bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–09–13
forty-one papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Macrophages tune NK cell IFNγ production through direct lipid transfer.
  2. Immunometabolism drives metabolic and infectious disease progression through bidirectional metabolic reprogramming and epigenetic remodeling.
  3. Mitochondrial immunometabolism in sepsis: bridging immune cell dysfunction and organ failure.
  4. Metabolomics of in vivo inflammation identifies soluble sialic acid as a conserved myeloid-cell metabolite.
  5. NAD+ Metabolic Reprogramming Drives CD8+ T Cells Senescence and Exacerbates Ulcerative Colitis.
  6. Siglec-7 orchestrates mitochondrial dynamics and metabolic reprogramming to restrain human NK cell cytotoxic function.
  7. D-mannose blocks S-adenosylmethionine generation to suppress macrophage IL-1β expression.
  8. Itaconate alleviates LPS-induced septic liver injury by regulating ROS-PAD4-mediated macrophages extracellular traps through Nrf2.
  9. T cell-derived CCL5 drives macrophage immunometabolic remodeling in chronic prostatitis via the CCR5-ERK-PKM2/HIF-1α axis.
  10. A Lactate-H4K12la-HDAC1 epigenetic axis governs microglial state transitions during experimental autoimmune encephalomyelitis in female mice.
  11. The role of B cell glycolysis in autoimmune diseases.
  12. Metabolite-driven protein modifications in immune signaling: from established principles to emerging pyruvylation.
  13. Vascular Immunometabolism in Atherosclerosis: Emerging Roles of Glycometabolic Reprogramming in Immune and Vascular Cells.
  14. WSSV exploits host glycolytic reprogramming to promote hemocyanin lactylation and enhance cell-associated WSSV levels in shrimp.
  15. Resveratrol Inhibits Macrophage Glucose Metabolism Reprogramming and Inflammatory Activation to Delay COPD Progression Through the TLR4/HK2 Pathway.
  16. Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
  17. Mitochondrial dysfunction and glycolytic shift define the metabolic profile of hydatid fluid-stimulated dendritic cells.
  18. CAFs-mediated histone lactylation reprograms cholesterol metabolism in colorectal cancer to drive CD8+ T cell immunosuppression.
  19. When the Pathogen Shapes the Host: Metabolic Divergence in COVID-19 and Community-Acquired Pneumonia.
  20. H4K5 lactylation exacerbates acute myocarditis by driving a positive feedback loop between inflammation and metabolic dysfunction.
  21. Short-chain fatty acids act as metabolic and epigenetic regulators in CAR T cell therapy.
  22. Immunometabolic Reprogramming as a Therapeutic Platform: Integrating Systems Immunology with Precision Biopharmaceutical Engineering.
  23. Metabolic reprogramming rewires aberrant immune responses to drive endothelial dysfunction in Kawasaki disease: a narrative review.
  24. Type 3 Inflammation-Specific Keratinocyte Glutaminolysis Promotes Skin Inflammation.
  25. Dual metabolic checkpoint blockade via a 3D-Printed metalloplatform remodels the tumor ecosystem for systemic antitumor immunity.
  26. Regulation of macrophage polarization in chronic airway inflammatory diseases: immune interactions, metabolic reprogramming, and beyond.
  27. HDCA suppresses exosomal lncRNA MSTRG171708 release to inhibit Treg-mediated immunometabolism in hepatocellular carcinoma.
  28. Deficiency of protein kinase Cδ reprograms macrophage immunometabolism to suppress pyroptosis and stabilize atherosclerotic plaques.
  29. HIF-1α-associated macrophage metabolic reprogramming mediates intestinal injury induced by acrylamide and 5-hydroxymethylfurfural co-exposure.
  30. SIRT7-Mediated H2BK120 Succinylation Drives Aberrant Mitophagy in Sepsis-Associated Cognitive Dysfunction.
  31. Glutamine-dependent biosynthetic pathways fuel autoreactive T and B cells in Foxp3 deficiency-mediated disease.
  32. Activation of lipid synthesis following glycolysis is required for CD8+ T cells to acquire antitumor immune activity.
  33. Depleting luminal cysteine with engineered bacteroides vulgatus alleviates experimental colitis by suppressing Th17 differentiation through an ATF6-dependent mechanism.
  34. Upadacitinib Restrains the Pathogenic Fitness of CD4+ T Cells and Aberrant B Cell Programming in Optic Neuritis.
  35. Itaconate.
  36. Metabolic and epigenetic plasticity of tumor-associated macrophages shapes immunosuppressive outputs and immune checkpoint response.
  37. Disulfidptosis as an immunometabolic rheostat in gastrointestinal cancers: tuning the balance between T Cell exhaustion and immunogenic cell death.
  38. HNRNPK Lactylation Amplifies Inflammation and Exacerbates Myocardial Ischemia/Reperfusion Injury by Regulating Jag2 Splicing.
  39. Commensal bacteria inhibit viral infections via a tryptophan metabolite.
  40. Covalently Self-Polymerized Bioactive Poly(dopamine-silicon) Nanoplatform Reprograms Macrophage Metabolism, Modulates Redox Homeostasis, and Promotes Efficient Angiogenesis for Inflammation Injury Repair.
  41. Metabolic-epigenetic reprogramming of airway fibroblasts by K + N therapy suppresses IL-33 and ameliorates allergic asthma.
  1. Nat Commun. 2026 Aug 08. pii: 9527. [Epub ahead of print]17(1):
    Macrophages tune NK cell IFNγ production through direct lipid transfer.
    Cathal Keane, Shauna Mayock, Carrie Corkish, Ella Rogerson, Cristhiane Favero de Aguiar, Ya Gao, Sarah Kenny, Lorraine Brennan, Suzanne M Cloonan, David K Finlay.
      Natural killer (NK) cells are critical effectors of innate immunity, but their activity is strongly influenced by metabolic state. While intrinsic NK metabolism has been studied extensively, less is known about how surrounding immune cells shape NK cell function. Here, we identify a direct metabolic communication axis between macrophages and NK cells. Using co-culture and in vivo models, we show that lipopolysaccharide-stimulated macrophages induce lipid accumulation in NK cells that suppresses mTORC1 activity and the production of IFNγ. This lipid accumulation is visualised as increased lipid droplets content in NK cells, generated using fatty acids synthesised within the macrophages. Genetic and pharmacological approaches show that fatty acid transfer from macrophages to NK cells requires cell-cell contact and is associated with CD36 protein transfer via trogocytosis. Blocking fatty acid synthesis specifically in macrophages prevents lipid accumulation in NK cells and restores both mTORC1 activity and IFNγ production. These findings define a previously unrecognized mechanism of macrophage-NK cell cross-regulation, revealing how metabolic exchange constrains NK effector function and establishing a feedback circuit with implications for hyperinflammation and immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-76444-0
  2. Front Immunol. 2026 ;17 1914506
    Immunometabolism drives metabolic and infectious disease progression through bidirectional metabolic reprogramming and epigenetic remodeling.
    Wenbin Tan.
      Immunometabolism has become a central mechanism governing innate and adaptive immune responses. The field has moved from cataloguing metabolic shifts during immune activation to understanding how specific pathways control immune cell fate and function. This review brings together current knowledge on immunometabolic regulation in metabolic and infectious diseases, emphasizing bidirectional crosstalk between these domains. We address controversies over whether inflammation causes insulin resistance or follows from it, examine the distinct metabolic programs of different immune cell types, and explore trained immunity as a link between innate immune memory and metabolic disease. The review also covers pathogen-specific metabolic strategies and host countermeasures, surveys emerging immunometabolic therapies, and flags unresolved questions for future work. Among promising strategies, mechanistic target of rapamycin (mTOR) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have advanced to clinical trials for immunometabolic indications, whereas epigenetic reprogramming and nanoparticle-based metabolic delivery remain in preclinical development.
    Keywords:  epigenetic remodeling; immunometabolism; infection; inflammation; innate immune memory; metabolic diseases; metabolic reprogramming; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1914506
  3. Front Immunol. 2026 ;17 1921226
    Mitochondrial immunometabolism in sepsis: bridging immune cell dysfunction and organ failure.
    Xingzhan Zhang, Ling Zhao, Wei Fu, Lili Pan, Huanhuan Wu, Jie Peng.
      Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of mortality in critical care, and sepsis-associated multiple organ failure continues to defy effective therapy. Increasing evidence positions mitochondria at the interface of cellular bioenergetics and innate immune signaling, making mitochondrial immunometabolism a compelling framework for understanding sepsis pathophysiology. In this mini-review, we synthesize how mitochondrial bioenergetic dysfunction shapes immune cell function across the dynamic course of sepsis, from the glycolytic, oxidative phosphorylation (OXPHOS)-uncoupled state of the hyperinflammatory phase to the bioenergetic failure of the immunoparalytic phase. We examine the contested roles of mitochondrial quality-control mechanisms: mitophagy, dynamics, and biogenesis, in immune cell remodeling, and propose that their net effect follows a time- and cell-type-dependent pattern rather than a fixed protective or deleterious role. We further discuss how mitochondrial damage-associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA), reactive oxygen species (mtROS), and remodeled cardiolipin activate the cGAS-STING pathway and the NLRP3 inflammasome and cross-regulate one another to amplify inflammation and drive organ injury. Integrating these themes, we highlight mitochondrial immunometabolic crosstalk between key immune cell subsets (macrophages, neutrophils, and lymphocytes) and the parenchymal cells of vulnerable target organs (heart, kidney, lung, and the gut-liver axis). Finally, we identify knowledge gaps spanning temporal dynamics, cellular heterogeneity, and clinical translation, acknowledge the limitations of the current evidence, and outline emerging therapeutic and monitoring strategies. Collectively, mitochondrial immunometabolism links immune cell dysfunction to organ failure and may guide stage- and endotype-specific interventions in sepsis.
    Keywords:  NLRP3 inflammasome; immune cell dysfunction; immunometabolism; metabolic reprogramming; mitochondria; mitochondrial DNA; multiple organ failure; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1921226
  4. J Biol Chem. 2026 Sep 07. pii: S0021-9258(26)02391-4. [Epub ahead of print] 113519
    Metabolomics of in vivo inflammation identifies soluble sialic acid as a conserved myeloid-cell metabolite.
    Helen A Jordan, Joseph A Tandurella, Vineeth Vengayil, Tanay S Parnaik, Swechha Mainali Pokharel, Kathleen Mulka, Sara Cherry, E John Wherry, Caroline R Bartman.
      During an immune response, metabolism changes dramatically. Metabolites are oxidized to power immune cell functions, serve as building blocks for proliferation, and act as effectors to regulate pathogen or host cells. Though metabolic changes in cultured cells have been studied extensively, metabolism changes in vivo are less understood. Here, we measured metabolomic changes across six mouse tissues in three models of immune activation: CpG-DNA cytokine storm, lymphocytic choriomeningitis virus infection, and polyI:C viral mimetic injection; and carried out metabolomics in cultured macrophages activated with different stimuli. We found most metabolomic changes were exclusive to either inflamed tissues or cultured macrophages, although itaconate was strongly induced in both contexts. We then mechanistically dissected the role of the soluble sialic acid N-glycolylneuraminic acid, which is highly induced in inflamed tissues yet only modestly in cultured macrophages. This metabolite increases in tissues in different models of inflammation, and the analogous human metabolite, N-acetylneuraminic acid, rises in human patients experiencing inflammation. We found that N-glycolylneuraminic acid is produced in CD11b+ myeloid cells by cleavage of protein-bound sialic acid. However, blocking its production did not affect CpG-DNA liver inflammation or LCMV infection in mice. Therefore, these experiments identify soluble sialic acid as a conserved biomarker of inflammation in mice and humans and highlight the differences in metabolism between in vitro and in vivo models of inflammation.
    Keywords:  inflammation; isotopic tracer; macrophage; metabolism; metabolomics; sialic acid
    DOI:  https://doi.org/10.1016/j.jbc.2026.113519
  5. Aging Cell. 2026 Sep;25(9): e70706
    NAD+ Metabolic Reprogramming Drives CD8+ T Cells Senescence and Exacerbates Ulcerative Colitis.
    Maolin Ye, Qi Zhou, Mingjia Kong, Suhan Zhao, Lingxi Lin, Lirong Chen, Jianghong Yu, Feifei Luo, Jie Liu, Jun Zhang.
      While immunosenescence is increasingly implicated in chronic inflammatory disorders, its precise pathogenic contribution to ulcerative colitis (UC) remains elusive. Here, we identify senescent CD8+ T cells as a distinct pathogenic population that exacerbates colitis, demonstrating that systemic senolytic treatment significantly attenuates disease severity. Mechanistically, nicotinamide adenine dinucleotide (NAD+) metabolic dysregulation triggers mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, promoting CD8+ T cell senescence through the activation of the cGAS-STING signaling pathway. Spatial transcriptomic mapping reveals that senescent CD8+ T cells are enriched within mucosal niches experiencing NAD+ metabolic dysregulation. Crucially, this senescent-metabolic signature correlates with severe disease phenotypes and predicts non-response to biologic therapies in UC patients. Collectively, our findings uncover a critical NAD+-cGAS-STING axis driving T cell senescence, establishing the clearance of senescent immune cells as a promising therapeutic strategy for UC.
    Keywords:  NAD+; immunosenescence; inflammatory bowel disease; senolytic therapy
    DOI:  https://doi.org/10.1111/acel.70706
  6. J Biol Chem. 2026 Sep 08. pii: S0021-9258(26)02415-4. [Epub ahead of print] 113543
    Siglec-7 orchestrates mitochondrial dynamics and metabolic reprogramming to restrain human NK cell cytotoxic function.
    Shih-Chi Su, Nai-Ting Tsao, Tzu-Ling Wang, Yi-Chen Shih, Yuh-Ching Twu.
      Natural killer (NK) cells are innate lymphocytes that directly eliminate tumor and virus-infected cells by integrating signals from activating and inhibitory receptors, and their effector functions are tightly coupled to cellular metabolism. Given that the inhibitory receptor PD-1 reprograms T cell metabolism to shape functional fate, the bioenergetic consequences of inhibitory receptor engagement on human NK cells remain largely unexplored, particularly for sialic acid-binding immunoglobulin-like lectin (Siglec-7), a glyco-immune checkpoint receptor. Here, we investigated metabolic programs and effector functions associated with Siglec-7 expression and antibody-mediated Siglec-7 ligation in primary NK cells and NK-92MI cells. Siglec-7POS NK cells exhibited selectively impaired CD107a degranulation under glycolytic and oxidative phosphorylation inhibition, whereas Siglec-7NEG cells remained relatively resistant, indicating distinct energetic wiring between these subsets. Engagement of Siglec-7 by an agonistic antibody induced mitochondrial fission with altered Drp1 phosphorylation, transient mitochondrial depolarization, and broadly suppressed mitochondrial respiration, while concurrently enhancing glycolytic capacity, consistent with a dual metabolic shift upon Siglec-7 ligation. In contrast, sustained Siglec-7 expression in NK-92MI-S cells was associated with globally enhanced mitochondrial respiratory capacity, indicating that sustained Siglec-7 expression and short-term treatment with an agonistic anti-Siglec-7 antibody were associated with distinct metabolic profiles in NK cells. Furthermore, Siglec-7POS NK cells showed increased accumulation of autophagic vacuole, reduced proliferation, and heightened apoptotic susceptibility compared with Siglec-7NEG counterparts. Collectively, these findings support an association between Siglec-7 status, mitochondrial homeostasis, and metabolic fitness in NK cells, with Siglec-7NEG cells retaining a metabolically robust, cytotoxic phenotype.
    DOI:  https://doi.org/10.1016/j.jbc.2026.113543
  7. Front Immunol. 2026 ;17 1895029
    D-mannose blocks S-adenosylmethionine generation to suppress macrophage IL-1β expression.
    Yingyi Chen, Junji Xu, Jingfei Fu, Juan Du, Ziqing Feng, Minfeng Wang, Yi Liu, Yitong Liu.
       Background and aims: Inflammatory stimuli drive metabolic reprogramming in macrophages, supplying energy, reducing equivalents, and methyl donors required for the production of inflammatory mediators such as IL-1β; however, metabolic strategies to regulate this pathway remain unclear. Here, we aimed to define the mechanism by which D-mannose suppresses one-carbon metabolism in inflammatory macrophages and thereby epigenetically restrains inflammatory responses.
    Methods: Untargeted metabolomics was used to define the global metabolic effects of D-mannose in inflammatory macrophages. 6-phosphogluconate dehydrogenase activity and real-time ATP rate assays were performed to assess nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine triphosphate (ATP) generation. S-adenosylmethionine (SAM) and cytokine levels were measured by enzyme-linked immunosorbent assay, and epigenetic regulation at the Il1b promoter was examined by chromatin immunoprecipitation-qPCR and immunoblotting. A murine full-thickness skin wound model with macrophage depletion was used for in vivo validation.
    Results: D-mannose suppressed metabolic flux through glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway, resulting in reduced ATP and NADPH production. This metabolic restriction impaired one-carbon metabolism, decreased SAM abundance, and reduced histone H3 lysine 36 trimethylation enrichment at the Il1b promoter, thereby repressing Il1b transcription. These effects were reversed by exogenous SAM supplementation. Macrophages exhibited a metabolic bottleneck associated with low mannose phosphate isomerase (Mpi) expression. Consistently, Mpi overexpression reversed the D-mannose-induced reductions in ATP and SAM levels, as well as Il1b expression. Topical D-mannose also lowered SAM and IL-1β levels in wound tissues and accelerated wound healing in vivo.
    Conclusions: D-mannose suppresses macrophage pro-inflammatory transcription through a one-carbon metabolism-epigenetic axis, supporting its potential as a metabolism-targeted strategy for inflammatory wound repair.
    Keywords:  D-mannose; Histone Methylation; Macrophages; One-carbon metabolism; SAM
    DOI:  https://doi.org/10.3389/fimmu.2026.1895029
  8. Inflamm Res. 2026 Sep 05. pii: 204. [Epub ahead of print]75(1):
    Itaconate alleviates LPS-induced septic liver injury by regulating ROS-PAD4-mediated macrophages extracellular traps through Nrf2.
    Liwu Zeng, Yaxin Wang, Gan Mao, Yisong Gao, Kaixiong Tao, Ruidong Li.
      Activated macrophages release macrophage extracellular traps (METs), which are a major cause of tissue damage in sepsis. However, the molecular mechanisms governing their production remain poorly characterized. In this study, we demonstrate that MET levels are markedly elevated in both the liver and circulation in a lipopolysaccharide (LPS)-induced sepsis model. The immunometabolite itaconate-a product of the enzyme aconitate decarboxylase 1 (Acod1)-emerged as a critical suppressor of this pathway. Genetic ablation of immune responsive gene 1 (Irg1) resulted in heightened MET release, exacerbated hepatic injury, and decreased survival in septic mice. In contrast, the itaconate derivative 4-octyl itaconate (4-OI) robustly suppressed MET formation and ameliorated liver damage. Mechanistically, 4-OI activated the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in scavenging of intracellular reactive oxygen species (ROS), which suppressed ROS-dependent activation of peptidylarginine deiminase 4 (PAD4), thereby inhibiting histone citrullination and subsequent MET release. The suppression of MET formation by 4-OI is mediated through an Nrf2-dependent mechanism, as its absence abolishes this suppression, revealing the Nrf2-ROS-PAD4 axis's key role. The findings reveal a new metabolic-immune pathway: itaconate reduces sepsis-linked liver injury by using Nrf2 to suppress METs, suggesting a novel clinical treatment approach.
    Keywords:  Itaconate; MET; Nrf2; Sepsis
    DOI:  https://doi.org/10.1007/s00011-026-02359-7
  9. Redox Biol. 2026 Sep 03. pii: S2213-2317(26)00365-4. [Epub ahead of print]97 104366
    T cell-derived CCL5 drives macrophage immunometabolic remodeling in chronic prostatitis via the CCR5-ERK-PKM2/HIF-1α axis.
    Xianhong Liu, Boyang Li, Xianchao Dou, Wenyue Ju, Weihao Liu, Fei Zhang, Chen Jin, Yifeng Lu, Ronghao Wang, Xianguo Chen, Chaozhao Liang, Meng Zhang.
      Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) affects millions of men, yet the immune circuits that sustain sterile prostatic inflammation and pain remain poorly defined. Here we identify a T cell-macrophage metabolic signaling axis that drives chronic prostatitis. Integrated analysis of mouse experimental autoimmune prostatitis, chronically inflamed human prostate tissue, single-cell transcriptomes and spatial profiles revealed a population of glycolytic, HIF-1α-activated inflammatory macrophages enriched in diseased prostate niches. T cell-derived CCL5 was markedly induced and spatially positioned adjacent to CCR5+ macrophages, where it licensed M1-like polarization, glycolytic remodeling and inflammatory transcription. Using T cell-specific Ccl5 knockout mice, we established CCL5 as a genetic driver of macrophage inflammation, prostate tissue injury and pelvic pain hypersensitivity, and these pathogenic features were further suppressed by CCL5 neutralization or pharmacological CCR5 blockade. Mechanistically, rmCCL5 stimulation promoted CCR5-sensitive ERK1/2 activation, PKM2 Ser37 phosphorylation and nuclear accumulation, enhanced the PKM2-HIF-1α interaction, and increased HIF-1α occupancy at the Il1b and Nos2 promoters. Targeting ERK1/2, PKM2 remodeling or HIF-1α collapsed this program and protected against prostatitis pathology. Together, these findings show how T cell-derived chemokine signals are translated into macrophage metabolic reprogramming and persistent inflammatory activation, nominating the CCL5-CCR5-ERK-PKM2/HIF-1α pathway as a genetically validated and pharmacologically tractable therapeutic axis in CP/CPPS.
    Keywords:  CCR5; Chronic prostatitis/chronic pelvic pain syndrome; Macrophage immunometabolism; PKM2/HIF-1α; Single-cell and spatial transcriptomics; T cell-derived CCL5
    DOI:  https://doi.org/10.1016/j.redox.2026.104366
  10. Nat Commun. 2026 Aug 04. pii: 9593. [Epub ahead of print]17(1):
    A Lactate-H4K12la-HDAC1 epigenetic axis governs microglial state transitions during experimental autoimmune encephalomyelitis in female mice.
    Jiahong Li, Su Meng, Jiajian Li, Quanfeng Wei, Xin Hua, Jinzhou Feng, WenYu Hu, Hongxing Wang, Yinan Zhao.
      Microglial functional plasticity is shaped by metabolic and epigenetic reprogramming, but how these processes regulate central nervous system autoimmunity remains unclear. We find that cerebrospinal fluid lactate levels correlate with multiple sclerosis severity. Using female mouse models of experimental autoimmune encephalomyelitis, spinal lactate accumulation drives persistent microglial histone lactylation, coupling to glycolytic activation. Microglia-specific deletion of lactate dehydrogenase A reduces this lactylation and exacerbates disease severity. Exogenous lactate ameliorates pathology without altering peripheral immune infiltration by suppressing inflammatory states and promoting reparative programs. Epigenomic profiling demonstrates direct lactylation enrichment at promoters of neurotrophic genes, linking metabolic flux to transcriptional activation. Histone deacetylase 1 acts as an epigenetic brake by erasing this modification; its inhibition restores neurotrophic signaling and mitigates pathology. In this work, we show that a lactate-driven epigenetic axis governs microglial state transitions, highlighting a tractable therapeutic target for metabolic intervention in neuroinflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-026-76302-z
  11. Transl Res. 2026 Sep 11. pii: S1931-5244(26)00190-8. [Epub ahead of print]
    The role of B cell glycolysis in autoimmune diseases.
    Mengyao Shu, Yiman Peng, Zhiguang Zhou, Jingyue Li.
      Autoimmune diseases are a category of chronic disorders in which the body's immune system fails to distinguish between self-antigens and foreign substances, leading to attacks on its own tissues and subsequent damage. B cells play critical roles in humoral immunity, including antibody production, antigen presentation, and immune regulation. When B cell function is impaired, these cells can contribute to autoimmune diseases by producing autoantibodies and pro-inflammatory cytokines, causing an imbalance in immune regulation. Recent advances in immunometabolism research have revealed that B cell metabolism plays a significant role in immune responses by providing energy and substrates for B cell activation, differentiation, and function. However, dysregulated B cell metabolism disrupts self-tolerance mechanisms, which can trigger autoimmune diseases. This article systematically reviews the manifestations and pathogenic mechanisms of glycolysis dysregulation in B cells in both patients with autoimmune diseases and animal models, and explores the therapeutic potential of targeting glycolysis in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D). A deeper understanding of the metabolic regulatory mechanisms of B cells will provide an important theoretical foundation for developing novel therapies for autoimmune diseases.
    Keywords:  Autoimmune diseases; B cell; B cell glycolysis; B cell metabolism; Systemic lupus erythematosus; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.trsl.2026.09.005
  12. Front Immunol. 2026 ;17 1912474
    Metabolite-driven protein modifications in immune signaling: from established principles to emerging pyruvylation.
    Ziye Zhang, Mingze Xu, Sen Zhang, Zhikun Zhang, Hongguang Zhang, Zhenjie Wang, Min Zhu, Hongchang Zhao.
       Background: Immune signaling is tightly coupled to cellular metabolic state. Beyond supplying energy, metabolites can directly regulate immune responses by driving post-translational modifications of proteins and chromatin, shifting immunometabolism toward a model in which metabolic state encodes signaling outputs.
    Findings: Protein pyruvylation has recently emerged as a metabolite-responsive lysine modification linking glycolytic metabolism to both immune signaling and transcriptional regulation. Established examples, including histone lactylation and acylation marks linked to acetyl-CoA and crotonyl-CoA, illustrate how metabolite availability shapes chromatin state and transcriptional competence. A recent Cell study showed that high glucose-enhanced glycolysis and pyruvate kinase M2 activity promotes STAT1 pyruvylation at Lys201, thereby disrupting STAT1-STAT2 interaction and suppressing type I interferon signaling. Complementing this signaling-centered mechanism, a subsequent Nature Metabolism study systematically characterized a broader lysine pyruvylation landscape, identified histone and non-histone substrates, linked pyruvylation to glycolytic flux and pyruvyl-CoA metabolism, and implicated HAT1 and p300 as pyruvylation writers and SIRT3 as an eraser. Together, these findings expand pyruvylation from a single signaling event into an emerging metabolite-responsive regulatory system operating across protein signaling and chromatin-associated transcriptional control. In this review, we summarize the conceptual framework of metabolite-driven protein modifications, compare established marks, and discuss the remaining questions surrounding pyruvylation chemistry, enzyme and substrate specificity, reader mechanisms, compartmentalization, detection strategies, physiological relevance, and potential immunopharmacological implications.
    Conclusions: Metabolite-driven protein modifications represent an important regulatory layer linking metabolic rewiring to immune reprogramming. Elucidating the chemistry, regulatory machinery, substrate landscape, and physiological functions of pyruvylation will not only advance our understanding of immunometabolism but may also facilitate the development of metabolite-based biomarkers and therapeutic strategies for inflammatory and immune-related disease.
    Keywords:  acetylation; crotonylation; immunometabolism; immunopharmacology; lactylation; pyruvylation
    DOI:  https://doi.org/10.3389/fimmu.2026.1912474
  13. Cardiovasc Drugs Ther. 2026 Sep 10.
    Vascular Immunometabolism in Atherosclerosis: Emerging Roles of Glycometabolic Reprogramming in Immune and Vascular Cells.
    Haoshuang Li, Anni Song, Jiachen Zhang, Hongwei Dong, Xiaoci Li, Ying Zhao.
      The progression of atherosclerosis is closely associated with alterations in cellular glucose metabolism and vascular immunometabolic regulation. Increasing evidence indicates that glycometabolic reprogramming in macrophages, ECs, and vascular smooth muscle cells contributes to plaque development by modulating inflammatory activation, oxidative stress, lipid metabolism, and cellular phenotypic changes. In this review, we summarize recent advances in glycometabolic reprogramming during atherosclerosis, focusing on glycolysis, the pentose phosphate pathway, and lactate-mediated epigenetic regulation. We further discuss how metabolic alterations interact with immune responses, trained immunity, epigenetic remodeling, and cellular senescence to regulate the atherosclerotic microenvironment. In addition, we highlight potential therapeutic targets involved in metabolic regulation, including key glycolytic enzymes such as 6-phosphofructo-2-kinase and lactate dehydrogenase A, as well as metabolic-epigenetic pathways such as the TRAP1/HDAC3/H4K12la axis. However, significant challenges remain regarding cell-type specificity, therapeutic selectivity, and clinical translation of metabolic interventions. Understanding the complex relationship between glycometabolic reprogramming and vascular immunometabolism can provide mechanistic insights and guide future investigations of metabolic interventions for atherosclerosis.
    Keywords:  Atherosclerosis; Glycolysis; Glycometabolic; Vascular cells
    DOI:  https://doi.org/10.1007/s10557-026-07956-6
  14. Fish Shellfish Immunol. 2026 Sep 10. pii: S1050-4648(26)00612-1. [Epub ahead of print] 111708
    WSSV exploits host glycolytic reprogramming to promote hemocyanin lactylation and enhance cell-associated WSSV levels in shrimp.
    Xinyue Ren, Baiqiao Chen, Kai Luo, Yayan Zhou, Yuxi Wu, Mingming Jiang, Ziyi Zhang, Yinghao Zhang, Yuqing Lv, Yueling Zhang, Zhihong Zheng.
      White spot syndrome virus (WSSV) is a major pathogen in shrimp aquaculture, yet how virus-induced metabolic rewiring alters immune effector function remains poorly understood. Here, we show that WSSV infection in Litopenaeus vannamei induces a Warburg-like metabolic shift characterized by increased glucose uptake, transcriptional activation of glycolytic genes, lactate accumulation, and reduced acetyl-CoA levels. This metabolic state is accompanied by enhanced lactylation and reduced acetylation of hemocyanin, a major respiratory and immune protein in shrimp. Through transcriptome-guided candidate screening and in vivo RNA interference, we identify Tip60 as a positive regulator of hemocyanin lactylation, whereas HDAC3 and SIRT2 act as negative regulators. Functional assays further demonstrate that hemocyanin samples isolated from sodium L-lactate-injected shrimp exhibit enhanced capacities to increase cell-associated WSSV on hemocytes and promote viral proliferation. Together, these findings support a model in which WSSV hijacks host glycolytic reprogramming to reshape the post-translational modification landscape and convert hemocyanin into a proviral factor. This study establishes a non-histone lactylation mechanism in crustacean antiviral biology and identifies the Tip60/HDAC3/SIRT2 axis as a potential target for host-directed control of WSSV infection.
    Keywords:  Hemocyanin lactylation; Host-virus interactions; Litopenaeus vannamei; Metabolic reprogramming; WSSV
    DOI:  https://doi.org/10.1016/j.fsi.2026.111708
  15. J Cell Physiol. 2026 Sep;241(9): e70227
    Resveratrol Inhibits Macrophage Glucose Metabolism Reprogramming and Inflammatory Activation to Delay COPD Progression Through the TLR4/HK2 Pathway.
    Zhu Li, Bin Zhang, Kun Li, Jinghui Yan, Na Li, Lijuan Sun, Wei Zhao.
      Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and metabolic dysregulation in immune cells, particularly macrophages. This study aimed to determine whether resveratrol (RES) delays COPD progression by modulating macrophage inflammatory activation and glycolytic reprogramming through the Toll-like receptor 4/hexokinase 2 (TLR4/HK2) signaling pathway. A COPD mouse model was established by lipopolysaccharide (LPS) instillation combined with cigarette smoke exposure, followed by treatment with RES at 50 mg/kg. Lung histopathology, mean linear intercept (MLI), destructive index (DI), bronchoalveolar lavage fluid (BALF) inflammatory cell counts, cytokine levels, macrophage polarization, and TLR4/HK2 pathway protein expression were assessed. In vitro, LPS-stimulated RAW264.7 macrophages were treated with RES, with or without TLR4 overexpression and HK2 silencing, to evaluate inflammatory responses, M1 polarization, glycolytic activity, and mitochondrial respiration. RES significantly alleviated lung tissue injury, decreased inflammatory scores, MLI, and DI, and reduced BALF inflammatory cell counts in COPD mice. RES also decreased inflammatory cytokine levels, suppressed macrophage M1 polarization, and downregulated TLR4, p-p65, and HK2 expression. In LPS-stimulated macrophages, RES reduced NO, IL-6, TNF-α, glucose uptake, lactate production, and ECAR, while improving OCR. TLR4 overexpression reversed the inhibitory effects of RES on inflammatory activation, M1 polarization, glycolytic reprogramming, and HK2 expression, whereas HK2 silencing partially restored the protective effects of RES under TLR4 overexpression. RES alleviates macrophage inflammatory activation, M1 polarization, and glycolytic reprogramming, in part through inhibition of the TLR4/HK2 pathway, suggesting its therapeutic potential for delaying COPD progression.
    Keywords:  COPD; TLR4/HK2 pathway; glycolytic reprogramming; inflammation; macrophage; resveratrol
    DOI:  https://doi.org/10.1002/jcp.70227
  16. Cell. 2026 Sep 11. pii: S0092-8674(26)00996-7. [Epub ahead of print]
    Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
    Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.
      Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.
    Keywords:  BAF; CD8 T cell effector function; D-alpha-hydroxybutyrate; OXPHOS; chromatin remodeling; creatine; phosphocreatine; tumor immunology
    DOI:  https://doi.org/10.1016/j.cell.2026.08.023
  17. Infect Immun. 2026 Sep 11. e0010726
    Mitochondrial dysfunction and glycolytic shift define the metabolic profile of hydatid fluid-stimulated dendritic cells.
    Maia Chop, Gianluca N Demare, Luciano N Lausero, Dalila E Orallo, María C Nicolao, Ágata C Cevey, Andrea C Cumino, Christian Rodriguez Rodrigues.
      Dendritic cells (DCs) require substantial metabolic reprogramming to mount an immune response against parasites. In the context of Echinococcus granulosus infection, parasite antigens can modulate host immune responses; however, their specific impact on DC metabolism remains poorly defined. We measured mitochondrial membrane potential (ΔΨM), intracellular reactive oxygen species (ROS), and nitric oxide (NO) production in FMS-like tyrosine kinase 3 ligand (FLT3-L)-derived DC (FL-DCs) stimulated with hydatid fluid (HF) or purified laminar layer (pLL) from E. granulosus. Gene expression profiling of key metabolic enzymes involved in glycolysis and oxidative phosphorylation (OXPHOS) was performed using RT-qPCR. Functional metabolic flux was analyzed using the Seahorse glycolysis stress test, while key metabolites from both pathways were quantified by HPLC. Our results showed that HF-stimulated FL-DCs exhibited marked mitochondrial dysfunction, evidenced by reduced ΔΨM and diminished mitochondrial network complexity, in contrast to the preserved mitochondrial morphology in pLL-stimulated cells. Gene expression analysis revealed that both stimuli enhanced glycolytic enzyme transcripts; however, only pLL induced OXPHOS-related genes, suggesting divergent bioenergetic adaptations. HF-stimulated FL-DCs produced elevated levels of ROS and NO, indicative of oxidative stress and a glycolysis-favored metabolic state, whereas pLL maintained mitochondrial respiration without excessive ROS production. Metabolic flux assays corroborated these findings; HF-stimulated cells displayed an increased extracellular acidification rate and a decreased oxygen consumption rate, indicating a glycolytic shift. In contrast, pLL-stimulated FL-DCs preserved oxidative metabolism and aerobic glycolysis. Our findings demonstrate that HF and pLL from E. granulosus differentially modulate metabolic programs in FL-DCs and highlight potential targets for modulating DC function in echinococcosis pathogenesis.
    Keywords:  Echinococcus granulosus; autophagy; dendritic cells; glycolysis; hydatid fluid; mitochondrial membrane potential; purified laminar layer; reactive oxygen species
    DOI:  https://doi.org/10.1128/iai.00107-26
  18. J Pathol. 2026 Sep 08.
    CAFs-mediated histone lactylation reprograms cholesterol metabolism in colorectal cancer to drive CD8+ T cell immunosuppression.
    Huachi Li, Jun Hu, Lei Huang, Zihao Wang, Haoran Tao, Feng Cao, Min Xie.
      The progression of colorectal cancer (CRC) is critically regulated by cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), yet the specific molecular mechanisms by which CAFs influence CRC remain unclear. This study reveals the mechanism by which CAFs promote CRC malignant progression and immune suppression through metabolic reprogramming. Findings indicate that lactate secreted by CAFs induces lactylation modifications of histone H3K9La and H3K18La, thereby upregulating the expression of key cholesterol synthesis enzymes DHCR7 and CYP51A1, which in turn enhances the malignant properties of CRC cells. In vivo and in vitro experiments confirm that inhibiting DHCR7 significantly reverses CAF-mediated tumor promotion. More importantly, this study revealed that CAF-induced CRC cells with elevated cholesterol metabolism deliver DHCR7 to CD8+ T cells via exosomes, thereby triggering mitochondrial dysfunction and driving the cellular senescence process. This senescence manifests as reduced IFN-γ secretion capacity and enhanced senescence-associated secretory phenotype (SASP). In summary, this study systematically elucidates the central role of the CAF-CRC cell-CD8+ T cell regulatory axis: CAF-derived lactate modulates cholesterol metabolism in CRC cells via histone lactylation. Subsequently, CRC cells with enhanced cholesterol metabolism deliver DHCR7 to CD8+ T cells via exosomes, inducing mitochondrial dysfunction, which in turn leads to CD8+ T-cell senescence and immunosuppression. This provides a new theoretical foundation and therapeutic rationale for metabolic-immune combination strategies in CRC. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  CAFs; CD8+ T cells; CRC; DHCR7; cholesterol metabolism; histone lactylation; immunosuppression
    DOI:  https://doi.org/10.1002/path.70119
  19. Crit Care Explor. 2026 Sep 01. 8(9): e1478
    When the Pathogen Shapes the Host: Metabolic Divergence in COVID-19 and Community-Acquired Pneumonia.
    Narges Alipanah-Lechner.
      
    Keywords:  COVID-19; community-acquired pneumonia; host response; immunometabolism; metabolomics; precision medicine
    DOI:  https://doi.org/10.1097/CCE.0000000000001478
  20. Front Immunol. 2026 ;17 1896701
    H4K5 lactylation exacerbates acute myocarditis by driving a positive feedback loop between inflammation and metabolic dysfunction.
    Yawei Zhao, Yue Cai, Song Shen, Yuchen Wen, Tianyue Li, Lina Kang, Biao Xu, Xuan Sun.
      Acute myocarditis is a non-ischemic cardiomyopathy with rapid onset and high mortality. Immunometabolic reprogramming of macrophages is a key pathological feature. However the understanding of its mechanisms remains to be clarified. In this study, we found that acute myocarditis induced an increase in glycolysis and lactate accumulation. Inhibition of lactate production ameliorated myocardial injury. Further, we demonstrated that lactate promoted a pro-inflammatory transition of macrophages, thereby amplifying the inflammatory response. Inhibition of lactate in macrophage shifted its phenotype from a pro-inflammatory to an anti-inflammatory subtype. We also observed a significant increase in H4K5 lactylation in macrophages. Next, we identified that H4K5la drove the transcriptional expression of the Rap1, which in turn upregulated the TNF/NF-κB signaling. This lactate-dependent H4K5la was enriched in inflammatory pathways, forming a positive feedback loop that amplified inflammation. Inhibition of Rap1 reduced cardiac inflammation and broke this loop. These consequently lowered H4K5la levels and delayed ventricular remodeling. Collectively, this study reveals the role of H4K5la in promoting inflammatory cascades in myocarditis, and provides a potential therapeutic target for inflammatory cardiomyopathy.
    Keywords:  H4K5la; acute myocarditis; histone lactylation; immune metabolism; macrophage
    DOI:  https://doi.org/10.3389/fimmu.2026.1896701
  21. Mol Ther Oncol. 2026 Sep 17. 34(3): 201322
    Short-chain fatty acids act as metabolic and epigenetic regulators in CAR T cell therapy.
    Ming-Yang Ma, Chen-Xin Zhou, Xin-Yu Shi, Jian-Min Zhu, Cai-Wen Duan.
      Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, but its efficacy in solid tumors remains constrained by poor infiltration, metabolic stress, and limited persistence. Short-chain fatty acids (SCFAs), particularly butyrate and pentanoate, offer a way to influence CAR T metabolism and chromatin state during manufacturing. Butyrate combines class I histone deacetylase inhibition with acetyl-CoA metabolism and AMP-activated protein kinase (AMPK)-associated restraint of mTORC1, whereas pentanoate can reinforce effector programs through mTOR signaling and a distinct TCA-ATP-citrate lyase carbon-routing pathway. Direct CAR T studies and clinical associations now support the biological relevance of both metabolites, although their effects depend on dose, exposure schedule, cell composition, and experimental context. Building on their complementary actions, we propose sequential butyrate-pentanoate conditioning, with early butyrate exposure used to support oxidative and progenitor-associated features and later pentanoate exposure used to reinforce effector function. This review develops the mechanistic basis for that strategy, defines the experiments needed to distinguish cooperation from antagonism, and considers its manufacturing and translational implications.
    Keywords:  CAR T; HDAC inhibition; butyrate; epigenetic reprogramming; ex vivo conditioning; mitochondrial metabolism; pentanoate; short-chain fatty acids; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.omton.2026.201322
  22. Immunol Invest. 2026 Sep 11. 1-20
    Immunometabolic Reprogramming as a Therapeutic Platform: Integrating Systems Immunology with Precision Biopharmaceutical Engineering.
    Hosein Yousefi, Cobra Moradian.
       INTRODUCTION: Immunometabolism integrates energy demands, biosynthesis, redox homeostasis, and immune-cell function, yet metabolic phenotypes remain context dependent. This review conceptualizes immunometabolic reprogramming as a multiscale regulatory network connecting microenvironmental pressures, nutrient sensing, metabolic flux, metabolite-mediated regulation, immune-cell states, systems-level biomarkers, and precision therapeutic engineering.
    METHODS: A structured narrative review synthesized literature published from January 2022 onward across five domains: microenvironmental metabolic control; metabolic signaling and pathway interactions; systems immunology and biomarker discovery; engineered therapeutic platforms; and translational evidence, safety, and patient stratification. Quantitative findings were retained only when their experimental context supported interpretation.
    RESULTS: Oxygen, nutrient, pH, cytokine, and metabolite availability can reshape AMPK, mTOR, HIF-1α, and related signaling, thereby altering glycolytic, mitochondrial, lipid, amino-acid, and redox metabolism. These changes interact with transcriptional and epigenetic mechanisms to regulate immune-cell states. Systems-level profiling enables biomarker development, while engineered biologics, targeted delivery systems, extracellular-vesicle platforms, and metabolically conditioned immune cells offer emerging therapeutic opportunities. However, translational maturity varies substantially across interventions.
    CONCLUSION: Immunometabolic reprogramming should be interpreted as a context-dependent network rather than a collection of isolated pathways. Clinical translation requires evidence-graded interventions, tissue- and dose-aware strategies, validated biomarkers, and patient stratification to distinguish established benefit from promising but unproven engineering approaches.
    Keywords:  Biomarkers; immunometabolism; immunotherapy; metabolic reprogramming; patient stratification; precision biopharmaceutical engineering; systems immunology; tumor microenvironment
    DOI:  https://doi.org/10.1080/08820139.2026.2731116
  23. Transl Pediatr. 2026 Aug 31. 15(8): 348
    Metabolic reprogramming rewires aberrant immune responses to drive endothelial dysfunction in Kawasaki disease: a narrative review.
    Zixuan Zhao, Shuhui Wang, Xuan Li, Liyan Zhu, Haitao Lv, Guanghui Qian.
       Background and Objective: Kawasaki disease (KD) is a systemic pediatric vasculitis characterized by dysregulated immune activation and substantial risk of coronary artery lesions. Emerging evidence suggests metabolic reprogramming is a critical link between immune responses and endothelial dysfunction during KD progression. This review aims to provide an integrated overview of metabolic alterations in KD pathogenesis, focusing on clinical observations, mechanistic insights, and experimental evidence.
    Methods: A literature search was conducted using PubMed and Web of Science to identify studies published up to July 2026, combining "Kawasaki disease" with terms related to metabolism and metabolic pathways, including metabolites, glucose, glycolysis, amino acids, lipids, fatty acid oxidation, succinic acid, the tricarboxylic acid (TCA) cycle, nitric oxide, urine, gut microbiota, mouse models, and therapeutic strategies. Relevant clinical, experimental, and mechanistic studies were reviewed and synthesized.
    Key Content and Findings: Accumulating evidence indicates extensive metabolic remodeling in KD, including enhanced glycolysis, disrupted lipid metabolism and fatty acid oxidation, altered amino acid metabolism, and TCA cycle perturbations. These abnormalities are closely linked to immune activation, mitochondrial dysfunction, oxidative stress, and vascular inflammation. KD mouse models further support metabolic reprogramming, marked by altered tryptophan and amino acid metabolism, lipid metabolism, and lactate production. Notably, kynurenine pathway activation with reduced tryptophan availability is associated with inflammatory amplification and mitochondrial impairment. Beyond host-derived changes, gut microbiota dysbiosis and its metabolites appear to correlate with immune responses and disease severity. However, clinical translation of these metabolic signatures into reliable biomarkers or therapeutic targets remains limited.
    Conclusions: This review highlights metabolic reprogramming as a key interface linking immune dysregulation, endothelial injury, and vascular complications in KD. Metabolic abnormalities may act not merely as consequences of inflammation but as active regulators of vascular dysfunction and disease progression. Significant gaps remain in establishing causal relationships between specific metabolic alterations and KD pathogenesis. Future studies integrating multicenter cohorts with cellular, multi-omics, and animal model approaches, particularly centered on the metabolic-immune-vascular injury axis, will be essential for identifying novel biomarkers and therapeutic strategies.
    Keywords:  Kawasaki disease (KD); endothelial dysfunction; immune response; metabolism
    DOI:  https://doi.org/10.21037/tp-2026-0494
  24. JCI Insight. 2026 Sep 08. pii: e203626. [Epub ahead of print]
    Type 3 Inflammation-Specific Keratinocyte Glutaminolysis Promotes Skin Inflammation.
    Yongfei Hu, Hai Yu, Kaiyu Liang, Liyan Yuan, Wenjun Zhang, Zhe Zhuang, Suyun Ji, Xichun Xia.
      Inflammatory cytokines reprogram keratinocyte metabolism, but the metabolic pathways that couple immune signals to pathological epidermal growth remain incompletely defined. Here, we identify GLS1-mediated glutaminolysis as a metabolic program preferentially induced in keratinocytes under type 3 inflammatory conditions. Integrated transcriptomic, metabolomic, genetic, and functional analyses showed that IL-17A induced GLS1 expression and glutaminolysis in keratinocytes. Keratinocyte-specific Gls1 deletion reduced the intracellular availability of arginine, proline, and methionine, impaired amino acid-dependent mTORC1 activation, disrupted redox homeostasis, and limited keratinocyte proliferation. Amino acid or antioxidant supplementation partially rescued these defects, whereas rapamycin blocked the amino acid-mediated proliferative rescue. Gls1 deletion did not impair steady-state skin development or homeostasis and did not alter MC903-induced type 2 dermatitis, but it delayed wound re-epithelialization and attenuated IMQ-induced psoriasiform inflammation. Loss of keratinocyte GLS1 also reduced epidermal chemokine expression and the accumulation of neutrophils and IL-17A-producing γδ T cells, revealing a role for glutaminolysis in amplifying epithelial-immune crosstalk. These findings define GLS1-mediated glutaminolysis as a context-specific metabolic checkpoint linking type 3 inflammation to keratinocyte proliferation and cutaneous immune amplification, and support locally or temporally controlled GLS1 inhibition as a potential therapeutic strategy for psoriasis.
    Keywords:  Autoimmunity; Dermatology; Metabolism; Skin; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.203626
  25. Bioact Mater. 2027 Feb;68 27-41
    Dual metabolic checkpoint blockade via a 3D-Printed metalloplatform remodels the tumor ecosystem for systemic antitumor immunity.
    Xiaoyan Meng, Zhonglong Liu, Yongqiang Hao, Yingchun Zhu, Jianfeng Gu, Haozhang Zhong, Yue He, Jingke Fu.
      The immunosuppressive tumor microenvironment limits the efficacy of therapies that target metabolism. Here we show a strategy of dual metabolic regulation that simultaneously reprogramming glycolysis in cancer cells and fructose metabolism in tumor-associated macrophages, transforms the metabolic ecosystem from pro-tumor to antitumor, eliciting systemic immunity. Through pan-cancer single-cell analysis, we identified a metabolic division of labor: cancer cells exhibit hyperactive glycolysis, while immunosuppressive macrophages display elevated fructose metabolism. We uncovered that manganese ions (Mn2+) selectively suggest a potential inhibitory effect on glycolysis, induce pyroptosis, yet paradoxically upregulate fructose metabolism in M2-like macrophages, creating an exploitable vulnerability. To harness this dual activity, we engineered a 3D-printed nanoporous Cu-Mn alloy (CuMn) that provides sustained intratumoral release of Mn2+ and delivers a fructokinase inhibitor. In a bilateral breast carcinoma model, a single intratumoral implantation of this platform suppressed primary tumor growth and eradicated distant untreated lesions. Therapeutic efficacy was associated with macrophage reprogramming, which remodeled the immune microenvironment, alleviated T cell exhaustion, and inhibited distant tumor growth, suggesting potential systemic antitumor effects. Local delivery of the nano platform offers a strategy to overcome tumor immunosuppression and enhance cancer immunotherapy.
    Keywords:  Cancer metabolism; Manganese; Metabolic reprogramming; Metalloimmunotherapy; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.08.034
  26. Front Immunol. 2026 ;17 1923683
    Regulation of macrophage polarization in chronic airway inflammatory diseases: immune interactions, metabolic reprogramming, and beyond.
    Hongyang Zhang, Cuida Meng, Dongdong Zhu.
      Chronic upper and lower airway inflammatory diseases (such as allergic rhinitis, chronic rhinosinusitis, and bronchial asthma) are a group of highly heterogeneous disorders primarily characterized by immune imbalance and persistent inflammation as their core features, which seriously affect patients' quality of life. As an important component of the immune system, macrophages can undergo functional polarization in response to distinct inflammatory microenvironments, exerting divergent pro-inflammatory or anti-inflammatory effects. They also form intricate interaction networks with other immune cells to jointly regulate the progression of chronic airway inflammation. Although the regulation of macrophage plasticity is regulated by multiple aspects, metabolic reprogramming has emerged as a pivotal mechanism modulating macrophage polarization and function. This review systematically summarizes the interplay between macrophage polarization and other immune cells, focusing on the impact of distinct phenotypes and their regulatory pathways on chronic airway inflammatory diseases. Furthermore, we discuss the therapeutic potential of targeting metabolic reprogramming, providing new insights for the precise treatment of chronic upper and lower airway inflammatory diseases.
    Keywords:  allergic rhinitis; asthma; chronic airway inflammation; chronic rhinosinusitis; immune cells; macrophage polarization; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1923683
  27. Mol Biomed. 2026 Sep 11. pii: 168. [Epub ahead of print]7(1):
    HDCA suppresses exosomal lncRNA MSTRG171708 release to inhibit Treg-mediated immunometabolism in hepatocellular carcinoma.
    Feng Yang, Wenqiong Huang, Chongkai Fang, Chong Zhong, Chaoyuan Huang, Meijun Liu, Zongzhen Meng, Xiaoli Chen, Claudio Mauro, Aiping Lyu, Kenneth C P Cheung.
      Hepatocellular carcinoma (HCC) exhibits poor patient outcomes due to its propensity for metastasis, yet the mechanisms linking metabolic dysregulation and immune evasion remain unclear. This study reveals that reduced hyodeoxycholic acid (HDCA) levels, coupled with elevated tumor-derived extracellular vesicles (EVs) carrying the long non-coding RNA MSTRG171708, correlate with aggressive HCC progression and enhanced lung metastasis. Mechanistically, MSTRG171708-enriched EVs are internalized by regulatory T (Treg) cells, stabilizing the HIF-1α/PKM2/PHD3 axis and triggering a metabolic shift toward glycolysis, thereby augmenting Treg migratory capacity and fostering an immunosuppressive microenvironment conducive to metastasis. Furthermore, HDCA suppresses EVs release by transcriptionally downregulating RAB27 and SNAP23, key mediators of exosome biogenesis, and effectively curtails metastatic burden in vivo. Clinically, high MSTRG171708 levels in HCC patients are associated with decreased HDCA levels and increased Treg infiltration. These findings establish HDCA-mediated regulation of EVs trafficking as a critical link between epigenetic modulation and immunometabolic reprogramming, proposing HDCA restoration as a novel therapeutic strategy to impede HCC metastasis.
    Keywords:  Extracellular vesicles; HCC metastasis; Hyodeoxycholic acid; Immunometabolic reprogramming; LncRNA MSTRG171708; Regulatory T cells
    DOI:  https://doi.org/10.1186/s43556-026-00550-0
  28. Exp Mol Med. 2026 Sep 10.
    Deficiency of protein kinase Cδ reprograms macrophage immunometabolism to suppress pyroptosis and stabilize atherosclerotic plaques.
    Chih-Feng Lien, Hsin-Yi Chang, Shu-Han Yu, Rou-Ling Cho, Sy-Jou Chen, Tzu-Ting Kuo, Patrick Chun-Theng Chong, Chih-Hung Ye, Feng-Yen Lin, Wan-Lin Wu, Shih-Hua Lin, Chien-Sung Tsai, Chin-Sheng Lin.
      While atherosclerotic plaque vulnerability drives acute coronary syndrome, the regulatory mechanisms underlying plaque stability remain unclear. Protein kinase Cδ (PKCδ) has been implicated in atherosclerosis progression, but its specific role in plaque vulnerability and the underlying mechanisms require clarification. We analyzed PKCδ expression in human atheroma datas and investigated its role using low-density lipoprotein receptor-knockout mice with global and myeloid-specific PKCδ deletion. Plaque morphology, necrotic core formation, and fibrous cap thickness were evaluated. Macrophage metabolic profiling, mitochondrial function, inflammatory responses, and pyroptosis markers were assessed using biochemical and molecular approaches. Human atheroma analysis revealed elevated PKCδ expression, particularly in macrophages within ruptured plaques. PKCδ deletion in mice reduced necrotic core formation and increased fibrous cap thickness in both global and myeloid-specific models. Mechanistically, macrophage PKCδ deficiency improved mitochondrial fitness by promoting mitochondrial oxidative phosphorylation and elevating α-ketoglutarate (α-KG) levels. This metabolic shift reduced pro-inflammatory responses through PIK3AP1-mTORC2 activation and downregulated NLRP3 inflammasome-mediated pyroptosis. Dimethyl α-ketoglutarate (DKG) supplementation provided similar protective effects. Both human and in vivo analyses revealed PKCδ association with pyroptosis markers, including NLRP3, caspase-1, IL-1β, and GSDMD, whereas PKCδ deficiency reduced their co-localization with CD68⁺ macrophages. In conclusion, PKCδ serves as a key regulator of macrophage inflammation, pyroptosis, and mitochondrial dysfunction in atherosclerotic plaques. PKCδ deficiency promotes metabolic reprogramming that stabilizes plaques through reduced pyroptosis and enhanced mitochondrial function. These findings highlight PKCδ as a potential therapeutic target to reduce acute cardiovascular events by modulating plaque stability.
    DOI:  https://doi.org/10.1038/s12276-026-01842-9
  29. J Hazard Mater. 2026 Sep 02. pii: S0304-3894(26)02400-3. [Epub ahead of print]517 143420
    HIF-1α-associated macrophage metabolic reprogramming mediates intestinal injury induced by acrylamide and 5-hydroxymethylfurfural co-exposure.
    Jiawen Lu, Yangchun Shen, Xingtao Zhou, Yuting Wang, Hui Ye, Qiang Yu, Jianhua Xie, Yi Chen.
      Acrylamide (AA) and 5-hydroxymethylfurfural (HMF) are processing-derived contaminants that frequently co-occur in environmental and dietary exposure, yet the health effects of their co-exposure remain poorly understood. Here, we show that co-exposure to AA and HMF induces duodenal injury in mice, whereas neither toxin alone causes significant damage. Macrophage depletion using clodronate liposomes significantly attenuates this pathology, identifying macrophages as important mediators of the intestinal injury. Co-exposure promotes macrophage polarization toward a pro-inflammatory phenotype. Notably, direct exposure of intestinal epithelial cells to AA and HMF produces limited cytotoxicity. In contrast, conditioned medium from AA+HMF-treated macrophages compromises epithelial viability and barrier integrity in both intestinal epithelial cells and mouse intestinal organoids. These findings indicate that macrophage-mediated inflammatory responses, rather than direct epithelial toxicity, contribute substantially to AA+HMF-induced intestinal injury. Mechanistically, AA and HMF co-exposure triggers mitochondrial dysfunction and elevated mitochondrial reactive oxygen species (mtROS) production in macrophages, accompanied by enhanced glycolysis and hypoxia-inducible factor-1α (HIF-1α) activation. Pharmacological inhibition or genetic silencing of HIF-1α attenuates metabolic and inflammatory responses, while scavenging mtROS or iNOS inhibition reduces macrophage activation. Collectively, these findings reveal an immune-mediated mechanism underlying AA and HMF co-exposure-induced intestinal injury and highlight macrophage responses as a determinant of contaminant mixture toxicity.
    Keywords:  5-hydroxymethylfurfural (HMF); Acrylamide (AA); Co-exposure; Inflammatory effects; Macrophages
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.143420
  30. Adv Sci (Weinh). 2026 Sep 08. e77642
    SIRT7-Mediated H2BK120 Succinylation Drives Aberrant Mitophagy in Sepsis-Associated Cognitive Dysfunction.
    Na Meng, Jiateng Zhou, Xiaoyu Guo, Ting Hong, Xuelian Li, Xingyu Wei, Chanhua Zhang, Xixue Zhang, Songbin Liu, Yulin Zhang, Liangfang Yao, Lina Huang, Weidong Gu.
      Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, yet how metabolic disturbances engage epigenetic regulation in SAE remains unclear. We found that septic mice exhibited hippocampal succinate and succinyl-CoA accumulation, accompanied by enhanced neuronal histone H2BK120 succinylation (H2BK120su). Pharmacological reduction of succinylation alleviated neuronal injury and improved cognitive function. Mechanistically, integrated CUT&Tag and transcriptomic analyses identified Pdcd1 as a downstream gene associated with H2BK120su enrichment. H2BK120su enrichment at the Pdcd1 promoter activated the PD-1/PD-L1 axis, promoted mitochondrial translocation of PD-L1 and its interaction with PINK1, and triggered PINK1/Parkin-dependent mitophagy, leading to mitochondrial dysfunction and neuronal apoptosis. Neutralization of PD-1/PD-L1 or knockdown of Pdcd1 attenuated mitophagy and neuronal injury. We further identified SIRT7 downregulation as a major cause of H2BK120su accumulation in the septic hippocampus. Neuron-specific Sirt7 deletion exacerbated H2BK120su enrichment, PD-1/PD-L1 activation, excessive mitophagy, and cognitive impairment, whereas SIRT7 overexpression reversed these pathological changes. Together, our findings define a SIRT7-H2BK120su-PD-1/PD-L1-PINK1 axis linking metabolic reprogramming to aberrant mitophagy in SAE and suggest SIRT7-dependent succinylation as a potential therapeutic target.
    Keywords:  SIRT7; citric acid cycle; epigenetics; histone; mitochondrion; mitophagy; succinylation
    DOI:  https://doi.org/10.1002/advs.77642
  31. JCI Insight. 2026 Sep 08. pii: e200076. [Epub ahead of print]11(17):
    Glutamine-dependent biosynthetic pathways fuel autoreactive T and B cells in Foxp3 deficiency-mediated disease.
    Mohammad Adeel Zafar, Charlotte N Hill Machado, Jyotirmaya Behera, Yuelin Zhong, Xiao Li, Shakchhi Joshi, Yassine El Fazaa, Virginia Camacho, Peter Georgiev, Kiran Kurmi, Marcia Haigis, Louis-Marie Charbonnier.
      Foxp3 deficiency causes a profound loss of immune tolerance, unleashing autoreactive T and B cells, lymphoproliferation, cytokine-driven inflammation, and autoantibody production. This autoimmune pathology is fueled by increased glutamine usage, but it remains unresolved whether glutamine is necessary to produce energy or for intermediate metabolite biosynthesis responsible for immunomodulation. Here, we demonstrate that glutamine utilization for biosynthetic pathways supported autoimmune inflammation in the settings of Foxp3 deficiency and dextran sodium sulfate-induced colitis. By employing a model of autoimmunity driven by Treg-specific loss of Foxp3, we showed that this effect is independent of pathogenic Foxp3-deficient Treg reprogramming. Mechanistically, glutamine biosynthetic pathways sustained conventional T cell activation and proinflammatory cytokine production by preventing inosine accumulation and signaling, thus implicating adenosine pathway modulation in autoreactive T cell dysregulation. Conversely, autoreactive B cell activation and autoantibody production relied on glutamine-dependent asparagine availability, which we identified as a targetable vulnerability for autoantibody formation. These findings highlighted glutamine-driven biosynthetic processes as critical drivers of autoimmunity and revealed distinct metabolic vulnerabilities in autoreactive T and B cells that could be targeted for therapeutic intervention.
    Keywords:  Autoimmune diseases; Autoimmunity; Inflammation; Metabolism; Mouse models; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.200076
  32. Biochem Biophys Res Commun. 2026 Sep 05. pii: S0006-291X(26)01297-0. [Epub ahead of print]835 154533
    Activation of lipid synthesis following glycolysis is required for CD8+ T cells to acquire antitumor immune activity.
    Taisuke Hamada, Makoto Kuwahara, Hiroki Tokiwa, Waichi Yamamoto, Junpei Suzuki, Shunsuke Nomura, Yuko Matsuoka, Takahumi Matsushita, Sakiko Kitamura, Ayato Kawashima, Tasuku Nishihara, Masakatsu Yamashita.
      Activated CD8+ T cells undergo metabolic reprogramming and shift to aerobic glycolysis to fulfill their energy and biosynthetic demands. However, the downstream pathways linking glycolytic flux to potent antitumor immunity remain unclear. In this study, we used a T-cell-specific phosphoglycerate mutase 1 (Pgam1)-deficient mouse model to demonstrate that accelerated lipid synthesis induced by glycolysis is necessary for CD8+ T cells to acquire antitumor activity. Pgam1 deficiency severely impaired antitumor activity and intratumoral infiltration in the MC38-OVA tumor model. Transcriptomic profiling of Pgam1-deficient CD8+ T cells activated in vitro revealed that Pgam1 deficiency caused a marked reduction in the lipid biosynthetic program and altered lipid composition. We found that in Pgam1-deficient CD8+ T cells, TCR stimulation dose not induce the upregulation of the Srebf1 and Srebf2 genes, which encode the master transcription factors Srebp1 and Srebp2, respectively, that regulate lipid synthesis. Pharmacological inhibition of SREBPs by fatostatin attenuated effector functions, such as TCR-induced proliferation, cytokine production, and cytotoxicity. These findings indicate that the activation of SREBP-dependent lipid synthesis pathways, which follow glycolysis, is important for the acquisition of antitumor activity by CD8+ T cells.
    Keywords:  Antitumor activity; CD8(+) T cells; Glycolysis; Lipid synthesis; SREBP
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154533
  33. Inflamm Res. 2026 Sep 05. pii: 200. [Epub ahead of print]75(1):
    Depleting luminal cysteine with engineered bacteroides vulgatus alleviates experimental colitis by suppressing Th17 differentiation through an ATF6-dependent mechanism.
    Jianghao Wang, Zhe-Xian Tian, Shanwen Chen, Grace Y Chen, Yi-Ping Wang, Pengyuan Wang.
       BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by dysregulated immune responses, particularly the aberrant activation of T helper 17 (Th17) cells. While microbiome-based therapies show promise, wild-type probiotics often lack specific mechanisms to target the metabolic and immunological drivers of inflammation.
    METHODS: In this study, we engineered a cysteine-auxotrophic strain of Bacteroides vulgatus (BV1608) by chromosomally integrating the E. coli cyuP gene to enhance cysteine uptake. We evaluated its colonization capability, safety, and therapeutic efficacy in dextran sulfate sodium (DSS)-induced acute and chronic colitis murine models.
    RESULTS: BV1608 exhibited superior colonization and cysteine assimilation compared to the wild-type strain. Oral administration of BV1608 significantly alleviated colitis symptoms, reduced pro-inflammatory cytokines, and restored intestinal barrier integrity. Mechanistically, BV1608 created a localized cysteine-restricted microenvironment in the gut and suppressed pathogenic Th17 differentiation. Under cystine-restricted conditions, ATF6 was activated in CD4⁺ T cells, and its inhibition partially restored IL-17A⁺ CD4⁺ T cell differentiation, indicating a functional role for ATF6. Meanwhile, cystine restriction was associated with increased BATF2 expression and enhanced ATF6 binding at the BATF2 promoter, suggesting BATF2 as a potential downstream node.
    CONCLUSION: Our findings demonstrate that metabolically engineered B. vulgatus BV1608 ameliorates colitis by coupling microbial cysteine sequestration with host immune modulation via the ATF6-dependent suppression of Th17 differentiation, while implicating BATF2-associated transcriptional regulation as a potential downstream mechanism. This study provides a novel synbiotic strategy for treating UC by targeting the immunometabolic interface.
    Keywords:  Gut microbiota; Th17 differentiation; Ulcerative colitis
    DOI:  https://doi.org/10.1007/s00011-026-02341-3
  34. Adv Sci (Weinh). 2026 Sep 09. e77701
    Upadacitinib Restrains the Pathogenic Fitness of CD4+ T Cells and Aberrant B Cell Programming in Optic Neuritis.
    Gengchen Jiang, Qi Jiang, Lian Han, Yue Peng, Xingyu Liu, Tong Yang, Hao Huang, Jiaying Liu, Yuan Gao, Hui Yang, Wenjun Zou, Zhaohuai Li, Wenru Su.
      Optic neuritis (ON) is a neuroinflammatory autoimmune disease harboring autoreactive lymphocytes. Effector memory CD4+ T cells (CD4+ Tem) represent a prominently expanded and pro-inflammatory subset within this compartment, yet their pathogenic metabolic programs remain poorly defined. B cell dysfunction also contributes to ON pathogenesis. However, whether T cell-intrinsic metabolic rewiring directly fuels this B cell dysregulation awaits elucidation. Here, through single-cell transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from ON patients, we conceptualized a pathological circuit linking T cell metabolic reprogramming to aberrant T-B crosstalk. In pathogenic CD4+ Tem, JAK1 upregulation and enhanced STAT3 phosphorylation propagated a metabolic rewiring transcriptional program and secured T cell fitness via MCL1 induction. An inferred cholesterol export signature distinguished this subset and engaged the nuclear sensor RORA on B cells to instruct pro-inflammatory polarization and humoral commitment. In turn, subverted B cells perpetuated exaggerated antigen presentation and cytokine secretion, cementing pathogenic CD4+ Tem differentiation and sustaining a self-amplifying inflammatory loop. Cross-disease profiling extended this axis to allied autoimmune disorders. Selective JAK1 blockade with upadacitinib (UPA) restored immune homeostasis and attenuated experimental autoimmune encephalomyelitis (EAE), phenocopied by MCL1 inhibition. Together, these findings nominate UPA as a targeted therapy for ON and allied autoimmune disorders.
    Keywords:  MCL1; autoimmune diseases; optic neuritis; t helper 17 cells; upadacitinib
    DOI:  https://doi.org/10.1002/advs.77701
  35. Trends Endocrinol Metab. 2026 Sep 09. pii: S1043-2760(26)00202-X. [Epub ahead of print]
    Itaconate.
    Eva M Pålsson-McDermott, Luke A J O'Neill.
      
    DOI:  https://doi.org/10.1016/j.tem.2026.07.012
  36. Biochim Biophys Acta Rev Cancer. 2026 Sep 08. pii: S0304-419X(26)00174-5. [Epub ahead of print]1881(6): 189702
    Metabolic and epigenetic plasticity of tumor-associated macrophages shapes immunosuppressive outputs and immune checkpoint response.
    Jinghao Pan, Boyang Li, Lucy Yue Lau, Zehao Hong, Yi Chen.
      Immune checkpoint blockade (ICB) has transformed cancer therapy, but durable responses are frequently limited by tumor microenvironment-driven resistance. Tumor-associated macrophages (TAMs) are central mediators of this process because they sense metabolic stress and convert it into immunosuppressive programs that restrict antigen presentation, effector T cell entry, and cytotoxic function. This review conceptualizes the tumor microenvironment as a metabolic ecosystem shaped by hypoxia, lactate accumulation, acidosis, nutrient competition, lipid-rich niches, and amino-acid scarcity. We propose a context-dependent state-transition model in which these pressures are decoded by interconnected nutrient- and stress-sensing pathways, integrated through mitochondrial bioenergetic and redox adaptation, and translated by metabolite-dependent chromatin remodeling into persistent TAM functional programs that constrain the depth and durability of ICB responses. We further link glucose, lipid, and amino-acid metabolic circuitry to checkpoint resistance and propose therapeutic leverage tiers and biomarker layers for TAM metabolic reprogramming combined with ICB. This framework highlights actionable routes to overcome myeloid-driven immune resistance.
    Keywords:  Epigenetic imprinting; Immune checkpoint blockade; Immunometabolism; Metabolic plasticity; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189702
  37. Front Cell Dev Biol. 2026 ;14 1932382
    Disulfidptosis as an immunometabolic rheostat in gastrointestinal cancers: tuning the balance between T Cell exhaustion and immunogenic cell death.
    Yachao Li, Huaijue Qiu, Zexing Li, Xiang Gao.
      Disulfidptosis is a recently characterized regulated cell death pathway driven by disulfide stress. However, its immunological consequences in the tumor microenvironment remain poorly defined. In this review, we propose a conceptual framework in which disulfidptosis functions as an immunometabolic rheostat, wherein the net outcome-T cell exhaustion versus immunogenic cell death-is critically dependent on stress intensity, kinetics, and cellular context. We hypothesize that in glucose-deprived gastrointestinal tumors, chronic sub-lethal disulfide stress may erode CD8+ T cell effector function through F-actin crosslinking at the immunological synapse, potentially involving STAT3-LDHB-G6PD-driven transcriptional reprogramming toward a TOX-associated exhaustion state. Conversely, acute synchronous tumor lysis releases damage-associated molecular patterns (DAMPs); however, productive dendritic cell (DC) cross-presentation requires that adenosine triphosphate (ATP)/adenosine conversion and high mobility group box 1 (HMGB1) redox state meet quantitative thresholds. The DPP7-GPX4 axis suppresses disulfidptosis to limit DAMP release and facilitate natural killer (NK) cell evasion, positioning it as a candidate innate immune checkpoint. We advance testable predictions for tuning this rheostat via timed nanodelivery, dietary sensitization, and DPP7/GPX4 targeting, while explicitly distinguishing correlative biomarkers from causal mechanisms. Priority experiments to validate-or falsify-the rheostat hypothesis are outlined.
    Keywords:  dendritic cell cross-presentation; disulfidptosis; gastrointestinal cancers; immunometabolism; immunotherapy; innate immune checkpoint; tumor immune microenvironment; t cell exhaustion
    DOI:  https://doi.org/10.3389/fcell.2026.1932382
  38. Circulation. 2026 Sep 08.
    HNRNPK Lactylation Amplifies Inflammation and Exacerbates Myocardial Ischemia/Reperfusion Injury by Regulating Jag2 Splicing.
    Suyun Chen, Siman Shen, Wenmei Su, Linhang Fu, Jianning Chen, Li Xu, Ziqiang Yang, Simeng Li, Kun Ding, Yulong Zhang, Ruizhao Shao, Yaofeng Wen, Jing Tang, Yang Wang, Fu-Li Xiang, Liangqing Zhang.
       BACKGROUND: Myocardial ischemia/reperfusion injury triggers profound metabolic reprogramming and lactate accumulation. However, how this metabolic stress regulates inflammatory gene expression remains poorly understood. We hypothesized that lactylation, a lactate-derived posttranslational modification, links metabolic stress to aberrant RNA splicing and cardiac inflammation through the RNA-binding protein HNRNPK (heterogeneous nuclear ribonucleoprotein K).
    METHODS: We analyzed atrial tissues from patients undergoing cardiopulmonary bypass and murine ischemia/reperfusion hearts to assess lactylation dynamics. Lactylation-specific proteomics, RNA sequencing, and crosslinking and immunoprecipitation followed by quantitative polymerase chain reaction were used to identify HNRNPK targets. Mechanisms were defined using site-directed mutagenesis (HNRNPK-K405R), isoform-specific overexpression, and a therapeutic splice-switching antisense oligonucleotide in mice and cardiomyocytes.
    RESULTS: Reperfusion significantly increased global protein lactylation in human and murine myocardium. Proteomics identified HNRNPK as a key target, specifically lactylated at lysine 405 (K405la). Ischemia-induced K405la promoted HNRNPK binding to Jag2 pre-mRNA, suppressing exon 10 skipping and shifting splicing from the Jag2 (Jagged2) short (Jag2-S) to the long (Jag2-L) isoform. Jag2-L, but not Jag2-S, exhibited high affinity for Notch1, hyperactivating Notch-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and exacerbating inflammation and infarct size. Mice expressing a lactylation-deficient variant (HNRNPK-K405R) were protected from ischemia/reperfusion injury. Treatment with a specific antisense oligonucleotide (Jag2-i9) that blocks the HNRNPK-Jag2 interaction prevented Jag2-L production and attenuated cardiac dysfunction.
    CONCLUSIONS: HNRNPK lactylation acts as a metabolic sensor coupling lactate accumulation to pathogenic Jag2 splicing. Targeting this metabolic-splicing axis offers a precise therapeutic strategy to limit inflammation and preserve cardiac function in ischemic heart disease.
    REGISTRATION: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR2400091959.
    Keywords:  alternative splicing; inflammation; metabolic reprogramming
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.081410
  39. Nat Commun. 2026 Aug 13. pii: 9701. [Epub ahead of print]17(1):
    Commensal bacteria inhibit viral infections via a tryptophan metabolite.
    Danting Jiang, Nicole Soo, Chin Yee Tan, Sedem Dankwa, Hsuan-Yuan Wang, Barbara S Theriot, Keyi Xue, Demitrius Hill, Amir Ardeshir, James R Bain, Sarah M Heston, Jillian H Hurst, Nazema Y Siddiqui, Koen K A Van Rompay, Luisa Cervantes-Barragan, Jonathan P Smith, Rinn Song, Jatin Roper, Matthew S Kelly, Michael G Hudgens, Kristina De Paris, Sallie R Permar, Ria Goswami, Neeraj K Surana.
      Clinical outcomes following viral exposures exhibit substantial interindividual variability. Although developing evidence suggests commensal bacteria modulate viral infections, the specific bacteria and mechanisms remain underexplored. Here, we define a pathway by which viral infections are inhibited by specific tryptophan-catabolizing bacteria. Using HIV as a model, we bioinformatically associated and experimentally validated several bacterial species that inhibited viral replication. This activity required the aromatic amino acid aminotransferase (ArAT) to metabolize tryptophan into 3-indolelactic acid, which agonizes the aryl hydrocarbon receptor (AhR). Given that AhR regulates multiple viral infections, we found that commensal bacteria also inhibit cytomegalovirus (CMV) in an ArAT-dependent manner. Finally, we used fecal shotgun metagenomic data to confirm that ArAT is associated with improved disease outcomes in three distinct human cohorts at-risk for HIV, CMV, or symptomatic COVID-19. Taken together, our results provide mechanistic insight into how commensal bacteria impact viral infections, thereby adding to an emerging field focused on host-commensal-virus interactions.
    DOI:  https://doi.org/10.1038/s41467-026-76412-8
  40. ACS Nano. 2026 Sep 08. 20(35): 24284-24304
    Covalently Self-Polymerized Bioactive Poly(dopamine-silicon) Nanoplatform Reprograms Macrophage Metabolism, Modulates Redox Homeostasis, and Promotes Efficient Angiogenesis for Inflammation Injury Repair.
    Yidan Wang, Ting Li, Tongtong Leng, Meng Luo, Mi Chen, Wenhao Zhou, Bo Lei.
      The inflammation-related tissue injury repair is still a challenge, in which the metabolic disturbance of macrophages induces cascade amplification of inflammatory mediators and hinders tissue repair. Herein, we developed covalently self-assembled poly(dopamine-silicon) nanoparticles (DS NPs) that integrate enzyme-mimetic catalysis with bioactive ion release to achieve sequential redox modulation and metabolic immune regulation in infected wounds and lung injury models. The covalent linkage reorganized dopamine into a stable amorphous network, preventing π-π stacking and exposing reactive catechol groups, thereby enhancing antioxidant and superoxide dismutase-like activities, which efficiently eliminated reactive oxygen/nitrogen species and corrected oxidative imbalance. Meanwhile, DS NPs supported mitochondrial oxidative phosphorylation and modulated macrophage polarization toward an M2 phenotype with an 89% reduction in TNF-α expression. The immunometabolic reprogramming promoted the transition from inflammation to regeneration, while the sustained release of bioactive silicate ions synergistically promoted angiogenesis by upregulating ANG expression in HUVECs by 2.06-fold. As a proof of concept, in MRSA-infected wound and the early inflammatory stage of acute lung injury models, DS NPs suppressed cytokine overexpression, accelerated re-epithelialization, and restored microvascular integrity. This work demonstrates a biomimetic hybrid platform that can integrate modulation of the inflammatory microenvironment, metabolic reprogramming, and tissue regeneration, offering a promising therapeutic strategy for early intervention in inflammation-associated tissue injuries.
    Keywords:  anti-inflammation; mitochondrial homeostasis; polydopamine; self-assembly; siloxane
    DOI:  https://doi.org/10.1021/acsnano.5c20148
  41. Int Immunopharmacol. 2026 Sep 09. pii: S1567-5769(26)01233-6. [Epub ahead of print]189 117386
    Metabolic-epigenetic reprogramming of airway fibroblasts by K + N therapy suppresses IL-33 and ameliorates allergic asthma.
    Xiangdong Sun, Yuanyi Zhang, Yadong Zheng, Yang Mi, Huang Huang, Yong Yu, Liguo Li, Pingchang Yang, Pengyuan Zheng.
       BACKGROUND: Allergic asthma is a prevalent Th2-driven chronic inflammatory airway disease. While lung fibroblasts and fibroblast-derived IL-33 critically regulate airway inflammation, the fibroblast-specific role of IL-33 and the therapeutic mechanism of the immune regulatory small-molecule KQS1 and nicotinamide (K + N) remain poorly understood.
    METHODS: We utilized fibroblast-specific Il33 conditional knockout mice in an ovalbumin-induced allergic asthma model. We characterized baseline fibroblast physiology, K + N therapeutic efficacy, and the underlying metabolic and epigenetic mechanisms. Partial shRNA-mediated knockdown of Il33 was performed to rule out therapeutic floor effects, and primary human airway fibroblasts from healthy donors and patients with asthma were used for translational validation.
    RESULTS: Fibroblast-specific Il33 deletion did not alter homeostatic fibroblast physiology but significantly attenuated allergen-induced asthmatic pathology. The therapeutic benefits of K + N-including reduced airway hyperresponsiveness, inflammation, and goblet cell hyperplasia-were completely abrogated in fibroblast-specific Il33 knockout mice, demonstrating strict dependency on fibroblast IL-33. Mechanistically, K + N retained the capacity to elevate NAD/α-KG ratios and reduce Il33 locus H3K27ac enrichment even in IL-33-deficient fibroblasts, uncoupling K + N's upstream metabolic/epigenetic reprogramming from its downstream IL-33-mediated anti-asthmatic effects. Partial Il33 knockdown confirmed IL-33 as a non-redundant target. In human asthmatic fibroblasts, K + N rescued dysregulated NAD-glycolysis metabolism and suppressed elevated IL33 and IL13 expression via conserved reduction of IL33 promoter H3K27ac enrichment.
    CONCLUSION: This study identifies a conserved fibroblast-intrinsic NAD-epigenetic-IL-33 axis. K + N-driven metabolic and epigenetic reprogramming relies on intact fibroblast IL-33 to exert its anti-asthmatic functions, highlighting this axis as a promising translational therapeutic target for allergic asthma.
    Keywords:  Allergy; Fibroblast; Immunity; Inflammation; Therapy
    DOI:  https://doi.org/10.1016/j.intimp.2026.117386
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