bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–10–04
fifty-two papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.
  2. Metabolic licensing and restriction of innate immunity in the tumor microenvironment.
  3. Macrophage-derived CD38 mediates colitis through NAD+ depletion.
  4. ASNS-dependent asparagine availability supports intestinal ILC2 responses and type 2 immunity under nutrient-limited conditions.
  5. Metabolic reprogramming in neuromyelitis optica spectrum disorder: From astrocyte dysfunction to immune-mediated neuroinflammation.
  6. Coupling and uncoupling cell cycle and metabolism in CD8+ T cells.
  7. Macrophage Immunometabolism in Epicardial Adipose Tissue and Obesity-Related Atrial Fibrillation.
  8. TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia.
  9. Glycolytic reprogramming and cell-specific lactylation in asthma: an evidence-graded framework for testable metabolic-epigenetic profiles.
  10. Intestinal lipid metabolism controls molecular and behavioral immunity through NHR-68 and gut-brain signaling in Caenorhabditis elegans.
  11. Extracting interpretable single-cell metabolic states with graph-guided representation learning.
  12. In vivo CRISPR Screening Reveals LBR as a Regulator of CD8+ T Cell Fate Decision.
  13. The impact of macrophage metabolism on idiopathic pulmonary fibrosis development and treatment prospectives.
  14. Histone lactylation regulates macrophage polarization and metabolic homeostasis during hypoxic lung injury.
  15. Beyond Fuel: Metabolic Intermediates as Signaling Molecules in Neuroinflammation and Neurodegeneration.
  16. When Cold Gets Under the Skin: An Immunometabolic Circuit in Psoriasis.
  17. P. aeruginosa liquid-based pathogenesis triggers HLH-30-dependent metabolic rewiring in C. elegans.
  18. Targeting the ENO1 metabolic checkpoint via microenvironment-responsive nanotherapeutics promotes postinfarction cardiac repair.
  19. Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism.
  20. Prodh2-Mediated Mitochondrial Stress Drives TNF-α-Induced Myoblast Dysfunction and Sarcopenia in COPD.
  21. scH16S-Seq Maps Klebsiella pneumoniae-Associated Myeloid States and Reveals a CD38-NAD Immunometabolic Axis That Impairs Lysosomal Acidification in Sepsis.
  22. SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.
  23. IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma.
  24. Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection.
  25. Mapping immune cell metabolic reprogramming from mechanistic hotspots to translational directions: A bibliometric analysis with exploratory clinical evidence.
  26. Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
  27. Nomilin Rewires mTOR-Driven Immunometabolism via DDIT4 to Restrain Psoriasis.
  28. Hypermetabolic State Drives Platelet Dysfunction in Human and Mouse Metabolic Dysfunction-Associated Steatotic Liver Disease.
  29. NETs drive CD4⁺ T cell dysfunction in sepsis via mitochondrial ROS and impaired calcium signalling.
  30. Post-translational modification crosstalk in acute pancreatitis: linking acinar stress to innate immune amplification and tissue repair.
  31. Microglial FKBP51 drives immunometabolic dysfunction linking perioperative neurocognitive disorders and Alzheimer's disease.
  32. Salicylic acid engages central metabolic regulators SnRK1 and TOR to govern immunity by differential phosphorylation of NPR1.
  33. Understanding the Mechanistic Connection between Dysbiosis and Polyamine Regulation in Oral and Intestinal Inflammation- Role of Tregs and Th17 Cells.
  34. Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer.
  35. Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review.
  36. Nucleotide metabolic reprogramming: a "double-edged sword" in obesity-related inflammation-from metabolic adaptation to pathological imbalance.
  37. Hepatic cholinergic T cell signaling mediates an adaptive response to alcohol-induced liver stress.
  38. Trained immunity and related memory responses in lung health and disease.
  39. Immunometabolic Profiling of T Cells and Innate Lymphoid Cells Uncovers Therapeutic Targets to Enhance Immunotherapy in Head and Neck Cancer.
  40. Carbon source-dependent metabolic states govern redox homeostasis and cofactor biosynthesis in Propionibacterium freudenreichii.
  41. SPTLC2-driven sphingolipid reprogramming of neutrophils impairs anti-tumour immunity and drives liver cancer progression.
  42. A Gut-Brain Axis Underlying Succinate-Associated Compulsive-Like Behavior.
  43. Mechanism of SGLT2 inhibitors in improving immune imbalance in diabetic mice with sepsis via regulating macrophage M2 polarization through the APOC1/HMGB1/TLR4 axis.
  44. Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia.
  45. Metabolic reprogramming in ulcerative colitis: integrating dietary drivers, pathogenesis, and therapeutic advances.
  46. CAF-derived BHB modulates FXR1-Kbhb and NK-cell lipid metabolism in osteosarcoma.
  47. MITF-associated metabolic signature in mast cells: A potential link to food anaphylaxis.
  48. CD38-activated macrophages drive age-related placental senescence by depleting NAD+ in decidual stromal cells.
  49. Fatty acid synthesis restricts HIV-1 infection through regulation of the nuclear envelope in CD4+ T cells.
  50. H4K12 Lactylation Regulates NDUFS7 to Drive Microglia Reverse Electron Transport in Spinal Cord Injury.
  51. A systematic transcriptomic atlas and predictive framework for metabolite-driven T cell state transitions.
  52. ZBP1-mediated Treg cell dysfunction exacerbates neuroimmune dysregulation in Alzheimer's disease under metabolic stress.
  1. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2606579123
    α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.
    Fei Li, Xiaorong Xie, Tongran Xu, Yu Tang, Yuting Xia, Yali Tang, Shijie Yuan, Mengdi Zhu, Xuwei Wu, Lan He, Shu-Hai Lin, Ran He.
      Tumor-associated macrophages (TAMs), the most abundant immune cell subset in the tumor microenvironment (TME), exhibit phenotypic plasticity and exert critical roles in tumor progression and antitumor immunity. Targeting TAM polarization has emerged as a promising strategy for cancer immunotherapy, yet the key regulators governing this process remain incompletely defined. Here, we identified α-aminobutyric acid (AABA) as a pro-tumor metabolite that drives M2-like polarization of TAMs to promote tumor progression. Mechanistically, AABA binds to asparagine synthetase (ASNS), reinforcing the mTORC2-IRF4 signaling axis to reprogram TAMs, switching macrophage metabolism from glycolysis to oxidative phosphorylation, a hallmark of pro-tumor M2-like phenotypes. Moreover, tumor-derived AABA was transported into macrophages by monocarboxylate transporters 1 and compromised the therapeutic efficacy of PD-1 checkpoint inhibition. Collectively, our findings uncover AABA as a previously unrecognized signaling metabolite to control TAM polarization, providing insights into the metabolic crosstalk within the TME and offering a potential therapeutic target to improve cancer immunotherapy outcomes.
    Keywords:  asparagine synthetase; mTORC2; macrophage; tumor microenvironment; α-aminobutyric acid
    DOI:  https://doi.org/10.1073/pnas.2606579123
  2. Front Immunol. 2026 ;17 1935435
    Metabolic licensing and restriction of innate immunity in the tumor microenvironment.
    Ji Min Shin, Hye Yeon Choi, Jihyoun Kim, Seon Ah Lim.
      Tumor progression is driven by metabolic remodeling that generates a microenvironment characterized by nutrient deprivation, hypoxia, lactate accumulation, lipid dysregulation, and oxidative stress. These conditions affect innate immune populations, including natural killer (NK) cells, dendritic cells (DCs), macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs), shaping their activation, persistence, and functional states. Although many studies have defined metabolic pathways that regulate innate immune function in cancer, these findings are often discussed at the level of individual pathways or individual cell types, obscuring shared principles by which the tumor microenvironment controls innate immunity. Here, we use the concepts of metabolic licensing and metabolic restriction to describe how metabolic capacity and environmental constraints interact to shape innate immune function. Metabolic licensing refers to context-dependent metabolic states that provide sufficient bioenergetic and biosynthetic capacity to support sustained antitumor effector function, whereas metabolic restriction describes conditions in which nutrient limitation, mitochondrial dysfunction, redox imbalance, or suppressive metabolites constrain or progressively erode these functions. Rather than representing fixed binary states, licensing and restriction can occur along a continuum shaped by cell identity, signal duration, and local tumor conditions. We discuss how metabolic licensing and restriction shape antitumor and immunosuppressive innate immune populations, examine the stress-sensing pathways that connect environmental cues to innate immune fate, and summarize therapeutic strategies aimed at restoring metabolic fitness or alleviating metabolic restriction. Considering innate immune responses in terms of metabolic licensing and restriction helps explain how shared metabolic pressures within tumors can impair effector cells while supporting suppressive innate populations and may inform the development of immunometabolic approaches to cancer therapy.
    Keywords:  immunometabolism; innate immunity; metabolic licensing; metabolic restriction; metabolic stress; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1935435
  3. J Physiol. 2026 Sep 29.
    Macrophage-derived CD38 mediates colitis through NAD+ depletion.
    Yanni Wu, Xiaohan Yang, Xianyang Jin, Xuemei Jiang, Chao Jin, Bin Feng, Lianqiang Che, Shengyu Xu, Yan Lin, De Wu, Lun Hua, Yong Zhuo.
      Colitis, a chronic inflammatory bowel disease (IBD), is pathologically linked to immune dysregulation; however, the contribution of cellular metabolic alterations to its pathogenesis remains incompletely understood. In this study, untargeted metabolomic analysis revealed marked disruption of NAD+ metabolism, accompanied by increased expression of CD38, a major NAD+-glycohydrolase, in colitis. Restoring NAD+ levels through supplementation with its precursors or pharmacological inhibition of CD38 activity effectively alleviated the pathological symptoms of colitis. Mechanistically, colitis induced a pronounced upregulation of CD38 specifically in macrophages. Myeloid-specific deletion of Cd38 significantly attenuated both metabolic disturbances and inflammatory responses associated with colitis. These findings identify macrophage CD38 as a critical regulator of intestinal inflammation and highlight the CD38/NAD+ axis as a potential therapeutic target for IBD. KEY POINTS: Altered NAD+ metabolism is closely associated with intestinal inflammation, yet the specific cellular mechanisms contributing to this decline remain to be fully elucidated. By supplementing with nicotinamide mononucleotide or inhibiting the enzyme CD38 that consumes NAD+ with drugs, the NAD+ level can be effectively restored, which can alleviate the colitis induced by dextran sulphate sodium to a certain extent. During intestinal inflammation, the upregulation of CD38 is predominantly driven by infiltrating macrophages. Myeloid-specific deletion of CD38 preserves NAD+ homeostasis and ameliorates colitis, highlighting its essential role in disease progression. Targeting macrophage CD38 establishes a key regulatory link between NAD+ metabolism and intestinal inflammation, providing a potential therapeutic strategy for inflammatory bowel diseases.
    Keywords:  CD38; NAD+ metabolism; inflammatory bowel disease; macrophages
    DOI:  https://doi.org/10.1113/JP291548
  4. Front Immunol. 2026 ;17 1878920
    ASNS-dependent asparagine availability supports intestinal ILC2 responses and type 2 immunity under nutrient-limited conditions.
    Wenyu Tian, Xuesong Liu, Mengqi Zheng, Jing Shen.
       Introduction: Nutrient availability critically governs group 2 innate lymphoid cell (ILC2) function and type 2 immunity. Here, we identify the non-essential amino acid asparagine (Asn) as a critical metabolite required for ILC2 survival and function.
    Methods: We investigated the roles of extracellular Asn availability and asparagine synthetase (ASNS)-mediated de novo Asn biosynthesis in ILC2 responses using complementary in vitro and in vivo approaches, including amino acid restriction, ILC2-specific Asns deletion, dietary Asn restriction, and Nippostrongylus brasiliensis infection.
    Results: ASNS, the rate-limiting enzyme for de novo Asn synthesis, was rapidly induced upon ILC2 activation under type 2 inflammatory conditions. When extracellular Asn was limited, ILC2s depended on ASNS-mediated Asn synthesis fueled by glutamine (Gln). Genetic ablation of Asns was well tolerated under Asnreplete conditions but severely impaired ILC2 viability and overall effector cytokine output upon Asn restriction. Dietary Asn restriction compromised ILC2s, and this effect was further aggravated by Asns deficiency. During N. brasiliensis infection, reduced intestinal Asn availability enhanced ILC2 reliance on Asns, whose deficiency impaired ILC2 abundance in the mLNs and protective anti-helminth immunity.
    Discussion: These findings identify Asn as a context-dependent metabolic adaptor that supports ILC2 viability and function under nutrient-limited and type 2 inflammatory conditions.
    Keywords:  anti-helminth immunity; asparagine; asparagine synthetase; group 2 innate lymphoid cell; immunometabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1878920
  5. Mult Scler Relat Disord. 2026 Sep 26. pii: S2211-0348(26)00981-8. [Epub ahead of print]115 107946
    Metabolic reprogramming in neuromyelitis optica spectrum disorder: From astrocyte dysfunction to immune-mediated neuroinflammation.
    Xinyue Jin, Nannan Cao.
      Neuromyelitis optica spectrum disorders comprise a group of autoimmune diseases of the central nervous system, defined primarily by astrocyte injury mediated by anti-aquaporin-4 antibodies. Although targeted therapies directed against B cells, complement, and inflammatory mediators have substantially reduced the relapse risk in recent years, a subset of patients still exhibits persistent neurological impairment. Recent advances in immunometabolic research suggest that metabolic reprogramming may be a potentially important regulatory process linking immune abnormalities to neurological damage.This review synthesizes the current understanding of metabolic abnormalities and their underlying mechanisms in NMOSD from an immunometabolic perspective, with a particular focus on the interplay between astrocyte damage and disruption of metabolic homeostasis. Current research suggests that AQP4-IgG-mediated astrocyte dysfunction may disrupt the metabolic support network of the central nervous system, which in turn may lead to energy metabolism disorders and mitochondrial dysfunction, and further affect the metabolic state of immune cells. Metabolically reprogrammed T cells and B cells may exhibit functional shifts, which could contribute to the persistence of inflammation and the progression of tissue damage.Among these, metabolic regulatory pathways, including mTOR, AMPK, and HIF-1α, appear to participate in metabolic adaptation and immune regulation across various cell types. Based on these findings, targeting the regulatory networks of glycolysis, mitochondrial homeostasis, and immunometabolic regulation may offer new therapeutic approaches for NMOSD; however, most intervention strategies are still in the experimental exploration phase.Research into metabolic reprogramming in NMOSD remains in its nascent stages. Future investigations, integrating multi-omics approaches and relevant disease models, will be essential to further identify key metabolic targets and to explore the potential synergy between metabolic interventions and existing immunotherapies.
    Keywords:  Aquaporin-4 immunoglobulin G; Astrocyte dysfunction; Immunometabolism; Metabolic reprogramming; Mitochondrial dysfunction; Neuroinflammation; Neuromyelitis optica spectrum disorders
    DOI:  https://doi.org/10.1016/j.msard.2026.107946
  6. Trends Immunol. 2026 Sep 29. pii: S1471-4906(26)00256-5. [Epub ahead of print]
    Coupling and uncoupling cell cycle and metabolism in CD8+ T cells.
    Floortje J van Haften, Hanna S Hepp, Melissa Biemond, Ramon Arens.
      CD8+ T cells eliminate infected and malignant cells through coordinated proliferation and effector differentiation, processes supported by metabolic reprogramming that together form an interconnected, cross-regulated network. Emerging evidence indicates, however, that cell cycle progression and effector programming can be transiently uncoupled, with implications for T cell function and fate. Short-term modulation of cell cycle dynamics creates a window for metabolic rewiring, reshaping nutrient utilization, cytokine responsiveness, and bioenergetic capacity. This uncoupling can enhance T cell expansion, effector function, and antitumor activity. Collectively, these findings indicate that the cell cycle functions as an instructive checkpoint integrating metabolic and differentiation programs, not merely supporting proliferation. Understanding this interplay provides a conceptual framework to optimize T cell-based immunotherapies and rationally design chemoimmunotherapy combinations.
    Keywords:  CD8(+) T cells; T cell differentiation; adoptive cell transfer; cell cycle progression; immunotherapy; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.it.2026.09.001
  7. J Inflamm Res. 2026 ;19 640949
    Macrophage Immunometabolism in Epicardial Adipose Tissue and Obesity-Related Atrial Fibrillation.
    Linrui Xia, Xiaoxiang Sun, Luyi Xie, Shuang Liu, Teva Phanaksri, Zhi Yu, Zefei Jiang, Xin Cao.
      Obesity is a crucial risk factor for atrial fibrillation (AF). The underlying mechanism is partly related to increased epicardial adipose tissue (EAT). EAT directly contacts the adjacent cardiac myocardium where immune and metabolic activities interact. Obesity induces inflammatory and metabolic signals within EAT, which directly influence atrial structure and electrical remodeling. However, the specific immunometabolic mechanisms linking EAT macrophages to atrial arrhythmogenesis remain unclear. We highlight evidence that nutrient excess, hypoxia, oxidative stress, and adipocyte-derived inflammatory signals reprogram glucose, lipid, and amino acid metabolism in EAT macrophages, promoting persistent pro-inflammatory and profibrotic states. Metabolic pathways involving mechanistic target of rapamycin (mTOR)-hypoxia-inducible factor-1α (HIF-1α) signaling, fatty acid and ceramide metabolism, the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, and metabolic-epigenetic interactions may sustain macrophage activation and amplify local inflammation. These metabolically reprogrammed macrophages subsequently promote atrial fibrosis, electrical heterogeneity, and autonomic dysfunction, while systemic inflammation, insulin resistance, and neurohumoral activation further reinforce the EAT-atrial pathological circuit. Emerging evidence also suggests that EAT characteristics may improve AF risk stratification and that weight loss and metabolic interventions can attenuate EAT inflammation. More importantly, targeting macrophage immunometabolism may offer a mechanistically distinct approach to interrupt the link between obesity and atrial remodeling rather than treating AF solely after its substrate has developed. Collectively, targeting EAT immunometabolism may shift obesity-related AF management from treating an established arrhythmia toward identifying and modifying the metabolic-inflammatory substrate that promotes its development and recurrence, potentially complementing conventional rhythm-control and ablation strategies. Future studies should establish causal relationships and identify clinically actionable metabolic targets for EAT macrophage-directed therapy.
    Keywords:  atrial fibrillation; epicardial adipose tissue; inflammation; macrophage; obesity
    DOI:  https://doi.org/10.2147/JIR.S640949
  8. bioRxiv. 2026 Sep 27. pii: 2026.09.24.754254. [Epub ahead of print]
    TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia.
    Zahrasadat Navaeiseddighi, Kai Guo, Syed Shafat Hasan, Zhihan Wang, Rutuparnna Mishra, Taylor Schmit, Jamanah Ahsan, Emily J Moser, Junguk Hur, Jacob S Yount, Ramkumar Mathur, Liang Zhou, Nadeem Khan.
      During respiratory virus infection, CD8⁺ T cells kill infected cells and establish antigen-specific memory, but mechanisms regulating these functions remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM)-dependent mitochondrial fitness as a regulator of CD8⁺ T cell function during influenza infection. Human CD8⁺ T cells exhibited an age-associated decline in TFAM expression and mitochondrial function. To model this physiologically relevant decline and determine its consequences for antiviral immunity, we generated CD8⁺ T cell-specific TFAM-haploinsufficient mice. TFAM insufficiency disrupted mitochondrial integrity and bioenergetics and increased mitochondrial DNA and oxidative stress. During influenza infection, TFAM-insufficient CD8⁺ T cells exhibited increased cytotoxic and inflammatory activity associated with lung immunopathology without improved viral control. This early phenotype was followed by loss of effector function, diminished antigen-specific responses, reduced protection following adoptive transfer, and impaired heterosubtypic recall immunity. Thus, TFAM-dependent mitochondrial fitness is a cell-intrinsic regulator that limits immunopathology while sustaining recall immunity.
    DOI:  https://doi.org/10.64898/2026.09.24.754254
  9. Front Immunol. 2026 ;17 1955426
    Glycolytic reprogramming and cell-specific lactylation in asthma: an evidence-graded framework for testable metabolic-epigenetic profiles.
    Shu Li, Haoxiang Fang, Kun Wang.
      Asthma is metabolically heterogeneous, but existing syntheses often place patient observations, animal perturbations, cross-disease mechanisms, and therapeutic concepts on the same evidentiary plane. This review addresses that problem by organizing glycolytic reprogramming and lysine lactylation through a three-tier hierarchy: human asthma observations, mechanistic perturbation in asthma-relevant models, and cross-disease or conceptual precedents. Mitochondrial and redox disturbances alter glycolytic and oxidative capacity across immune and structural cells, whereas lactate can function separately as an exported acidifying metabolite and as an intracellular substrate for site-specific lactylation. Four asthma-associated circuits have the strongest direct mechanistic support: epithelial histone H3 lysine 18 lactylation (H3K18la)-colony-stimulating factor 1 receptor (CSF1R) signaling; cluster of differentiation 4-positive (CD4+) T-cell H3K18la-dipeptidyl peptidase 4 (DPP4) regulation; mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2)-dependent polyglutamine-binding protein 1 (PQBP1) K223 lactylation coupled to protein arginine methyltransferase 5 (PRMT5) inhibition; and macrophage sirtuin 6 (SIRT6)-lactate dehydrogenase A (LDHA)-histone H4 lysine 12 lactylation (H4K12la) signaling. Their prevalence, effect size, temporal stability, and distribution across human asthma phenotypes remain unknown, so they should not be considered validated endotypes or biomarkers. We therefore propose five mechanistically anchored research profiles and sequential analytical, biological, clinical, and external-replication gates, with falsification criteria and no universal numerical cutoffs absent empirical calibration. We further distinguish airway-restricted delivery from regional and cellular selectivity and define deposition, diseased-mucus transport, cell-resolved pharmacokinetics and pharmacodynamics, intracellular target engagement, and local-to-systemic safety as translational gates. The distinctive contribution is an evidence-graded, falsifiable framework that links metabolic state to cell- and residue-specific lactylation while making explicit what remains to be demonstrated in human asthma.
    Keywords:  asthma; chromatin regulation; glycolytic reprogramming; immunometabolism; lysine lactylation
    DOI:  https://doi.org/10.3389/fimmu.2026.1955426
  10. PLoS Biol. 2026 Sep 29. 24(9): e3004026
    Intestinal lipid metabolism controls molecular and behavioral immunity through NHR-68 and gut-brain signaling in Caenorhabditis elegans.
    Jie Ren, Yu Sang, Young-Mo Kim, Ernesto S Nakayasu, Alejandro Aballay.
      Animals must allocate limited energetic resources across competing defense programs in response to infection. Here, we show that the conserved nuclear hormone receptor NHR-68 integrates fatty acid metabolism with the neural control of molecular and behavioral immunity in Caenorhabditis elegans. Acting in parallel with NHR-10, NHR-68 controls genes involved in polyunsaturated fatty acid (PUFA) metabolism. Loss of NHR-68 disrupts linoleic acid (LA) homeostasis, impairing pathogen avoidance behavior. Supplementation with LA restores avoidance, and fat-3 inhibition, which elevates LA, enhances pathogen avoidance, whereas loss of LA synthesis by fat-2 inhibition diminishes this behavior, indicating that LA promotes behavioral immunity. We further show that NHR-68 acts in the intestine to regulate linoleic acid homeostasis, and that changes in intestinal lipid metabolism influence an AWC-dependent pathogen-avoidance circuit through intestine-to-neuron communication. NHR-68 suppresses activation of the PMK-1/p38 MAPK and DAF-16/FOXO pathways, which mediate molecular immune responses. These findings identify a gut-brain transcriptional circuit that connects intestinal lipid metabolism to neural and immune outputs, revealing a mechanism by which the metabolic state coordinates behavioral and molecular defenses to optimize host protection.
    DOI:  https://doi.org/10.1371/journal.pbio.3004026
  11. bioRxiv. 2026 Sep 24. pii: 2026.09.17.751504. [Epub ahead of print]
    Extracting interpretable single-cell metabolic states with graph-guided representation learning.
    Daniel P Lewinsohn, Nicolas Dias, Adelina Chau, Yuko Koike, Zachary D Smith, Nilah M Ioannidis, Allon Wagner.
      Metabolism shapes cellular function and state, yet measuring single-cell metabolic states at scale remains a challenge. We present Metabolic Representation Net (MeRN), a graph-guided variational autoencoder that leverages prior metabolic knowledge as a topology graph to learn latent representations of metabolic state and reaction activity from single-cell transcriptomes. MeRN's scalable estimation of reaction activity enables the definition of data-driven pathways (DDPs): context-specific metabolic modules supported by transcriptomic evidence and agnostic of standard pathway definitions. Using DDPs, we introduce the weakest link analysis to identify metabolic network rewiring. MeRN recovers metabolic zonation in the mouse intestine, links a folate deficiency-induced break in de novo purine synthesis to embryonic neural tube defects, shows cytokines with similar non-metabolic effects can elicit divergent T cell metabolism, and identifies metabolic drivers of T cell exhaustion and therapy response in human cancers. Our results establish MeRN as a unified method for metabolic analysis of single-cell transcriptomes.
    Research highlights: MeRN leverages the metabolic topology to comprehensively predict reaction- and pathway-level metabolic activitiesMeRN enables data-driven pathways (DDPs) that capture empirically supported cell-type-specific metabolic modules, agnostic of standard pathway definitions MeRN-based DDPs identify metabolic network rewiring of de novo purine synthesis due to folate deficiency during embryonic neural tube development MeRN identifies human pan-cancer metabolic drivers of T cell exhaustion and Treg-specific metabolic adaptations.
    DOI:  https://doi.org/10.64898/2026.09.17.751504
  12. FASEB J. 2026 Oct 15. 40(19): e72318
    In vivo CRISPR Screening Reveals LBR as a Regulator of CD8+ T Cell Fate Decision.
    Qiying Zhang, Shuya Chang, Shengli Zhao, Weixin Zhang, Rong Wang, Mingyang Zhong, Guanfeng Liu, Xiaojing Li, Ao Guo.
      CD8+ T cells play an important role in anti-infection and anti-tumor immunity. Metabolic reprogramming has emerged as a critical regulator of T cell function, yet the roles of specific cholesterol-associated proteins during T cell fate trajectories remain unclear. Here, using an in vivo CRISPR screen in CD8+ T cells during infection with a customized sgRNA library targeting key cholesterol metabolism-associated proteins, we successfully identified several candidate targets, including the LBR (Lamin B Receptor). Lbr knockout significantly reduced the proportion and absolute number of short-lived effector cells (SLECs), severely impairing effector responses, while concomitantly increasing the memory precursor population upon LCMV infection. Furthermore, transcriptomic analysis revealed that Lbr depletion markedly altered signaling pathways governing effector T cell differentiation. These findings reveal the role of LBR in modulating effector and memory T cell differentiation, suggesting it as a potential target for metabolic reprogramming to enhance T cell-based immunotherapies.
    Keywords:  CD8+ T cells; LBR; T cell fate decisions; cholesterol metabolism; in vivo CRISPR screen
    DOI:  https://doi.org/10.1096/fj.202602909R
  13. Front Immunol. 2026 ;17 1892250
    The impact of macrophage metabolism on idiopathic pulmonary fibrosis development and treatment prospectives.
    Guangyan Mu, Shan Chong, Jiulong Li, Hanping Wang, Huan Meng, Qian Xiang, Yimin Cui.
      Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic interstitial pneumonia of unknown etiology, in which macrophages serve as central orchestrators of the pathological microenvironment. During IPF progression, the alveolar macrophage pool undergoes a critical compositional shift: tissue-resident alveolar macrophages (TR-AMs) are progressively depleted and replaced by monocyte-derived alveolar macrophages (Mo-AMs) harboring a distinct pro-fibrotic transcriptional and metabolic identity. These populations differ fundamentally in their baseline metabolic programs, and both undergo further reprogramming within the fibrotic niche that sustains myofibroblast activation and extracellular matrix (ECM) deposition. This review systematically examines how metabolic reprogramming across three principal axes (glucose metabolism, lipid metabolism, and amino acid metabolism) drives pro-fibrotic macrophage polarization in IPF. Within each axis, alterations in metabolic flux and intermediate accumulation converge to reinforce the pro-fibrotic phenotype, promote fibroblast activation, and perpetuate ECM deposition. Importantly, these metabolic alterations differ between TR-AM and Mo-AM subpopulations in ways that reflect their distinct ontogenetic origins and predispose Mo-AMs to preferential pro-fibrotic polarization within the fibrotic microenvironment. Building on this mechanistic framework, we systematically categorize pharmacological modulators targeting these metabolic checkpoints and evaluate the integration of advanced drug delivery systems for precision intervention within the alveolar macrophage niche. This review ultimately proposes a therapeutic strategy that co-targets macrophage ontogenetic origin, polarization state, and metabolic reprogramming as an interconnected axis, offering new perspectives for re-educating macrophages to attenuate fibrotic progression in IPF.
    Keywords:  idiopathic pulmonary fibrosis; immunometabolism; macrophage polarization; metabolic reprogramming; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1892250
  14. Cell Rep. 2026 Sep 25. pii: S2211-1247(26)01138-1. [Epub ahead of print]45(10): 118059
    Histone lactylation regulates macrophage polarization and metabolic homeostasis during hypoxic lung injury.
    Xingwang Zhao, Mengjie Zhang, Jun Yin, Jingyi Liao, Denghui Li, Zhiqiang Tian, Yi You, Longlong Zhang, Bing Ni.
      The M1-to-M2 macrophage phenotypic switch is critical for resolving inflammation and restoring homeostasis in hypoxic lung injury, but the underlying molecular mechanisms are unclear. Here, we show that hypoxia-induced histone lactylation (Kla) upregulates FTO via HIF1a-P300 interaction; lactylation-driven FTO then promotes late-stage M2 polarization by stabilizing Arg1 mRNA through the m6A-YTHDF2 axis. Mechanistically, HIF1a/YY1 liquid-liquid phase separation (LLPS) regulates macrophage glycolysis and oxidative phosphorylation (OXPHOS) via the cGAS-STING pathway downstream of lactylation. Importantly, lactylation exerts context-dependent dual effects: physiological lactylation in wild-type mice facilitates M2 polarization, maintains metabolic balance, and promotes lung repair, whereas excessive lactylation in IL-10-deficient mice disrupts the FTO-Arg1 cascade, perturbs metabolism, blocks M2 polarization, and aggravates injury. Collectively, histone lactylation is a core switch governing macrophage polarization and metabolic homeostasis in hypoxic lung injury, with its function dictated by IL-10 status and lactylation abundance.
    Keywords:  Arg1; CP: immunology; CP: molecular biology; FTO; HIF1a; YY1; cGAS-STING; lactylation; metabolic reprogramming; phase separation
    DOI:  https://doi.org/10.1016/j.celrep.2026.118059
  15. Curr Neuropharmacol. 2026 Sep 30.
    Beyond Fuel: Metabolic Intermediates as Signaling Molecules in Neuroinflammation and Neurodegeneration.
    Song Wang, Sichen Wang, Yuhan Sun, Song Zhang, Jiangxu Wu, Dan Xie.
      Historically, research has viewed substantial brain metabolic activity through the lens of energy production, primarily treating metabolites as substrates and products in bioenergetic pathways. However, this paradigm is now evolving. Key metabolic intermediates are recognized not only as components of Adenosine Triphosphate (ATP) synthesis, but also as potent signaling molecules that establish intricate communication networks. This "metabolic signaling language" profoundly influences inflammation, epigenetics, and cell fate by translating cellular metabolic conditions into certain functional outcomes. In this review, three prototypical metabolites, namely succinate, itaconate, and α-Ketoglutarate (α-KG), were discussed. We investigated succinate accumulation during ischemia and mitochondrial stress, which serves as an early alarm that drives inflammation through both intracellular and extracellular receptor-mediated mechanisms. Conversely, itaconate, an inducible metabolite produced by myeloid cells, exerts inhibitory effects and actively alleviates inflammation by covalently modifying proteins. Finally, we highlighted α-KG, a central metabolic hub that links metabolic status to cellular identity and aging by epigenetically regulating DNA and histone demethylase activity. By summarizing the functions of these metabolites across neurological disorders, including ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, we delineate a fundamental layer of biological regulation. Deciphering and therapeutic modulation of this metabolic language represent a frontier in neuroscience, offering novel targets for intractable neurological diseases.
    Keywords:  Metabolism; epigenetics.; itaconate; neuroinflammation; succinate; α-ketoglutarate
    DOI:  https://doi.org/10.2174/011570159X486332260921110838
  16. Exp Dermatol. 2026 10;35(10): e70368
    When Cold Gets Under the Skin: An Immunometabolic Circuit in Psoriasis.
    Young In Lee, Tae-Gyun Kim.
      Psoriasis is a common immune-mediated inflammatory disease that often worsens during cold weather, yet the mechanisms linking cold exposure to enhanced psoriatic inflammation remain poorly understood. Shuai and colleagues identify a distinct macrophage population induced by cold stress in the dermal adipose layer, characterized by heightened lipid metabolism and IL-1β production. These macrophages promote IL-17A-producing γδT-cell responses in a mouse model of psoriasis, uncovering a potential cellular mechanism through which cold environments exacerbate psoriatic inflammation via immune-metabolic pathways.
    Keywords:  cold; lipid metabolism; macrophages; psoriasis
    DOI:  https://doi.org/10.1111/exd.70368
  17. bioRxiv. 2026 Sep 07. pii: 2026.09.03.749215. [Epub ahead of print]
    P. aeruginosa liquid-based pathogenesis triggers HLH-30-dependent metabolic rewiring in C. elegans.
    Lois A Armendariz, Elissa Tjahjono, Yvette Acevedo, Fernanda Vaca, Jane Lowder, Anna Singh, Nikita Singh, Alexey V Revtovich, Ainsley High, Evan Park, Natalia V Kirienko.
      Innate immunity is the first line of defense against invading pathogens and is essential for maintaining host survival. While the majority of innate immunity studies have focused on pathogen recognition and antimicrobial responses, increasing evidence suggests that lipid metabolism plays a fundamental role in shaping immune function. Understanding how these metabolic pathways contribute to immunity is crucial in the context of bacterial infections caused by opportunistic pathogens such as Pseudomonas aeruginosa . Host defense against P. aeruginosa requires the coordination of innate immune and metabolic responses; however, the mechanisms linking lipid metabolism to pathogen resistance remain poorly understood. Research into the relationship between lipid homeostasis and innate immunity may reveal factors governing host-pathogen interactions and identify novel strategies to enhance resistance to infection. Here, we demonstrate that P. aeruginosa liquid-based pathogenesis (LK- Pa ) triggers a shift in host metabolism which differs from the one observed in response to agar-based pathogenesis. Our bioinformatic analyses revealed a highly similar metabolic profile (enrichment of lipid metabolism) in worms exposed to LK- Pa or the iron chelator phenanthroline, suggesting a shared host response to iron deprivation. We further characterized the host genetic factors driving this metabolic shift and established their importance for host defense against LK- Pa as well as liquid-based pathogenesis by Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus . Notably, our results indicate that LK- Pa triggers host lipid droplet depletion, an upstream component that leads to increased β-oxidation. Finally, we demonstrate that LK- Pa triggers repression of MXL-3 which results in HLH-30-dependent metabolic rewiring.
    Author Summary: Pathogenesis alters host metabolism in ways that can either enhance survival or promote disease. Understanding how pathogenesis triggers host metabolic rewiring may reveal novel strategies to combat antimicrobial-resistant infections. Using Caenorhabditis elegans , we studied how the opportunistic pathogen P. aeruginosa reshapes host metabolism during liquid-based infection. Our results reveal that liquid-based pathogenesis induces extensive activation of host lipid metabolism, a distinct transcriptional response from the one triggered during agar-based pathogenesis. This lipid signature closely resembles the host response to iron deprivation, suggesting that in the case of P. aeruginosa , bacterial siderophore production is a major driver of host metabolic rewiring. We identified seventeen lipid genes crucial for survival during P. aeruginosa exposure in liquid; most of them were also needed for defense against the Gram-positive pathogens E. faecalis and S. aureus . Notably, most of these genes function independently of activating known organellar surveillance pathways. Instead, we show that P. aeruginosa liquid-based pathogenesis triggers host lipid droplet depletion and induces a metabolic shift towards β-oxidation. This process is driven by inhibition of the nutrient-responsive transcription factor MXL-3 and subsequent activation of the lysosomal transcription factor HLH-30, which drives expression of β-oxidation genes. Altogether, our findings identify an MXL-3 -HLH-30 regulatory axis that couples pathogen-induced metabolic stress to lipid mobilization and reveal metabolic rewiring as a host defense mechanism during bacterial infection.
    DOI:  https://doi.org/10.64898/2026.09.03.749215
  18. Sci Adv. 2026 Oct 02. 12(40): eaeg3270
    Targeting the ENO1 metabolic checkpoint via microenvironment-responsive nanotherapeutics promotes postinfarction cardiac repair.
    Ruoshui Li, Gaoyang Li, Jie Li, Zekun Lou, Xuerou Jin, Jun Yan, Hongping Chen, Fang Zhang, Xiaoran Deng, Tongda Xu.
      Myocardial infarction (MI) triggers persistent inflammatory dysregulation, wherein macrophages undergo glycolytic reprogramming and adopt an inflammatory phenotype that impairs cardiac repair. However, the specific metabolic drivers underlying post-MI macrophage dysfunction remain unclear. Here, we identify enolase 1 (ENO1)-a glycolytic enzyme up-regulated in post-MI macrophages-as a critical regulator of macrophage metabolic fate and inflammatory function. To intervene, we engineered an acid-responsive nanocarrier (PECS) that externalizes phosphatidylserine within the acidic infarct microenvironment, facilitating selective macrophage uptake. Intracellular delivery of siENO1 suppressed glycolytic flux, thereby curbing lactate accumulation and relieving its metabolic inhibition of KLF4, which initiated anti-inflammatory reprogramming. In vivo, PECS-loaded siENO1 (siENO1@PECS) treatment attenuated infarct size, fibrosis, and cardiomyocyte apoptosis while improving ventricular function. Collectively, these findings identify ENO1 as a critical metabolic checkpoint in post-MI macrophage regulation and demonstrate a bioresponsive nanocarrier strategy for precise gene modulation to enhance cardiac repair.
    DOI:  https://doi.org/10.1126/sciadv.aeg3270
  19. Nat Metab. 2026 Sep 29.
    Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism.
    Nikola Makdissi, Maria Francesca Viola, Lisa Maria Steinheuer, Nelli Blank-Stein, Ronja Kardinal, Fabrizio Musacchio, Eliana Franco Taveras, Virginia Aliprandi, Katharina Sieckmann, Akram Abdulkadyrov, Marina L Mayer, Marie-Louise Diefenbach-Wilke, Diana Fink, Hannes Beckert, Stefan Böhmdorfer, Quentin Deveuve, Frederike J Graelmann, Katharina Mauel, Nele Kronau, Jake Thomas, David Bejarano, Andreas Schlitzer, Sandra Högler, Mohamed H Yaghmour, Joerg Heeren, Christoph Thiele, Lukas Kenner, Felix Meissner, Falk Nimmerjahn, Martin Fuhrmann, Dagmar Wachten, Kevin Thurley, Elvira Mass.
      Plastic pollution is an emerging yet understudied environmental risk to the immune system. Once ingested, microplastic and nanoplastic particles (MNPs) can translocate from the gut to internal organs1-3, with macrophages serving as primary targets4. Kupffer cells (KCs), the liver-resident macrophages, have a central role in immune surveillance and metabolism5, yet their response to MNPs remains unclear. Here we identify KCs as the primary hepatic reservoir for MNPs in young male mice. Chronic plastic exposure over 12 weeks alters their transcriptional profile, impairs phagocytic function and is associated with metabolic dysregulation of hepatocytes. Microplastics, but not nanoplastics, reduce KC-mediated clearance of circulating cells. Under diet-induced obesity, microplastics exacerbate hepatic lipid accumulation, while nanoplastics alter systemic glucose metabolism and energy expenditure. These findings demonstrate that chronic MNP exposure disrupts macrophage function in a size-dependent manner, with subsequent distinct consequences for liver and systemic metabolism.
    DOI:  https://doi.org/10.1038/s42255-026-01615-8
  20. Aging Cell. 2026 Oct;25(10): e70739
    Prodh2-Mediated Mitochondrial Stress Drives TNF-α-Induced Myoblast Dysfunction and Sarcopenia in COPD.
    Gang Chen, Zhitao Shangguan, Jingjing Gong, Dalu Cheng, Penghong Chen, Jiandong Li, Qiong Lin.
      Sarcopenia in chronic obstructive pulmonary disease (COPD) is driven by elevated tumor necrosis factor-alpha (TNF-α), yet the underlying mechanism remains unclear. Here, we identify the mitochondrial metabolic enzyme Prodh2 as a pivotal mediator. Prodh2 was significantly upregulated in sarcopenic COPD patients and a corresponding mouse model. Mechanistically, TNF-α induced Prodh2 transcription in myoblasts via a p53-dependent pathway. This upregulation triggered excessive mitochondrial reactive oxygen species, leading to the release of mitochondrial DNA (mtDNA). Cytosolic mtDNA subsequently activated the cGAS/STING innate immune pathway, causing myoblast apoptosis, proliferation arrest, and atrophy. While Prodh2 knockdown reversed these effects in vitro, muscle-specific knockdown of Prodh2 in vivo critically ameliorated muscle atrophy and restored strength. Our study unveils a novel TNF-α-p53-Prodh2-cGAS/STING axis that links chronic inflammation to sarcopenia through metabolic-immune crosstalk, validating Prodh2 as a promising therapeutic target.
    Keywords:  Prodh2; cGAS/STING; chronic obstructive pulmonary disease; mitochondrial DNA; sarcopenia
    DOI:  https://doi.org/10.1111/acel.70739
  21. Adv Sci (Weinh). 2026 Sep 30. e78127
    scH16S-Seq Maps Klebsiella pneumoniae-Associated Myeloid States and Reveals a CD38-NAD Immunometabolic Axis That Impairs Lysosomal Acidification in Sepsis.
    Yangguang Li, Yilong Yu, Fang Qin, Shenxing Li, Xuanheng Li, Peizhao Liu, Juanhan Liu, Haiqing Liu, Songqi Jing, Jianghao Zou, Sicheng Li, Jiayang Li, Tao Zheng, Yun Zhao, Jianan Ren, Xiuwen Wu.
      Sepsis arises from heterogeneous host-cell states that influence bacterial clearance, yet single-cell transcriptomic approaches do not directly connect microbial signals with host transcriptional programs. This study introduces single-cell host-bacterial 16S co-sequencing (scH16S-seq), which couples host transcriptomes with barcode-resolved bacterial 16S-derived UMI signals to resolve bacterial signal-enriched host-cell states. Applied to Klebsiella pneumoniae (KP) sepsis, scH16S-seq mapped cell-associated bacterial 16S-derived signals to discrete CD38+ myeloid states, including Acod1+ monocyte-derived macrophages, Lyve1+ interstitial macrophages, and hypoxic neutrophils sharing inflammatory, hypoxic, and metabolically stressed programs. Increased myeloid CD38 expression is also observed across human sepsis cohorts. Mechanistically, KP induces CD38-associated NAD+depletion, mitochondrial bioenergetic failure, reduced ATP, and impaired lysosomal acidification. CD38 inhibition, NAD-related metabolic intervention, or Cd38 deficiency restores NAD homeostasis and mitochondrial function, whereas blockade of mitochondrial ATP synthesis or V-ATPase-dependent acidification attenuates lysosomal and antibacterial rescue. Lyz2-Cre-mediated Cd38 deletion improves bacterial control and sepsis outcomes in vivo. Together, scH16S-seq resolves KP 16S signal-enriched myeloid states and identifies a targetable CD38-NAD-mitochondrial-lysosomal axis linking immunometabolic dysfunction to impaired antibacterial defense in sepsis.
    Keywords:  CD38; Klebsiella pneumoniae; nicotinamide; scH16S‐seq; sepsis
    DOI:  https://doi.org/10.1002/advs.78127
  22. Nat Commun. 2026 09 11. pii: 10407. [Epub ahead of print]17(1):
    SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.
    Ke Hu, Yin-Hu Wang, Anthony Y Tao, Maxwell McDermott, Miki Jishage, Li Zhong, Thomas Boehringer, Marcus J Hines, Sergei B Koralov, Ebbe Boedtkjer, Stefan Feske.
      Antibody-producing plasmablasts (PB) and plasma cells (PC) are critical for humoral immunity, autoimmunity and vaccine responses. Despite the importance of environmental stressors in regulating humoral immune responses, the influence of pH on PB and PC differentiation remains elusive. Here, we identify SLC4A7/NBCn1, a Na+/HCO3- cotransporter, as a selective regulator of PB differentiation in vitro. SLC4A7 deletion also impairs the formation of antibody secreting cells (ASCs) and antibody responses in mice in vivo following immunization and influenza A virus infection. Mechanistically, SLC4A7 deletion results in intracellular acidification and lysosomal alkalinization, and is associated with impaired function of the mechanistic target of rapamycin complex 1 (mTORC1). Enforcing mTORC1 activation in SLC4A7-deficient B cells or B cells in which intracellular pH is acidified by blocking Na+/H+ exchanger (NHE) function restores PB differentiation in vitro. Moreover, ASC differentiation and antibody responses are impaired under conditions of extracellular acidosis in vitro and in a mouse model of metabolic acidosis. Altogether, we identify a critical relationship between intracellular pH regulation through SLC4A7 and mTORC1-dependent ASC differentiation and humoral immunity.
    DOI:  https://doi.org/10.1038/s41467-026-77588-9
  23. Nat Commun. 2026 08 31. pii: 10375. [Epub ahead of print]17(1):
    IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma.
    Sae Bom Lee, Allan Pavy, Nolan Beatty, Justin C Boucher, Jay K Mandula, Emiliano Roselli, Darwin C Chang, Rachel V Jimenez, Hiroshi Kotani, Kayla Reid, Julio Vazquez-Martinez, Payal Goala, Max Ilecki, Cooper J Sailer, Shannon L McSain, Showkat Hamid, Muhammad Junaid Tariq, Rosa A Sierra-Mondragon, Min Liu, John M Koomen, Jonathan Nguyen, Mohammad Hussaini, Timothy I Shaw, Xuefeng Wang, Jianmin Wang, Julieta Abraham-Miranda, Rawan Faramand, Michael D Jain, Meredith L Stone, Frederick L Locke, Paulo C Rodriguez, Yun Pyo Kang, Marco L Davila.
      Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but many patients with large B cell lymphoma (LBCL) experience primary resistance or relapse. To uncover resistance mechanisms, here we examine pre-infusion tumor biopsies and observe that increased immunoregulatory macrophages correlate with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-γ) upregulates inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Proteomic profiling reveals that iNOS-expressing macrophages promote apoptosis and cell cycle arrest while downregulating protein synthesis machinery in CAR T cells. Metabolically, CAR T cells exhibit reduced glycolytic intermediates and altered tricarboxylic acid (TCA) cycle activity. Pharmacological inhibition of iNOS enhances CAR T cell treatment efficacy in vivo. Elevated levels of iNOS+CD14+ monocytes in leukaphereses are associated with non-durable responses to CAR T cells. Targeting iNOS in immunoregulatory macrophages, potentially by modulating CAR T-produced IFN-γ, could improve LBCL outcomes.
    DOI:  https://doi.org/10.1038/s41467-026-76972-9
  24. bioRxiv. 2026 Sep 08. pii: 2026.09.04.749543. [Epub ahead of print]
    Loss of Mitochondrial Respiratory Capacity Reshapes Myeloid Cell Function during Mycobacterium tuberculosis infection.
    Eduardo L Martinez, Cory J Mabry, Aja K Coleman, Morgan S Osborne, Joshua Simmons, Stacy Hahn, Jessica B Huskey, Kaitlyn S Armijo, Taylor Newbolt, Jacob R Davis, Lianna Zhou, Spyros Kalams, Denis Mogilenko, Kristin L Patrick, Robert O Watson.
      Myeloid cells are essential mediators of host defense against Mycobacterium tuberculosis (Mtb), yet the metabolic programs that sustain their function during chronic infection remain poorly defined. Here, using scRNA-seq we identified a striking, coordinated decline in mitochondrial electron transport chain gene expression across diverse myeloid populations as Mtb disease progressed in mice. This transcriptional remodeling was associated with broad changes in immune and metabolic pathways, including reduced antigen presentation, interferon responses, protein synthesis, and glycolysis. Accordingly, loss of Complex I in macrophages ( Ndufs4 knockdown) reduced MHC-II surface expression, dysregulated inflammatory gene expression, and limited control of Mtb replication. Finally, analysis of single-cell transcriptomic data from Mtb-exposed human household contacts identified an almost identical transcriptional program enriched in IGRA+ individuals, supporting a role for mitochondrial respiratory remodeling in human TB. Together, these findings demonstrate that mitochondrial bioenergetic competence is required to sustain macrophage effector function during chronic Mtb infection and suggest that mitochondrial restoration may boost protective responses in TB patients.
    DOI:  https://doi.org/10.64898/2026.09.04.749543
  25. Hum Immunol. 2026 Sep 26. pii: S0198-8859(26)00434-9. [Epub ahead of print]87(11): 112088
    Mapping immune cell metabolic reprogramming from mechanistic hotspots to translational directions: A bibliometric analysis with exploratory clinical evidence.
    Linxin Liu, Sixian Chen, Haoyu Wan.
       BACKGROUND: Immune cell metabolic reprogramming links immune function, disease microenvironments, and therapeutic responses. Although research in this field has expanded rapidly, the relationships among immune cell types, metabolic pathways, and clinical scenarios remain fragmented.
    METHODS: English language articles and reviews published from 2008 to 2025 were retrieved from the Web of Science Core Collection on June 14, 2025, and 3137 records were finally included. Bibliometrix, CiteSpace, VOSviewer, and related visualization tools were used for bibliometric and visual analyses. In addition, a PubMed clinical subset was established by retrieving human clinical studies published between January 1, 2008 and August 26, 2025. A total of 11 clinical studies were included.
    RESULTS: The results showed that research on immune cell metabolic reprogramming entered a phase of rapid growth after 2016, with China and the United States as the leading contributing countries. The knowledge base of the field was mainly centered on T cell metabolic regulation, macrophage function, the tumor microenvironment, and changes in immune function. Research hotspots gradually shifted from early topics such as differentiation, activation, memory, and mTOR related immunometabolic mechanisms to the tumor microenvironment, immunosuppression, single cell analysis, efficacy evaluation, and model construction. Literature derived high frequency gene terms highlighted immune regulatory clues, including CD4, STAT3, and CD44, as well as metabolic flow related clues, including HK2, PFKFB3, LDHA, and PC. The PubMed clinical subset further showed that mitochondrial function, glycolytic changes, trained immunity, and cell therapy related metabolic states have been investigated in disease state identification, therapeutic response monitoring, and cell therapy optimization.
    CONCLUSIONS: This study quantitatively and visually evaluated the overall development of immune cell metabolic reprogramming research. The findings suggest that the field is moving from single pathway descriptions toward a research model that integrates immune cell stratification, disease context stratification, and context specific translational investigation. By integrating the research landscape, thematic structure, molecular clues, and clinical entry points, this study provides candidate directions for independent molecular, functional, and clinical validation in immunometabolism.
    Keywords:  Bibliometric analysis; High frequency gene terms; Immune cell metabolic reprogramming; Immunometabolism
    DOI:  https://doi.org/10.1016/j.humimm.2026.112088
  26. Sci Adv. 2026 Oct 02. 12(40): eaei2831
    Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
    Nancy T Santiappillai, Andrew Cho, Georg Verch, Ana C Codo, Achuth Nair, Ya-Ting Wang, Allie Lipshutz, Celia Martínez de la Torre, Eric Minwei Liu, Marjan Berishaj, Alissa J Trzeciak, Zhaoquan Wang, Michelle Saoi, Waleska Saitz Rojas, Justin R Cross, Ed Reznik, Justin S A Perry, Kayvan R Keshari.
      Triple-negative breast cancer (TNBC) develops in hypoxic, nutrient-limited tumors enriched with macrophages and cell death. We show that metabolically distinct TNBCs differentially exploit macrophage-derived nutrients, influencing tumor growth and therapeutic response. Prolonged hypoxia reprogrammed mouse and human macrophages, enabling them to release metabolites that rescued the growth of select TNBC cell lines during glutamine deprivation or glutamine metabolism inhibition. Hypoxic macrophages reduced glutamine consumption, increased arginine utilization, and secreted higher levels of ornithine, an intermediate of arginine metabolism. Exogenous ornithine, but not arginine, restored the growth of responsive TNBC cells. Mechanistically, TNBC cells diverted ornithine into proline biosynthesis, supporting oxidative pentose phosphate pathway activity. In vivo, depletion of tumor-associated myeloid cells reduced tumor growth and impaired proline synthesis in glutaminase inhibitor-resistant TNBC. These findings identify hypoxia-driven metabolic cross-talk between macrophages and TNBC cells, revealing ornithine-dependent proline metabolism as a mechanism by which macrophages sustain tumor growth under nutrient stress and contribute to resistance to glutamine-targeted therapies.
    DOI:  https://doi.org/10.1126/sciadv.aei2831
  27. Int J Biol Sci. 2026 ;22(14): 7512-7532
    Nomilin Rewires mTOR-Driven Immunometabolism via DDIT4 to Restrain Psoriasis.
    Ha Eun Kim, Seung Taek Lee, Hee-Suk Park, Hyun-Su Lee, Jong Yeong Lee, Dae-Ki Kim, Si-Gyun Roh, Kyung-Hwa Nam, Sang-Hyun Kim, Jin Kyeong Choi.
      Nomilin, a citrus-derived limonoid belonging to the tetranortriterpenoid family, has been reported to exert anti-inflammatory and antioxidant effects; however, its therapeutic relevance and underlying mechanisms in psoriasis remain unclear. Here, we investigated the effects of nomilin in 12-O-tetradecanoylphorbol-13-acetate (TPA)- and imiquimod (IMQ)-induced psoriasis-like mouse models, IL-17A-stimulated primary human keratinocytes, Th17-polarized CD4⁺ T cells, and peripheral blood mononuclear cells (PBMCs) from patients with psoriasis. Nomilin markedly alleviated epidermal hyperplasia and inflammatory symptoms, suppressed pro-inflammatory cytokines and psoriasis-associated mediators, and reduced the expansion of inflammatory myeloid and Th1/Th17 cells in lesional skin. Mechanistically, nomilin decreased glucose uptake, glycolytic activity, oxidative phosphorylation, mitochondrial mass, and mitochondrial ROS production, thereby preventing metabolic overactivation and mitochondrial dysfunction. At the molecular level, nomilin upregulated DDIT4 and inhibited mTOR signaling, as evidenced by reduced phosphorylation of mTOR, RAPTOR, p70S6K, and 4EBP1. Genetic silencing of DDIT4 abrogated the anti-inflammatory and metabolic effects of nomilin in keratinocytes, while skin-specific DDIT4 knockdown markedly attenuated its therapeutic efficacy in vivo, demonstrating an essential role for DDIT4 in nomilin-mediated mTOR suppression. Furthermore, molecular docking and cellular thermal shift assay (CETSA) analyses revealed a direct interaction between nomilin and DDIT4. In addition, nomilin suppressed Th17 differentiation and reduced TNF-α-, IFN-γ-, and IL-17A-producing CD4⁺ T cells in PBMCs from patients with psoriasis. Collectively, these findings identify nomilin as a modulator of the DDIT4-mTOR axis that alleviates psoriasis-like inflammation through the rewiring of pathogenic immunometabolic programs and highlight its potential as a therapeutic strategy for psoriasis.
    Keywords:  DDIT4; immunometabolism; mTOR; mitochondrial ROS; nomilin; psoriasis
    DOI:  https://doi.org/10.7150/ijbs.133330
  28. Arterioscler Thromb Vasc Biol. 2026 Oct 01.
    Hypermetabolic State Drives Platelet Dysfunction in Human and Mouse Metabolic Dysfunction-Associated Steatotic Liver Disease.
    Precision Medicine Liver Group
       BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern given rising global prevalence, limited diagnostic and therapeutic tools, and strong association with cardiovascular disease. Platelets and oxidized phospholipids have been implicated in MASLD pathogenesis; however, the drivers and activities of platelets in MASLD remain overlooked.
    METHODS: We conducted a cross-sectional study to determine platelet metabolic and functional states in MASLD and to investigate whether oxidized phospholipids, which accumulate during MASLD, contribute to platelet dysfunction. The study included age-matched individuals with simple steatosis (n=42), steatohepatitis (n=28), metabolic dysfunction-associated cirrhosis (n=16), and controls without steatosis (n=23). Platelet function and metabolism were characterized by flow cytometry and Seahorse analysis. In vivo markers of platelet activation and plasma oxidized low-density lipoprotein were quantified by ELISA. The causal relationship between oxidized phospholipids and the platelet phenotype was investigated by comparing Ldlr-/- mice fed an Amylin Liver NASH diet to Amylin Liver NASH-fed E06-scFv/Ldlr-/-, transgenic mice that express a natural antibody (E06) that neutralizes oxidized phospholipids.
    RESULTS: We report that, since early MASLD in vivo markers of platelet secretion were elevated in plasma and platelets displayed a heightened metabolic activity. In advanced MASLD, associated with MASH and cirrhosis, platelets were refractory to G-protein-coupled receptor stimulation, but more responsive to GPVI stimulation, promoting a secretory and procoagulant phenotype. Platelet dysfunction correlated with increased platelet mitochondrial activity and with blood levels of oxidized low-density lipoprotein, a major source of oxidized lipids. Ex vivo, the oxidized phospholipid oxPAPC recapitulated the increased mitochondrial activity and functional reprogramming observed in MASH platelets. In a mouse model of MASLD, neutralization of oxidized phospholipids partially mitigated diet-induced platelet dysfunction and binding to liver macrophages.
    CONCLUSIONS: In MASLD, we observed heightened platelet metabolic activity and changes in platelet reactivity, providing the basis to target platelet dysfunction for preventing hepatic and extra-hepatic complications of MASLD.
    REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05128253.
    Keywords:  cardiovascular diseases; metabolism; mitochondria; phenotype; phospholipids
    DOI:  https://doi.org/10.1161/ATVBAHA.126.325001
  29. Mol Med. 2026 Aug 19. pii: 163. [Epub ahead of print]32(1):
    NETs drive CD4⁺ T cell dysfunction in sepsis via mitochondrial ROS and impaired calcium signalling.
    Hongru Li, Xuan Wang, Keran Sun, Jiachao Wang, Jiao Li, Enhao Zhang, Xiaoqing Li, Changwei Su, Zixin Li, Yushan Lin, Miao Li, Xiurong Wang, Hong Zhang, Chenhui Li, Lin Wei, Cuiqing Ma.
       BACKGROUND: Sepsis is a life-threatening condition with high mortality, in which sepsis-induced immunosuppression-characterized by CD4+ T cell dysfunction and apoptosis-worsens clinical outcomes. The mechanistic link between neutrophil extracellular traps (NETs) and CD4+ T cell fate in sepsis remains poorly elucidated.
    METHODS: We integrated plasma analysis from 50 sepsis patients and 31 healthy controls, a murine cecal ligation and puncture (CLP) sepsis model, and in vitro assays with Jurkat cells and primary CD4+ T cells. We investigated the effects of NETs on CD4+ T cell calcium signaling and mitochondrial function, and verified the therapeutic efficacy of DNase I combined with the mitochondrial-targeted antioxidant mitoTEMPO.
    RESULTS: Circulating NETs were significantly elevated in sepsis patients, positively correlated with disease severity (SOFA score) and negatively correlated with peripheral CD4+ T cell counts. NETs disrupted intracellular calcium homeostasis by inhibiting store-operated calcium entry, suppressing calcineurin activity and NFAT nuclear translocation, thus impairing T cell activation and IL-2 production. Additionally, NETs induced mitochondrial dysfunction via excessive mitochondrial reactive oxygen species (mtROS) production and reduced mitochondrial calcium uptake, leading to loss of mitochondrial membrane potential, structural damage, and subsequent CD4+ T cell apoptosis. In CLP mice, monotherapy with either DNase I or mitoTEMPO partially attenuated CD4+ T cell injury, while the combination significantly improved 7-day survival compared with monotherapy or vehicle, reduced plasma organ injury markers, and alleviated splenic lymphocyte apoptosis.
    CONCLUSION: The NETs-mtROS axis represents an important pathway driving CD4+ T cell death in sepsis. Dual targeting of NETs and mitochondrial oxidative stress holds promising therapeutic potential for ameliorating sepsis-induced immunosuppression.
    Keywords:   CD4 + T cells ; Immunosuppression ; Mitochondrial dysfunction ; NETs ; Sepsis
    DOI:  https://doi.org/10.1186/s10020-026-01607-0
  30. Front Immunol. 2026 ;17 1935553
    Post-translational modification crosstalk in acute pancreatitis: linking acinar stress to innate immune amplification and tissue repair.
    Mengwei Chen, Peng An, Shenglong Jing, Longlong Wu, Rong Wang.
      Acute pancreatitis (AP) is a sterile inflammatory disease initiated by acinar cell stress and amplified through innate immune, vascular, and inter-organ responses, yet effective disease-modifying therapies remain unavailable. Although premature digestive enzyme activation, organelle stress, sterile inflammation, and microvascular failure are well-recognized features of AP, the mechanisms linking early acinar stress to coordinated injury across epithelial, immune, stromal, and vascular compartments remain insufficiently integrated. Emerging evidence suggests that post-translational modifications (PTMs) constitute a dynamic regulatory layer through which metabolic stress is converted into damage-associated molecular pattern release, innate immune activation, inflammatory cell death, tissue repair, and disease progression. This review examines how metabolic stress remodels lactylation, acetylation, phosphorylation, ubiquitination, and related PTMs in AP and how their functional convergence and selected PTM interactions shape DAMP sensing, inflammasome activation, macrophage reprogramming, neutrophil recruitment and extracellular trap formation, cytokine amplification, mitochondrial dysfunction, apoptosis, pyroptosis, ferroptosis, microvascular barrier failure, and systemic complications. We propose an integrated framework linking acinar stress to PTM remodeling, innate immune amplification, and inflammatory resolution. Across acinar, ductal, immune, stellate, and endothelial compartments, PTMs regulate protein stability, subcellular localization, transcriptional programs, organelle quality control, and intercellular signaling. Selected PTM pathways exhibit stage- and cell-dependent effects; for example, lactate-associated lactylation may exacerbate early ferroptotic injury while promoting reparative macrophage polarization during recovery. This framework positions PTM remodeling as a context-dependent immunometabolic control system while recognizing that direct molecular PTM-PTM crosstalk remains incompletely demonstrated in AP.
    Keywords:  acute pancreatitis; immunometabolism; innate immunity; macrophage polarization; neutrophil extracellular traps; post-translational modifications; sterile inflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1935553
  31. Biochem Biophys Res Commun. 2026 Sep 24. pii: S0006-291X(26)01394-X. [Epub ahead of print]838 154628
    Microglial FKBP51 drives immunometabolic dysfunction linking perioperative neurocognitive disorders and Alzheimer's disease.
    Shan Yang, Dan Wu, Yanjun Li, Yi Ding.
       BACKGROUND: Perioperative neurocognitive disorders (PND) and Alzheimer's disease (AD) are both important aging related cognitive disorders. Accumulating evidence suggests that they share common pathological mechanisms involving Aβ deposition, neuroinflammation, and immunometabolic imbalance. However, the key regulatory molecules linking these two conditions remain unclear. FKBP prolyl isomerase 51 (FKBP51) is an immune regulatory molecule widely involved in inflammation control and metabolic homeostasis maintenance, but its role in PND and AD is still unknown. This study aimed to investigate whether FKBP51 participates in the shared pathological processes of PND and AD by regulating microglial immunometabolism.
    METHODS: This study integrated transcriptomic data from PND and AD brain tissues to screen for commonly abnormally expressed metabolism related genes and analyzed key hub genes in relation to clinical cognitive scores. The Brain RNA-seq database, single cell RNA sequencing data, and immunofluorescence staining were used to determine the cellular localization and expression characteristics of FKBP51. Primary microglia were stimulated with oligomeric Aβ42, and Fkbp5 expression was knocked down using siRNA to evaluate its effects on microglial inflammatory responses and Aβ phagocytosis. Furthermore, single gene GSEA, Seahorse metabolic analysis, and ROS and JC-1 detection were combined to investigate the regulatory role of FKBP51 on microglial mitochondrial function and oxidative phosphorylation.
    RESULTS: Bioinformatics analysis identified FKBP51 as a key metabolism related hub gene that was commonly abnormally elevated in both PND and AD brain tissues, and its expression level was significantly correlated with cognitive decline in AD patients. Further studies revealed that FKBP51 was enriched in microglia and was significantly upregulated in brain tissues from AD patients and model mice. Aβ42 stimulation markedly induced FKBP51 expression in microglia. Functional experiments demonstrated that Fkbp5 knockdown enhanced microglial phagocytic capacity for Aβ and reduced the expression and secretion of proinflammatory factors. Mechanistic studies showed that FKBP51 was closely associated with pathways related to fatty acid oxidation and oxidative phosphorylation. Following FKBP51 inhibition, maximal respiration capacity and ATP production in microglia were significantly increased, mitochondrial membrane potential was improved, and ROS accumulation was markedly reduced. These metabolic improvements were accompanied by restoration of microglial phagocytic function and alleviation of the inflammatory state.
    CONCLUSIONS: This study reveals that FKBP51 is an important immunometabolic regulatory molecule linking the shared pathological processes of PND and AD. Abnormal upregulation of FKBP51 promotes microglial functional imbalance by inhibiting mitochondrial oxidative phosphorylation and inducing oxidative stress, thereby exacerbating Aβ related neuroinflammation and cognitive impairment. Targeting FKBP51 mediated microglial metabolic reprogramming may provide a novel intervention strategy for aging related cognitive disorders such as PND and AD.
    Keywords:  Alzheimer's disease; Bioinformatics; FKBP51; Immunometabolic; Microglia; Perioperative neurocognitive disorders
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154628
  32. Cell. 2026 Sep 30. pii: S0092-8674(26)01080-9. [Epub ahead of print]
    Salicylic acid engages central metabolic regulators SnRK1 and TOR to govern immunity by differential phosphorylation of NPR1.
    Yixuan Chen, John Withers, Yulin Sun, Tianyuan Chen, Sargis Karapetyan, Jan Draken, Yezi Xiang, Yuzhe Yuan, Yang He, Wolfgang Dröge-Laser, Jing-Ke Weng, Xinnian Dong.
      Immunity requires a delicate balance between combating infection and preserving metabolic functions. However, the mechanisms by which immune responses are coordinated with cellular metabolism remain largely unknown. Here, we show that NONEXPRESSER OF PR GENES 1 (NPR1), the central plant immune regulator of salicylic acid (SA)-mediated defense responses, is controlled by a cascade of post-translational modifications (PTMs) involving two master nutrient-sensing kinases. In the absence of pathogen challenge, TARGET OF RAPAMYCIN (TOR) inhibits NPR1 through phosphorylation at Ser-55/59. During defense responses, elevated SA reduces sugar phosphate levels and enhances SNF1-RELATED PROTEIN KINASE 1 (SnRK1) activity, which in turn inhibits TOR signaling and phosphorylates NPR1 at Ser-557, a modification required for subsequent PTMs and NPR1 activation. Together, our findings identify SA as a coordinator of growth and immunity in response to pathogen challenge by modulating the central metabolic regulators SnRK1 and TOR, which antagonistically control NPR1 immune activity through differential phosphorylation.
    Keywords:  NPR1; SA; SAR; SnRK1; TOR; metabolism; phosphorylation; plant immune response; salicylic acid; systemic acquired resistance
    DOI:  https://doi.org/10.1016/j.cell.2026.09.011
  33. J Cell Immunol. 2026 ;8(2): 65-73
    Understanding the Mechanistic Connection between Dysbiosis and Polyamine Regulation in Oral and Intestinal Inflammation- Role of Tregs and Th17 Cells.
    Pushpa Pandiyan.
      Periodontitis and inflammatory bowel disease (IBD) are chronic inflammatory conditions driven by dysbiotic microbial communities that subvert host mucosal immunity. Central to the immunopathology of both diseases is the disruption of the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells, an equilibrium that governs tissue homeostasis versus inflammatory destruction. Polyamines, principally putrescine (PUT), spermidine (SPD), and spermine (SPN), are emerging as critical immunometabolic regulators that modulate the plasticity and functional identity of both cell populations. Dysbiosis, particularly the enrichment of microbial communities that drive aberrant polyamine biosynthesis through ornithine decarboxylase (ODC)-dependent pathways, generates a polyamine-rich microenvironment that further dysregulates T cell function and promotes sustained inflammation. Experimental evidence demonstrates that mucosal polyamine levels correlate with dysbiosis, dysfunctional Treg (TregDys) expansion, and CD4+CD4+T cell hyperactivation, collectively contributing to and perpetuating chronic inflammation. The striking parallels between periodontitis and IBD reinforce the existence of conserved mechanisms linking mucosal dysbiosis to polyamine-driven immune dysregulation, with shared therapeutic implications for targeting the dysbiosis-T cell-polyamine axis to restore immune homeostasis. This review presents a unified mechanistic framework connecting oral and intestinal dysbiosis, polyamine dysregulation, and disruption of the Treg/Th17 balance, linking both diseases along the oral-gut axis.
    Keywords:  Inflammatory bowel disease; Intestinal inflammation; T cells
  34. bioRxiv. 2026 Sep 25. pii: 2026.09.21.753167. [Epub ahead of print]
    Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer.
    Joshua Schoenfeld, Jahi Noel, Christopher McGinnis, Chenlian Fu, Brinda Alagesan, Eduardo Hernandez, Justin Jee, Nikolaus Schultz, Quaid Morris, Scott Lowe, Suzanne Cloonan, John Connolly, Ronan Chaligne, David Kelsen, Kenneth Yu, William Zhang, Eileen OReilly, Ansuman Satpathy, Tomas Ganz, Santosha Vardhana.
      Systemic iron sequestration occurs frequently in cancer due to inflammation-driven expression of the iron-regulatory hormone hepcidin. The impact of systemic iron availability on tumoral immunity is unclear. Here, we show that elevated serum hepcidin is associated with reduced survival and decreased intratumoral CD8+ T cells in patients with pancreas cancer. While hepcidin is not induced in murine tumor models, administration of a hepcidin mimetic phenocopies the T-cell-depleted tumor microenvironment seen in patients. Mechanistically, chronic antigen-driven mitochondrial dysfunction disrupts iron metabolism and selectively depletes high avidity CD8+ T cells during iron restriction. These findings establish a direct link between hepcidin-mediated iron sequestration and tumoral immunity and nominate systemic iron dysregulation as a therapeutic target to enhance anti-tumoral CD8+ T cell responses.
    DOI:  https://doi.org/10.64898/2026.09.21.753167
  35. Front Immunol. 2026 ;17 1963310
    Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review.
    Qianqian Zhong, Wanruo Lyu, Jieying Li, Yiming Song, Yunxin Huang, Chunbin Wang, Juling Ji.
      Type 2 diabetes mellitus and metabolic dysfunction associated steatotic liver disease contribute to the growing burden of hepatocellular carcinoma, yet their effects on hepatic antitumor immunity remain incompletely defined. Recent single-cell and spatial profiling studies indicate that hepatocellular carcinoma contains diverse CD8+ T cell states, including cytotoxic, exhausted, tissue-resident, progenitor-like, and transitional phenotypes. This review synthesizes evidence linking hyperglycemia, insulin resistance, lipotoxic injury, chronic inflammation, fibrosis, altered antigen presentation, stromal remodeling, chemokine signaling, and nutrient availability to CD8+ T-cell remodeling in HCC arising in the context of metabolic dysfunction. Particular attention is given to GZMK+ CD8+ T cells, which may reflect non-terminal differentiation, inflammatory adaptation, or transitional immune states rather than conventional cytotoxic effector function. Although GZMK-high CD8+ T cell populations have been reported in hepatocellular carcinoma and therapy-associated immune contexts, direct evidence that type 2 diabetes induces these cells in the liver remains limited. This review specifically examines GZMK+ CD8+ T-cell states within the immunometabolic context of HCC, distinguishes direct hepatic and tumor evidence from extrapolated findings in metabolic liver disease and other inflammatory conditions, and proposes a testable framework for phenotypic, spatial, and functional validation. Integrated single-cell, spatial, protein level, T cell receptor clonality, functional, and clinical studies are needed to define their biological significance and translational value.
    Keywords:  CD8+ T cells; GZMK; hepatocellular carcinoma; immunometabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1963310
  36. J Physiol Biochem. 2026 Sep 26. pii: 97. [Epub ahead of print]82(1):
    Nucleotide metabolic reprogramming: a "double-edged sword" in obesity-related inflammation-from metabolic adaptation to pathological imbalance.
    Zijing Li, Yushang Liu, Xinye Ouyang, Wenjuan Wu, Maoyuan Wang.
      Obesity has become a serious global public health challenge, characterized by chronic, sterile, low-grade inflammation with excessive NLRP3 inflammasome activation; however, the mechanism underlying the reduced activation threshold remains unclear. A recent study by Liu et al. demonstrated that obesity induces the phosphorylation and inactivation of SAMHD1, leading to a massive accumulation of cytosolic dNTPs. This causes excess dNTPs to enter mitochondria via the PNC1/2 transporters, bypassing the classical CMPK2 salvage synthesis pathway and triggering uncontrolled mtDNA synthesis and oxidative damage, ultimately resulting in the excessive activation of NLRP3 and an inflammatory response. Based on this finding, this paper presents a "double-edged sword" model of nucleotide metabolic reprogramming in obesity-related inflammation. Early reversible inactivation of SAMHD1 may represent a metabolic adaptive response that confers functional benefits to macrophages; however, once metabolic stress persists and causes nucleotide metabolic reprogramming to exceed a yet-to-be-defined threshold, an inflammatory positive feedback loop may be established. In terms of clinical translation, targeting PNC1/2 could specifically inhibit NLRP3 activation, which may provide new upstream intervention strategies for various aseptic inflammatory conditions such as gout; however, this approach also carries potential risks of mitochondrial toxicity and impaired anti-infective immunity. Future efforts should focus on macrophage-specific delivery, precision interventions tailored to disease stages, and precise anti-inflammatory strategies based on biomarkers such as circulating dNTPs, p-SAMHD1, and ox-mtDNA, thereby advancing the clinical translation of metabolism-related inflammation within safe parameters.
    Keywords:  Metabolic inflammation; NLRP3 inflammasome; Nucleotide metabolic reprogramming; Obesity; SAMHD1; mtDNA
    DOI:  https://doi.org/10.1007/s13105-026-01238-3
  37. bioRxiv. 2026 Sep 24. pii: 2026.09.18.752097. [Epub ahead of print]
    Hepatic cholinergic T cell signaling mediates an adaptive response to alcohol-induced liver stress.
    Alexander J Knights, Shanshan Liu, Evan J Kim, Jun Wu.
      Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, yet no targeted, disease-modifying therapy exists and the immune mechanisms driving disease progression remain poorly defined. Acetylcholine-producing cholinergic immune cells have emerged as regulators of homeostasis across tissues and in disease, but their role in alcohol-induced hepatic stress is unknown. Here, we characterized the hepatic cholinergic immune landscape during alcohol-induced stress using flow cytometry and single-cell RNA-sequencing of ChAT-eGFP reporter mice. Alcohol feeding expanded hepatic cholinergic immune cells, with T cells constituting a substantial and dynamic fraction of this population that showed a broad increase in acetylcholine signaling and shifted towards a repressed, anergy-like transcriptional state. CD4 T cells underwent coordinated suppression of cholesterol biosynthesis, while CD8 T cells instead adopted a cytotoxic activation program. Together, these findings identify cholinergic T cell signaling, and cholesterol metabolism within CD4 T cells specifically, as a previously unrecognized adaptive response to alcohol-induced liver stress, nominating candidate therapeutic targets for a disease that is marred by critically limited treatment options.
    DOI:  https://doi.org/10.64898/2026.09.18.752097
  38. Front Immunol. 2026 ;17 1937777
    Trained immunity and related memory responses in lung health and disease.
    Xin Sun, Dan Zhao, Lei Zhang, Jiao Liu, Ting Liu, Yao Liu, Anying Xiong, Jiahui Li, Qin Ran, Xiang He, Min Wu, Guoping Li, Junyi Wang.
      Immune memory has long been attributed to adaptive immunity, but trained immunity has broadened this view by showing that innate immune cells can retain altered function after prior stimulation and mount an enhanced response upon rechallenge. In the lung, prior local exposures can alter resident alveolar macrophages, whereas systemic immune stimulation can reprogramme bone-marrow progenitors and alter their myeloid output. Epithelial signals and alveolar-capillary barrier integrity help determine whether these changes protect tissue or promote injury. Reported metabolic pathways and chromatin features differ among cell types and experimental models; mTOR- and HIF-1α-mediated glycolysis and changes in H3K4me3 or H3K27ac can support altered innate responses. These responses may improve host defence or preserve tissue function without reducing pathogen burden, but can also contribute to barrier injury, chronic inflammation and fibrosis; in established tumours, ongoing local signals support immunosuppressive and angiogenic myeloid functions. We compare trained immunity in pulmonary myeloid cells, including trained alveolar macrophages, with other forms of alveolar macrophage memory, innate lymphoid memory-like responses and memory in pulmonary epithelial and stromal cells, and examine how these responses shape pulmonary infection, acute lung injury, chronic airway inflammation, pulmonary fibrosis and lung tumours.
    Keywords:  alveolar macrophages; immunometabolism; lung diseases; pulmonary innate immunity; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1937777
  39. Cancer Immunol Res. 2026 Sep 28.
    Immunometabolic Profiling of T Cells and Innate Lymphoid Cells Uncovers Therapeutic Targets to Enhance Immunotherapy in Head and Neck Cancer.
    Sujeetha A Rajakumar, Namya Nanda, Chloe Kim, Dustin Dikeman, Tanguy Y Seiwert, Zubair Khan, Sewon Kang, Carole Fakhry, Martin P Alphonse.
      Immunometabolic reprogramming governs antitumor immunity, yet its role in checkpoint blockade responses remains poorly defined. Using functional-metabolic flow cytometry, we characterized tumor-infiltrating mucosal-associated invariant T (MAIT) cells, CD8 T cells, and innate lymphoid cells (ILCs) from head and neck squamous cell carcinoma (HNSCC) patients receiving neoadjuvant anti-programmed cell death protein 1 (PD-1) monotherapy or combined anti-PD-1/anti-interleukin-8 (IL-8) therapy. We identified CD39-negative OX40 MAIT and CD8 tumor-infiltrating lymphocytes (TILs) as metabolically fit, less-exhausted populations. In contrast, OX40- cells exhibited elevated glucose-6-phosphate dehydrogenase (G6PD) expression, identifying the pentose phosphate pathway as a targetable metabolic vulnerability. Ex vivo transcriptomic analysis of CD8 TILs from untreated patients revealed CD39-stratified responses to anti-PD-1/polydatin (G6PD inhibitor) combination treatment: CD39-negative cells amplified effector programs; CD39-medium cells shifted toward lipid catabolism; and CD39-high exhausted cells showed downregulation of STAT3 and mTOR-pathway genes only under combination treatment, consistent with a shift in metabolic regulation. Secretome profiling confirmed the functional translation of this reprogramming, with combination treatment significantly increasing soluble CD27 secretion in CD39-high TILs-indicating enhanced activation in terminally exhausted populations. ILC profiling identified immunosuppressive CD294-high ILC2s, marked by elevated C-C-motif chemokine receptor 8 (CCR8) and carnitine palmitoyltransferase 1A (CPT1A) protein expression, as a potential barrier to checkpoint blockade efficacy. Conversely, CD39-negative ILC3s emerged as metabolically active populations amenable to therapeutic reprogramming. These findings establish immunometabolic profiling as a framework for guiding precision checkpoint blockade combinations in HNSCC.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-26-0245
  40. mSystems. 2026 Sep 28. e0102326
    Carbon source-dependent metabolic states govern redox homeostasis and cofactor biosynthesis in Propionibacterium freudenreichii.
    Kirsi Savijoki, Bhawani Chamlagain, Minnamari Edelmann, Kaisa Hiippala, Paulina Deptula, Susanna Kariluoto, Tuula A Nyman, Vieno Piironen, Pekka Varmanen.
      Microbial adaptation to fluctuating nutrient and oxygen conditions requires coordinated regulation of the metabolic network to maintain redox homeostasis within physicochemical and energetic constraints. While oxygen-dependent responses in Propionibacterium freudenreichii (PFR) have been characterized at the transcriptomic level, the role of carbon source in defining system-level metabolic states remains unclear. Here, we investigated carbon source-dependent metabolic reprogramming and cofactor biosynthesis in PFR strain DSM 20271T using label-free quantitative proteomics integrated with physiological and metabolite analyses. Distinct carbon sources defined discrete metabolic states shaped by redox constraints, carbon routing, and biosynthetic prioritization. Lactate supported a comparatively balanced physiological state characterized by enhanced respiratory metabolism, amino acid biosynthesis, and riboflavin metabolism, enabling high specific vitamin B12 yields (~100 µg g-1 wet biomass). In contrast, hexose metabolism (glucose and fructose) imposed a redox-constrained state marked by upregulation of transport systems, glycolysis, and the pentose phosphate pathway, resulting in increased biomass but reduced biosynthetic efficiency. A defining feature of the hexose-driven state was activation of aspartate metabolism. Proteomic and metabolite data, together with functional assays, support a model in which aspartate is converted to fumarate and subsequently reduced to succinate consistent with an alternative electron sink that could facilitate NADH reoxidation under redox-constrained conditions. Together, these findings establish that carbon source shapes physiological state through carbon routing, redox homeostasis, and differential resource allocation, with cofactor biosynthesis emerging as a system-level property rather than a simple consequence of biosynthetic enzyme abundance.
    IMPORTANCE: Propionibacterium freudenreichii is used in food fermentations and is one of the few microorganisms able to synthesize biologically active vitamin B12, making it valuable for industry and biotechnology. Yet the metabolic principles governing its performance across growth conditions remain poorly understood. Here, we show that carbon source is a key determinant of metabolic state, dictating how cells resolve redox constraints and allocate biosynthetic resources. We identify an adaptation in sugar-grown cells in which aspartate metabolism provides a potential alternative electron sink to sustain redox balance under constrained conditions. By contrast, lactate supports a physiological state that promotes efficient vitamin B12 biosynthesis. These findings reveal a central role for carbon source in shaping metabolic configuration and identify redox balancing as a critical lever linking environmental inputs to biosynthetic output. This work provides mechanistic insight into redox-constrained metabolism and a framework for improving vitamin B12 production and other microbial bioprocesses.
    Keywords:  Propionibacterium; amino acid biosynthesis; carbon metabolism; cellular redox status; organic acids, oxidative stress; proteomics; vitamin B12
    DOI:  https://doi.org/10.1128/msystems.01023-26
  41. Oncogene. 2026 Sep 28.
    SPTLC2-driven sphingolipid reprogramming of neutrophils impairs anti-tumour immunity and drives liver cancer progression.
    Zhe Yang, Yun Wang, Jianhao Li, Zishuo Wang, Jianan Chen, Ding Zhang, Guorui Zhao, Liwen Liu, Zhibo Liu, Ning Wang, Ranran Sun.
      Liver cancer exhibits limited and heterogeneous responses to immune checkpoint blockade, underscoring the need to elucidate tumour microenvironmental mechanisms sustaining immune dysfunction. Here, we integrated single-cell transcriptomic annotation with BayesPrism deconvolution across multiple bulk cohorts and combined these analyses with in vivo liver cancer models, functional assays, and mechanistic investigations to define tumour-associated neutrophil (TAN) programmes linked to clinical outcome. We identified a neutrophil subset characterized by elevated sphingolipid metabolism as the predominant poor-prognosis signature, with SPTLC2 serving as the key molecular marker. High SPTLC2 expression defining this sphingolipid metabolism-high neutrophil population correlated significantly with advanced disease stage, inferior overall survival, and increased tumour infiltration. Tumour cell co-culture induced SPTLC2 upregulation and enhanced sphingolipid metabolic activity in neutrophils. Functional assays verified that myriocin, an SPTLC2 inhibitor, suppressed the proliferation and metastasis of Liver cancer cells and remodelled the antitumour immune function of neutrophils. Myriocin attenuated neutrophil sphingolipid metabolism and restored ROS production and neutrophil extracellular trap (NETosis) formation, revealing a critical regulatory role for sphingolipid metabolism in neutrophil-mediated innate immunity, as corroborated by single-cell analyses showing impaired innate immune function in sphingolipid metabolism-high neutrophils. Mechanistically, we uncovered an SPTLC2-dependent sphingolipid-lipid raft checkpoint that remodels plasma membrane microdomains to constrain neutrophil anti-tumour effector functions. Specifically, myriocin restored NOX2-dependent ROS generation by reducing ceramide accumulation in lipid rafts, thereby facilitating p47phox-p22phox interaction and productive NOX2 complex assembly in tumour-conditioned neutrophils. Collectively, these findings reveal a previously unrecognized immunometabolic axis governing TAN dysfunction in liver cancer, establish SPTLC2 as a rational combinatorial target for cancer immunotherapy, and highlight the therapeutic potential of targeting sphingolipid metabolism to restore neutrophil-mediated antitumour immunity and restrain hepatocellular carcinoma progression.
    DOI:  https://doi.org/10.1038/s41388-026-03996-2
  42. Adv Sci (Weinh). 2026 Sep 27. e77836
    A Gut-Brain Axis Underlying Succinate-Associated Compulsive-Like Behavior.
    Yi Li, Ying-Dan Zhang, Wei Wang, Xin-Yi Wu, Di Li, Xin Gong, Fei Tian, Meng-Yu Dai, Jian Gao, Zi-Feng Zheng, Zi-Yang Bi, Dong-Dong Shi, Zhen Wang.
      Emerging evidence indicates that gut microbiota influences host physiology and behavior through the microbiota-gut-brain axis, potentially contributing to the pathogenesis of obsessive-compulsive disorder (OCD). Our preliminary research demonstrated that mice colonized with fecal microbiota from OCD patients developed compulsive-like behaviors, associated with a significant increase in the microbial metabolite succinate. However, the mechanisms linking succinate to compulsive-like behavior remain to be fully elucidated. Here, we demonstrate that succinate is associated with significant compulsive-like behaviors. Succinate is associated with disruptions of glutamatergic neurons within the dorsal medial prefrontal cortex (dmPFC), and we characterize dual pathways linked to the behavioral abnormality: both by dmPFC microglial engagement via the succinate cognate receptor SUCNR1, and by gut-to brain signaling conveyed through vagal afferents and the 5-HT4 receptor. Pharmacological modulation of the succinate metabolism pathway through succinate dehydrogenase inhibition ameliorates compulsive-like behavior in Hoxb8-/- OCD-model mice. Circulating succinate levels significantly distinguish OCD patients from healthy controls with an AUC of 0.73, and correlate with prefrontal cortex activity on functional imaging. Collectively, our study delineates a gut-brain axis implicating succinate in central nervous system dysregulation associated compulsive-like behavior, elucidates novel immunometabolism and neural circuit mechanisms underlying OCD pathogenesis, and identifies druggable targets for potential precise interventions.
    Keywords:  SUCNR1; gut‐brain axis; microglia; obsessive‐compulsive disorder; succinate; vagus nerve
    DOI:  https://doi.org/10.1002/advs.77836
  43. J Immunol. 2026 Aug 29. pii: vkag240. [Epub ahead of print]215(9):
    Mechanism of SGLT2 inhibitors in improving immune imbalance in diabetic mice with sepsis via regulating macrophage M2 polarization through the APOC1/HMGB1/TLR4 axis.
    TingTing You, HuoBao Yang, Gang Chen.
      This study aimed to investigate the mechanism by which the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin improves immune imbalance in sepsis with diabetes, focusing on its regulation of macrophage M2 polarization through the APOC1/HMGB1/TLR4 axis. A mouse model of type 2 diabetes was established through intraperitoneal injection of streptozotocin, after which sepsis was induced by cecal ligation and puncture. For in vitro studies, RAW264.7 macrophages and bone marrow-derived macrophages were exposed to high glucose and lipopolysaccharide. Molecular docking was employed to examine potential binding between dapagliflozin and APOC1. Organ pathology in lung, liver, and kidney was evaluated using hematoxylin and eosin staining and biochemical assay kits. Expression levels of APOC1, HMGB1, TLR4, and macrophage M1/M2 markers were analyzed via immunohistochemistry and immunofluorescence. Inflammatory cytokine levels were quantified with enzyme-linked immunosorbent assay. The SGLT2 inhibitor dapagliflozin effectively alleviated lung, liver, kidney injury and dysfunction and reduced inflammatory responses in diabetic mice with sepsis. The treatment also decreased inflammatory cytokine levels in the high glucose/lipopolysaccharide-stimulated cellular model. Furthermore, dapagliflozin treatment significantly increased the levels of M2 macrophage markers in both in vivo and in vitro models. Mechanistically, dapagliflozin was found to target, bind to, and downregulate APOC1 expression. Further investigations revealed that APOC1 promotes macrophage M1 polarization via the APOC1/HMGB1/TLR4 axis, an effect reversed by dapagliflozin. The SGLT2 inhibitor dapagliflozin ameliorates organ damage and inflammation in sepsis with diabetes by promoting macrophage M2 polarization through inhibition of the APOC1/HMGB1/TLR4 axis.
    Keywords:  APOC1/HMGB1/TLR4 axis; SGLT2 inhibitor; diabetes-related sepsis; macrophage polarization
    DOI:  https://doi.org/10.1093/jimmun/vkag240
  44. Cancer Res. 2026 Sep 28.
    Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia.
    Xinrong Xiang, Baozhu Luo, Lei Zhao, Jing Sui, Yi Wu, Jiasheng Huang, Song Liu, Hexian Li, Fangfang Wang, Mengran Chen, Ying Qu, Aiping Tong, Chong Chen, Yu Wu, Youfu Luo.
      Acute myeloid leukemia (AML) critically depends on oxidative phosphorylation (OXPHOS). Mitochondrial targeted therapies are advancing into clinical trials, but metabolic vulnerabilities have been primarily explored from a tumor-intrinsic perspective. Leukemic cells can actively reshape an immunosuppressive tumor microenvironment through metabolic competition, highlighting the importance of evaluating the impact of mitochondrial targeted therapies on antitumor immunity. Here, we showed that elevated expression of the mitochondrial caseinolytic protease P (ClpP) is associated with advanced AML. Development of IMP125, a potent ClpP agonist, enabled dual targeting of AML to elicit robust anti-leukemic activity. In addition to direct cytotoxicity, IMP125 induced immunometabolic reprogramming of AML models. Owing to differential ClpP expression, IMP125 preferentially suppressed mitochondrial respiration and oxygen consumption in AML cells while exerting minimal direct effects on T-cell respiration. By reducing AML oxygen consumption and metabolic demand, IMP125 alleviated hypoxia and metabolic competition within the leukemic niche. In this remodeled microenvironment, T cells exhibited recovery of OXPHOS, effector function, and memory-associated features, consistent with an indirect mechanism mediated through metabolic suppression in AML cells. The anti-leukemic efficacy of IMP125 was dependent on T cells and was synergistically enhanced by PD-1 blockade. Collectively, this work reframes ClpP agonism from a tumor-intrinsic therapy to a strategy that actively induces metabolic-immune rewiring, bridging ClpP-targeted and immunotherapeutic approaches for mitochondrial-dependent AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0477
  45. Front Immunol. 2026 ;17 1894784
    Metabolic reprogramming in ulcerative colitis: integrating dietary drivers, pathogenesis, and therapeutic advances.
    Yunze Liu, Yisha Wan, Xinyu Lu, Aili Xu, Xia Ding, Yuan Li.
      Ulcerative colitis (UC) is a complex disorder characterized by gene-environment interactions that compromise the integrity of the mucosa and submucosa. The current evidence indicates a significant correlation between the increasing incidence of UC and the consumption of a Western diet. Dietary patterns alter the nutritional composition, thus inducing metabolic shifts in the intestinal microenvironment that disrupt gut homeostasis and contribute to the development of UC. Mechanistically, metabolic abnormalities in epithelial cells, macrophages, neutrophils, and other cell types compromise the integrity of the intestinal epithelial barrier and modulate immune-inflammatory responses, promoting the onset and progression of UC. Furthermore, the dysregulation of microbial metabolites disrupts gut microbiota homeostasis, contributing to disease progression. Here, we summarize the association between the dietary pattern and UC risk; we further elaborate on the metabolic alterations in colonic epithelial cells, immune cells, and the gut microbiota during UC; and we discuss how these changes influence disease progression. Finally, we discuss potential therapeutic strategies targeting metabolic reprogramming for UC management. By integrating insights from macroepidemiology and micromolecular mechanisms, we delineate the association between metabolic reprogramming and UC and provide a valuable reference for future research into key mechanisms and novel treatment approaches.
    Keywords:  diet; epidemiology; mechanisms; metabolic reprogramming; ulcerative colitis
    DOI:  https://doi.org/10.3389/fimmu.2026.1894784
  46. Int J Biol Sci. 2026 ;22(14): 7714-7736
    CAF-derived BHB modulates FXR1-Kbhb and NK-cell lipid metabolism in osteosarcoma.
    Yihan Yu, Wei Wu, Anzhen Ju, Lei Zhao, Guohui Liang, Yun Liu, Zengwu Shao, Feifei Pu, Binlong Zhong, Fengxia Chen, Jianxiang Liu, Zhicai Zhang.
      Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents and is characterized by high aggressiveness and poor prognosis. Although surgery and chemotherapy have improved overall survival, outcomes for relapsed or metastatic disease remain extremely poor, thus underscoring the urgent need for novel therapeutic strategies. Natural killer (NK) cells are key cytotoxic effectors in tumor immunity, but their function is profoundly suppressed within the OS tumor microenvironment. Furthermore, the role of cancer-associated fibroblasts (CAFs) in mediating NK-cell dysfunction through metabolic regulation remains insufficiently understood. We established coculture systems of NK cells, OS cells, and CAFs and assessed NK-cell activation and cytotoxicity by using functional assays, flow cytometry, and immunofluorescence. Metabolic profiling was performed with extracellular acidification rate, oxygen consumption rate, reactive oxygen species detection, MitoTracker staining, and electron microscopy. Integrated proteomics and mechanistic studies were used to identify CAF-derived metabolites and their effects on NK-cell metabolism. CAFs markedly impaired NK-cell recognition and cytotoxicity toward OS cells, accompanied by metabolic reprogramming characterized by enhanced glycolysis, increased reactive oxygen species production, and reduced mitochondrial activity. Multiomics and functional analyses identified β-hydroxybutyrate (BHB) as a key CAF-derived metabolite that contributed to reduced NK-cell FAO and effector function. BHB treatment increased FXR1 Kbhb and reduced FAO, cytokine secretion, and tumor-cell killing, whereas FXR1 K56 mutation attenuated these functional changes. In vivo, CAF-CM treatment was accompanied by elevated circulating BHB, reduced NK-cell activation, and accelerated tumor growth. Targeting the CAF-BHB- FXR1 axis may represent a promising therapeutic strategy to restore NK cell-mediated antitumor immunity and improve treatment outcomes.
    Keywords:  cancer-associated fibroblasts (CAFs); lipid metabolism; natural killer (NK) cells; osteosarcoma; β-hydroxybutyrate (BHB)
    DOI:  https://doi.org/10.7150/ijbs.128764
  47. J Allergy Clin Immunol. 2026 Sep 28. pii: S0091-6749(26)00673-1. [Epub ahead of print]
    MITF-associated metabolic signature in mast cells: A potential link to food anaphylaxis.
    Laia Ollé, Mónica Barrios, Lihong Song, Sofia Carreras-Kàtcheff, Patricia Mir-Ihara, Laura Valls-Roca, Mariona Guitart-Mampel, Glòria Garrabou, Carmen García, Jose C Fernandez-Checa, Magda Babina, Rosa Muñoz-Cano, Margarita Martín.
       BACKGROUND: Microphthalmia-associated transcription factor (MITF) is a master regulator of mast cell (MC) differentiation and effector function and is essential for anaphylaxis (severe allergic reactions). Although MITF has been linked to mitochondrial regulation through pyruvate dehydrogenase, whether it broadly controls mitochondrial fitness and metabolic programs that exacerbate MC activation remains unclear.
    OBJECTIVE: To determine how MITF regulates MC mitochondrial function and metabolic fitness beyond pyruvate dehydrogenase control, and to define its contribution to heightened MC activation and food anaphylaxis.
    METHODS: MITF was silenced, pharmacologically inhibited, or overexpressed in human MCs, followed by IgE- and MRGPRX2-dependent activation. Transcriptomic profiling, and mitochondrial functional analyses were then performed. In parallel, MCs from patients with food anaphylaxis and from healthy controls were analyzed to assess clinical relevance.
    RESULTS: Transcriptomic analysis of MITF-silenced MCs revealed a distinct metabolic signature characterized by downregulation of mitochondrial pathways and metabolic cellular compartments. MITF knockdown reduced mitochondrial fission, membrane potential, mitochondrial respiration, and mitochondrial marker expression of TOM20 and COX-IV, supporting a role for MITF in mitochondrial activity and metabolic regulation. Furthermore, MCs from patients with food anaphylaxis exhibited increased MITF expression, elevated mitochondrial markers, enhanced mitochondrial respiration, and a glycolytic shift after allergen activation, compared with those from sensitized and healthy individuals. Notably, pharmacological inhibition of MITF reduced mitochondrial membrane potential in patient-derived MCs.
    CONCLUSIONS: MITF is a central regulator of MC mitochondrial function and is associated with enhanced metabolic activity in anaphylaxis, highlighting MITF-driven pathways as potential therapeutic targets in MC-mediated allergic disease.
    Keywords:  Anaphylaxis; Food Allergy; IgE; MITF; MRGPRX2; Mast cells; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.jaci.2026.09.015
  48. Nat Commun. 2026 Aug 27. pii: 10286. [Epub ahead of print]17(1):
    CD38-activated macrophages drive age-related placental senescence by depleting NAD+ in decidual stromal cells.
    Lun Hua, Xiaohan Yang, Dengfeng Gao, Xintong Yang, Xianyang Jin, Lulu Ma, Wenting Liu, Jing Li, Zhaoli Shen, Luting Liu, Yanni Wu, Yi Yang, Chunli Zhu, Litong Li, Xuemei Jiang, Xingfa Han, Chao Jin, Guangmang Liu, Bin Feng, Lianqiang Che, Shengyu Xu, Yan Lin, Zhengfeng Fang, Long Jin, Ting Luo, Yong Zhuo, Mingzhou Li, De Wu.
      As delayed childbearing becomes increasingly common, elucidating the mechanisms of age-related placental senescence is critical for the development of effective therapeutic strategies. Here, we integrate metabolomics, single-cell RNA sequencing, and spatial transcriptomics to uncover conserved features of aged placentas in humans, mice, and pigs, namely, increased macrophage CD38 expression and NAD⁺ deficiency. Through pharmacological and genetic approaches, we demonstrate that macrophage CD38 depletes NAD⁺ in decidual stromal cells, thereby promoting placental senescence. Mechanistically, early-onset inflammation and senescence-associated secretory phenotype activity drive CD38 expression in macrophages via the IRF5 pathway. Importantly, treatment with NAD⁺ precursors or CD38 inhibitors attenuates age-related placental senescence, rescues intrauterine growth restriction, and improves long-term metabolic outcomes in offspring. These findings reveal a critical role for macrophage-driven metabolic dysregulation in reproductive aging and establish CD38 as a potential therapeutic target for age-associated pregnancy complications.
    DOI:  https://doi.org/10.1038/s41467-026-77217-5
  49. bioRxiv. 2026 Sep 23. pii: 2026.09.22.753563. [Epub ahead of print]
    Fatty acid synthesis restricts HIV-1 infection through regulation of the nuclear envelope in CD4+ T cells.
    Joshua A Acklin, Ming Ye, Erika A Pontillo, Marc E Wörös, Ethan H Krupa, Bruce D Walker, Alison E Ringel.
      HIV-1 must breach intracellular defenses to establish infection in CD4+ T cells, yet the metabolic activities that sustain these barriers remain poorly understood. Using a metabolically targeted small molecule screen, we identify de novo fatty acid synthesis as an unexpected determinant of resistance to HIV-1 infection in activated CD4+ T cells. Inhibition of acetyl-CoA carboxylase 1 (ACC1) or fatty acid synthase (FASN) increased cellular susceptibility to infection, while fatty acid supplementation restored baseline levels of anti-viral resistance. Saturated fatty acids conferred the strongest protection, revealing that susceptibility depends on both cellular metabolic state and the composition of the extracellular lipid environment. Blocking fatty acid synthesis remodeled the cellular lipid pool, particularly for the membrane lipid phosphatidylcholine, and was accompanied by structural disruption of the nuclear envelope that serves as a physical barrier limiting passage of the HIV-1 capsid into the nucleus. FASN inhibition also selectively altered sensitivity to antiretroviral drugs that target the interaction between capsid and the nuclear pore. Broadly, these findings uncover a previously unrecognized role for cellular fat synthesis in the maintenance of the nuclear envelope and reveal that anti-viral pathways can emerge at the interface between cellular state and exposure.
    DOI:  https://doi.org/10.64898/2026.09.22.753563
  50. Adv Sci (Weinh). 2026 Sep 29. e78057
    H4K12 Lactylation Regulates NDUFS7 to Drive Microglia Reverse Electron Transport in Spinal Cord Injury.
    Chenglong Hong, Zhichen Jiang, Zhouwei Wu, Chenyu Wu, Jiang Liu, Kaijie Guo, Yihui Liang, Shaobo Xu, Yuchen Jin, Yong Xiao, Lei Guo, Hui Xu, Sunren Sheng, Chenggui Wang.
      Microglial polarization toward the pro-inflammatory state drives secondary injury following spinal cord injury (SCI), yet the mechanisms of metabolic reprogramming governing this phenotypic shift remain elusive. Here, we identify a lactate-dependent signaling axis linking histone lactylation to mitochondrial reverse electron transport (RET) that sustains neuroinflammation. We demonstrate that SCI-induced accumulation of lactate promotes histone H4 lysine 12 lactylation (H4K12la), which directly upregulates NDUFS7, a core subunit of mitochondrial Complex I. Elevated NDUFS7 triggers mitochondrial hyperactivity and RET, resulting in a reactive oxygen species (ROS) burst that enforces pro-inflammatory polarization. To intervene in this cascade, we engineered a biomimetic nanotherapeutic, MM@mPTC, comprising an LDHA-targeting PROTAC encapsulated within ROS-responsive micelles and coated with microglial membranes (MM). The biomimetic MM@mPTC system actively targets activated microglia and undergoes ROS-responsive payload release to specifically degrade LDHA. This targeted degradation dismantles the pathogenic "LDHA-H4K12la-NDUFS7-RET" axis, halting RET-driven ROS production and reprogramming microglia toward a reparative phenotype. Consequently, this intervention significantly mitigates neuroinflammation, preserves neuronal tissue, and promotes robust locomotor recovery, presenting a precise metabolic-epigenetic therapeutic paradigm for central nervous system trauma.
    Keywords:  LDHA; NDUFS7; PROTAC; histone lactylation; reverse electron transport; spinal cord injury
    DOI:  https://doi.org/10.1002/advs.78057
  51. iScience. 2026 Oct 16. 29(10): 117527
    A systematic transcriptomic atlas and predictive framework for metabolite-driven T cell state transitions.
    Yiyang Xu, Yiheng Zhao, Sizhe Yang, Huimin Li, Xiangrong Diao, Qianqian Zhang, Shuting Yu, Shuai Wang, Fangying Jiang, Qiang Wang, Yuhua Ma, Bo Jiao, Yun Tan, Yabin Liu.
      Gut microbial and endogenous metabolites are key regulators at the interface of host metabolism and immunity, yet their global effects on human T cell states remain poorly defined. Here, we profile primary human T cell responses to 364 endogenous and microbiota-derived metabolites using high-throughput digital RNA with perturbation of genes sequencing (DRUG-seq), revealing structured transcriptional trajectories spanning baseline, metabolically primed, and highly activated states. We develop DRUG-seq-PerturbFormer, a multi-task deep learning framework that quantitatively captures perturbation magnitude and directionality across these states. This analysis identifies a subset of metabolites that robustly reprogram T cell transcriptional programs. In a dextran sulfate sodium (DSS)-induced colitis model, representative candidates attenuated disease severity and were associated with suppression of inflammatory programs and partial restoration of immune homeostasis. Collectively, these findings show that metabolites act as signals shaping T cell function via transcription, nominating immunomodulatory targets for inflammatory diseases.
    Keywords:  DRUG-seq; T cell; metabolites; perturbation atlas; predictive framework
    DOI:  https://doi.org/10.1016/j.isci.2026.117527
  52. Alzheimers Dement. 2026 Oct;22(10): e71896
    ZBP1-mediated Treg cell dysfunction exacerbates neuroimmune dysregulation in Alzheimer's disease under metabolic stress.
    Shanshan Huang, Zengyu Zhang, Jiajie Xia, Mengqiu Deng, Fangzheng Chen, Meng Wang, Yuchao Fei, Zhiwen Jiang, Chenyu Lu, Jiayu Fu, Jingchun Guo, Houguang Zhou.
       INTRODUCTION: Metabolic stress increases Alzheimer's disease (AD) risk, but mechanisms linking metabolic dysfunction to neuroimmune dysregulation remain unclear.
    METHODS: We assessed cognition in community-dwelling participants and used high-fat diet (HFD)-fed 5xFAD mice, high glucose and high palmitate (HGHP)-treated regulatory T cell (Treg) co-cultures, and adoptive Treg transfer to evaluate metabolic stress-associated neuroimmune dysfunction. Flow cytometry, RNA sequencing, positron emission tomography computed tomography, and electrophysiology assessed Treg function, AD pathology, cerebral metabolism, and synaptic plasticity.
    RESULTS: Metabolic stress impaired Treg stability and function, accompanied by increased Z-DNA-binding protein 1 (ZBP1) expression and activation of apoptotic and necroptotic signaling. Treg dysfunction was associated with enhanced glial activation and neuronal injury. Under HGHP stress, ZBP1-deficient Tregs showed improved survival and stronger immunosuppressive activity, more effectively limiting glial activation and preserving neuronal integrity. In vivo, ZBP1-deficient Treg transfer conferred greater neuroprotection than wild-type Treg transfer in HFD-fed AD mice.
    DISCUSSION: ZBP1 may contribute to metabolic stress-induced Treg dysfunction and represent a candidate target to improve Treg-based therapy in HFD-fed AD mice.
    Keywords:  Alzheimer's disease; Z‐DNA‐binding protein 1; metabolic stress; neuroimmune; regulatory T cells
    DOI:  https://doi.org/10.1002/alz.71896
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