatty acids (SCFAs) derived from the gut microbiota fine tune pro-versus anti-inflammatory responses via epigenetic regulation of immune cells. We further discuss how metabolic reprogramming governs macrophage polarization and T cell exhaustion, and we summarize therapeutic strategies that target key metabolic nodes. This review provides an integrated perspective on the immunometabolic mechanisms of sepsis and offers a rationale for metabolism-based precision interventions.
    Keywords:  T cells; macrophages; metabolic reprogramming; sepsis; short-chain fatty acids
    DOI:  https://doi.org/10.3389/fimmu.2026.1731995
  2. Biology (Basel). 2026 Mar 31. pii: 561. [Epub ahead of print]15(7):
    Metabolic Programming of Tumor-Associated Macrophages in Head and Neck Squamous Cell Carcinoma: Implications for Innate Immunity and Therapeutic Response.
    Vincent G Yuan.
      Head and neck squamous cell carcinoma (HNSCC) develops within a chronically inflamed and metabolically constrained tumor microenvironment that profoundly shapes innate immune function. Tumor-associated macrophages (TAMs) are abundant in HNSCC and display marked plasticity, yet predominantly acquire immunosuppressive states that promote tumor progression and therapeutic resistance. Traditional M1/M2 polarization models fail to capture this dynamic behavior. Emerging evidence instead identifies metabolic reprogramming as a central regulator of macrophage function in cancer. Hypoxia, nutrient limitation, extracellular acidification, and tumor-derived metabolites such as lactate and lipids rewire macrophage metabolism, directly influencing inflammatory signaling and immune suppression. This review integrates recent advances in immunometabolism to examine how metabolic adaptations govern macrophage innate functions in HNSCC and highlights therapeutic opportunities targeting macrophage metabolism to overcome immune resistance.
    Keywords:  head and neck squamous cell carcinoma; hypoxia; immunometabolism; innate immunity; lactate; metabolic reprogramming; therapeutic resistance; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/biology15070561
  3. Clin Transl Immunology. 2026 ;15(4): e70091
    Fatty acid metabolism-an emerging regulatory node in T-cell immunometabolism.
    Brett Chapel Arenberg, Michael N Sack, Jing Wu.
      While the roles of glucose metabolism and tricarboxylic acid (TCA) cycle intermediates in immune regulation are well established, the contribution of fatty acid metabolism remains less well defined. In this review, we examine current knowledge on the immunomodulatory functions of fatty acid metabolism, with a particular focus on T-cell biology. We discuss the catabolic, anabolic and signalling aspects of lipid metabolism and their influence on immune function. Short-chain fatty acids modulate T-cell epigenetics through histone acetylation, thereby impacting gene expression. Medium- and long-chain fatty acids augment fatty acid oxidation (FAO), which supports the expansion and function of regulatory T-cell populations. Very-long-chain polyunsaturated fatty acids, when cleaved from the membrane, serve as precursors for both pro-inflammatory and pro-resolving signalling molecules. Additionally, de novo fatty acid synthesis contributes to membrane biogenesis and alters acetyl-CoA availability, linking lipid metabolism to epigenetic regulation. The mechanisms described above present promising opportunities to modulate inflammation through targeted therapies. In this review, we focus on emerging targets within fatty acid metabolism pathways that show potential for influencing inflammatory responses in translational models. Specifically, we review key transcription factors, metabolic enzymes and dietary interventions, while also addressing current limitations and challenges in translating these findings to clinical settings. Although studies in murine models have yielded encouraging results, substantial gaps remain-particularly in applying these metabolic strategies to human T-cell biology. We conclude by emphasising the importance of validating these targets in ex vivo human models as a critical step towards future clinical intervention.
    Keywords:  T‐cell inflammation; T‐cell polarisation; fatty acid metabolism; immunometabolism
    DOI:  https://doi.org/10.1002/cti2.70091
  4. Pharmacol Res. 2026 Apr 15. pii: S1043-6618(26)00109-X. [Epub ahead of print] 108194
    Metabolic Control of Immunity and Inflammation: Mitochondrial Dynamics, Pharmacological Targets, and Therapeutic Opportunities.
    Chunling Wang, Wangzheqi Zhang, Yue Shu, Lizhou Song, Yiwen Wan, Haoling Zhang, Lulong Bo, Yadong Guo.
      Immune responses and inflammation are not stand-alone processes linearly regulated by the canonical signaling pathways but complex systems biology events, which are deeply rooted in the metabolic state of cells and dynamically modulated. However, immunometabolic studies have identified that programmed alterations of metabolic circuits also occur during activation of immune cells, effector function maintenance and the induction of tolerance. Mitochondria represent a unique point of convergence between energetics, inflammation and immunity, particularly as they are key orchestrators of immune responses. In addition to their classical roles in oxidative phosphorylation (OXPHOS) and metabolic intermediate synthesis, mitochondria are involved in innate immune perception of inflammatory signals and the amplification of these responses by generating reactive oxygen species (ROS), bioenergetic signaling intermediates, and mitochondrial DNA. Crucially, mitochondria are not stable entities but are tightly regulated by dynamic events such as fusion, fission, trafficking and selective degradation. These structural alterations dynamically influence the metabolic commitment, inflammatory response potency and fate choices of immune cells. Mitochondrial dynamics should not be regarded as a mere auxiliary regulatory layer of immunometabolism; instead, they represent the central organizing principles between metabolic states, inflammatory cues, and immune cell fate determination, thereby defining a new hierarchical organization of immune and inflammatory regulation.
    Keywords:  Immunometabolism; immune cell fate; inflammatory responses; mitochondrial dynamics; pharmacological targets; therapeutic opportunities
    DOI:  https://doi.org/10.1016/j.phrs.2026.108194
  5. bioRxiv. 2026 Apr 10. pii: 2026.04.07.717012. [Epub ahead of print]
    Multimodal profiling reveals Mycobacterium tuberculosis restricts lung mitochondrial immunometabolism to promote pathogenesis.
    Hedwin Kitdorlang Dkhar, Prashant Bajpai, Ana Beatriz Enriquez, Louis Brown Hopkins, Stanzin Dawa, Jonathan Kevin Sia, Ayana Paul, Ranjna Madan-Lala, Mark Cole Keenum, AshishKumar Sharma, Adam Nicolas Pelletier, Shu Ling Goh, Terra Laretta Brown Riddick, Ted Joseph Whitworth, Keith Eric Prater, Ricardo Cèsar Guerrero-Ferreira, Jeffrey Collins, Jyothi Rengarajan.
      Early events in the lung that shape protective immune responses to M. tuberculosis (Mtb) infection are not well understood but are critical for developing better vaccines and immunomodulatory therapies for tuberculosis. Here, we used high-dimensional flow cytometry, single-cell transcriptomics, and untargeted metabolomics to define the early lung immune environment that precedes the development of protective versus pathogenic outcomes following aerosolized Mtb infection of mice. We show that Mtb induced sustained glycolysis in the lung while restricting oxidative phosphorylation (OXPHOS) and impairing mitochondria, in part through the Mtb serine protease Hip1, leading to low energy output and suboptimal macrophage-T cell interactions that promoted pathogenic immunity. However, robust induction of mitochondrial OXPHOS, amino acid metabolism, and fatty acid oxidation in the early lung resulted in high ATP output and enhanced innate-T cell signaling networks that stimulated protective immune responses. Moreover, we identified a novel mitochondrial immunometabolic lung signature associated with protective outcomes to Mtb infection in animal models and humans. Our studies identify induction of mitochondrial dysfunction as a mechanism employed by Mtb to manipulate lung immunometabolism to its benefit and reveal that maintenance of intact mitochondrial metabolism in the early lung is pivotal for generating protective outcomes to Mtb infection.
    DOI:  https://doi.org/10.64898/2026.04.07.717012
  6. Biomed Pharmacother. 2026 Apr 13. pii: S0753-3322(26)00383-5. [Epub ahead of print]198 119350
    Branched-chain amino acids and innate immunity in metabolic disease: Mechanisms, paradox, and therapeutic opportunities.
    Martínez-Aguilar Magnolia, Abdullah Zeinab, Blokzijl Hans, Moshage Han.
      Metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), dyslipidaemia, and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly recognised as chronic inflammatory conditions driven in part by innate immune dysregulation. Among the metabolic factors implicated in this process, branched-chain amino acids (BCAAs) have emerged as key regulators linking nutrient sensing to immune cell function. Circulating BCAA concentrations are consistently elevated in these metabolic diseases. However, experimental and clinical studies also show that BCAA supplementation can improve metabolic and immune outcomes in specific contexts, revealing a paradoxical relationship between BCAA metabolism and inflammation. This narrative review examines how dysregulated BCAA metabolism and accumulation of branched-chain keto acids (BCKAs) shape the functional programming of innate immune cells across these conditions, including monocytes/macrophages, granulocytes, dendritic cells, and natural killer cells. Evidence indicates that the immunometabolic effects of BCAAs depend not solely on circulating concentrations but on the efficiency of their intracellular catabolism. When BCAA oxidation is preserved, these amino acids support mitochondrial metabolism and immune competence. Conversely, impaired catabolism leads to the accumulation of branched chain ketoacids, which activate inflammatory pathways and contribute to metabolic dysfunction. Resolving this paradox requires the need of targeting catabolic flux restoration rather than simple BCAA restriction or supplementation, and requires stratifying patients by enzymatic capacity, BCAA/BCKA ratios, and disease stage. Pharmacological modulators, including BCKDK inhibitors and BCAT1-targeted agents, show promise in simultaneously addressing metabolic and immune dysregulation.
    Keywords:  Branched chain amino acids (BCAA); Inflammation; Innate immunity; Metabolic Diseases; immunometabolism
    DOI:  https://doi.org/10.1016/j.biopha.2026.119350
  7. EMBO Rep. 2026 Apr 14.
    Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
    Manami Tanaka, Takako Hishiki, Tomomi Matsuura, Masato Yasui, Shunsuke Chikuma, Mariko Hara-Chikuma.
      Although glycerol is a ubiquitous metabolite in mammalian systems, its cellular metabolic pathways and functions have not been fully elucidated. Here, we find that elevated extracellular glycerol modulates intracellular metabolism and pro-inflammatory responses of macrophages. In pro-inflammatory macrophages stimulated with lipopolysaccharide, glycerol is taken up through glycerol channels including Aquaporin 3 (AQP3) and metabolized to glycerol-3-phosphate (G3P), which is then converted to dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenase 2 (GPD2). This glycerol-driven pathway enhances mitochondrial ATP production, potentially by supplying electrons to the electron transport chain (ETC) via GPD2, and by upregulating the transcription of genes encoding ETC complexes.　In addition, glycerol supplementation elevates intracellular acetyl-CoA levels, promotes histone acetylation at the promoters of pro-inflammatory cytokine genes, and consequently increases cytokine gene expression, suggesting enhanced pro-inflammatory response. In vivo experiments, macrophage-specific AQP3 conditional knockout mice exhibit reduced weight gain and adipose tissue inflammation in a high-fat diet-induced obesity model. Our findings provide novel insights into the metabolic regulation and macrophage inflammation by extracellular glycerol.
    Keywords:  Glycerol; Inflammation; Macrophage; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/s44319-026-00747-y
  8. Front Immunol. 2026 ;17 1736082
    Amino acid metabolism modulates macrophage polarization: implications for autoimmune-related diseases.
    Yuzhe Yin, Chaosheng Yan, Xinyu Pei, Jingjing Rao, Ling Wu, Yuzheng Xue, Haowen Sun, Yingyue Sheng.
      Amino acid metabolic reprogramming is an important component of immunometabolism. In addition to providing biosynthetic substrates and energetic support for macrophages, distinct amino acid metabolic pathways can also reshape the inflammatory and reparative functional states of macrophages by regulating redox homeostasis, epigenetic modifications, signal transduction, and the accumulation of metabolic intermediates. Despite rapid progress in this field, there remains a lack of systematic integration regarding how key metabolic axes, including arginine metabolism, tryptophan catabolism, and glutamine metabolism, coordinately or antagonistically drive macrophage functional reprogramming, as well as the conservation, heterogeneity, and translational significance of these changes across different autoimmune-related diseases. This review summarizes the roles of arginine, tryptophan, glutamine, branched-chain amino acid, serine/glycine/threonine, aspartate/asparagine, and sulfur-containing amino acid metabolism in the dynamic spectrum of macrophage polarization, and further outlines recent advances in systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, psoriasis, autoimmune hepatitis, and vasculitis. This review emphasizes that amino acid metabolism is not an isolated regulatory module, but rather part of an interconnected network that, together with glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle anaplerosis, one-carbon metabolism, and lipid metabolism, determines macrophage fate. Given the existing differences in evidence strength and metabolic phenotypes among in vitro systems, animal models, and human studies, caution is still required when extrapolating these conclusions to clinical settings. Overall, therapeutic interventions targeting amino acid metabolism may provide novel biomarkers and treatment strategies for autoimmune-related diseases, but their clinical translation still depends on higher-resolution human validation and mechanism-oriented precision studies.
    Keywords:  arginine metabolism; glutamine metabolism; immunometabolism; metabolic reprogramming; therapeutic targeting; tryptophan catabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1736082
  9. Biomed Res Int. 2026 ;2026(1): e7838997
    Effects of CMV on T and NK Cells; With Emphasis on Immunometabolism.
    Haideh Namdari, Mohsen Keshavarz, Maryam Hosseini, Farzad Parvizpour, Asrin Emami, Elahe Izadi, Milad Shahbazi Asl, Mehdi Shahgolzari, Farhad Rezaei.
      CMV is masterful at manipulating stress responses and conducting them in a way that yields beneficial outcomes. CMV always causes metabolic changes in the infected cells. However, nutritional status affects the pattern of events following CMV infection. Oxidative phosphorylation (OXPHOS) and glycolysis are two vital pathways for energy generation in mammalian cells, which differ in terms of ATP production and location. Understanding metabolic alterations required for CMV infection may lead to the design of novel therapeutic methods based on targeted inhibition of these cellular metabolic pathways. This review explores how CMV mimics, exploits, or interferes with the host cell, with emphasis on immunometabolism, and how, in doing so, it may evade immune responses.
    Keywords:  ATP; CMV; glycolysis; immunometabolism; phosphorylation
    DOI:  https://doi.org/10.1155/bmri/7838997
  10. NAR Mol Med. 2026 Apr;3(2): ugag017
    Human pneumovirus induces IFN-dependent expression of the immune-responsive gene 1 and is inhibited by 4-octyl itaconate in human macrophages.
    Alix S Spahn, Kristin Rian, Alexandre Gidon, Claire Louet, Victor Boyartchuk, Trude H Flo, Marit W Anthonsen.
      The immunometabolite itaconate, generated by immune-responsive gene 1 (IRG1/ACOD1), and its derivative 4-octyl itaconate (4OI) have been found to modulate inflammation and progression of viral infections, but their effects on the significant respiratory pathogen human metapneumovirus (HMPV) is unknown. Here, we demonstrate that HMPV induces IRG1 expression via a TANK-binding kinase 1, NF-κB-, and interferon (IFN)-dependent manner in human primary macrophages. We further show that the addition of a cell-permeable derivative of itaconate, 4OI, but not itaconate itself or its natural isomer citraconate, reduces HMPV and IFN-β levels in human macrophages. 4OI additionally activated Nrf2, while Nrf2 depletion enhanced HMPV levels, suggesting that Nrf2 mediates the antiviral effect of 4OI on HMPV. Also, we found that 4OI reduced expression of ATP-dependent citrate lyase, a lipid metabolic enzyme that supports HMPV replication. Our study suggests 4OI as a potential compound for targeting HMPV-IFN-β-driven disease and highlights Nrf2-dependent lipid reprogramming as a potential modulator of 4OI antiviral effects.
    DOI:  https://doi.org/10.1093/narmme/ugag017
  11. Front Immunol. 2026 ;17 1745195
    Monophosphoryl lipid A boosts macrophage antimicrobial immunity by metabolically regulating source-specific ROS generation.
    Dan Hao, Benjamin D Klein, Margaret A McBride, Julia K Bohannon, Naeem K Patil, Xenia D Davis, Mary A Oliver, Mei Lin Ning Dye, Sara Weidenbach, Jamey D Young, Edward R Sherwood.
       Introduction: Monophosphoryl lipid A (MPLA), a toll-like receptor (TLR) 4 agonist and licensed vaccine adjuvant, reprograms innate immune cells to confer protection against diverse pathogens. However, the metabolic and molecular adaptations supporting this response remain poorly defined.
    Methods: The contributions of discrete reactive oxygen species (ROS) sources-including NADPH oxidase 2 (NOX2), xanthine oxidase (XO), mitochondria, and inducible nitric oxide synthase (iNOS)-to MPLA-induced macrophage antimicrobial activity were examined using genetic deletion or pharmacologic inhibition. Metabolic and redox adaptations supporting this response were assessed by analyzing oxidative pentose phosphate pathway (oxPPP) activity, glutathione-dependent antioxidant systems, and mitochondrial oxidative phosphorylation in MPLA-primed macrophages.
    Results: MPLA enhanced macrophage clearance of Pseudomonas aeruginosa by coordinating source-specific ROS generation. NOX2 was essential for this response, as its pharmacologic inhibition or genetic deletion markedly diminished MPLA-induced microbicidal responses. MPLA also induced XO, providing auxiliary ROS that acted additively with NOX2-derived ROS to support bacterial clearance. MPLA activated the oxPPP to generate NADPH, which was essential for supporting phagocytosis and maintaining glutathione-dependent redox homeostasis. Additionally, MPLA promoted mitochondrial oxidative phosphorylation to sustain phagocytic capacity. Mitochondrial ROS (mROS) were tightly constrained by induction of antioxidant systems, including superoxide dismutase 2 (SOD2), heme oxygenase-1 (HO-1) and glutathione, and were dispensable for antimicrobial protection. iNOS-derived nitric oxide did not contribute to the MPLA-induced antimicrobial phenotype.
    Conclusion: These findings define the metabolic and redox circuits driving MPLA-induced antimicrobial immunity and establish its potential as a host-directed antimicrobial therapy beyond vaccine adjuvancy.
    Keywords:  NADPH; NADPH oxidase (NOX); innate immune memory; monophosphoryl lipid A (MPLA); reactive oxygen species (ROS); trained immunity; xanthine oxidase (XO)
    DOI:  https://doi.org/10.3389/fimmu.2026.1745195
  12. Nat Rev Immunol. 2026 Apr 15.
    Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
    Neil T Sprenkle, Evanna L Mills.
      Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, these cells have major roles in the pathogenesis of numerous diseases, including obesity-associated metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated fatty liver disease and atherosclerotic cardiovascular disease. Cellular and phenotypic remodelling of macrophage populations in response to metabolic alterations linked to obesity perturbs homeostatic interactions and promotes low-grade sterile tissue inflammation, which propagates tissue dysfunction. Much of the seminal initial work in the field of 'immunometabolism' explored the role of metabolic pathways in the regulation of distinct immune cell types. More recently, however, it has become appreciated that intermediary metabolites can function as signals that regulate macrophages at the level of the whole tissue or organism. As we discuss here, recent work has identified intermediary metabolites such as lactate, succinate and itaconate, and nutrients including glucose, amino acids and free fatty acids, as crucial regulatory signals that control macrophage function in obesity and metabolic disease.
    DOI:  https://doi.org/10.1038/s41577-026-01292-4
  13. Int J Inflam. 2026 ;2026 6298730
    Roles of Oxidative Phosphorylation and Fatty Acid Oxidation in Neuroinflammation Induced by Lipopolysaccharide in Hypothalamic Neuronal Cells.
    Mohsine-Ali El-Hamri, Meriem Lahmouad, Jihane Zerrouk, Rafik El-Mernissi, Lhoussain Hajji, Khayelihle Brian Makhathini, Hanane Khalki, Oualid Abboussi.
      Neuroinflammation is intricately associated with impaired neuronal function and is a contributing factor in the development of neurodegenerative diseases. Significant alterations in cellular metabolism often accompany these inflammatory changes. Although considerable research has focused on understanding these metabolic shifts in astrocytes and microglia, the precise mechanisms linking neuroinflammation and cellular metabolism in neurons remain poorly understood. This study explores the connection between neuroinflammation and neuronal cell metabolism through a lipopolysaccharide (LPS)-induced neuroinflammation model utilizing GT1-7 hypothalamic neuron cultures. Our findings indicate that LPS-induced neuroinflammation in GT1-7 hypothalamic neurons is marked by reduced oxidative phosphorylation (OXPHOS) and decreased endogenous fatty acid oxidation (FAO). In contrast, exogenous FAO increases, leading to elevated ATP production, while glycolysis remains unchanged. These metabolic changes are associated with increased inflammatory markers (IL-6, TNF-α) and oxidative stress indicators (ROS, NO), as well as decreased synaptic plasticity (as indicated by synaptophysin) and impaired cellular function, as evidenced by reduced gonadotropin-releasing hormone (GnRH) release. Our study highlights the intricate interplay between neuroinflammation and neuronal cell metabolism. These findings emphasize the significance of metabolic changes in neuroinflammatory processes, offering potential insights for therapeutic interventions in neurodegenerative diseases.
    Keywords:  gonadotropin-releasing hormone; neuroinflammation; neuronal cell metabolism; oxidative stress; synaptic plasticity
    DOI:  https://doi.org/10.1155/ijin/6298730
  14. Front Mol Biosci. 2026 ;13 1815835
    Sensing succinate: SUCNR1 as a context-dependent metabolic and cellular signal integrator.
    Aenne-Dorothea Liebing, Claudia Stäubert.
      Succinate (SUC), a central intermediate in the mitochondrial tricarboxylic acid (TCA) cycle, functions not only as a metabolic substrate but also acts as the endogenous ligand for succinate receptor 1 (SUCNR1), a Gi- and Gq protein-coupled receptor. SUC accumulates when energy demand exceeds oxygen supply or during metabolic rewiring, including hypoxia, endurance exercise, inflammation, and tumor progression. SUC can be released into the extracellular space, reaching levels sufficient to activate SUCNR1. SUCNR1 is expressed in various tissues, including the kidney, liver, and adipose tissue, as well as in immune cells and cancer subtypes. Rather than functioning as a simple pro- or anti-inflammatory receptor, SUCNR1 acts as a metabolic signal integrator whose output is determined by G protein preferences, receptor trafficking, and the balance between intra- and extracellular SUC pools. In immune cells, particularly macrophages, SUCNR1 signaling promotes either inflammatory activation or resolution depending on the metabolic state. In metabolic tissues and cancer, SUCNR1 coordinates adaptive responses to nutrient and oxygen stress while shaping the tissue microenvironment. Here, we review recent advances in SUC-SUCNR1 signaling across immune and metabolic systems, discuss unresolved controversies regarding signaling selectivity and spatial encoding, and evaluate the therapeutic opportunities and challenges of targeting this metabolic checkpoint.
    Keywords:  G protein-coupled receptor (GPCR); cancer; metabolism; pro- and anti-inflammatory immune responses; signal selectivity; signal transduction; succinate; succinate receptor 1 (SUCNR1)
    DOI:  https://doi.org/10.3389/fmolb.2026.1815835
  15. J Invertebr Pathol. 2026 Apr 09. pii: S0022-2011(26)00096-0. [Epub ahead of print]217 108622
    Apolipophorin-III inhibits BmNPV replication by reprogramming sphingolipid metabolism to accumulate ceramide.
    Xinhao Jiao, Zi Liang, Lulai Wang, Na Zhang, Shuyi Liu, Wenwen Jiang, Tao Geng, Quadsia Jabeen, Ping Wu.
      The silkworm industry faces a significant threat from Bombyx mori nucleopolyhedrovirus (BmNPV). While Apolipophorin-III (ApoLp-III) is known for its roles in lipid transport and antibacterial immunity, its function in antiviral defense and the underlying mechanisms remain poorly understood. In this study, we investigated the impact of ApoLp-III on BmNPV proliferation and explored the associated mechanism. We found that BmNPV infection significantly induced ApoLp-III expression in a tissue- and time-specific manner. Knockdown of ApoLp-III in vitro enhanced BmNPV replication, whereas its overexpression suppressed viral replication and induced G1 cell cycle arrest. Lipidomics analysis revealed that ApoLp-III overexpression triggered significant sphingolipid metabolic reprogramming, resulting in the specific accumulation of ceramide species. Furthermore, exogenous C6-ceramide treatment was found to inhibit both BmNPV proliferation and the transcription of some key genes in mTORC1 pathway. Mechanistically, this inhibition was linked to the downregulation of RPTOR, a critical component of the mTORC1 complex. Consequently, key mTORC1 effectors including c-Myc, S6K1, and PCK2 were transcriptionally downregulated, leading to G1 cell cycle arrest. Notably, pharmacological inhibition of de novo ceramide synthesis with myriocin significantly attenuated both the suppression of these key genes and the antiviral effect mediated by ApoLp-III. Our findings reveal a novel immunometabolic pathway in which ApoLp-III exerts its antiviral function by promoting ceramide accumulation, which likely inhibits mTORC1 signaling, leading to G1 cell cycle arrest and the subsequent suppression of BmNPV replication. This study identifies ApoLp-III as a key nexus linking lipid metabolism to antiviral immunity in silkworms, providing new insights for developing strategies against viral infections.
    Keywords:  Apolipophorin-III; BmNPV; Ceramide; Immunometabolism; mTOR
    DOI:  https://doi.org/10.1016/j.jip.2026.108622
  16. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2528843123
    SCD1 licenses STING signaling through fatty acid desaturation-mediated membrane remodeling.
    Danhui Qin, Yanjie Gao, Haojia Jiang, Xintong Meng, Ying Qin, Hui Song, Yue Fu, Chengjiang Gao, Mutian Jia, Chunyuan Zhao, Wei Zhao.
      The stimulator of interferon genes (STING) is a critical mediator of innate immunity against cytosolic DNA pathogens, requiring precise regulation to balance antiviral defense and immune tolerance. While lipid metabolism influences immune signaling, the role of stearoyl-CoA desaturase 1 (SCD1), a key enzyme converting saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), in STING activation remains unexplored. Here, we identify SCD1 as a metabolic checkpoint that licenses STING activation through biophysical membrane remodeling. Mechanistically, SCD1-generated MUFAs incorporate into endoplasmic reticulum (ER) phospholipids, enhancing membrane curvature and fluidity. This biophysical remodeling facilitates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) binding to STING and promotes its dimerization, enabling downstream TBK1-IRF3 signaling and type I interferons (IFNs) production. Consequently, Scd1 deficiency or pharmacological inhibition impairs STING activation, attenuates antiviral responses against herpes simplex virus-1 (HSV-1), and exacerbates viral replication in vitro and in vivo. Conversely, MUFAs supplementation rescues STING activation in Scd1-deficient models. Our findings establish SCD1-mediated lipid desaturation as a fundamental regulator of STING-driven immunity, highlighting its therapeutic potential for disorders of aberrant STING activation.
    Keywords:  SCD1; STING; cellular lipid metabolism; innate immunity; membrane architecture
    DOI:  https://doi.org/10.1073/pnas.2528843123
  17. Curr Med Sci. 2026 Apr 17.
    Therapeutic Regulation of Macrophage Polarization for Diabetic Kidney Disease by Targeted Metabolic Reprogramming.
    Si-Ying Fei, Rui-Tong Liu, Wen-Xiao Yang, Bing-Shu Wu, Xiao-Bin Mei, Mao-Jin Xu.
      Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes. It can be identified by thickening of the glomerular basement membrane, reduced glomerular filtration rate, and persistent proteinuria. Macrophages play a key role in the pathogenesis of DKD, and their phenotype (M1 and M2) is finely regulated by metabolic reprogramming. M1 macrophages exacerbate inflammatory damage and fibrosis in renal tissue by secreting pro-inflammatory mediators and reactive oxygen species (ROS). M2 macrophages (further subdivided into M2a, M2b, M2c and M2d subtypes) primarily exert anti-inflammatory and tissue-repairing effects. Of these, the M2a and M2c subtypes are particularly crucial for anti-inflammatory repair. This study aimed to systematically review the mechanisms by which glucose, lipid, amino acid, and mitochondrial function-related metabolism influence macrophage polarization. It further explored therapeutic strategies to mitigate renal inflammation and fibrosis by regulating macrophage polarization through targeted metabolic pathways, including inhibiting glycolysis, promoting fatty acid oxidation, modulating amino acid metabolism, and enhancing mitochondrial biogenesis and oxidative phosphorylation (OXPHOS). Several natural compounds and synthetic drugs exhibit the potential to induce M2 polarization and suppress M1 polarization through metabolic reprogramming, thereby offering new directions for optimizing therapeutic strategies for DKD.
    Keywords:  Diabetes complications; Diabetic kidney disease; Macrophage phenotype; Macrophage polarization; Metabolic reprogramming; Mitochondrial function; Renal fibrosis
    DOI:  https://doi.org/10.1007/s11596-026-00192-x
  18. Pharm Sci Adv. 2026 Dec;4 100111
    NAD+ precursor supplementation reverses CD36-mediated lipid accumulation and ferroptosis to restore antitumor function of NK cells in DLBCL.
    Lizhi Shi, Xuezhu Huang, Xiao Han, Chenchen Ning, Xinyi Zhao, Haohao Li, Zhe Yu, Qiuju Han.
      Natural killer (NK) cells play a key role in the standard treatment of diffuse large B-cell lymphoma (DLBCL). However, NK cells in DLBCL patients frequently display an exhausted phenotype, which is associated with poor clinical outcomes. The metabolic mechanisms contributing to this functional impairment remain poorly understood. We assessed degranulation (CD107a), cytokine secretion (IFN-γ, TNF-α), mitochondrial activity, and lipid metabolism in NK cells from DLBCL patients and healthy donors. Dysregulated lipid species were identified by GC-MS lipidomics and validated in NK-92MI and primary NK cells. The functional involvement of CD36 was assessed using the specific inhibitor, with subsequent examination of its correlation with cytotoxic activity. NAD+ metabolism was evaluated via NAMPT and NAD+ levels, and rescue assays involved nicotinamide mononucleotide (NMN). For in vivo validation, a murine lymphoma model was treated with nicotinamide riboside (NR), and tumor-infiltrating NK cell function and lipid accumulation were analyzed. NK cells from DLBCL patients demonstrated significantly reduced proliferative capacity and cytotoxicity, accompanied by substantial lipid accumulation. This dysfunction was linked to upregulated CD36 expression and associated with ferroptosis-a form of regulated necrotic cell death. Mechanistically, CD36-mediated lipid uptake induced metabolic reprogramming and promoted ferroptotic cell death, concurrently depleting intracellular NAD+ levels. Importantly, supplementation with NAD+ precursors effectively reversed NK cell exhaustion and restored antitumor activity both in vitro and in vivo. CD36-driven lipid metabolic disruption leads to NK cell dysfunction and ferroptosis in DLBCL. Thus, restoration of NAD+ levels represents a promising therapeutic strategy to enhance NK cell effector function and improve antitumor immunity in DLBCL.
    Keywords:  CD36; DLBCL; Lipid metabolism; NAD+; NK cell
    DOI:  https://doi.org/10.1016/j.pscia.2026.100111
  19. Front Immunol. 2026 ;17 1754832
    Immunometabolic dysregulation in autoimmune rheumatic diseases: the central role of glycolytic reprogramming in pathogenesis and traditional Chinese medicine therapy.
    Jianting Wen, Jian Liu, Lei Wan, Fanfan Wang, Yang Li.
      Immunometabolic dysregulation has emerged as a key driver in the pathogenesis of autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA), osteoarthritis (OA), and systemic lupus erythematosus (SLE). This review highlighted the central role of glycolytic reprogramming in driving immune cell dysfunction and disease progression. In RA, enhanced glycolysis promoted T cell dysregulation, synovial fibroblast activation, and macrophage polarization. In OA, glycolytic alterations in chondrocytes and synovial tissues were central to disease pathology, while SLE was characterized by metabolic shifts in podocytes, T cells, and NETosis processes. Traditional Chinese medicine (TCM) may be a promising therapeutic strategy by targeting glycolytic pathways to modulate immune responses and restore metabolic balance. Despite existing challenges, the integration of multi-omics and artificial intelligence (AI) may facilitate the development of personalized immunometabolic therapies. This review underscored glycolysis as a pivotal therapeutic target and advocated for interdisciplinary approaches in future ARD research.
    Keywords:  autoimmune rheumatic diseases; glycolytic reprogramming; immunometabolic dysregulation; rheumatoid arthritis; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fimmu.2026.1754832
  20. Nat Commun. 2026 Apr 13.
    Multiomics-guided discovery of protective microbiome signatures in lupus-prone mice treated with Faecalibacterium prausnitzii.
    Ni Zhao, Peiling Geng, Damian Jimenez, Abigail Castellanos Garcia, Natalie Six, Cassandra Isabelle LaPlante, Alejandro Gaher Perez, Gregg J Silverman, Laurence Morel, Yong Ge.
      Gut microbiome dysbiosis has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, microbiota-targeted therapeutic strategies have been lacking. Here, we report the potential of Faecalibacterium prausnitzii (strain UT1) to ameliorate gut dysbiosis and alleviate disease progression in the B6.Sle1.Yaa male mouse model of SLE. Fecal metagenomes of patients with SLE shifted carbohydrate catabolism from dietary fibers to host glycans, coinciding with depletion of F. prausnitzii. Oral administration of UT1 partially reversed lupus-associated microbiome alterations and rescued carbohydrate metabolic deficiency in lupus-prone mice. Using correlative metatranscriptomics and metabolomics, we observed restricted expression of bacterial genes related to mucin degradation, elevated pentose phosphate pathway and bile acid-modifying activities, and redirected tryptophan catabolism toward indoleacetic and indoleacrylic acids. Further host cell profiling showed that UT1 rebalanced colonic regulatory T (Treg) and T helper 17 (Th17) cell responses, suppressed systemic autoimmune activation and autoantibody production, and reduced renal pathology. Thus, our findings identify SLE-associated active microbiome signatures and provide a probiotic candidate for the treatment of lupus disease.
    DOI:  https://doi.org/10.1038/s41467-026-71718-z
  21. Int Immunol. 2026 Apr 16. pii: dxag015. [Epub ahead of print]
    Lipid metabolic regulation of pathogenic type 2 immunity in the airway.
    Hiroyuki Yagyu, Masahiro Kiuchi, Kiyoshi Hirahara.
      Immune memory is central to host protection against pathogens and contributes to the pathogenesis of chronic inflammatory diseases. Beyond canonical cytokines and antigenic stimuli, metabolic signals have emerged as pivotal regulators of T-cell activation, differentiation, and memory formation. However, the mechanisms by which metabolic and tissue-derived cues imprint pathogenic features on T cells remain poorly understood. Dysregulation of type 2 immune memory is a major driver of chronic inflammation in allergic diseases. A distinct subpopulation of memory T helper 2 (Th2) cells that express the interleukin (IL)-33 receptor ST2 has emerged as a key contributor to the pathogenesis of chronic allergic inflammation. Recent studies have revealed a close link between lipid metabolism and pathogenic type 2 immunity, highlighting how fatty acid uptake, storage within lipid droplets, and catabolism through lipolysis and lipophagy regulate the expression of ST2 and cytokine production. Moreover, transcriptional regulators such as peroxisome proliferator-activated receptor γ (PPARγ) integrate lipid-derived signals with transcriptional and metabolic programs that induce pathogenic memory. In this review, we summarize the current understanding of CD4+ T cell-mediated immune memory, with a particular focus on pathogenic Th2 cells and airway type 2 immunity, and discuss emerging concepts that connect lipid metabolic programs, transcriptional regulation, and chronic allergic inflammation.
    Keywords:  IL-33/ST2 axis; PPARγ; allergic airway inflammation; fatty acids; tissue-resident memory T cells
    DOI:  https://doi.org/10.1093/intimm/dxag015
  22. Cell Metab. 2026 Apr 15. pii: S1550-4131(26)00106-3. [Epub ahead of print]
    Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
    Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A Zuriaga, José J Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S Chandel, Esteban Ballestar, Stefanie K Wculek, David Sancho.
      Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by Tet2 deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.
    Keywords:  DNA methylation; dendritic cells; electron transport chain; immunity; metabolites; mitochondria; redox balance
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.012
  23. Nat Commun. 2026 Apr 14.
    Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion.
    Zhou Sha, Kun Yang, Shoupeng Fu, Xiaoyong Tong, Hui Yang, Huiling Fang, Qianqian He, Ning Li, Xinyu Shu, Qi Liu, Beibei Fu, Jin Liu, Qian Li, Hao Zeng, Xiaokai Zhang, Rui Yao, Xushuo Zhang, Wenjin Guo, Xuhu Mao, Mian Long, Xiaoyuan Lin, Quanming Zou, Haibo Wu.
      Acute central nervous system infection is highly lethal, yet the mechanisms by which intracellular bacteria infiltrate the brain remain unclear. Phagocytes are central to host defense, but how infected cells facilitate bacterial access to the brain is poorly defined. In this study, we characterize a CD36+ Fabp4+ Pparg+ macrophage subset that mediates bacterial penetration of the brain without disrupting the blood-brain barrier. Biomechanical analysis reveals that CD36+ macrophages exhibit abundant protrusions and adhesion molecules, enabling resistance to blood flow shear stress and promoting endothelial adhesion. Metabolomic profiling reveals dysregulated lipid metabolism during neuroinvasion, with β-hydroxybutyrate promoting the differentiation and survival of CD36+ macrophages. Importantly, ketogenesis exacerbates symptoms during bacterial neuroinvasion, which could be halted by physiological glucose supplementation. Here, we show that intracellular bacteria exploit metabolically reprogrammed macrophages to access the brain, highlighting glycolipid metabolic homeostasis as a potential therapeutic target in bacterial neuroinvasion.
    DOI:  https://doi.org/10.1038/s41467-026-71791-4
  24. J Neurochem. 2026 Apr;170(4): e70434
    Early Effects of Poly(I:C)-induced Neuroinflammation on Hippocampal Astrocyte Function and Glycolytic Metabolism.
    Adriana Fernanda K Vizuete, João Pedro Montandon Garcez, Maria Cristina M Pellenz, Jordana Agliardi de Lima, Jéssica Taday, Jéssica Maria Souza, Marina Concli Leite, Carlos Alberto Gonçalves.
      Concern is growing about the role of neurotropic viruses, such as Zika virus, West Nile virus, herpes simplex virus, SARS-CoV-2, and human immunodeficiency virus, in central nervous system (CNS) infections, which trigger host immune responses, neuronal dysfunction and brain injury. Astrocytes function as immune system cells and, together with microglia, participate in the activation and maintenance of neuroinflammatory responses, a common pathophysiological event in neurodegenerative diseases. The reactive phenotype of glial cells leads to the synthesis and release of inflammatory mediators inducing a neurometabolic shift to nonoxidative glycolysis, a phenomenon similar to the Warburg effect. However, since viruses require energy from host cells to replicate, it is essential to understand the increase in glucose consumption during viral infections. For this purpose, we used an early polyinosinic:polycytidylic acid [Poly(I:C)] induced neuroinflammation model to investigate its effects on astrocyte function and neurometabolic responses in two approaches: acute hippocampal slices and in vivo intraperitoneal administration from male Wistar rats (PN30). We evaluated the effects of a dose-response curve of Poly(I:C), an immunostimulant agent that mimics double-stranded RNA virus infection, on the neuroinflammatory response, astrocyte reactivity, and glycolytic parameters. Poly(I:C) induced neuroinflammation and astrocyte reactivity in a dose-dependent manner. Both models of Poly(I:C)-induced early neuroinflammation and astrocyte reactivity which leads to neurometabolic reprogramming with enhanced several glycolytic parameters, such as glucose uptake and hexokinase activity, methylglyoxal (MG) synthesis and affect the glyoxalase-1 (GLO1) activity. Accordingly, inflammatory and glycolytic inhibitors reduced the glycolytic parameters induced by Poly(I:C). As expected, the inflammatory inhibitors downmodulated neuroinflammatory parameters, with arundic acid in particular reversing astrocyte reactivity. Moreover, the downregulation of the glycolytic pathway had a greater effect on the pronounced inflammatory process, and reversed the astrocyte reactivity induced by Poly(I:C) neuroinflammation. Our data are consistent with the hypothesis that a metabolic shift is required to maintain neuroinflammatory signaling, particularly in early Poly(I:C) induced neroinflammation, and highlight the glycolytic pathway as a potential target for controlling the neuroinflammatory response.
    Keywords:  Poly(I:C); astrocytes; glycolysis; neuroinflammation
    DOI:  https://doi.org/10.1111/jnc.70434
  25. Front Immunol. 2026 ;17 1734880
    Mitochondrial dysfunction in immune cells during the perioperative period: mechanisms, emerging therapeutic strategies, and implications for multi-organ protection.
    Ziyu Wang, Lu Wang, Maolin Ji, Jie Lou, Yuchuan Yuan, Yuanxu Cui, Gang Xiang, Xing Zhou.
      Mitochondrial health is increasingly recognized as a critical determinant of immune competence during the perioperative period. Surgical interventions impose unique metabolic and inflammatory stresses-such as ischemia-reperfusion injury, anesthetic exposure, and systemic inflammatory responses-that impair immune cell bioenergetics and redox balance. Dysfunctional mitochondria in neutrophils, macrophages, and T lymphocytes alter cytokine production, phagocytic activity, and antigen presentation, tipping the balance toward excessive inflammation or postoperative immunosuppression, thereby exacerbating organ injury. This review integrates current knowledge of the mechanisms linking perioperative mitochondrial dysfunction to immune dysregulation, and systematically evaluates emerging therapeutic strategies, including mitochondrial-targeted antioxidants, permeability transition pore inhibitors, metabolic reprogramming agents, mitochondrial transplantation, and gene-based interventions. By bridging experimental evidence with translational and early clinical studies in cardiac, neurological, hepatic, and renal surgeries, we argue that precise modulation of immune cell mitochondrial function represents a promising and underexplored frontier for comprehensive perioperative organ protection.
    Keywords:  immune cells; immunomodulation; mitochondrial dysfunction; organ protection; perioperative period
    DOI:  https://doi.org/10.3389/fimmu.2026.1734880
  26. Int J Mol Sci. 2026 Mar 31. pii: 3169. [Epub ahead of print]27(7):
    Extracellular ATP Functions as a Metabolic Lineage Selection Signal That Stabilizes Tc9 Cells During Adoptive T Cell Therapy.
    Jie Ren, Zhengrong Gong, Yutong Zhong, Ruipei Xiao, Khadija Urooj, Yuan Gao, Enguang Bi, Handuo Wang.
      Adoptive T cell therapy (ACT) remains limited in solid tumors by poor T cell persistence within the metabolically hostile tumor microenvironment (TME). Although IL-9-producing CD8+ T cells (Tc9) consistently demonstrate superior antitumor efficacy compared with conventional Tc1 cells, the selective pressures that shape their functional advantage remain unclear. Here, we show that effective ACT-mediated tumor control is accompanied by a marked increase in intratumoral extracellular ATP (eATP), representing a common metabolic consequence of tumor cell destruction. Despite comparable ATP accumulation following Tc1 or Tc9 treatment, these subsets exhibit strikingly distinct responses to ATP stress. Tc1 cells are highly susceptible to ATP-induced apoptosis, whereas Tc9 cells display intrinsic resistance, resulting in superior in vivo persistence. Mechanistically, Tc9 cells actively convert ATP signaling into enhanced mitochondrial fitness, characterized by increased oxidative phosphorylation and spare respiratory capacity. ATP exposure further drives Tc9 cells toward a tissue-resident memory (TRM) phenotype through activation of the TGF-β signaling axis. Transcriptomic and molecular analyses reveal that purinergic signaling pathways, including elevated expression of the ATP receptor P2RX7, are intrinsically enriched in Tc9 cells and are further amplified upon ATP stimulation. Collectively, our findings identify extracellular ATP as a metabolic lineage selection signal in ACT, demonstrating that ATP stress preferentially stabilizes metabolically resilient Tc9 cells by linking purinergic sensing to mitochondrial remodeling and TRM programming, thereby providing a conceptual basis for enhancing the persistence and efficacy of engineered T cell therapies in solid tumors.
    Keywords:  ATP; IL-9+ CD8+ T cells; adoptive T cell therapy (ACT); cancer immunotherapy; mitochondria; resident memory T cells (TRM)
    DOI:  https://doi.org/10.3390/ijms27073169
  27. Transl Cancer Res. 2026 Mar 31. 15(3): 148
    Targeting LRPPRC lactylation disrupts metabolic-immune crosstalk and restores antitumor immunity in hepatocellular carcinoma.
    Na Li, Qian He, Qi Huang, Yongqing Zhu.
       Background: The Warburg effect drives lactate accumulation in the tumor microenvironment (TME), where it functions as a signaling molecule. Lactate-derived lysine lactylation (Kla) is a novel post-translational modification (PTM) implicated in regulating immune cell function. Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is overexpressed in hepatocellular carcinoma (HCC) and plays key roles in mitochondrial metabolism and immune evasion. However, whether and how LRPPRC is regulated by lactylation to coordinate metabolic-immune crosstalk in HCC remains unknown. This study aims to investigate the role and mechanism of LRPPRC lactylation in linking tumor glycolysis to macrophage polarization in HCC.
    Methods: Bioinformatics analysis identified lactate metabolism-related genes and hub nodes in HCC datasets. LRPPRC lactylation was detected via immunoprecipitation and western blot using pan-Kla antibody. The specific lactylation site was mapped by prediction database and validated by site-directed mutagenesis (K326R). Functional impacts of LRPPRC-Kla326 on HCC cell proliferation, invasion, and glycolysis were assessed using Cell Counting Kit-8 (CCK-8), Transwell, wound-healing, and Seahorse assays. The role of LRPPRC-Kla326 in macrophage polarization was examined in bone marrow-derived macrophages (BMDMs) from LRPPRCWT and LRPPRCK326R knock-in mice using flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR), and cytokine measurement. An in vivo tumor admix model co-injecting Lewis lung carcinoma (LLC) cells with polarized BMDMs was used to evaluate tumor growth and immune cell infiltration.
    Results: LRPPRC was identified as a hub gene among lactate metabolism-related genes in HCC and was upregulated in tumor tissues, correlating with poor prognosis. LRPPRC undergoes lactylation in a lactate-dependent manner, with K326 being the major modification site. The LRPPRCK326R mutation impaired HCC cell proliferation, invasion, and glycolytic flux. In macrophages, lactylation at LRPPRCK326was required for lactate-induced M2 polarization and glycolytic reprogramming; the K326R mutation skewed polarization towards an M1 phenotype with reduced glycolysis. In the tumor admix model, co-injection of LRPPRCK326R M2 macrophages significantly suppressed tumor growth compared to LRPPRCWT M2 macrophages, which was associated with increased infiltration of activated IFN-γ+ CD8+ and CD4+ T cells.
    Conclusions: Lactate-induced lactylation of LRPPRC at K326 serves as a critical metabolic-immune switch in HCC. It enhances tumor glycolysis and simultaneously drives M2-like macrophage polarization, fostering an immunosuppressive TME conducive to tumor progression. Targeting the LRPPRC-Kla326 axis may represent a promising therapeutic strategy to disrupt the metabolic symbiosis between tumor cells and immune cells in HCC.
    Keywords:  Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC); antitumor immunity; hepatocellular carcinoma (HCC); lactylation; macrophage polarization
    DOI:  https://doi.org/10.21037/tcr-2025-aw-2533
  28. Front Immunol. 2026 ;17 1770063
    Fumarate inhibits the formation of neutrophil extracellular traps (NETs) in a Nrf2-controlled and Annexin-A1-dependent manner associated with mitochondrial fusion.
    Gabriela Burczyk, Elzbieta Kolaczkowska.
      Neutrophil extracellular traps (NETs) constitute a critical antimicrobial mechanism, yet excessive or dysregulated NET release contributes to endothelial injury and tissue damage. Therefore, identifying physiological and pharmacological regulators of NET formation remains an important goal. Although the role of mitochondrial dynamics in NETs remains incompletely elucidated, accumulating evidence suggests that mitochondria may be underexplored regulators with therapeutic potential. In fact, in certain NET forms, their DNA is of mitochondrial origin. Here, we investigated how exogenous dimethyl fumarate (DMF), an ester of the tricarboxylic acid cycle (TCA) metabolite fumarate, modulates NET formation. Foremost, we observed that DMF markedly suppresses PAD4-dependent NET release by LPS-stimulated neutrophils of wild-type and PAD4-deficient mice. Mechanistic analyses demonstrated that DMF activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and increases the secretion of anti-inflammatory Annexin A1 (ANXA1). Functionally, inhibition of either Nrf2 or the ANXA1 receptor Fpr2 restores NET formation. To integrate these observations with mitochondrial function, we examined markers of mitochondrial dynamics. We found that DMF decreases phosphorylation of dynamin-related protein 1 (DRP1) at Serine 616, a modification typically associated with reduced mitochondrial fission. Consistently, pharmacological inhibition of DRP1 (Mdivi-1) also diminishes NET formation, whereas induction of mitochondrial fragmentation (CCCP) triggers PANoptotic neutrophil death and extracellular DNA release, both of which were prevented by DMF. Collectively, these data identify DMF as a mitochondria-linked immunometabolic regulator that suppresses NET formation through coordinated engagement of Nrf2 and ANXA1 signaling and modulation of mitochondrial dynamics. These findings highlight mitochondrial remodeling as a promising avenue for future exploration and position DMF as a potential pharmacological tool for controlling excessive neutrophil activation.
    Keywords:  ANXA1; Annexin A1; Nrf2; PANoptosis; fumarate; mitochondria fission; mitochondria fusion; neutrophils
    DOI:  https://doi.org/10.3389/fimmu.2026.1770063
  29. Nat Immunol. 2026 Apr 13.
    Purine salvage pathway protects CD8+ T cells from metabolic stress.
    Masaki Tajima, He Hao, Baihao Zhang, Yuta Matsuoka, Kazuhiro Sonomura, Koshi Imami, Yosuke Isobe, Rae Maeda, Yu-Hsien Lin, Akihiro Shimba, Ryoma Kato, Pedro Henrique Costa Cruz, Sayaka Washizu, Yosuke Ikejiri, Akiyo Morinibu, Clive Steven Barker, Jun Seita, Yibo Wu, Satomi Ito, Seiko Narushima, Rei Nakano, Mikako Maruya, Wakana Kobayashi, Sai Shanmukha Priya Narayanan, Jumana Shaheen, Hiroyuki Neyama, Ken-Ichi Yamada, Makoto Arita, Yuki Sugiura, Sidonia Fagarasan.
      Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8+ T cell metabolism remain unknown. Here, we found that even temporary exposure to a HFD impaired antitumor immunity 10 weeks after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in phospholipids sensitive to peroxidation and depletion of antioxidants, affecting the survival and function of CD8+ T cells. Under oxidative stress, CD8+ T cells utilized the xanthine salvage pathway to produce guanosine triphosphate, enhancing the amount of tetrahydrobiopterin. Xanthine supplementation reduced lipid peroxidation in tumor-draining lymph nodes and improved antitumor immunity in mice previously on a HFD. Our data indicate that metabolic stress in CD8+ T cells persists long after restoration of a balanced diet, and manifests as vulnerability to ferroptosis, which could be mitigated by replenishing biopterins through the xanthine salvage pathway.
    DOI:  https://doi.org/10.1038/s41590-026-02491-w
  30. QJM. 2026 Apr 08. pii: hcag090. [Epub ahead of print]
    Iron in Respiratory Immunity and Infection.
    Anthony W Martinelli, Ruaraidhrí Jordan, Sophia Wugk, James A Nathan, Suzanne M Cloonan.
      Iron is essential for the survival of both humans and pathogens, creating intense competition for the metal during infection. Whilst hosts seek to restrict access to iron via nutritional immunity, microbes including bacteria, viruses, and fungi have adapted unique mechanisms to acquire it. The lungs function as a key battleground in this contest, with local iron homeostasis mediated by tissue-resident alveolar macrophages. Systemic iron status-either overload or deficiency-also dictates the efficacy of innate and adaptive immunity, thus directly influencing the outcomes of respiratory disease. This review will examine our current understanding of the host-iron-pathogen axis in the lung, as well as consider how it could be exploited to improve health outcomes in respiratory infection.
    DOI:  https://doi.org/10.1093/qjmed/hcag090
  31. Front Immunol. 2026 ;17 1748519
    Itaconate ameliorates cardiovascular inflammation in a mouse model of Kawasaki disease vasculitis - brief report.
    Youngho Lee, Takahiro Namba, Asli E Atici, Emily Aubuchon, Malcolm E Lane, Benjamin L Ross, Magali Noval Rivas, Moshe Arditi.
       Background: Kawasaki disease (KD), a systemic vasculitis and the leading cause of acquired heart disease in children, stems from an uncontrolled inflammatory response that fails to resolve in up to 20% of IVIG-treated patients. This treatment resistance increases the risk of cardiovascular complications and highlights the need for more targeted therapeutics.
    Methods: We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to investigate the therapeutic potential of itaconate, an anti-inflammatory metabolite, in the pathogenesis of KD. The expression of aconitate decarboxylase 1 (Acod1), which encodes the mitochondrial enzyme that produces itaconate, was assessed in both samples from KD patients and vascular tissues of LCWE-injected mice. LCWE-injected mice were treated with itaconate, and the severity of LCWE-induced KD vasculitis was evaluated.
    Results: LCWE injection led to the development of cardiovascular lesions, specifically aortitis, coronary arteritis, and abdominal aorta dilatation. Expression of ACOD1 was upregulated in KD patients during the acute phase of the disease and in cardiovascular lesions of LCWE-injected mice. Treatment with itaconate significantly reduced the development of LCWE-induced cardiovascular lesions. Mechanistically, exogenous itaconate suppressed NLRP3 inflammasome activation in LCWE-induced cardiovascular lesions and decreased IL-1β secretion.
    Conclusions: Itaconate treatment provides cardiovascular protection in an experimental mouse model of KD vasculitis by decreasing NLRP3 inflammasome activation and reducing vascular inflammation. Itaconate may be a promising therapeutic agent for patients with KD.
    Keywords:  IL-1β; Kawasaki disease; NLRP3; itaconate; vasculitis
    DOI:  https://doi.org/10.3389/fimmu.2026.1748519
  32. Front Microbiol. 2026 ;17 1783835
    Adaptive metabolic strategies of intracellular bacterial pathogens.
    Tripti Nair, Eric H Rosenn, Biplab Singha, Shagun Shukla, Sharad Vashisht, Aditya Upadhyay, Murugesh Padmanarayana, Vijay Soni.
      Intracellular bacterial pathogens have evolved sophisticated metabolic strategies to persist and replicate within the hostile intracellular environments of their hosts. By leveraging their metabolic plasticity, these pathogens dynamically modulate host metabolic processes in response to immunological, environmental, and pharmacological stressors. This review examines the diverse metabolic adaptations employed by intracellular pathogens, including nutrient acquisition, modulation of host metabolism, and stress-induced metabolic shifts that contribute to persistence and virulence. Emphasis is placed on how distinct intracellular niches- such as vacuoles and the cytosol- shape pathogen metabolism, and how bipartite metabolic strategies enable pathogens to balance energy production with biosynthetic demands. Species-specific adaptations in representative pathogens, including Listeria monocytogenes, Legionella pneumophila, Shigella flexneri, and Chlamydia trachomatis, are analyzed, with a focus on mechanisms of metabolic reprogramming (the alteration of cellular metabolic pathways in response to environmental cues, such as infection or stress, which allows the pathogen to adapt its metabolic state to support survival, replication, and virulence within the host), stress tolerance (refers to a pathogen's ability to survive and function under harsh environmental conditions, such as oxidative stress, nutrient scarcity, and antimicrobial exposure), and lifecycle transitions (refer to the changes in a pathogen's developmental or replication stages, such as switching from active growth to a dormant or persistent state during infection). Finally, the review considers how these metabolic strategies intersect with antimicrobial resistance and highlights the potential of targeting host-pathogen metabolic interactions for the development of novel interventions, including host-directed therapies (HDTs).
    Keywords:  antimicrobial resistance (AMR); bipartite metabolism; host-directed therapies (HDTs); host-pathogen interactions; immunometabolic signaling; intracellular bacterial pathogens; metabolic reprogramming; metabolomics
    DOI:  https://doi.org/10.3389/fmicb.2026.1783835
  33. Gut. 2026 Apr 15. pii: gutjnl-2025-337344. [Epub ahead of print]
    Targeting PKM2-dependent glycolysis reprogrammes monocytes into Cadm1+ macrophages to promote mucosal repair and attenuate colitis progression.
    Di Zhang, Ping Tao, Jinying Li, Xingyan Zhou, Hengdong Qu, Yaobin Li, Haoxian Chen, Hui Yuan, Jiabin Huang, Ziyi Ji, Pengqing Sun, Haoting Lin, Keke Zhang, Wei Huang, Huixin Chen, Wencai Ye, Jian Hong.
       BACKGROUND: Incomplete mucosal healing contributes to progression and relapse in ulcerative colitis (UC). Currently, therapeutic strategies that promote mucosal healing and regeneration are limited and may potentiate oncogenic transformation.
    OBJECTIVE: We aimed to identify whether modulating macrophage metabolism may facilitate mucosal healing without driving tumourigenesis.
    DESIGN: Potential therapeutic targets associated with UC disease activity and relapse were assessed in multiple omics datasets and three clinical UC studies. The function and mechanism of macrophage pyruvate kinase M2 (PKM2) in UC progression were demonstrated by macrophage-specific PKM2 knockout mice, single-cell and spatial transcriptomic profiling, and human macrophage-colonic organoid coculture models.
    RESULTS: Glycolysis was markedly upregulated in intestinal macrophages within damaged regions in UC patients, whereas PKM2 expression was associated with increased disease severity and a greater incidence of relapse. PKM2 depletion in macrophages enhanced intestinal barrier function and ameliorated colitis progression in mice. Mechanistically, PKM2 deficiency promoted monocyte differentiation into reparative Cadm1+ macrophages and enhanced Lgr5+ stem cell self-renewal via the PGE2/EP4 axis. Cross-species analysis revealed that human STAB1+ macrophages, which exhibit transcriptomic and metabolic similarities to mouse Cadm1+ macrophages, were positively associated with UC remission and spatial distribution of CD8+ T cells in colorectal cancer. Interestingly, macrophage PKM2 deletion greatly suppressed tumourigenesis in mice, accompanied by an increased abundance of Cadm1+ macrophages and enhanced CD8+ T-cell infiltration. Furthermore, targeting PKM2 in intestinal macrophages attenuated colitis progression in mice.
    CONCLUSIONS: Therapeutic targeting of PKM2-dependent glycolysis in macrophages enhanced Cadm1+ macrophage-mediated mucosal healing without driving tumourigenesis.
    Keywords:  EXPERIMENTAL COLITIS; GLUCOSE METABOLISM; INTESTINAL STEM CELL; MACROPHAGES; ULCERATIVE COLITIS
    DOI:  https://doi.org/10.1136/gutjnl-2025-337344
  34. J Immunol. 2026 Apr 15. pii: vkag051. [Epub ahead of print]215(4):
    Folate receptor beta drives NLRP3 inflammasome activation and pyroptosis in macrophages independent of folate binding.
    Lisa M Rogers, Kyle Firestone, Riya Chinni, Anna C Branco, Kayla Wrobleski, Teresa Chou, Jeffery A Goldstein, Xiaoping Gu, Emily Mason, Shaoyou Chu, Michael Rubart-von der Lohe, Philip Low, David M Aronoff.
      Folate receptor beta (FRβ), encoded by FOLR2, is selectively expressed in monocytes and macrophages, yet its function in innate immune signaling remains poorly defined. Here, we identify FRβ as a novel regulator of NLRP3 inflammasome activation and pyroptosis in human THP-1 macrophages. Using CRISPR/Cas9-mediated gene deletion, we show that loss of FOLR2 severely impaired caspase-1 activation, gasdermin D cleavage, and IL-1β release in response to multiple NLRP3 stimuli, without altering pro-IL-1β induction. These defects were not rescued by exogenous folate and were independent of extracellular folate concentrations. Mechanistically, FOLR2/FRβ appears to potentiate potassium efflux and the expression of multiple potassium channel-encoding genes. Single-cell RNA sequencing revealed broad transcriptional repression in FRβ-deficient macrophages, including genes involved in inflammasome signaling and ion transport. Genome-wide methylation profiling showed increased CpG hypermethylation in FOLR2-deficient cells, consistent with reduced transcriptional activity. Our findings indicate that FRβ promotes NLRP3 activation in a folate-independent manner potentially by regulating DNA methylation, gene transcription, and K+ efflux in macrophages. These findings uncover a previously unrecognized immunoregulatory function for FRβ, positioning it as a potential modulator of macrophage-driven inflammation in contexts such as host defense, autoimmunity, and tissue-specific immune responses at the tumor and maternal-fetal interface.
    Keywords:  DNA methylation; FRβ; NLRP3 inflammasome; folate receptor beta; macrophage activation
    DOI:  https://doi.org/10.1093/jimmun/vkag051
  35. Int Immunopharmacol. 2026 Apr 15. pii: S1567-5769(26)00468-6. [Epub ahead of print]179 116623
    Targeting HIF-1α rescues microglial efferocytosis via the SLC7A11-TAM pathway to ameliorate Sepsis-associated encephalopathy.
    Shengnan Wang, Youfang Chen, Zhendong Sun, Yafen Zeng, Guidan Wang, Qingfan Lin, Chunnuan Chen, Hefan He.
      Sepsis-associated encephalopathy (SAE) is a common and debilitating complication of sepsis, yet its cellular mechanisms and targeted therapies remain unclear. Microglia preserve neuroinflammatory homeostasis and neural circuit integrity through efferocytosis, but how this process is altered in SAE and regulated by immunometabolism is poorly defined. Here, we investigated the molecular basis of microglial efferocytosis impairment using LPS-stimulated BV2 cells and a cecal ligation and puncture (CLP) murine SAE model. We integrated RNA sequencing, HIF-1α and SLC7A11 gain- and loss-of-function approaches and in vitro functional assays. In vivo, HIF-1α was pharmacologically inhibited (KC7F2) or stabilized (DMOG) to evaluate its role in SAE. We assessed microglial efferocytosis and polarization, neuronal and synaptic integrity, cognition, survival, and brain metabolomics. LPS induced a pro-inflammatory microglial phenotype and reduced efferocytosis mediators (Tyro3, Mertk, Axl), impairing clearance of apoptotic neurons. HIF-1α upregulation interacted with SLC7A11 to suppress the TAM-Rac1-NCKAP1 axis, leading to efferocytic failure; knockdown of HIF-1α or SLC7A11 restored efferocytosis. In CLP mice, HIF-1α/SLC7A11 elevation coincided with TAM-Rac1-NCKAP1 suppression. These results reveal that impaired microglial efferocytosis is a key but overlooked feature in SAE. KC7F2 restored efferocytosis, shifted cytokines toward anti-inflammatory profiles, improved cognition and survival, and normalized metabolomic signatures, while DMOG produced opposite effects. This work uncovers a previously unknown HIF-1α-SLC7A11 pathway driving microglial dysfunction in SAE, offering fresh insight into disease mechanisms and pointing to HIF-1α as a promising therapeutic target.
    Keywords:  Efferocytosis; HIF-1α; Metabolic reprogramming; Microglia; SLC7A11; Sepsis-associated encephalopathy; TAM receptors
    DOI:  https://doi.org/10.1016/j.intimp.2026.116623
  36. J Clin Transl Hepatol. 2026 Mar 28. 14(3): 245-257
    Association of Changes in Portal Insulin with Immunometabolism During and After Hepatitis C Virus Infection.
    Matthew G Menkart, Jenna L Oringher, Moumita Chakraborty, James A Haddad, Gabriella M Quinn, Grace Zhang, Elizabeth C Townsend, Kareen L Akiva, Lisa Scheuing, Anjali Rai, Shakuntala Rampertaap, Sergio D Rosenzweig, Christopher Koh, Rebecca J Brown, Regina Umarova, Elliot B Levy, David E Kleiner, Rabab O Ali, Ohad Etzion, Rownock Afruza, Theo Heller.
       Background and Aims: Insulin resistance is a common extrahepatic manifestation of hepatitis C virus (HCV) infection (HCVi), but its mechanism is poorly understood. While systemic insulin resistance is documented, portal insulin dynamics, a key regulator of hepatic metabolism, remain unexplored. This study aimed to investigate the relationship between insulin, the gut-liver axis, and immunometabolic changes in patients with HCV.
    Methods: HCV patients were evaluated before (HCVi; n = 29) and after sustained virologic response (SVR) achieved with sofosbuvir/velpatasvir treatment (SVR, n = 23) (NCT02400216). Liver biopsies, portal blood, and peripheral blood were collected at both phases. Statistical analyses were conducted using Wilcoxon rank-sum tests, Mann-Whitney tests, and Pearson's correlation coefficients to assess differences and associations across insulin, glucose, cytokines, metabolites, immune cells, and hepatic liver transcriptomics to elucidate impaired insulin homeostasis in HCVi.
    Results: HCV patients had significantly reduced portal insulin compared to SVR (p = 0.02), while peripheral insulin, portal glucose, and peripheral glucose remained unchanged. Portal insulin correlated positively with proinflammatory cytokines and vascular injury markers and negatively with CD8/CD62L/CD45RA/CD3 cells (naive cytotoxic T-cells) and non-standard nucleotides. Hepatic transcriptomic analysis revealed portal insulin correlated positively with immune and negatively with amino acid pathways, reflecting insulin's role in the perturbations of immunometabolism during HCVi.
    Conclusions: Lower portal insulin during HCVi is associated with changes consistent with altered pancreatic insulin secretion and decreased hepatic insulin extraction. The observed correlations support a potential relationship between the immune response and insulin dynamics, indicating an interplay between the immune system, metabolism, and insulin in HCVi, with clinical implications for the management of dysglycemia.
    Keywords:  Cytokine; Hepatitis C; Insulin; Liver disease; Metabolic disorder; Nucleotide; Portal Vein
    DOI:  https://doi.org/10.14218/JCTH.2025.00498
  37. Front Immunol. 2026 ;17 1743261
    Mitochondrial transfer as a driver of immune microenvironment remodeling.
    Xiaoya Zhang, Danmei Zhang, Jin Guo, Chunxia Shi, Zuojiong Gong.
      Mitochondria are central regulators of immunometabolism, and emerging evidence identifies intercellular mitochondrial transfer as a key driver of immune microenvironment remodeling. Beyond energy production, transferred mitochondria reshape immune niches by reprogramming metabolic fitness, redox balance, inflammatory tone, and immune cell interactions. Through multiple transfer routes, including tunneling nanotubes, extracellular vesicles, and gap junctions, mitochondrial exchange modulates immune activation, immunosuppression, and tolerance across diverse physiological and pathological contexts. In this review, we summarize current mechanisms of mitochondrial transfer and highlight how this process directionally remodels the immune microenvironment in inflammation, cancer, and autoimmune diseases. We further discuss therapeutic strategies aimed at modulating mitochondrial transfer to reprogram immune responses, providing new perspectives for immunomodulation and disease intervention.
    Keywords:  cancer; immune cell; immune microenvironment; inflammation; mitochondria transfer
    DOI:  https://doi.org/10.3389/fimmu.2026.1743261
  38. ACS Chem Neurosci. 2026 Apr 15.
    Stimulus-Driven Remodeling of Microglial Endocannabinoid Metabolism Illuminates ABHD12 Function in Immunity.
    Noëlle van Egmond, Elisabeth A Jalink, Daan van der Vliet, Anniek J Henselijn, Marleen E Ridder, Berend Gagestein, Anna F Stevens, Sander I van Kasteren, Mario van der Stelt.
      Microglia, the brain's macrophages, dynamically reprogram their metabolism to acquire appropriate and unique states to coordinate neuroinflammatory responses. Lipid metabolism, such as endocannabinoid signaling, is increasingly acknowledged for playing a central role in regulating these states. However, the enzymatic activities underlying these processes remain poorly characterized. Here, we combine activity-based protein profiling (ABPP) with targeted lipidomics to map lipid metabolism across distinct pro- and anti-inflammatory microglial states. We reveal stimulus-dependent remodeling of endocannabinoid metabolism, identifying DAGLβ and ABHD12 as key enzymes with opposing activity patterns. Correlation analysis across the differential expression and activity levels in microglial states revealed DAGLβ activity aligns with transcript and protein abundance, while ABHD12 activity is uncoupled from expression levels indicative of post-translational regulation. To enable cellular activity profiling, we developed a tailored ABHD12 probe (LEI-612), which demonstrated that cellular ABHD12 activity inversely correlated with 2-AG levels. Pharmacological inhibition of ABHD12 with DO264 elevated 2-AG, reduced AA, and modulated cytokine release through dual mechanisms: CB2R-dependent suppression of TNF-α and PGE2-dependent regulation of IL-6. Our integrated chemical proteomics and lipidomics approach highlights the importance of activity-based profiling of enzymes in defining microglial states and uncover ABHD12 as a key regulator of 2-AG metabolism and microglial immune function.
    Keywords:  ABHD12; activity-based protein profiling; endocannabinoid; lipidomics; microglia
    DOI:  https://doi.org/10.1021/acschemneuro.5c00985
  39. Int Immunopharmacol. 2026 Apr 13. pii: S1567-5769(26)00485-6. [Epub ahead of print]179 116640
    Ailanthone ameliorates CCl4-induced liver fibrosis by targeting PKM2-mediated macrophage M1 polarization and glycolytic reprogramming.
    Yue Wan, Tiantian Wang, Kang Wang, Qiang Huo, Xiu Cheng.
       BACKGROUND: Liver fibrosis is a chronic wound-healing response characterized by excessive extracellular-matrix deposition. Pro-inflammatory M1 macrophages drive fibrogenesis, whereas M2 macrophages support repair. Ailanthone (AIL), a plant-derived natural compound, has been suggested to regulate macrophage polarization, but its role and mechanism in liver fibrosis remain unclear.
    METHODS: Mice with CCl₄-induced fibrosis received AIL for 3 weeks; liver injury, fibrosis, and serum biochemistry were assessed. In vitro, LPS-stimulated RAW264.7 macrophages and TGF-β1-activated LX-2 cells were used to assess AIL's effects on PKM2/AKT signaling and glycolysis through Western blot, qPCR, enzyme assays, siRNA, and the PKM2 activator TEPP-46.
    RESULTS: AIL reduced collagen deposition and lowered α-SMA, collagen III, and fibronectin expression, while normalizing ALT and AST levels in fibrotic mice. AIL also suppressed TGF-β1-induced LX-2 activation and reduced LPS-driven M1 polarization in macrophages (TNF-α, IL-1β, IL-6, iNOS). AIL lowered PKM2 expression and activity and inhibited aerobic glycolysis (lactate, PK activity, GLUT-1, HIF-1α, LDHA). PKM2 knockdown or tetramer stabilization with TEPP-46 produced similar effects, confirming PKM2 as the critical target.
    CONCLUSION: By targeting PKM2, AIL regulates macrophage metabolism and polarization while concurrently reducing hepatic stellate-cell activation and fibrosis. These findings position AIL as a promising PKM2-directed candidate for anti-fibrotic therapy.
    Keywords:  Ailanthone; Glycolysis; Hepatic stellate cells; Liver fibrosis; Macrophage polarization; PKM2
    DOI:  https://doi.org/10.1016/j.intimp.2026.116640
  40. Nat Aging. 2026 Apr 16.
    p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease.
    Ivan A Salladay-Perez, Itzetl Avila, Lizeth Estrada, Andreea C Alexandru, Cristian Ponce, Anika Dhingra, Grasiela Torres, Christina Y Deng, Ronak Hegde, Julia Gensheimer, Abhijit Kale, Indra Heckenbach, Simon Hui, Chantle Edillor, Jose A Soto, Alexander J Napior, Isaiah Little, Mark Larsen, Jacob Rose, Lia Farahi, Edwin D J Lopez Gonzalez, Matthew R Krieger, Kushan Chowdhury, Mridul Sharma, Yuming Jiang, Kevin Williams, Morten Scheibye-Knudsen, Carla M Koehler, Jesse G Meyer, Julia J Mack, Charles Brenner, Steven J Bensinger, Cyril Lagger, João Pedro de Magalhães, Birgit Schilling, Rajat Singh, Eric Verdin, Aldons J Lusis, Anthony J Covarrubias.
      Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.
    DOI:  https://doi.org/10.1038/s43587-026-01101-6
  41. Adv Sci (Weinh). 2026 Apr 14. e75125
    Kinsenoside Targets IDH1 to Restore Microglial Immune-Metabolic Homeostasis for Alzheimer's Disease Therapy.
    Qianqian Li, Yajin Liao, Yan-Bo Zhao, Hongxing Wu, Tong Jin, Shuoshuo Li, Yuhan Liu, Peng Li, Songying Ouyang, Zekai Li, YuTing Xia, Qian Hua, Rui-Yuan Pan, Zengqiang Yuan.
      Dysregulated tricarboxylic acid (TCA) cycle activity is increasingly recognized as a contributor to Alzheimer's disease (AD) pathogenesis, yet the mechanistic underpinnings of the relationship remain unclear. Here, we identify isocitrate dehydrogenase 1 (IDH1), a key enzyme in the TCA cycle, as a critical pathogenic driver of AD in microglia. IDH1 expression was markedly upregulated in microglia from both AD patients and 5×FAD mice. Elevated IDH1 promoted excessive cytosolic citrate consumption, which restricted citrate shuttling into mitochondria and impaired mitochondrial TCA cycle function. This citrate metabolic imbalance further disrupted epigenetic regulation, thereby exacerbating AD-related pathological processes. Using structure-based screening and co-crystallization analysis, we identified Kinsenoside (KIN), a natural small molecule, as a selective competitive inhibitor of IDH1 that binds to its isocitrate-binding pocket. Targeting IDH1 with KIN inhibited its activity, which restored intracellular citrate distribution, reactivated mitochondrial TCA cycle flux, and reestablished metabolic homeostasis. Notably, this intervention not only attenuated neuroinflammation but also reduced β-amyloid (Aβ) deposition and significantly improved cognitive performance in 5×FAD mice. Collectively, our findings establish IDH1-mediated metabolic dysregulation as a pivotal pathogenic mechanism in AD and highlight KIN as a promising therapeutic candidate by targeting microglial IDH1 to restore metabolic and functional homeostasis.
    Keywords:  IDH1; alzheimer's disease; kinsenoside; microglia; neuroinflammation; tca cycle
    DOI:  https://doi.org/10.1002/advs.75125
  42. Nat Commun. 2026 Apr 17.
    Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.
    Yunjuan Nie, Li Xu, Yanyan Liu, Jiao Li, Zhixu Wang, Xiaorun Zhai, Xiaoru Sun, Chunxiao Hu, Bo Xu, Yaxian Wu, Haitao Yu, Manjula Karpurapu, Huaqi Guo, Gaoshang Chai.
      Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease where macrophages drive fibrogenesis, yet Hdac11's role is unclear. We first identify pronounced Hdac11 upregulation in IPF lungs, which is associated with an enrichment in alveolar macrophages (AMs). Genetic ablation of Hdac11 or adoptive transfer of Hdac11-deficient macrophages markedly attenuates fibrosis. Specifically, Hdac11 deficiency significantly reduces M2 macrophage polarization in vivo and vitro and is associated with reduced macrophage-myofibroblast transition (MMT) like phenotypic reprogramming, thereby decreasing myofibroblast accumulation and profibrotic gene expression. Mechanistically, impaired mitophagy mediates Hdac11-mediated M2 macrophage polarization and is associated with MMT-like changes. Hdac11 regulates mitochondrial quality control by deacetylating Parkin at lysine 76, promoting its ubiquitination and degradation, which impairs mitophagy and drives profibrotic macrophage activation. Pharmacological Hdac11 inhibition effectively reverses bleomycin-induced fibrosis. Taken together, our work identifies Hdac11 as a target of Parkin-mediated mitophagy in macrophages, establishing Hdac11-Parkin axis disruption as an important mechanism in IPF and highlighting Hdac11 inhibition as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41467-026-71639-x
  43. Trends Mol Med. 2026 Apr 14. pii: S1471-4914(26)00083-3. [Epub ahead of print]
    β-hydroxybutyrate supplementation boosts the tumor-killing potential of CAR T cells.
    Christos Adamopoulos, Kostas A Papavassiliou, Athanasios G Papavassiliou.
      In a recent study in Cell, Liu et al. identify β-hydroxybutyrate as a practical metabolic adjuvant for CAR-T cells. By fueling the TCA cycle and reshaping transcriptional and epigenetic programs, this ketone body enhances proliferation, persistence, and tumor control, suggesting that metabolic supplementation may offer a simple route to more effective adoptive immunotherapy.
    Keywords:  CAR T cells; adoptive immunotherapy; immunometabolism; ketogenic diet; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.molmed.2026.04.001
  44. Free Radic Biol Med. 2026 Apr 10. pii: S0891-5849(26)00308-4. [Epub ahead of print]251 60-74
    Heme oxygenase-1-enriched tolerogenic dendritic cell-derived exosomes attenuate lupus nephritis by restoring immune balance and iron homeostasis.
    Zhouhang Xing, Jinlin Yang, Huan Zhang, Yuanyuan Xie, Qianru Yang, Min Wu, Wenqian Wang, Sheng Gao, Chunyan Hua.
      Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by chronic inflammation, oxidative stress, and multi-organ damage, with lupus nephritis (LN) constituting a major cause of morbidity and mortality. Dysregulated iron metabolism and insufficient expression of heme oxygenase-1 (HO-1), a pivotal antioxidant enzyme regulating iron homeostasis and immune responses, have been implicated in LN pathogenesis. However, therapeutic strategies targeting HO-1 and iron dysregulation remain underexplored. Here, we demonstrate that HO-1 expression is markedly decreased in peripheral blood mononuclear cells from SLE patients, particularly those with LN, correlating inversely with disease activity and markers of iron homeostasis disruption. We established that IL-10 induces tolerogenic dendritic cells (tolDCs) through activation of the Nrf2-HO-1 pathway, concomitant with modulation of iron metabolism and oxidative stress genes. Leveraging this mechanism, we generated HO-1-enriched tolDC-derived exosomes (HO-1high-tolDex) and characterized their immunomodulatory properties in vitro, showing effective suppression of pro-inflammatory cytokines and restoration of iron regulatory gene expression in recipient DCs. In vivo, HO-1high-tolDex administered intravenously preferentially accumulated in kidneys of lupus-prone mice, exhibiting superior stability and targeting compared to parental tolDCs. Repeated dosing ameliorated renal pathology, concomitant with decreased DC activation and pathogenic autoantibody titers. Importantly, HO-1high-tolDex reversed oxidative stress imbalances and normalized iron homeostasis markers, mitigating abnormal renal iron accumulation. These findings establish HO-1high-tolDex as a potent, novel cell-free therapeutic agent that simultaneously modulates immune dysregulation, oxidative stress, and iron metabolism in SLE.
    Keywords:  Dendritic cell-derived exosome; Heme oxygenase-1; Lupus nephritis; Systemic lupus erythematosus; Tolerogenic dendritic cell
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.024
  45. Nat Aging. 2026 Apr 13.
    Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
    Manish Mishra, Hee-Hoon Kim, Yun-Hee Youm, Elsie Gonzalez-Hurtado, Konstantin Zaitsev, Tamara Dlugos, Irina Shchukina, Christy Gliniak, Eric Ravussin, Subhasis Mohanty, Albert C Shaw, Philipp E Scherer, Maxim N Artyomov, Vishwa Deep Dixit.
      Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging. In humans, the C3a/C3 ratio was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Furthermore, circulating C3a is elevated during aging in humans and in mice; we identified a non-senescent age-associated macrophage subset that expands in visceral fat as the predominant source. In macrophages, C3a-C3AR1 autocrine signaling via extracellular signal-regulated kinase (ERK) regulates age-related inflammation. Intra-adipose administration of a C3a-specific neutralizing antibody reduced inflammaging in mice. In addition, fibroblast growth factor 21 (FGF21) overexpression and deficiency of phospholipase A2 group VII (PLA2G7/lp-PLA2), which enhance lifespan and healthspan in mice, lowered C3a in aging. Thus, complement C3a reduction is a metabolically regulated inflammatory checkpoint that can be harnessed to attenuate inflammaging.
    DOI:  https://doi.org/10.1038/s43587-026-01107-0
  46. Front Immunol. 2026 ;17 1746810
    Integrative multi-omics dissection identifies ACO2, KLF5, and IMP4 as central regulators of the mitochondrial-immune axis in ulcerative colitis.
    Yuanyuan Tian, Xiaori Qin, Shibing Li, Jiao Wang, Cheng Lan.
       Background: Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease characterized by persistent mucosal inflammation and epithelial barrier disruption. Emerging evidence suggests that metabolic reprogramming plays a pivotal role in regulating immune responses and epithelial homeostasis in UC. However, the key metabolic-immune regulatory genes and their cellular mechanisms remain poorly defined.
    Methods: We integrated publicly available genome-wide association study (GWAS) summary statistics for UC (n = 394,626), along with expression quantitative trait loci (eQTL) resources and multiple independent bulk transcriptomic datasets (total n = 215 cases and 134 controls). Summary-based Mendelian randomization (SMR), genome-wide Mendelian randomization (MR), and transcriptomic analyses were performed to systematically identify causal genes associated with UC. Cross-validation was conducted using immune infiltration analyses and single-cell RNA sequencing (scRNA-seq) datasets from human UC colonic tissues (n = 18 cases and 12 controls), as well as a dextran sulfate sodium (DSS)-induced murine colitis model. Gene set enrichment and network analyses were applied to explore potential metabolic and immune pathways.
    Results: Through integrative multi-omics analysis, we identified ACO2, KLF5, IMP4, and AGPS as key hub genes linking mitochondrial metabolism with immune regulation in UC. Among them, ACO2, KLF5, and IMP4 were consistently downregulated in UC tissues and negatively correlated with macrophage and dendritic cell infiltration. Although AGPS did not show consistent transcriptional changes across UC datasets, it may still contribute to lipid remodeling based on its metabolic function. Single-cell analyses revealed that ACO2 and KLF5 were primarily expressed in macrophage populations and markedly reduced in inflamed colonic regions, while IMP4 exhibited context- and cell-type-specific dynamics. In the DSS mouse model, Aco2 and Klf5 expression decreased progressively with disease severity, accompanied by metabolic pathway enrichment in oxidative phosphorylation and glycolysis.
    Conclusion: Our findings reveal a set of metabolic-immune regulatory genes that orchestrate mitochondrial function, epithelial integrity, and immune activation in UC. The integration of genetic, transcriptomic, and single-cell data highlights ACO2, KLF5, and IMP4 as promising biomarkers and potential therapeutic targets, offering novel insights into the immunometabolism mechanisms driving UC pathogenesis.
    Keywords:  ACO2; IMP4; KLF5; immune–metabolic regulation; ulcerative colitis
    DOI:  https://doi.org/10.3389/fimmu.2026.1746810
  47. PLoS Pathog. 2026 Apr 17. 22(4): e1014164
    Japanese encephalitis virus orchestrates GLUT4-mediated glucose metabolism to potentiate viral replication via insulin receptor signaling.
    Qi Wang, Ping Hao, Sheng-Yan Zhu, Jiang-Fei Zhou, Sheng Feng, Qi Dai, Jian-Chao Wei, Yun Young Go, Jing Chen, Bin Zhou.
      Flaviviruses intricately rewire host metabolic networks to establish a replication-permissive environment; however, the role of glucose transporter-mediated uptake, particularly via glucose transporter 4 (GLUT4), remains insufficiently defined. Japanese encephalitis virus (JEV) infection induces extensive remodeling of glucose metabolism, exemplified by the coordinated upregulation of critical metabolic effectors. Pharmacological blockade of glucose metabolic pathways markedly attenuates JEV replication, whereas exogenous glucose supplementation enhances viral propagation in a concentration-dependent manner. A targeted screen of 111 metabolism-oriented compounds identified selective GLUT4 inhibitors with potent antiviral efficacy. Notably, GLUT4 expression is consistently upregulated during JEV infection across multiple cell types, albeit to varying degrees, and is similarly induced by duck Tembusu virus (DTMUV), suggesting a potentially conserved mechanism shared by these two flaviviruses. However, broader validation across additional members of the Flavivirus genus remains warranted. Mechanistically, the viral nonstructural protein 3 (NS3) engages insulin receptor substrate 1 (IRS1), thereby activating the IRS1-PI3K-Akt-mTORC1-SREBP-1c signaling axis to transcriptionally drive GLUT4 expression. Concurrently, JEV infection induces PI3K-Akt-dependent phosphorylation of AS160, promoting GLUT4 vesicular trafficking via the coordinated action of Rab8 and Rab10. Collectively, these findings delineate a previously unrecognized mechanism whereby JEV commandeers host insulin signaling to orchestrate GLUT4 biosynthesis and membrane translocation, thereby ensuring continuous metabolic substrate availability to sustain replication. This GLUT4-centric metabolic circuitry represents a mechanistically tractable target for host-directed antiviral strategies against Flavivirus.
    DOI:  https://doi.org/10.1371/journal.ppat.1014164
  48. BMC Infect Dis. 2026 Apr 16.
    Characterising the urinary metabolome in HIV/TB coinfection and the impact of antiretroviral treatment.
    Bianca Allen, Robin Wood, Laneke Luies.
       BACKGROUND: HIV/TB coinfection poses significant challenges due to complex interactions between both pathogens and the metabolic disruptions they induce. Although antiretroviral treatment (ART) has transformed disease management, its impact on metabolism is not fully understood. Metabolomics offers an in-depth approach to explore the metabolic changes in this coinfected population, providing information into disease mechanisms and the effects of ART.
    METHODS: This exploratory study used untargeted urine gas chromatography mass spectrometry metabolomics to profile metabolic alterations in treatment-naïve HIV/TB coinfected patients and those on ART. Healthy controls were included for comparison. Metabolite changes were analysed using univariate statistical methods, including Kruskal-Wallis tests and pairwise comparisons, to identify key metabolites associated with coinfection and ART.
    RESULTS: Findings revealed significant disruptions in several metabolic pathways. Mitochondrial dysfunction was evident, contributing to altered lipid metabolism, impaired energy production, and increased cardiovascular risk. Disruptions in glucose metabolism, including compromised insulin secretion, were observed, alongside evidence of gut dysbiosis linked to inflammation and microbial imbalance. These metabolic disturbances were also associated with increased oxidative stress, reflected in changes to protein metabolism and the development of cachexia. Although ART partially alleviated some metabolic alterations, disruptions remained evident in treated patients.
    CONCLUSION: This study provides a comprehensive view of the metabolic disturbances in HIV/TB coinfection and the impact of ART. Our findings suggest that persistent mitochondrial dysfunction, altered lipid metabolism, and gut dysbiosis contribute to ongoing metabolic imbalances, underscoring the need for targeted therapeutic strategies to address these challenges.
    Keywords:  Antiretroviral therapy (ART); Exploratory research; Gas chromatography mass spectrometry (GC-MS); HIV/TB coinfection; Metabolomics; Urine
    DOI:  https://doi.org/10.1186/s12879-025-12389-x
  49. Front Immunol. 2026 ;17 1799086
    Cell-specific exosomes in sepsis-associated ARDS: from immunometabolic reprogramming to precision medicine.
    Yihan Dang, Caifeng Yan, Haiying Rui, Xiaoxi Yan, Miaobo Li, Xiaorong Dong, Li Ma.
      The publication of the 2023 Global Definition of ARDS has further unveiled the clinical heterogeneity of sepsis-induced acute respiratory distress syndrome (ARDS), rendering traditional systemic biomarkers insufficient for precisely characterizing lung-specific pathological changes. Cell-specific exosomes, owing to their high stability and high fidelity to the molecular signatures of their parent cells, have emerged as a highly promising tool for liquid biopsy. This review aims to elucidate how exosomes construct a multidimensional communication network within the compromised alveolar-capillary barrier. Beyond exploring the traditional function of exosomes as inflammatory vectors, we provide an in-depth analysis of the mechanisms by which alveolar epithelial exosomes propagate ferroptosis and mitochondrial damage in a wave-like manner, and how macrophage exosomes drive immunometabolic reprogramming via glycolysis and histone lactylation to sustain the inflammatory state. Furthermore, we elaborate on the central role of endothelial exosomes in vascular leakage and immunothrombosis, proposing a novel hypothesis that they may serve as mediators propagating cuproptosis within the vascular bed. Finally, by integrating advances in single-cell omics and analyzing technical barriers such as isolation specificity and timeliness, we propose a precision medicine framework based on exosomal molecular fingerprints. This strategy aims to utilize exosomes for ARDS subphenotyping, thereby promoting a paradigm shift in clinical practice from syndrome management to mechanism-driven theranostics.
    Keywords:  acute respiratory distress syndrome; cuproptosis; exosomes; ferroptosis; immunometabolism; liquid biopsy; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1799086
  50. NPJ Precis Oncol. 2026 Apr 16.
    AI-guided discovery of the IRF4-PAICS-LDHA axis as a multitarget hub linking tumor metabolism to CD8+ T cell exhaustion in DLBCL.
    Zeyuan Wang, Liye Wang, Siyu Qian, Yue Zhang, Qing Yang, Zhenzhen Yang, Shaoxuan Wu, Meng Dong, Zhiqi Zhang, Xufeng Wei, Minglei Yang, Hui Meng, Enjie Liu, Guozhong Jiang, Xudong Zhang, Wencai Li, Qingjiang Chen.
      Diffuse large B-cell lymphoma (DLBCL) features an immunosuppressive tumor microenvironment (TME), yet the molecular drivers connecting metabolic reprogramming to immune evasion remain poorly defined. Here, we deployed an integrative single-cell transcriptomic analysis combined with a machine learning (ML) framework to systematically identify key immune-suppressive hubs in DLBCL. Through ML-driven prioritization of a 33-gene panel, PAICS emerged as a central node within an immunosuppressive B-cell subgroup. Functional assays confirmed that PAICS promotes lymphoma proliferation, survival, and tumor growth while establishing an immunosuppressive TME-marked by reduced IFN‑γ, elevated TGF‑β and IL‑10, and enhanced CD8⁺ T cell exhaustion. Mechanistically, we uncovered the IRF4-PAICS-LDHA axis: IRF4 transcriptionally activates PAICS, which physically interacts with LDHA to augment its activity, thereby skewing the NAD⁺/NADH balance toward metabolic immunosuppression. Importantly, our AI-aided approach not only identified this axis but also predicted its vulnerability to metabolic intervention: both methotrexate treatment and LDHA knockdown restored metabolic balance, reversed T‑cell exhaustion, and suppressed tumor growth. These findings highlight the power of ML in uncovering multi-targetable metabolic-immune networks and in guiding therapeutic strategies to overcome immune evasion in DLBCL.
    DOI:  https://doi.org/10.1038/s41698-026-01428-8
  51. J Mol Med (Berl). 2026 Apr 11. pii: 63. [Epub ahead of print]104(1):
    Kv1.3 regulates macrophage immune function through PI3K/AKT signaling pathway to alleviate metabolic dysfunction-associated steatohepatitis.
    Ting Ke, Wen-Jun Zhen, Xi-Xi Chen, Hao Wang, Shi Chen, Yuan-Yuan Tian, Ye-Tao Wang, Lei Zhang, Bao-Ming Wu.
       BACKGROUND AND AIM: The progression of metabolic dysfunction-associated steatohepatitis (MASH) is closely linked to macrophage-mediated inflammatory responses. The role of Kv1.3, a key voltage-gated potassium channel regulating macrophage function, in MASH remains unclear. This study investigated Kv1.3 blockade's therapeutic potential in MASH and its mechanism, focusing on the PI3K/AKT signaling pathway.
    METHODS: A Western diet (WD)-induced mouse model of MASH was established, and hepatic Kv1.3 was knocked down via AAV8-Kv1.3-shRNA. Hepatic steatosis, inflammation, and macrophage infiltration were evaluated. In vitro, LPS-stimulated RAW264.7 macrophages were treated with the Kv1.3 inhibitor ShK-186 to assess inflammatory cytokine (IL-6, TNF-α) production and migration. The GEO dataset (GSE222922) validated the PI3K/AKT signaling pathway involvement.
    RESULTS: Kv1.3 expression was significantly increased in WD-induced MASH mouse livers. Hepatic Kv1.3 knockdown alleviated liver injury, steatosis, and inflammation. In vitro, ShK-186 inhibited LPS-induced macrophage migration and cytokine production, and significantly reduced the PI3K/AKT phosphorylation. These effects were reversed by the PI3K agonist 740Y-P, confirming that Kv1.3 regulates macrophage function via the PI3K/AKT signaling.
    CONCLUSION: Kv1.3 modulates macrophage inflammation and migration through the PI3K/AKT signaling pathway, promoting MASH progression. Kv1.3 knockdown ameliorates MASH pathology, highlighting it as a promising therapeutic target.
    KEY MESSAGES: Kv1.3 drives MASH via macrophage PI3K/AKT signaling, worsening liver inflammation Macrophage Kv1.3 knockdown alleviates MASH pathology in WD-fed mice Kv1.3 is a potential therapeutic target for MASH, modulating liver inflammation.
    Keywords:  Kv1.3; Metabolic dysfunction-associated steatohepatitis; PI3K/AKT signaling pathway
    DOI:  https://doi.org/10.1007/s00109-026-02666-w
  52. BMC Infect Dis. 2026 Apr 17.
    Long-term bone metabolism outcomes in critically Ill patients with sepsis: a prospective series study.
    Qinyue Guo, Jiamei Li, Ruohan Li, Jing Xu, Kang Huo, Ying Pan, Gang Wang.
      
    Keywords:  Intensive care unit; Osteoporosis; Prospective; Sepsis; Vitamin D
    DOI:  https://doi.org/10.1186/s12879-026-13318-2
  53. Nucleic Acids Res. 2026 Apr 13. pii: gkag311. [Epub ahead of print]54(7):
    Phosphorothioate antisense oligonucleotide induced innate immune activation is attenuated by tryptophan oxidation products.
    Julia Pytte, Lesley Saldana, Wei Zhang, Konstantina Skourti-Stathaki, Stanley T Crooke.
      Phosphorothioate antisense oligonucleotides (PS ASOs) are a clinically validated therapeutic modality, yet their capacity to activate innate immunity through Toll-Like Receptors, specifically Toll-Like Receptor 9 (TLR9), remains a challenge. While the molecular mechanisms governing TLR9 activation, including PS content, CpG motifs, 2' modifications, sequence composition, and protein interactions, are well defined, far less is understood about the mechanisms that resolve these responses. Here, we investigate how PS ASO-mediated innate immune activation interfaces with tryptophan metabolizing enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and interleukin-4-induced-1 (IL4I1), which generate immunomodulatory tryptophan oxidation products. Across lymphoid and myeloid cell systems, we demonstrate that PS ASOs differing in TLR9 agonist potency and kinetics elicit differential induction of IDO1/IL4I1, accompanied by proportional changes in downstream metabolites. Complementary IDO1 knockdown and IL4I1 overexpression experiments alter TLR9-dependent signaling, indicating that these enzymes actively constrain PS ASO-driven immune activation. Finally, exogenous kynurenine and indole pathway metabolites attenuate PS ASO-induced signaling, supporting their role as negative-feedback regulators. Together, these findings solidify a mechanistic link between PS ASO innate immune activation and tryptophan catabolism, revealing enzymatic and metabolite feedback mechanisms that attenuate innate immune signaling, which may be leveraged to enhance the tolerability of immunostimulatory PS ASOs.
    DOI:  https://doi.org/10.1093/nar/gkag311
  54. Adv Sci (Weinh). 2026 Apr 13. e20095
    A Microbial Lipid-ATP Synthase Axis Fuels NK Cell Antitumor Activity.
    Kaiyuan Yu, Xinyu Sun, Wanxia Ma, Jianming Yang, Xuan Sun, Lisong Zhang, Yumeng Liu, Tianshu Ren, Qi Wang, Jingyu Wang, Xiao Li, Xianping Peng, Liu Yang, Junqiang Lv, Zhi Yao, Zhi-Song Zhang, Quan Wang.
      The gut microbiota influences systemic immunity and cancer through inter-organ communication, but OMV-mediated mechanisms remain unclear. Here, we uncover a previously unrecognized role of Bacteroides intestinalis in restraining extra-intestinal tumor growth via OMVs enriched in sphingosine (SP), a bioactive lipid that directly binds to ATP5F1A-a subunit of the mitochondrial ATP synthase-to enhance NK cell function. This microbial lipid-ATP synthase interaction augments mitochondrial efficiency, reduces reactive oxygen species (ROS) production, and potently upregulates IFN-γsecretion in NK cells, driving increased cytotoxicity and tumor infiltration. Remarkably, OMVs from B. intestinalis or SP administration greatly inhibit murine tumor growth, while their combination with anti-PD-1 therapy enhances systemic antitumor immunity. This study establishes the specific immune activation ability for gut microbial OMVs and highlights microbiota-derived lipid-based immunotherapies.
    Keywords:  ATP5F1A; NK cells; antitumor immunity; outer membrane vesicles; sphingosine
    DOI:  https://doi.org/10.1002/advs.202520095
  55. Nat Commun. 2026 Apr 11.
    PDK4 drives abdominal aortic aneurysm by promoting smooth muscle cell metabolic reprogramming and NLRP3-mediated pyroptosis.
    Li Zhao, Xuefeng Lin, Zhengqiang Zhu, Ranxin Liu, Lingna Zhao, Xuekun Wu, Mengru Zheng, Rihua Huang, Pengyu Zhou, Fangze Huang, Deshen Liu, Chuanjie Niu, Xiaoxia He, Zean Wang, Xin Li, Jiale Li, Shengping He, Jun Lu, Shaoyi Zheng, Jiaguo Zhou, Qinbao Peng, Xiu Liu.
      Abdominal aortic aneurysm (AAA) is a progressive dilation of the abdominal aorta that can rupture and cause catastrophic internal bleeding, yet the mechanisms driving AAA remain poorly understood. Here we show that pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic regulator, is upregulated in human and mouse AAA tissues. Deletion of Pdk4 in vascular smooth muscle cells (VSMCs) significantly reduces AAA formation in male mice. Mechanistically, PDK4 promotes metabolic reprogramming in VSMCs, disrupts mitochondrial respiration, and activates the NLRP3 inflammasome and pyroptosis, thereby exacerbating vascular inflammation and AAA progression. Genetic deletion of Pdk4 in VSMCs or pharmacological inhibition of NLRP3 attenuates AAA development in mice. These findings identify PDK4 as a driver of AAA and suggest that targeting PDK4 may represent a therapeutic strategy for this life-threatening disease.
    DOI:  https://doi.org/10.1038/s41467-026-71610-w
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