bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–05–10
forty-nine papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Cooling inflammation through metabolism with 4-octyl itaconate.
  2. Sugar-coated immunometabolism: functionalized biomaterials as metabolic regulators of immune responses.
  3. mGem: More than building blocks? Mitochondrial metabolism, viruses, and the host response to infection.
  4. Gut microbiota and immunometabolism in obesity.
  5. Iron as an immunometabolic signal in infection and inflammation.
  6. The role of glycolysis in inflammation.
  7. HIV inhibits Warburg metabolism in human macrophages infected with Mycobacterium tuberculosis.
  8. Metabolic modulation of immune cell function: mechanisms and therapeutic implications in cancer immunotherapy.
  9. Ubiquitylation by the GID/CTLH complex regulates the metabolic and innate immune response of macrophages to infection by Mycobacterium tuberculosis.
  10. Lifelong Exercise as a Modulator of CD4+ T Cell Immunometabolism.
  11. Relaxin-3 attenuates lipid-induced macrophage immunometabolic changes in diabetic adipose tissue associated with LDHA-related histone lactylation.
  12. Sleep regulates hepatic neutrophil trafficking by modulating uric acid metabolism via sympathetic nervous system activity.
  13. Acarbose modulates microglial Pkm2 acetylation to reshape immunometabolism and preserve retinal neurons after ischemia-reperfusion.
  14. Lysine Acetyltransferase 6A Drives M1 Macrophage Polarization Through Metabolic Reprogramming in Sepsis-Induced Acute Lung Injury.
  15. Macrophage metabolic reprogramming via HIF-1α-glycolysis drives osteoblast ferroptosis and bone loss through an IL-6-STAT3-dependent redox axis.
  16. GLUT1-mediated glucose flux constrains autoreactive but not foreign antigen-specific B-cell responses.
  17. A new twist in metabolic T cell exhaustion.
  18. Plant Immunometabolism: Metabolic Reprogramming Linking Developmental Signaling and Defense Metabolites.
  19. Micro- and nanoplastics-mediated immunometabolic reprogramming: a systemic nexus for chronic inflammation and multi-organ disease risk.
  20. Pestivirus bovine viral diarrhea virus infection induces ROS-HIF-1a axis-driven glycolytic reprogramming, which increases viral replication by impairing RIG-I-dependent type I interferon response.
  21. Onalespib enhances antitumor immunity through coordinated catalytic and chaperone-dependent regulation of tryptophan metabolism.
  22. The Host NADase CD38 Promotes JEV Replication by Targeting the NAD+/SIRT1 Axis.
  23. Energy metabolism dysregulation in idiopathic inflammatory myopathies: mechanisms and therapeutic implications.
  24. Myeloid Cell States in Influenza-Associated Pulmonary Aspergillosis Are Shaped by Iron Overload and Metabolic Reprogramming.
  25. Lactylation landscape of mitochondrial proteins in myocardial infarction.
  26. 25-Hydroxycholesterol Restricts Japanese Encephalitis Virus via Metabolic Suppression of the SREBP2-Mediated Signaling Axis.
  27. Metabolic adaptations of immunosuppressive cells in cancer: mechanisms and therapeutic targets.
  28. Fasting opens a metabolic window that favors anti-tumor immunity.
  29. Ex vivo cytokine responses and metabolic reprogramming are associated with γδ T cell differentiation in Plasmodium falciparum placental malaria.
  30. Hydrogen cyanide generation by Pseudomonas aeruginosa blunts the host innate immune response.
  31. Targeting purinergic signaling and MTAP-associated metabolism in cancer: A functional immunometabolic convergence framework.
  32. Immune checkpoint blockade targets macrophage PD-1 to exacerbate metabolic dysfunction.
  33. IL-36γ enhanced bactericidal effects of macrophages to Mycobacterium tuberculosis via the IFN-γ/HIF-1ɑ/glycolysis pathway.
  34. 4-Octyl itaconate-induced Nrf2 nuclear translocation mitigates Caspase-11-dependent noncanonical macrophage pyroptosis and acute lung injury.
  35. Disruption of macrophage cell volume drives inflammatory responses and type I interferon signaling.
  36. It's Not Rewarding for Mitochondria: Dopamine-Induced Mitochondrial Dysfunction Activates cGAS-STING to Drive IL-6 Secretion in Macrophages.
  37. Lipid mobilization establishes metabolic tolerance and prevents autonomic collapse in infection.
  38. JAK/STAT inhibition reprograms T cell activation and metabolism in inflammatory arthritis patients.
  39. Butyrate-loaded gelatin methacryloyl microneedle accelerates diabetic wound healing through enhanced lipid metabolism and M2 macrophage polarization.
  40. Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke.
  41. NLRX1 alleviates sepsis-induced acute lung injury by activating mitophagy and suppressing NLRP3 inflammasome activation.
  42. Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
  43. Staphylococcus aureus adapts to the host nutritional environment by coordinating the activity of central metabolic enzymes.
  44. Lactate reprograms PGE2 metabolism via GPR81 inhibits COX2 to relieved psoriasis.
  45. Proteasome-Heme Axis Links Mitochondrial Stress to T-Cell Exhaustion.
  46. PKCθ: from T cell kinase to immunometabolic integrator.
  47. Orientia tsutsugamushi Alters Mitochondrial Function and Selectively Associates with VDAC.
  48. A sodium-HIF1α axis coordinates immune metabolic reprogramming and mitochondrial remodeling in salt-sensitive hypertension.
  49. HBV-Induced Pyruvate Increases Lactylation of Pyruvate Kinase M2 (PKM2) at K206 to Promote Liver Fibrosis.
  1. Trends Immunol. 2026 May 01. pii: S1471-4906(26)00097-9. [Epub ahead of print]
    Cooling inflammation through metabolism with 4-octyl itaconate.
    Hanna F Voß-Willenbockel, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that links metabolism and inflammation. Li et al. uncover a mechanism by which itaconate and 4-octyl itaconate suppress cytokine signaling through the alkylation of tyrosine kinase 2 and Janus kinase 1. This study reveals a direct metabolic control of inflammation and highlights its therapeutic potential in sepsis.
    Keywords:  JAK–STAT signaling; immunometabolism; itaconate; mitochondria; post-translational modification; sepsis
    DOI:  https://doi.org/10.1016/j.it.2026.04.004
  2. J Mater Chem B. 2026 May 05.
    Sugar-coated immunometabolism: functionalized biomaterials as metabolic regulators of immune responses.
    Francesca Taraballi, Bruna Corradetti.
      Immunometabolism, the intersection of immune function and cellular metabolism, has emerged as a powerful lens for understanding and directing host response to biomaterials. Upon implantation, biomaterials often provoke immune activation, potentially leading to chronic inflammation, fibrotic encapsulation, and impaired integration. Recent advances point to sugar functionalization as a promising strategy to steer immunometabolic pathways, enhance biocompatibility, and promote regenerative outcomes. Naturally derived monosaccharides (e.g., mannose, glucose, galactose), polysaccharides (e.g., dextran, chitosan), and glycosaminoglycans (e.g., hyaluronic acid, heparin) engage distinct immune receptors to induce targeted metabolic reprogramming in macrophages, dendritic cells, and other innate effectors. This minireview synthesizes recent breakthroughs in the field, elucidating how distinct sugar classes reshape immunometabolism by modulating glycolysis, oxidative phosphorylation, fatty acid metabolism, and associated inflammatory pathways and highlighting their translational applications in precision medicine. We discuss design considerations for sugar-functionalized scaffolds and outline future directions centered on precision glycoengineering, integrated metabolic analyses, and personalized therapeutic platforms.
    DOI:  https://doi.org/10.1039/d6tb00355a
  3. mBio. 2026 May 05. e0250125
    mGem: More than building blocks? Mitochondrial metabolism, viruses, and the host response to infection.
    Jessica Alvarez, Dustin C Hancks.
      Beyond essential roles as central hubs integrating homeostatic cellular metabolism, mitochondria have emerged as critical determinants of infection outcomes. Mitochondrial activities, like MAVS signaling and the release of cytochrome c and mitochondrial DNA, drive host defenses. Across cell types, mitochondrial metabolism and antiviral responses are also increasingly being connected by evidence such as viral-encoded antagonists. Nonetheless, metabolic rewiring in infected cells is still largely viewed as a means to satisfy biosynthetic demands for both viral replication and the host response. However, perturbation of metabolic states within infected and bystander cells seemingly has consequences for outcomes, implying an incompletely understood metabo-immunoregulatory logic. Here, we consider roles for mitochondrial metabolism reprogramming as an active cue that licenses progressive immune states to adapt host responses. In the coming years, integration of mitochondrial biology and new methodologies, including spatial approaches, will illuminate the interplay of mitochondrial metabolism on primary antiviral responses.
    Keywords:  OXPHOS; immune response; immunometabolism; mitochondria; mitochondrial dysfunction; sterile inflammation; viral infection
    DOI:  https://doi.org/10.1128/mbio.02501-25
  4. Gut Microbes. 2026 Dec 31. 18(1): 2667610
    Gut microbiota and immunometabolism in obesity.
    Alba Torres-Mayo, Rebeca Liébana-García, Marta Olivares, Aize Pellón, Juan Anguita, Yolanda Sanz.
      The gut microbiota plays a central role in modulating both immunity and metabolism. Obesity-associated microbiota configuration is a critical driver of persistent inflammatory activation and immune dysfunction, ultimately leading to chronic metabolic disorders. Immunometabolism examines how metabolic demands shape immune cell function and how immune responses influence cellular metabolism. Emerging research on how the gut microbiota contribute to immune cell metabolic processes and the resulting health outcomes is deepening our understanding of the mechanisms underlying obesity and metabolic diseases. In this review, we summarize how intracellular metabolic pathways and master regulators, such as mTOR and AMPK, orchestrate immune cell function and how their dysregulation contributes to obesity-associated immune and metabolic dysfunction. We also discuss how gut microbiota influences the immunometabolism of different myeloid and lymphoid cell subsets and intestinal epithelial cells. Finally, we review the role of microbially produced metabolites, including short-chain fatty acids, lactate, succinate, bile acids, and amino acids, in reprogramming immune cell metabolism. We also discuss whether modulating gut microbiota function to regulate immunometabolic pathways could help restore immune homeostasis and reduce obesity-related complications.
    Keywords:  Gut microbiota; diet; immunometabolism; obesity
    DOI:  https://doi.org/10.1080/19490976.2026.2667610
  5. Front Immunol. 2026 ;17 1810718
    Iron as an immunometabolic signal in infection and inflammation.
    Alexander Hoffmann, Laura Homs Pérez, Günter Weiss.
      Iron availability is dynamically remodeled during infection and inflammation and has traditionally been interpreted within the framework of nutritional immunity, where iron sequestration restricts microbial growth. Increasing evidence, however, indicates that inflammatory iron redistribution has broader immunological consequences. Systemic and cell-intrinsic iron levels actively shape immune cell production, differentiation, metabolic configuration, and effector function across innate and adaptive immune compartments. Rather than uniformly suppressing immunity, inflammation-driven hypoferremia selectively biases hematopoiesis and immune output, while locally regulated cellular and subcellular iron handling determines microbe-specific immune effector functions. In addition, the availability of metabolically active iron further defines immunometabolic state by regulating mitochondrial respiration, tricarboxylic acid cycle activity, and redox balance, thereby shaping both immune cell function and the host-pathogen interface. Together, these observations support a view of iron as an instructive immunometabolic signal that integrates systemic regulation with cellular and organelle-specific programs during infection and inflammation. This review synthesizes recent evidence across these organizational scales, highlights emerging trade-offs between host defense and iron homeostasis, and discusses how mechanistic insight into iron-sensitive immune pathways may inform strategies to modulate inflammation and antimicrobial immune effector function.
    Keywords:  host-pathogen interaction; immuno-metabolism; inflammation; innate and adaptive immunity; iron homeostasis; iron signaling; lysosomal iron; mitochondrial respiration
    DOI:  https://doi.org/10.3389/fimmu.2026.1810718
  6. Am J Physiol Cell Physiol. 2026 May 08.
    The role of glycolysis in inflammation.
    Ethan T Dehantschutter, Cormac T Taylor.
      A characteristic feature of inflamed tissue is hypoxia, which arises from elevated oxygen consumption and impaired perfusion. Inflammation is accompanied by metabolic reprogramming enabling immune and non-immune cells to meet increased bioenergetic and biosynthetic demands. Glycolysis is among the most ancient and fundamental metabolic pathways in biology. Hypoxia reduces mitochondrial oxidative phosphorylation, driving cells towards a reliance on glycolysis to sustain ATP production. This requires an increase in flux through the glycolytic pathway, which is mediated through rapid allosteric regulation of glycolytic enzymes, transcriptional upregulation of glucose transporters and glycolytic enzymes, and the formation of glycolytic enzyme complexes. In immune cells such as macrophages, neutrophils, and lymphocytes, enhanced glycolytic flux determines effector functions including, but not limited to, cytokine production, phagocytosis, migration, and antimicrobial activity, as well as maintaining bioenergetic homeostasis. Similarly, non-immune cells within inflamed tissues, including epithelial cells and stromal cells, utilize glycolysis to influence barrier function, tissue remodelling, and inflammation. In this review, we summarize our current understanding of how hypoxia drives glycolytic reprogramming during inflammation, examine the cell-type-specific impact of this, and discuss the therapeutic potential of targeting glycolytic pathways for inflammatory diseases.
    DOI:  https://doi.org/10.1152/ajpcell.00113.2026
  7. Sci Rep. 2026 May 07.
    HIV inhibits Warburg metabolism in human macrophages infected with Mycobacterium tuberculosis.
    Kevin Brown, Aaron Walsh, Anjali S Yennemadi, Dearbhla M Murphy, Sarah A Connolly, Grainne Jameson, Mary P O'Sullivan, Sharee A Basdeo, Seonadh O'Leary, Gina Leisching, Joseph Keane.
      Tuberculosis (TB)-associated mortality remains disproportionately high among people living with HIV (PLWH), with macrophage dysfunction representing a key mechanism of impaired host defence against Mycobacterium tuberculosis (Mtb) infection. Macrophage metabolic switching has emerged as a paradigm of host success, yet the influence of HIV on this 'Warburg' response in the context of Mtb infection has not been studied. Using the U1 chronically HIV-infected macrophage cell line model coupled with primary human monocyte-derived macrophages (MDMs) exposed to HIV-1 gp120, we systematically characterized transcriptomic and immunometabolic perturbations during Mtb infection. Nanostring RNA analysis revealed that Mtb monoinfection upregulated glycolytic genes while suppressing oxidative phosphorylation (OXPHOS) transcripts, consistent with a Warburg-type metabolic shift. Conversely, HIV infection downregulated glycolytic enzymes and enhanced OXPHOS. Coinfection studies demonstrated HIV-mediated suppression of Mtb-induced glycolytic reprogramming. Extracellular flux analysis demonstrated that gp120 exposure increased basal oxygen consumption rate while impairing spare respiratory capacity in Mtb-infected MDMs, effectively blocking the Warburg metabolic transition. Notably, gp120 attenuated Mtb-induced TNF-α secretion and impaired macrophage control of Mtb growth. This study reveals that HIV gp120 blocks the protective Warburg response to Mtb and highlights the potential of host-directed therapies that boost glycolysis or its downstream effectors (e.g. TNF-α) as adjunctive strategies in TB/HIV co-infection.
    Keywords:  HIV co-infection; Host-directed therapy; Macrophage metabolism; Oxidative phosphorylation; Tuberculosis; Warburg effect; gp120
    DOI:  https://doi.org/10.1038/s41598-026-50059-3
  8. Oncogenesis. 2026 May 07.
    Metabolic modulation of immune cell function: mechanisms and therapeutic implications in cancer immunotherapy.
    Nina Fenouille, Camille Lobry, Lina Benajiba, Alexandre Puissant.
      Immune cell function is remarkably plastic, allowing T cells, NK cells, and macrophages to transition from resting or quiescent states to proliferative, cytotoxic, or inflammatory programs. These functional shifts are tightly coupled to metabolic reprogramming, which not only fuels energy and biosynthesis but also shapes epigenetic and transcriptional landscapes that guide immune responses. In this review, we highlight how intrinsic metabolic pathways which include glycolysis, fatty acid oxidation, amino acid metabolism, and TCA cycle intermediates, regulate T and NK cell proliferation, cytotoxicity, memory formation, and epigenetic programs. We also examine macrophages, whose polarization into pro-inflammatory M1 or tissue-reparative M2 states is orchestrated by distinct metabolic programs such as arginine metabolism, oxidative phosphorylation, and fatty acid oxidation, with consequences for local immune regulation. We then explore how tumors exploit these metabolic dependencies to create hostile microenvironments that restrict nutrients, accumulate immunosuppressive metabolites, and dampen immune cell activity. Finally, we discuss emerging metabolic interventions designed to restore immune fitness, enhance the efficacy of immune checkpoint inhibitors, and improve the persistence and cytotoxicity of adoptive T cell therapies, including CAR-T cells, in nutrient-deprived and hypoxic tumor niches. By linking immune cell plasticity to metabolic control, this review provides a framework for understanding how metabolism shapes immunity and identifies strategies to harness these pathways for next-generation cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41389-026-00622-4
  9. bioRxiv. 2026 Apr 27. pii: 2026.04.24.720540. [Epub ahead of print]
    Ubiquitylation by the GID/CTLH complex regulates the metabolic and innate immune response of macrophages to infection by Mycobacterium tuberculosis.
    Nelson V Simwela, Luana Johnston, Christopher M Sassetti, David G Russell.
      The GID/CTLH E3 ligase complex is implicated in several biological processes, yet its full substrate repertoire remains poorly defined. We recently identified the complex as a broad modulator of macrophage responses to Mycobacterium tuberculosis (Mtb) infection. Here, we use label-free proteomics and diGly capture analysis of Mtb-infected macrophages to define the GID/CTLH-dependent ubiquitylome. We identify thousands of dynamically altered ubiquitylation sites, with strong enrichment among proteins involved in cellular metabolism and innate immune signaling. Concurrent proteome analysis revealed extensive rewiring in GID/CTLH-deficient macrophages, with >90% of enriched pathways among increased proteins consisting of metabolic targets. Notably, inhibitory phosphatases (PTEN, INPP5D) also emerged as candidate substrates. Functional studies revealed proteasome-dependent stabilization of PTEN and INPP5D in GID/CTLH-deficient macrophages with each phosphatase individually exerting an influence on Mtb intracellular survival. Together, our study defines a GID/CTLH-dependent ubiquitylome in macrophages and identifies the complex as a central regulator of metabolism and antimicrobial immunity.
    Author summary: Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), survives and replicates within macrophages, key immune cells that normally eliminate pathogens. How macrophages control their internal cellular environment in response to infection remains incompletely understood. One such important cellular control system is ubiquitylation, in which proteins are tagged with ubiquitin to determine their functional fate or target them for degradation. We recently identified the GID/CTLH E3 ligase ubiquitylation complex as a critical modulator of macrophage antimicrobial responses to Mtb. Here, we used proteomics approaches to define the proteins controlled by the GID/CTLH complex in Mtb-infected macrophages. We found that this complex ubiquitylates a broad network of proteins involved in cellular metabolism and immune signaling. When the complex is disrupted, macrophages undergo extensive metabolic reprogramming, particularly increased mitochondrial energy production, while showing reduced inflammatory signaling. Despite this dampened immune response, these cells are better able to restrict Mtb growth. We also identified the phosphatases PTEN and INPP5D as targets controlled by the GID/CTLH complex that independently influence intracellular bacterial survival. Our findings demonstrate that the GID/CTLH complex is a critical regulator of metabolism and immune function, shaping the outcomes of Mtb infection.
    DOI:  https://doi.org/10.64898/2026.04.24.720540
  10. Eur J Clin Invest. 2026 May;56(5): e70204
    Lifelong Exercise as a Modulator of CD4+ T Cell Immunometabolism.
    Bruna Spolador de Alencar Silva, Amanda Veiga Sardeli, Ricardo R Agostinete, Helena Batatinha, Alessandra Peres, José César Rosa-Neto, José Teixeira, Manuel J Coelho-E-Silva, Paulo J Oliveira, Fábio Santos Lira.
       BACKGROUND: It is commonly assumed that aging and chronic low-grade inflammation compromise adaptive immunity, particularly the function and metabolism of CD4+ T cells. The preceding are key regulators of immune responses. These immunological alterations contribute to increased susceptibility to infections, diminished vaccine efficacy and the progression of age-related diseases. In contrast, adolescence and young adulthood tend to be characterized by more robust immune responses, though these are heavily influenced by modifiable lifestyle factors such as habitual physical activity, level of cardiorespiratory fitness, diet and body adiposity. Emerging evidence suggests that sustained physical activity throughout life may preserve CD4+ T cell competence by favourably modulating their metabolic programming.
    METHODS: The current narrative review explores how lifelong physical exercise impacts CD4+ T cell metabolism, with particular emphasis on the developmental window of adolescence and the long-term benefits of early and sustained physical training across the lifespan. Molecular mechanisms linking exercise to metabolic reprogramming of T cells were summarised in parallel with attenuation of immunosenescence and inflammation over the lifespan.
    RESULTS: This review suggests that lifelong exercise may reprogram CD4+ T cell metabolism, enhancing oxidative phosphorylation at rest and glycolytic control upon activation, thereby improving Th17/Treg balance, reducing chronic inflammation and enabling effective effector T cell responses. In this context, exercise initiated early in life may act as a critical modulator by promoting optimal immune function from childhood and establishing a functional peak that helps preserve immune competence during aging.
    CONCLUSIONS: Lifelong and early-life exercise may reprogram CD4+ T cell metabolism, strengthening immune balance and preserving immune function during aging.
    Keywords:  Aging; Energy metabolism; Exercise; Immune function; Immunosenescence
    DOI:  https://doi.org/10.1111/eci.70204
  11. Int Immunopharmacol. 2026 May 04. pii: S1567-5769(26)00614-4. [Epub ahead of print]181 116768
    Relaxin-3 attenuates lipid-induced macrophage immunometabolic changes in diabetic adipose tissue associated with LDHA-related histone lactylation.
    Jingzhi Wang, Xinfang Liang, Jiaxin Xue, Yuxin Yang, Xiaoqi Liu, Siting Hong, Xiao Ma, Xiaohui Zhang.
       AIMS: Dysregulated lipid metabolism and chronic inflammation in diabetic adipose tissue jointly contribute to metabolic dysfunction. This study investigated whether Relaxin-3 modulates lipid overload-induced macrophage immunometabolic changes and inflammatory responses, with a focus on LDHA-related histone lactylation.
    METHODS: RAW264.7 macrophages were exposed to high glucose and palmitate (HG + PA) to model lipid overload-associated metabolic stress. LDHA-knockdown macrophages were used to assess the involvement of LDHA in lactate-associated signaling and macrophage polarization-related changes. In vivo, diabetic rats induced by streptozotocin combined with a high-fat diet were treated with Relaxin-3 to evaluate its effects on adipose tissue inflammation and diabetes-related metabolic changes. Glycolysis-related enzymes, lactate production, H3K18la, macrophage polarization-related markers, inflammatory mediators, and selected metabolic indices were assessed.
    RESULTS: HG + PA induced changes in glycolysis-related enzymes, increased intracellular and extracellular lactate accumulation, elevated H3K18la, and altered macrophage polarization-related markers. Relaxin-3 treatment was associated with reduced M1-related markers, increased selected M2-related markers, and further changes in lactate accumulation, H3K18la, and LDHA-related signaling. These effects were attenuated after LDHA knockdown. In diabetic rats, Relaxin-3 reduced adipose tissue inflammation and was associated with improvement in selected metabolic changes.
    CONCLUSION: Relaxin-3 alleviates adipose tissue inflammation in diabetes and is associated with changes in macrophage polarization, lactate metabolism, and H3K18la-related signaling. The available data support the involvement of LDHA in this process. These findings provide a basis for further investigation of lactylation-associated immunometabolic regulation in diabetic adipose tissue.
    Keywords:  Adipose tissue; Histone lactylation; LDHA; Lipid-induced inflammation; Macrophage metabolism; Relaxin-3
    DOI:  https://doi.org/10.1016/j.intimp.2026.116768
  12. bioRxiv. 2026 Apr 30. pii: 2026.04.28.721287. [Epub ahead of print]
    Sleep regulates hepatic neutrophil trafficking by modulating uric acid metabolism via sympathetic nervous system activity.
    Pawan K Jha, Utham K Valekunja, Jing Chen-Roetling, Akhilesh B Reddy.
      Sleep is essential for survival and serves as a key regulator of metabolic and immune function. Sleep loss is strongly associated with metabolic stress and liver inflammation. The mechanisms linking sleep disruption to hepatic metabolic inflammation (metaflammation) remain poorly defined. Here, we show that sleep loss triggers metaflammation through a sympathetic-metabolic-immune axis. Acute sleep deprivation (SD) activates hepatic sympathetic signaling, leading to increased uric acid (UA) synthesis driven by enhanced expression and activity of xanthine dehydrogenase/xanthine oxidase (XDH/XO) in the liver. Elevated UA, acting as an immune-stimulatory metabolic signal, promotes hepatic neutrophil recruitment and pro-inflammatory cytokine production, a response that is rapidly reversed upon sleep recovery. Our findings identify sleep-dependent sympathetic control of hepatic UA metabolism as a driver of acute liver inflammation and reveal how acute sleep loss reprograms liver immune-metabolic homeostasis.
    DOI:  https://doi.org/10.64898/2026.04.28.721287
  13. J Neuroinflammation. 2026 May 02.
    Acarbose modulates microglial Pkm2 acetylation to reshape immunometabolism and preserve retinal neurons after ischemia-reperfusion.
    Yuwen Wen, Ya-Nan Dou, Xiaohong Chen, Xiuxing Liu, Zhenlan Yang, Yingting Zhu, Zhidong Li, Caibin Deng, Ye Deng, Wenru Su, Yehong Zhuo.
      Retinal ischemia-reperfusion (IR) elicits microglia-driven neuroinflammation and mitochondrial failure that led to retinal ganglion cell (RGCs) loss, yet effective disease-modifying therapies remain limited. Acarbose (ACA), an α-glucosidase inhibitor widely used for diabetes, has recently been recognized for its dual regulatory potential on immune metabolism and aging-associated neurodegeneration. Here, we demonstrate that intravitreal ACA administration attenuates retinal inflammation and improves RGCs survival following IR injury. Single-cell RNA sequencing revealed extensive inflammatory activation and metabolic reprogramming across the retina, characterized by enhanced nicotinamide adenine dinucleotide (NAD) catabolism, particularly in microglia. ACA treatment was associated with reversal of these alterations, replenished NAD levels, and restored mitochondrial integrity. Integrative proteomic and biochemical analyses identified pyruvate kinase, muscle-type 2 (Pkm2) as a candidate regulatory node affected by ACA. Intravitreal delivery of siPkm2 partially protected against IR injury, and co-administration with ACA produced an additive trend in neuroprotection. Mechanistically, ACA upregulated sirtuin 1 (Sirt1) and reduced Pkm2 acetylation at lysine 270 (K270), which was linked to pro-inflammatory microglial activation. Structure-based virtual screening further identified HY-113082, a small molecule targeting Pkm2-K270, which synergized with ACA to suppress inflammation and enhance retinal protection. Moreover, Pkm2fl/flCx3cr1-Cre mice conferred partial resistance to IR injury, but blunted the additional benefit of HY-113082 when combined with ACA, consistent with on-target engagement. Our findings support that ACA exerts retinal protection through the Sirt1-Pkm2-NAD axis, suggesting a metabolic checkpoint that integrates immune and mitochondrial regulation. This study provides mechanistic insight into ACA's dual immunometabolic and neuroprotective actions, holding promise for therapeutic insights into neuroinflammation.
    Keywords:  Acarbose; Acetylation; Immunometabolism; Microglia; Pkm2; Retinal ischemia and reperfusion
    DOI:  https://doi.org/10.1186/s12974-026-03838-8
  14. Biomolecules. 2026 Apr 20. pii: 609. [Epub ahead of print]16(4):
    Lysine Acetyltransferase 6A Drives M1 Macrophage Polarization Through Metabolic Reprogramming in Sepsis-Induced Acute Lung Injury.
    Xin Wang, Junlin Chen, Yimei Lai, Yumeng Wang, Kaixia Hu, Mengshi Wu, Niansheng Yang, Yuefang Huang.
      Macrophage-mediated inflammation is a key driver of sepsis-induced acute lung injury (ALI). M1 macrophage polarization relies on metabolic reprogramming, yet the upstream regulatory factors remain unclear. Lysine acetyltransferase 6A (KAT6A), a MYST-family acetyltransferase, regulates transcriptional programs in immune cells, but its role in macrophage function and ALI progression remains unknown. Public single-cell and bulk transcriptomic datasets were used to assess KAT6A expression changes and its association with inflammatory and metabolic pathways in macrophages. KAT6A inhibition with WM1119 was used to evaluate effects on M1 polarization, cytokine production, metabolic reprogramming, and PI3K-AKT-mTOR signaling. The therapeutic potential of KAT6A inhibition was validated in a cecal ligation and puncture (CLP)-induced sepsis model by assessing lung injury, bacterial clearance, and survival. KAT6A expression was upregulated in sepsis and particularly enriched in M1 macrophages. Inhibition of KAT6A reduced inflammatory and glycolytic transcriptional programs, suppressed glycolysis and enhanced oxidative phosphorylation, leading to decreased cytokine production and limited M1 polarization accompanied by suppression of PI3K-AKT-mTOR pathway. In CLP-induced septic mice, treatment with the KAT6A inhibitor WM1119 alleviated lung injury, improved bacterial clearance, and prolonged survival. KAT6A expression is associated with macrophage glucose metabolism, pro-inflammatory responses, and M1 macrophage polarization in sepsis-induced acute lung injury. Pharmacologic inhibition of KAT6A may provide a promising therapeutic strategy for reducing macrophage-driven lung injury.
    Keywords:  KAT6A; M1 macrophage; PI3K-AKT-mTOR signaling; acute lung injury; metabolic reprogramming; sepsis
    DOI:  https://doi.org/10.3390/biom16040609
  15. Redox Rep. 2026 Dec 31. 31(1): 2667673
    Macrophage metabolic reprogramming via HIF-1α-glycolysis drives osteoblast ferroptosis and bone loss through an IL-6-STAT3-dependent redox axis.
    Yifan Gu, Kun Wang, Yicong Wang, Ziru Wang, Yiheng Li, Lei Li, Shuai Jiang, Yu Zheng, Run Feng, Min Yang.
       BACKGROUND: Postmenopausal osteoporosis (PMOP) is characterized by exacerbated bone resorption and inadequate bone formation, with macrophage-driven inflammation playing a key role. However, how immunometabolic reprogramming of macrophages modulates osteoblast fate remains unknown.
    METHODS: Using integrated single-cell and bulk transcriptomics, we identified a hypermetabolic macrophage subpopulation in PMOP marrow reliant on HIF-1α-glycolysis. We pharmacologically disrupted this axis with the HDAC inhibitor valproic acid (VPA) and validated its function using the HIF-1α stabilizer DMOG. The paracrine effects on osteoblasts were assessed via conditioned medium, focusing on ferroptosis and differentiation. Therapeutic efficacy was tested in ovariectomized rats.
    RESULTS: VPA upregulated HIF1AN, enhancing its binding to HIF-1α and promoting its degradation. This suppressed glycolytic flux and M1 polarization, reducing IL-6 secretion. The altered secretome protected osteoblasts from ferroptosis by inhibiting the IL-6/p-STAT3/HIF-1α/TFRC axis and rebalancing GPX4/ACSL4. Osteogenic differentiation was restored. In OVX rats, VPA improved bone mass and microstructure, effects abolished by DMOG.
    CONCLUSION: We unveil a macrophage-centric immunometabolic checkpoint that is linked to osteoblast ferroptosis via IL-6/STAT3 signaling. Targeting this HIF-1α-glycolysis axis, exemplified by VPA, represents a novel therapeutic strategy for PMOP.
    Keywords:  HIF-1α; Osteoporosis; ferroptosis; glycolysis; immunometabolism; macrophage polarization
    DOI:  https://doi.org/10.1080/13510002.2026.2667673
  16. J Immunol. 2026 Apr 15. pii: vkag092. [Epub ahead of print]215(4):
    GLUT1-mediated glucose flux constrains autoreactive but not foreign antigen-specific B-cell responses.
    Yanan Zhu, Seung Chul Choi, Mark J Shlomchik, Laurence Morel.
      Emerging evidence from lupus-prone mice and patients with systemic lupus erythematosus implicates enhanced glycolysis in lymphocytes as a driver of disease. We previously showed that the pharmacologic blockade of glycolysis reduced the production of autoantibodies without affecting antibodies induced by immunization to a foreign protein. Here we used CRISPR/Cas9 to reduce the expression of glucose transporter GLUT1 in B cells from autoreactive AM14 Vk8R (AM14) and antigen-specific B1-8 Jκ (B1-8) transgenic mice, comparing intrinsic glycolytic requirements across disease-relevant contexts. Following adoptive transfer into BALB/c recipients, Glut1 knockdown (Glut1KD) decreased the persistence of AM14 B cells, their differentiation into plasmablasts, and production of antibodies upon immunization with the PL2-3 hybridoma that activates both their B-cell receptor and endosomal TLR. In addition, PL2-3-stimulated Glut1KD AM14 B cells selectively reduced their CD80 expression both in vivo and in vitro, as well as ATP production and mammalian target of rapamycin (mTOR) signaling in vitro. In contrast, Glut1KD B1-8 B cells retained persistence, plasmablast output, and nitrophenyl (NP)-specific IgM production after NP-OVA immunization, with a selective reduction in the proliferation of naive B cells. Bioenergetic output was preserved despite Glut1KD in both clones stimulated with TLR7 agonist R848, but CD80 and mTOR signaling were differentially affected. Thus, GLUT1-dependent glycolysis is essential for immune complex-driven autoreactive B-cell activation yet largely dispensable for antigen-specific responses, identifying metabolic checkpoints that may selectively restrain pathogenic B cells while sparing protective humoral immunity.
    Keywords:  B cells; GLUT1; glycolysis; lupus
    DOI:  https://doi.org/10.1093/jimmun/vkag092
  17. Immunometabolism (Cobham). 2026 Apr;8(2): e00080
    A new twist in metabolic T cell exhaustion.
    Konstantinos Aliazis, Vassiliki A Boussiotis.
      Metabolic reprogramming of T lymphocytes has a decisive role in their activation, differentiation, and functional fate commitment. Metabolic reprogramming guides not only the generation of T effector and T memory cells but also the development of dysfunctional exhausted (TEX) cells. A recent study by Haku et al published in Nature Immunology provides new insights into the role of mitochondria in regulating the metabolic capabilities of TEX cells and their implications for antitumor immunity.
    Keywords:  T cell exhaustion; cancer immunotherapy; checkpoints; metabolism; programmed cell death protein 1
    DOI:  https://doi.org/10.1097/IN9.0000000000000080
  18. Int J Mol Sci. 2026 Apr 19. pii: 3635. [Epub ahead of print]27(8):
    Plant Immunometabolism: Metabolic Reprogramming Linking Developmental Signaling and Defense Metabolites.
    Wajid Zaman, Asma Ayaz, Adnan Amin.
      Plant metabolism is essential for coordinating growth, development, and defense under changing environmental conditions. Plants continuously adjust their metabolic pathways to balance resource allocation between growth and immune responses. Under stress, metabolic reprogramming redirects energy and resources toward the production of defense compounds and activation of immune signaling pathways. These changes involve complex interactions among primary metabolism, specialised metabolites, and regulatory networks, including calcium signaling, reactive oxygen species, and phytohormones. Advances in metabolomics and multi-omics technologies have improved understanding of the metabolic control of plant immunity; however, knowledge remains fragmented, and an integrated framework linking metabolism, development, and defense is still emerging. This review examines plant immunometabolism by highlighting the dynamic relationships between metabolic networks and immune functions during development and stress. It discusses pathways that influence growth, stress-induced metabolic shifts linked to defense, and how signaling interacts with metabolism. Progress in metabolomics, transcriptomics, proteomics, and computational modeling that supports systems-level analysis of plant metabolism is also summarized. In addition, potential applications in agriculture and biotechnology, including metabolic engineering, genome editing, and metabolomics-based breeding, are considered in relation to crop resilience. By integrating metabolism, signaling, and systems biology, this review provides a broad perspective on how metabolic reprogramming shapes the growth-defense trade-off in plants and outlines future directions for developing climate-resilient crops.
    Keywords:  crop resilience; metabolic reprogramming; plant defense signaling; plant immunometabolism; plant metabolomics; secondary metabolites; stress adaptation
    DOI:  https://doi.org/10.3390/ijms27083635
  19. J Immunotoxicol. 2026 Dec;23(1): 2665189
    Micro- and nanoplastics-mediated immunometabolic reprogramming: a systemic nexus for chronic inflammation and multi-organ disease risk.
    Jingxuan Dai, Kun Yuan, Keming Huang, Yingyan Sun, Xuancheng Zhou, Ying Zhang.
      Micro- and nanoplastics (MNP) are ubiquitous environmental stressors increasingly detected in human tissues and directly linked to clinical cardiovascular events. This review proposes immunometabolic reprogramming as the central nexus through which MNP drive systemic immune dysregulation and chronic inflammation. Upon entering via multiple routes, MNP selectively sequester in immune organs, disrupting mitochondrial quality control via Drp1-mediated fission and activating the cGAS-STING pathway. Furthermore, MNP induce a pseudohypoxic state that stabilizes HIF-1a, driving a glycolytic "Warburg-like" shift that promotes pro-inflammatory macrophage polarization. These intracellular perturbations are further amplified by "lipid corona" formation and gut microbiota dysbiosis, which depletes anti-inflammatory short-chain fatty acids. Collectively, this systemic immunometabolic remodeling provides a mechanistic framework for understanding MNP-related risks for cardiovascular, metabolic, and neurodegenerative disorders.  This review emphasizes the necessity of integrating immunometabolic parameters into future environmental health risk assessment frameworks.
    Keywords:  Micro- and nanoplastics; chronic systemic inflammation; glycolytic reprogramming; gut-microbiota-metabolite axis; immunometabolism; mitochondrial quality control
    DOI:  https://doi.org/10.1080/1547691X.2026.2665189
  20. J Virol. 2026 May 07. e0032026
    Pestivirus bovine viral diarrhea virus infection induces ROS-HIF-1a axis-driven glycolytic reprogramming, which increases viral replication by impairing RIG-I-dependent type I interferon response.
    Yuan Li, Jiangfei Zhou, Jing Wang, Kai Yan, Yueming Guan, Mengmeng Wang, Jiayi Xiang, Yimei Liu, Han Yu, Shuo Jia, Wentao Yang, Yigang Xu.
      Pestivirus bovine viral diarrhea virus (BVDV) is a major causative agent of bovine viral diarrhea-mucosal disease, responsible for substantial economic losses in the global cattle industry. BVDV employs sophisticated strategies to evade host antiviral innate immune responses; however, the precise mechanisms remain incompletely understood. In this study, we demonstrate that BVDV infection induces HIF-1α-mediated glycolytic reprogramming, which, in turn, antagonizes the RIG-I/MAVS pathway and suppresses type I interferon (IFN-I) production, thereby facilitating viral replication. We show that BVDV infection activates endoplasmic reticulum stress, leading to a marked increase in reactive oxygen species (ROS) that promote both the expression and stabilization of HIF-1α. As a key regulator of glycolysis, nuclear translocation of HIF-1α upregulates glycolysis-related proteins, including GLUT1, PFKP, HK2, and LDHA, thereby enhancing glycolytic flux. Furthermore, BVDV-induced glycolysis stimulates the formation of an HK2/MAVS/VDAC1 complex, which disrupts RIG-I-MAVS interaction and impairs pathway activation, inhibiting IFN-I production. Additionally, we found that lactate, a glycolytic byproduct, competitively binds to MAVS, impedes its mitochondrial localization, and consequently disrupts the engagement between RIG-I and MAVS. Collectively, our findings reveal a novel mechanism by which BVDV exploits the ROS-HIF-1α-glycolysis axis to attenuate MAVS-mediated antiviral signaling and promote viral replication.
    IMPORTANCE: Bovine viral diarrhea virus (BVDV), a member of the genus Pestivirus, is the causative agent of bovine viral diarrhea-mucosal disease, one of the most significant infectious diseases affecting cattle worldwide. BVDV employs diverse mechanisms to evade host innate antiviral immune response, while the precise processes remain incompletely understood. Here, we reveal that BVDV infection drives glycolytic reprogramming through the ROS-HIF-1α axis, leading to the formation of an HK2/MAVS/VDAC1 complex. This complex impairs the interaction between RIG-I and MAVS, resulting in suppressed IFN production. Moreover, we show that lactate, produced via LDHA-mediated glycolysis, binds to MAVS, inhibiting its mitochondrial localization and subsequent association with RIG-I. Together, these mechanisms reveal how BVDV harnesses glycolytic remodeling to dampen RIG-I/MAVS signaling and facilitate viral replication. Our study not only uncovers a potential therapeutic target for combating pestivirus infection but also provides valuable insights into immune evasion strategies shared within the Flaviviridae family, particularly among pestiviruses.
    Keywords:  RIG-I/MAVS pathway; bovine viral diarrhea virus; glycolysis reprogramming; lactate; type I interferon
    DOI:  https://doi.org/10.1128/jvi.00320-26
  21. Toxicol Appl Pharmacol. 2026 May 05. pii: S0041-008X(26)00150-X. [Epub ahead of print] 117854
    Onalespib enhances antitumor immunity through coordinated catalytic and chaperone-dependent regulation of tryptophan metabolism.
    Linhan Yang, Ruiyang Zhang, Lingyu Li, Minghui Ji, Ruiying Xi, Fei Wang, Yuwen Sheng.
      Tryptophan metabolism via the kynurenine (Kyn) pathway represents a central mechanism of tumor immune tolerance. Although HSP90 inhibitors have been extensively investigated as anticancer agents, their role in metabolic immune regulation remains incompletely unknown. Here, we identify the HSP90 inhibitor onalespib as a potent suppressor of IDO1-dependent tryptophan metabolism in breast cancer. Mechanistically, onalespib suppresses the tryptophan-kynurenine pathway through coordinated catalytic modulation of IDO1 and interference with HSP90 chaperone-associated regulation of IDO1, accompanied by attenuation of IFN-γ-induced JAK-STAT and NF-κB signaling programs. In vivo, onalespib remodels the tumor immune microenvironment, promotes CD8+ effector T-cell infiltration, and enhances the antitumor efficacy of cisplatin without compromising tolerability. Collectively, these findings define a functional HSP90-IDO1 regulatory axis and provide a mechanistic rationale for combination strategies targeting metabolic immune tolerance.
    Keywords:  HSP90; IDO1; Immunometabolism; Onalespib; Tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.taap.2026.117854
  22. Microorganisms. 2026 Apr 01. pii: 796. [Epub ahead of print]14(4):
    The Host NADase CD38 Promotes JEV Replication by Targeting the NAD+/SIRT1 Axis.
    Yuanyuan Yang, Ruiqin Zhang, Xinran Li, Xinlei Liu, Yu Dai, Yu Gu, Jiahui Li, Haodong Chen, Yi Zheng, Rui Wu.
      The manipulation of host cellular metabolism is a key strategy for flaviviruses like Japanese encephalitis virus (JEV) to establish a productive infection. This study identifies the host NADase CD38 as a central regulator of this process. Using a CRISPR/Cas9-generated CD38 knockout (KO) TM3 cell model, we found that CD38 deficiency significantly restricted the production of infectious viral particles. While loss of CD38 also partially impaired viral entry, our central finding is that CD38 primarily promotes JEV infection by suppressing a host-intrinsic metabolic defense. We show that CD38 deficiency leads to a surge in intracellular NAD+, which sustains SIRT1 activity and inactivates p53, thereby blocking the mitochondrial apoptosis required for viral propagation. The dominance of this metabolic axis was confirmed through bidirectional pharmacological interventions; while SIRT1 inhibition using EX527 restored JEV replication, SIRT1 activation using SRT1720 suppressed it in wild-type cells. Our work reveals that JEV hijacks the CD38-NAD+-SIRT1-p53 axis to overcome host metabolic defenses in reproductive cell models, establishing CD38 as a promising therapeutic target.
    Keywords:  CD38; Japanese encephalitis virus; NAD+ metabolism; SIRT1/p53 axis
    DOI:  https://doi.org/10.3390/microorganisms14040796
  23. Front Immunol. 2026 ;17 1781434
    Energy metabolism dysregulation in idiopathic inflammatory myopathies: mechanisms and therapeutic implications.
    Yuan Fang, Huihui Chi, Jialin Teng, Chengde Yang, Yue Sun, Yutong Su.
      Idiopathic inflammatory myopathies (IIMs) are being increasingly recognized as disorders driven by profound disturbances in cellular energy metabolism rather than inflammation alone. Recent studies have highlighted mitochondrial dysfunction, oxidative stress, and metabolic reprogramming across glucose, lipid, and amino acid pathways as central mechanisms linking energy metabolism dysregulation to sustained muscle injury. Defective mitophagy, mitochondrial DNA (mtDNA) depletion, and excessive reactive oxygen species (ROS) production create a self-amplifying loop with interferon-driven inflammation, whereas abnormal glycolysis, impaired fatty acid oxidation, and dysregulated tryptophan-kynurenine metabolism further shape the immunometabolic landscape of IIMs. These metabolic shifts not only contribute to muscle weakness and tissue degeneration but are also correlated with disease severity, autoantibody profiles, and treatment resistance. Emerging therapeutic strategies, including antioxidant approaches, mitochondrion-targeted agents, metabolic modulators, and exercise-based interventions, underscore the translational potential of targeting energy homeostasis. This review synthesizes current evidence on energy metabolism abnormalities in IIMs, integrates molecular findings with clinical implications, and highlights future directions for immunometabolic-based precision therapies.
    Keywords:  energy metabolism; idiopathic inflammatory myopathies; immunometabolism; metabolic reprogramming; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3389/fimmu.2026.1781434
  24. bioRxiv. 2026 Apr 25. pii: 2026.04.22.720189. [Epub ahead of print]
    Myeloid Cell States in Influenza-Associated Pulmonary Aspergillosis Are Shaped by Iron Overload and Metabolic Reprogramming.
    Madeleine S Grau, Brian P Jackson, Carol Ringelberg, Fred W Kolling, George S Deepe, Robert A Cramer, Joshua J Obar.
      Virus-associated pulmonary aspergillosis is a life-threatening secondary infection that substantially increases morbidity and mortality in critically ill patients with respiratory virus infections. Influenza A virus (IAV) and SARS-CoV2 are known to disrupt pulmonary homeostasis, the mechanisms by which these perturbations render the host susceptibility to Aspergillus fumigatus (Af) remain incompletely understood. Here, we integrate an established murine model of influenza-associated pulmonary aspergillosis (IAPA) with single-cell RNA sequencing (scRNA-seq) to define the myeloid cell dysfunction that underlies IAPA establishment and progression. Single-cell transcriptomic profiling of pulmonary monocytes and macrophages revealed that IAV- Af coinfection drives a marked shift away from interferon-mediated antiviral and antigen presentation programs toward stress-associated and redox-regulatory transcriptional states. Pathway analyses demonstrated coordinated suppression of phagocytic and interferon signaling pathways alongside enrichment of oxidative stress and mitochondrial metabolic signatures - changes that closely recapitulate transcriptional defects previously reported in human IAPA patients. Myeloid cells from IAV- Af coinfected mice further exhibited increased oxidative phosphorylation alongside reduced glycolytic and phagocytic activity, consistent with impaired antifungal effector function. To elucidate how prior IAV infection generates a pulmonary microenvironment permissive to Af growth, we evaluated airway iron availability - a critical determinant of both fungal pathogenicity and immune regulation. IAV infection alone produced a significant elevation in bronchoalveolar iron levels accompanied by induction of iron-associated inflammatory mediators. Paradoxically, during IAV- Af coinfection, myeloid cells displayed markedly reduced expression of iron-sequestering and storage genes, revealing a fundamental disconnect between iron burden and cellular iron-handling capacity. Functionally, elevated iron accelerated Af germination and impaired macrophage-mediated fungal killing. Collectively, these findings identify IAV-induced pulmonary iron accumulation as a key driver of immunometabolic reprogramming in myeloid cells, resulting in compromised antifungal immunity and heightened susceptibility to secondary Af infection.
    DOI:  https://doi.org/10.64898/2026.04.22.720189
  25. bioRxiv. 2026 Apr 28. pii: 2026.04.27.718938. [Epub ahead of print]
    Lactylation landscape of mitochondrial proteins in myocardial infarction.
    Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.
      Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently described lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we define the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocytes-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.
    Highlights: Myocardial infarction (MI) increases mitochondrial protein lactylation, with 361 identified lactylated proteins.AZD3965-mediated MCT1 inhibition further elevates mitochondrial lactylation.Distinct alterations in mitochondrial proteins and pathways (TCA cycle, amino acid metabolism, gene expression) were observed.AZD3965 reduces cardiac fibrosis and inflammation and partly improves mitochondrial respiration post-MI, but cardiac function remains impaired.
    DOI:  https://doi.org/10.64898/2026.04.27.718938
  26. Microorganisms. 2026 Mar 26. pii: 740. [Epub ahead of print]14(4):
    25-Hydroxycholesterol Restricts Japanese Encephalitis Virus via Metabolic Suppression of the SREBP2-Mediated Signaling Axis.
    Xinlei Liu, Yu Gu, Yuanyuan Yang, Xinran Li, Yu Dai, Ruiqin Zhang, Jiahui Li, Haodong Chen, Yi Zheng, Rui Wu.
      Host lipid metabolism is a critical determinant of viral pathogenesis. Although the interferon-inducible cholesterol 25-hydroxylase (CH25H) typically acts as a broad-spectrum antiviral protein, its expression and regulatory patterns during Japanese Encephalitis Virus (JEV) infection display unique features. Here, we demonstrate that 25-hydroxycholesterol (25HC), the product of CH25H, potently inhibits JEV proliferation by suppressing SREBP2 activation. Distinct from the majority of viral infections that induce CH25H upregulation, JEV infection elicits a transient reduction in CH25H abundance immediately after infection, coupled with a persistent elevation in SREBP2 expression. This inverse correlation suggests that JEV actively suppresses the CH25H-mediated metabolic checkpoint to maintain a cholesterol-synthetic environment favorable for replication. By pharmacologically simulating the activity of 25HC, we further verify that targeting the SREBP2 signaling axis can efficiently counteract this virally induced metabolic reprogramming. Our study identifies CH25H downregulation and concomitant SREBP2 activation as a key metabolic signature of JEV pathogenesis.
    Keywords:  25HC; HMGCR; Japanese encephalitis virus; SREBP2; cholesterol biosynthesis
    DOI:  https://doi.org/10.3390/microorganisms14040740
  27. Exp Mol Med. 2026 May 07.
    Metabolic adaptations of immunosuppressive cells in cancer: mechanisms and therapeutic targets.
    Jihyoun Kim, Ji Min Shin, Yunju Um, Sujing Yuan, Seon Ah Lim.
      The tumor microenvironment harbors diverse immunosuppressive cell populations-including regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages and other tolerogenic subsets-that drive immune evasion and therapeutic resistance. These cells are metabolically reprogrammed to sustain their suppressive function and survive under conditions of hypoxia, nutrient deprivation and oxidative stress. Importantly, their metabolic activity not only supports their own fitness but also creates a hostile environment that antagonizes effector T and natural killer cells by depleting essential nutrients, generating inhibitory metabolites, and altering signaling thresholds. This immunometabolic competition reinforces immune dysfunction and limits the efficacy of checkpoint blockade and adoptive cell therapies. Here we delineate the immunosuppressive cell types within the TME, their key metabolic adaptations and the mechanisms by which they suppress antitumor immunity. Finally, we discuss therapeutic strategies aimed at disrupting these metabolic programs to remodel the TME and enhance the success of current and next-generation immunotherapies. Collectively, understanding the metabolic crosstalk between suppressive and effector immune cells will provide new opportunities to design precision metabolic interventions and improve durable responses to cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s12276-026-01713-3
  28. Cell Metab. 2026 May 05. pii: S1550-4131(26)00109-9. [Epub ahead of print]38(5): 833-834
    Fasting opens a metabolic window that favors anti-tumor immunity.
    Ling Cai, Tao Dai.
      Short-term fasting reshapes the metabolic landscape of the tumor microenvironment, creating a transient window of altered nutrient availability that cytotoxic CD8⁺ T cells can exploit. Chen and colleagues report that intratumoral isoleucine accumulation during fasting supports T cell effector programs, enhancing responses to immune checkpoint blockade in mice and humans.
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.015
  29. Front Immunol. 2026 ;17 1803384
    Ex vivo cytokine responses and metabolic reprogramming are associated with γδ T cell differentiation in Plasmodium falciparum placental malaria.
    Chris Marco Nana Mbianda, Bodin Darcisse Kwanou Tchakounte, Bernard Marie Bitye Zambo, Joséphine Ntankheuh Tchinkou, Derrick Atchombat Nyasse, Balotin Fogang, Rafael José Argüello, Lawrence Ayong, Rosette Megnekou.
       Background: γδ T cells play a key role in modulating immune responses to pregnancy-associated malaria and can enhance vaccine efficacy through their activation and cytotoxic functions. However, the mechanisms guiding γδT cell differentiation in placental malaria (PM) remain poorly understood. We examined ex vivo associations between cytokines, metabolic profiles and γδ T-cell differentiation in women with PM.
    Methods: A case-control study including 50 women at delivery (21 PM+, 29 PM-) was carried out. Peripheral, placental intervillous space, and cord blood mononuclear cells were isolated, and multiparametric flow cytometry was performed to characterize γδT-cells and memory phenotypes, its subsets (Vδ1+, Vδ2+, Vδ3+), and the expression of exhaustion (TIM-3, PD1) and activation (HLA-DR) markers. Ex vivo plasma levels of IL-8, IL-33, and IL-35 were quantified by Luminex assay or ELISA. Immunometabolic profiles were assessed in a subset of 15 samples from uninfected women following cell stimulation with phytohemagglutinin (PHA) by SCENITH assay.
    Results: In general, the frequency of γδ T cells and their subsets varied depending on the different blood compartments, with naïve and central memory (CM) phenotypes observed mainly in CBMC, while effector memory (EM) and terminally differentiated effector memory (TEMRA) phenotypes were found mainly in PBMC and IVBMC. Ex vivo analyses showed that γδ T cell-modulating cytokine IL-8 were associated, in a compartment-dependent manner, with down-regulation of immunoregulatory markers TIM-3 and PD-1. Interestingly, IL-8 and IL-33 were associated with increased frequency of the TEMRA cell phenotype in peripheral blood, consistent with enhanced differentiation of naïve γδT cells during PM. Metabolic profiling of the different cell types further established an enhanced mitochondrial metabolic activity in predominantly terminally differentiated γδ T cells in PBMC, compared to the mainly glycolytic activities of non-terminally differentiated cells in CBMC and IVBMC.
    Conclusion: Placental malaria is associated with a compartment-specific memory γδ T cell differentiation, with cytokines and metabolic reprogramming regulating exhaustion. These findings reveal key regulatory processes that determine the function of γδ T cells during placental malaria, which constitute potential targets for new therapeutic intervention against PM.
    Keywords:  Plasmodium falciparum; cytokines; metabolic reprogramming; placental malaria; γδT cells memory
    DOI:  https://doi.org/10.3389/fimmu.2026.1803384
  30. J Infect Dis. 2026 May 06. pii: jiag244. [Epub ahead of print]
    Hydrogen cyanide generation by Pseudomonas aeruginosa blunts the host innate immune response.
    Csaba Szabo, Sidnéia Sousa Santos, Jacqueline Findlay, Olivier Bremer, Maria Petrosino, Thilo Magnus Philipp, Anna Kierońska-Rudek, Karim Zuhra, Gerry R Boss, Patrice Nordmann.
       BACKGROUND: The biological mediator hydrogen cyanide (HCN) is produced by certain pathogenic bacteria. HCN exerts multiple effects in mammalian cells: at low concentrations it has cytoprotective regulatory effects, whereas at high concentrations it blocks mitochondrial electron transport by inhibiting cytochrome c oxidase, thereby halting cellular metabolism. Here, we evaluated whether bacterial HCN confers resistance to the host immune response. We used Pseudomonas aeruginosa as a model organism, since it is a clinically significant HCN-generating bacterial species and a common cause of nosocomial infections.
    METHODS: The study used bacterial mutants, macrophage co-cultures, cyanide quantification, phagocytosis and bioenergetics assays, and mouse infection models to assess HCN's role in immune evasion.
    RESULTS: Compared to wild type P. aeruginosa, genetically HCN-deficient bacteria were more susceptible to killing by immune cells in vitro and were cleared more rapidly in mouse models of systemic infection. Increased leukocyte killing was not due to increased phagocytosis. Pharmacological scavenging of HCN (by vitamin B12 or trihistidyl cobinamide) also enhanced leukocyte bacterial killing.
    CONCLUSIONS: These findings support the concept that HCN acts as a bacterial defense mechanism against the host's immune response. Targeting bacterial HCN (through inhibition of its biogenesis or by scavenging) could be a potential therapeutic strategy to improve the immune clearance of P. aeruginosa infections.
    Keywords:  bioenergetics; cyanide; infection; macrophage; mitochondria; sepsis
    DOI:  https://doi.org/10.1093/infdis/jiag244
  31. Biochem Pharmacol. 2026 May 02. pii: S0006-2952(26)00363-1. [Epub ahead of print]250(Pt 2): 118030
    Targeting purinergic signaling and MTAP-associated metabolism in cancer: A functional immunometabolic convergence framework.
    Vandriel Pedone da Rosa, Michelli Fontana, Carine Raquel Richter Schmitz, Maike Valentim Buzatto, Iuri Raiel Giacomelli, Walter Antônio Roman Junior, Detlev Boison, Margarete Dulce Bagatini, Sarah Franco Vieira de Oliveira Maciel.
      Cancer progression is closely associated with metabolic reprogramming and immune evasion. Extracellular adenosine (eADO) metabolism regulates adenosine receptor activation within the tumor microenvironment (TME). Predominantly through the adenosine A2A receptor, and, in some contexts through the adenosine A2B receptor, eADO signaling suppresses antitumor immune responses and contributes to resistance to immunotherapy. Production of eADO is largely driven by ecto-5'-nucleotidase (CD73), which catalyzes the conversion of eADO monophosphate (AMP) into eADO. In parallel, methylthioadenosine phosphorylase (MTAP) deletion - frequently co-occurring with loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) - does not increase eADO levels but, instead, leads to intracellular accumulation of methylthioadenosine (MTA), reshaping methylation homeostasis and creating selective metabolic dependencies involving protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A). Recent evidence further indicates that nucleoside transport dynamics, particularly via equilibrative nucleoside transporter 1 (ENT1), regulate intracellular adenosine (iADO) availability in T cells, and represent an additional regulatory layer, linking extracellular purinergic signaling with intracellular immunometabolic control. Accordingly, we propose a functional immunometabolic convergence framework in which CD73-dependent extracellular eADO signaling, ENT1-regulated iADO handling, and MTAP loss-associated metabolic rewiring function as parallel yet cooperative processes that stabilize tumor immune escape.
    Keywords:  CD73; Methylthioadenosine phosphorylase deficiency; Purinergic signaling; Tumor immunometabolism
    DOI:  https://doi.org/10.1016/j.bcp.2026.118030
  32. Immunometabolism (Cobham). 2026 Apr;8(2): e00079
    Immune checkpoint blockade targets macrophage PD-1 to exacerbate metabolic dysfunction.
    Zikuan Song, Christian Frezza.
      Immune checkpoint inhibitor therapies induce metabolic dysfunction. A study by Wu et al now pinpoints macrophage programmed cell death protein 1 (PD-1) as a key molecular mediator of the anti-PD-1 treatment-triggered exacerbation of systemic metabolic disorders. Macrophage PD-1 blockade disrupts the moonlighting function of PD-1 in suppressing endoplasmic reticulum stress-mediated inflammatory responses, thereby impairing adipose tissue thermogenesis, reducing energy expenditure, and ultimately leading to systemic metabolic dysfunction.
    Keywords:  cancer; immunity; macrophages; metabolism; programmed cell death protein 1
    DOI:  https://doi.org/10.1097/IN9.0000000000000079
  33. Respir Res. 2026 May 04.
    IL-36γ enhanced bactericidal effects of macrophages to Mycobacterium tuberculosis via the IFN-γ/HIF-1ɑ/glycolysis pathway.
    Yuchi Gao, Longbin Cao, Xiuhua Huang, Guikai Duan, Bingying Lin, Junai Zhang, Wenyi Liu, Chen Chen, Junxiang Li, Mi Liu, Xiang Li, Hao Chen, Rong Liu, Juan Tang, Jing Xiao, Yuanbin Lu.
       BACKGROUND: IL-36γ coordinates macrophage activation and is essential for defense against Mycobacterium tuberculosis (Mtb), but the mechanisms remains poorly understood. Aerobic glycolysis plays a critical role in macrophages intrinsic control of Mtb infection. This study aimed to investigate the potential effects of IL-36γ on macrophages energy metabolism transformation from mitochondrial oxidative phosphorylation to aerobic glycolysis in response to Mtb infection.
    METHODS: The expression of IL-36γ in lung tissues, PBMCs and serum was analyzed using Immunohistochemistry, ELISA and RT-qPCR, while the role and mechanism of IL-36γ on macrophages energy metabolism transformation duing Mtb infection were investigated by RT-qPCR, ELISA, Western blot and colony-forming unit assay.
    RESULTS: We demonstrated IL-36γ enhanced the aerobic glycolysis, and downregulated the mitochondrial oxidative phosphorylation in Mtb infected macrophages. Furthermore, IL-36γ upregulated the expression of HIF-1α and IFN-γ in macrophages through the NF-κB/ERK/JNK signaling pathway, especially in macrophages infected with Mtb, where it induced the expression of large amounts of HIF-1α and IFN-γ. Moreover, IL-36γ promoted aerobic glycolysis through inducing the expression of HIF-1α in macrophages during Mtb infection. Meanwhile, HIF-1α was required for IL-36γ-mediated control of Mtb infection. Interestingly, the expression of IL-36γ was increased in lung tissues, PBMCs and serum from patients with active pulmonary tuberculosis and correlated with monocytes/macrophages immune response and IFN-γ levels, displayed an appreciable diagnostic value.
    CONCLUSION: IL-36γ enhanced bactericidal effects of macrophages to Mycobacterium tuberculosis via the IFN-γ/HIF-1α/ glycolysis pathway. IL-36γ may be a potential treatment target and useful biomarker for tuberculosis.
    Keywords:  Aerobic glycolysis; Biomarker; HIF-1α; IFN-γ; IL-36γ; Tuberculosis
    DOI:  https://doi.org/10.1186/s12931-026-03700-8
  34. J Adv Res. 2026 May 04. pii: S2090-1232(26)00378-4. [Epub ahead of print]
    4-Octyl itaconate-induced Nrf2 nuclear translocation mitigates Caspase-11-dependent noncanonical macrophage pyroptosis and acute lung injury.
    Tingyu Wen, Jindian Shi, Minkang Guo, Bei Ma, Chen Zhang, Yisi Zhao, Fang Xu.
       INTRODUCTION: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory conditions, with mortality rates reaching 40%. A key driver of their pathogenesis is macrophage pyroptosis, which results in excessive inflammation and tissue damage.
    OBJECTIVES: The aim of this study was to investigate the regulatory effect and underlying mechanism of the itaconate derivative 4-octyl itaconate (4-OI) on macrophage pyroptosis and sepsis-induced ALI/ARDS.
    METHODS: The study employed a cecal ligation and puncture (CLP)-induced septic mouse model and LPS-stimulated RAW264.7 cells, and bone marrow-derived macrophages. Pyroptosis was assessed using propidium iodide (PI) staining to detect membrane pore formation, as well as quantitative fluorescence analysis and immunohistochemical quantitative analysis of GSDMD-NT. Additional evaluations included the western blot analysis of pyroptosis-related proteins (GSDMD-NT, IL-1β p17). Mechanistic insights were explored using the Nrf2 inhibitor ML385, Acod1⁻/⁻ mice, Casp4⁻/⁻ mice, and Nfe2l2⁻/⁻ mice, along with a parallel experiment of DOTAP-transfected LPS.
    RESULTS: Based on the increase induced by LPS stimulation, 4-OI significantly reduced the proportion of PI-positive cells and also decreased the fluorescence expression of GSDMD-NT, thereby confirming its inhibition of pyroptotic pore formation. It alleviated pulmonary edema, cytokine release, and histological damage in CLP-induced septic mice. Mechanistically, Nrf2 specifically inhibited the transcription of Casp4, thereby reducing Caspase-11-dependent non-canonical macrophage pyroptosis. Casp4⁻/⁻ mice and Casp4 siRNA experiments demonstrated that 4‑OI specifically attenuates Caspase‑11‑dependent noncanonical pyroptosis. Mechanistically, experiments in Nfe2l2⁻/⁻ mice and with ML385 revealed that this effect is mediated by Nrf2‑dependent transcriptional inhibition of Casp4. Furthermore, Acod1 deficiency mice exacerbated Caspase‑11‑driven noncanonical pyroptosis.
    CONCLUSION: The results demonstrate that 4-OI effectively inhibits Caspase-11-mediated pyroptosis and subsequent inflammation in experimental ALI/ARDS. This effect is mechanistically dependent on the activation of the Nrf2-Caspase-11 axis. The study thus identifies a novel therapeutic strategy whereby 4-OI targets pyroptotic pore formation, offering a potential therapeutic intervention for ALI/ARDS.
    Keywords:  4-OI; ALI/ARDS; Caspase-11; Macrophage pyroptosis; Nrf2
    DOI:  https://doi.org/10.1016/j.jare.2026.05.011
  35. J Cell Biol. 2026 Jun 01. pii: e202411133. [Epub ahead of print]225(6):
    Disruption of macrophage cell volume drives inflammatory responses and type I interferon signaling.
    James R Cook, Tara A Gleeson, Sara Gago, Stuart M Allan, Kevin N Couper, Catherine B Lawrence, David Brough, Jack P Green.
      Macrophages coordinate inflammatory and immune responses to threats, yet how they interpret diverse danger signals to tailor inflammation remains unclear. Disturbances in extracellular and intracellular homeostasis alter cell volume, but the consequences for macrophage inflammatory responses are poorly understood. We demonstrate that macrophages use cell volume control as a danger-sensing mechanism to promote and augment inflammation. Using volume-regulated anion channel (VRAC)-deficient macrophages, which lack cell volume control under hypo-osmotic conditions, we show that cell volume disruptions drive transcriptomic reprogramming and induction of inflammation. Cell volume disruption induced type I interferon signaling through a DNA- and TBK1-dependent mechanism, but independent of cGAS and 2'3'-cGAMP transport. VRAC deficiency enhanced macrophage antiviral responses to influenza infection. Cell volume changes synergized with diverse pathogen-associated molecular pattern-mediated signaling to augment type I interferon responses and exacerbate the cytokine storm in mouse models of hyperinflammation. Our findings highlight cell volume as an important regulator in shaping inflammatory responses, expanding our understanding of how macrophages sense complex danger signals.
    DOI:  https://doi.org/10.1083/jcb.202411133
  36. bioRxiv. 2026 Apr 25. pii: 2026.04.23.719926. [Epub ahead of print]
    It's Not Rewarding for Mitochondria: Dopamine-Induced Mitochondrial Dysfunction Activates cGAS-STING to Drive IL-6 Secretion in Macrophages.
    Marzieh Daniali, Breana Channer, Erin O Curley, Amirali Amirfallah, Taylor Kist, John Montilla, Stephanie Kosashvili, Lexi Sheldon, Kelly Stauch, Joshua G Jackson, Anneliese M Faustino, Thomas Beer, Hsin-Yao Tang, Stephanie M Matt, Will Dampier, Howard Fox, Peter J Gaskill.
      Despite increasing data demonstrating dopamine as an inflammatory mediator of the innate immune system, the molecular mechanisms underlying its effects in human cells remain incompletely defined. Here, we define an unrecognized pathway in which dopamine induces robust IL-6 secretion in primary human monocyte-derived macrophages (hMDMs) through mitochondrial stress. Dopamine initiates a transient mitochondrial membrane depolarization that leads to sustained alterations in mitochondrial dynamics, including morphology and metabolism, in a time-dependent manner. These events promote the mtDNA release into the cytoplasm, triggering cGAS-STING pathway and downstream NF-κB signaling. Pharmacological inhibition at multiple nodes of this pathway attenuates IL-6 secretion, establishing mitochondrial dysfunction and cGAS-STING signaling as central mediators of dopamine-driven IL6 secretion. Variability in dopamine receptor expression across donors correlates with the magnitude of IL-6 responses. Together, these findings redefine the interface between dopamine signaling and systemic inflammation and highlight an unrecognized source of inter-individual variation in immune responses.
    DOI:  https://doi.org/10.64898/2026.04.23.719926
  37. bioRxiv. 2026 Apr 21. pii: 2026.04.16.717052. [Epub ahead of print]
    Lipid mobilization establishes metabolic tolerance and prevents autonomic collapse in infection.
    Ankita Sarkar, Shangkui Xie, Syed Muhammad Musa Ali Rizvi, Tadiwanashe Gwatiringa, Sophie Heston, Samuel Piaker, Narges Alipanah-Lechner, Jianyi Yin, Laurent Gautron, Soumya Kamath, Neethu Alex, Ashutosh Shukla, Lin Jia, Rani Shiao, Lauren E Kemp, David G Thomas, Alexander M Tatara, Catherine Chen, Mujeeb Basit, Xiaofei Kong, Vanessa Nomellini, Anoj Ilanges, Samuel Heaselgrave, Joel K Elmquist, Heather W Stout-Delgado, Edward J Schenck, Angela J Rogers, Carolyn S Calfee, Michael A Matthay, Shunxing Rong, Jay D Horton, Kartik N Rajagopalan, Suraj J Patel.
      Survival during infection depends on both pathogen clearance and the ability to tolerate infection-induced physiological changes. Metabolic adaptations are a central component of this tolerance, but the mechanisms underlying these responses remain incompletely defined. Here, we identify white adipose tissue (WAT) lipolysis as a central regulator of metabolic tolerance to infection. In patients with sepsis, higher circulating non-esterified fatty acid (NEFA) levels were associated with reduced mortality. In mouse models of polymicrobial sepsis, infection induced robust adipose lipolysis and increased circulating NEFAs. Genetic ablation of adipose triglyceride lipase (ATGL) in adipose tissue impaired lipolysis, leading to hypothermia, bradycardia, and increased mortality without altering immune cell populations or pathogen burden, consistent with a defect in tolerance rather than resistance. Mechanistically, lipolysis-derived NEFAs, but not glycerol, were required for protection, as restoring circulating NEFAs rescued autonomic stability and survival in adipose tissue ATGL-deficient mice. Infection-induced lipolysis was redundantly regulated and did not depend on any single upstream signaling pathway. Both pharmacologic activation of lipolysis using a β3-adrenergic agonist and exogenous fatty acid supplementation increased circulating NEFAs, improved survival, and promoted tolerance in mice. Consistent with these findings, analysis of real-world electronic health record data demonstrated that septic patients receiving FDA-approved β3-adrenergic agonists had reduced mortality or hospice discharge in a propensity-matched cohort. Together, these results identify WAT lipolysis and circulating fatty acids as key mediators of tolerance to infection and support a therapeutic strategy based on repurposing clinically available β3-adrenergic agonists to improve outcomes in sepsis.
    One Sentence Summary: White adipose tissue lipolysis promotes metabolic tolerance to infection through circulating fatty acids and is associated with improved survival in sepsis.
    DOI:  https://doi.org/10.64898/2026.04.16.717052
  38. Inflamm Res. 2026 May 05. pii: 108. [Epub ahead of print]75(1):
    JAK/STAT inhibition reprograms T cell activation and metabolism in inflammatory arthritis patients.
    Viviana Marzaioli, Aenea A I Brugman, Niamh O'Dowd, Achilleas Floudas, Aine Gorman, Carl Orr, Douglas J Veale, Ursula Fearon.
       OBJECTIVES: Inflammatory arthritis (IA) is a group of autoimmune diseases characterised by joint inflammation and progressive damage, thus impairing the patient's quality of life. The JAK/STAT pathway inhibitor Tofacitinib has been successfully introduced into the clinic to treat patients with IA, however its direct effect on T cell responses is widely unknown. This study aims to assess the effect of Tofacitinib on T cell activation, polyfunctionality, proliferation and metabolism.
    METHODS: The effect of Tofacitinib on T cells from peripheral blood, synovial fluid and synovial tissue was evaluated with multidimensional flow cytometric analysis. T cell proliferation was assessed by flow cytometry and T cell metabolism was examined by qPCR and Seahorse XF analyser. To investigate the effect of Tofacitinib on T cell polarisation, naïve T cells were differentiated into Th1, Th2 and Th17 with specific cytokine cocktails. Soluble mediators were evaluated by MSD multiplex analysis.
    RESULTS: Tofacitinib significantly inhibited T helper cell activation as evidenced by a marked reduction in the frequency of PD-1/CD69/CD25-positive cells (p < 0.01). Reduced activation was consistent with impairment of pathogenic polyfunctionality of peripheral blood and synovial tissue-derived T cells. The impact of Tofacitinib on T cell plasticity was further substantiated by reduced T cell polarisation towards Th1 (p < 0.05), Th2 (p < 0.05), Th17 (p < 0.05) and a reduction in genes associated with T cell functions. The attenuation of pathogenic T cell responses is linked to metabolic adaptation, with Tofacitinib leading to a switch in metabolic capacity, mainly ascribed to the CD4-CD8+ T cell compartment.
    CONCLUSIONS: Tofacitinib strongly alters T cell responses and potentially limits T cell pathogenicity by decreasing their activation, polyfunctionality, differentiation, and metabolic potential in both the circulation and the joints of patients with inflammatory arthritis.
    Keywords:  Inflammatory arthritis; JAK/STAT inhibition; Metabolism; Polyfunctionality; T cells
    DOI:  https://doi.org/10.1007/s00011-026-02242-5
  39. Int J Biol Macromol. 2026 May 01. pii: S0141-8130(26)02250-6. [Epub ahead of print]364 152323
    Butyrate-loaded gelatin methacryloyl microneedle accelerates diabetic wound healing through enhanced lipid metabolism and M2 macrophage polarization.
    Xingtang Niu, Kaiheng Li, Peiqi Wen, Yuanyuan Chen, Jiehua Deng, Jinghui Chen, Lianghai Lai, Chujun Mo, Ling Wu, Shi Tang.
      Diabetic wound healing is significantly impaired by persistent inflammation, metabolic dysregulation, and dysfunctional macrophage polarization. Addressing these intertwined pathologies requires innovative therapeutic strategies. Here, we developed a butyrate-loaded gelatin methacryloyl microneedle patch (Buty@MN) designed to locally reprogram metabolic-immune crosstalk within the diabetic wound microenvironment. The Buty@MN system demonstrated excellent biocompatibility, and exhibited a sustained release. In vitro, Buty@MN significantly enhanced fibroblast migration and promoted a metabolic shift in macrophages toward fatty acid oxidation (FAO), concomitant with a marked increase in anti-inflammatory M2 polarization (evidenced by upregulated IL-10, Arg-1, CD206 and downregulated IL-1β, IL-6, CD86). In vivo, treatment of full-thickness diabetic wounds in mice with Buty@MN accelerated wound closure (95.5 ± 1.8% vs. 72.0 ± 7.4% in controls at day 14, P < 0.01), enhanced re-epithelialization, promoted collagen deposition, and stimulated angiogenesis. These findings establish Buty@MN as a potent therapeutic platform, which offers a promising approach for enhancing diabetic wound repair.
    Keywords:  Butyrate; Diabetic wound; Macrophage; Metabolic reprogramming; Microneedle
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152323
  40. Nat Commun. 2026 May 07.
    Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke.
    Xiao-Wen Zhang, Xiao-Ming Ye, Ran Wang, Yong-Dong Guo, Ling Li, Yang Chen, Ting-Ting Liu, Xiao-Qing Zhou, Yu-Qi Wang, Zhong-Yao Li, Zhi-Yuan Lu, Zhi-Yong Du, Wei Zhou, Bo Han, Peng-Fei Tu, Qi-Xin Chen, Chun-Hong Zheng, Ke-Wu Zeng.
      Mitochondrial cristae ultrastructure enables ATP synthase organization for adaptive energy production. This process is critical for regulating microglia mediated neuroinflammation in ischemic stroke pathology. However, therapeutic strategies targeting cristae remodeling remain unexplored. We identified a chemical probe, icariin II (ICS), which restores mitochondrial cristae by targeting triose phosphate isomerase 1 (TPI1). ICS-induced TPI1 conformational switching recruits ATP5MF to drive F1Fo-ATP synthase dimerization, thereby resulting in cardiolipin-mediated membrane curvature generation for cristae morphogenesis. Functionally, TPI1-targeted intervention reprograms microglial immunometabolism by rescuing oxidative phosphorylation, suppressing mtDNA-STING neuroinflammation, and promoting M2 polarization. In vivo, pharmacologically targeting TPI1 inhibits microglial activation to reverse the pathological processes in a middle cerebral artery occlusion rat model (male only). Further, evidence from stroke patients suggests an association between TPI1 and microglial activation. Collectively, our findings reveal that cristae plasticity is a promising therapeutic target for mitochondrial disorders, with TPI1 as a central regulator for ischemic stroke.
    DOI:  https://doi.org/10.1038/s41467-026-72779-w
  41. Front Pharmacol. 2026 ;17 1797066
    NLRX1 alleviates sepsis-induced acute lung injury by activating mitophagy and suppressing NLRP3 inflammasome activation.
    Zilong Hu, Jing Ding, Meng Huo, Yuqing Lu, Rui Wang, Liyuan Zhang, Dawei Li.
       Background: Sepsis-induced acute lung injury (ALI) is a life-threatening condition with limited therapeutic options. The mitochondrial protein NOD-like receptor X1 (NLRX1) has emerged as a potential immunometabolic modulator, but its functional role and mechanism in septic ALI remain poorly defined.
    Methods: Bioinformatic analysis was performed on the GSE4607 sepsis dataset. A murine model of sepsis-induced ALI was established using cecal ligation and puncture (CLP), with NLRX1 overexpression achieved through adeno-associated virus serotype 9 (AAV9)-mediated gene delivery. Histopathological evaluation, TUNEL staining, and transmission electron microscopy, ELISA were employed to assess lung injury. Mouse lung epithelial cells (MLE-12) were stimulated with lipopolysaccharide (LPS), combined with NLRX1 overexpression and Mdivi-1-mediated mitophagy inhibition to explore the key mechanism by which NLRX1 improves ALI.
    Results: NLRX1 was significantly downregulated in septic patients and mouse lungs, correlating with mitochondrial damage and NOD-like receptor protein 3 (NLRP3) inflammasome activation. NLRX1 overexpression in CLP mice attenuated pulmonary injury, edema, inflammation, and systemic cytokine release by enhancing mitophagy and suppressing apoptosis. Mechanistically, NLRX1 directly interacted with LC3B to promote mitophagy, thereby preserving mitochondrial membrane potential, reducing superoxide production and mtDNA release, and maintaining ATP levels. By improving mitochondrial homeostasis, NLRX1 overexpression indirectly suppressed NLRP3 inflammasome activation and pyroptosis. Crucially, the mitochondrial fission and mitophagy inhibitor Mdivi-1 abolished all beneficial effects of NLRX1, underscoring the essential role of comprehensive mitochondrial quality control.
    Conclusion: Our findings identify NLRX1 as a critical protective regulator of mitochondrial integrity that alleviates septic ALI by orchestrating mitophagy and mitochondrial quality control to restrain NLRP3-driven inflammation, presenting a promising therapeutic target.
    Keywords:  NLRP3; NLRX1; acute lung injury; mitochondrial autophagy; sepsis
    DOI:  https://doi.org/10.3389/fphar.2026.1797066
  42. Sci Transl Med. 2026 May 06. 18(848): eads2673
    Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
    David R Ziehr, Fei Li, K Mark Parnell, Nathan M Krah, Kevin J Leahy, Christelle Guillermier, Ce Gao, Sean A Prell, Niv Vigder, Sergio Poli, Jack Varon, Rebecca M Baron, Bradley A Maron, Nancy J Philp, Lida P Hariri, Edy Y Kim, Kevin S Wei, Matthew L Steinhauser, Rachel S Knipe, Jared Rutter, William M Oldham.
      Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. Although glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how monocarboxylate transporters (MCTs) 1 and 4, key pulmonary lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings revealed that inhibiting MCT1 or MCT4 using RNA interference or small molecules reduced transforming growth factor-β1 (TGFβ)-stimulated myofibroblast differentiation in lung fibroblasts from healthy donors and patients with idiopathic pulmonary fibrosis. Small-molecule MCT inhibitors also decreased bleomycin-induced pulmonary fibrosis in C57Bl6/N mice aged 10 to 12 weeks. Through bioenergetic analyses, stable isotope tracing, metabolomics, and imaging mass spectrometry in both human cells and mice, we demonstrate that inhibiting lactate transport enhanced oxidative phosphorylation, reduced reactive oxygen species production, and diminished glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, an MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors as a therapy for patients with limited treatment options.
    DOI:  https://doi.org/10.1126/scitranslmed.ads2673
  43. PLoS Pathog. 2026 May;22(5): e1014183
    Staphylococcus aureus adapts to the host nutritional environment by coordinating the activity of central metabolic enzymes.
    Reginald A Woods, Iván C Acosta, Zachary J Resko, Charles Agbavor, Luka Svet, Manaar Yousef, Wei Ping Teoh, Victor J Torres, Laty A Cahoon, Francis AlonzoIII.
      The nutritional demands imposed by disparate infection sites represent a significant barrier to bacterial survival. Yet, the proclivity of pathogens such as Staphylococcus aureus to cause disease at nearly all host sites implies significant metabolic flexibility to promote infection. S. aureus catabolizes glucose in several ways, including the phosphotransacetylase (Pta) - acetate kinase (AckA) pathway. The Pta-AckA pathway uses acetyl-CoA derived from the major glycolytic end-product, pyruvate, to rapidly generate ATP, producing acetate as a byproduct. Yet, flux through Pta-AckA necessitates coordinating glycolytic activity with the production of acetyl-CoA and its delivery to Pta-AckA. The generation of acetyl-CoA occurs through the pyruvate dehydrogenase (PDH) complex, an enzyme that requires attachment of the metabolic cofactor, lipoic acid, for its function. Thus, delivery of lipoic acid to enzyme complexes has the potential to serve as a determinant of metabolic adaptation. Here, we provide evidence for a functional link between the lipoic acid transfer enzyme, LipL, and Pta. We demonstrate pta and lipL are transcriptionally coupled and that Pta and LipL directly interact, with potential to direct metabolic flux through Pta-AckA. Both Δpta and ΔlipL mutants are defective for acetate production with evidence for alternative fates for pyruvate that depend on blockade upstream or downstream of the pyruvate node. The functional pairing of Pta and LipL is required for optimal skin infection, whereas Pta and LipL have separable functions in bloodstream infection. Furthermore, we found that a complete block to acetate production leads to significant attenuation in vivo, cementing a direct role for acetogenesis in infection. Together, our results establish a mechanism by which S. aureus regulates metabolite flux by coupling enzymes in linked metabolic pathways to promote energy balance and survival during infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1014183
  44. Sci Rep. 2026 May 06.
    Lactate reprograms PGE2 metabolism via GPR81 inhibits COX2 to relieved psoriasis.
    Yajun An, Bin Wang, Jing He, Xunru Qu, Yishen Tian, Guangshi Du, Zuli Wang, Rong Hu, Min Su, Youbo Zhao.
      Psoriasis is an autoimmune skin disease whose precise pathogenesis remains incompletely understood. This study uncovered a critical role of lactate-induced metabolic reprogramming via GPR81 in the development of imiquimod-induced murine psoriasis. The activation of the lactate receptor GPR81 was found to be essential for reducing prostaglandin E2 (PGE2), a known lipid marker associated inflammation. GPR81 knockout (GPR81⁻/⁻) mice exhibited elevated PGE2 levels in epidermis, further supporting PGE2 as a metabolic indicator of psoriasis and suggesting its role in disease exacerbation. Similarly, treatment with reserpine, a newly identified GPR81 inhibitor, led to increased PGE2 levels compared to the control group. Mechanistically, inhibition of GPR81 upregulated cyclooxygenase-2 (COX-2), a rate-limiting enzyme in PGE2 synthesis. Moreover, GPR81⁻/⁻ mice displayed enhanced immune cell activation and proliferation relative to wild-type (WT) mice, including a marked increase in M1-polarized macrophages, elevated CD8⁺ and CD4⁺ T cell populations, and heightened secretion of pro-inflammatory cytokines such as IL-17, IL-23, and TNF-α. These alterations were associated with aggravated dermatological manifestations, including pronounced scaling, epidermal hyperplasia, and inflammatory cell infiltration accompanied by elevated cytokine production. Conversely, administration of the GPR81 agonist 3,5-Dihydroxybenzoic Acid (3,5-DHBA) significantly suppressed COX-2 expression and PGE2 levels by inhibiting PKA activation, thereby alleviating psoriatic symptoms. Collectively, these findings reveal a novel mechanism whereby GPR81 reprograms PGE2 synthesis through PKA-mediated downregulation of COX-2, highlighting GPR81 as a promising therapeutic target. The use of 3,5-DHBA demonstrates significant therapeutic potential for the treatment of autoimmune disease.
    Keywords:  GPR81; Lactate; Lipid metabolism; Metabolism reprogramming; Psoriasis
    DOI:  https://doi.org/10.1038/s41598-026-50834-2
  45. Cancer Discov. 2026 May 05. OF1
    Proteasome-Heme Axis Links Mitochondrial Stress to T-Cell Exhaustion.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-043
  46. Trends Pharmacol Sci. 2026 May 07. pii: S0165-6147(26)00087-8. [Epub ahead of print]
    PKCθ: from T cell kinase to immunometabolic integrator.
    Yongqi Li, Weiguang Sun, Yonghui Zhang.
      Protein kinase C theta (PKCθ) has long been viewed as a core T cell signaling molecule. Recent work, however, reveals functions far beyond this classic role. In this review, we integrate recent evidence to redefine PKCθ as a pan-immune and immunometabolic integrator that controls not only T cell activation but also macrophage phagocytosis, natural killer cell (NK) function, and systemic metabolism. We analyze its paradoxical roles in cancer-where it drives some tumors but is lost in others-and summarize the evolution of therapeutic strategies beyond ATP-competitive inhibition, including allosteric modulation, proteolysis-targeting chimera degradation, and disruption of protein-protein interactions (PPIs). This aims to move the PKCθ field from fragmented descriptions toward mechanistic understanding and precision intervention.
    Keywords:  T cell; immunometabolism; precision immunomodulation; protein kinase C theta; tumor biology
    DOI:  https://doi.org/10.1016/j.tips.2026.04.003
  47. Pathogens. 2026 Mar 31. pii: 372. [Epub ahead of print]15(4):
    Orientia tsutsugamushi Alters Mitochondrial Function and Selectively Associates with VDAC.
    Savannah E Sanchez, Travis J Chiarelli, John S Billingsley, Richard T Marconi, Jason A Carlyon.
      Orientia tsutsugamushi is an obligate intracellular alphaproteobacterium and the causative agent of the potentially fatal rickettsiosis, scrub typhus. During infection, O. tsutsugamushi replicates exclusively in the eukaryotic cytosol near mitochondria and alters host metabolic pathways governed by mitochondria. We report that O. tsutsugamushi induces mitochondrial enzymatic impairment and structural abnormalities without altering mitochondrial abundance or the levels of proteins that maintain mitochondrial homeostasis. Confocal and structured illumination microscopy revealed a selective spatial association between O. tsutsugamushi and the mitochondrial membrane protein, voltage-dependent anion channel (VDAC) but not other mitochondrial proteins. Immunosignal for VDAC paralogs 1 and 3 colocalized with cytosolic O. tsutsugamushi organisms whereas VDAC2 did not. Additionally, the antibody specific for VDAC1 and VDAC3 detected proteins of the expected sizes in Orientia membrane fractions. These findings indicate that O. tsutsugamushi negatively impacts mitochondrial function without overt organelle loss and selectively associates with VDAC1/VDAC3.
    Keywords:  Orientia tsutsugamushi; host–pathogen interactions; mitochondrial dysfunction; obligate intracellular bacterium; scrub typhus; voltage-dependent anion channel (VDAC)
    DOI:  https://doi.org/10.3390/pathogens15040372
  48. Res Sq. 2026 Apr 24. pii: rs.3.rs-9504540. [Epub ahead of print]
    A sodium-HIF1α axis coordinates immune metabolic reprogramming and mitochondrial remodeling in salt-sensitive hypertension.
    Ronald McMillan, Selam Desta, Jeremiah Afolabi, Ariel Thorson, Olivia Pierre-Louis, Ashley Mutchler, Joyanna Gamble-George, Prasanna Katti, Suraj Thapliyal, Mohammad Saleem, Mert Demirci, Lale A Ertuglu, Sergey Dikalov, Alexandria Porcia Haynes, Andrea Marshall, Mohd Khan, Jenny Schafer, Oleg Kovtun, Justin Van Beusecum, Max Kushner, Sharia Yasmin, Cheryl L Laffer, Thomas R Kleyman, Celestine Wanjalla, Jeanne A Ishimwe, Sydney Jamison, Quanhu Sheng, Antentor Hinton, Annet Kirabo.
      Salt-sensitivity of blood pressure (SSBP) is associated with immune-metabolic dysfunction, yet the mechanism that coordinates sodium exposure, mitochondrial remodeling, and blood pressure response remains undefined. Phenome-wide and laboratory-value association studies (PheWAS and LabWAS) in the All of Us Research Program identified fluid, electrolyte, and acid-base balance disorders and renal phenotypes as the strongest disease associations. At the same time, hypertension was linked to reduced serum potassium, chloride, and eGFR, corroborating the centrality of renal-electrolyte physiology in blood pressure regulation. Using a within-subject sodium challenge in humans, we show that sodium loading reorganizes circulating tricarboxylic acid (TCA) cycle intermediates in proportion to the individual blood pressure response. Transcriptomic profiling of immune cells under high sodium revealed suppression of oxidative phosphorylation, induction of HIF1α-dependent glycolytic gene networks, and rebalancing of the pyruvate dehydrogenase complex. Single-cell chromatin accessibility profiling demonstrated that HIF1α motif activity in circulating immune cells correlates with changes in systolic blood pressure and pulse pressure in salt-sensitive individuals. High sodium induced mitochondrial fragmentation with increased organelle mass and glycolytic capacity. Pharmacological HIF1α inhibition reversed fragmentation while only partially normalizing metabolic output, indicating structural and metabolic remodeling are partially dissociable downstream of HIF1α. Renal HIF1α gain-of-function in mice recapitulated the glycolytic transcriptional response with medullary specificity. Concordantly, Drosophila melanogaster subjected to a high-salt diet exhibited impaired locomotor performance, mitochondrial dysmorphology, intestinal barrier disruption, and cardiac remodeling, establishing evolutionary conservation of sodium-induced end-organ dysfunction independent of an adaptive immune system. Together, these findings identify a HIF1α-dependent axis of mitochondrial metabolic adaptation providing a mechanistic basis for SSBP.
    DOI:  https://doi.org/10.21203/rs.3.rs-9504540/v1
  49. Pathogens. 2026 Apr 16. pii: 431. [Epub ahead of print]15(4):
    HBV-Induced Pyruvate Increases Lactylation of Pyruvate Kinase M2 (PKM2) at K206 to Promote Liver Fibrosis.
    Wenxian Wen, Qin Du, Shuhan Li, Youmin Yang, Xianding Wang, Shasha Li, Yujia Li, Shilin Li, Chunhui Yang, He Xie, Xiaoqiong Duan, Limin Chen.
      We previously demonstrated that HBV promotes liver fibrosis through the enhanced production of pyruvate. Pyruvate kinase M2 (PKM2), a key enzyme in pyruvate metabolism, plays an important role in liver fibrogenesis. Recently, lactylation of PKM2 has been identified, which contributes to stabilize its catalytically active tetrameric conformation. Therefore, we hypothesize that PKM2 lactylation is involved in the regulation of HBV-induced liver fibrosis. In this study, we found that sera lactate levels were increased in CHB patients and HBV-Tg mice. Moreover, the lysine lactylation levels of proteins in liver tissues were significantly increased in the HBV-Tg mice. In LX2 cells, we found that pyruvate treatment significantly increased the profibrotic gene expression and lactylation level of PKM2, which promoted its tetramer-to-dimer transition, inhibited its pyruvate kinase activity, and facilitated its nuclear distribution. Through immunoprecipitation, we identified that pyruvate induced PKM2 lactylation at the K206 site. PKM2 knockdown or K206 mutation reduced PKM2 lactylation and abrogated the induction of profibrotic gene expression by pyruvate. Collectively, our findings indicate that HBV infection stimulated pyruvate production, which increased PKM2 lactylation at K206 to promote the expression of profibrogenic genes in HSCs, leading to liver fibrogenesis.
    Keywords:  PKM2; hepatitis B virus; lactylation; liver fibrosis; pyruvate
    DOI:  https://doi.org/10.3390/pathogens15040431
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