bims-imicid 2025-08-31 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–08–31
33 papers selected by
Dylan Ryan, University of Cambridge

Mitochondria and lysosomes in T cell immunometabolism.
Targeting pyruvate metabolism generates distinct CD8+ T cell responses to gammaherpesvirus and B lymphoma.
The effects of microbiota-derived short-chain fatty acids on T lymphocytes: From autoimmune diseases to cancer.
Immunomodulatory effects of phthiocol: An aryl hydrocarbon receptor ligand regulating conventional dendritic cells and macrophages to alleviate sepsis and lupus severity.
Immune mitochondrial complex I mediates vascular damage in toll-like receptor 7 (TLR7)-induced lupus.
Bacterial membrane vesicles of Pseudomonas aeruginosa activate adenosine monophosphate-activated protein kinase signaling through inhibition of mitochondrial complex III.
Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism.
Innate Immunity Reimagined: Metabolic Reprogramming as a Gateway to Novel Therapeutics.
PKM2's Dual Role in Periodontitis: Regulating Inflammation and Bone Metabolism Imbalance.
Microglial metabolic reprogramming: Aucubin inhibits aldose reductase to reverse diabetic neuropathic pain.
NAD+ Metabolism-Mediated SURF4-STING Axis Enhances T-Cell Anti-Tumor Effects in the Ovarian Cancer Microenvironment.
Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β-mediated inflammation in mice and humans.
Single cell autofluorescence imaging reveals immediate metabolic shifts of neutrophils with activation across biological systems.
Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis.
Reprogramming CAR-T cells: Targeting SLC transporters for tumor microenvironment adaptation.
Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment.
Lactate metabolic reprogramming and histone lactylation modification in sepsis.
Transient Nutrient Sensing Shapes T Cell Exhaustion.
Application of Multiplatform Mass Spectrometry to the Study of Babesia divergens Metabolism and the Pathogenesis of Human Babesiosis.
CpG-oligodeoxynucleotides challenged macrophages ameliorate acetaminophen induced liver injury by activating TLR9/IRG1/itaconate metabolic pathway.
NMR-Based Clinical Metabolomics Reveals Distinctive Metabolic Signatures in Systemic Sclerosis and Systemic Lupus Erythematosus.
Slc7a5 promotes T cell anti-tumor immunity through sustaining cytotoxic T lymphocyte effector function.
ACLY promotes NK cell effector function by regulating glycolysis and histone acetylation.
Targeting spermine metabolism to overcome immunotherapy resistance in pancreatic cancer.
Mechanisms and therapeutic perspectives of mitochondrial dysfunction of macrophages in periodontitis.
High fructose consumption aggravates inflammation by promoting effector T cell generation via inducing metabolic reprogramming.
Hexanoic Acid Intake Enhances Anti-Tumor Immune Responses in Colorectal Cancer by Reducing the Immunosuppressive Function of Tregs.
Helicobacter hepaticus promotes hepatic steatosis through CdtB-induced mitochondrial stress and lipid metabolism reprogramming.
Adenosine deprivation modulates purine metabolism and enhances Trichomonas vaginalis cytotoxicity.
Multi-omics insights into the metabolic reprogramming of host cells triggered by Entamoeba histolytica Gal/GalNAc lectin intermediate subunit.
Systemic inflammation-induced adipose tissue remodeling drives psoriasis exacerbation in obesity through epigenetic and immunometabolic dysregulation.
Histone H3 lysine 18 lactylation attenuates neuroinflammation and neurological damage by regulating microglial plxnb2 after ischemic stroke.
Metabolism-dependent succinylation governs resource allocation for antibiotic resistance.

Trends Immunol. 2025 Aug 22. pii: S1471-4906(25)00181-4. [Epub ahead of print]

Mitochondria and lysosomes in T cell immunometabolism.

Erienne G Norton, Nicole M Chapman, Hongbo Chi.

  Metabolic reprogramming and signaling are key orchestrators of T cell immunity. Recent studies have illustrated important roles for intracellular organelles, especially mitochondria and lysosomes, in enforcing T cell metabolism and signaling in response to various extracellular cues. As such, mitochondrial and lysosomal function contributes to adaptive immunity by regulating T cell activation, differentiation, and functional adaptation. In this Review, we discuss how the interplay between organelle biology and metabolism instructs T cell-mediated immunity, with a particular focus on mitochondria and lysosomes. We also summarize how mitochondria and lysosomes, or their crosstalk with other organelles, orchestrate downstream signaling processes and functional reprogramming of T cells. We conclude with a discussion of the pathophysiological outcomes associated with dysregulation of these organelles.

Keywords:  T cells; immunometabolism; lysosomes; metabolic signaling; mitochondria; organelle crosstalk

DOI:  https://doi.org/10.1016/j.it.2025.07.014
JCI Insight. 2025 Aug 22. pii: e187680. [Epub ahead of print]10(16):

Targeting pyruvate metabolism generates distinct CD8+ T cell responses to gammaherpesvirus and B lymphoma.

Taewook Kang, Young-Kwang Usherwood, Julie A Reisz, Sukrut C Kamerkar, Rachel Culp-Hill, Owen M Wilkins, Andreia F Verissimo, Fred W Kolling, Anton M Hung, Shawn C Musial, Pamela C Rosato, Angelo D'Alessandro, Henry N Higgs, Edward J Usherwood.

  T cells rely on different metabolic pathways to differentiate into effector or memory cells, and metabolic intervention is a promising strategy to optimize T cell function for immunotherapy. Pyruvate dehydrogenase (PDH) is a nexus between glycolytic and mitochondrial metabolism, regulating pyruvate conversion to either lactate or acetyl-CoA. Here, we retrovirally transduced pyruvate dehydrogenase kinase 1 (PDK1) or pyruvate dehydrogenase phosphatase 1 (PDP1), which control PDH activity, into CD8+ T cells to test effects on T cell function. Although PDK1 and PDP1 were expected to influence PDH in opposing directions, by several criteria they induced similar changes relative to control T cells. Seahorse metabolic flux assays showed both groups exhibited increased glycolysis and oxidative phosphorylation. Both groups had improved primary and memory recall responses following infection with murine gammaherpesvirus-68. However, metabolomics using labeled fuels indicated differential usage of key fuels by metabolic pathways. Importantly, CD8+ T cell populations after B cell lymphoma challenge were smaller in both groups, resulting in poorer protection, which was rescued by glutamine and acetate supplementation. Overall, this study indicates that PDK1 and PDP1 both enhance metabolic capacity, but the context of the antigenic challenge significantly influences the consequences for T cell function.

Keywords:  Adaptive immunity; Immunology; Immunotherapy; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.187680
Semin Oncol. 2025 Aug 19. pii: S0093-7754(25)00090-9. [Epub ahead of print]52(5): 152398

The effects of microbiota-derived short-chain fatty acids on T lymphocytes: From autoimmune diseases to cancer.

Mohamed J Saadh, Omer Qutaiba B Allela, Suhas Ballal, Morug Salih Mahdi, Mamata Chahar, Rajni Verma, Rouaida Kadhim A Al-Hussein, Mohaned Adil, Mahmood Jasem Jawad, Ali M Ali Al-Nuaimi.

  Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are the microbial metabolites that have significant functions in host immune modulation, especially T lymphocyte function. Implication by recent evidence indicates SCFAs regulate T-cell growth, differentiation, metabolism, effector function, and apoptosis through histone deacetylase (HDAC) inhibition, G-protein-coupled receptor (GPCR) signaling, and metabolic reprogramming processes. Butyrate, for example, enhances regulatory T cell (Treg) and Interleukin 10 (IL-10)-producing T helper 1 (Th1) cell differentiation as well as context-dependent regulation on T helper 17 (Th17) cell development. SCFAs also impact cytotoxic CD8+ T cells through augmented production of IFN-γ and memory formation, which enhances antiviral and antitumor immunity. SCFAs reprogram T-cell metabolism through enhanced acetyl-CoA, mechanistic target of rapamycin (mTOR) signaling, and fatty acid oxidation (FAO), thus promoting the unique metabolic requirements of effector and memory T-cell subsets. In addition, SCFAs induce apoptosis of activated T cells through the Fas upregulation by inhibiting HDAC1. SCFA dysregulation plays a role in disease and autoimmune disorders like type 1 diabetes and rheumatoid arthritis, whereas therapeutic supplementation reduces inflammation and immune tolerance. SCFAs also amplify the antitumor effect of immune checkpoint inhibitors (eg, anti-programmed cell death protein 1 (anti-PD-1)) in cancer by driving CD8+ T-cell activation, infiltration, and Interferon gamma (IFNγ) production, partially through the transcriptional regulator Inhibitor of DNA binding 2 (ID2). Significantly, tissue- and disease-specific differential expression and functional implication of SCFA receptors (eg, GPR43, GPR41, GPR109A) emphasize the complexity of SCFA-mediated signaling. In conclusion, the current review emphasizes the multifunctional role of microbiota-derived SCFAs in T lymphocyte biology and their therapeutic potential in cancer, infection, and autoimmune diseases.

Keywords:  Autoimmune diseases; Cancer; Immunomodulation; SCFAs; Th1; Th17; Tregs

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152398
Biomed Pharmacother. 2025 Aug 20. pii: S0753-3322(25)00669-9. [Epub ahead of print]191 118475

Immunomodulatory effects of phthiocol: An aryl hydrocarbon receptor ligand regulating conventional dendritic cells and macrophages to alleviate sepsis and lupus severity.

Areerat Kunanopparat, Warerat Kaewduangduen, Promchat Chareanpat, Asada Leelahavanichkul, Amanee Samaeng, Chonlada Chaiwichit, Nattakan Ariyaraphong, Tanapat Palaga, Patcharee Ritprajak.

  Excessive inflammation in sepsis and systemic lupus erythematosus (SLE) is driven by immune dysregulation involving conventional dendritic cells (cDCs), which regulate adaptive immunity, and macrophages, which mediate inflammation and tissue repair. The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating these innate immune cells, suggesting that targeting AhR is a promising strategy to mitigate hyperinflammation in sepsis and SLE. In this study, we demonstrate that phthiocol, a vitamin K analog and AhR ligand, ameliorates hyperinflammation and improves outcomes in both cecal ligation and puncture (CLP)-induced sepsis and Fcgr2b-/- lupus mouse models. Phthiocol-treated bone-marrow-derived dendritic cells (BM-cDCs) displayed a tolerogenic-like phenotype with increased IL-10 and CD206 expression, and promoted regulatory T cell (Treg) proliferation and IL-10 production, while suppressing IL-17-producing T cell responses. Phthiocol induced M2-like polarization in bone-marrow-derived macrophages (BMMs) with high IL-10 production, in contrast to other AhR ligands, including 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 6-Formylindolo[3,2-b]carbazole (FICZ) that induced M1 polarization. Chromatin immunoprecipitation confirmed AhR binding to the Il10 promoter, revealing direct transcriptional regulation. Furthermore, phthiocol reprogrammed macrophage metabolism by enhancing oxidative phosphorylation and suppressing glycolysis. These immunoregulatory and metabolic effects were abrogated by an AhR antagonist, confirming AhR dependency. Notably, phthiocol exerted similar immunoregulatory effects in activated human monocyte-derived dendritic cells and macrophages, indicating translational potential. Together, these findings position phthiocol as a selective AhR ligand with therapeutic promise for controlling inflammation and restoring immune homeostasis in inflammatory diseases.

Keywords:  Aryl hydrocarbon receptor; Conventional dendritic cells; Immunomodulation; Lupus; Macrophage polarization; Phthiocol; Sepsis

DOI:  https://doi.org/10.1016/j.biopha.2025.118475
Pharmacol Res. 2025 Aug 25. pii: S1043-6618(25)00335-4. [Epub ahead of print]220 107910

Immune mitochondrial complex I mediates vascular damage in toll-like receptor 7 (TLR7)-induced lupus.

Sofía Miñano, Javier Moleón, Cristina González-Correa, Iñaki Robles-Vera, Manuel Gómez-Guzmán, Manuel Sánchez, Semih Bayraktar, Néstor de la Visitación, Natividad Martín-Morales, Francisco O'Valle, Miguel Romero, David Sancho, Marta Toral, Juan Duarte.

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and high cardiovascular risk, including hypertension and endothelial dysfunction. Metabolic reprogramming of immune cells, particularly CD4 + T cells, contributes to SLE pathogenesis. We investigated the role of mitochondrial metabolism, specifically the NDUFS4 subunit of complex I, in immune cells during lupus induced by toll-like receptor (TLR)7 activation with imiquimod (IMQ). We analyzed transcriptomic data from peripheral blood mononuclear cells obtained from SLE patients and their matched healthy controls showing that dendritic cells and undetermined cells exhibited the highest mean expression levels of NDUFS4. Using bone marrow chimeric mice, we demonstrate that NDUFS4 deficiency in hematopoietic cells prevents IMQ-induced hypertension, reduces autoantibody production, and limits vascular oxidative stress, inflammation, and kidney injury. These effects are associated with a shift in CD4 + T cell polarization toward regulatory T cells and a reduction in Th1 and Th17 subsets in the spleen and blood. Pharmacological dual inhibition of glycolysis with 2-deoxy-D-glucose and mitochondrial metabolism with metformin further supports the therapeutic potential of metabolic targeting, improving vascular function and preventing aortic remodeling, characterized by proteoglycan and collagen accumulation, increased aortic stiffness, and secretory and profibrotic phenotypes. These interventions reduce oxidative stress and immune cell infiltration in the vascular wall, mitigating endothelial dysfunction and the shift to a synthetic phenotype. Our findings highlight mitochondrial complex I as a critical modulator of immune-mediated vascular damage in lupus induced by TLR7 activation and propose metabolic reprogramming as a promising therapeutic strategy for lupus-associated cardiovascular complications.

Keywords:  Endothelial dysfunction; Hypertension; Immune system; Mitochondrial metabolism; Oxidative stress; Systemic lupus erythematosus; TLR7 activation

DOI:  https://doi.org/10.1016/j.phrs.2025.107910
PNAS Nexus. 2025 Aug;4(8): pgaf248

Bacterial membrane vesicles of Pseudomonas aeruginosa activate adenosine monophosphate-activated protein kinase signaling through inhibition of mitochondrial complex III.

Julia Müller, Marcel Kretschmer, Elise Opitsch, Svea Holland, José Manuel Borrero-de Acuña, Dieter Jahn, Meina Neumann-Schaal, Andre Wegner.

  Bacterial membrane vesicles (BMVs) are secreted by many pathogenic bacteria and known to stimulate various host responses upon infection, thereby contributing to the pathogenicity of bacterial pathogens like Pseudomonas aeruginosa. While the effects of BMVs on host immune responses are well studied, little is known about their impact on cell metabolism and mitochondrial respiration. Here, we show that P. aeruginosa BMVs (i) reprogram cell metabolism of human lung cells, (ii) negatively affect mitochondrial respiration by (iii) specifically inhibiting complex III of the electron transport chain, leading to (iv) the activation of adenosine monophosphate-activated protein kinase (AMPK) signaling, which in turn results in (v) AMPK-dependent inhibition of global protein synthesis.

Keywords:  AMPK; Pseudomonas aeruginosa; bacterial membrane vesicles (BMVs); electron transport chain; metabolism

DOI:  https://doi.org/10.1093/pnasnexus/pgaf248
Cell Rep. 2025 Aug 25. pii: S2211-1247(25)00948-9. [Epub ahead of print]44(9): 116177

Nrf2 drives activation-driven expansion of CD4+T cells by modulating glucose and glutamine metabolism.

Aprajita Tripathi, Debolina Dasgupta, Michael S Dahabieh, Rachel Griffard-Smith, Anil Pant, Ashlyn Bugbee, Nanda Kumar Yellapu, Emily Burt, Ben H Y Choi, Abigail E Ellis, Ryan D Sheldon, Shailendra Giri, Devin Koestler, Russell G Jones, Viveka Nand Yadav, Kalyani Pyaram.

  Upon antigenic stimulation, CD4+T cells undergo clonal expansion elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid-2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T cells remains unexplored. We report that Nrf2 protein levels are temporally regulated in activated CD4+T cells, with elevated expression during early activation followed by a decline. T cell-specific constitutive activation of Nrf2, by deletion of its negative regulator Keap1, enhances early activation and interleukin-2 (IL-2) expression, upregulates T cell receptor (TCR) signaling, and increases activation-driven expansion of CD4+T cells. Mechanistically, elevated Nrf2 activity in activated CD4+T cells increases chromatin accessibility and proliferation-associated gene expression. Metabolically, high Nrf2 alters glucose metabolism and promotes glutamine metabolism via glutaminolysis to support CD4+T cell hyperproliferation. In summary, we elucidate the role of Nrf2 beyond traditional antioxidation in modulating the activation-driven expansion of CD4+T cells by influencing their nutrient metabolism and gene expression.

Keywords:  CP: Immunology; CP: Metabolism; T cell activation; T cell expansion; adaptive immune cells; antioxidation; immunometabolism

DOI:  https://doi.org/10.1016/j.celrep.2025.116177
Int J Biol Sci. 2025 ;21(11): 5056-5078

Innate Immunity Reimagined: Metabolic Reprogramming as a Gateway to Novel Therapeutics.

Chuan-Han Deng, Chen-Tong Wang, Xin Zhou, Xin Chen, Ying Wang.

  The interplay between cellular metabolism and innate immunity critically shapes the body's ability to fight infections, repair tissue, and manage stress. Metabolic reprogramming not only drives innate immune activation but also regulates the resolution of inflammation. Phenotypes of immune cell are closely linked to metabolic shifts that adapt to varying energy demands. However, the precise relationship between perturbations in the cellular respiratory-metabolic axis and the inflammatory response remains a critical field of investigation. In depth understanding of key metabolic pathways, such as glycolysis, NADPH oxidase activity, mitochondrial ROS production, TCA cycle metabolites, and cGAS-STING/AIM2 inflammasome activation, is essential to unravel the complexities of innate immunity. This article highlights the central role of metabolic reprogramming mainly in innate immunity and explores its potential as a therapeutic target for modulating inflammatory response.

Keywords:  cellular respiration; inflammation; innate immune response; metabolism programming; mitochondria

DOI:  https://doi.org/10.7150/ijbs.114010
Oral Dis. 2025 Aug 24.

PKM2's Dual Role in Periodontitis: Regulating Inflammation and Bone Metabolism Imbalance.

Han Gao.

   OBJECTIVE: Given the recognized importance of pyruvate kinase M2 isoform (PKM2) in immunometabolism and periodontitis, yet a lack of synthesis on its dual metabolic and non-metabolic functions across key periodontal cell types, this short review aims to explore the central mechanisms by which PKM2 drives sustained inflammation and bone metabolic imbalance. It examines its role as a molecular hub linking "metabolism-immune-bone destruction" to provide insights into disease mechanisms and targeted therapies.
SUBJECTS AND METHODS: The review integrates recent advances in immunometabolism and periodontitis research. Through comprehensive analysis of PKM2's dual "metabolic and non-metabolic" roles in macrophage polarization, T-cell subset regulation, neutrophil function, and bone metabolism, its molecular network mediating host immune dysregulation and tissue destruction is revealed.
RESULTS: PKM2 activates glycolysis to promote M1 macrophage polarization and enhance pro-inflammatory cytokine release. PKM2 induces T-cell subset imbalance (Th17/Treg dysregulation), exacerbating inflammatory responses. PKM2 mediates neutrophil oxidative stress damage, amplifying local tissue destruction. PKM2 drives alveolar bone resorption by regulating osteoclast differentiation and osteoblast dysfunction.
CONCLUSION: As a core hub connecting microbial dysbiosis, host metabolic reprogramming, and pathological outcomes, PKM2's dual functional properties offer a novel therapeutic target for periodontitis beyond conventional antimicrobial/anti-inflammatory strategies. Targeting PKM2 or its downstream metabolic-immune crosstalk may represent a breakthrough for halting disease progression.

Keywords:  glycolysis; metabolic reprogramming; periodontitis; pyruvate kinase M2 (PKM2)

DOI:  https://doi.org/10.1111/odi.70075
World J Diabetes. 2025 Aug 15. 16(8): 110285

Microglial metabolic reprogramming: Aucubin inhibits aldose reductase to reverse diabetic neuropathic pain.

Bin Li.

  This letter critically comments on the article by Zheng et al investigating the role of aucubin in alleviating diabetic neuropathic pain (DNP). DNP arises from hyperglycaemia-induced nerve injury and microglial reprogramming toward aerobic glycolysis. Aldose reductase (also known as AKR1B1) redirects excess glucose flux through the polyol pathway, thus increasing oxidative stress and inflammation. Zheng et al show that aucubin, a plant iridoid glycoside, reverses streptozotocin-induced mechanical and thermal hypersensitivity and anxiety-like behaviour in mice. Mechanistically, aucubin restores microglial morphology, reduces glycolytic flux, enhances oxidative phosphorylation and lowers tumour necrosis factor-α, interleukin (IL)-1β and IL-6 levels in spinal tissue and cultures of the BV-2 microglial cell line. Network pharmacology and molecular docking analyses identify AKR1B1 as a key target, confirmed by the fact that short hairpin RNA knockdown of AKR1B1 eliminates the effects of aucubin. Contrary to the other studies, this study uniquely implicates the polyol pathway in microglial immunometabolism.

Keywords:  Aldose reductase; Diabetic neuropathic pain; Metabolism; Microglia; Neuroinflammation

DOI:  https://doi.org/10.4239/wjd.v16.i8.110285
Cell Death Dis. 2025 Aug 23. 16(1): 640

NAD+ Metabolism-Mediated SURF4-STING Axis Enhances T-Cell Anti-Tumor Effects in the Ovarian Cancer Microenvironment.

Jiacheng Shen, Fangfang Xu, Tingwei Liu, Yingjun Ye, Shaohua Xu.

The anti-tumor function of T cells in the ovarian cancer (OC) microenvironment influences the prognosis of OC. Previous studies have indicated that metabolic competition among microenvironmental cells regulates the function of immune cells. Recent research has shown that NAD+ metabolism plays a significant role in modulating immune cell activity, and increasing NAD+ levels is a promising therapeutic strategy to enhance the effector functions of immune cells. However, the regulatory mechanisms of NAD+ metabolism on the anti-tumor function of T cells in the OC microenvironment remain unclear. This study found that exogenous supplementation of NAM to increase NAD+ levels in T cells significantly activates the endogenous p-STING axis and downstream interferon signaling within T cells, thereby enhancing T cell activation and anti-tumor effects. Concurrently, we discovered that elevated NAD+ levels promote the retention of STING on the Golgi apparatus. Mechanistically, we elucidated that the increase in NAD+ levels mediated by NAM downregulates the expression of SURF4 protein through ubiquitination and degradation, subsequently activating the p-STING axis in T cells. Furthermore, exogenous NAM supplementation can further enhance the activation of the T cell STING axis by PARP inhibitor (PARPi)-treated OC cells, and the combination of PARPi and NAM significantly augments the anti-tumor function of T cells, inhibiting the progression of OC. Our findings provide a molecular basis for the regulation of T cell anti-tumor function by NAD+, highlighting the potential strategy of targeting T cell metabolic reprogramming for the treatment of OC.

DOI: https://doi.org/10.1038/s41419-025-07939-9
Sci Transl Med. 2025 Aug 27. 17(813): eadp5653

Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β-mediated inflammation in mice and humans.

Sam J McCright, Olivia Harding, Julia Chini, Nicole DeMarco, Li-Yin Hung, Christopher F Pastore, Wenyun Lu, Joshua Rabinowitz, Jorge Henao-Mejia, De'Broski R Herbert, Lisa R Young, David A Hill.

Resident tissue macrophages and monocytes (RTMs) integrate local and systemic signals to coordinate immune cell function at homeostasis and in response to inflammatory stimuli. Obesity-associated metabolic dysfunction drives the development of RTM populations that contribute to disease states in multiple tissues. However, the contribution of specific dietary components to innate immune cell activation and function, as opposed to the direct effects of obesity, is largely unknown. Here, we studied the mechanisms by which high-fat (HF) diets shape lung RTM phenotype and function at steady state and influence responses to inflammatory insults. We found that, during HF diet feeding, lung RTMs accumulate saturated long-chain fatty acids, specifically stearic acid (SA), and demonstrate features of NLRP3 inflammasome priming and activation. In vivo, increased dietary SA was sufficient to cause neutrophil-predominant lung inflammation in the steady state and exacerbate a model of innate airway inflammation, whereas increased dietary oleic acid, the monounsaturated counterpart of SA, was sufficient to reduce inflammasome activation in the steady state and attenuate airway inflammation. Depletion of interleukin-1β (IL-1β) or pharmacologic inhibition of the endonuclease inositol requiring enzyme 1α (IRE1α) protected against SA-induced exacerbated lung inflammation. Last, we identified a population of lung monocytes with hallmarks of HF diet-induced RTM activation that were present in samples from obese humans with asthma. Together, these results identify a class of dietary lipids that regulate lung RTM phenotype and function in the steady state and modulate the severity of inflammation in the lung.

DOI: https://doi.org/10.1126/scitranslmed.adp5653
Front Immunol. 2025 ;16 1617993

Single cell autofluorescence imaging reveals immediate metabolic shifts of neutrophils with activation across biological systems.

Rupsa Datta, Veronika Miskolci, Gina M Gallego-López, Emily Britt, Amani Gillette, Aleksandr Kralovec, Morgan A Giese, Tongcheng Qian, James Votava, Wenxuan Zhao, Jing Fan, Anna Huttenlocher, Melissa C Skala.

   Introduction: Neutrophils are critical innate immune cells that heterogeneously respond to infection and inflammation by performing functions such as oxidative burst and NETosis, which require significant metabolic adaptation. Deeper insights into the single cell diversity of such metabolic changes will help identify regulation of neutrophil functions in health and diseases. Due to their short lifespan and associated technical challenges, the early metabolic processes of neutrophil activation are not completely understood. New tools are needed to measure rapid changes in neutrophil metabolism on a single cell level.
Methods: To address this, we use optical metabolic imaging (OMI), which entails optical redox ratio and fluorescence lifetime imaging microscopy of intrinsic metabolic coenzymes NAD(P)H and FAD to assess the metabolic state of single neutrophils. Primary human neutrophils were imaged in vitro under a variety of activation conditions and metabolic pathway inhibitors, while metabolic and functional changes were confirmed with mass spectrometry, oxidative burst, and NETosis measurements.
Results: Our findings show rapid metabolic remodeling to a reduced redox state during activation. Additionally, heterogeneous metabolic response to pathogens (Pseudomonas aeruginosa and Toxoplasma gondii) was observed across neutrophils and human donors. Finally, consistent OMI changes with activation were confirmed between in vitro human and in vivo zebrafish larvae neutrophils. This study demonstrates the potential of OMI as a versatile tool for studying neutrophil metabolism and underscores its use across different biological systems, offering insights into neutrophil metabolic activity and function at a single cell level.
Conclusion: This work addresses the critical need for advanced single-cell tools to monitor rapid and diverse metabolic changes in neutrophils, an underexplored area with significant implications for understanding immune responses and developing therapies for inflammatory diseases. Neutrophils, the body's first responders to infection and inflammation, undergo rapid metabolic changes upon activation. Using label-free optical metabolic imaging of intrinsic metabolic coenzymes NAD(P)H and FAD, we reveal distinct metabolic signatures in activated primary human neutrophils as well as neutrophils in live zebrafish larvae. Our findings highlight how pathogens and pharmacological stimuli heterogeneously rewire neutrophil metabolism within minutes, influencing immune responses. This noninvasive method offers insights into single-cell neutrophil metabolism immediately following activation, with implications for infection, inflammation, and immune disorders.

Keywords:  fluorescence lifetime imaging microscopy (FLIM); label-free; metabolism; neutrophil; optical metabolic imaging; single-cell

DOI:  https://doi.org/10.3389/fimmu.2025.1617993
Sci Adv. 2025 Aug 29. 11(35): eadw9952

Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis.

Laura Boccuni, Frieda Marka, Manuel Salzmann, Alessia Schirripa, Elisabeth Ableitner, Magdalena Siller, Mira Brekalo, Patrick Haider, Stefan Stojkovic, Christoph Neumayer, Tiit Örd, Karoline Kollmann, Alice Assinger, Thomas Decker, Thomas Köcher, Michael B Fischer, Marion Mußbacher, Andreas Bergthaler, Christian Hengstenberg, Bruno K Podesser, Minna U Kaikkonen, Johann Wojta, Philipp J Hohensinner.

Macrophage-to-foam cell transition is an integral part of atherosclerotic plaque progression. Particularly, oxidized low-density lipoprotein (oxLDL) is a driving factor in foam cell formation, altering macrophage function and metabolism. The aim of our research was to understand the impact of oxLDL-induced mitochondrial reactive oxygen species on macrophage-to-foam cell differentiation. We demonstrate that macrophage oxLDL-derived superoxide modulates mitochondrial metabolic reprogramming, facilitating foam cell formation. Mechanistically, mitochondrial superoxide drives signal transducers and activators of transcription 5 (STAT5) activation, leading to reduced tricarboxylic acid cycle activity. In parallel, mitochondrial superoxide enhances chromatin accessibility at STAT5 target genes, establishing a distinct STAT5 signaling signature in foam cells ex vivo and in human and mouse plaques in vivo. Inhibition of STAT5 during atherosclerosis progression prevents the differentiation of macrophages to mature Trem2hiGpnmbhi foam cells. Collectively, our data describe an oxLDL-induced, mitochondrial superoxide-dependent STAT5 activation that leads to a self-amplifying feedback loop of reciprocal mitochondrial superoxide production and STAT5 activation, ultimately driving macrophage-to-foam cell transition.

DOI: https://doi.org/10.1126/sciadv.adw9952
Pharmacol Res. 2025 Aug 21. pii: S1043-6618(25)00353-6. [Epub ahead of print]220 107928

Reprogramming CAR-T cells: Targeting SLC transporters for tumor microenvironment adaptation.

Beatriz Perucha, Maialen Martinez-Tabar, Inés Sanchez-Moreno, Pedro Justicia, Teresa Lozano, Juan José Lasarte.

  T cell activation, triggered by antigen recognition via the T cell receptor, initiates crucial physiological changes necessary for proliferation and survival. This process encompasses epigenetic modifications that open chromatin for transcription factor binding, transcriptomic shifts activating key genes, and structural adaptations, including increased cell size and cytoskeletal changes. Activated T cells experience heightened metabolic demands, requiring efficient nutrient uptake primarily via Solute Carrier (SLC) transporters. These transporters, regulated by transcription factors such as c-Myc, HIF-1α, NF-κB, and mTORC1, optimize nutrient acquisition to support glycolysis and macromolecule synthesis. In the tumor microenvironment, however, aberrant tumor metabolism depletes nutrients and produces metabolites that impair T cell function and reduce the efficacy of adoptive cell therapies, which are not metabolically adapted to survive in such hostile conditions. Modulating SLC transporters presents a promising strategy to enhance chimeric antigen receptor T cell (CAR-T) effectiveness by improving their persistence and antitumor activity. Personalized approaches targeting SLC transporters, tailored to the metabolic profiles of specific tumor types, are crucial for maximizing the therapeutic potential of adoptive T cell therapies. This review explores the critical role of SLC transporters in CAR-T cell functionality and discusses strategies to optimize their expression and activity within the challenging TME.

Keywords:  CAR-T cells; Immunotherapy; Solid tumors; Solute carrier transporters; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.phrs.2025.107928
Nat Metab. 2025 Aug 22.

Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment.

Nannan Xu, Yemin Zhu, Yichao Han, Qi Liu, Lingfeng Tong, Yakui Li, Zhangbing Chen, Sijia Shao, Wenrui He, Mingrui Li, Yi Wang, Siyuan Qiang, Peiwei Chai, Peng Du, Wenyi Zhao, Lifang Wu, Ping Zhang, Jianli He, Hecheng Li, Jinke Cheng, Renbing Jia, Bin Li, Ying Lu, Xuemei Tong.

In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg cells, loss of MondoA enhanced CD8+ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA-TXNIP axis, which impaired TCR/CD28-signal-induced CD8+ T cell activation. Importantly, targeting the MondoA-TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA-TXNIP axis is a promising therapeutic target for improving cancer immunotherapy.

DOI: https://doi.org/10.1038/s42255-025-01347-1
Int J Biol Sci. 2025 ;21(11): 5034-5055

Lactate metabolic reprogramming and histone lactylation modification in sepsis.

Ji Zhang, Dan Wu, Fu Zeng, Haiyun Gu, Chengbao Li, Juan P Cata, Kefang Guo, Changhong Miao, Hao Zhang.

  Sepsis, a serious condition characterized by life-threatening organ dysfunction owing to infection, lacks specific therapeutic interventions. Lactate serves as a crucial biomarker in sepsis, reflecting both the patient's metabolic state and the severity of the condition. Lactylation, the process whereby lactate is conjugated to lysine residues in proteins, profoundly alters protein structure and function. This review delves into the crucial roles of lactate and lactylation within the septic environment, illuminating the intricate feedback loop between metabolic reprogramming and lactylation in sepsis. Herein, fluctuations in lactate levels influence patterns of lactylation, which subsequently regulate energy metabolism. Lactylation is essential for modulating immune responses, adjusting gene expression profiles in immune cells, and shifting the balance between pro-inflammatory and anti-inflammatory pathways. The discovery of these pathways has significant implications for development of targeted therapies against sepsis. Furthermore, this review addresses the advancements and current limitations associated with lactylation research methodologies, and proposes new directions for future research. Overall, this narrative underscores the transformative potential of lactylation in understanding and managing sepsis, advocating for a multidisciplinary approach to unravel the complex interplay between metabolic processes and epigenetic regulation in critical illnesses.

Keywords:  inflammation; lactylation; sepsis; therapeutic targets

DOI:  https://doi.org/10.7150/ijbs.116088
Cancer Res. 2025 Aug 21.

Transient Nutrient Sensing Shapes T Cell Exhaustion.

Julian J Lum.

The fate of CD8⁺ T cells is sculpted not only by antigenic stimulation and cytokine milieu but, increasingly, by metabolic context. In their recent Nature Immunology study, Sharma and colleagues report a previously underappreciated and temporally constrained nutrient-sensing mechanism where methionine (Met) availability during the earliest minutes of T cell receptor (TCR) engagement exerts durable control over T cell function, exhaustion, and anti-tumor efficacy. Their findings expose a critical metabolic window, within just 30 minutes of activation, during which extracellular Met shapes intracellular signaling and transcriptional fate decisions through a post-translational mechanism involving arginine methylation of the calcium-activated potassium channel KCa3.1. These findings open the door to timed interventions that modulate methionine and potentially enhance T cell responses.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3656
Int J Mol Sci. 2025 Aug 08. pii: 7677. [Epub ahead of print]26(16):

Application of Multiplatform Mass Spectrometry to the Study of Babesia divergens Metabolism and the Pathogenesis of Human Babesiosis.

Miguel Fernández-García, Luis Miguel Gonzalez, Elena Sevilla, Aitor Gil, Henrique Santos-Oliveira, Belen Revuelta, Coral Barbas, Mª Fernanda Rey-Stolle, Estrella Montero, Antonia García.

  Babesia divergens is a tick-borne apicomplexan parasite that causes human babesiosis, a malaria-like disease. B. divergens metabolism remains poorly characterized. Here, we employed a multiplatform mass spectrometry-based metabolomics approach (using CE-TOF/MS, GC-QTOF/MS, LC-QTOF/MS, and LC-QqQ/MS) to profile intra- and extracellular metabolic changes in B. divergens-infected and uninfected red blood cells (RBCs) and their supernatants. Our results indicate alterations in the metabolome caused by B. divergens infection and proliferation within RBCs. These findings are consistent with the major metabolic dependencies of B. divergens, including extracellular glucose, glutamine, and arginine, accompanied by the accumulation of glycolytic and TCA cycle intermediates. We identified altered nucleotide metabolism, pentose phosphate pathway activity, and redox imbalance. Depletion of lysoglycerophospholipids, glucose, arginine, and glutamine, and accumulation of free heme and sphingolipids suggested pathogenic effects. Growth experiments indicate that glucose and glutamine, but not hypoxanthine, are required for parasite growth. We additionally discovered a phosphorylated HEPES derivative (PEPES) produced upon B. divergens infection of RBCs in vitro. Collectively, these findings and their global interpretation provide insights into B. divergens metabolism and metabolic dependencies and host-parasite metabolic interactions and outline potential directions for future studies on human babesiosis diagnosis, prognosis assessment, and treatment.

Keywords:  Babesia divergens; Babesia divergens metabolism; human babesiosis; multiplatform metabolomics

DOI:  https://doi.org/10.3390/ijms26167677
Mol Med. 2025 Aug 25. 31(1): 282

CpG-oligodeoxynucleotides challenged macrophages ameliorate acetaminophen induced liver injury by activating TLR9/IRG1/itaconate metabolic pathway.

Yibai Qu, Zehui Jiang, Zhixia Chen, Sidan Luo, Bingyao Xie, Xubo Wu, Gang Yuan, Kan Wu, Li Chen, Tian Tian, Shan Li, Haihua Luo, Quan Li, Ding Yuan, Yan Zhang, Yanxia Gao, Jun Zhou, Zhengzheng Yan, Yong Jiang.

   BACKGROUND: Acetaminophen, or N-acetyl-para-aminophenol (APAP), causes severe liver damage and acute liver failure when overdosed. Oligodeoxynucleotides containing CpG motifs (CpG ODN) can regulate the function of macrophages, which play an important role in drug-induced liver injury. It is unclear whether CpG ODN-treated macrophages play an immune regulation role in APAP-induced liver injury. In the present study, we aim to explore the role of CpG ODN-activated macrophages in APAP-induced liver injury and the underlying mechanism in protecting against the cytotoxicity of APAP.
METHODS: In vivo, C57BL/6 mice were treated with APAP (300 mg/Kg) or/and CpG ODN (ODN 1826, 1.65 mg/Kg) by intraperitoneal injection, then survival rate, histopathological evaluation, and inflammatory factors were observed to ascertain the protective effect of CpG ODN. Then, CpG ODN-treated macrophages were reinfused into the animal model to determine the effector cells. In vitro, RNA sequencing and untargeted metabolomics detection were performed to illustrate the underlying mechanism. Last, Acod1 siRNA interference was used to clarify the role of IRG1 in resistance to APAP cytotoxicity by ROS and apoptosis indicator detections.
RESULTS: We found that CpG ODN showed a protective effect against APAP cytotoxicity by stimulating macrophages rather than hepatic parenchymal cells. In particular, reinfusion of CpG ODN-treated macrophages to mice can alleviate APAP-induced liver injury. Transcriptome and metabolome analysis revealed that the expression of aconitate decarboxylase 1 (Acod1; also known as immune responsive gene 1, IRG1) and the metabolite itaconate generated by IRG1 catalysis increased after CpG ODN stimulation. In addition, we found that the mechanism of this protective effect is ascribed to the increased expression of Acod1 and the antioxidative function of itaconate by the activation of the TLR9/NF-κB signaling pathway.
CONCLUSION: CpG ODN alleviated liver injury induced by APAP through the activation of the TLR9/NF-κB signaling pathway in macrophages, upregulating the expression of IRG1 protein, promoting the production of endogenous metabolite itaconate, and inhibiting macrophage apoptosis which was regulated by upregulating the expression of Nrf2 to inhibit ROS production. This study sheds new light on CpG ODN as a therapeutic strategy in resistance to APAP-induced liver injury.

Keywords:  Acetaminophen; IRG1; Itaconate; Liver injury; Macrophage apoptosis; Mitochondrial dysfunction

DOI:  https://doi.org/10.1186/s10020-025-01324-0
Magn Reson Chem. 2025 Aug 20.

NMR-Based Clinical Metabolomics Reveals Distinctive Metabolic Signatures in Systemic Sclerosis and Systemic Lupus Erythematosus.

Gurvinder Singh, Mohit Kumar Rai, Vikas Agarwal, Dinesh Kumar.

  Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are chronic and complex autoimmune diseases with shared clinical features complicating differential disease diagnosis. Despite similarities, they exhibit distinct pathophysiological mechanisms and disease progression. This study is an attempt to investigate disease-specific metabolic alterations and identify potential biomarkers for differential diagnosis using a nuclear magnetic resonance (NMR)-based serum metabolomics approach. 1D 1H Carr-Purcell-Meiboom-Gill (CPMG) NMR spectra were recorded, and a total of 35 serum metabolites were quantified using CHENOMX software across SSc, SLE, and healthy control (HC) groups. Multivariate and univariate statistical analyses revealed significant metabolic distinctions between the diseases. SLE is primarily characterized by disruptions in glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative stress, indicating compromised energy metabolism and immune-mediated mitochondrial dysfunction. In contrast, SSc showed distinct perturbations in inositol and amino acid metabolism linked to fibrosis and endothelial dysfunction. Significantly elevated levels of acetate emerged as a key discriminatory metabolite in SSc patients, implying a shift towards enhanced fatty acid oxidation in SSc, potentially fueling fibrotic processes and contributing to the energy demands of chronic inflammation. Specific metabolic ratios (with acetate as the numerator) demonstrated high accuracy in distinguishing SSc from SLE and HC, highlighting their potential as diagnostic biomarkers; including multivariate and multiclass ROC, supported the diagnostic relevance of these markers. The study underscores the metabolic heterogeneity of SLE and SSc, offering new insights and a deeper understanding into their distinct pathological mechanisms and supporting the development of biomarker-based strategies for improved diagnosis, classification, and personalized therapeutic approaches.

Keywords:  NMR‐based metabolomics; autoimmune diseases; metabolic biomarkers; systemic lupus erythematosus; systemic sclerosis

DOI:  https://doi.org/10.1002/mrc.70026
Oncogene. 2025 Aug 26.

Slc7a5 promotes T cell anti-tumor immunity through sustaining cytotoxic T lymphocyte effector function.

Chunwan Lu, Liyan Liang, Yanmin Wu, Yingcui Yang, Dakota Poschel, Yang Zhao, Lirong Pei, Miao Yu, Martina Zoccheddu, Sergei Bombin, Han-Fei Ding, Huidong Shi, Kebin Liu.

Tryptophan (Trp) metabolites have emerged as key regulators of host tumor immunity and cancer patient response to immunotherapy. However, the function of and mechanism underlying Trp in tumor-activated CTLs in the tumor microenvironment are incompletely understood. Using a defined co-culture system of tumor-specific CTLs and cognate antigen-expressing tumor cells, we performed a genome-wide metabolomics screening and observed that Trp level is elevated in the tumor cell-activated CTLs. Parallel genome-wide RNA-Sequencing and ATAC-Sequencing analysis determined that tumor-specific CTLs respond to tumor cells by transcriptionally activating Slc7a5 expression. Pharmacological inhibition of Slc7a5 decreased Trp uptake in tumor-activated CTLs and suppressed CTL lytic activity in killing tumor cells in vitro. Mice with Slc7a5 deficiency only in T cells exhibited diminished level of tumor-infiltrating T cells and increased tumor growth and metastasis. scRNA-sequencing analysis revealed that Slc7a5 deficiency resulted in decreased activation of the aryl hydrocarbon receptor (AhR) pathway and repressed FasL expression in tumor-infiltrating T cells. Chromatin immunoprecipitation determined that AhR binds to Faslg promoter in tumor-infiltrating T cells. FasL blockade therapy promotes tumor growth and metastasis in tumor-bearing mice. In human cancer patients, AhR expression correlates with FasL expression in tumor-infiltrating T cells. Furthermore, FasL expression is correlated with patient response to pembrolizumab and survival time. Our finding determines that the Slc7a5-Trp metabolic pathway activates AhR to up-regulate FasL expression in tumor-infiltrating T cells to sustain CTL anti-tumor immunity. Targeting CAR-T cells to up-regulate Slc7a5 to maintain T cell proliferation and function therefore could be a promising direction in cancer immunotherapy.

DOI: https://doi.org/10.1038/s41388-025-03543-5
J Immunol. 2025 Aug 25. pii: vkaf209. [Epub ahead of print]

ACLY promotes NK cell effector function by regulating glycolysis and histone acetylation.

Hyogon Sohn, Ana Kolicheski, Jennifer Poursine-Laurent, Jennifer Tran, Yongjun Wang, Kelly Gan, Joshua M Tobin, Nermina Saucier, Todd A Fehniger, Jacqueline E Payton, Megan A Cooper.

  Natural killer (NK) cells are innate immune lymphocytes important for host viral and tumor immunity. We investigated the requirement for ATP citrate lyase (ACLY) in NK cell function using an inducible genetic mouse model. ACLY regulates the citrate-malate shuttle, generating cytosolic acetyl-coenzyme A that is primarily used for acetylation or lipid synthesis. ACLY-deficient NK cells upon IL-15 activation exhibited significant defects in glycolysis, proliferation, cytokine production, and cytotoxicity, without decreased intracellular lipids. Notably, ACLY deficiency specifically resulted in reduced NK cell responses to activating receptors associated with the adapter proteins DAP10 or DAP12. This is due to decreased DAP12 and increased DAP10 transcript and protein, coupled with epigenetic profiling that demonstrated altered histone acetylation of these genes in ACLY KO. Supplementation of ACLY-deficient NK cells with acetate was sufficient to overcome most functional defects, including restoring DAP10/12 expression and activating receptor function, emphasizing the importance of ACLY-generated cytosolic acetyl-coenzyme A for NK effector functions.

Keywords:  cell activation; cytokines; epigenetics; natural killer cells; rodent

DOI:  https://doi.org/10.1093/jimmun/vkaf209
Nat Commun. 2025 Aug 22. 16(1): 7827

Targeting spermine metabolism to overcome immunotherapy resistance in pancreatic cancer.

Hanshen Yang, Xiaozhen Zhang, Sirui Zhang, Yanqing Yang, Yan Chen, Yangwei Jiang, Qingsong Lu, Lingyue Liu, Mengyi Lao, Weiran Du, Kang Sun, Lihong He, Jiatao Shi, Xinyuan Liu, Jinyuan Song, Na Lu, Junming Huang, Jinyan Huang, Ruhong Zhou, Xiongbin Lu, Tingbo Liang, Xueli Bai.

While dysregulation of polyamine metabolism is frequently observed in cancer, it is unknown how polyamines alter the tumor microenvironment (TME) and contribute to therapeutic resistance. Analysis of polyamines in the plasma of pancreatic cancer patients reveals that spermine levels are significantly elevated and correlate with poor prognosis. Using a multi-omics approach, we identify Serpinb9 as a vulnerability in spermine metabolism in pancreatic cancer. Serpinb9, a serine protease inhibitor, directly interacts with spermine synthase (SMS), impeding its lysosome-mediated degradation and thereby augmenting spermine production and secretion. Mechanistically, the accumulation of spermine in the TME alters the metabolic landscape of immune cells, promoting CD8+ T cell dysfunction and pro-tumor polarization of macrophages, thus creating an immunosuppressive microenvironment. Small peptides that disrupt the Serpinb9-SMS interaction significantly enhance the efficacy of immune checkpoint blockade therapy. Together, our findings suggest that targeting spermine metabolism is a promising strategy to improve pancreatic cancer immunotherapy.

DOI: https://doi.org/10.1038/s41467-025-63146-2
Front Cell Infect Microbiol. 2025 ;15 1634909

Mechanisms and therapeutic perspectives of mitochondrial dysfunction of macrophages in periodontitis.

Yibing Jia, Zili Li, Pengjie Huang, Yan Wang, Bo Yang.

  Periodontitis is a global inflammatory oral disease, and plaque-induced host excessive immune response is recognized as a major cause of its pathogenesis. In recent years, the relevance of mitochondrial dysfunction to periodontitis has been increasingly investigated, particularly with respect to macrophages, the key immune cells in the periodontal immune microenvironment. Mitochondrial dysfunction drives macrophage M1 polarization and osteoclast differentiation through mechanisms such as metabolic reprogramming, reactive oxygen species release, abnormal mitophagy, abnormal mitochondrial biogenesis and damaged mitochondrial dynamic. In addition, mitochondrial transfer in the periodontitis setting has been reported in several researches. In this review, we highlight the impact of mitochondrial dysfunction on macrophages in the periodontitis setting and summarize emerging therapeutic strategies for targeting mitochondria in periodontitis, including antioxidants, modulators of metabolic reprogramming, nanomaterials and photodynamic therapy.

Keywords:  macrophage polarization; mitochondrial dysfunction; osteoclast differentiation; periodontitis mechanism; periodontitis treatment

DOI:  https://doi.org/10.3389/fcimb.2025.1634909
Signal Transduct Target Ther. 2025 Aug 26. 10(1): 271

High fructose consumption aggravates inflammation by promoting effector T cell generation via inducing metabolic reprogramming.

Xiao Ma, Jiao Chen, Fang Wang, Xinzou Fan, Zhenhong Li, Hantian Liang, Hao Cheng, Fang Nan, Yubin Lin, Xiaoshuang Song, Jianan Zhang, Fan Gao, Wei Zhang, Wenwen Jin, Huiyuan Zhang, Jiyu Tong, Hong Jiang, Xikun Zhou, Qiang Zou, Hongbo Hu, Aiping Tong, WanJun Chen, Dunfang Zhang.

The intake of sugars, especially glucose and fructose, has significantly increased with the change of lifestyle. Excessive intake of sugar has been proven to be associated with tumors and inflammatory diseases. Fructose directly mediates innate immune responses; however, whether it can directly regulate T-cell immunity remains unknown. We show that high fructose consumption accelerates the development of inflammatory bowel disease (IBD) by promoting the generation of T helper 1 (Th1) and T helper 17 (Th17) cells. It was demonstrated that fructose promotes the differentiation of Th1 and Th17 cells directly by enhancing mechanistic target of rapamycin complex 1 (mTORC1) activation through the glutamine metabolism-dependent pathway. Reactive oxygen species (ROS)-induced activation of transforming growth factor-β (TGF-β) is also involved in fructose-induced Th17 cell generation. Moreover, metformin can reverse Th1 and Th17 cell generation induced by fructose by suppressing mTORC1 activation and reducing ROS-mediated TGF-β activation. Finally, we identified metformin as an in vivo therapeutic drug for relieving high fructose consumption-induced T-cell inflammation and colitis aggravation. Our study revealed a previously unknown adverse effect of high fructose consumption in disrupting immune homeostasis and exacerbating IBD by directly promoting T-cell immunity, and showed metformin is a potential therapeutic for reversing the T cell immune imbalance caused by long-term high fructose consumption.

DOI: https://doi.org/10.1038/s41392-025-02359-9
Mol Nutr Food Res. 2025 Aug 23. e70229

Hexanoic Acid Intake Enhances Anti-Tumor Immune Responses in Colorectal Cancer by Reducing the Immunosuppressive Function of Tregs.

Daichi Seta, Kenta Nagahori, Yuki Katoh, Tadashi Ogawa, Takashi Iwata, Hiroshi Nishio, Masaki Sugawara, Yosuke Fujii, Ayano Yoshido, Hiroshi Seno, Shuichi Hirai.

  Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide. Regulatory T cells (Tregs) are key immune regulators that inhibit anti-tumor immune responses by suppressing effector T-cell functions and fostering an immunosuppressive tumor microenvironment. Despite epidemiological evidence showing an inverse association between milk consumption and CRC risk, the underlying mechanisms remain unclear. While milk-derived fatty acids have demonstrated tumor-suppressive activities, the anti-tumor effects of hexanoic acid, a characteristic component of milk fat, have not been thoroughly investigated. Model tumor mice orally administered hexanoate, the sodium salt of hexanoic acid, showed increased hexanoic acid concentrations in tumor-draining lymph nodes and tumor sites, with enhanced anti-tumor immune responses that significantly suppressed cancer cell growth. These effects were mediated through the following: (1) suppressed differentiation of naïve CD4+ T cells into Tregs; (2) decreased Treg-mediated inhibition of CD8+ T cells; and (3) suppressed intratumoral infiltration of Tregs, indirectly enhancing the effector function of CD8+ T cells. Furthermore, hexanoate enhanced the therapeutic effect of immune checkpoint inhibition therapy. Part of the protective effect of milk intake against CRC development may be mediated by hexanoic acid, which enhances anti-tumor immune responses through its actions on Tregs.

Keywords:  anti‐tumor immune response; colorectal cancer; hexanoic acid; milk; regulatory T cell

DOI:  https://doi.org/10.1002/mnfr.70229
Nat Commun. 2025 Aug 26. 16(1): 7954

Helicobacter hepaticus promotes hepatic steatosis through CdtB-induced mitochondrial stress and lipid metabolism reprogramming.

Shanhao Jin, Liqi Zhu, Ruoyu Bao, Linghan Yang, Tinglong Zhuang, Liyou Lian, Tao Wang, Jun Yin, Shilei Zhang, Lei Zhou, Minghua Zheng, Quan Zhang.

Host-pathogen interaction influences many non-infectious diseases, including metabolic diseases. Helicobacter hepaticus (H. hepaticus) has been found in some metabolic dysfunction-associated steatotic liver disease (MASLD) patients, however, the causal link and underlying mechanisms remain unclear. Here we report that H. hepaticus infection or overexpression of CdtB of H. hepaticus induces lipid deposition in hepatocytes, both in vivo and in vitro. Furthermore, we identify that CdtB translocates to mitochondria with the help of Hsp90, interacts with ATP5A1, reduces mitochondrial respiratory complex V activity, damages mitochondria, and disrupts lipid metabolism. Mechanistically, CdtB-induced lipogenesis depends on the CdtB-mitochondrial ROS-mTORC1-SREBP1 axis and CdtB-mediated NONO expression to enhance nuclear localization of SREBP1 that promote the de novo fatty acid synthesis in the hepatocytes. Neutralization of CdtB significantly alleviates hepatic lipidosis in mice upon H. hepaticus infection. Furthermore, the nucleic acid of H. hepaticus has been detected in the liver tissues of some patients with MASLD, which suggests a certain correlation between liver infection with H. hepaticus and the occurrence and progression of MASLD. Our findings highlight the critical role of CdtB in the pathogenesis of H. hepaticus infection-induced hepatic lipidosis and its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-63351-z
Biochimie. 2025 Aug 22. pii: S0300-9084(25)00194-4. [Epub ahead of print]

Adenosine deprivation modulates purine metabolism and enhances Trichomonas vaginalis cytotoxicity.

Saulo Almeida Menezes, Fernanda Gomes Cardoso, Caroline Rita Venturi, Amanda Thomas Barden, Tiana Tasca.

  Trichomonas vaginalis, the causative agent of human trichomoniasis, relies on host-derived nutrients such as purines and glucose to support survival during infection. As an auxotrophic protozoan, T. vaginalis is incapable to synthesize purine nucleotides de novo and depends entirely on salvage mechanisms, particularly those involving adenosine. However, how nutrient availability modulates the parasite's virulence and purine metabolism remains unclear. Here, we demonstrate that serum and glucose limitation modulate the purine metabolism in T. vaginalis, enhancing extracellular nucleotide hydrolysis by ectonucleoside triphosphate diphosphohydrolase (NTPDase). Serum limitation, a condition that mimics reduced adenosine levels, increased the cytotoxicity of T. vaginalis towards human vaginal epithelial cells (HVECs). When adenosine was added to the culture, it reversed the increase in NTPDase activity and cytotoxicity caused by serum limitation. The protective effect promoted by adenosine during co-incubation of serum-limited T. vaginalis and HVECs was reduced by dipyridamole, possibly indicating a critical role for adenosine uptake by the parasites. Gene expression analysis revealed differential regulation of T. vaginalis equilibrative nucleoside transporter genes, with downregulation under serum limitation and upregulation under glucose restriction, suggesting an adaptative transcriptional response to stress in nutrient availability. These findings reveal that adenosine deprivation modulates purine metabolism in T. vaginalis and enhances parasite cytotoxicity. Furthermore, our results uncover adenosine as a pivotal regulator of T. vaginalis virulence under metabolic stress and highlight purine salvage pathways and nucleoside transport as promising targets for therapeutic intervention against trichomoniasis.

Keywords:  Adenosine; Cytotoxicity; Nucleoside transporters; Serum limitation; Trichomonas vaginalis

DOI:  https://doi.org/10.1016/j.biochi.2025.08.015
Microbiol Spectr. 2025 Aug 20. e0038125

Multi-omics insights into the metabolic reprogramming of host cells triggered by Entamoeba histolytica Gal/GalNAc lectin intermediate subunit.

Yanqing Zhao, Hongze Zhang, Shaokun Pan, Ruixue Zhou, Hiroshi Tachibana, Meng Feng, Xunjia Cheng.

  The Gal/GalNAc lectin in ‌Entamoeba histolytica‌ is pivotal for its pathogenicity, and its intermediate subunit (Igl) is a crucial virulence factor. Here, the interference of eukaryotically expressed Igl on normal metabolic processes within Caco-2 cells was explored. Targeted metabolomic analysis detected 232 metabolites in Caco-2 cells, revealing 63 with significant alterations after Igl treatment. Notably, the lactate content significantly increased, indicating that Igl activates aerobic glycolysis. Metabolic flux analysis demonstrated that Igl could inhibit aerobic respiration and the tricarboxylic acid cycle in host cells. It significantly increased glucose intake, lactate production, and ATP generation, demonstrating its ability to induce a Warburg-like effect. Through single-cell transcriptomic experiments, significant increases in changes were observed in 4 out of 12 individual host cell groups after Igl treatment. Group marker genes identified these cell groups as having inhibited aerobic respiration and activated stress responses, further indicating that Igl stimulation can affect the aerobic respiration and normal metabolic processes of cells. Additionally, RNA interference experiments were performed to verify the effect of Igl on host cell autophagy when PRKAA1 was silenced. Confocal microscopy and western blotting revealed significantly enhanced autophagy signals after Igl treatment, and it was confirmed that mammalian target of rapamycin was involved in this process. These results indicate that Igl induces metabolic reprogramming and a Warburg-like shift in host epithelial cells, thereby activating aerobic glycolysis and regulating host cell autophagy. This represents a novel mechanism of Igl in the pathogenicity of E. histolytica.IMPORTANCEEntamoeba histolytica causes amoebiasis, an infection manifesting as colitis and extraintestinal abscesses. Multi-omics approaches provide critical insights into the role of the Gal/GalNAc lectin intermediate subunit (Igl) within host cells, offering a foundation for developing effective treatments. Our findings indicate that Igl induces metabolic reprogramming in host epithelial cells. Specifically, Igl can trigger a Warburg-like shift, a phenomenon characterized by the activation of aerobic glycolysis. This shift results in increased glucose intake, lactate production, and ATP generation while inhibiting aerobic respiration and the tricarboxylic acid cycle. Furthermore, Igl regulates host cell autophagy, a process further confirmed through RNA interference experiments targeting PRKAA1, which revealed the involvement of mammalian target of rapamycin. Taken together, our data suggest that Igl promotes trophozoite virulence through a novel mechanism that involves metabolic reprogramming and a Warburg-like shift in host cells.

Keywords:  Entamoeba histolytica; Gal/GalNAc lectin; autophagy; metabolic reprogramming; single-cell transcriptomics; targeted metabolomics

DOI:  https://doi.org/10.1128/spectrum.00381-25
Theranostics. 2025 ;15(16): 8639-8657

Systemic inflammation-induced adipose tissue remodeling drives psoriasis exacerbation in obesity through epigenetic and immunometabolic dysregulation.

Jinsun Jang, Mijoo Ahn, Jiyeong Jeong, Eun-Hui Lee, Ok-Hee Kim, Seul-A Joo, Seung Eun Baek, Han-Joo Maeng, Yun Hak Kim, In-Sun Hong, Byung-Chul Oh, Ik Soo Kim, Hee Joo Kim, YunJae Jung.

  Rationale: Disruption of adipose tissue homeostasis is increasingly recognized as a key driver of psoriatic inflammation in the context of obesity. However, the mechanisms linking adipose dysfunction to disease severity remain incompletely understood. Methods: We employed an obese mouse model of psoriasis induced by topical imiquimod application or dermal IL-23 injection. Inflammatory profiling from these mice was integrated with multi-omic single-nucleus sequencing targeting RNA and chromatin accessibility to investigate genetic and epigenetic alterations in adipose tissue. Results: Obese mice developed markedly aggravated psoriatic dermatitis following imiquimod treatment, accompanied by increased systemic inflammatory responses and a significant reduction in fat mass. Histological and molecular analyses revealed extensive monocyte-macrophage infiltration into perigonadal adipose tissue, increased expression of pro-inflammatory genes, and upregulation of cell death-associated molecules in obese mice relative to lean counterparts. In contrast, IL-23 injection elicited comparable skin inflammation in both lean and obese mice without inducing adipose tissue loss or systemic inflammation. Multi-omic profiling of imiquimod-treated obese mice revealed genetic and epigenetic changes in adipocytes that promote fatty acid consumption. Furthermore, a shift was observed in macrophage populations-from a lipid-associated subset with active intercellular communication in IL-23-treated mice to disorganized macrophage compartments with monocyte accumulation in imiquimod-treated mice. Conclusions: These findings suggest that obesity sensitizes adipose tissue to homeostatic disruption, establishing it as a critical immunometabolic interface that drives psoriasis exacerbation in response to systemic inflammatory cues.

Keywords:  adipocytes; macrophages; obesity; psoriasis; single-nucleus multiome

DOI:  https://doi.org/10.7150/thno.116796
Neurobiol Dis. 2025 Aug 18. pii: S0969-9961(25)00277-3. [Epub ahead of print]215 107061

Histone H3 lysine 18 lactylation attenuates neuroinflammation and neurological damage by regulating microglial plxnb2 after ischemic stroke.

Ping Li, Yao Wang, Yuan Xu, Linyu Feng, Na Jiang, Yongkang Fang, Guini Song, Lingling Yu, Li Xu, Zhou Zhu, Suiqiang Zhu, Wei Wang, Minjie Xie.

  Microglia are major resident immune cells in the central nervous system and are actively involved in the pathogenesis of ischemic stroke. Histone lactylation confers macrophage homeostatic gene expressions and regulates physiological and immune-related pathological conditions. However, the spatiotemporal expression and functional role of histone lactylation in microglial reprogramming and neurological injuries after ischemic stroke remain elusive. In this study, we observed increased levels of histone lactylation in peri-infarct areas after the middle cerebral artery occlusion-induced focal cerebral ischemia in mice. The enhanced histone lactylation favored an anti-inflammatory micro-environment and provided neuroprotective effects after ischemia, which might be mediated by histone H3 lysine 18 lactylation (H3K18la)-regulated plxnb2 expression in microglia. Microglia-specific inhibition of plxnb2 abrogated the neuroprotective effects of lactate after ischemic stroke. These findings suggest that interventions aimed at the lactate/lactylation(H3K18la)/plxnb2 axis may represent a promising therapeutic strategy for ischemic stroke treatment.

Keywords:  Histone lactylation; Ischemic stroke; Microglia; Neuroinflammation; Plxnb2

DOI:  https://doi.org/10.1016/j.nbd.2025.107061
Sci Adv. 2025 Aug 22. 11(34): eadu2856

Metabolism-dependent succinylation governs resource allocation for antibiotic resistance.

Jia-Han Wu, Xuan-Wei Chen, Ying-Li Liu, Jia-Yao Wu, Zhuang-Gui Chen, Bo Peng.

The mechanisms that organisms allocate resources to sustain biological phenotypes remain largely unknown. Here, we use mobilized colistin resistance (mcr-1), which modifies lipopolysaccharide (LPS) to confer colistin resistance, as a model to explore how bacteria reallocate resources to support mcr-1-mediated resistance. We show that bacteria redirect resources from glycolysis, the pyruvate cycle, and LPS biosynthesis toward glycerophospholipid metabolism to produce phosphatidylethanolamine, the substrate for mcr-1 to modify LPS, while reducing LPS content to limit colistin binding. This reallocation down-regulates succinyl-coenzyme A (CoA) to diminish succinylation of proteins including triosephosphate isomerase (TPI), CpxR, and PdhR, thereby sustaining resistance. Exogenous succinate or α-ketoglutarate restores succinylation in a succinyl-CoA-dependent manner. Succinylation of TPI redirects metabolic flux to glycolysis and the pyruvate cycle, while succinylation of CpxR and PdhR up-regulates LPS biosynthesis, ultimately attenuating colistin resistance. Thus, we reveal a previously unrecognized mechanism by which bacteria regulate resource allocation through metabolism-driven posttranslational protein modification, offering strategies to combat antibiotic resistance.

DOI: https://doi.org/10.1126/sciadv.adu2856