bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–09–27
53 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. HSV-1 UL42 and UL47 hijack cellular nucleotide synthetic enzyme CAD to promote lytic replication.
  2. Metabolic Reprogramming Of Macrophages In Breast Cancer: Mechanisms And Therapeutic Implications.
  3. Green Pomegranate Waste Extract Modulates Macrophage Immunometabolism by Suppressing the ACLY-ME1 Axis and Promotes Pro-Resolving Macrophage Functions.
  4. The kynurenine pathway in RNA virus infection: immunometabolic control of antiviral defense and viral persistence.
  5. Itaconate metabolism in regulated cell death.
  6. Serine protease inhibitor from Trichinella spiralis ameliorates diet-induced obesity and adipose tissue inflammation through TIM-3-dependent macrophage reprogramming.
  7. Immunometabolism in Obesity-Associated Type 2 Diabetes: Molecular Mechanisms and Emerging Therapeutic Targets.
  8. Linoleic Acid Enhances Murine Natural Killer Cell Function In Vitro but Compromises Mitochondrial Bioenergetic Function During Retroviral Infection.
  9. Type VI secretion system effectors as modulators of host immunometabolism: organelle stress, nutritional immunity, and therapeutic opportunities.
  10. Chemoproteomic profiling of itaconate-derived protein modifications.
  11. Lactate as a Potential Exercise-Induced Signaling Molecule: Implications for Immunometabolic Adaptation Following HIIT.
  12. Metabolic reprogramming of decidual macrophages impairs maternal-fetal interface homeostasis and contributes to recurrent spontaneous abortion.
  13. Itaconation and Succination as Metabolite-Derived Cysteine Modifications in Inflammatory Signalling: Biochemical Mechanisms, Chemoproteomic Mapping, and Therapeutic Opportunities.
  14. The Role of Glucose Metabolism in Xenopus Primitive Myeloid Cell Development and Function.
  15. S-palmitoylation at the interface between lipophagy and macrophage immunometabolism in sepsis: mechanistic evidence and translational questions.
  16. Mitochondrial phosphatase PGAM5 negatively regulates the induction of anti-inflammatory macrophages.
  17. The plasticity and metabolic reprogramming of macrophage in ulcerative colitis.
  18. Immunometabolic regulation of cardiac macrophages in heart failure with preserved ejection fraction.
  19. Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells.
  20. A metabolic-oxidative axis contributes to NK cell cryo-vulnerability.
  21. Adipose ILC2s depend on acetyl-CoA carboxylase 1 to maintain metabolic health.
  22. Metabolic profiling of CAR T-cells in patients reveals a shift toward amino acid-supported OXPHOS and informs transporter engineering.
  23. Targeting Metabolic Pathways to Direct T-Cell Trafficking: Therapeutic Perspectives.
  24. Patient-Derived Transcriptomics Reveals Distinct IFNγ-Associated Myeloid States and Mitochondrial Complex I Programs in Rheumatoid Arthritis and Osteoarthritis.
  25. Integrated single-cell multiomics reveals neutrophil-driven immune-metabolic reprogramming of Kupffer cells via thrombospondin-1/CD36 after surgical stress.
  26. mtROS-NF-κB signaling supports ILC3 function and survival during sepsis-induced intestinal injury.
  27. A commensal-derived sugar protects against obesity by regulating immunometabolism.
  28. SLC25 in intestinal inflammation: mechanisms, pathological roles, and therapeutic implications.
  29. Metabolic Reprogramming in Gastric Cancer Immunity Mechanisms and Therapeutic Implications.
  30. Roles of inflammation and metabolic dysfunction in cardiovascular diseases: molecular mechanisms and therapeutic targets.
  31. Magnesium Enhances Immune Clearance of P. gingivalis in Macrophages by Suppressing MCU-Mediated Mitochondrial Calcium Overload.
  32. Single-Cell RNA Sequencing Combined with MEBOCOST Reveals Alveolar Macrophage-Mediated Immunometabolic Communication Mechanisms in Sepsis-Induced Acute Lung Injury.
  33. Engineered Extracellular Vesicle Revitalizing Macrophage Energy Metabolism for Aged Wound Repair.
  34. Gut microbiota-derived riboflavin mediates protective effects of MUC2 in acute pancreatitis via CD40-macrophage pathway.
  35. Mechanistic Study of SRSF1-Mediated Inhibition of Treg Cell Function via the mTORC1/ULK1 Signalling Axis Through Mitophagy in Asthma.
  36. The Caenorhabditis elegans microbiome impacts microsporidia infection through nutrient limitation and spore inactivation.
  37. African swine fever virus remodels cellular host metabolism and promotes lipid droplet formation in macrophages and cell lines.
  38. Alcohol reshapes liver zonal plasticity and immune-metabolic reprogramming in metabolic-syndrome associated hepatocellular carcinoma.
  39. Short-Chain Fatty Acids at the Crossroads of Microbiota, Immunometabolism, and Inflammation.
  40. Δ9-Tetrahydrocannabinol exposure shifts eosinophil and macrophage transcriptional programs towards an anti-inflammatory phenotype in helminth infection.
  41. Myosteatosis in type 1 diabetes: immunometabolic mechanisms, biomarkers, and therapeutic targets.
  42. A Unified Mechanistic Framework for Copper Toxicity in Neutrophils: Metabolic Rewiring, Cell-Death Crosstalk, and Immune Dysfunction.
  43. Untargeted Lipidomics Reveals Lipid Alterations in Colonic Contents of C57BL/6J Mice with Acute Toxoplasma gondii Infection.
  44. Vibrio vulnificus hemolysin drives NLRP3 inflammasome activation in platelets via TRPC6-mediated calcium signaling.
  45. Microbial-associated acylated putrescines as immunomodulatory molecules in inflammatory bowel diseases.
  46. Photoreceptor outer segments promote the accumulation of lipid droplets in microglia by reprogramming lipid metabolism.
  47. Copper homeostasis in macrophages: regulatory mechanisms and immunological implications.
  48. Short-chain fatty acids promote post-myocardial infarction cardiac repair via FFAR2-dependent suppression of osteoclast-like macrophage differentiation.
  49. FABP4/5-Mediated Lipid Reprogramming Is Associated with Immunosuppressive T Cell Crosstalk in Cervical Cancer After Chemoradiotherapy.
  50. Gas6/Axl-mediated macrophage hyporesponsiveness drives severe pulmonary mucormycosis in diabetic mice.
  51. Microbiota-Associated Amino Acid Metabolites in Inflammatory Bowel Disease: Emerging Key Players in the Host-Microbe Interface.
  52. Host soluble inositol phosphate signaling promotes coronavirus replication.
  53. A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer.
  1. J Virol. 2026 Sep 24. e0092026
    HSV-1 UL42 and UL47 hijack cellular nucleotide synthetic enzyme CAD to promote lytic replication.
    Chao Qin, Xinchi Xie, Taolin Xie, Zhenhao An, Woo-Chang Chung, Pinghui Feng.
      Cellular metabolic enzymes are well defined for their roles in metabolism, and their function beyond metabolism is poorly defined. Here, we report that herpes simplex virus 1 (HSV-1) couples evasion of the inflammatory response to metabolic activation to promote lytic replication. Specifically, HSV-1 activates carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD), which catalyzes the rate-limiting steps of de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. RelA deamidation suppresses NF-κB activation and the inflammatory response while simultaneously upregulating key glycolytic enzymes to promote aerobic glycolysis. Further affinity purification and functional assays identified HSV-1 UL42 and UL47 that interact with and activate CAD, recapitulating the phenotypes of RelA deamidation. Collectively, our work uncovers a role for a metabolic enzyme in coupling immune evasion to metabolic activation through its protein deamidase activity during HSV-1 infection, highlighting a potential therapeutic target.IMPORTANCEHost immune defense and cellular metabolism are two fundamental processes that shape viral pathogenesis. Here, we revealed that herpes simplex virus 1 (HSV-1) activates a nucleotide synthetic enzyme not only to support nucleotide synthesis but also to exploit its unconventional activity for immune evasion and metabolic reprogramming, highlighting a potential therapeutic target.
    Keywords:  CAD; HSV-1; aerobic glycolysis; deamidation; inflammatory response; pyrimidine synthesis
    DOI:  https://doi.org/10.1128/jvi.00920-26
  2. Cancer Treat Res Commun. 2026 Sep 19. pii: S2468-2942(26)00287-X. [Epub ahead of print]49 101376
    Metabolic Reprogramming Of Macrophages In Breast Cancer: Mechanisms And Therapeutic Implications.
    Jiaoyu Zhang, Rui Yang.
      As key immune cells in the tumor microenvironment (TME), macrophages polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, with their functional states tightly linked to metabolic pathway dynamics. This review comprehensively examines macrophage metabolic reprogramming in glycolysis, lipid metabolism, glutamine metabolism, the pentose phosphate pathway (PPP), mitochondrial function, the tricarboxylic acid (TCA) cycle, and amino acid metabolism, while exploring their implications for breast cancer's immune microenvironment and therapeutic approaches. In M1 macrophages, glycolysis is significantly enhanced, promoting the inflammatory response through lactate accumulation and reactive oxygen species (ROS) production. Simultaneously, the TCA cycle is disrupted at the citrate and succinate nodes, leading to the accumulation of metabolic intermediates and further strengthening the pro-inflammatory phenotype. On the other hand, M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). They regulate epigenetic modifications through metabolites such as alpha-ketoglutarate (α-KG) to maintain anti-inflammatory and tissue repair functions. Breast cancer cells reprogram macrophages via glutamine competition and exosome secretion, driving M2 polarization to support tumor progression. Different molecular subtypes exhibit distinct metabolic features: triple-negative breast cancer (TNBC) shows high glycolytic activity and glutamine addiction, whereas hormone receptor-positive breast cancer relies more on exogenous amino acid uptake. Targeting glycolysis or glutamine metabolism can revert tumor-associated macrophages (TAMs) to an anti-tumor M1-like state, boosting immunity. Although metabolic intervention strategies (such as inhibiting key enzymes hexokinase 2 (HK2), glutaminase (GLS), or fatty Acid Binding Protein 4 (FABP4)) show therapeutic potential, existing studies still have limitations: the compensatory effects between metabolic pathways, tumor heterogeneity, and insufficient clinical translation. Emerging strategies, including metabolic checkpoint targeting, CAR-macrophages (CAR-M), and biomimetic nanocarrier-based delivery systems, hold promise for overcoming these challenges. In summary, in-depth elucidation of the molecular mechanisms underlying macrophage metabolic reprogramming and their metabolic crosstalk with breast cancer cells will provide new insights and novel therapeutic targets for the precise immunometabolic therapy of breast cancer.
    Keywords:  Breast cancer; Macrophage; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ctarc.2026.101376
  3. Biomedicines. 2026 Aug 29. pii: 1948. [Epub ahead of print]14(9):
    Green Pomegranate Waste Extract Modulates Macrophage Immunometabolism by Suppressing the ACLY-ME1 Axis and Promotes Pro-Resolving Macrophage Functions.
    Paolo Convertini, Simona Todisco, Michela Marsico, Alessandro Santarsiere, Ernesto Santoro, Antonio Evidente, Pierluigi Reveglia, Lucia Lecce, Stefano Superchi, Anna Santarsiero, Vittoria Infantino.
      Background: Immunometabolic reprogramming is increasingly recognized as a fundamental driver of macrophage inflammatory activation. Although pomegranate polyphenols have been widely investigated for their anti-inflammatory activity, the underlying metabolic mechanisms remain poorly understood. Here, we investigated whether a pomegranate waste extract (PWE), obtained through a sustainable dimethyl carbonate (DMC)-based extraction process, modulates macrophage activation by targeting immunometabolic pathways. Methods: Human PBMC-derived macrophages stimulated with LPS and IFN-γ were treated with PWE. Inflammatory mediators, NF-κB transcription factor, histone H3 acetylation, and markers of inflammatory resolution were evaluated. Furthermore, the enzymatic activity of ATP citrate lyase (ACLY) and malic enzyme 1 (ME1) was determined. Rescue experiments with acetate, malate, and NADPH were performed to investigate the functional contribution of the ACLY-ME1 metabolic axis. Results: PWE significantly reduced NF-κB activation and the production of IL-1β, IL-6, TNF-α, ROS, NO•, and PGE2 without affecting cell viability. Mechanistically, PWE functionally suppressed ACLY and ME1, two central enzymes linking citrate metabolism to cytosolic acetyl-CoA and NADPH generation. Indeed, acetate supplementation restored PGE2 production and inflammatory cytokine secretion, whereas malate and NADPH rescued oxidative mediator production. PWE also lowered histone H3 acetylation, indicating that metabolic remodeling affected epigenetic regulation of inflammatory gene expression. Finally, PWE increased the expression of CPT1A, SLC25A20, Annexin A1, and FPR2, while enhancing IL-10 and 15-HETE secretion, consistent with activation of pro-resolving macrophage programs. Conclusions: These findings demonstrate that DMC-extracted PWE suppresses inflammatory macrophage activation primarily through immunometabolic modulation. By targeting the ACLY-ME1 metabolic axis, PWE limits acetyl-CoA- and NADPH-dependent inflammatory processes and fosters a shift toward a pro-resolving macrophage phenotype. Our work identifies this sustainable pomegranate waste extract as a promising modulator of macrophage immunometabolism.
    Keywords:  ACLY; ME1; immunometabolism; macrophage; pomegranate; pro-resolving macrophage program
    DOI:  https://doi.org/10.3390/biomedicines14091948
  4. Front Immunol. 2026 ;17 1923351
    The kynurenine pathway in RNA virus infection: immunometabolic control of antiviral defense and viral persistence.
    Daniela Nahomi Calderón-Sandate, Manuel Josafat Huerta-Garza, Blanca Azucena Márquez-Reyna, David Mauricio Cañedo-Figueroa, Ximena Hernández-Rodríguez, Flor Itzel Lira-Hernández, Juan Fidel Osuna-Ramos, Jaime Cardoso-Ortiz, Rosa María Del Ángel, Alan Orlando Santos-Mena, Luis Adrián De Jesús-González.
      RNA virus infections are shaped by the interplay among viral replication, innate immune sensing, and host metabolism, which together determine the magnitude, duration, and quality of antiviral responses. The tryptophan-kynurenine (Trp-Kyn) pathway has emerged as an important immunometabolic axis linking interferon-driven inflammation, amino acid availability, immune-cell function, tissue homeostasis, and viral persistence. This review examines the roles of indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, tryptophan 2,3-dioxygenase (TDO), Trp depletion, general control nonderepressible 2 (GCN2) signaling, mechanistic target of rapamycin complex 1 (mTORC1), Kyn-derived metabolites, and aryl hydrocarbon receptor (AhR) activation in host responses to RNA virus infection. We integrate genetic, pharmacological, cellular, animal, and clinical evidence across positive-sense and negative-sense single-stranded RNA viruses, double-stranded RNA viruses, and reverse-transcribing RNA viruses, including SARS-CoV-2, dengue virus, Zika virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, rotavirus, reovirus, HIV-1, and SIV. Across these systems, the Trp-Kyn-AhR axis can influence interferon responses, viral replication, immune-cell function, tissue injury, and disease outcome. EMCV myocarditis provides causal proof of principle, whereas other RNA-virus models provide complementary functional and clinical evidence. Importantly, pathway activation does not confer a uniform antiviral or pathogenic phenotype; its biological consequences depend on viral class, tissue tropism, viral burden, inflammatory intensity, cell type, and disease stage. On this basis, we propose a time-phase model in which early or excessive IDO1-Kyn-AhR signaling may impair type I interferon responses, NK-cell function, CD8+ T-cell expansion, and viral clearance, whereas appropriately regulated activation during later inflammatory or resolution phases may limit immunopathology, support epithelial repair, and preserve tissue homeostasis. Persistent or dysregulated activation may instead contribute to exhaustion-like immune states, chronic inflammation, neuroimmune dysfunction, and post-acute viral sequelae. Finally, we discuss phase-adapted therapeutic strategies, including IDO1 inhibition, AhR agonism or antagonism, KMO-directed modulation, Trp-based entry inhibitors, and biomarker-guided combination approaches. Together, these findings position the Trp-Kyn-AhR axis as a dynamic, context-dependent target for precision host-directed antiviral immunometabolism.
    Keywords:  IDO1; RNA viruses; antiviral immunity; aryl hydrocarbon receptor; host-directed antiviral therapy; immunometabolism; tissue repair; tryptophan-kynurenine pathway
    DOI:  https://doi.org/10.3389/fimmu.2026.1923351
  5. Mol Cell Biochem. 2026 Sep 21.
    Itaconate metabolism in regulated cell death.
    Daolin Tang, Rui Kang.
      Itaconate, a metabolite generated from the tricarboxylic acid cycle through aconitate decarboxylase 1 (ACOD1, also known as IRG1), has emerged as a key link between cellular metabolism, immunity, and regulated cell death. Although initially recognized for its anti-inflammatory properties, accumulating evidence indicates that the biological functions of itaconate extend far beyond immunomodulation to encompass multiple forms of regulated cell death. The ACOD1-itaconate axis regulates apoptosis, ferroptosis, pyroptosis, necroptosis, and other emerging cell-death programs through coordinated control of mitochondrial metabolism, redox homeostasis, inflammatory signaling, and covalent protein modification. These effects are context dependent and are further shaped by the distinct biological activities of endogenous itaconate, synthetic derivatives, and the recently recognized itaconate-independent functions of ACOD1. In this review, we summarize recent advances in immunometabolism and regulated cell death, discuss the mechanistic basis by which the ACOD1-itaconate axis governs cell fate, and highlight how intercellular metabolic communication and non-canonical ACOD1 signaling expand its biological functions. We also highlight unresolved questions regarding target selectivity, context-dependent signaling, and therapeutic translation. A deeper understanding of the ACOD1-itaconate network may provide new insights into therapeutic strategies targeting regulated cell death in inflammatory diseases, infection, and cancer.
    Keywords:  ACOD1; Immunometabolism; Itaconate; Protein itaconation; Regulated cell death
    DOI:  https://doi.org/10.1007/s11010-026-05743-3
  6. PLoS Pathog. 2026 Sep;22(9): e1014606
    Serine protease inhibitor from Trichinella spiralis ameliorates diet-induced obesity and adipose tissue inflammation through TIM-3-dependent macrophage reprogramming.
    Mingwei Tong, Ge Liu, Guidong Ren, Wangxuan Zhang, Yuyu Qiao, Xiaodan Yang, Weiping Fan, Hui Yang, Yong Yang.
      Pro-inflammatory M1 polarization of adipose tissue macrophages (ATMs) drives adipose inflammation and obesity, suggesting that reprogramming ATM polarization holds therapeutic promise. Parasitic helminths have co-evolved with hosts to induce immune tolerance via M2 polarization, making helminth-derived M2-inducing molecules a potential therapeutic strategy against metabolic disorders. This study aimed to develop a defined serine protease inhibitor derived from Trichinella spiralis (Ts-SPI) as a novel immunomodulatory candidate against diet-induced metabolic disorders. In a high-fat diet (HFD)-induced obese mouse model, recombinant Ts-SPI (rTs-SPI) attenuated obesity and adipose tissue inflammation, and this effect was associated with its ability to reprogram macrophage polarization. In vitro studies confirmed that rTs-SPI drives phenotypic changes in both RAW264.7 cells and bone marrow-derived macrophages (BMDMs). Notably, a free fatty acid (FFA)-stimulated inflammatory adipocyte model and adoptive transfer assays demonstrated that rTs-SPI-reprogrammed macrophages mediate the anti-obesity and anti-inflammatory effects. Mechanistically, TIM-3 was identified as a key mediator through in vivo TIM-3 blockade assays. Pharmacological inhibition revealed downstream PI3K/AKT/mTOR signaling. In summary, this study identifies a parasite-derived protein as a potent TIM-3-targeting biologic candidate for treating metabolic inflammation, proposes a novel "helminth-inspired checkpoint modulation" strategy, and provides new insight into parasite-host immune crosstalk.
    DOI:  https://doi.org/10.1371/journal.ppat.1014606
  7. Int J Mol Sci. 2026 Sep 10. pii: 8063. [Epub ahead of print]27(18):
    Immunometabolism in Obesity-Associated Type 2 Diabetes: Molecular Mechanisms and Emerging Therapeutic Targets.
    Carlo Acierno, Massimiliano Cavallo, Damiano D'Ardes, Andrea Boccatonda, Davide Nilo, Alfredo Caturano.
      Type 2 diabetes (T2D) is increasingly understood as a chronic, low-grade inflammatory disease in which immune and metabolic signalling are bidirectionally coupled. Nutrient excess drives glucolipotoxic stress in adipose tissue, liver, skeletal muscle and pancreatic islets, engaging innate immune sensors. Responding immune cells then reconfigure their own intermediary metabolism, and the resulting metabolites-succinate, which stabilises hypoxia-inducible factor-1α, and the itaconate that opposes it-themselves specify inflammatory output. These signals converge on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, gasdermin D-mediated pyroptosis and interleukin-1β (IL-1β) release, which interrupt insulin signalling through inhibitory serine phosphorylation of insulin receptor substrate-1. Mitochondrial dysfunction, impaired mitophagy and cytosolic mitochondrial DNA sensing sustain the loop, while gut barrier failure supplies a parallel systemic input that converges on beta-cell dysfunction. This narrative review synthesises these mechanisms and examines how metformin, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors and inflammasome-directed agents intersect with them. The chain described is that of obesity-associated T2D, and the heterogeneity that limits its generalisation across the recognised subgroups of the disease is addressed explicitly rather than assumed away. We give particular weight to a dissociation that constrains the field: sustained IL-1β neutralisation reduced cardiovascular events without preventing incident diabetes. Establishing why is, in our view, the central question for immunometabolic therapeutics in T2D.
    Keywords:  NLRP3 inflammasome; adipose tissue macrophages; beta-cell dysfunction; gut microbiota; immunometabolism; insulin resistance; macrophage metabolic reprogramming; metaflammation; mitochondrial dysfunction; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms27188063
  8. Immunology. 2026 Sep 20.
    Linoleic Acid Enhances Murine Natural Killer Cell Function In Vitro but Compromises Mitochondrial Bioenergetic Function During Retroviral Infection.
    Vaasudevan Sridhar, Simone Schimmer, Tanja Werner, Rachel Giesen, Mohamed Saad, Constantin P Krempe, Sven W Meckelmann, Ulf Dittmer, Elisabeth Littwitz-Salomon.
      Natural killer (NK) cells are innate immune cells that eliminate virus-infected and tumour cells by a plethora of signalling pathways, involving the production of cytokines and cytotoxic molecules. NK cell activation and functions demand substantial energy and fatty acids are energy-rich molecules reported to be important for NK cell functions upon viral infections. However, it remains unclear whether NK cells preferentially take up a specific fatty acid. Here, we show in the acute Friend retrovirus infection of mice that linoleic acid (LA) exerts a dual role in modulating NK cells. Interestingly, NK cells increased the uptake of LA upon virus infection in vitro and in vivo, with higher LA uptake correlating with increased activation of NK cells. While ex vivo stimulation with LA increased the expression of cytolytic molecules and subsequently elicited increased target cell killing, it paradoxically decreased the NK cell proliferative capacity, mitochondrial metabolism and increased the cellular stress. To further elucidate the role of LA in vivo, we treated mice with exogenous LA during retrovirus infection. While we observed a significant increase of LA levels in the spleen, splenic NK cell activation, cytotoxicity and viral loads were not altered by LA therapy. In addition, we found a decrease in mitochondrial mass and energy levels in NK cells after LA treatment, reflecting its strong effect on mitochondrial metabolism. Our results demonstrate the importance and direct impact of LA for NK cell functions and their metabolic profile. The dual role of LA in enhancing NK cell responses while compromising mitochondrial integrity highlights its potential as a therapeutic adjuvant, alongside other fatty acids, to modulate NK cell functions.
    Keywords:  fatty acids; linoleic acid; metabolism; natural killer cells; retrovirus infection
    DOI:  https://doi.org/10.1111/imm.70205
  9. Front Microbiol. 2026 ;17 1951748
    Type VI secretion system effectors as modulators of host immunometabolism: organelle stress, nutritional immunity, and therapeutic opportunities.
    Zhenzhen Zhang, Zhen Hou.
      Metabolic reprogramming is a central determinant of host defense and pathogen persistence during infection. Although the bacterial type VI secretion system (T6SS) is primarily recognized as a contact-dependent apparatus for interbacterial competition and effector delivery, emerging evidence indicates that T6SS activity can also influence host metabolism at cellular, nutritional, and microbial-community levels. Here, we organize current evidence into three mechanistic tiers: direct biochemical interference with lipids, metabolites, or metal ions; organelle- and signaling-mediated immunometabolic reprogramming; and indirect metabolic effects arising from T6SS-dependent remodeling of microbial communities. T6SS effectors can disrupt endoplasmic-reticulum lipid homeostasis, activate the unfolded protein response and autophagy, alter mitochondrial Ca2+ handling and dynamics, promote redox imbalance, and modulate metabolically sensitive immune pathways including phosphoinositide 3-kinase (PI3K)-Akt, inflammasome, and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. T6SS-associated proteins also mediate manganese and zinc acquisition or sequestration, linking microbial nutrient acquisition to host nutritional immunity. At the community level, T6SS-mediated competition may reshape resource allocation, horizontal gene transfer, and microbiome-derived metabolite production. However, while T6SS-induced organelle stress is well established, direct causal links to systemic metabolic diseases, including type 2 diabetes and dyslipidemia, remain unproven. We therefore distinguish direct metabolic measurements from inferences based on organelle damage or signaling changes and discuss strategies to define T6SS-driven metabolic fluxes and evaluate host-directed, anti-virulence, and microbiome-engineering approaches. Viewing the T6SS through an immunometabolic framework may reveal therapeutic vulnerabilities overlooked by conventional models of bacterial toxicity and competition.
    Keywords:  endoplasmic reticulum stress; host-directed therapy; immunometabolism; metabolic reprogramming; mitochondrial dynamics; nutritional immunity; redox homeostasis; type VI secretion system
    DOI:  https://doi.org/10.3389/fmicb.2026.1951748
  10. Cell Chem Biol. 2026 Sep 23. pii: S2451-9456(26)00326-0. [Epub ahead of print]
    Chemoproteomic profiling of itaconate-derived protein modifications.
    Youjia Wang, Chu Wang.
      Itaconate is an emerging immunomodulatory metabolite produced in macrophages upon inflammatory activation and exhibits both immunoregulatory and bacterial-regulatory properties. Structurally, itaconate is a reactive α,β-unsaturated carboxylic acid that undergoes Michael addition with nucleophilic cysteine residues in proteins, generating a unique type of covalent post-translational modification termed itaconation. Here, we review recent progress in the systematic identification of itaconation by chemoproteomic methods. These studies have identified an expanding repertoire of itaconation targets in both host cells and pathogens, providing mechanistic insight into how itaconate regulates immune responses and modulates pathogen tolerance. We further highlight the recent discovery of lysine itaconylation, a novel acylation mediated by itaconate, and briefly review chemoproteomic studies that have globally profiled the non-covalent targets of this immunoregulatory metabolite. Collectively, these chemoproteomic efforts provide rich resources to guide future functional studies and deepen our understanding of the multifaceted roles of itaconate in host-pathogen interactions.
    Keywords:  chemoproteomics; host-pathogen interface; immunomodulatory metabolite; itaconate; post-translational modifications
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.016
  11. Muscles. 2026 Sep 03. pii: 62. [Epub ahead of print]5(3):
    Lactate as a Potential Exercise-Induced Signaling Molecule: Implications for Immunometabolic Adaptation Following HIIT.
    Amirhossein Ahmadi Hekmatikar, Ana M Celorrio San Miguel, Hamid Rajabi, Farhad Daryanoosh, Enrique Roche, Diego Fernández-Lázaro.
      High-intensity interval training (HIIT) is widely recognized as an effective strategy for improving cardiorespiratory fitness and metabolic health. Beyond these physiological benefits, growing evidence indicates that HIIT may also induce beneficial immunometabolic adaptations. A key exercise-responsive metabolite in this context is lactate, which is increasingly being recognized not as a metabolic waste product but as a bioactive signaling metabolite capable of coordinating metabolic, inflammatory, and immune processes. This narrative review examines current evidence suggesting a potential role for exercise-induced lactate in immune responses associated with HIIT. We summarize the molecular pathways through which lactate may interact with immune cells, including uptake via monocarboxylate transporters (MCT1/MCT4) and SLC5A12, receptor-dependent signaling through GPR81/HCAR1, and epigenetic regulation via histone lactylation. We further discuss the cell-specific effects of lactate on macrophages, dendritic cells, neutrophils, and T lymphocytes, highlighting how these mechanisms may influence immune-cell metabolism, inflammatory regulation, and functional remodeling. A central concept emerging from the current literature is that the biological actions of lactate are highly dependent on the kinetics, duration, and physiological context of exposure. Unlike pathological lactate elevations observed in conditions such as cancer, sepsis, or mitochondrial myopathies-the latter potentially involving an exaggerated lactate response during exercise due to impaired oxidative metabolism-HIIT generates transient systemic lactate elevations as part of a coordinated neuroendocrine and metabolic response. When combined with adequate recovery, these repeated metabolic perturbations may promote hormetic adaptations characterized by improved inflammatory regulation, enhanced immune resilience, and more efficient immunometabolic homeostasis. Conversely, excessive training loads or inadequate recovery may shift these responses toward maladaptive immune stress. Overall, current evidence suggests a paradigm shift in exercise immunology in which lactate should be regarded as one component of an integrated immunometabolic signaling network rather than simply as a marker of anaerobic metabolism. Future mechanistic studies integrating lactate kinetics, immune-cell phenotyping, transporter expression, and lactate-dependent post-translational modifications are needed to clarify the extent to which lactate may contribute to exercise-induced immune remodeling and to guide the development of immunologically informed HIIT protocols.
    Keywords:  GPR81/HCAR1; MCT1; exercise immunology; high-intensity interval training; hormesis; immune adaptation; immunometabolism; inflammation; lactate kinetics; lactate signaling
    DOI:  https://doi.org/10.3390/muscles5030062
  12. Biochem Pharmacol. 2026 Sep 21. pii: S0006-2952(26)00835-X. [Epub ahead of print]254(Pt 2): 118493
    Metabolic reprogramming of decidual macrophages impairs maternal-fetal interface homeostasis and contributes to recurrent spontaneous abortion.
    Shujuan Wu, Huifan Liu, Liangfei Ao, Gengxiang Wu, Jie Li, Zhuoni Xiao, Jing Yang, Hong Zhang, Jiao Chen.
      Recurrent spontaneous abortion (RSA) is a troublesome pregnancy disorder, and metabolic reprogramming of decidual macrophages is implicated in disrupted maternal-fetal interface homeostasis and RSA pathogenesis, yet the specific mechanism remains poorly defined. This study aimed to explore the regulatory role of GTP-binding protein 10 (GTPBP10) in RSA by targeting macrophage metabolic reprogramming. We detected GTPBP10 expression in decidual macrophages from RSA patients and healthy controls, and investigated its effects on macrophage phenotypes, glycolysis and fatty acid oxidation (FAO) via gene overexpression/knockdown, metabolic detection, and multiple molecular experiments. The direct interaction between GTPBP10 and AMPK was verified, and in vivo mouse models and cell co-culture systems were constructed for functional validation. Results showed that GTPBP10 was markedly upregulated in RSA-derived decidual macrophages and induced a pro-inflammatory macrophage phenotype. Mechanistically, GTPBP10 bound and inhibited AMPK phosphorylation, promoting glycolysis while suppressing FAO and causing mitochondrial damage; these aberrations were rescued by the AMPK activator AICAR. In vivo, GTPBP10-overexpressing macrophages increased embryo resorption, impaired placental vasculature and triggered pro-inflammatory immune imbalance. Moreover, macrophage GTPBP10 overexpression inhibited trophoblast motility, impaired endometrial decidualization and biased CD4+ T cells toward Th1/Th17 phenotypes. In conclusion, GTPBP10-mediated AMPK inhibition triggers immunometabolic reprogramming of decidual macrophages, disrupts maternal-fetal immune homeostasis, and ultimately drives the occurrence of RSA, providing a promising therapeutic target for RSA.
    Keywords:  Decidual macrophages; GTPBP10; Maternal–fetal interface; Metabolic reprogramming; Recurrent spontaneous abortion
    DOI:  https://doi.org/10.1016/j.bcp.2026.118493
  13. Cell Biochem Biophys. 2026 Sep 23.
    Itaconation and Succination as Metabolite-Derived Cysteine Modifications in Inflammatory Signalling: Biochemical Mechanisms, Chemoproteomic Mapping, and Therapeutic Opportunities.
    Asif Ahmad Bhat, Shivkanya Fuloria, Riya Thapa, Nina Varghese, Rohini Karunakaran, Sumita Bhatia, Kamal Narain, Anupam Biswas, Sangita Biswas, Neeraj Kumar Fuloria.
      Inflammatory activation rewires cellular metabolism and generates electrophilic metabolites that can modify reactive cysteine residues. This review focuses on two metabolite-derived cysteine modifications: itaconation, driven by aconitate decarboxylase 1 (ACOD1)-dependent itaconate production, and succination, driven by fumarate accumulation. Although both involve cysteine engagement, they differ in chemical stability, metabolite source, cellular distribution, glutathione competition, and functional outcome. Itaconation is linked to Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2) signalling, glycolytic control, kinase regulation, innate immune sensing, interferon responses, and inflammatory cell death, whereas succination is most strongly associated with stable S-(2-succino)cysteine (2SC) formation, fumarate excess, mitochondrial dysfunction, redox stress, inflammasome regulation, and pyroptosis. A central theme of this review is that endogenous itaconate and fumarate must be distinguished from electrophilic derivatives such as 4-octyl itaconate, dimethyl itaconate, and dimethyl fumarate, because these compounds differ in uptake, reactivity, target engagement, and pharmacological interpretation. We distinguish direct adduct mass spectrometry from competitive cysteine profiling and metabolite-mapping approaches, which can quantify bulk adduct burden, relative cysteine engagement, metabolite distribution, or compartment-specific cysteine state, but do not necessarily establish endogenous site occupancy. Proteomic and chemoproteomic approaches can prioritise metabolite-responsive cysteines, but functional relevance requires site-level validation, residue perturbation, and biochemical rescue. By comparing itaconation and succination across chemistry, target selection, inflammatory signalling, and therapeutic translation, this review defines the evidence needed to identify metabolite-sensitive cysteines as genuine regulatory nodes rather than detectable covalent adducts.
    Keywords:  Chemoproteomics; Cysteine Modification; Immunometabolism; Inflammatory Signalling; Itaconation; Succination
    DOI:  https://doi.org/10.1007/s12013-026-02184-z
  14. Int J Mol Sci. 2026 Sep 14. pii: 8175. [Epub ahead of print]27(18):
    The Role of Glucose Metabolism in Xenopus Primitive Myeloid Cell Development and Function.
    Loucas Demetriou, Paris A Skourides, Neophytos Christodoulou.
      Primitive Myeloid Cells (PMCs) arise from the anterior ventral blood islands during Xenopus laevis embryogenesis and migrate to colonize embryonic tissues, contributing to wound healing, innate immunity, and development. Because cell movement and growth are metabolically demanding, we investigated whether metabolic pathways regulate PMC behaviour integrating public single-cell RNA-seq data with whole-mount in situ hybridization (WMISH) to profile metabolic gene expression in PMCs, followed by functional assays using pathway-specific inhibitors: 2-deoxy-D-glucose 2-DG (global glucose metabolism), YZ-9 (glycolysis), 6-AN (pentose phosphate pathway, PPP), and ST045849 (hexosamine biosynthetic pathway, HBP). The analyses showed that PMCs express high levels of glycolytic and ancillary metabolic enzymes. Global inhibition impaired PMC colonization and wound recruitment and modestly reduced the size of the specification domain, confirming a requirement for glycolytic flux. PPP and downstream glycolysis inhibition produced only modest, non-significant shifts in recruitment, whereas HBP inhibition abolished wound recruitment and reduced PMC numbers. These findings identify glucose metabolism as a regulator of PMC colonization and immune function, revealing how metabolic reprogramming governs early immune cell behaviour independent of a functional vasculature.
    Keywords:  Xenopus laevis; cell migration; embryonic development; glucose metabolism; glycolysis; hexosamine biosynthetic pathway; immunometabolism; pentose phosphate pathway; primitive myeloid cells; wound healing
    DOI:  https://doi.org/10.3390/ijms27188175
  15. Int Immunopharmacol. 2026 Sep 20. pii: S1567-5769(26)01288-9. [Epub ahead of print] 117441
    S-palmitoylation at the interface between lipophagy and macrophage immunometabolism in sepsis: mechanistic evidence and translational questions.
    Yisen Wang, Liang Zhang, Liyao Zhang, Hongkun Jiang, Meiling Cao.
      Sepsis seldom presents as a uniform immune phenotype. Inflammation and immune suppression often overlap, but their balance shifts across patients, organs, and illness stages. Macrophages sit within this variation, coordinating cytokine output, microbial clearance, antigen processing, and presentation. Lipophagy removes lipid droplets through selective autophagy. The released fatty acids can feed mitochondrial β-oxidation, helping macrophages balance lipid storage with energy demand. Reduced flux may instead leave excess droplets, compromise mitochondrial function, and blunt antimicrobial activity. Whether this sequence directly drives sepsis-associated immunoparalysis remains uncertain. Protein S-palmitoylation offers a second potential control point through reversible cysteine S-acylation. Studies have linked this modification to ATG16L1 and ATG4B, and to immune regulators including MYD88, NLRP3, and CD80. Most of that evidence, however, comes from models other than sepsis, so its relevance cannot be assumed. This review therefore examines the proposed links among macrophage lipophagy, immunometabolic failure, and sepsis-associated immunoparalysis while keeping experimentally established observations separate from mechanistic inference. Taken together, current findings support S-palmitoylation as a plausible regulatory layer, but they do not establish an integrated causal axis linking S-palmitoylation, lipophagy, and immunometabolism in sepsis. This framework awaits direct testing in primary macrophages, organ-specific sepsis models, and longitudinal clinical cohorts.
    Keywords:  Immunometabolism; Immunoparalysis; Lipophagy; Macrophage; S-palmitoylation; Sepsis
    DOI:  https://doi.org/10.1016/j.intimp.2026.117441
  16. J Leukoc Biol. 2026 Aug 27. pii: qiag127. [Epub ahead of print]118(9):
    Mitochondrial phosphatase PGAM5 negatively regulates the induction of anti-inflammatory macrophages.
    Young Jun Kang.
      Macrophage polarization toward anti-inflammatory phenotypes is essential for the resolution of inflammation and restoration of tissue homeostasis, yet the mitochondrial mechanisms governing this process remain poorly defined. This study identifies a novel role for the mitochondrial membrane protein, phosphoglycerate mutase 5 (PGAM5), as a negative regulator of IL-4-driven anti-inflammatory macrophage polarization. PGAM5 selectively controls IL-4-induced phosphorylation of Janus kinase 1 (JAK1), driving the activation of the downstream transcription factor Signal transducer and activator of transcription 6 (STAT6) and thereby regulating anti-inflammatory macrophage polarization. Importantly, PGAM5-dependent regulation of anti-inflammatory responses is independent of dynamin-related protein 1 (DRP1), contrasting with the DRP1-dependent mechanism by which PGAM5 promotes pro-inflammatory macrophage responses. Furthermore, knockdown of PGAM5 markedly potentiated the IL-4-induced expression of the anti-inflammation markers, such as Il10, Tgfb, Arg1, Fizz1, and Ym1, as well as surface expression of CD163 and CD206. At the metabolic level, PGAM5 knockdown facilitated the metabolic reprogramming of macrophages toward enhanced oxidative phosphorylation and fatty acid oxidation, consistent with the bioenergetic demands of anti-inflammatory polarization. Collectively, these findings establish PGAM5 as a central regulator that oppositely controls macrophage polarization, highlighting its potential as a therapeutic target to modulate macrophage-driven inflammation and resolution.
    Keywords:  gene expression; inflammation; macrophage; metabolism; mitochondrial phosphatase
    DOI:  https://doi.org/10.1093/jleuko/qiag127
  17. Front Immunol. 2026 ;17 1903462
    The plasticity and metabolic reprogramming of macrophage in ulcerative colitis.
    Yi Zhang, Dingquan Yang, Junnan Jiang, Dongxu Wang, Fujian Ji, Ziqian Sun.
      Macrophages exhibit phenotypic plasticity, which plays a role in driving tissue injury and promoting mucosal repair in ulcerative colitis (UC). Intestinal macrophages originate from both embryo-derived resident cells and circulating monocytes. Macrophage polarization influences inflammatory responses and is regulated by cytokines, chemokines, growth factors, and adhesion molecules. Tissue-specific metabolic reprogramming governs macrophage plasticity. Glucose metabolic reprogramming drives M1-like polarization. During glycolysis, mitochondria influence reactive oxygen species (ROS) production which alters the fate of macrophages in UC. Moreover, the communication of cell to cell can also regulate macrophage plasticity. Transcriptomics, proteomics, and single-cell sequencing can be employed to dissect the phenotypes and heterogeneity of macrophage polarization. Numerous clinical trials suggest that regulating macrophage polarization, inhibiting excessive activation of macrophages, blocking the abnormal recruitment of macrophages to intestinal inflammatory sites, macrophage-directed cell therapy, and combination therapy can effectively treat patients with UC. Indeed, the macrophage polarization is characterized by ROS, microbial community and bacterial products in inflammation of the colonic mucosa which is regulated by metabolic programming of macrophages. Indeed, macrophage polarization is characterized by ROS, microbial community, and bacterial products in the inflamed colonic mucosa. The macrophage polarization process is tightly regulated by the metabolic programming. In summary, this review analyzes macrophage plasticity and functional diversity, as well as the metabolic reprogramming and microenvironmental signals that shape macrophage polarization, and offers new insights for macrophage-based clinical interventions in UC.
    Keywords:  inflammation; macrophage polarization; metabolic reprogramming; mitochondrial dynamics; ulcerative colitis
    DOI:  https://doi.org/10.3389/fimmu.2026.1903462
  18. Front Immunol. 2026 ;17 1896936
    Immunometabolic regulation of cardiac macrophages in heart failure with preserved ejection fraction.
    Jiayun Liang, Manman Su, Renjie Liu, Tianlang Li, Ziyan Qin, Yi Wang.
      Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome driven by comorbidities, chronic low-grade inflammation, and cardiac remodeling. Cardiac resident macrophages (CRMs) and monocyte-derived macrophages (MDMs) play central roles in linking immunometabolism to HFpEF pathogenesis. Resident CCR2- macrophages maintain homeostasis and tissue repair, whereas monocyte-derived CCR2+ macrophages drive inflammation, fibrosis, and diastolic dysfunction. In HFpEF, comorbidity-induced metabolic shifts promote pro-inflammatory macrophage polarization, while metabolites like fatty acids, lactate, and succinate modulate these responses through metabolic and epigenetic pathways. Targeting specific macrophage subsets offers promising therapeutic avenues, though challenges like off-target effects and clinical translation remain. This review summarizes cardiac macrophage heterogeneity, immunometabolic crosstalk, and regulatory mechanisms in HFpEF, highlighting emerging subset-specific therapeutic strategies.
    Keywords:  cardiac resident macrophages; heart failure with preserved ejection fraction; immunometabolism; inflammation; monocyte-derived macrophages
    DOI:  https://doi.org/10.3389/fimmu.2026.1896936
  19. Blood. 2026 Sep 21. pii: blood.2026034660. [Epub ahead of print]
    Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells.
    Priyasmita Chakrabarti, Abhishek K Singh, Nicola K Wilson, Iwo Kucinski, Orit Kollet, Lizeth-Alejandra Ordonez Moreno, Arturo Simoni-Nieves, M S Vijayabaskar, Sarah J Kinston, Tzu-Hsuan Chang, Yi-Hao Wang, Montaser Haddad, Angelica Varesi, Ekaterina Petrovich-Kopitman, Ziv Porat, Tatiana Smirnova, Jiffin Paulose, Avik Choudhuri, John Hogenesch, You-Yang Zhao, Ping-Chih Ho, Amnon Buxboim, Leonard I Zon, Marie-Dominique Filippi, Regina P Markus, John E Dick, Stephanie Z Xie, Berthold Gottgens, Jose A Cancelas, Tsvee Lapidot.
      Primitive hematopoietic stem cells (pHSCs) sustain lifelong hematopoiesis through tightly regulated transitions between quiescence and activation. Circadian oscillations influence hematopoiesis; however, the mechanisms coordinating metabolic state and stem cell function daily remain incompletely defined. Here, we show that circadian cues coordinated a program of mitochondrial remodeling, metabolic reprogramming, and structural adaptation in pHSCs. At night, peak melatonin levels were associated with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and activation of DRP1 and PINK1 dependent mitophagy, resulting in enhanced long term repopulating capacity. In parallel, pHSCs exhibited increased glycolytic activity characterized by elevated glucose uptake, GLUT1 expression, AMPK phosphorylation, and HIF1α signaling. Mechanistically, mitochondrial remodeling was regulated in part by melatonin signaling, whereas glycolytic reprogramming was modulated by systemic circadian inputs, including feeding associated cues and Wnt/β-catenin signaling. FoxM1 and DRP1 contributed to mitochondrial quality control, while PGC1α dependent transcription supported compensatory mitochondrial biogenesis across the daily circadian cycle. These metabolic transitions were accompanied by dynamic changes in cell and nuclear size, linked to lamin A/C phosphorylation modulation. These coordinated processes defined a nocturnal state of enhanced stem cell fitness characterized by improved regenerative potential. Key features of glycolytic regulation were conserved in human HSCs, and in vitro melatonin treatment reduced the mitochondrial membrane potential and cell size of human pHSCs. Together, these findings establish a temporally regulated metabolic framework in which circadian cues partition mitochondrial and glycolytic programs to preserve stem cell maintenance and function, adding a new layer to pHSC metabolic physiology with clinical transplantation implications.
    DOI:  https://doi.org/10.1182/blood.2026034660
  20. iScience. 2026 Oct 16. 29(10): 117508
    A metabolic-oxidative axis contributes to NK cell cryo-vulnerability.
    Zujian Mo, Hongwei Yang, Meng Zhang, Huimei Cao, Lingqi Wang, Kun Tao, Xiaoshuai Chen, Caixia Han, Carlos Bustamante, Zhang Liu, Jianjun Wang.
      While immunotherapy has revolutionized cancer and other disease treatment, its clinical application requires effective cryopreservation for scalable manufacturing and global distribution. However, many immune cells exhibit substantial freeze-thaw sensitivity, limiting their scalable production and distribution. Using metabolic flux analysis, ROS quantification, lipidomics, and xenograft models, we identified metabolic state as a determinant of immune cell cryo-sensitivity. Natural killer (NK) cell activation induced a metabolic shift with elevated glucose utilization and excessive ROS, causing profound post-thaw viability and functional loss (∼25% survival). Targeted pretreatments-glucose metabolism inhibitors, antioxidants, and lipid peroxidation inhibitors-restored post-thaw recovery to ∼90% while preserving effector activity and antitumor efficacy in immunodeficient mice. Similar protection in αβ T cells, γδ T cells, and macrophages indicates that metabolic and oxidative features broadly emerge as key determinants of immune cell cryopreservation sensitivity. These findings support a metabolic-oxidative axis as an important feature associated with NK cell cryo-vulnerability.
    Keywords:  ACSL4; NK cells; ROS; cryo-induced cellular injury; cryopreservation; ferroptosis-related pathways; glucose metabolism; immune cell therapy; lipid peroxidation; metabolic reprogramming; natural killer cells; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.isci.2026.117508
  21. Cell Metab. 2026 Sep 23. pii: S1550-4131(26)00371-2. [Epub ahead of print]
    Adipose ILC2s depend on acetyl-CoA carboxylase 1 to maintain metabolic health.
    Fotios Karagiannis, Maria Rafailia Theodorou, Fabian Nikolka, Maria Doverman, Dhruvi Shah, Chantal Wientjens, Timothy R McCulloch, Ronja Kardinal, David Colon, Jelena Zurkovic, Jiangyan Yu, Julia Anna Noras, Patricia Weiss, Roman Rombo, Tim Sparwasser, Zeinab Abdullah, Felix Meissner, Christoph Thiele, Jan Hasenauer, Dagmar Wachten, Karsten Hiller, Christoph Wilhelm.
      Adipose group 2 innate lymphoid cells (ILC2s) are essential to maintain metabolic homeostasis. Obesity severely impairs the number and function of ILC2s, resulting in the progression of metabolic inflammation. How ILC2s are perturbed in obesity remains unknown. Here, we find that high-fat diet (HFD)-induced obesity in mice increases fatty acid oxidation, leading to suppression of acetyl-coenzyme A (CoA) carboxylase 1 (ACC1) in adipose ILC2s. ACC1 is essential for maintaining the citrate shuttle, NAD+/NADH balance, and cellular metabolism. Mimicking the effects of HFD, ACC1 deletion impairs differentiation, maintenance, and function of ILC2s. This results in adipose tissue hypertrophy and inflammation at steady state, predisposing mice to the development of diabetes. Supplementing with the NAD+ precursor nicotinamide riboside rescues ACC1 deficiency, restoring ILC2 function and adipose tissue homeostasis. These findings establish ACC1 as a critical regulator of adipose ILC2 maintenance and function and provide a rationale for the adverse effects of ACC inhibition in obesity.
    Keywords:  ACC1; ILC2; NAD+/NADH; SLC25A1; adipose tissue; fatty acids; innate lymphoid cells; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.019
  22. Res Sq. 2026 Sep 15. pii: rs.3.rs-10832865. [Epub ahead of print]
    Metabolic profiling of CAR T-cells in patients reveals a shift toward amino acid-supported OXPHOS and informs transporter engineering.
    Naomi Taylor, Josquin Moraly, Taisuke Kondo, King Chan, Sooraj Achar, Makoto Ando, Marie Pouzolles, Bonnie Yates, Alexandra Dreyzin, Mehdi Benzaoui, Alka Dwivedi, Saliha Majdoul, Justin Mirazee, Jaehyun Suh, Angela Su, Cedric Mongellaz, Hannah Dada, Swapna Vidhur Dautalabad, Krithikha Bhuvaneshwar, Mina O Seedhom, Valerie Zimmermann, Sandrina Kinet, Daniel Crooks, Hannah Song, Jonathan Yewdell, Christopher Chien, Olivier Hermine, Valerie Dardhalon, Steven Highfill, Thorkell Andresson, Grégoire Altan-Bonnet, Nirali Shah.
      CAR T-cell efficacy requires post-infusion expansion and persistence, yet metabolic programs supporting T-cells in patients remain poorly defined. Here, we developed a high-throughput single-cell immunometabolic profiling pipeline and applied it across pediatric leukemia trials, revealing a conserved post-infusion CAR T-cell shift from glycolysis toward amino acid-driven oxidative phosphorylation (OXPHOS). Within this remodeling, OXPHOS-dependent stem-like CAR T-cell subsets were enriched in patients achieving complete remission. Longitudinal plasma metabolomics revealed cytokine release syndrome-associated depletion of multiple amino acids, including glutamine and arginine, during CAR T-cell expansion, creating a nutrient-restricted environment. Analysis of public CAR T-cell datasets showed that responders upregulated amino-acid solute carrier transporters, whereas disrupting uptake impaired translation, OXPHOS, stemness, and cytotoxicity. Guided by these findings, we screened amino-acid transporters for CAR T-cell engineering. SLC1A5-, SLC7A1-, and SLC38A9-armored CAR T-cells emerged as the most promising, with enhanced oxidative capacity and anti-leukemic efficacy, establishing amino acid transport as a targetable metabolic checkpoint.
    DOI:  https://doi.org/10.21203/rs.3.rs-10832865/v1
  23. Biomedicines. 2026 Sep 17. pii: 2100. [Epub ahead of print]14(9):
    Targeting Metabolic Pathways to Direct T-Cell Trafficking: Therapeutic Perspectives.
    Xiayinan Song, Shengxuan Zhao, Weiheng Zhang, Yan Wang, Fengjie Zheng.
      Despite advances in immunomodulatory therapies, dysregulated T-cell trafficking persists as a pathological cornerstone in chronic inflammation, autoimmunity, and cancer. This spatially precise navigation-orchestrated by receptor-ligand cascades-ensures immune surveillance but drives disease when impaired. Targeting individual receptors faces limitations due to functional redundancy. Emerging research establishes metabolic reprogramming as a critical regulator of trafficking efficiency, where glucose, amino acid, lipid, and mitochondrial metabolism dynamically control all stages: from chemotaxis, selectin-mediated rolling, and integrin-dependent adhesion to transendothelial migration and interstitial migration. Critically, these pathways integrate energy supply, metabolite signaling, and epigenetic modulation to influence T-cell trafficking fates. Here, we dissect how reprogramming core metabolic networks calibrates trafficking cascades and highlight therapeutic strategies targeting key nodes to correct pathological migration in autoimmunity, cancer, and transplantation.
    Keywords:  T cell; immunotherapy; metabolic reprogramming; trafficking
    DOI:  https://doi.org/10.3390/biomedicines14092100
  24. Biomedicines. 2026 Sep 17. pii: 2094. [Epub ahead of print]14(9):
    Patient-Derived Transcriptomics Reveals Distinct IFNγ-Associated Myeloid States and Mitochondrial Complex I Programs in Rheumatoid Arthritis and Osteoarthritis.
    Heekyong R Bae, Byeongchan Son, Seong-Su Choi, Hye-Bin Jeong, Howard A Young, Eun-Young Kwon.
      Background/Objectives: Macrophages are key contributors to the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA), but their disease-associated immunometabolic states remain incompletely understood. Methods: Here, we comparatively analyzed patient-derived transcriptomic data from synovial tissues and synovial macrophages in RA and OA. Results: RA synovial tissues showed stronger interferon-γ (IFNγ)-associated signatures and reduced mitochondrial Complex I-related programs compared with OA. Similar reductions in oxidative phosphorylation, mitochondrial translation, and Complex I-related transcription were observed in synovial fluid-derived RA macrophages relative to control macrophages. In an independent dataset of synovial tissue-derived OA macrophages, inflammatory-like OA macrophages exhibited concurrent enrichment of glycolytic and oxidative metabolic programs. Bulk RNA-seq analysis of synovial monocytes within a common study framework further showed that reduced mitochondrial translation and Complex I-related programs were preferentially associated with leukocyte-rich inflammatory RA. At single-cell resolution, IFN-responsive monocytes enriched in leukocyte-rich RA showed reduced transcriptional representation of both nuclear- and mtDNA-encoded Complex I components. Conclusions: Collectively, these findings link an IFN-responsive inflammatory myeloid state in RA with coordinated suppression of mitochondrial translation and Complex I-related transcription, suggesting a transcriptional state that may increase susceptibility to mitochondrial Complex I dysfunction during persistent inflammation.
    Keywords:  immunometabolism; interferon-gamma; mitochondrial Complex I; mitochondrial translation; osteoarthritis; rheumatoid arthritis; synovial macrophages; synovial monocytes
    DOI:  https://doi.org/10.3390/biomedicines14092094
  25. JCI Insight. 2026 Sep 22. pii: e203495. [Epub ahead of print]11(18):
    Integrated single-cell multiomics reveals neutrophil-driven immune-metabolic reprogramming of Kupffer cells via thrombospondin-1/CD36 after surgical stress.
    Hongji Zhang, Xingping Huang, Preethi Jayakumar, Yunwei Zhang, Ti Yang, Xiaorong Guo, Grace Wu, Amrendra Kumar, Vijaya Bharti, Amblessed Onuma, Chengli Shen, Dequan Lou, Patricia S Latham, James M Crawford, Kong Chen, Anna E Vilgelm, Lopa Mishra, Allan Tsung, Meihong Deng, Hai Huang.
      Surgical stress, such as liver ischemia/reperfusion (I/R) injury characterized by robust neutrophil infiltration and immune activation, induces sterile inflammation that reshapes tissue immunity and contributes to organ dysfunction, yet the intercellular circuits that spatially orchestrate these responses within the hepatic immune microenvironment remain incompletely defined. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, high-dimensional spectral flow cytometry, and metabolomics to resolve the hepatic immune landscape following I/R at cellular and spatial resolution. While confirming extensive immune remodeling, we identify a dominant neutrophil-Kupffer cell communication axis mediated by neutrophil-derived thrombospondin-1 (TSP-1), which selectively engages CD36 on Kupffer cells. This interaction drives coordinated immune-metabolic reprogramming in Kupffer cells, characterized by suppression of oxidative phosphorylation, enhanced glycolysis, and remodeling of sphingolipid metabolism, including accumulation of hexosylceramides. Spatial analyses reveal preferential neutrophil-Kupffer cell colocalization within necrotic niches, and cross-species integration with human liver transplant datasets demonstrates conserved upregulation of the TSP-1/CD36 axis following reperfusion. Pharmacologic inhibition of TSP-1 attenuates liver injury and inflammatory responses in vivo. Together, these findings define a spatially organized, neutrophil-driven immune-metabolic circuit that governs functional reprogramming of Kupffer cells during surgical stress and identify the TSP-1/CD36 pathway as a conserved and targetable mediator of sterile liver injury.
    Keywords:  Adaptive immunity; Hepatology; Immunology; Inflammation; Innate immunity; Surgery
    DOI:  https://doi.org/10.1172/jci.insight.203495
  26. Front Immunol. 2026 ;17 1843175
    mtROS-NF-κB signaling supports ILC3 function and survival during sepsis-induced intestinal injury.
    Limin Chen, Haochen Zhang, Sisi Huang, Yizhu Chen, Dongdi Wang, Xiaojun Pan, Lidi Zhang, Zhenliang Wen, Xiaohui Su, Sheng Zhang, Jiao Liu, Lei Shen, Dechang Chen.
      Sepsis frequently induces intestinal barrier injury, which exacerbates systemic inflammation, and contributes to high mortality. Group 3 innate lymphoid cells (ILC3s) are key regulators of mucosal immunity, yet their role in sepsis-associated intestinal injury remains incompletely understood. We found circulating ILCPs were reduced in patients with sepsis. In an LPS-induced murine sepsis model, colonic ILC3 numbers declined whereas the residual population showed increased frequencies of IL-22- and GM-CSF-producing cells. RORγt-deficient mice exhibited impaired induction of colonic IL-22 and GM-CSF, increased intestinal permeability, and aggravated histopathological injury. Adoptive transfer of purified wild-type ILC3s restored colonic IL-22 and GM-CSF levels and partially improved barrier integrity. Mechanistically, septic ILC3s showed hypoxia-associated mitochondrial impairment and accumulation of mitochondrial ROS. increased mtROS contributed to enhanced NF-κB p65 phosphorylation and selectively supported IL-22 and GM-CSF production. Recombinant IL-22 or GM-CSF ameliorated intestinal injury. However, ROS scavenging or NF-κB inhibition increased ILC3 apoptosis, indicating that ROS-NF-κB axis also supports residual ILC3 survival. Together, these findings identify a mitochondria-associated ROS-NF-κB program that sustains protective cytokine production and survival in residual intestinal ILC3s during sepsis, although it is insufficient to prevent ongoing ILC3 loss and intestinal injury.
    Keywords:  ILC3s; NF-κB; colonic injury; mitochondrial impairment; mtROS; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1843175
  27. Cell Host Microbe. 2026 Sep 23. pii: S1931-3128(26)00360-4. [Epub ahead of print]
    A commensal-derived sugar protects against obesity by regulating immunometabolism.
    Chin Yee Tan, Yinghui Li, Danting Jiang, Barbara S Theriot, Meghana V Rao, Neeraj K Surana.
      Obesity is a worsening global epidemic that is partially regulated by the microbiota through unknown factors. We discovered a human commensal bacterium, Clostridium immunis, which prevents and treats obesity in mice by secreting a phosphocholine-modified exopolysaccharide. Loss- and gain-of-function bacterial mutants involving the phosphocholine biosynthesis locus (licABC) revealed that the phosphocholine moiety is required to protect against metabolic disease. This C. immunis exopolysaccharide decreases small-intestinal and visceral fat levels of IL-22, which increases metabolic activity specifically in visceral adipose tissue; C. immunis lacks activity against obesity when IL-22 or group 3 innate lymphoid cells, predominant secretors of IL-22, are absent. Importantly, phosphocholine biosynthesis genes are less abundant in humans with obesity or hypertriglyceridemia, suggesting conserved functions of bacterial phosphocholine. These results define a bacterial molecule-and its key structural motif-that provides immunometabolic control of obesity. More broadly, they highlight a clinically translatable strategy to reduce visceral fat.
    Keywords:  IL-22; bacterial polysaccharides; group 3 innate lymphoid cells; microbiota; phosphocholine; thermogenesis; visceral fat
    DOI:  https://doi.org/10.1016/j.chom.2026.08.018
  28. Front Immunol. 2026 ;17 1915452
    SLC25 in intestinal inflammation: mechanisms, pathological roles, and therapeutic implications.
    Juan Xu, Zan Zuo, Pei Wang, Tian He, Linting Xun, Ying An, Mei Luo, Jialong Qi, Ping Wan.
      Inflammatory bowel diseases (IBD) represent a spectrum of chronic gastrointestinal disorders fueled by a complex multifactorial interplay, where mitochondrial dysfunction has emerged as a critical contributor. The SLC25 family of mitochondrial transporters mediates the exchange of essential metabolites across the mitochondrial inner membrane, serving as pivotal regulators of cellular energy homeostasis in both the intestinal epithelium and immune cells. Accumulating evidence indicates that dysregulation of SLC25-dependent metabolic transport disrupts the crosstalk between cellular metabolism and immune signaling, driving chronic intestinal inflammation. This review comprehensively examines the pathological roles of SLC25 proteins across three interconnected dimensions: epithelial barrier disruption, immune dysregulation, and host-microbiota metabolic crosstalk. Specifically, we synthesize current findings on how altered SLC25 function compromises the intestinal barrier via oxidative stress and energy deficits, skews immune cell polarization toward pro-inflammatory states, and perpetuates a vicious cycle of microbial dysbiosis. Ultimately, this review provides a comprehensive theoretical basis for the central role of SLC25-mediated metabolic reprogramming in IBD pathogenesis, and establishes a critical mechanistic foundation for the development of novel metabolism-targeted therapeutics and diagnostic biomarkers.
    Keywords:  SLC25 transporters; immunometabolism; inflammatory bowel disease; intestinal immunity; macrophage polarization; mitochondrial dysfunction; mucosal inflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1915452
  29. Oncol Res. 2026 ;34(10): 10
    Metabolic Reprogramming in Gastric Cancer Immunity Mechanisms and Therapeutic Implications.
    Xiangyang Wang, Ying Wu, Yutong Fu, Ejakpovi Emmanuel Oghenefejiro, Zakari Shaibu, Cunxi Li, Qi Zhou, Liang Yin.
      Gastric cancer (GC) remains a leading cause of global cancer mortality, with progression and therapy resistance heavily influenced by the dynamic tumor microenvironment (TME). Despite advances in surgical techniques, chemotherapy, targeted therapy, and immunotherapy, overall survival for advanced disease remains poor, underscoring the need for a deeper understanding of resistance mechanisms. A hallmark of the TME is metabolic reprogramming, which sustains tumor growth and actively shapes an immunosuppressive landscape. This review aims to detail the coordinated metabolic adaptations of GC cells, cancer-associated fibroblasts (CAFs), and immune cells within the TME, focusing on nutrient competition, immunosuppressive metabolite accumulation, and dysregulated lipid metabolism. We analyze how glucose depletion, lactate accumulation, and amino acid deprivation establish a hostile metabolic niche that impairs cytotoxic T lymphocyte (CTL) function while paradoxically supporting regulatory T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). We examine four major immunosuppressive metabolic pathways, lactate, adenosine, tryptophan-kynurenine, and arginine and demonstrate their convergence on immune checkpoint upregulation, forming an integrated metabolic-immune checkpoint axis. These pathways establish a self-reinforcing immunosuppressive circuit that drives T cell exhaustion and limits immune checkpoint blockade efficacy. We highlight emerging therapeutic strategies targeting this crosstalk, including inhibitors of glycolysis, glutaminolysis, indoleamine 2,3-dioxygenase 1 (IDO1), and adenosine signaling, often combined with immunotherapy. The metabolic supply-demand mismatch explains why certain interventions can revive effector cells while potentially harming other cell types. Finally, we discuss challenges and future directions, emphasizing the need for spatially resolved metabolic profiling, biomarker-driven patient stratification, and personalized therapies to overcome metabolic immunosuppression and improve clinical outcomes in GC.
    Keywords:  Gastric cancer (GC); immunometabolism; immunotherapy; metabolic reprogramming; tumor microenvironment (TME)
    DOI:  https://doi.org/10.32604/or.2026.087144
  30. Mol Biomed. 2026 Sep 24. pii: 185. [Epub ahead of print]7(1):
    Roles of inflammation and metabolic dysfunction in cardiovascular diseases: molecular mechanisms and therapeutic targets.
    Yue Pan, Wan-Hong Li, Wei Zhang, Wan-Jing Ma, Hui Sun.
      Cardiovascular disease progression is shaped by a close interaction between metabolic adaptation and inflammatory signaling. In injured cardiac and vascular tissues, ischemia, pressure overload, lipid stress and metabolic excess reshape how cardiomyocytes, endothelial cells, immune cells and fibroblasts sense damage and communicate with their microenvironment. Cardiovascular inflammation follows a staged tissue response, from danger-signal sensing and nuclear factor-κB-related priming to inflammasome activation, cytokine amplification, leukocyte recruitment, efferocytosis and chronic remodeling. Metabolic reprogramming shapes this sequence by altering substrate use, redox control, biosynthetic routing and metabolite signaling. A major challenge is that glycolysis, fatty acid oxidation and amino-acid metabolism do not carry fixed biological meanings; their effects depend on the cell type, measurement layer and disease phase in which they occur. This review examines metabolism-inflammation crosstalk in cardiovascular disease by linking core inflammatory pathways with metabolic sensors, immune-cell metabolic reprogramming and signaling metabolites, then comparing disease-specific mechanisms in myocardial infarction/ischemia-reperfusion injury, heart failure, atherosclerosis, hypertrophic remodeling and myocardial fibrosis. We emphasize how apparently similar metabolic shifts can represent adaptive repair, inflammatory amplification or maladaptive remodeling in different compartments. The therapeutic discussion separates pathway activity from targetability and uses anti-inflammatory trials and metabolic interventions to define when patient selection, pathway engagement and safety considerations support targeted treatment.
    Keywords:  Cardiovascular disease; Cardiovascular inflammation; Metabolic reprogramming; Metabolism–inflammation crosstalk; Therapeutic targets, Amino acid metabolism, Glucose metabolism, Fatty acid metabolism
    DOI:  https://doi.org/10.1186/s43556-026-00599-x
  31. Cell Prolif. 2026 Sep 25. e70282
    Magnesium Enhances Immune Clearance of P. gingivalis in Macrophages by Suppressing MCU-Mediated Mitochondrial Calcium Overload.
    Dao-Kun Deng, Meng-Jie Su, Min-Yi Zhang, Yu-Jie Tan, Wenyao Kongling, Hong-Yu Wang, Mei Xu, Shi-Yu Liu, Xiao-Tao He, Fa-Ming Chen, Bei-Min Tian, Xuan Li.
      P. gingivalis, a keystone periodontal pathogen in periodontitis, is recognized for its capacity to evade host immune clearance. Its intracellular survival leads to both local and systemic infection, thereby increasing the risk of periodontitis and its associated systemic diseases. However, macrophages have limited capacity to clear P. gingivalis, which contributes to disease establishment and progression. Our findings confirmed P. gingivalis presence in periodontitis tissue, with intracellular P. gingivalis mainly located in macrophages. However, P. gingivalis cannot be completely cleared by macrophages and enters the blood circulation through damaged periodontal tissue, leading to systemic infection. Transcriptomic analysis identified mitochondrial calcium uniporter (MCU) as a potential key molecule associated with P. gingivalis immune evasion in macrophages. In vitro functional analyses further confirmed that P. gingivalis infection increased MCU expression and led to both cytosolic and mitochondrial calcium overload, thereby impairing intracellular P. gingivalis clearance in macrophages. Notably, as a natural calcium antagonist, magnesium could inhibit the MCU pathway, reverse calcium overload, and enhance the macrophage-mediated P. gingivalis clearance. Local administration of magnesium-containing alginate methacryloyl (AlgMA) hydrogel significantly reduced both local and systemic P. gingivalis infection, relieved inflammation, and alleviated periodontal tissue destruction. Collectively, our findings identify MCU-mediated calcium overload as a previously unrecognized mechanism by which P. gingivalis evades macrophage immune clearance. Moreover, magnesium-mediated restoration of Ca2+ homeostasis offers a promising host-directed immunomodulatory therapy for periodontitis and other infectious diseases.
    Keywords:   P. gingivalis ; immune escape; macrophage; magnesium; mitochondrial calcium uniporter; periodontitis
    DOI:  https://doi.org/10.1111/cpr.70282
  32. Genes (Basel). 2026 Aug 27. pii: 1019. [Epub ahead of print]17(9):
    Single-Cell RNA Sequencing Combined with MEBOCOST Reveals Alveolar Macrophage-Mediated Immunometabolic Communication Mechanisms in Sepsis-Induced Acute Lung Injury.
    Lixia Zhao, Xin Liu, Yubang Hu, Yuming Yang, Yue Peng, Youtan Liu.
      Background: Sepsis-induced acute lung injury (SI-ALI) leads to high mortality in critically ill patients, and no specific targeted treatments are available. Current studies mainly characterize intercellular crosstalk via protein-ligand-receptor frameworks, while metabolite-derived immune signal transmission is largely unclarified. Alveolar macrophages are located at the alveolar barrier and may act as central metabolic coordinators to trigger neutrophil-mediated lung inflammation, yet the complete metabolite signaling network has not been systematically mapped. Methods: We integrated single-cell and bulk transcriptomic datasets from CLP-induced septic mouse lungs. CellChat and MEBOCOST were jointly used to reconstruct protein-metabolite dual communication networks. LASSO regression and random forest were combined to screen core metabolic hub genes, followed by single-cell expression mapping and in vivo histology & qPCR validation. Results: We identified a pivotal alveolar macrophage-neutrophil immunometabolic axis dominated by iron-Slc40a1 and LTB4-Ltb4r1 signaling. Three hub genes (Pmvk, Slc2a1, Slc7a11) coordinately regulate inflammatory pathways, among which myeloid-enriched Slc7a11 balances cellular redox and paracrine inflammatory responses. Conclusions: This study establishes the first dual-layer cell communication atlas for SI-ALI, proposes a macrophage-centered metabolic inflammatory regulatory model, and highlights Slc7a11 as a potential therapeutic target for septic lung injury.
    Keywords:  MEBOCOST; Slc7a11; alveolar macrophage; cystine metabolism; metabolite–sensor communication; sepsis-induced acute lung injury; single-cell RNA sequencing
    DOI:  https://doi.org/10.3390/genes17091019
  33. Adv Mater. 2026 Sep 23. e75099
    Engineered Extracellular Vesicle Revitalizing Macrophage Energy Metabolism for Aged Wound Repair.
    Jiayi Ding, Jie Li, Tongyao Ji, Mengjie Huang, Peiyao Liu, Kun Zhang, Jian Li, Ji Ma, Xiaoxiao Chen, Fengkai Qiu, Minjiang Chen, Gaofeng Shu, Weiqian Chen, Jiansong Ji.
      One major obstacle for aged wound healing is the abnormal senescence of macrophages in chronic wounds which causes immunosenescence. Tissue homeostasis depends on regulation of metabolism in accumulating senescent cells (SnCs) with aging, and cell activation for aged tissue repair requires sufficient energy. Therapeutic advancements are potential by employing metabolic strategies for intervention. First, a disorder of arginine-oxidative phosphorylation metabolism in aging skin was found, which may be the main culprit of aging. Engineered EVs (4-octyl itaconate (4OI)-EVs) which possess naturally abundance of mitochondrial proteins have been developed here. Our findings demonstrate that 4OI-engineered EV (4OI-EV) may accelerate the repair of aged mouse skin and diabetic mouse skin, reduce cellular senescence, and recover cell dysfunctions. After 4OI-EV therapy, metabolism has been notably altered, with decreased glycolysis and increased arginine-oxidative phosphorylation axis through enhanced argininosuccinate synthetase 1 (ASS1) level. We demonstrate how 4OI-EV partially restores macrophages senescence by reversing mitochondrial dysfunctions and mitophagy suppressions via ASS1 which may be identified as a potential effective target for alleviating skin aging.
    Keywords:  ASS1; extracellular vesicles; metabolism; skin aging; wound repair
    DOI:  https://doi.org/10.1002/adma.75099
  34. Microbiome. 2026 Aug 12. pii: 220. [Epub ahead of print]14(1):
    Gut microbiota-derived riboflavin mediates protective effects of MUC2 in acute pancreatitis via CD40-macrophage pathway.
    Yang Fu, Nuoming Yin, Zehua Huang, Wenfei Qin, Binqiang Xu, Huizhen Huang, Jia Hu, Mengyan Cui, Qixiang Mei, Junjie Fan, Yingying Lu, Qiaoli Jiang, Junjie Hu, Chunlan Huang, Yue Zeng.
       BACKGROUND: Gut barrier dysfunction is critical in the pathogenesis of acute pancreatitis (AP), yet the underlying mechanisms remain unclear. Mucin 2 (MUC2), the primary component of the intestinal mucus layer, is essential for gut homeostasis and microbial eubiosis. This study aimed to elucidate the protective mechanism of intestinal MUC2 in AP.
    RESULTS: We reported that intestinal MUC2 expression was decreased in AP patients and correlated with disease severity. Intestinal epithelial-specific Muc2 knockout (Muc2ΔIEC) mice demonstrated exacerbated AP in a gut microbiota-dependent manner. Decreased abundance of Lactobacillus and correlated reduced levels of riboflavin were found in Muc2ΔIEC mice after AP induction. Supplementation with riboflavin effectively ameliorated AP in Muc2ΔIEC mice, whereas administration of an engineered strain deficient in riboflavin synthesis failed to provide a protective effect. MUC2 deficiency aggravated a macrophage-dominant immune imbalance in the pancreas, which was reversed by riboflavin. In vitro experiments revealed that riboflavin suppresses pro-inflammatory macrophage activation by inhibiting the CD40 signaling pathway. This inhibition preserved mitochondrial function and reversed the histone H3 acetylation at pro-inflammatory gene promoters.
    CONCLUSION: Our study demonstrates that intestinal MUC2 deficiency is associated with reduced levels of microbiota-derived riboflavin, which could partially suppress pro-inflammatory macrophage activation via the CD40 pathway. Targeting the microbiota-derived riboflavin in AP may help to ameliorate the disease course. Video Abstract.
    DOI:  https://doi.org/10.1186/s40168-026-02375-z
  35. Clin Exp Pharmacol Physiol. 2026 Oct;53(10): e70157
    Mechanistic Study of SRSF1-Mediated Inhibition of Treg Cell Function via the mTORC1/ULK1 Signalling Axis Through Mitophagy in Asthma.
    Chunhua Ye, Yifu Chen, Qinjun Yi, Zhu Ming, Tuoyu Gan, Rong Xiang.
       OBJECTIVE: This study examines the role of serine/arginine-rich splicing factor 1 (SRSF1) in airway inflammation in asthma and the molecular mechanisms in mitophagy and metabolic homeostasis in regulatory T cells (Tregs).
    METHODS: Bronchoalveolar lavage fluid (BALF) was collected from asthma patients and healthy controls to assess SRSF1 expression and autophagy, and to analyse the correlation of SRSF1 with Treg cell functional markers and lung function. The ovalbumin (OVA)-induced asthma mouse model was established, with the OVA, OVA+shSRSF1, OVA+rapamycin, and OVA+shSRSF1+MHY1485 groups established. Additionally, an OVA+PM2.5 group was set up. Treg cells were isolated from lung tissue to evaluate Treg cell mitophagy, glucose metabolism reprogramming, mitochondrial function, and immunosuppressive activity.
    RESULTS: SRSF1 levels in BALF cells from asthma patients were notably elevated and showed negative correlations with FOXP3 expression in Treg cells and FEV1% pred. In OVA-induced asthmatic mice, SRSF1 was upregulated in Treg cells, accompanied by increased phosphorylation of mTOR and ULK1 at Ser757, leading to defects in mitophagy and metabolic reprogramming. Silencing SRSF1 or rapamycin treatment reversed the aforementioned autophagy inhibition and metabolic dysregulation, restored Treg cell numbers and suppressive function, and alleviated airway inflammation and airway hyperresponsiveness. In contrast, the mTORC1 activator MHY1485 counteracted the protective effects of shSRSF1. PM2.5 exposure further exacerbated these changes, which were dependent on SRSF1 expression.
    CONCLUSION: SRSF1 modulates the mTORC1/ULK1 axis and is associated with impaired Treg mitophagy and metabolic reprogramming in asthma. Targeting SRSF1 or mTORC1 may represent a promising therapeutic strategy for the prevention and treatment of asthma.
    Keywords:  SRSF1; Treg cells; ULK1; bronchial asthma; mTOR; metabolic reprogramming; mitophagy
    DOI:  https://doi.org/10.1111/1440-1681.70157
  36. Nat Commun. 2026 Aug 26. pii: 10193. [Epub ahead of print]17(1):
    The Caenorhabditis elegans microbiome impacts microsporidia infection through nutrient limitation and spore inactivation.
    Hala Tamim El Jarkass, Stefanie Castelblanco, Winnie Zhao, Manpreet Kaur, Yin Chen Wan, Abigail E Ellis, Ryan D Sheldon, Barbara Pees, Katja Dierking, Evan C Lien, Nick O Burton, Gerard D Wright, Aaron W Reinke.
      Microsporidia are fungal parasites that can only reproduce inside the cells of a host, and they infect most animal groups, including humans and agriculturally important species. Animals also harbor a microbiome, which can shape resistance to infection, but the mechanisms by which bacteria influence microsporidia infection are poorly understood. To address this, we tested how bacteria associated with the nematode Caenorhabditis elegans affect infection by its natural microsporidian parasite, Nematocida parisii. Here we show that nematodes grown on Chryseobacterium scophthalmum or Sphingobacterium multivorum exhibit increased initial parasite invasion but reduced subsequent growth. Broad profiling of host lipids reveals that these bacteria disrupt levels of unsaturated fatty acids, and adding back one such fatty acid, linoleic acid, restores parasite growth in animals raised on S. multivorum. We also found that Pseudomonas lurida and Pseudomonas mendocina secrete molecules that inactivate N. parisii spores, with P. lurida activity depending on the antimicrobial lipopeptide massetolide. We tested 53 additional Pseudomonas strains, 64% of which significantly reduced N. parisii infection. Our results indicate that bacterial interference with microsporidia is widespread, acting both by reshaping host metabolism and by directly inactivating parasite spores.
    DOI:  https://doi.org/10.1038/s41467-026-77106-x
  37. Front Cell Infect Microbiol. 2026 ;16 1913777
    African swine fever virus remodels cellular host metabolism and promotes lipid droplet formation in macrophages and cell lines.
    Inmaculada Galindo, Lucía Barrado-Gil, Miguel Ángel Cuesta-Geijo, Stuart D Armstrong, Isabel García-Dorival, Ana Del Puerto, Jesús Urquiza, Paula Gil-Cortés, Covadonga Alonso.
       Background: African swine fever virus (ASFV) is a large cytoplasmic DNA virus that causes a highly lethal disease in pigs and poses a major threat to global animal health and food security. ASFV infection is characterized by extensive reprogramming of host cellular pathways to support viral replication, including immune regulation, stress responses, and metabolic processes. Increasing evidence indicates that lipid metabolism is actively modulated during infection; however, the functional contribution of specific lipid-related organelles to the ASFV replicative cycle remains to be fully defined.
    Methods: We characterized the host response to ASFV infection in primary porcine alveolar macrophages using Illumina-based RNA sequencing at two representative post-infection time points. Transcriptomic analyses were complemented by functional assays in Vero cells, employing pharmacological inhibitors of lipid droplet (LD) biogenesis, quantitative measurements of viral replication, infectivity, and gene expression, as well as proteomic profiling of purified LDs from infected cells.
    Results: ASFV infection induced profound changes in host gene expression, with significant enrichment of pathways involved in immune modulation, apoptosis, autophagy, and cellular metabolism. A remarkable finding was the marked upregulation of enzymes driving LD biogenesis. Functional studies showed that LDs were dynamically remodeled during infection, increasing in abundance and redistributing toward viral replication factories. Proteomic analysis of LDs from infected macrophages identified both structural and non-structural ASFV proteins, including subunits of the viral transcription machinery. Accordingly, pharmacological disruption of LD formation pathway prominently reduced viral genome replication, viral protein synthesis, infectivity, and virus production, exceeding 95% in some conditions.
    Conclusions: These findings establish lipid droplets as central host organelles that support efficient ASFV replication and reveal a tight physical and functional coupling between viral replication and host lipid metabolism. Targeting LD biogenesis represents a promising host-directed antiviral strategy against ASFV.
    Keywords:  African swine fever virus; antivirals; enzyme inhibitors; lipid droplets; proteomics; transcriptome
    DOI:  https://doi.org/10.3389/fcimb.2026.1913777
  38. Nat Commun. 2026 Aug 22. pii: 10047. [Epub ahead of print]17(1):
    Alcohol reshapes liver zonal plasticity and immune-metabolic reprogramming in metabolic-syndrome associated hepatocellular carcinoma.
    Tian Tian, Yuhua Xue, Chunbao Sun, Lu Yang, Jinhui Wang, Brady Jin-Smith, Joshua M Barkin, Martin Nzegwu, Lin Jia, Huiping Zhou, Bilon Khambu, Xiao-Ming Yin, Daohong Zhou, Anastasia G Chambers, Dongtao Fu, Zhen Lin, Shengmin Yan, Lizi Wu, Bryon Petersen, Chenglong Li, Li Zuo, Sergio Duarte, Ali Zarrinpar, Hua Wang, Liya Pi.
      Hepatocellular carcinoma (HCC) commonly arises in metabolic dysfunction-associated steatohepatitis (MASH), alcohol-related liver disease (ALD), and metabolic dysfunction-associated ALD (MetALD), yet how zonal metabolic programs govern tumor lineage and immune responses remains unclear. Here, using complementary murine models of steatohepatitis-associated hepatocarcinogenesis, we show that CTNNB1-mutant MASH-HCC originates from periportal and midlobular hepatocytes through perivenous reprogramming. This transition is characterized by β-catenin activation, loss of periportal metabolic functions, and induction of the immunosuppressive IDO1-kynurenine-AhR axis. In contrast, ethanol exposure suppresses perivenous xenobiotic programs, destabilizes the β-catenin/AhR/CAR axis, and increases tumor heterogeneity by generating both progenitor/biliary- and hepatocyte-derived MetALD-HCC that remain sensitive to anti-programmed death-1 (aPD1) therapy. Pharmacologic AhR inhibition or hepatocyte-specific β-catenin deletion reduces MASH-HCC burden and restores sensitivity to aPD1 treatment. Together, these findings identify AhR as a central mediator of β-catenin-driven tumor immunosuppression and a potential therapeutic target in CTNNB1-mutant HCC, highlighting context-dependent mechanisms of immune escape in alcohol-associated HCC.
    DOI:  https://doi.org/10.1038/s41467-026-77089-9
  39. Biomedicines. 2026 Aug 31. pii: 1967. [Epub ahead of print]14(9):
    Short-Chain Fatty Acids at the Crossroads of Microbiota, Immunometabolism, and Inflammation.
    Łucja Rolek, Agata Sowa, Milena Czosnek, Ewelina Grywalska, Paulina Mertowska, Sebastian Mertowski.
      The rising incidence of chronic autoimmune and autoinflammatory diseases has been increasingly associated with environmental and lifestyle factors, including Western dietary patterns, intestinal dysbiosis, and reduced production of short-chain fatty acids (SCFAs). Reduced production of acetate, propionate, and butyrate has been associated with impaired epithelial barrier function, altered peripheral immune tolerance, and low-grade systemic inflammation. This article integrates and systematizes current knowledge in the field of immunometabolism, focusing on the role of the microbiota-metabolism-immunity axis. The molecular mechanisms by which these bacterial metabolites modulate immune function-both through the activation of specific surface receptors and direct epigenetic regulation-are analyzed in detail. SCFAs have been shown to actively reprogram the metabolic and transcriptional profiles of effector cells, stimulating anti-inflammatory macrophage polarization, suppressing cellular inflammatory cascades, and inducing the differentiation of protective regulatory T cells. To address the pharmacokinetic limitations of natural fatty acids, this study critically evaluates modern translational strategies. The clinical potential of synthetic receptor agonists, selective epigenetic modulators, and advanced next-generation bacterial consortia is analyzed. The presented data synthesis not only organizes the pathophysiological foundations but, above all, points to promising new directions for personalized non-pharmacological immunomodulation in the treatment of inflammatory diseases.
    Keywords:  gut–immune axis; histone deacetylase inhibitors; immune system; immunometabolism; microbiota-accessible carbohydrates; next-generation probiotics; short-chain fatty acids
    DOI:  https://doi.org/10.3390/biomedicines14091967
  40. J Leukoc Biol. 2026 Sep 24. pii: qiag131. [Epub ahead of print]
    Δ9-Tetrahydrocannabinol exposure shifts eosinophil and macrophage transcriptional programs towards an anti-inflammatory phenotype in helminth infection.
    Jennell Jennett, Martin Olmos, Ka Man Lam, Sarah Midou, Nicholas V DiPatrizio, Meera G Nair.
      Cannabis use is increasing globally, yet the immunological effects of Δ9-tetrahydrocannabinol (THC), the main intoxicating component of cannabis, remain incompletely understood. Given prior evidence that endocannabinoid signaling influences helminth immunity and type 2 inflammation, we investigated how sustained THC exposure alters immune responses to the helminth Nippostrongylus brasiliensis (Nb), which infects the lung and small intestine of mice. C57BL/6J mice were treated with THC (5 mg/kg/day) or vehicle for 14 days prior to helminth infection and assessed for parasite burden, innate immune cell and T cell responses, and transcriptional changes in lung eosinophils and macrophages. THC exposure did not significantly alter infection-associated weight loss or helminth burden; however, THC selectively restrained infection-induced circulating eosinophils and monocytes while increasing regulatory T cells. T cell activation assays showed reduced TNFα and IFNγ secretion in splenocytes from THC-treated infected mice. Bulk RNA sequencing showed that THC shifted lung eosinophils and CD11c+ lung macrophage-enriched cells from inflammatory, fibrotic, and costimulatory pathways toward stress and metabolic-adaptive transcriptional programs. Within the infected macrophage-enriched population, THC reduced CD80 expression while increasing MHC class II and antigen presentation-associated genes, suggesting a potential shift in macrophage-mediated T cell activation. Consistent with altered inflammatory and tissue remodeling-associated programs, immunofluorescent staining showed that THC mitigated infection-associated loss of lung collagen. Collectively, these findings indicate that THC reshapes the immune response to helminth infection by restraining innate and T cell effector responses while altering lung eosinophil and macrophage activation programs.
    Keywords:  THC; eosinophils; helminth infection; macrophages; type 2 inflammation
    DOI:  https://doi.org/10.1093/jleuko/qiag131
  41. Front Endocrinol (Lausanne). 2026 ;17 1900161
    Myosteatosis in type 1 diabetes: immunometabolic mechanisms, biomarkers, and therapeutic targets.
    Fatema Al-Rashed, Halemah AlSaeed, Kevin Patrick Fennelly, Fahd Al Mulla, Rasheed Ahmad.
      Myosteatosis, defined as pathological lipid accumulation within and between skeletal muscle fibers, is increasingly recognized as a determinant of impaired muscle quality, metabolic inflexibility, and adverse clinical outcomes. Although well described in ageing, obesity, and cancer, its relevance to type 1 diabetes (T1D) remains underexplored. T1D is characterized by lifelong insulin deficiency, persistent autoimmune activation, and glycemic variability, conditions that profoundly disrupt cellular energy metabolism and substrate utilization in skeletal muscle, even in the absence of obesity or overt sarcopenia. This review integrates evidence from human imaging, metabolic phenotyping, immunological profiling, and multi-omics analyses to define myosteatosis as an immunometabolic phenotype in T1D. Central to this framework is dysregulation of the AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor (PPAR)-mitochondrial axis, which normally coordinates fatty-acid oxidation, mitochondrial biogenesis, and energy efficiency in skeletal muscle. In T1D, chronic immune activation and metabolic stress suppress AMPK and PPARδ signaling, impair PGC-1α-dependent mitochondrial function, and reduce oxidative capacity, promoting intramyocellular lipid accumulation despite preserved muscle mass. These defects are reinforced by persistent inflammatory signaling (IL-6, TNF-α, IL-1β; NF-κB, JNK, and NLRP3 pathways), accumulation of lipotoxic intermediates (ceramides and diacylglycerols), dysregulated myokine secretion (increased myostatin with reduced IL-15 and irisin), and infiltration of pro-inflammatory macrophages and CD8+ T cells. Mitochondrial stress, reflected by impaired phosphocreatine recovery, altered acylcarnitine profiles, increased oxidative damage, and reduced NAD+-SIRT1/3 activity, further consolidates immunometabolic dysfunction and lipid deposition. Collectively, this review positions myosteatosis as a clinically relevant and potentially modifiable consequence of immune-driven failure of cellular energy utilization in T1D. Because direct mechanistic data from T1D skeletal muscle remain scarce, the framework presented here is deliberately hypothesis-generating: it is assembled substantially by inference from type 2 diabetes (T2D), obesity and ageing models, and we map the resulting evidence gaps explicitly in order to define a research agenda rather than to assert a validated T1D-specific mechanism. Targeting the AMPK-PPAR-mitochondrial axis and its inflammatory and lipotoxic modifiers may enable earlier detection and mechanism-based interventions to preserve muscle metabolic resilience and functional capacity in autoimmune diabetes.
    Keywords:  AMPK; PPARδ; SIRT1; inflammation; mitochondrial dysfunction; myosteatosis; oxidative capacity; type 1 diabetes
    DOI:  https://doi.org/10.3389/fendo.2026.1900161
  42. Antioxid Redox Signal. 2026 Sep 20. 15230864261489976
    A Unified Mechanistic Framework for Copper Toxicity in Neutrophils: Metabolic Rewiring, Cell-Death Crosstalk, and Immune Dysfunction.
    Rui Shi, Siyue Chen, Tingting Chen, Tongyu Zhu, Cheng Yang.
       SIGNIFICANCE: Copper is an essential redox-active micronutrient, but failure of copper compartmentalization can convert it from a catalytic cofactor into a source of oxidative, proteotoxic, and mitochondrial stress. Neutrophils are a plausible target of this transition because their antimicrobial functions depend on tightly organized redox reactions, whereas their short lifespan and limited biosynthetic reserve may restrict adaptation to metal stress.
    RECENT ADVANCES: This review develops a unified framework in which copper dyshomeostasis first reshapes intracellular copper pools, antioxidant buffering, reduced nicotinamide adenine dinucleotide phosphate-dependent redox metabolism, and mitochondrial signaling; these metabolic disturbances then lower the threshold for several copper-associated cell-death programs; and the combined lesions alter granulopoiesis, chemotaxis, phagocytic killing, neutrophil extracellular trap formation, survival, and inflammatory resolution. Canonical ferredoxin 1-dihydrolipoamide S-acetyltransferase-dependent cuproptosis is treated as a testable, but not yet established, mechanism in mature neutrophils. Stronger evidence supports a broader spectrum of copper-induced injury that includes mitochondrial apoptosis, inflammasome-associated pyroptotic signaling, lipid peroxidation with ferroptosis-like features, and dysregulated neutrophil extracellular trap formation (NETosis).
    CRITICAL ISSUES: The inflammatory outcome of neutrophil death cannot be inferred from cell loss alone: Efficiently cleared apoptotic or early ferroptotic cells may contract the functional neutrophil pool, whereas lytic death, late membrane rupture, defective efferocytosis, and release of oxidized lipids, chromatin, histones, or granular proteins may amplify local inflammation.
    FUTURE DIRECTIONS: By tracing individual routes from copper-pool disruption to defined cellular and tissue-level outcomes, this model distinguishes systemic copper overload from inflammatory copper redistribution and identifies the measurements required to establish copper-dependent neutrophil pathology in human disease. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  NETosis; copper dyshomeostasis; cuproptosis; ferroptosis; inflammatory resolution; mitochondrial stress; neutrophils; redox metabolism
    DOI:  https://doi.org/10.1177/15230864261489976
  43. Microorganisms. 2026 Sep 17. pii: 2077. [Epub ahead of print]14(9):
    Untargeted Lipidomics Reveals Lipid Alterations in Colonic Contents of C57BL/6J Mice with Acute Toxoplasma gondii Infection.
    Wen-Jie Cheng, Bo-Fang Duan, Cai-Qin Deng, Peng-Hao Wei, Min-Min Sui, Yi-Dan Wang, Xing-Quan Zhu, Feng-Cai Zou, Zhao Li.
       BACKGROUND: Although Toxoplasma gondii has been recognized as an obligate intracellular parasite, the lipid metabolic alterations it induces in colonic contents during acute infection remain poorly characterized.
    METHODS: An acute infection model was established using C57BL/6J mice by oral inoculation with the T. gondii ME49 strain. Untargeted lipidomics analysis was performed on the colonic contents collected at day 10 post-infection.
    RESULTS: Acute infection significantly elevated glycerophospholipids (GPs) and reduced glycerolipids (GLs), and prenol lipids (PRs), leading to 136 differentially abundant lipids. Pathway enrichment analysis identified the two most significantly affected pathways: choline metabolism in cancer and glycerophospholipid metabolism, with lysophosphatidic acid (LPA(16:0)) and lysophosphatidylcholine (LPC(18:1)) functioning as core hub nodes. Receiver operating characteristic (ROC) analysis identified phosphatidylethanolamine (PE(20:1e_22:4)), PE(16:0_22:6), hexosylceramide (Hex1Cer(m18:0_20:4)), and Hex1Cer(t17:0_22:6) as exploratory candidate biomarkers with high discriminatory performance (AUC > 0.94).
    CONCLUSIONS: Acute T. gondii infection induces lipid metabolic reprogramming in colonic contents of C57BL/6J mice. The findings provide a novel metabolic perspective on the intestinal pathogenesis of toxoplasmosis and offer exploratory candidate lipid markers for diagnosing acute infection.
    Keywords:  Toxoplasma gondii; acute infection; colonic contents; lipidomics
    DOI:  https://doi.org/10.3390/microorganisms14092077
  44. J Biol Chem. 2026 Sep 22. pii: S0021-9258(26)02459-2. [Epub ahead of print] 113587
    Vibrio vulnificus hemolysin drives NLRP3 inflammasome activation in platelets via TRPC6-mediated calcium signaling.
    Shi-Qing Li, Yan Wang, Zi-Han Feng, Jian-Hao Xu, Bin Ji, Jing-Lin Wang, Yuan Yuan.
      Vibrio vulnificus, an opportunistic pathogenic species, predominantly induces sepsis in patients with liver disease rather than in healthy individuals, although its opportunistic pathogenic mechanisms are unclear. The role and mechanisms behind the NLRP3 inflammasome activation induced by V. vulnificus infection in normal mice or healthy humans, serving as a core sensor and signal amplifier of the innate immune system in platelets, have not been elucidated. Here we discovered that V. vulnificus hemolysin (VVH), a member of Cholesterol-dependent cytolysins (CDCs), rather than multifunctional auto processing Repeats-in-Toxins (MARTX), is the specific effector of V. vulnificus, activating the NLRP3 inflammasome, platelet pyroptosis, necroptosis, and increasing IL-1β expression. Mechanistically, rather than ROS production, VVH-induced the intracellular Ca2+ increasing is essential for triggering NLRP3 inflammasome activation in platelet, which are mediated by the classical transient receptor potential channel 6 (TRPC6)-triggering Ca2+ influx and calcium-induced calcium release (CICR). The pharmacological inhibition of TRPC (SKF-96365) partially alleviated inflammation and increased mortality in murine infection models. Furthermore, activating VVH toxin-NLRP3 inflammasome axis in platelets contributes to bacterial clearance in host. This study provides a novel perspective on opportunistic pathogen-host interactions, in which CDC acts as danger signals sensed by the host to activate NLRP3 inflammasome to trigger host immune defense.
    Keywords:  Cholesterol-dependent cytolysins (CDCs); IL-1β; NLRP3; platelet; transient receptor potential channel 6 (TRPC6)
    DOI:  https://doi.org/10.1016/j.jbc.2026.113587
  45. bioRxiv. 2026 Aug 25. pii: 2026.08.24.746719. [Epub ahead of print]
    Microbial-associated acylated putrescines as immunomodulatory molecules in inflammatory bowel diseases.
    Sena Bae, Julian Avila-Pacheco, Slater L Clay, Sunghee Bang, Milcah C Scott, Natalia Andreeva, Monia Michaud, Diogo Fonseca-Pereira, Eunyoung Chun, Y Grace Cao, Yancong Zhang, Amrisha Bhosle, Rosa M Perez, Gleb Pishchany, Hera Vlamakis, Geniver El Tekle, Xochitl C Morgan, Sway P Chen, Jonathan N Glickman, Ramnik J Xavier, Daniel B Graham, Clary B Clish, Jon Clardy, Eric A Franzosa, Curtis Huttenhower, Wendy S Garrett.
      The gut microbiota profoundly shapes intestinal immunity through the production of small-molecule metabolites; yet in inflammatory bowel diseases (IBD), where the microbial metabolome is substantially altered, the identities and immunological functions of most disease-associated metabolites remain unknown. Here, we integrate untargeted fecal metabolomics from two independent IBD patient cohorts with gnotobiotic mouse metabolomic data to identify N-acyl putrescines as a class of microbiome-associated metabolites consistently enriched in both Crohn's disease (CD) and ulcerative colitis (UC). Among these, N-oleoylputrescine (NOP) induces potent and selective transcriptional responses in bone marrow-derived dendritic cells (BMDCs) and colonic organoids, establishing it as the primary immunomodulatory candidate in this metabolite class. Enterocloster species harboring nonribosomal peptide synthetase (NRPS) biosynthetic gene clusters produce NOP via conjugation of oleic acid with putrescine, confirmed by isotope-tracing in vitro and germ-free mouse mono-colonization in vivo. NOP suppresses five core IBD-associated inflammatory pathways in mouse dendritic cells and human monocytes, reduces gene signatures of histologic inflammation and IBD therapy non-response, and ameliorates colitis in four murine models. NOP dampens NF-κB activation and iNOS expression in myeloid cells and suppresses type 1 immune responses through a T cell-intrinsic mechanism. The enrichment of NOP in IBD despite its anti-inflammatory activity supports a holobiont defense hypothesis: that the gut microbiota mounts a compensatory metabolic response to intestinal inflammation that may contribute to the restoration of organismal homeostasis.
    In Brief: Bae et al. identify N-acyl putrescines as gut microbiota-associated metabolites enriched in IBD and demonstrate that N-oleoylputrescine (NOP), produced by Enterocloster species via NRPS biosynthetic machinery, broadly suppresses innate and adaptive inflammatory programs and ameliorates colitis in mice, supporting a holobiont defense hypothesis for microbiota-mediated immunomodulation.
    Highlights: N-acyl putrescines are microbiome-associated metabolites enriched in IBD feces across two independent human cohorts Enterocloster species harboring NRPS biosynthetic gene clusters produce NOP via oleic acid- putrescine conjugation NOP suppresses NF-κB, iNOS, and IBD therapy non-response gene signatures in mouse and human myeloid cellsNOP ameliorates colitis in four distinct murine models and suppresses type 1 immunity via a T cell-intrinsic mechanism.
    DOI:  https://doi.org/10.64898/2026.08.24.746719
  46. Front Immunol. 2026 ;17 1892763
    Photoreceptor outer segments promote the accumulation of lipid droplets in microglia by reprogramming lipid metabolism.
    Lingling Ge, Danyang Yu, Lingyan Yan, Yingnan Lv, Ruiyao He, Ling Yuan, Ping Duan, Juncai He.
      Retinal degeneration (RD) ultimately leads to blindness owing to progressive photoreceptor loss. Previous studies have shown that microglia play a key role in photoreceptor degeneration through multiple phenotypes. However, the determinants of their phenotypic regulation remain unclear. As microglia migrate into the subretinal space and engulf photoreceptor outer segments (POSs), we aim to investigate how POSs affect microglial activation and the relevant pathways. A classic mouse microglial cell line (BV2) was used to explore the effect of POS exposure on microglia activation. Transcriptomic and lipidomic analyses were used to investigate the mechanisms by which POS treatment influenced microglial lipid metabolism. A classic RD model induced by sodium iodate (SI) was used to confirm the microglial phenotype activated by POS in vivo. Using a mouse microglial cell line (BV2), we found that POS exposure induced a novel microglial state distinguished by a distinctive morphological feature, a specific transcriptional signature, and a distinct lipidomic profile compared with the LPS and untreated groups. BV2 cells with prolonged POS exposure showed significantly different lipid metabolic pathways, particularly genes associated with cholesterol metabolism. This lipidomic analysis further identified a parallel increase in free fatty acid (FFA) and cholesterol ester (CE) levels, with FFA-22:6 (DHA) and CE-22:6 being the most upregulated, a key metabolic transition that might play a crucial role in promoting lipid droplet (LD) formation in POS-treated microglia. Consistent with these findings, LD accumulation was also observed in the microglia located in the photoreceptor layer of the SI-induced retinal degeneration model. Functionally, POS-treated microglia showed the suppression of interferon-responsive transcriptional programs and anti-inflammatory effects, and exhibited impaired engulfment capabilities while maintaining normal lysosomal function. Taken together, these findings reveal a lipid-mediated mechanism that drives microglial phenotypic switching and provide a more physiologically relevant in vivo model to mimic microglial activation in degenerative retinas than LPS stimulation.
    Keywords:  cholesterol metabolism; lipid droplets; lipid-droplet-accumulating microglia; microglia; photoreceptor outer segments; retinal degeneration
    DOI:  https://doi.org/10.3389/fimmu.2026.1892763
  47. Front Chem. 2026 ;14 1924097
    Copper homeostasis in macrophages: regulatory mechanisms and immunological implications.
    Wanting Yang, Junfeng Wang, Zhenbin Dong, Fangming Zhang, Guofeng Li, Xing Wang, Wensheng Xie.
      Copper is an essential micronutrient whose redox activity underpins a dual role in immunity: it serves as both an antimicrobial effector and a regulator of inflammatory signaling. Macrophages, as central orchestrators of innate and adaptive immunity, maintain sophisticated copper homeostasis mechanisms that dynamically adapt to distinct activation states and environmental cues. This review synthesizes current knowledge around three interconnected themes: (1) the molecular machinery governing copper transport and regulation-including CTR1, ATP7A, ATP7B, and copper chaperones; (2) the functional interplay between copper metabolism, macrophage polarization, and immunometabolism; and (3) the pathophysiological consequences of copper dysregulation in infection, chronic inflammation, and cancer. Emerging evidence reveals that copper exerts dose-dependent effects on macrophage polarization: low-to-moderate copper promotes an anti-inflammatory M2 phenotype via STAT6 and PI3K/Akt pathways, whereas high copper concentrations trigger oxidative stress and NF-κB activation, driving pro-inflammatory M1 polarization. Furthermore, recent findings highlight crosstalk among copper metabolism, cuproptosis, and tumor-associated macrophage function, opening new avenues for copper-based immunotherapy. This review identifies critical knowledge gaps-including tissue-specific copper regulation, single-cell dynamics of copper trafficking, and the therapeutic potential of copper-targeted interventions. While acknowledging the bidirectional causality between copper metabolism and macrophage activation, we argue that copper homeostasis functions as a rheostat of immune competence with substantial translational promise.
    Keywords:  copper homeostasis; immunological regulation; inflammation; macrophage polarization; molecular mechanisms
    DOI:  https://doi.org/10.3389/fchem.2026.1924097
  48. Basic Res Cardiol. 2026 Sep 21.
    Short-chain fatty acids promote post-myocardial infarction cardiac repair via FFAR2-dependent suppression of osteoclast-like macrophage differentiation.
    Qun Zhang, Xue Jiang, Lu Liu, Yu-Meng Jia, Pan-Pan Yu, Jie Zhang, Xin-Ying Guo, Jing-Jing Wang, Cai-Xia Guo, Lei Wang.
      Adverse cardiac remodeling leads to the development of heart failure following myocardial infarction (MI), yet the immunometabolic signals governing early infarct repair remain poorly understood. Short-chain fatty acids (SCFAs) are important immunometabolic regulators, but their relevance and mechanistic contribution to post-MI repair remain unclear. Here, we integrated clinical observations with genetic and pharmacological intervention studies to investigate the role of the SCFAs-free fatty acid receptor 2 (FFAR2) axis in post-MI repair. Circulating SCFAs levels were markedly decreased in patients with MI, and associated with more complex coronary lesions and a higher risk of major adverse cardiovascular events. In murine MI, SCFAs supplementation reduced infarct expansion, cardiomyocyte death, and cardiac rupture, and improved left-ventricular function. These benefits were lost in global and myeloid-specific Ffar2-deficient mice, demonstrating an essential role for myeloid FFAR2 in SCFA-mediated cardioprotection. Mechanistically, SCFAs activated FFAR2-Gαi signaling in macrophages to suppress RANKL-RANK-driven osteoclast-like macrophage differentiation. thereby enhancing early fibrotic stabilization, reducing cardiomyocyte apoptosis, and improving infarct healing. Pharmacological blockade of osteoclast-like macrophage activation partially rescued impaired healing and cardiac dysfunction in myeloid-specific Ffar2-deficient mice after MI. These findings identify circulating SCFAs as clinically relevant biomarkers associated with coronary lesion complexity and adverse clinical outcomes after MI, and establish the SCFAs-FFAR2 axis as an immune-metabolic pathway that orchestrates macrophage fate and infarct healing. Targeting SCFAs-FFAR2 signaling may represent a therapeutic strategy to limit adverse post-MI remodeling and prevent heart failure.
    Keywords:  Adverse cardiac remodeling; Free fatty acid receptor 2; Myocardial infarction; Osteoclast-like macrophage; Short-chain fatty acids
    DOI:  https://doi.org/10.1007/s00395-026-01212-6
  49. Biomedicines. 2026 Sep 15. pii: 2072. [Epub ahead of print]14(9):
    FABP4/5-Mediated Lipid Reprogramming Is Associated with Immunosuppressive T Cell Crosstalk in Cervical Cancer After Chemoradiotherapy.
    Tianhan Xu, Mingjun Ma, Jiawen Zhang, Yanan Wang, Xiaoxia Tang, Sufang Wu.
      Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer, but resistance and recurrence remain major clinical challenges. Tumor immune-metabolic reprogramming profoundly affects treatment response and immune evasion; however, the molecular mechanisms of lipid metabolism remodeling and its interaction with T cells after CCRT in cervical cancer are still unclear. This study aimed to investigate how CCRT-induced metabolic changes in cervical cancer cells influence T cell function and immune evasion. Methods: We performed metabolic pathway activity analysis, cell-cell communication prediction, and transcriptomic analysis on paired single-cell transcriptomic data from three cervical cancer patients before and after CCRT (n = 3 paired). Validation was conducted using multiple independent GEO cohorts, in vitro cell culture experiments, and multi-sample immunofluorescence staining. Results: CCRT was associated with upregulation of FABP4/5 in malignant epithelial cells and activation of the PPAR and adipocytokine signaling pathways, leading to lipid metabolic reprogramming. Epithelial cells with high FABP4/5 expression showed enhanced predicted intercellular communication with T cells via the computationally inferred ligand-receptor axes PTGER4 and CXCR4. T cells with high communication intensity exhibited an immunosuppressive phenotype signature, accompanied by metabolic alterations in lipid and carbohydrate pathways and enrichment of regulatory T cell subsets. Validation experiments confirmed the association between FABP4/5 and inhibitory T cells. Conclusions: This study suggests that FABP4/5-mediated lipid metabolism reprogramming may represent a key mechanism contributing to the immunosuppressive crosstalk between cervical cancer epithelial cells and T cells after CCRT. Targeting this axis may reverse T cell dysfunction and provide a potential immunometabolic strategy to reduce post-CCRT recurrence.
    Keywords:  FABP4/5; T cell immune suppression; cervical cancer; concurrent chemoradiotherapy (CCRT); lipid metabolism reprogramming; single-cell transcriptome; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines14092072
  50. Front Cell Infect Microbiol. 2026 ;16 1939483
    Gas6/Axl-mediated macrophage hyporesponsiveness drives severe pulmonary mucormycosis in diabetic mice.
    Shotaro Kondo, Keito Owaki, Gento Hamasaki, Tatsuya Inukai, Jotaro Kinoshita, Toshihiro Ito, Shigeki Nakamura, Takehiko Shibata.
       Background: Pulmonary mucormycosis is a life-threatening fungal infection with a mortality rate exceeding 50%, and diabetes mellitus is one of its strongest risk factors. However, the molecular mechanisms linking diabetes to impaired pulmonary innate immunity remain poorly understood.
    Methods: A streptozotocin-induced type 1 diabetes (T1D) mouse model was used to investigate host responses to intratracheal Cunninghamella bertholletiae infection. Genetic Axl deficiency, pharmacological Axl inhibition with BGB324, histopathological analyses, and ex vivo and in vitro macrophage assays were performed to define the role of the Gas6/Axl axis in antifungal immunity.
    Results: T1D mice exhibited rapid mortality after pulmonary C. bertholletiae infection, accompanied by markedly impaired early neutrophil recruitment. Elevated lung and serum levels of growth arrest-specific protein 6 (Gas6) were intrinsic features of the diabetic state and correlated with blood glucose levels. Genetic ablation or pharmacological blockade of Axl restored macrophage chemokine responses, increased neutrophil recruitment into the airspace, reduced fungal burden, and significantly improved survival in T1D mice. Mechanistically, the Gas6/Axl axis directly suppressed fungus-induced chemokine production by alveolar macrophages, establishing a pre-existing state of innate immune hyporesponsiveness before infection.
    Conclusions: These findings identify the Gas6/Axl axis as a mechanistic link between diabetes and impaired pulmonary innate immunity. Targeting this pathway may represent a promising host-directed therapeutic strategy for pulmonary mucormycosis in patients with diabetes.
    Keywords:  GAS6/AXL; innate immune paralysis; mucormycosis; neutrophil recruitment; type 1 diabetes
    DOI:  https://doi.org/10.3389/fcimb.2026.1939483
  51. Microorganisms. 2026 Sep 20. pii: 2108. [Epub ahead of print]14(9):
    Microbiota-Associated Amino Acid Metabolites in Inflammatory Bowel Disease: Emerging Key Players in the Host-Microbe Interface.
    Xianwen Meng, Chunyang Tian, Yijun Zhu, Danping Zheng.
      Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic relapsing intestinal inflammatory disorder driven by complex interactions among host genetics, immune dysregulation, and gut microbiota dysbiosis. The functional contribution of microbial metabolites beyond short-chain fatty acids and bile acids remains incompletely understood. A critical and unresolved question is whether microbiota-associated amino acid metabolites are merely passive indicators of dysbiosis or active drivers of intestinal inflammation and tissue repair. In this review, we summarize recent advances in the roles of microbiota-associated amino acid metabolites and their derivatives in IBD, highlighting that amino acid metabolites constitute a functionally distinct class of bioactive signaling molecules that operate through four representative metabolic networks: tryptophan metabolism, aspartate-related metabolism, branched-chain amino acid (BCAA) metabolism, and arginine-polyamine metabolism. We synthesize recent clinical metabolomic data and identify reductions in tryptophan-derived indoles, glutamate, histidine, and selected BCAAs across IBD clinical cohorts and sample matrices, whereas metabolites such as serine, proline, and polyamine degradation products are frequently elevated or associated with disease activity or therapeutic response. Mechanistically, microbiota-associated amino acid metabolites are implicated in intestinal homeostasis and IBD pathogenesis through multifaceted pathways, including modulation of intestinal epithelial barrier integrity (e.g., cell-cell junction, mucus secretion, and stem cell-driven mucosal repair), innate and adaptive immune responses, host-pathogen interactions, and extraintestinal inflammatory signaling (e.g., systemic inflammation, and brain-gut axis communication). Finally, we highlight current challenges and limitations in achieving a causal understanding of microbiota-associated amino acid metabolic alterations in IBD, particularly regarding their origin, spatial distribution, and functional relevance, as well as their potential utility for disease stratification and treatment-response assessment, and discuss how these insights may inform the future development of next-generation biomarkers and precision therapeutic strategies tailored to individual metabolic phenotypes in IBD.
    Keywords:  amino acids; gut microbiome; host-microbiota interaction; inflammatory bowel disease; metabolites; metabolomics
    DOI:  https://doi.org/10.3390/microorganisms14092108
  52. bioRxiv. 2026 Sep 15. pii: 2026.09.12.751050. [Epub ahead of print]
    Host soluble inositol phosphate signaling promotes coronavirus replication.
    Igor Shats, Huanchen Wang, Yubai Zhou, Chunfang Gu, Adam Carr, Carlos M Guardia, Stephen Shears, Robin Stanley, Qisheng Zhang, Raymond D Blind, Xiaodong Wang, Xiaoling Li.
      Coronaviruses rely extensively on host pathways for replication, making host-directed therapies an attractive strategy for broad-spectrum antivirals with reduced risk of viral resistance. Here we identify the host soluble inositol phosphate pathway as a previously unrecognized dependency for coronavirus infection. Genetic or pharmacologic inhibition of several kinases in this pathway markedly suppresses replication of both alpha- and betacoronaviruses, while increasing pathway activity promotes viral replication. We developed UNC7844, a potent multi-target inhibitor of these kinases, which reduces coronavirus replication by more than four orders of magnitude in cultured cells and suppresses coronavirus infection in mice. Mechanistically, UNC7844 suppresses inositol (pyro)phosphates production, disrupts phosphoinositide homeostasis, and impairs late endosomal dynamics, blocking early post-entry steps required for viral genome release and replication. Together, our findings establish the soluble inositol (pyro)phosphate pathway as an important regulator of coronavirus infection and highlight its inhibition as a promising host-directed antiviral strategy.
    DOI:  https://doi.org/10.64898/2026.09.12.751050
  53. bioRxiv. 2026 Sep 14. pii: 2026.09.07.749862. [Epub ahead of print]
    A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer.
    Kayla Carter, Olajumoke Ogunlusi, Mrinmoy Sarkar, Stephen Akanbi, Christian Nguyen, Manasa Nekkanti, Akash Agarwal, Danielle Fails, Gayan I Nawaratna, Cory Klemashevich, James Cai, Devon J Boland, Tapasree Roy Sarkar.
      Cancer-associated fibroblasts (CAFs) are major regulators of the tumor microenvironment, yet how distinct CAF states suppress innate immunity in HER2-low breast cancer remains poorly understood. Here, we identify an S100A4-enriched CAF population that expands during HER2-low breast tumor progression and establishes a metabolically immunosuppressive niche. Spatial transcriptomics and multiplex imaging of human HER2-low tumors reveal progressive CAF accumulation and an inverse spatial association between S100A4-enriched CAFs and immune infiltration, including natural killer (NK) cells. Using an immunocompetent HER2-low mammary tumor model, we show that S100A4-enriched CAFs promote tumor initiation and progression while suppressing NK-cell cytotoxicity, IFN-γ production, perforin, and granzyme B. Fractionation of CAF-conditioned media and metabolic profiling identify a low-molecular-weight immunosuppressive program characterized by enhanced branched-chain amino acid catabolism and accumulation of branched-chain α-keto acids (BCKAs). Mechanistically, BCKAs directly suppress NK-cell IFN-γ production, whereas inhibition of the branched-chain aminotransferase BCAT1 reduces CAF-mediated NK-cell suppression and restores antitumor cytotoxicity. BCAT1 inhibition also suppresses HER2-low tumor growth in vivo , an effect attenuated by NK-cell depletion, establishing NK-cell restoration as a functional component of its antitumor activity. Together, these findings uncover a CAF-driven metabolic immune checkpoint in which S100A4-enriched CAFs exploit BCAT1-dependent BCKA production to suppress NK-cell surveillance and promote HER2-low breast tumor progression. Targeting stromal BCAT1 therefore represents a potential strategy to dismantle CAF-mediated immune suppression and restore innate antitumor immunity.
    DOI:  https://doi.org/10.64898/2026.09.07.749862
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