bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–07–26
39 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Metabolic Regulation of Macrophages in Health and Disease.
  2. Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities.
  3. Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in HIV-1 Infection.
  4. SIRT3 in post-myocardial infarction macrophage reprogramming: linking mitochondrial fitness to inflammation resolution and repair.
  5. Targeting the CD31 immunometabolic axis: Precision strategies for modulating T cell activation, migration, and autophagy.
  6. Using a liver-on-chip model to evaluate the effects of vancomycin and daptomycin on host immunometabolism and clearance of intracellular reservoirs of Staphylococcus aureus during bacteremia.
  7. Neonatal monocyte iron metabolism and immunometabolic responses in sepsis: a comparative ex vivo investigation.
  8. SREBP1c modulates Treg immunobiology through a phospholipid-dependent adenosine pathway.
  9. Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8+ T-cell dysfunction in cancer.
  10. Exercise, mitochondrial stress, and trained immunity: metabolic adaptation of innate immunity.
  11. Temporal control of macrophage pro-inflammatory phenotype by a biphasic HIF-1α regulatory program.
  12. Yersiniabactin-producing adherent-invasive Escherichia coli exploit host glycolysis to drive macrophage HIF-1α stabilization.
  13. The mechanism of macrophage glycolysis regulating Th17 cell differentiation and promoting the progression of EAN mice.
  14. Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer.
  15. The mitochondrial DNA signal in rheumatoid arthritis: From metabolic victim to inflammatory driver.
  16. STXBP6-driven signaling cascade alters lipid peroxidation in tumor-associated macrophages to facilitate ovarian cancer progression.
  17. Mitochondrial microprotein MOCCI controls neuroinflammation by altering glial activation states.
  18. The metabolic roles of immune checkpoint molecules.
  19. Lipid metabolic reprogramming of macrophage by host APOBEC3 deficiency enhances anti-tumor immunity.
  20. Ferroptosis at the intersection of metabolism and immunity in pancreatitis and pancreatic cancer.
  21. Hyperglycemia drive neutrophil extracellular trap formation and subsequent tissue injury in sepsis via PI3K/AKT-mediated glycolysis.
  22. Targeting macrophage metabolism: mechanisms, cellular crosstalk and implications in obesity-associated metabolic diseases.
  23. Palmitic acid coordinates impaired visceral adipose ICOShi Treg-mediated immunosuppression and systemic metabolic disturbance during obesity.
  24. Cholesterol metabolic rewiring shapes immune remodeling across hepatocarcinogenesis.
  25. Dynamic alterations in labile heme levels and heme biosynthesis during inflammatory activation of macrophages.
  26. DRP1 lysine 616 lactylation exacerbates cerebral ischemia-reperfusion injury by activating the STING inflammatory pathway.
  27. Cystine Restriction Alleviates T Cell Exhaustion and Enhances CAR-T Cell Potency.
  28. High-Salt Diet Links Gut Microbiota, Intestinal Barrier Function, and Macrophage Responses.
  29. Circadian immunometabolic states impart a temporal response to SARS-CoV-2 spike proteins in mammalian macrophages.
  30. All-trans retinoic acid suppresses systemic inflammation induced by severe fever with thrombocytopenia syndrome virus in mice.
  31. Uridine cytidine kinase 1 promotes phosphatidylcholine biosynthesis, facilitating SARS-CoV-2 infection.
  32. Hypoxia as an amplifier of synovial inflammation in rheumatoid arthritis.
  33. Non-targeted metabolomics reveals the metabolic atlas of macrophages remodeled by SVPLA2 in Naja atra venom.
  34. Antiretroviral regimen and sex-specific metabolic heterogeneity in pediatric HIV.
  35. Monomethyl Fumarate Modulates Iron Metabolism and Mitochondrial Function in Microglia with Implications for Multiple Sclerosis Progression.
  36. Lactylation Orchestrates Immune Evasion in Gastric Cancer through KDM5B-Mediated Histone Demethylation.
  37. The Legionella pneumophila effector SidL is an adenylyltransferase that modifies the glycolytic intermediate 3-phosphoglycerate.
  38. Targeted lipid metabolism screening uncovers regulatory effects on the STING immune response in mevalonate, eicosanoid and fatty acid pathways.
  39. Reassessment of Hematopoietic Stem Cell Aging through Metabolic Uncoupling and Mitochondrial Resilience.
  1. MedComm (2020). 2026 Aug;7(8): e70868
    Metabolic Regulation of Macrophages in Health and Disease.
    Shan Huang, Yu Zhang, Jiali Min, Jiahui Yang, Yuchen Li, Hao Zhang, Shanshan Liu.
      Macrophages orchestrate immune responses through remarkable phenotypic plasticity, which is intrinsically linked to their ability to reprogram intracellular metabolic pathways in response to microenvironmental cues. While recent advances have highlighted the role of aberrant macrophage metabolism in diverse diseases, a systematic synthesis integrating both intracellular and extracellular metabolic signals remains lacking. This review provides a comprehensive framework for understanding how core metabolic pathways-glycolysis, the TCA cycle, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and amino acid metabolism-are rewired during macrophage polarization under the orchestration of upstream signaling cascades, including NF-κB, PI3K/AKT/mTOR, JAK-STAT, and MAPK. We examine how exogenous metabolites such as succinate, itaconate, lactate, and amino acids reciprocally regulate macrophage function and discuss tissue-specific metabolic signatures of macrophage subsets-including alveolar macrophages （AMs), Kupffer cells (KCs), and tumor-associated macrophages (TAMs)-in the context of obesity, Type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), infections, autoimmune disorders, and cancer. We further evaluate emerging therapeutic strategies targeting macrophage metabolism, summarizing preclinical and clinical advances across signaling pathways, metabolic nodes, cytokines, and cell-based therapies with detailed trial data. By integrating cell-intrinsic metabolic circuitry with extracellular signals, this review establishes a theoretical foundation for metabolism-targeted immunotherapies and identifies key knowledge gaps for future investigation.
    Keywords:  immunometabolism; macrophage polarization; macrophages; metabolic diseases; metabolic regulation
    DOI:  https://doi.org/10.1002/mco2.70868
  2. Front Immunol. 2026 ;17 1878140
    Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities.
    Jingyun Chen, Xin Wang, Meiheng Gong, Yufeng Wang, Tingting Yu.
      Tumor immune escape is increasingly recognized as an immunometabolic process shaped not only by immune checkpoints and suppressive cell populations, but also by nutrient competition and metabolic signaling within the tumor microenvironment. This nutrient-competitive environment is not limited to tryptophan depletion, but also involves glucose restriction, glutamine dependence, arginine metabolism, amino acid transporter competition, and impaired mitochondrial fitness of effector T cells. Among amino acid pathways, tryptophan metabolism has emerged as a central regulator of tumor-immune interactions. Through the activity of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), kynurenine-producing branches, and both AHR-dependent and AHR-independent downstream programs, tumors establish a metabolic state that couples tryptophan depletion, metabolite signaling, redox adaptation, and immune suppression. Recent evidence further shows that tryptophan metabolism is not restricted to tumor cells, but also involves cancer-associated fibroblasts, macrophages, and T cells, thereby shaping multicellular crosstalk within immunosuppressive niches. Beyond immune suppression, this pathway contributes to ferroptosis resistance, stemness, metastatic adaptation, and resistance to chemotherapy, targeted therapy, and immune checkpoint blockade. In parallel, circulating metabolites and tissue-level metabolic profiling are being explored as potential biomarkers for patient stratification and treatment response prediction. In this review, we summarize the molecular basis of tryptophan catabolism in cancer, discuss its role in tumor-immune-stromal communication, and highlight emerging translational and therapeutic opportunities. Rather than reviewing tryptophan metabolism as a linear IDO1/TDO2-centered pathway, we define it as a multicellular immunometabolic communication network in which tumor cells, stromal fibroblasts, myeloid cells, and lymphocytes exchange metabolic and signaling cues to create spatially organized immunosuppressive niches. This network-based view helps explain why single-enzyme inhibition is often insufficient and supports the development of biomarker-guided, multi-branch, and cell-context-specific therapeutic strategies.
    Keywords:  immunometabolism; kynurenine; tryptophan metabolism; tumor immune escape; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1878140
  3. JCI Insight. 2026 Jul 21. pii: e204383. [Epub ahead of print]
    Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in HIV-1 Infection.
    Amanda Cabral da Silva, Luke Flantzer, Jaclyn Weinberg, Shuya Kyu, Lisa P Daley-Bauer, Anyce Godoy, Ana Carolina Santana, Aarthi Talla, Amber Rittgers, Sarah Welbourn, David E Gordon, Jeffrey A Tomalka, Vincent C Marconi, Dean P Jones, Souheil-Antoine Younes.
      The role of aromatic gut-derived bacterial metabolites (GDBMs) in shaping immune cell metabolism and function remains poorly explored. Using ex vivo metabolomic profiling of paired plasma and CD4⁺ T-cells from people living with HIV-1 (PLWH), we identified a network of aromatic GDBMs whose cell-associated abundance, rather than systemic levels, was linked to broad alterations in CD4⁺ T-cell metabolic and functional states. Among these, p-cresol sulfate (PCS) emerged as a mechanistic prototype. Ex vivo flow cytometry and single-cell RNA sequencing of CD4⁺ T-cells stratified by cell-associated PCS levels revealed dose-dependent enrichment of transcriptional programs associated with impaired differentiation, regulatory-like identity, and cellular senescence. In vitro transcriptomic and proteomic analyses of PCS-exposed CD4⁺ T cells demonstrated induction of cell-cycle arrest, mitochondrial dysfunction, and senescence-associated programs, including upregulation of p16 and p21. Integration of these immunometabolic findings with HIV-1 reservoir measurements revealed that CD4⁺ T-cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. These findings define a microbiome-derived axis that reshapes CD4⁺ T-cell metabolism and fate, promotes immune aging in PLWH, and may foster immunometabolic states linked to long-term HIV-1 reservoir persistence.
    Keywords:  AIDS/HIV; Adaptive immunity; Aging; Cellular senescence; Immunology; Metabolomics
    DOI:  https://doi.org/10.1172/jci.insight.204383
  4. Front Immunol. 2026 ;17 1848626
    SIRT3 in post-myocardial infarction macrophage reprogramming: linking mitochondrial fitness to inflammation resolution and repair.
    Xin Li, Xiaofei Luo, Zeng Zhang, Linya Tang, Xiudong Meng.
      Myocardial infarction (MI) remains a leading cause of cardiovascular mortality worldwide. Despite significant advances in reperfusion strategies and pharmacotherapy, persistent inflammation and adverse ventricular remodeling continue to underlie poor long-term clinical outcomes. Macrophages serve as central orchestrators of post-MI healing, coordinating the clearance of necrotic debris, resolution of inflammation, remodeling of the extracellular matrix, and maturation of the fibrotic scar. However, the conventional M1/M2 dichotomy fails to fully capture the dynamic, phenotypically heterogeneous, and metabolically constrained macrophage states that emerge during infarct healing. In this review, we synthesize current evidence supporting a trajectory-based framework for macrophage reprogramming following MI and emphasize mitochondrial fitness as a critical determinant governing the transition from sustained inflammation to reparative resolution. We summarize key metabolic checkpoints regulating this functional shift-including glycolytic rewiring, tricarboxylic acid (TCA) cycle remodeling, mitochondrial reactive oxygen species (mtROS) accumulation, efferocytosis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and mitochondrial quality control. Furthermore, we advance the hypothesis that SIRT3-the principal mitochondrial NAD+-dependent deacetylase-may act as a central regulatory node linking mitochondrial protein acetylation to macrophage state transitions after MI. Specifically, we outline a staged dual-axis working model, generated from convergent but largely indirect evidence, in which the SOD2-mtROS axis is more closely linked to early nonresolving inflammation, whereas the PDHA1-metabolic flexibility axis may be more relevant to efferocytosis-associated reparative transition. We further highlight NAD+ availability as an upstream limiting factor that may constrain SIRT3 activity in macrophages under ischemic-inflammatory stress. Finally, we critically evaluate the current evidence hierarchy, human translatability, therapeutic strategies, and key translational challenges-emphasizing considerations of timing, cellular specificity, delivery modalities, and target engagement. Although macrophage-specific causal evidence in myocardial infarction (MI) remains sparse, this framework is intended as a mechanistically coherent and experimentally tractable working hypothesis to guide future investigations into macrophage immunometabolism and mitochondrial-targeted interventions in post-infarction cardiac repair. Accordingly, the proposed framework should be viewed as a testable working hypothesis rather than a settled causal model of macrophage fate control in MI.
    Keywords:  NAD+; SIRT3; efferocytosis; immunometabolism; inflammation resolution; macrophage reprogramming; mitochondrial fitness; myocardial infarction
    DOI:  https://doi.org/10.3389/fimmu.2026.1848626
  5. Pathol Res Pract. 2026 Jul 22. pii: S0344-0338(26)00282-7. [Epub ahead of print]286 156629
    Targeting the CD31 immunometabolic axis: Precision strategies for modulating T cell activation, migration, and autophagy.
    Xumeng Han, Feng Yang, Chaoyuan Huang, Zongzhen Meng, Aiping Lyu, Kenneth Cp Cheung.
      CD31 (PECAM-1) is broadly expressed on endothelial cells, platelets, and immune cells, where it helps set thresholds for immune activation and coordinates energy use. This Review synthesizes evidence that CD31 is a key regulator of immunometabolic pathways relevant to metabolic disease. We outline how CD31 restrains T-cell activation, guides T-cell migration, and adjusts metabolic reprogramming by balancing glycolysis with mitochondrial function to fine-tune effector responses. We also describe how CD31-dependent signaling at the vascular-immune interface shapes tissue inflammation in obesity, diabetes, and atherosclerosis. Both membrane CD31 and its soluble form (sCD31) show promise as biomarkers and as therapeutic entry points, and we summarize emerging strategies to modulate this pathway. We highlight outstanding challenges including pathway complexity, context dependence, and inter-individual variability that must be addressed to achieve clinical translation. By linking molecular mechanisms to disease phenotypes, this Review positions CD31 as a unifying node connecting vascular and immune control with metabolism, pointing to testable avenues for precision treatment of metabolic inflammation.
    Keywords:  CD31; ITIM; Immunometabolism; Inflammation; Metabolic diseases; PECAM-1
    DOI:  https://doi.org/10.1016/j.prp.2026.156629
  6. Antimicrob Agents Chemother. 2026 Jul 23. e0025426
    Using a liver-on-chip model to evaluate the effects of vancomycin and daptomycin on host immunometabolism and clearance of intracellular reservoirs of Staphylococcus aureus during bacteremia.
    Brent Beadell, Sujung Yi, Makayla Roberts, Kyu Shik Mun, Annie Wong-Beringer.
      Staphylococcus aureus bacteremia (SAB) causes significant morbidity and mortality, despite treatment with guideline-recommended antibiotics. A critical contributor to SAB treatment failure is the intracellular persistence of SA within liver sinusoidal macrophages (Kupffer cells [KCs]). Antibiotics have been shown to modulate immune cell function, which is governed by cellular metabolism; yet, the effect of antibiotics on host immunometabolic response relative to bacterial clearance is understudied. We developed a liver-on-chip (LoC) model of SAB to recapitulate the liver sinusoid during systemic infection using exclusively liver-derived cells and the GFP USA300 LAC SA strain and compared the effects of vancomycin and daptomycin on host immunometabolism by fluorescence lifetime imaging microscopy and related to intracellular antimicrobial efficacy. Utilizing both murine and human-based LoC infection models, we found that DAP was superior to VAN treatment in clearing intracellular SA from the liver microenvironment, which corresponded to differential host immunometabolic responses. DAP showed low NAD(P)H fluorescence lifetime and low mitochondrial ROS, suggestive of a redox-buffered state that balanced pathogen containment with hepatic metabolic homeostasis, while VAN treatment biased towards greater utilization of OXPHOS. Our findings using a novel in vitro microphysiological system mimicking the liver tissue microenvironment offer insights into antibiotic-mediated bacterial clearance that accounts for host immunometabolism beyond direct antimicrobial activity.
    Keywords:  Kupffer cell; S. aureus; bacteremia; daptomycin; liver; organ-on-chip; vancomycin
    DOI:  https://doi.org/10.1128/aac.00254-26
  7. Pediatr Res. 2026 Jul 18.
    Neonatal monocyte iron metabolism and immunometabolic responses in sepsis: a comparative ex vivo investigation.
    Soumya Lutterbach, Christina Mertens, Trim Lajqi, Judith Schenz, Eva Schöndorf-Holland, Markus A Weigand, Martina U Muckenthaler, Christian Gille, Dania Fischer.
       BACKGROUND: Neonatal sepsis is a leading cause of morbidity and mortality in neonates. The underdeveloped neonatal immune system, particularly innate immune cells such as monocytes, plays a critical role in susceptibility to infection. Monocyte-mediated regulation of iron metabolism, a key component of "nutritional immunity," is known to influence sepsis outcomes in adults. In this study, we investigated differences in iron sensing, iron-regulated gene expression, and intracellular iron content between neonatal and adult monocytes.
    METHODS: Monocytes were isolated from human umbilical cord blood and adult peripheral blood and stimulated in vitro with lipopolysaccharide (LPS), ferric nitrilotriacetate (FeNTA), or the iron chelator deferoxamine (DFO). Transferrin receptor 1 (TfR1) and differentiation markers were analyzed by flow cytometry, intracellular iron content by atomic absorption spectrometry, and metabolic and inflammatory responses via lactate and cytokine measurements.
    RESULTS: Neonatal monocytes exhibited lower basal TfR1 expression with a trend toward higher intracellular iron. LPS induced TfR1 upregulation exclusively in adult monocytes, while neonatal cells maintained consistently low expression. Although FeNTA increased intracellular iron in both groups, neonatal monocytes accumulated iron less efficiently.
    CONCLUSION: These findings indicate fundamental developmental differences in monocyte iron handling and immunometabolic adaptation, which may underlie the distinct immune profile observed in neonatal sepsis.
    IMPACT: Neonatal sepsis is a leading cause of morbidity and mortality in neonates. Particularly innate immune cells such as monocytes, play a critical role in susceptibility to infection. Monocyte-mediated regulation of iron metabolism, a key component of "nutritional immunity," is known to influence sepsis outcomes in adults. Our findings indicate fundamental developmental differences in monocyte iron handling and immunometabolic adaptation, which may play a role in both the distinct immune profile observed in neonatal sepsis and, consecutively, sepsis outcome. These findings imply that host-directed iron modulation could be a viable strategy to counteract immunoparalysis in neonatal sepsis without compromising cellular activation.
    DOI:  https://doi.org/10.1038/s41390-026-05298-5
  8. J Clin Invest. 2026 Jul 21. pii: e201325. [Epub ahead of print]
    SREBP1c modulates Treg immunobiology through a phospholipid-dependent adenosine pathway.
    Fabrizia Bonacina, Claudio Procaccini, Marta Iaia, Arianna Moretti, Monika Svecla, Silvia Pedretti, Jeroen Fj Bogie, Giovani Battista Vingiani, Annalisa Moregola, Francesca Genova, Claudia Russo, Giusy De Rosa, Claudia La Rocca, Giada Mondanelli, Marco Gargaro, Nico Mitro, Giuseppe Matarese, Giuseppe Danilo Norata.
      Regulatory T cells (Tregs) maintain immune tolerance through mechanisms tightly coupled to cellular metabolism. Whereas glycolysis supports Treg migration, lipid metabolism sustains their suppressive phenotype. Here, we identify the sterol regulatory element-binding protein 1c (SREBP1c) as a central regulator of Treg immunobiology. Tregs from Srebp1c-deficient mice displayed impaired suppressive function, reduced frequencies in circulation and lymphoid tissues, and diminished expression of functional markers. These defects stemmed from intrinsic metabolic rewiring rather than systemic alterations, as both ex vivo Tregs (CD4+CD25hiFoxP3+) and in vitro-derived Tregs lacking Srebp1c were shifted toward glycolysis. Integrated transcriptomic and lipidomic analyses revealed that Srebp1c-deficient Tregs exhibited defective phospholipid remodeling, with an accumulation of lysophosphatidylcholines over phosphatidylcholines, which we attributed to enhanced cytosolic phospholipase A2 (cPLA2α) activity and disruption of the Lands cycle. Altered lipid composition impaired adenosine-mediated immunosuppression by reducing CD73 expression and extracellular adenosine generation. Accordingly, pharmacological inhibition of cPLA2α restored adenosine signaling, CD73 expression, and Treg suppressive capacity. Thus, by preserving phospholipid homeostasis, SREBP1c functions as an immunometabolic checkpoint that links lipid metabolism to adenosine-dependent Treg suppression.
    Keywords:  Immunology; Lipidomics; Metabolism; Metabolomics; Tregs
    DOI:  https://doi.org/10.1172/JCI201325
  9. Immunometabolism (Cobham). 2026 Jul;8(3): e00086
    Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8+ T-cell dysfunction in cancer.
    Desh Raj, Mahesh Kathania, Tuoqi Wu, Arianne L Theiss, K Venuprasad.
      In a recent study published in Science Immunology, Tiberti and colleagues demonstrate that palmitate, a saturated fatty acid enriched in tumors, directly impairs CD8+ cytotoxic T lymphocyte function through mitochondrial and epigenetic reprogramming. Palmitate exposure reduced mitochondrial fitness, oxidative phosphorylation, and adenosine triphosphate production, resulting in defective proliferation, cytokine production, and antitumor activity. Mechanistically, mitochondrial dysfunction decreased intracellular acetyl-CoA availability, leading to reduced histone acetylation and loss of chromatin accessibility at loci that control effector programs. The study further identifies sphingosine kinase 2 as a critical mediator of lipid-induced dysfunction. Importantly, SPHK2 inhibition restored mitochondrial function, histone acetylation, and cytotoxic T lymphocyte antitumor activity, highlighting a potential therapeutic strategy for enhancing cancer immunotherapy.
    Keywords:  T-cell exhaustion; acetyl CoA; cytotoxic T cells; palmitate
    DOI:  https://doi.org/10.1097/IN9.0000000000000086
  10. Front Immunol. 2026 ;17 1902029
    Exercise, mitochondrial stress, and trained immunity: metabolic adaptation of innate immunity.
    Enli Xie, Yushan He, Yongjun Sun.
      Traditionally recognized as "cellular powerhouses", mitochondria have gained relevance as pivotal nodes in the integration of metabolism, stress signaling, and innate immunity. In this context, the present work seeks to answer the following question: Does the continuous, exercise-induced mitochondrial stress contribute towards training of innate immune cells by promoting the generation of DAMPs such as mtDNA and succinate? Exercise can be considered as a form of controllable mitochondrial stressor. Mechanistically, the temporary release of mtDAMPs through exercise results in activation of pattern recognition receptors (NLRP3, TLR9, cGAS-STING). Subsequently, there is a metabolic reprogramming event favoring switch from oxidative phosphorylation to aerobic glycolysis along with epigenetic changes (H3K4me3, H3K27ac) priming pro-inflammatory genes for enhanced secondary response. Moderate-intensity exercise develops an immune homeostatic condition with reduced low-grade inflammation and increased reactivity, while sedentary behavior fosters chronic low-grade inflammation, and excessive high-volume exercise can temporarily reduce immune competency. Herein, we present an integrative model where exercise-induced mitochondrial stress as a physiological "training vaccine" to enhance immune surveillance via trained immunity principles. The current model helps differentiate the immune status of elite athletes from sedentary subjects and paves the way for understanding the immunological benefit of exercise prescription in infection prevention, metabolic health, and cancer immunotherapy.
    Keywords:  DAMPs; epigenetic reprogramming; exercise immunology; metabolic reprogramming; mitochondrial stress; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1902029
  11. Mol Cell. 2026 Jul 21. pii: S1097-2765(26)00465-X. [Epub ahead of print]
    Temporal control of macrophage pro-inflammatory phenotype by a biphasic HIF-1α regulatory program.
    Gustavo Gastão Davanzo, Guilherme Ribeiro, Douglas Dos-Santos, Marcelo Rodrigues Berçot, Isabella Zaidan, Larissa Menezes Dos Reis, João Victor Virgilio-da-Silva, Bianca Gazieri Castelucci, Paulo Estevão, Wanderson Dourado Souza, Henver S Bruneta, José Luis Fachi, Webster Leonardo Costa, João Nilton Barreto Andrade, Gerson S Profeta, Rodrigo Requião Dias, Natália S Wassano, Lauar de Brito Monteiro, Jessica Aparecida da Silva Pereira, Cristhiane Favero de Aguiar, Monara Kaélle Sérvulo Cruz Angelim, Wilias Greison Santos, Victor Corasolla Carregari, Jonathan Peña, Carlos Alberto de Carvalho Fraga, Marcelo A Mori, Silvio Roberto Consonni, Daniel Martins-de-Souza, Marco Aurélio Ramirez Vinolo, Helder Nakaya, Peter J Murray, Afshin Beheshti, Larissa Dias Cunha, Pedro M Moraes-Vieira.
      Hypoxia-inducible factor 1α (HIF-1α) broadly orchestrates metabolic reprogramming in inflammatory macrophages. However, how HIF-1α shapes the earliest events following activation of pattern recognition receptors and triggers inflammatory responses remain unclear. We found that HIF-1α is functionally active shortly after macrophage inflammatory stimulation via a Rubicon (RUBCN)-NADPH oxidase (NOX2) reactive oxygen species (ROS) circuit, driving glycolysis, cytokine production, and bacterial killing before maximal protein accumulation. Early HIF-1α stabilization primes inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, which subsequently suppresses electron transport chain function and induces mitochondrial dysfunction independently of RUBCN and NOX2. These findings elucidate a temporally coordinated HIF-1α pathway that integrates RUBCN-NOX2 redox signaling to control macrophage inflammation, metabolic adaptation, and antimicrobial defense.
    Keywords:  HIF-1α; NADPH oxidase 2; NOX2; glycolisis; hypoxia-inducible factor 1-alpha; macrophage metabolic reprogramming; mitochondria; rubicon
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.001
  12. Sci Adv. 2026 Jul 24. 12(30): eaeb7972
    Yersiniabactin-producing adherent-invasive Escherichia coli exploit host glycolysis to drive macrophage HIF-1α stabilization.
    Marlus S Pedrosa, Ju-Hyun Ahn, John D Sears, Kimberly A Walker, Lance Thurlow, Nathaniel J Moorman, Janelle C Arthur.
      The siderophore yersiniabactin (Ybt) produced by a subset of intestinal adherent-invasive Escherichia coli (AIEC) drive intestinal fibrosis in murine model of Crohn's disease (CD). This is linked to the Ybt-induced disruption of host metal homeostasis and activation of the hypoxia-inducible factor 1-alpha (HIF-1α) in macrophages. Elevated glycolytic activity has been documented in both intestinal tissues and macrophages from patients with CD, indicating that metabolic reprogramming is a characteristic feature of the disease. Here, we show that HIF-1α stabilization by Ybt+ AIEC requires active host glycolysis. This effect is independent of Hif1a transcription and lipopolysaccharide stimulation and is not solely explained by intracellular bacterial load but instead relies on host metabolic activity. Mechanistically, Ybt+ AIEC activated the Akt-mTOR pathway to support HIF-1α translation. Inhibition of glycolysis suppressed this signaling axis, reducing HIF-1α translation and nuclear localization. Given the association between Ybt+ AIEC and fibrosis in CD, these findings suggest that targeting host glycolysis may limit AIEC-driven macrophage HIF-1α activation and fibrotic progression in CD patients.
    DOI:  https://doi.org/10.1126/sciadv.aeb7972
  13. Int Immunopharmacol. 2026 Jul 24. pii: S1567-5769(26)01008-8. [Epub ahead of print]187 117162
    The mechanism of macrophage glycolysis regulating Th17 cell differentiation and promoting the progression of EAN mice.
    Shuping Liu, Huiying Lu, Yuge Kang, Qian Cao, Miao Liu, Zuneng Lu.
      This study investigates how macrophage glycolysis interacts with CD4+ T cells to drive experimental autoimmune neuritis (EAN) progression. In EAN mice, expression of key glycolytic genes (LDHA, GLUT1, HK2, and PKM2) was gradually upregulated in splenic macrophages and sciatic nerve. By the disease peak (day 18 p.i.), these genes reaching approximately 4-to-8-fold increase over controls, paralleling a continuous expansion of the splenic M1 macrophage population. Crucially, in vivo glycolysis inhibition via 2-deoxyglucose (2-DG) effectively suppressed splenic M1 polarization and sciatic nerve CD86 IHC intensity, thereby mitigating EAN clinical scores from day 10 onward. Further in vitro experiments revealed that M1-polarized macrophages exhibited significantly enhanced glycolytic activity, characterized by increased glucose uptake, ATP generation, and lactate secretion. Their conditioned medium successfully drove CD4+ T cell differentiation into the Th17 subset, upregulating RORγt expression and the secretion of IL-17 and IL-22. Mechanistically, extracellular lactate promoted Th17 differentiation by facilitating PKM2 nuclear translocation, which enhanced STAT3 phosphorylation and RORγt expression while reciprocally suppressing Foxp3. Genetically overexpressing PKM2 augmented lactate-induced Th17 cytokine secretion, whereas pharmacological stabilization of PKM2 tetramers via TEPP-46 blocked its nuclear entry and reduced Th17 differentiation. Ultimately, targeted in vivo intervention with TEPP-46 significantly improved neurological function scores in EAN mice, accompanied by diminished Th17 cell infiltration and alleviated inflammatory demyelination. Together, our findings elucidate the "macrophage glycolysis-lactate-PKM2" axis in regulating Th17 differentiation, offering a novel metabolic-immune therapeutic strategy for EAN and its clinical counterpart, acute inflammatory demyelinating polyneuropathy (AIDP).
    Keywords:  Experimental autoimmune neuritis; Lactate; Macrophage glycolysis; PKM2; Th17 cells
    DOI:  https://doi.org/10.1016/j.intimp.2026.117162
  14. Sci Immunol. 2026 Jul 24. 11(121): eaeb7315
    Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer.
    Weiwei Yu, Ruya Sun, Xiaoyang Lu, Qiqi Deng, Heng Zhang, Sheng Chen, Siqi Dai, Tianyi Hu, Xiangyuan Li, Yidong Yang, Lihao Chen, Zhexu Chi, Jian Zhang, Siwen Zhang, Yiyi Zhu, Dehang Yang, Qianzhou Yu, Zhen Wang, Quanquan Wang, Fan Yang, Qian Xiao, Kefeng Ding, Di Wang.
      Tumor cells promote metabolic dysregulation of immune cells by controlling the metabolic landscape of the tumor microenvironment. It is unclear whether tumors restrict specific nutrients to drive rapid growth and immune evasion in addition to the overconsumption of nutrients to support anabolism. We identified that up-regulation of solute carrier family 7 member 1 (SLC7A1) increased arginine utilization and promoted tumor growth, whereas down-regulation of SLC7A2 decreased lysine catabolism to support immune evasion. Repression of lysine catabolism in tumor cells reduced glutaconic acid (GC), a medium-chain acyl-CoA dehydrogenase-dependent lysine catabolite that has immunostimulatory effects on antitumor CD8 T cells. GC modified pyruvate kinase M2 (PKM2) through posttranslational glutaconylation at key lysine residues Lys336 (K336) and K337. This modification reinforced PKM2 dimers, transcriptionally driving metabolic reprogramming and reinvigorating antitumor CD8 T cells. Our study highlights an amino acid trade-off that dynamically optimizes the metabolic preferences of tumors to promote proliferation and immune evasion.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb7315
  15. Biochem Biophys Res Commun. 2026 Jul 16. pii: S0006-291X(26)01068-5. [Epub ahead of print]831 154304
    The mitochondrial DNA signal in rheumatoid arthritis: From metabolic victim to inflammatory driver.
    Ruoyi Zhang, Zhijie Song, Qimeng Xin, Wenbin Xing, Wenlan Zhang, Yanmei Yang.
      Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by sustained immune activation and profound metabolic dysregulation. Accumulating evidence indicates that mitochondrial DNA (mtDNA) plays an active role in linking mitochondrial stress to innate immune signaling in RA. This review synthesizes current findings within a unifying mechanistic framework centered on the mtDNA damage-release-immune activation axis. Owing to limited chromatin protection and constrained repair capacity, mtDNA is highly susceptible to oxidative injury in the inflammatory microenvironment of RA, leading to copy number alterations and mutational accumulation. Damaged or oxidized mtDNA can translocate to the cytosol or extracellular space, where it acts as an immunostimulatory danger signal and amplifies innate immune activation. Persistent mtDNA-related signaling, together with oxidative stress and impaired mitochondrial quality control, contributes to immunometabolic reprogramming in key effector populations. Clinically, circulating cell-free mitochondrial DNA has emerged as a dynamic biomarker associated with disease activity and therapeutic response. Collectively, this framework integrates mitochondrial dysfunction with immune activation in RA and highlights mtDNA-centered pathways as rational targets for mechanism-based intervention. Further standardization of mtDNA assays and mechanism-informed clinical studies will be essential to advance mtDNA-focused precision strategies in RA.
    Keywords:  Immunometabolism; Mitochondrial DNA; NLRP3 inflammasome; Rheumatoid arthritis; TLR9; cGAS-STING
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154304
  16. Redox Biol. 2026 Jul 11. pii: S2213-2317(26)00298-3. [Epub ahead of print]96 104299
    STXBP6-driven signaling cascade alters lipid peroxidation in tumor-associated macrophages to facilitate ovarian cancer progression.
    Min Wang, Jinlong Wang, Hang Xu, Siying Zhang, Fengzhen Jin, Qinke Li, Zhu Yang.
      Ovarian cancer (OC) is highly lethal, with late diagnosis and frequent treatment resistance. Tumor-associated macrophage (TAM) are key immunosuppressive cells whose metabolic state critically influences redox homeostasis and immune function in the tumor microenvironment (TME). Here, we show that STXBP6 expression is elevated in OC TAMs. Mechanistically, STXBP6 promotes cPLA2-mediated arachidonic acid release and PKCβ-dependent nuclear translocation and activation of arachidonate 5-lipoxygenase (ALOX5), driving alterations in arachidonic acid metabolism and downstream 5-HETE production. Lipidomics, transcriptomics, and functional assays demonstrated that STXBP6 regulates lipid droplet formation, lipid peroxidation, and TAM polarization, linking redox-regulated lipid metabolism to immunosuppressive phenotypes. Using in vitro TAM models and in vivo OC models, including TAMs-OC co-implantation, we further confirmed that the STXBP6/cPLA2/ALOX5/5-HETE axis enhances tumor growth, metastasis, and the establishment of an immunosuppressive microenvironment. These findings reveal a previously unrecognized mechanism by which STXBP6 drives TAM metabolic reprogramming and immune modulation in OC, highlighting STXBP6 as a potential target for immunometabolic therapy.
    Keywords:  ALOX5; Lipid peroxidation; Ovarian cancer; STXBP6; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.redox.2026.104299
  17. Front Immunol. 2026 ;17 1798798
    Mitochondrial microprotein MOCCI controls neuroinflammation by altering glial activation states.
    Kimberle Shen, Ke Guo, Sze Huey Leong, Radiance Lim, Wei Leong Chew, Cheryl Q E Lee, Lena Ho.
      Metabolic regulation and its underlying mechanisms play a critical role in controlling and resolving inflammation in the brain, directly shaping glial cell activation and the central nervous system's response to injury and disease. In our screen for microproteins that modify inflammatory outcomes, we discovered MOCCI (protein product of C15orf48/AA467197) as a significant regulator of gut and lung inflammation. However, its involvement in neuroinflammation is unknown. Here, we show that MOCCI is upregulated in microglia and astrocytes in both the mouse and human brain upon inflammation, and is required for orchestrating proper, complete, and beneficial activation of microglia and astrocytes. Induction of MOCCI triggers the transition of glia into a neuroprotective state and promotes the resolution of inflammation. In vitro, MOCCI deficiency leads to reduced migration, phagocytosis and cytokine secretion in microglia and astrocytes. In the cuprizone mouse model of multiple sclerosis, MOCCI plays a role in both demyelination and remyelination. These results position MOCCI as a molecular brake on neuroinflammation, highlighting its therapeutic potential for targeting glial metabolic health and resolving chronic CNS inflammation in neurodegenerative disease.
    Keywords:  C15orf48; MOCCI; astrocytes; glia; glia activation; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1798798
  18. Endocr Rev. 2026 Jul 21. pii: bnag030. [Epub ahead of print]
    The metabolic roles of immune checkpoint molecules.
    Yan Wang, Junxue Wang, Sijia Dan, Junke Zheng, Yingli Lu, Fangzhen Xia.
      Immune checkpoint molecules (ICMs) are a class of surface proteins predominantly expressed on immune cells that play a key role in maintaining immune homeostasis by regulating the functions of T cells and other immune cells. Beyond their established immunoregulatory roles, emerging evidence indicates that ICMs are also involved in metabolic regulation. Within the tumor microenvironment (TME), tumour-derived ICMs have been shown to modulate glucose, amino acid, and lipid metabolism in infiltrating T cells, thereby influencing their metabolic reprogramming and functional states. Certain ICMs expressed on immune cells may directly regulate systemic metabolism through cell-intrinsic, immune-independent mechanisms. Moreover, specific ICMs are constitutively expressed in key metabolic tissues, such as pancreatic islets, liver, and adipose tissue, where they are thought to contribute to the maintenance of systemic metabolic homeostasis. Clinically, host metabolic status can affect the efficacy of immune checkpoint inhibitor (ICI) therapies. Conversely, ICI treatment can lead to metabolism-related adverse effects, such as ICI-associated diabetes (ICI-DM), which may extend beyond classic autoimmune insulin-dependent diabetes. Accumulating evidence suggests that ICMs can exert direct regulatory roles in metabolism independent of their canonical immune functions. Elucidating how ICMs regulate metabolism could, on the one hand, improve ICI therapy by maintaining metabolic homeostasis and preventing T cell exhaustion, and on the other hand, facilitate the development of novel therapeutic strategies for metabolic diseases that simultaneously target metabolic and inflammatory pathways. This review synthesises current knowledge on the metabolic roles and regulatory mechanisms of ICMs.
    Keywords:  Crosstalk; ICI therapy; Immune checkpoint molecules; Metabolic disorders; Metabolism
    DOI:  https://doi.org/10.1210/endrev/bnag030
  19. Br J Cancer. 2026 Jul 24.
    Lipid metabolic reprogramming of macrophage by host APOBEC3 deficiency enhances anti-tumor immunity.
    Yuqi Yang, Fanglin Li, Mozi Lei, Yi Liu, Jiangling Lu, Chen Chen, Danyang Cui, Yiru Long, Xiaolu Yu, Jianhua Sun, Jing Chen, Nan Liu, Bingshun Wang, Likun Gong.
       BACKGROUND: Tumour-associated macrophages are an indispensable part of the tumour immune microenvironment, exhibiting phenotypic and functional plasticity that enables them to play an important role in modulating the immune response. A large number of RNA editing events have been identified during macrophage functional remodelling. APOBEC3 is a well-known family of base-editing enzymes, but whether and how it regulates macrophage function is unclear.
    METHODS: In this study, we mainly used genetically engineered mice to demonstrate how host APOBEC3 deficiency affects tumour progression.
    RESULTS: We found that the polarisation state of macrophages in the tumour microenvironment was altered by host APOBEC3 deficiency and that knockout of host APOBEC3 significantly inhibited tumour growth and metastasis in a macrophage-dependent manner. Moreover, APOBEC3 deficiency remodelled macrophage function, improved their polarisation state, and enhanced their phagocytic capacity. Mechanistically, APOBEC3 knockout attenuated lipid uptake by macrophages in a PPARγ pathway-dependent way, leading to an increase of M1/M2 ratio in macrophages.
    CONCLUSIONS: These findings reveal that APOBEC3 deficiency drives lipid metabolism reprogramming in macrophages and remodels their functions, thereby inducing a strong anti-tumour immune response, providing a proof-of-concept and new insights for the development of the APOBEC3 family for novel tumour therapies. Host APOBEC3 deficiency regulates macrophage function through lipid metabolic remodelling, ultimately leading to tumour suppression (Created with BioRender.com).
    DOI:  https://doi.org/10.1038/s41416-026-03550-7
  20. Semin Immunol. 2026 Jul 24. pii: S1044-5323(26)00036-9. [Epub ahead of print]83 102049
    Ferroptosis at the intersection of metabolism and immunity in pancreatitis and pancreatic cancer.
    Fangquan Chen, Xiutao Cai, Ruirui Liang, Rui Kang, Jiao Liu.
      Ferroptosis links cellular metabolism to immune regulation. Beyond its role as an iron-dependent form of regulated cell death, ferroptosis generates signals, including oxidized lipids, iron metabolites, and damage-associated molecular patterns, that influence inflammatory and immune responses. The pancreas is particularly susceptible to ferroptotic stress because of its high metabolic demand and close integration with immune and stromal networks. In pancreatitis, ferroptosis translates metabolic injury into innate immune activation, contributing to sterile inflammation and tissue damage. In pancreatic cancer, ferroptotic vulnerabilities can be exploited therapeutically, yet ferroptosis-associated signals may also support immune suppression, immune evasion, and treatment resistance. These findings suggest that ferroptosis functions as an immunometabolic checkpoint rather than simply a cell death program. Here, we discuss how ferroptosis shapes immune responses in pancreatitis and pancreatic cancer and examine the factors that determine whether it promotes inflammation, antitumor immunity, or immune tolerance. We also review ferroptosis-targeted therapies and the challenges associated with their clinical application.
    Keywords:  DAMPs; Ferroptosis; Immunity; Pancreatic cancer; Pancreatitis
    DOI:  https://doi.org/10.1016/j.smim.2026.102049
  21. Int Immunopharmacol. 2026 Jul 20. pii: S1567-5769(26)01009-X. [Epub ahead of print]186 117163
    Hyperglycemia drive neutrophil extracellular trap formation and subsequent tissue injury in sepsis via PI3K/AKT-mediated glycolysis.
    Rui Tian, Wenjing Wu, Xue Wang, Zhonghui Xue, Jingjing Li.
       BACKGROUND: Sepsis is frequently accompanied by metabolic disturbances, in which stress hyperglycemia is closely associated with adverse clinical prognoses. Neutrophil extracellular traps (NETs) are pivotal drivers of septic inflammatory injury and disease progression. Glycolysis dominates neutrophil metabolic reprogramming and critically controls NETosis activation in inflammatory states. However, how hyperglycemia modulates NET formation during sepsis and the underlying glycolytic regulatory mechanism remain poorly elucidated. This study investigated the effect of hyperglycemia on sepsis-related NET formation and further clarified the regulatory role of PI3K/AKT-dependent glycolysis in this pathological process.
    METHODS: A total of 347 septic patients were retrospectively enrolled and stratified into euglycemia, mild and severe hyperglycemia groups based on admission blood glucose levels. Clinical 28-day outcomes were analyzed, and Boruta algorithm and multivariate regression models were used to adjust confounders and assess the dose-response association between hyperglycemia and septic injury. In vivo, a cecal ligation and puncture (CLP) and LPS-induced murine septic models with exogenous glucose intervention were established. Primary neutrophils from mouse bone marrow and human peripheral blood were isolated and treated with high glucose in vitro. Neutrophil phenotypes and transcriptomic profiles were analyzed via flow cytometry and RNA sequencing. NET formation was validated by immunofluorescent detection of CitH3 and MPO, while NET-related and inflammatory factors were quantified using ELISA. Glycolytic activity was evaluated by lactate measurement. The expression levels of core PI3K/AKT glycolytic axis molecules were determined by Western blot and qRT-PCR, and histopathological staining was performed to evaluate organ tissue injury.
    RESULTS: Clinical analysis of 347 septic patients revealed that admission hyperglycemia was independently and dose-dependently correlated with elevated 28-day mortality. Hyperglycemia in septic patients promoted circulating NET formation independent of neutrophil counts. In vivo, superimposed hyperglycemia exacerbated NET release, inflammatory injury, hepatic and renal damage, and mortality in septic mice. Transcriptomic and functional assays verified that hyperglycemia upregulated key glycolytic molecules (GLUT1, PFKFB3, PDK1) to enhance glycolysis and lactate production in septic neutrophils. In vitro high-glucose stimulation augmented neutrophil NETosis via glycolytic activation. Mechanistically, hyperglycemia activated PI3K/AKT signaling to drive neutrophil glycolytic reprogramming and subsequent NET formation, whereas PI3K/AKT inhibition efficiently reversed these pathological alterations.
    CONCLUSION: In conclusion, admission hyperglycemia independently predicts poor prognosis in sepsis. Mechanistically, hyperglycemia activates PI3K/AKT signaling to upregulate key glycolytic molecules, thereby enhancing neutrophil glycolysis and excessive NET formation, which aggravates inflammatory organ damage and increases septic mortality. This study reveals a novel glycometabolic mechanism underlying hyperglycemia-mediated septic deterioration.
    Keywords:  GLUT1; Glycolysis; Hyperglycemia; Neutrophil extracellular traps (NETs); PFKFB3; Sepsis
    DOI:  https://doi.org/10.1016/j.intimp.2026.117163
  22. Front Immunol. 2026 ;17 1819389
    Targeting macrophage metabolism: mechanisms, cellular crosstalk and implications in obesity-associated metabolic diseases.
    Chensi Yao, Wei Zheng, Yamei Jin, Jiahao Sheng, Mengjiao Kang, Jijuan Zhong, Min Li, Liyun Duan, Xiao Yuan.
      Obesity and its associated metabolic disorders constitute a prominent public health challenge. Diverse environmental and metabolic cues trigger alterations in macrophage metabolism, thereby influencing their functional phenotypes. Due to their phenotypic plasticity, macrophages play beneficial roles in tissue homeostasis, yet they also contribute to the progression of metabolic diseases. Consequently, beyond systemic chronic low-grade inflammation, greater attention should be directed toward immunometabolic dysfunction in metabolic tissues during obesity and its related diseases. This review summarizes the functional phenotypes and metabolic characteristics of macrophages, with an emphasis on how tissue niches influence macrophage function in the context of various obesity-related metabolic diseases. Enhanced understanding of the interplay between macrophages and metabolic target organs/tissues may provide novel therapeutic strategies for managing obesity and associated metabolic disorders.
    Keywords:  inflammation; macrophages; metabolism; obesity-associated metabolic diseases; polarization; reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1819389
  23. J Clin Invest. 2026 Jul 23. pii: e207089. [Epub ahead of print]
    Palmitic acid coordinates impaired visceral adipose ICOShi Treg-mediated immunosuppression and systemic metabolic disturbance during obesity.
    Weitong Su, Yuxiao Liu, Xi Yan, Mengyao Huang, Linghao Xu, Jing Lin, Xufeng Chen, Puyuan Hu, Chenlin Gao, Jian Wen, Hongdong Wang, Dong Ding, Zengpeng Zheng, Wenjing Li, Lianjia Li, Zhan Liu, Keyu Qian, Jing Gao, Tingting Zhang, Xiaobing Mao, Haibing Zhang, Wei Lu, Bin Li, Hong Li, Aoyuan Cui, Yan Bi, Chunxiang Zhang, Yu Li.
      Regulatory T (Treg) cells in visceral adipose tissue (VAT) play essential roles in systemic metabolic homeostasis under distinct physiological and pathological conditions. However, the metabolic cues that drive Treg cell subset specialization in the obese VAT niche remain elusive. Here, we demonstrated that palmitic acid instigated chronic VAT inflammation and systemic metabolic disturbance by compromising the immunosuppressive function of the ICOShi Treg subset. Palmitic acid, but not oleic acid, activated Crebzf expression in VAT Treg cells from HFHS diet-induced obese and ob/ob mice. Crebzf deficiency significantly attenuated diet-induced obesity and inflammation by upregulating the suppressive function of VAT ICOShi Treg cells. Moreover, adoptive transfer of Crebzf-deficient ICOShi Treg cells into Rag1-/- mice alleviated HFHS diet-induced inflammation and metabolic disorders more effectively than transfer of Crebzf-sufficient ICOShi Treg cells. Mechanistically, CREBZF interacted with c-JUN to inhibit Foxp3 activity, thereby impairing the stability and inhibitory cytokine production of ICOShi Treg cells. In human subjects, CREBZF levels in VAT Treg cells were elevated and negatively correlated with FOXP3 activity. Collectively, these findings uncover a specific ICOShi Treg subset that responds to palmitic acid, thereby coupling obesogenic signals to VAT remodeling and systemic metabolic homeostasis.
    Keywords:  Inflammation; Metabolism; Obesity; T cells
    DOI:  https://doi.org/10.1172/JCI207089
  24. Front Immunol. 2026 ;17 1884948
    Cholesterol metabolic rewiring shapes immune remodeling across hepatocarcinogenesis.
    Wentao Ma, Fengxu Yan, Yu Cheng, Guoqing Zhang, Yanxi Mu, Zhiqiang Zhang, Xuefeng Liang, Jianxin Gan, Wenwei Yang, Weixiong Zhu, Yusheng Cheng.
      Cholesterol metabolism, hepatocellular carcinoma (HCC), and the tumor immune microenvironment are increasingly recognized as interconnected drivers of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis-related HCC (MASLD/MASH-HCC). However, cholesterol dysregulation during hepatocarcinogenesis is often discussed as isolated pathways or single-stage events, and evidence strength differs across human HCC tissues, preclinical HCC models, and non-HCC systems. This review integrates mechanistic, spatial multi-omics, and translational evidence to highlight cholesterol dyshomeostasis as a stage- and cell-type-specific rewiring of synthesis, uptake, esterification, efflux, and conversion rather than a uniform metabolic increase. In chronic metabolic liver disease, sterol regulatory element-binding protein 2 (SREBP2)-SREBP cleavage-activating protein (SCAP) activation, impaired bile acid-farnesoid X receptor (FXR) feedback, free-cholesterol loading, and oxysterol accumulation may connect hepatocyte stress with stellate-cell activation, macrophage remodeling, inflammation, and fibrosis. During preneoplastic transition and early HCC, squalene epoxidase (SQLE), sterol O-acyltransferase 1 (SOAT1), farnesyl-diphosphate farnesyltransferase 1 (FDFT1), 24-dehydrocholesterol reductase (DHCR24), and SCAP-regulatory circuits may support membrane remodeling, oncogenic signaling, metabolic autonomy, and impaired immune surveillance, although their evidence levels vary. In advanced and metastatic HCC, spatially resolved studies suggest cholesterol-active tumor regions may be coupled to exhausted T cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), extracellular vesicle signaling, and oxysterol-mediated communication. We further discuss stage-aligned diagnostic and therapeutic opportunities, proposing cholesterol metabolic rewiring as a hypothesis-generating and partially validated framework for HCC initiation, progression, recurrence, and therapeutic resistance.
    Keywords:  MASLD/MASH-HCC; cholesterol metabolism; hepatocellular carcinoma; immunometabolism; oxysterols; spatial omics; therapeutic resistance; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1884948
  25. Redox Biol. 2026 Jul 16. pii: S2213-2317(26)00304-6. [Epub ahead of print]96 104305
    Dynamic alterations in labile heme levels and heme biosynthesis during inflammatory activation of macrophages.
    Yan Jin, Pooja Pradhan, Hongxin Liang, Tomoyuki Nakagiri, Sebastian Mueller, Roberta Foresti, Roberto Motterlini, Tasuku Hirayama, Stephan Immenschuh.
      Heme is an iron-containing tetrapyrrole with dual biological functions. While it serves as an essential prosthetic group in various hemoproteins, heme is cytotoxic in its 'free', non-protein-bound, form. Labile heme (LH) denotes the intracellular fraction of bioavailable heme that is readily exchangeable for incorporation into hemoproteins. To investigate the regulatory role of this heme fraction in inflammatory activated macrophages, we applied the selective fluorescent small molecule H-FluNox for LH detection in lipopolysaccharide (LPS)-stimulated murine bone marrow-derived macrophages (BMDMs). Studies with H-FluNox and its cell-permeable derivative acetylated (Ac)-H-FluNox revealed a time-dependent decrease of LH levels in living BMDMs upon treatment with LPS. Expression of δ-aminolevulinate synthase 1, the rate-limiting enzyme of heme synthesis, was up-regulated in parallel to decreased LH. Studies in subcellular organelles of BMDMs demonstrated that LH concentrations were markedly higher in mitochondria compared to cytosol and nuclei. Furthermore, expression of inducible nitric oxide synthase (iNOS), a heme-containing pro-inflammatory enzyme, was linked to intracellular LH concentrations. Specifically, LPS-dependent iNOS induction was attenuated in BMDMs displaying decreased LH, either after treatment with pharmacological heme synthesis inhibitors, or with genetic deficiency of the nuclear heme sensor BACH1. By contrast, inducibility of iNOS by LPS was markedly higher in BMDMs exhibiting increased levels of LH following treatment with the heme synthesis substrate δ-aminolevulinate. Finally, pharmacological inhibition of succinate dehydrogenase, which enhances intracellular levels of δ-aminolevulinate and LH, was also associated with higher inducibility of iNOS by LPS. In conclusion, the data indicate that intracellular LH is modulated by inflammatory stimulation in mouse macrophages and is critical for heme incorporation into the hemoprotein iNOS. Thus, heme availability may serve as a regulatory link between metabolic and inflammatory pathways.
    DOI:  https://doi.org/10.1016/j.redox.2026.104305
  26. Cell Commun Signal. 2026 Jul 22.
    DRP1 lysine 616 lactylation exacerbates cerebral ischemia-reperfusion injury by activating the STING inflammatory pathway.
    Xiaoqi Ma, Dan Xin, Xianjia Li, Zhenhao Ying, Zifeng Li, Wenli Wang, Zhigang Mei, Jinwen Ge.
      Ischemia-hypoxia-induced inflammation and glycolysis are linked to the severity of cerebral ischemia-reperfusion injury (CIRI), but the mechanisms are unclear. Current research suggests that the inflammatory response of immune cells activated by STING is a key regulatory molecule in cellular inflammatory damage. However, the specific mechanisms underlying STING-mediated CIRI inflammatory responses remain unclear. This study found that STING expression was specifically elevated in microglia in the damaged side of the hippocampus in CIRI model mice, and this elevation was positively correlated with the severity of CIRI. Our previous research indicated that the dynamic process of mitochondrial fusion and fission is closely associated with CIRI. Building on this, we integrated glycolysis, mitochondrial fission, and the STING inflammatory pathway. Mechanistically, our data suggest that DRP1 K616 is a critical candidate site involved in DRP1 lactylation-associated regulation, which promotes STING pathway activation and contributes to the progression of CIRI. In conclusion, our findings offer substantial evidence that lactate-driven DRP1-mediated mitochondrial fission facilitates the involvement of the STING inflammatory pathway in CIRI. These results suggest that modulating lactate metabolism may serve as a crucial upstream strategy for therapeutic intervention in CIRI.
    Keywords:  DRP1; Ischemic stroke; Lactylation; Microglia; Mitochondrial fission; cGAS-STING pathway
    DOI:  https://doi.org/10.1186/s12964-026-03093-7
  27. Cancer Res. 2026 Jul 21.
    Cystine Restriction Alleviates T Cell Exhaustion and Enhances CAR-T Cell Potency.
    Xiaoxue Pan, Yuhang Yin, Haopeng Hong, Jichang Li, Jing Zhu, Xin Wang, Yucun Liu, Pengyuan Wang, Shanwen Chen.
      While chimeric antigen receptor (CAR) T cell therapy has demonstrated significant efficacy in treating hematological malignancies, its application in solid tumors remains challenging. A major limitation of CAR-T cell efficacy in solid tumors is the functional exhaustion of CD8⁺ T cells. Here, we investigated metabolic regulators of CD8⁺ T cell exhaustion, identifying that cystine promotes CD8+ T cell exhaustion. RNA sequencing analysis of an in vitro exhaustion model revealed that SLC7A11 was significantly upregulated in exhausted CD8⁺ T cells. A monoclonal antibody specifically targeting SLC7A11 was subsequently generated, and its binding affinity was rigorously validated. Single-cell RNA sequencing and functional studies demonstrated that inhibition of SLC7A11 promoted the expansion of CD8⁺ stem-like memory T cells and alleviated T cell exhaustion. In vivo, treatment with the anti-SLC7A11 antibody enhanced the antitumor efficacy of CAR-T cells. Mechanistically, SLC7A11 inhibition suppressed cystine uptake, which activated the GCN2-eIF2α-SLC1A5 signaling axis. Upregulation of SLC1A5 increased glutamine uptake to stimulate oxidative phosphorylation and support mitochondrial fitness. Together, these findings demonstrate that cystine restriction alleviates CD8+ T cell exhaustion and enhances the efficacy of CAR-T cell therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4375
  28. Eur J Immunol. 2026 Jul;56(7): e70234
    High-Salt Diet Links Gut Microbiota, Intestinal Barrier Function, and Macrophage Responses.
    Akram Abdulkadyrov, Marie-Louise Diefenbach-Wilke, Elvira Mass, Maria Francesca Viola.
      The Global North is increasingly exposed to a Western diet characterized by high fat, sugar, and salt content. Excess dietary salt has been linked to cardiovascular disease and hypertension and can accumulate in multiple tissues, exerting local immunomodulatory effects. Beyond these systemic consequences, a high-salt diet (HSD) is associated with gut dysbiosis, which alters the production of microbial metabolites, such as short-chain fatty acids (SCFAs), and compromises intestinal barrier integrity, thereby facilitating bacterial translocation and contributing to liver and kidney injury. These alterations are associated with inflammatory responses, although their direction and magnitude depend on dietary duration, microbial baseline composition, and experimental models. While most studies have focused on HSD-induced modulation of T cell responses, emerging data highlight macrophages as underexplored mediators of HSD-driven immune and metabolic effects. In this review, we summarize current knowledge on HSD-induced alterations of the intestinal microbiota, microbial metabolites, gut barrier function and macrophage function, and discuss their potential interplay along the gut-liver axis. In addition, we highlight key gaps and challenges that must be addressed to improve translational relevance.
    DOI:  https://doi.org/10.1002/eji.70234
  29. Microb Pathog. 2026 Jul 19. pii: S0882-4010(26)00442-0. [Epub ahead of print]219 108716
    Circadian immunometabolic states impart a temporal response to SARS-CoV-2 spike proteins in mammalian macrophages.
    Sharleen M Buel, Jayashree Balaraman, Meaghan S Jankowski, Kim Hixson, Yuqian Gao, Young-Mo Kim, Nathalie Muñoz, Jennifer E Kyle, Mary S Lipton, Carrie D Nicora, Paul D Piehowski, Scott E Baker, Jennifer M Hurley.
      Circadian rhythms, driven by 24-h molecular oscillators, or "clocks", widely tune physiology to the daily rhythms of light and dark to enhance organismal fitness. In mammals, the cellular immune response is tightly regulated by these rhythms such that immunometabolic output is coordinated across the day, consolidating macrophage physiology into temporally distinct phases that determine the macrophage response to stimuli. Importantly, key proteins in the macrophage response to viral infection have been found to be under circadian control, and time of day of adjuvant application is known to affect the efficacy of vaccinations, including in the case of the SARS-CoV-2 virus. However, little is known about the molecular changes that underly the temporal response to vaccine application. Therefore, to investigate the circadian response of macrophage physiology to adjuvant exposure, we exposed primary mouse and human macrophages to the SARS-CoV-1 and CoV-2 spike proteins at different times over the circadian day. To further explore the time-of-day effect, we performed a multi-omics analysis and in vitro tissue culture assays examining macrophage responses over circadian time. We found that, conserved across the species, the timing of spike protein exposure dictated two distinct temporal responses which were characterized by hallmarks of immunometabolic suppression and modest immunometabolic activation. Intriguingly, these temporal responses were driven by central metabolic and mitochondrial changes rather than classical immune activation, suggesting immunometabolic control is a primary regulator of the temporal response of immune cells to stimuli.
    DOI:  https://doi.org/10.1016/j.micpath.2026.108716
  30. Nat Microbiol. 2026 Jul 20.
    All-trans retinoic acid suppresses systemic inflammation induced by severe fever with thrombocytopenia syndrome virus in mice.
    Xin Yu, Jianan Wu, Xiaohong Yin, Mengjia Yue, Yunfa Zhang, Jinxin Meng, Jinyan Xie, Jialei Li, Xiaoai Zhang, Ning Cui, Zhen Wang, Zhi-You Wang, Wen-Wen Zhang, Xinyu Ni, Shuxian Chen, Hao Li, Wei Liu, Shu Jeffrey Zhu.
      The vitamin A metabolite all-trans retinoic acid (ATRA) has immunoregulatory features, but its systemic role during viral infection is unclear. Here we show that patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne infection, have depleted serum vitamin A and ATRA levels. This correlated with exacerbated systemic inflammatory response syndrome severity and mortality risk. In an SFTSV mouse model, intraperitoneal administration of ATRA suppresses virus-induced hyperinflammation via peroxisome proliferator-activated receptor-γ (PPARγ), which downregulates the transcriptional activity of activator protein-1 (AP-1 in macrophages. Mechanistically, ATRA binds retinoid X receptor-α (RXRα) and facilitates the formation of RXRα-PPARγ heterodimers. This complex sequesters the transcription factor JUN and suppresses the expression of AP-1 promoter-dependent genes, such as IL-6, thus attenuating inflammatory signalling pathways. Our study suggests a retinoid-mediated immunometabolic checkpoint during SFTSV infection and proposes retinoid signalling as a therapeutic target for cytokine storm management.
    DOI:  https://doi.org/10.1038/s41564-026-02411-6
  31. Mol Cell. 2026 Jul 21. pii: S1097-2765(26)00456-9. [Epub ahead of print]
    Uridine cytidine kinase 1 promotes phosphatidylcholine biosynthesis, facilitating SARS-CoV-2 infection.
    Guangda Shi, Jaeseung Lee, Smita Bhutda, Zienab Etwebi, Jesse Miller, Kasirajan Ayyanathan, Yue Li, David Nguyen, Yongqing Zhu, Wujuan Zhang, Aaron R Goldman, David C Schultz, Sara Cherry.
      RNA viruses require diverse metabolic intermediates for replication, including nucleotides, which are synthesized through two pathways: de novo biosynthesis and salvage. De novo nucleotide biosynthesis is required for viral replication, but the role of nucleotide salvage is less clear. Genetic screening of purine and pyrimidine salvage pathways revealed a requirement for pyrimidine salvage in SARS-CoV-2 viral replication. Although both UCK1 and UCK2 catalyze the rate-limiting monophosphorylation of pyrimidines for pyrimidine salvage, we show that UCK2 is the major enzyme for cytoplasmic salvage of extracellular pyrimidines, functioning redundantly with de novo biosynthesis for RNA replication, and is thus dispensable for SARS-CoV-2 infection under conditions where de novo biosynthesis is active. In contrast, we find that UCK1 supports SARS-CoV-2 replication by specifically promoting nuclear cytidine triphosphate (CTP) synthesis for phosphatidylcholine (PC) biosynthesis, regulating peroxisomal lipid metabolism, and facilitating organelle interactions with double-membrane vesicles (DMVs), lipid structures required for SARS-CoV-2 RNA replication.
    Keywords:  DMV; Kennedy pathway; SARS-CoV-2; double-membrane vesicle; lipidomics; metabolism; nucleotide biosynthesis; peroxisomes; phosphatidylcholine; pyrimidine salvage
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.040
  32. Nat Rev Rheumatol. 2026 Jul 22.
    Hypoxia as an amplifier of synovial inflammation in rheumatoid arthritis.
    Mary Canavan, Orla Tynan, Jean Fletcher, Ursula Fearon.
      Inflammatory arthritis is characterized by neovascularization, leukocyte extravasation and synovial hyperplasia, leading to joint destruction and functional disability. Although increased synovial angiogenesis is a hallmark of synovial inflammation, efficiency of the oxygen supply to the synovium is poor, leading to a hypoxic gradient that impacts differential cellular responses. This hypoxic gradient occurs as infiltrating cells and cells that reside within the joint increase their metabolic demand beyond what the highly dysregulated vasculature can supply. This hypoxic environment favours an increase in reactive oxygen species, leading to oxidative damage that further promotes inflammation. In this adverse microenvironment, synovial cells adapt to generate energy and switch their cellular metabolism from a resting regulatory state to a highly metabolically active state, enabling them to produce essential building blocks to support their proliferation. This metabolic shift results in the accumulation of metabolic intermediates that function as signalling molecules, which further dictate the inflammatory response. However, the synovium is a complex multicellular tissue, and the specific cellular reliance on oxygen and metabolites differs across the synovium. Cellular demands depend on anatomical location, cell-cell interactions and competition for nutrients. Understanding the complex interplay between hypoxia-induced signalling pathways, oxidative stress and inflammatory responses will provide a better insight into the underlying mechanisms of disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41584-026-01397-z
  33. Toxicon. 2026 Jul 21. pii: S0041-0101(26)00244-8. [Epub ahead of print]282 109226
    Non-targeted metabolomics reveals the metabolic atlas of macrophages remodeled by SVPLA2 in Naja atra venom.
    Qian Li, Sitong Chen, Jiajia Wu, Sunkun Tang, Zejing Wen, Xinyi Han, Xiaowen Bi, Chunhong Huang, Jiahao Liu.
      Snake venom phospholipase A2 (SVPLA2) is a key toxic component of Naja atra (N. atra) venom, yet its systematic impact on macrophage metabolism remains elusive. Using non-targeted metabolomics, combined with multivariate statistics and KEGG pathway enrichment, this study delineated the metabolic reprogramming of RAW 264.7 macrophages induced by SVPLA2 in N. atra venom and assessed the reversal effects of the specific inhibitor varespladib. SVPLA2 was associated with a a triple metabolic phenotype in macrophages: massive production of histamine and arachidonic acid derivatives, activating inflammatory lipid pathways; marked elevation of acylcarnitines, indicating disturbed fatty acid β-oxidation; and coordinated downregulation of de novo pyrimidine synthesis intermediates, leading to nucleotide starvation. Varespladib intervention effectively reversed the elevation of these inflammatory mediators and acylcarnitines and partially restored uridine levels. KEGG analysis further confirmed the involvement of arachidonic acid metabolism, PPAR signaling, peroxisome, and pyrimidine metabolism pathways. This study expands the functional role of SVPLA2 from conventional membrane phospholipid hydrolysis to the regulation of the macrophage metabolic reprogramming associated with inflammatory, energy-related, and pyrimidine metabolic pathways, providing a new insight for understanding snake venom pathogenesis.
    Keywords:  Fatty acid oxidation; Macrophages; Metabolomics; Naja atra; SVPLA(2); Snake venom
    DOI:  https://doi.org/10.1016/j.toxicon.2026.109226
  34. iScience. 2026 Aug 21. 29(8): 116865
    Antiretroviral regimen and sex-specific metabolic heterogeneity in pediatric HIV.
    Chandre Herbert, Louise Kuhn, Nicole H Tobin, Fan Li, Renate Strehlau, Faeezah Patel, Tian Wang, Shuang Wang, Grace M Aldrovandi, Caroline T Tiemessen.
      Host metabolism is increasingly recognized as relevant in HIV remission and cure research yet remains understudied in children living with perinatally acquired human immunodeficiency virus (CLWH). The relation between clinical factors and plasma metabolic profiles, generated by untargeted ultra high-performance liquid chromatography/tandem mass spectrometry, of pre-pubescent, virally suppressed CLWH (n = 155) and uninfected controls (UCs, n = 155) was investigated. The specific antiretroviral treatment (ART) regimen dominated the plasma metabolic profile and significantly influenced metabolic sexual dimorphism in CLWH. Two CD4%-associated metabotypes among well-controlled CLWH on the same regimen suggested divergent, sub-clinical responses to ART. Phospholipids were most frequently able to predict HIV status independent of treatment regimen. Metabolic biomarkers are unlikely to reliably predict outcomes in CLWH across regimens, if not curated for ART-induced divergence. Thus, grouping of treated individuals in metabolic studies should be done with careful consideration for the ART regimen used.
    Keywords:  HIV cure; antiretroviral therapy; children living with HIV; metabolomics; metabotypes; mitochondria; perinatally acquired HIV; prepubescent; sexual dimorphism; virally suppressed
    DOI:  https://doi.org/10.1016/j.isci.2026.116865
  35. Cell Mol Neurobiol. 2026 Jul 20. pii: 118. [Epub ahead of print]46(1):
    Monomethyl Fumarate Modulates Iron Metabolism and Mitochondrial Function in Microglia with Implications for Multiple Sclerosis Progression.
    Justus Dann, Katharina Klöster, Ulas Ceylan, Neele Heitmann, Britta Eggers, Svitlana Rozanova, Martin Eisenacher, Katrin Marcus-Alic, Konstanze F Winklhofer, Ralf Gold, Simon Faissner.
      Fumaric acid esters have proven to be effective medications in relapsing-remitting multiple sclerosis with neuroprotective effects. In this study, we investigated the impact of fumaric acid esters on primary murine microglia in vitro compared to DMSO vehicle control. Monomethyl fumarate (MMF) increased MTT reduction in a dose-dependent manner, whereas dimethyl fumarate (DMF) exhibited a biphasic response with low concentrations enhancing MTT reduction and higher concentrations inducing toxicity. Notably, complementary analyses of cell number and cell death did not reveal differences between MMF-treated and control conditions, indicating that the increased MTT reduction reflects enhanced cellular metabolic activity rather than increased viability. Consistent with this interpretation, MMF-treated cells exhibited higher basal and maximal oxygen consumption, spare respiratory capacity, and ATP production in the Seahorse XF Cell Mito Stress Test. Proteomic analysis did not indicate an upregulation of mitochondrial respiratory chain proteins, but instead suggested a qualitative shift in mitochondrial homeostasis, including increased expression of mitophagy-associated proteins. MMF-treated Nrf2-deficient microglia showed a blunted increase in MTT reduction, suggesting an involvement of Nrf2 in mediating MMF-induced metabolic effects. Additionally, MMF modulated the microglial iron metabolism and reduced the uptake of non-transferrin-bound iron and altered the gene expression of iron transport proteins, promoting a shift toward the uptake of less toxic, transferrin-bound iron. MMF mitigated iron-induced toxicity and was associated with upregulation of the ferroptosis suppressor protein, indicating a protective response to iron overload. Together, these findings suggest that MMF enhances microglial metabolic activity and mitochondrial function while reducing iron-mediated toxicity, thereby contributing to its neuroprotective effects.
    Keywords:  Microglia; Mitochondria; Neuroinflammation; Neuroprotection; Progressive multiple sclerosis
    DOI:  https://doi.org/10.1007/s10571-026-01775-x
  36. Cancer Res. 2026 Jul 23. OF1-OF19
    Lactylation Orchestrates Immune Evasion in Gastric Cancer through KDM5B-Mediated Histone Demethylation.
    Wenqi Du, Lina Ding, Jing Zhu, Linfeng Li, Xingyue Wang, Yuxiang Zhang, Xiaojin Wu, Dongsheng Pei.
      Immune evasion driven by the tumor microenvironment is a major obstacle to effective immunotherapy in gastric cancer. To overcome this barrier, a detailed understanding of the mechanisms by which gastric cancer circumvents antitumor immunity is essential. In this study, we identified KDM5B as a pivotal epigenetic-metabolic orchestrator of immune evasion in gastric cancer. Clinically, KDM5B overexpression correlated with poor prognosis and diminished CD8+ T-cell infiltration. Mechanistically, KDM5B suppressed NLRP3-dependent pyroptosis via H3K4me3 demethylation and inhibited JAK1-STAT1/3-driven chemokine production. Crucially, a lactate-KDM5B feedforward loop facilitated immunosuppression, with KDM5B promoting lactate production and K868 lactylation enhancing KDM5B activity. Therapeutically, dual targeting of KDM5B and glycolysis overcame anti-PD-L1 resistance. Overall, these findings establish KDM5B as a central hub integrating epigenetic reprogramming, metabolic rewiring, and immunosuppression to drive progression and immune escape, positioning KDM5B as an actionable therapeutic target for reversing immunotherapy resistance in gastric cancer.
    SIGNIFICANCE: KDM5B regulates an epigenetic-metabolic axis of immune evasion in gastric cancer that can be targeted to overcome anti-PD-L1 resistance, providing an effective combination immunotherapeutic strategy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5071
  37. Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00471-5. [Epub ahead of print]
    The Legionella pneumophila effector SidL is an adenylyltransferase that modifies the glycolytic intermediate 3-phosphoglycerate.
    Joshua J Black, A Maxwell Burroughs, Edrees H Rashan, Charles R Nosal, Katerina A Romanov, Marco A Catipovic, Catherine Valadez, L Aravind, Kevin G Hicks, Caren L Freel Meyers, Tamara J O'Connor, Matthew G Vander Heiden, Rachel Green.
      The large effector arsenal of the bacterial pathogen Legionella pneumophila has been a rich source of biochemistry, highlighting the immense diversity of strategies deployed in host-pathogen conflict. Here, we redefine the purported translation inhibitor SidL as an adenylyltransferase that targets a glycolytic metabolite, discovering that it modifies 3-phosphoglycerate with adenosine monophosphate (AMP) to produce the previously unknown molecule 2-AMP-3-phosphoglycerate. When expressed alone in mammalian cells, SidL adenylates 3-phosphoglycerate, disrupts glycolysis, and blocks the nutrient-responsive translation regulator mTORC1, which we propose indirectly causes translation inhibition. Moreover, we observe SidL-dependent production of 2-AMP-3-phosphoglycerate in macrophages during L. pneumophila infection, the timing of which is consistent with a role for SidL in the early stages of the infection cycle. Thus, our study uncovers a mechanism by which an intracellular pathogen uses the chemical modification of a glycolytic intermediate to target central carbon metabolism in the host.
    Keywords:  3-phosphoglycerate; AMP; AMPylase; Adenylyltransferase; Ceg14; Legionella pneumophila; Lpg0437; MCF1-SHE; PAP2; SidL; SidL/Ceg14/Lpg0437; bacterial pathogenesis; glycolysis; mTOR
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.007
  38. Front Immunol. 2026 ;17 1784556
    Targeted lipid metabolism screening uncovers regulatory effects on the STING immune response in mevalonate, eicosanoid and fatty acid pathways.
    Sofia Skobelkina, Ella L Brunsting, Darren J Perkins.
      The cGAS/STING pathway is a critical signaling hub that orchestrates type I interferon (IFN) responses, autophagy, and programmed cell death in response to double-stranded DNA (dsDNA) or cyclic dinucleotides. While traditionally characterized as a sensor of foreign or mis-localized self dsDNA, recent evidence demonstrates that STING also integrates information about the homeostasis of cellular lipid biosynthesis into the innate inflammatory response. This integration occurs most notably through STING's sensitivity to de novo cholesterol synthesis. However, given that mammalian cells undergo widespread lipid metabolic reprogramming, characterized by alterations in the synthesis of many lipid species in addition to cholesterol, during processes such as malignant transformation to cancer or during infection by intracellular pathogens, we hypothesized that STING function may be regulated by perturbations in other undescribed lipid pathways. To investigate potential other facets of the STING-lipid interface, we have performed a targeted small molecule screen across multiple lipid metabolic pathways, including the mevalonate, PPAR (fatty acid), and arachidonic acid pathways. Our findings reveal that positively and negatively perturbing enzymes within these diverse lipid paths including lipoxygenases and cyclooxygenases can significantly modulate STING-dependent signal transduction and transcriptional programs, identifying metabolic nodes that link lipid homeostasis with innate immune signaling. These results suggest that existing lipid-lowering and metabolic therapies may have unappreciated immunomodulatory effects on STING applicable in cancer and infectious disease, offering new opportunities for therapeutic intervention.
    Keywords:  5-lipoxygenase; PPAR gamma; STING; arachidonic acid; cholesterol; lipid; rosiglitazone
    DOI:  https://doi.org/10.3389/fimmu.2026.1784556
  39. Exp Hematol. 2026 Jul 22. pii: S0301-472X(26)00118-9. [Epub ahead of print] 105485
    Reassessment of Hematopoietic Stem Cell Aging through Metabolic Uncoupling and Mitochondrial Resilience.
    Chong Yang, Keiyo Takubo, Toshio Suda.
      Hematopoietic stem cell (HSC) aging is often described as a gradual loss of stem cell fitness that culminates in impaired blood production, immune dysfunction, and increased susceptibility to hematologic disease. However, recent work suggests that this view is too simple. Rather than a uniform decline, aging appears to remodel the HSC compartment into metabolically and functionally distinct states, including maladaptive trajectories as well as surprisingly resilient subsets. In this review, we argue that HSC aging is best understood through the interplay of mitochondrial regulation, metabolic uncoupling, and niche-derived stress, with particular emphasis on how recent findings revise several longstanding assumptions in the field (Box 1).
    Keywords:  HSC aging; Hematopoietic resilience; Metabolic uncoupling; Mitochondrial metabolism; Niche
    DOI:  https://doi.org/10.1016/j.exphem.2026.105485
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