bims-imicid 2025-09-21 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–09–21
thirty-two papers selected by
Dylan Ryan, University of Cambridge

Decoding immunometabolism with next-generation tools: lessons from dendritic cells and T cells.
Reprogramming immunity with itaconate: metabolic mechanisms and therapeutic perspectives.
Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.
Mitochondrial Activity Regulates Human T Helper 17 Differentiation and Function.
Metabolic hallmarks of type 2 diabetes compromise T cell function.
Label-free metabolic imaging monitors the fitness of chimeric antigen receptor T cells.
Intrinsic T cell glutaminolysis promotes autoimmunity in lupus-prone mice.
Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.
Temporal dynamics of macrophage activation during Salmonella enterica serovar Typhi infection: An integrated transcriptomic and metabolomic analysis.
Cellular cholesterol metabolism rewiring through SREBP2-LXR-mTOR signaling convergence orchestrates T cell fate and keratinocyte apoptosis in oral lichen planus.
Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications.
Dysregulation of innate immunity and cellular metabolism through virus-induced deISGylation.
Resolving vs. Non-resolving Sphingolipid Dynamics During Macrophage Activation: A Time-resolved Metabolic Analysis.
Polyamines in pancreatic cancer: reshaping the immunosuppressive tumor microenvironment.
Lactate and lactylation in tumor immunity.
Brg1-imprinted chromatin status controls the effector and memory ILC2 metabolism to exacerbate allergic lung inflammation.
Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.
A mesothelial differentiation gateway drives fibrosis.
Cannabis Improves Metabolic Dysfunction and Macrophage Signatures in Obese Mice.
Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure.
Single-cell multi-omics reveals SLC2A1-driven glycolytic reprogramming of pulmonary endothelial cells in sepsis-associated lung injury.
Interferon gamma signaling drives cardiac metabolic rewiring.
Mast Cell Immunometabolism in Type 2 Diabetes and Alzheimer's Disease.
Lactic acid regulates antitumor immunity in canine invasive urothelial carcinoma.
MASH: the nexus of metabolism, inflammation, and fibrosis.
Diacylglycerol metabolism drives host-pathogen responses during enteric infection in Drosophila.
Malignant epithelia cells-derived spermine induces APOE+ macrophages to suppress tumor immunity in adenocarcinoma of the esophagogastric junction.
Long-chain unsaturated fatty acids released during immune responses stimulate host-microbe trans-kingdom communication.
Non-hematopoietic tryptophan metabolism is a driver of ineffective T cell responses during secondary pulmonary bacterial infection.
Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond.
PKM2 orchestrates tumor progression via metabolic reprogramming and MDSCs-mediated immune suppression in the tumor microenvironment.
Sepsis-induced lipid droplet accumulation enhances antibacterial innate immunity through mechanisms dependent on DGAT-1 and interferon-beta.

EMBO J. 2025 Sep 16.

Decoding immunometabolism with next-generation tools: lessons from dendritic cells and T cells.

Yi-Hao Wang, Limei Wang, Ping-Chih Ho.

  Cellular metabolism plays a pivotal role in regulating the effector functions and fate decisions of immune cells, shaping immune responses in homeostasis and disease. Metabolic pathways also serve as critical signaling hubs governing immune cell behavior. Deregulated metabolic pathways contribute to immune dysfunction, fueling disease progression and creating challenges for therapeutic interventions. The recent development of advanced technologies to delineate immunometabolic regulation has revolutionized our understanding of immune cell biology. These tools, ranging from quantitative single-cell metabolomics to in vivo spatial tissue profiling and DC-based metabolic therapy, have shifted the focus from broad nutrient pathways to a detailed exploration of metabolic reprogramming within disease microenvironments, revealing how metabolic changes drive immune cell activation, differentiation, and effector responses. The integration of immunometabolic insights into clinical practice holds strong potential for advancing precision medicine and developing targeted therapies that restore immune balance in pathological conditions. Here, we summarize emerging cutting-edge technologies related to immunometabolism and critically reflect on their current limitations. Finally, we discuss potential needs for developing novel methods that can uncover the intricate interplay between metabolism and immune cell function.

Keywords:  Dendritic Cells; Immunometabolism; Metabolic Reprogramming; T Cells; Technological Advances

DOI:  https://doi.org/10.1038/s44318-025-00569-z
Inflamm Res. 2025 Sep 16. 74(1): 128

Reprogramming immunity with itaconate: metabolic mechanisms and therapeutic perspectives.

Hanlin Gao, Minting Ding, Yunchen Liu, Yiying Wang, Susu Zhao, Junyao Chen, Zhi Chen, Gang Wang.

  Itaconate, a mitochondrial metabolite generated from cis-aconitate via IRG1 (ACOD1), has emerged as a key immunometabolic signal that links metabolic reprogramming with immune regulation. Beyond its origin in the tricarboxylic acid (TCA) cycle, itaconate exemplifies how metabolic intermediates can reshape cell fate and function under stress and inflammation. Upon inflammatory stimulation, immune cells-particularly macrophages-undergo profound metabolic rewiring. Itaconate orchestrates this shift by inhibiting succinate dehydrogenase (SDH), accumulating succinate, activating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant responses, and modulating glycolytic flux, thus balancing inflammatory output and oxidative stress. This review provides an integrative overview of itaconate biosynthesis, metabolic regulation, and functional mechanisms across diverse physiological and pathological contexts. Itaconate and its derivatives, such as 4-octyl itaconate (4-OI), exhibit promising effects in preclinical models of sepsis, acute lung injury, autoimmune diseases (e.g., SLE and RA), ischemia-reperfusion injury, infection (bacterial and viral), and cancer. These effects are closely linked to itaconate's capacity to reprogram immune metabolism and modulate signaling pathways such as NF-κB, NLRP3, and JAK/STAT. Importantly, recent findings suggest that itaconate not only modulates inflammation but also affects immune cell death pathways, ferroptosis susceptibility, and tumor immune evasion. These multifaceted roles make itaconate a potential metabolic checkpoint in the development of new therapeutic strategies. However, challenges such as metabolic instability, limited bioavailability, and potential off-target effects remain to be addressed. In summary, itaconate represents a powerful endogenous modulator of immunometabolism. Its therapeutic utility, as a direct drug, as a scaffold for derivative design, or as a biomarker for inflammation resolution, holds significant promise for treating inflammation-driven diseases through the lens of metabolic reprogramming. This review summarizes itaconate biosynthesis, its molecular mechanisms in health and disease, and recent advances across multiple conditions, providing a foundation for future immunometabolic therapies.

Keywords:  Immunometabolism; Inflammation; Itaconate; Metabolic reprogramming; Therapeutic potential

DOI:  https://doi.org/10.1007/s00011-025-02087-4
Trends Immunol. 2025 Sep 16. pii: S1471-4906(25)00215-7. [Epub ahead of print]

Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.

Ana Belén Plata-Gómez, Weixin Chen, Ping-Chih Ho, Guang Sheng Ling.

  Mitochondrial lipid metabolism plays a pivotal role in tumor immunosurveillance and immune evasion. This review explores how mitochondrial regulation shapes immune cell metabolism within the tumor microenvironment (TME), focusing on the antitumor effects of the mitochondrial-fueled immune response and the detrimental impact of impaired mitochondrial function on immune cell cytotoxicity. Although current studies support this dual role, critical gaps remain, including how immune cells adapt differently to the lipid-rich TME, and how therapies can target lipid metabolism without harming immune memory. By synthesizing current findings and highlighting these uncertainties, this review highlights mitochondrial lipid metabolism as a promising therapeutic axis in cancer immunotherapy.

Keywords:  immunometabolism; lipid metabolism; mitochondria; tumor metabolic reprogramming

DOI:  https://doi.org/10.1016/j.it.2025.08.005
Immunology. 2025 Sep 17.

Mitochondrial Activity Regulates Human T Helper 17 Differentiation and Function.

Xinlai Chen, Theodoros Ioannis Papadimitriou, Anne H G van Essen, Britt van Brunschot, Monique M Helsen, Annet Sloetjes, Elly L Vitters, Werner J H Koopman, Peter M van der Kraan, Arjan P M van Caam, Marije I Koenders.

  Immunometabolism plays a pivotal role in T cell fate decisions, yet its specific contribution to human Th17 differentiation remains incompletely understood. Th17 cells, a subset of CD4+ T cells, are central to autoimmune pathogenesis through their secretion of pro-inflammatory cytokines. Elucidating the metabolic drivers of Th17 differentiation may reveal novel therapeutic targets. We investigated the role of mitochondrial activity in Th17 differentiation using an in vitro model with naïve human CD4+ T cells. Single-cell metabolic profiling and functional assays were used to characterise metabolic changes during differentiation. Th17 cells exhibited a hyperpolarised mitochondrial membrane potential (ΔΨ) compared to non-Th17 cells. Hyperpolarised ΔΨ cells displayed increased metabolic activity and enhanced differentiation capacity. Metabolic profiling at 48 h revealed an early reliance on glycolysis, followed by a shift toward increased dependence on oxidative phosphorylation (OXPHOS) by 96 h. Gene expression analysis indicated early upregulation of TEFM, a mitochondrial transcription regulator, at 48 h. By 96 h, ΔΨ hyperpolarised cells exhibited a downregulation of DRP1 and MFN2, genes responsible for mitochondrial fission and fusion. Functionally, ΔΨ hyperpolarised cells expressed elevated activation markers (CD69, CD25) but also showed increased exhaustion markers (TIGIT, PD-1), indicating a link between high metabolic activity and exhaustion. Additionally, these cells triggered weaker NF-κB and AP-1 signalling and secreted lower levels of effector molecules (IFN-γ, Granzyme B) than ΔΨ depolarised cells. In conclusion, mitochondrial activity critically shapes Th17 differentiation. Although hyperpolarised ΔΨ cells exhibit greater activation, they are more prone to exhaustion and reduced effector function. These findings offer insights into Th17 metabolic regulation and its therapeutic potential in autoimmune diseases.

Keywords:  T cell exhaustion; T cell metabolism; Th17 cells; Th17 differentiation; mitochondrial activity

DOI:  https://doi.org/10.1111/imm.70037
Trends Endocrinol Metab. 2025 Sep 12. pii: S1043-2760(25)00174-2. [Epub ahead of print]

Metabolic hallmarks of type 2 diabetes compromise T cell function.

Yuteng Liang, Weixin Chen, Qier Gao, Kathryn Choon-Beng Tan, Chi-Ho Lee, Guang Sheng Ling.

  Type 2 diabetes (T2D) manifests as profound systemic metabolic dysregulation. Mounting evidence indicates T2D significantly impairs T cell immunity, compromising both protective immune responses and immune homeostasis. This dysfunction stems from the multitude roles of metabolites in T cell biology: energy substrates, signaling molecules, and epigenetic regulators. In this review, we synthesize current evidence on how the metabolic hallmarks of T2D (hyperglycemia, hyperinsulinemia, and dyslipidemia) reprogram T cell metabolism and their functionalities. Notably, most patients with T2D receive combination antidiabetic therapies which not only correct systemic metabolism but also exert direct immunomodulatory effects on T cells. Unraveling the interplay between disease-driven metabolic perturbations and pharmacologically induced immunomodulation is essential to advance therapeutic strategies that restore immune competence while preserving immunoregulatory balance.

Keywords:  T cells; immunometabolism; type 2 diabetes

DOI:  https://doi.org/10.1016/j.tem.2025.08.005
Nat Biomed Eng. 2025 Sep 16.

Label-free metabolic imaging monitors the fitness of chimeric antigen receptor T cells.

Dan L Pham, Dan Cappabianca, Matthew H Forsberg, Cole Weaver, Katherine P Mueller, Anna Tommasi, Jolanta Vidugiriene, Anthony Lauer, Kayla Sylvester, Jorgo Lika, Madison Bugel, Jing Fan, Christian M Capitini, Krishanu Saha, Melissa C Skala.

Chimeric antigen receptor (CAR) T cell therapy for solid tumours is challenging because of the immunosuppressive tumour microenvironment and a complex manufacturing process. Cellular manufacturing protocols directly impact CAR T cell yield, phenotype and metabolism, which correlates with in vivo potency and persistence. Although metabolic fitness is a critical quality attribute, how T cell metabolic requirements vary throughout the manufacturing process remains unexplored. Here we use optical metabolic imaging (OMI), a non-invasive, label-free method to evaluate single-cell metabolism. Using OMI, we identified the impacts of media composition on CAR T cell metabolism, activation strength and kinetics, and phenotype. We demonstrate that OMI parameters can indicate cell cycle stage and optimal gene transfer conditions for both viral transduction and electroporation-based CRISPR/Cas9. In a CRISPR-edited anti-GD2 CAR T cell model, OMI measurements allow accurate prediction of an oxidative metabolic phenotype that yields higher in vivo potency against neuroblastoma. Our data support OMI as a robust, sensitive analytical tool to optimize manufacturing conditions and monitor cell metabolism for increased CAR T cell yield and metabolic fitness.

DOI: https://doi.org/10.1038/s41551-025-01504-7
JCI Insight. 2025 Sep 16. pii: e192286. [Epub ahead of print]

Intrinsic T cell glutaminolysis promotes autoimmunity in lupus-prone mice.

Seung-Chul Choi, Yong Ge, Milind V Joshi, Damian Jimenez, Abigail Castellanos Garcia, Cassandra LaPlante, Lauren T Padilla, Chaoyu Ma, Nu Zhang, Jeffrey C Rathmell, Mansour Mohamadzadeh, Laurence Morel.

  Glutaminolysis is enhanced in T cells of lupus patients and in follicular helper T (Tfh) cells, a critical subset of CD4+ T cells that provide help to autoreactive B cells, in lupus mice. Glutaminolysis inhibitors reduced lupus activity in association with a decreased frequency of Th17 cells in mice. Here, we thought to determine the role of glutaminolysis in murine Tfh cells. The pharmacological inhibition of glutaminolysis with DON reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production and B cell differentiation markers. Accordingly, profound transcriptomic and metabolic changes, including a reduction of glycolysis, were induced by DON in lupus Tfh cells, whereas healthy Tfh cells showed minor changes. The T cell-specific genetic inhibition of glutaminolysis largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with minor changes in Tfh and B cells in healthy controls. Furthermore, we showed that T cell-specific glutaminolysis inhibition impaired T-dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results suggest that lupus Tfh cells have a greater intrinsic requirement of glutaminolysis for their helper functions.

Keywords:  Adaptive immunity; Amino acid metabolism; Autoimmunity; Immunology; T cells

DOI:  https://doi.org/10.1172/jci.insight.192286
Trends Cancer. 2025 Sep 16. pii: S2405-8033(25)00204-3. [Epub ahead of print]

Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.

Huiyu Li, Wenyi Jin, Junhong Liu, Yundong Zhou, Xiaoli Shan, Yubiao Zhang, Yongliang Kou, Chunyan Deng, Cheng Jin, Junjie Kuang, Yui-Leung Lau, João Conde, Baozhen Huang, Queran Lin.

  The tumor microenvironment (TME) imposes profound metabolic and functional constraints on immune cells, with mitochondrial dysfunction emerging as a pivotal driver of immunosuppression. While mitochondrial metabolism is well recognized for its role in energy production and cellular homeostasis, its dynamic regulation of immune cell activation, differentiation, and exhaustion within the TME remains underexplored. In this review we summarize insights into how TME stressors such as hypoxia, nutrient competition, and metabolic byproducts subvert mitochondrial dynamics, redox balance, and mitochondrial DNA (mtDNA) signaling in T cells, natural killer (NK) cells, and macrophages, thereby directly impairing their antitumor efficacy. We emphasize that the restoration of mitochondrial fitness in immune cells, achieved by targeting metabolites in the TME and mitochondrial quality control, represents a pivotal axis for adoptive cell therapies (ACTs) and TME reprogramming.

Keywords:  ROS; chimeric antigen receptor (CAR); metabolism; mitochondria; tumor immunotherapy

DOI:  https://doi.org/10.1016/j.trecan.2025.08.006
Virulence. 2025 Dec;16(1): 2561828

Temporal dynamics of macrophage activation during Salmonella enterica serovar Typhi infection: An integrated transcriptomic and metabolomic analysis.

Fanfan Yang, Yuhui Liu, Ying Zhang, Dandan Wei, Zhongyi Xie.

  Salmonella enterica serovar Typhi (S. Typhi) is a major bacteria responsible for foodborne illnesses. Understanding the temporal dynamics of the host immune response and associated metabolic reprogramming is crucial for identifying potential therapeutic targets. This study employed an integrated transcriptomic and metabolomic approach to investigate the response of macrophages infected with S. Typhi over a defined stage (0 h, 2 h, 4 h, 8 h, and 24 h). RNA sequencing (RNA-seq) was used to profile gene expression changes, while untargeted metabolomics characterized metabolic shifts. Gene set enrichment and pathway analyses were conducted to identify key immune and metabolic pathways. Additionally, Convergent Cross-Mapping (CCM) analysis was applied to uncover causal relationships between gene expression and metabolite fluctuations. Transcriptomic revealed distinct temporal phases of immune activation. Early responses were dominated by interferon signaling, cytokine production, and inflammatory responses, whereas later stages involved sustained immune signaling and metabolic adaptation. Key pathways, including NF-κB, TNF, and cytokine-cytokine receptor interactions, were significantly enriched. Metabolomic profiling demonstrated a transition from glycolysis and amino acid metabolism in early infection stages to fatty acid oxidation and mitochondrial function in later stages, with glutathione metabolism playing a central role in oxidative stress regulation. CCM analysis identified critical genes (e.g. RGS4, KIF18A, RSPO1) exhibiting strong causal relationships with metabolic alterations, underscoring the tight integration between immune and metabolic responses. This study provides a comprehensive, time-resolved view of S. Typhi infection, highlighting dynamic immune activation and metabolic reprogramming in macrophages. These findings advance our understanding of host-pathogen interactions.

Keywords:  Salmonella enterica serovar Typhi; THP-1 macrophage; infection; metabolomic; transcriptomic

DOI:  https://doi.org/10.1080/21505594.2025.2561828
Int Immunopharmacol. 2025 Sep 15. pii: S1567-5769(25)01448-1. [Epub ahead of print]166 115457

Cellular cholesterol metabolism rewiring through SREBP2-LXR-mTOR signaling convergence orchestrates T cell fate and keratinocyte apoptosis in oral lichen planus.

Qin Jiang, Yu-Xi Tang, Gang Zhou.

   BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease with unknown etiology and lack of curative treatment, characterized by T-cell infiltration and basal keratinocyte degeneration. As an emerging regulatory switch in immune inflammation, cholesterol metabolism profoundly influenced the biological fate and functions of T cells. However, it remains completely unknown whether T cell cholesterol metabolism contributes to the pathogenesis of OLP.
METHODS: Single-cell RNA sequencing data screening and multi-platform validation (Immunohistochemistry, immunofluorescence, flow cytometry, PCR, co-immunoprecipitation) were performed to profile cholesterol metabolism dysregulation in OLP T cells, focusing on cholesterol accumulation, SREBP2-LXR imbalance and disease severity correlations. Functional validation employed cholesterol-modulated (fatostatin, GW3965, exogenous cholesterol) OLP plasma-pretreated Jurkat T cells and primary OLP T cells in keratinocyte co-cultures, with pathway analysis of STAT3, mTOR, STING and mTOR-SREBP2 crosstalk.
RESULTS: Local OLP T cells exhibited elevated cholesterol scores (erosive > non-erosive), with cholesterol-high clusters showing enhanced cell cycle, leukocyte transendothelial migration, Th17 cell differentiation, and STAT3/mTOR/STING pathways. OLP lesions, local OLP T cells and peripheral OLP T cells exhibited accumulated cholesterol and SREBP2-LXR axis imbalance characterized by upregulated SREBP2/LXRα/LXRβ with hyperactive SREBP2, impaired LXR activity and attenuated LXRβ-RXRα interaction. LXRβ positively correlated with disease severity, and SREBP2 levels peaked in atrophic OLP. Cholesterol accumulation in OLP plasma-pretreated Jurkat T cells enhanced proliferation, cell cycle progression, migration, pro-keratinocyte apoptotic capacity and Th1/Th17 polarization but suppressed apoptosis, though excess cholesterol tended to impair the survival and pro-keratinocyte apoptosis ability. OLP CD4+ T cells exhibited greater cholesterol dependence than CD8+ T cells for proliferation and migration. Mechanistically, cholesterol activated mTOR while tending to suppress STING in OLP T cells. Bidirectional mTOR-SREBP2 crosstalk was observed, wherein mTOR activated SREBP2 whereas SREBP2 reciprocally inhibited mTOR, and the dual-pathway inhibition synergistically promoted OLP T cell apoptosis and suppressed proliferation.
CONCLUSION: Cholesterol accumulation caused by OLP severity-associated SREBP2-LXR axis abnormalities promoted the immunobiological characteristics, pro-apoptotic effects on keratinocytes and mTOR pathway activation of OLP T cells, and the combined inhibition of mTOR-SREBP2 crosstalk alleviated T-cell responses in OLP.

Keywords:  Cholesterol; Keratinocyte; Oral lichen planus; SREBP2-LXR axis; T cell; mTOR

DOI:  https://doi.org/10.1016/j.intimp.2025.115457
Cancer Lett. 2025 Sep 11. pii: S0304-3835(25)00608-1. [Epub ahead of print]633 218038

Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications.

Zhe Wang, Ziyan Gu, Wendi Mo, Haijun Zhang.

  Immuno-Oncology has transformed cancer therapeutics, yet its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Once considered merely a metabolic byproduct of glycolysis, lactate is now recognized as a critical regulator of immune TME through both direct metabolic effects and its derivative modification, histone lysine lactylation (Kla). Within the TME, lactate and Kla reprogram signaling pathways that impair immune function, thereby facilitating tumor immune escape. This review synthesizes emerging evidence positioning lactate metabolism and histone Kla as pivotal immunosuppressive modulators within the TME. Tumor-derived lactate, produced through the Warburg effect, acidifies the TME and disrupts immune cell function via two interconnected mechanisms: direct metabolic interference and epigenetic reprogramming via Kla. Histone Kla represents a novel post-translational modification that drives immunosuppressive signaling in immune cells, serving as a prognostic biomarker across multiple cancers. Moreover, we highlight therapeutic strategies targeting lactate metabolism, which show considerable promise in overcoming the current limitations of immunotherapy and enhancing its clinical efficacy.

Keywords:  Immunotherapy; Lactate; Lactylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218038
bioRxiv. 2025 Sep 09. pii: 2025.09.08.674928. [Epub ahead of print]

Dysregulation of innate immunity and cellular metabolism through virus-induced deISGylation.

Junji Zhu, GuanQun Liu, Jielin Xu, Kun Li, Christopher M Goins, Huaxu Yu, Zuberwasim Sayyad, Yadi Zhou, Evangeline White, Oliver Fiehn, Shaun R Stauffer, Feixiong Cheng, Michaela U Gack.

Interferon-stimulated gene 15 (ISG15) regulates diverse cellular responses including antiviral immunity through its conjugation to proteins, a process known as ISGylation. Several pathogens, including SARS-CoV-2, subvert ISGylation by encoding deISGylating enzymes. However, the direct targets and physiological consequences of coronaviral deISGylation remain poorly defined. Here, we ablated the deISGylating activity of the SARS-CoV-2 papain-like protease (PLpro) and found that loss of deISGylation boosted innate immune activation, attenuated virus replication, and promoted viral clearance in human cells and in mice. Through untargeted metabolomics and ISGylome proteomics analyses, combined with functional studies, we discovered in molecular detail how the activities of key metabolic enzymes in glycolysis, the pentose phosphate pathway, and oxidative stress are controlled by PLpro deISGylation. These findings provide fundamental new insight into how reversible ISGylation regulates immunity and metabolic processes at the molecular level and highlight viral deISGylation as a major viral tactic for rewiring immunometabolism.

DOI: https://doi.org/10.1101/2025.09.08.674928
J Lipid Res. 2025 Sep 15. pii: S0022-2275(25)00161-0. [Epub ahead of print] 100899

Resolving vs. Non-resolving Sphingolipid Dynamics During Macrophage Activation: A Time-resolved Metabolic Analysis.

Nathan F Chiappa, Nidhi Lal, Edward A Botchwey.

  Sphingolipids are increasingly recognized as critical regulators of inflammation and cell fate decisions, with metabolites such as ceramide and sphingosine 1-phosphate exerting contrasting effects on cell survival and proliferation. In macrophages, this balance is especially important, given their central role in host defense, pathogenesis and wound healing. Here, we present a time-resolved model of sphingolipid metabolism in RAW 264.7 macrophages stimulated with KdO2-Lipid A. By integrating measured metabolite concentrations with dynamic flux estimation and established enzyme kinetics, we systematically map dynamic changes in the sphingolipid network during inflammation. Our results reveal a three-phase pattern of sphingolipid remodeling that correlates with distinct functional states of the cell. Moreover, metabolites can be classified into "resolving" or "non-resolving" lipids based on whether they return to basal levels or remain dysregulated through the later phases of the inflammatory response. This partitioning suggests that targeted modulation of specific metabolic nodes may influence the resolution of inflammation. Importantly, our computational approach can assist in the rational design of experimental studies by pinpointing putative drug targets with maximal impact on sphingolipid homeostasis. Such targeted interventions may prevent the pathological amplification of inflammatory signals without globally suppressing essential sphingolipid functions. These findings highlight the utility of an integrative systems-level analysis for elucidating sphingolipid dynamics in macrophages and underscore its potential to guide therapeutic strategies against conditions involving dysregulated inflammation.

Keywords:  ceramides; inflammation; lipidomics; sphingolipids; sphingosine phosphate

DOI:  https://doi.org/10.1016/j.jlr.2025.100899
Cancer Lett. 2025 Sep 11. pii: S0304-3835(25)00586-5. [Epub ahead of print] 218016

Polyamines in pancreatic cancer: reshaping the immunosuppressive tumor microenvironment.

Shijuan Jiang, Bo Ren, Chen Ding, Changwei Du, Zhe Cao, Gang Yang, Hua Huang, Taiping Zhang.

  Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, characterized by aggressive malignancy and poor outcomes. Emerging evidence implicates dysregulated polyamine metabolism as a key driver of pancreatic ductal adenocarcinoma immunosuppression, yet the mechanisms underlying this metabolic-immune crosstalk remain poorly defined. This review summarized recent findings demonstrating that pancreatic ductal adenocarcinoma is uniquely dependent on glutamine-derived ornithine for de novo polyamine synthesis, orchestrated by the KRAS-MYC axis. Through metabolic reprogramming of immune cells, polyamines polarize tumor-associated macrophages toward M2-like phenotypes, expand myeloid-derived suppressor cells, and impair T cell activation. Crucially, the immunomodulatory effects of polyamines are source-dependent: tumor-derived spermidine promotes T cell exhaustion, whereas dietary spermidine enhances antitumor immunity through fatty acid oxidation. Preclinical studies have highlighted that polyamine-targeted therapy, which including biosynthesis inhibitors, arginine deprivation agents and polyamine analogue, is a promising strategy to reverse immunosuppression and enhances the efficiency of checkpoint inhibitors. These evidences establish polyamine metabolism as a therapeutic vulnerability in pancreatic ductal adenocarcinoma, offering novel diagnostic tools and combination regimens to overcome therapeutic resistance.

Keywords:  immune cell; immunotherapy; pancreatic cancer; polyamine metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218016
Front Med. 2025 Sep 20.

Lactate and lactylation in tumor immunity.

Liu Song, Lingjuan Sun, Song Chen, Peixiang Lan.

  The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate's role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate's importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.

Keywords:  TME; immunosuppressive immune cells; lactate; lactylation; tumor immunity

DOI:  https://doi.org/10.1007/s11684-025-1148-0
J Allergy Clin Immunol. 2025 Sep 17. pii: S0091-6749(25)00948-0. [Epub ahead of print]

Brg1-imprinted chromatin status controls the effector and memory ILC2 metabolism to exacerbate allergic lung inflammation.

Jupei Tang, Hanxiao Sun, Huidan Chang, Liyun Yuan, Yue Chen, Xueliang Zhang, Yongzhen Tao, Lifeng Yang, Zhen Shao, Xiaohuan Guo, Hong Zhou, Huiming Sheng, Qiang Zou, Xiao Su, Jinxin Qiu, Jun Qin, Ju Qiu.

   BACKGROUND: The chromatin status fluctuates with effector and memory group 2 innate lymphoid cell (ILC2) responses. How this intricate coordination affects allergic lung inflammation remains unclear.
OBJECTIVE: We examined how the chromatin remodeler Brg1 regulates ILC2s in allergic lung inflammation.
METHODS: Acute lung allergic inflammation was induced with papain in wild-type, Il5Cre/+Smarca4f/f, Il5Cre/+Hif1af/f and Il5Cre/+Ldhaf/f mice. Secondary lung inflammation was induced with low-dose IL-33 in papain-primed Il5Cre/+Smarca4f/f mice. ATAC-seq, RNA-seq and Brg1 CUT&Tag analyses were performed on ILC2nav, ILC2eff, ILC2mem, IL-33 challenged Brg1-deficient ILC2, Brg1-deficient ILC2mem and human ILC2s treated with or without Brg1 inhibitor Compound14. ILC2 metabolism was analyzed with 13C glucose isotype tracing and metabolic flux, Seahorse and SCENITH assays. Compound14 was used to treat mouse and humanized mouse models of allergic lung inflammation.
RESULTS: Brg1 expression was upregulated in asthma patients' ILC2s and was induced by IL-33. Brg1 promoted IL-5+ and IL-13+ ILC2 expansion and exacerbated both acute and secondary lung inflammation. Brg1 imprinted the chromatin landscape favoring aerobic glycolysis, the metabolic process reinforced in effector and memory ILC2s. Brg1-augmented Hif1a enhancer accessibility was a sustained epigenetic signature in memory ILC2s inherited from effector ILC2s, and Hif1α enhanced effector and memory ILC2 responses. Pharmacological inhibition of Brg1, rather than dexamethasone treatment, in acute phase alleviated secondary lung inflammation.
CONCLUSION: Brg1 promotes the expansion of pathogenic effector and memory ILC2s and exacerbates allergic lung inflammation. Mechanistically, Brg1 increases the chromatin accessibility and transcription of Hif1a and Ldha, key factors reinforcing ILC2 glycolysis metabolism.

Keywords:  Allergic lung inflammation; Brg1; Group 2 innate lymphoid cell (ILC2); ILC2 memory; chromatin accessibility; glycolysis

DOI:  https://doi.org/10.1016/j.jaci.2025.08.029
Sci Adv. 2025 Sep 19. 11(38): eadw9095

Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.

Anthony W Martinelli, Chun-Pei Wu, Tristan Vornbäumen, Hudson W Coates, Louise H Jordon, Niek Wit, Jia J Sia, Anneliese O Speak, James A Nathan.

Cellular iron levels must be tightly regulated to ensure sufficient iron for essential enzymatic functions while avoiding the harmful generation of toxic species. Here, to better understand how iron levels are controlled, we carry out genome-wide mutagenesis screens in human cells. Alongside mapping known components of iron sensing, we determine the relative contributions of iron uptake, iron recycling, ferritin breakdown, and mitochondrial flux in controlling the labile iron pool. We also identify SETD2, a histone methyltransferase, as a chromatin modifying enzyme that controls intracellular iron availability through ferritin breakdown. Functionally, we show that SETD2 inhibition or cancer-associated SETD2 mutations render cells iron deficient, thereby driving resistance to ferroptosis and potentially explaining how some tumors evade antitumoral immunity.

DOI: https://doi.org/10.1126/sciadv.adw9095
Nat Commun. 2025 Sep 16. 16(1): 8295

A mesothelial differentiation gateway drives fibrosis.

Safwen Kadri, Adrian Fischer, Martin Mück-Häusl, Wei Han, Amal Kadri, Yue Lin, Lin Yang, Shaoping Hu, Haifeng Ye, Pushkar Ramesh, Meshal Ansari, Herbert B Schiller, Hans-Günther Machens, Yuval Rinkevich.

Internal organs are encased by a supportive epithelial monolayer of mesodermal origin, termed mesothelium. The nature, evolution and function of mesothelial cells, and their genetic regulation impacting disease development are insufficiently understood. Here, we generate a comprehensive organ-wide single-cell transcriptomic compendium of mesothelium across healthy and diseased mouse and human organs, delineating the evolution of conserved activated states of mesothelial cells in response to disease. We uncover genetic drives behind each cell state and reveal a conserved metabolic gate into multipotent proteolytic, inflammatory and fibrotic cell differentiation, in mouse and human. Using lung injury models in mice, in combination with mesothelial cell-specific viral approaches, we show that direct metabolic reprogramming using Ifi27l2a and Crip1 on organ surfaces, blocks multipotent differentiation and protects mouse lungs from fibrotic disease. These findings place mesothelial cells as cellular exemplars and gateway to fibrotic disease, opening translational approaches to subvert fibrosis across a range of clinical indications.

DOI: https://doi.org/10.1038/s41467-025-63990-2
Am J Physiol Cell Physiol. 2025 Sep 17.

Cannabis Improves Metabolic Dysfunction and Macrophage Signatures in Obese Mice.

Brandon N VanderVeen, Thomas D Cardaci, Christian A Unger, Mitchell M NeSmith, Jeffrey C Freeman, Arianna V Bastian, Kasie Roark, Mansi Upadhyay, Andrew G Levy, Brooke M Bullard, Sierra J McDonald, Kandy T Velázquez, Reilly T Enos, Jason L Kubinak, Lorne J Hofseth, James R Hebert, Daping Fan, E Angela Murphy.

  Obesity rates continue to rise, highlighting the need for new treatments that are effective, safe, and widely accessible. Aligned with the easing of restrictions on cannabis use, interest in its therapeutic potential is evolving. As such, we examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ9-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice. Briefly, female C57BL/6 mice were randomized into four groups (n=15/group): 1) Lean, 2) Obese Placebo, 3) Obese CBD, and 4) Obese THC. Lean mice consumed a low-fat diet for the study duration. Obese mice consumed a high-fat diet for 16 weeks prior to a 4-week cannabis (3x/week; high CBD = ~4.2 mg/kg and high THC = ~7.3 mg/kg) intervention. Consistent with our hypothesis, obesity increased Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH) both of which were significantly mitigated by either high (10.5%) CBD or high (18.16%) THC cannabis (p<0.05). Interestingly, these changes appeared to occur independent of significant weight loss or measurable changes in food intake. Diet-induced obesity also increased infiltrating macrophages, pan macrophages, and M1-like pro-inflammatory macrophages in adipose tissue and liver. These effects were rescued by high CBD and high THC (p<0.05), providing evidence consistent with causation for the improvements in HOMA-IR and MASH. Despite the legal complexities surrounding cannabis use, these data suggest both CBD and THC can be a viable therapy to target macrophages and improve metabolic health and immune dysregulation with obesity.

Keywords:  cannabidiol; immune cells; metabolism; obesity; Δ9-tetrahydrocannabinol

DOI:  https://doi.org/10.1152/ajpcell.00503.2025
Mol Metab. 2025 Sep 11. pii: S2212-8778(25)00157-7. [Epub ahead of print] 102250

Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure.

Andrea R Ortiz, Kevin Nay, Brittany A Stork, Adam M Dean, Sean M Hartig, Cristian Coarfa, Surafel Tegegne, Christopher Rm Asquith, Daniel E Frigo, Brian York, Anthony R Means, Mark A Febbraio, John W Scott.

  Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic metabolism, and a coordinator of macrophage-mediated inflammatory responses. Here, we demonstrate that myeloid-specific Camkk2 deficient mice are protected from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects are associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure. Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.

Keywords:  Glucose homeostasis; Inflammation; Insulin resistance; Kinase signaling; Liver steatosis

DOI:  https://doi.org/10.1016/j.molmet.2025.102250
Biochim Biophys Acta Mol Basis Dis. 2025 Sep 12. pii: S0925-4439(25)00398-9. [Epub ahead of print] 168050

Single-cell multi-omics reveals SLC2A1-driven glycolytic reprogramming of pulmonary endothelial cells in sepsis-associated lung injury.

Dingde Long, Tianyuan Li, Ziyun Lu, Bei Fang, Ying Tian, Huan Fu, Yang Dong.

  Sepsis-induced lung injury is driven by pathological remodeling of pulmonary microvascular endothelial cells (PMVECs), yet the metabolic underpinnings of endothelial dysfunction remain poorly understood. Using single-cell multi-omics analysis of PMVECs from septic patients, we identified profound metabolic reprogramming dominated by glycolysis upregulation, orchestrated through the HIF-1/PI3K-Akt signaling axis. Integrated bioinformatics (Seurat/WGCNA) and experimental validation in a murine sepsis model revealed that SLC2A1-mediated glycolytic flux sustains PMVEC dysfunction, exacerbating tissue inflammation, apoptosis, and fibrosis. Targeted inhibition of glycolysis via SLC2A1 siRNA attenuated metabolic stress, evidenced by reduced extracellular acidification rate (Seahorse) and tricarboxylic acid cycle suppression (metabolomics), while restoring endothelial proliferation, migration, and VEGF/HIF1A homeostasis. Mechanistically, glycolytic inhibition decreased leukocyte infiltration (IHC) and alveolar damage, correlating with improved lung repair metrics. This study establishes PMVEC glycolysis as a keystone of sepsis-associated acute lung injury (ALI), where metabolic reprogramming transitions from adaptive survival signaling to maladaptive tissue injury. Our findings highlight SLC2A1-driven glycolytic pathways as actionable targets for mitigating endothelial dysfunction and advancing metabolic intervention strategies in septic ALI.

Keywords:  Glycolysis; HIF-1 signaling; Metabolic reprogramming; SLC2A1; Sepsis-associated acute lung injury (ALI)

DOI:  https://doi.org/10.1016/j.bbadis.2025.168050
bioRxiv. 2025 Sep 07. pii: 2025.08.31.673391. [Epub ahead of print]

Interferon gamma signaling drives cardiac metabolic rewiring.

Ebram Tharwat Melika, DiyaaElDin Ashour, Kyoungmin Kim, Alexander Nickel, Paula Arias-Loza, Xinyu Chen, Panagiota Arampatzi, Mugdha Srivastava, Martin Väth, Edécio Cunha, Michaela Kuhn, Georg Gasteiger, Ulrich Hofmann, Takahiro Higuchi, Christoph Maack, Stefan Frantz, Anja Karlstaedt, Gustavo Campos Ramos.

   Background: IFN-gamma (IFN-γ) signaling influences myocardial inflammation and fibrosis across a wide range of conditions, including ischemic and non-ischemic heart failure (HF). However, the direct effects of IFN-γ on cardiomyocytes remain poorly understood. Here, we developed a novel in vivo model to investigate how IFN-γ impacts myocardial metabolism and function.
Methods: Male C57BL/6J mice were injected intravenously with hepatotropic adeno-associated virus (AAV2/8) carrying Ifng and nLuc reporter under the albumin promoter (AAV-Ifng) or empty vector control virus (AAV-ctrl). Cardiac alterations were monitored on day 28 through flow cytometry, bulk RNA sequencing, targeted metabolomics, isolated mitochondrial activity, echocardiography, and in vivo imaging using [18F]fluordeoxyglucose ([18F]FDG) and [18F]fluoro-6-thia-heptadecanoic acid. Additionally, mice lacking IFN-γ receptor expression in cardiomyocytes (Myh6 Cre Ifngr1 fl/fl) were used to further dissect the cell-intrinsic roles of IFN-γ signaling in cardiomyocyte metabolic reprograming.
Results: After confirming liver-specific viral transfection and elevated serum IFN-γ production at physiological levels, we observed cardiac metabolic adaptation and rewiring in animals treated with AAV-Ifng compared to control animals. Myocardial bulk RNA sequencing and gene set enrichment analysis identified an IFN-γ response signature accompanied by marked down-regulations of oxidative phosphorylation and fatty acid oxidation pathways. Functional assessment of isolated cardiac mitochondria showed decreased oxygen consumption, and targeted metabolomics confirmed metabolic shifts toward glycolysis in mice overexpressing IFN-γ. In vivo imaging confirmed increased cardiac glucose uptake following AAV-Ifng treatment. Notably, these metabolic alterations were abrogated in mice with cardiomyocyte-specific deletion of IFN-γ receptors (IFNGR).
Conclusions: Systemic IFN-γ induces pronounced metabolic reprogramming in the heart, characterized by increased glucose uptake and reduced oxidative phosphorylation, via direct signaling through cardiomyocyte IFNGR. These alterations mirror those observed in aging and some forms of HF, thereby highlighting that, beyond classical inflammation, this cytokine regulates cardiac metabolism.

Keywords:  T cells; cardiac metabolism; cardiomyocytes; interferon gamma; mitochondria

DOI:  https://doi.org/10.1101/2025.08.31.673391
J Cell Physiol. 2025 Sep;240(9): e70091

Mast Cell Immunometabolism in Type 2 Diabetes and Alzheimer's Disease.

Heather L Caslin, Munira Kapadia, Tameka A Clemons.

  Type 2 diabetes (T2D) and Alzheimer's Disease (AD) have seemingly different pathologies and symptoms. However, T2D is a risk factor for AD, and recent evidence suggests there are many mechanistic similarities between the etiologies of each disease including inflammation. Mast cells are tissue resident, sentinel immune cells that reside in the pancreas, adipose tissue, and brain, increase in T2D and AD, and have generally been shown to worsen T2D and AD. However, there are limited studies of local or temporal mast cell deletion, and different phenotypic and polarization states seemingly influence the role of mast cells in the progression of disease. As there are metabolic similarities between T2D and AD including insulin resistance and lipid influx into the brain, we discuss the impact of glucose, insulin, amylin, and different lipid species on the activation and polarization of mast cells, which generally reduce IgE-mediated degranulation and promote lipid droplet formation and arachidonic acid metabolism. Altogether, this review provides a framework for understanding a shared mechanism of immunometabolic regulation of T2D and AD and provides rationale for future work in this area.

Keywords:  amylin; chronic disease; fatty acids; glucose; insulin; metabolic disease

DOI:  https://doi.org/10.1002/jcp.70091
PLoS One. 2025 ;20(9): e0332825

Lactic acid regulates antitumor immunity in canine invasive urothelial carcinoma.

Taiki Kato, Nao Okauchi, Tomoki Motegi, Masashi Sakurai, Shingo Maeda, Daiki Kato, Takayuki Nakagawa, Kazuyuki Uchida, Takuya Mizuno, Masaya Igase.

Canine invasive urothelial carcinoma (iUC) is a fatal malignant neoplasm that closely resembles human muscle-invasive bladder cancer in terms of histopathological features, molecular alterations, and clinical behavior. These similarities suggest that canine iUC represents a valuable spontaneous model for studying human bladder cancer. Tumor microenvironment (TME) plays a crucial role in tumor progression. Tumor-derived lactic acid has been implicated in the suppression of antitumor immunity and the promotion of tumor growth by altering the metabolic status of immune cells within the TME. However, the interaction between tumor metabolism and immune cells in the TME remains unclear in dogs. This study reanalyzed previously reported RNA-seq data to investigate the mechanisms underlying enhanced glycolysis in canine iUC. ERBB2 overexpression was found to induce AKT phosphorylation and increase extracellular lactic acid levels in vitro, activating the ERBB2-AKT-glycolysis axis and upregulating monocarboxylate transporter 4 (MCT4). MCT4 knockdown by RNA interference or pharmacological inhibition with diclofenac reduced lactic acid levels in the culture supernatant. Furthermore, MCT4 expression in canine iUC tissues was positively correlated with infiltrating regulatory T cell (Treg) counts. Functional studies revealed that lactic acid promoted Treg differentiation and suppressed IFN-γ production by effector T cells. These findings indicate that MCT4 mediates lactic acid efflux from glycolytic tumor cells, contributing to the suppression of antitumor immunity. Targeting tumor metabolism through MCT4 inhibition may represent a promising therapeutic strategy for canine iUC. Therefore, insights from the metabolic and immunological landscape of canine iUC may inform the development of translational therapies for both veterinary and human oncology.

DOI: https://doi.org/10.1371/journal.pone.0332825
J Clin Invest. 2025 Sep 16. pii: e186420. [Epub ahead of print]135(18):

MASH: the nexus of metabolism, inflammation, and fibrosis.

Gregory R Steinberg, Andre C Carpentier, Dongdong Wang.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. The transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to MASH is driven by the accumulation of toxic lipid and metabolic intermediates resulting from increased hepatic uptake of fatty acids, elevated de novo lipogenesis, and impaired mitochondrial oxidation. These changes promote hepatocyte stress and cell death, activate macrophages, and induce a fibrogenic phenotype in hepatic stellate cells (HSCs). Key metabolites, including saturated fatty acids, free cholesterol, ceramides, lactate, and succinate, act as paracrine signals that reinforce inflammatory and fibrotic responses across multiple liver cell types. Crosstalk between hepatocytes, macrophages, and HSCs, along with spatial shifts in mitochondrial activity, creates a feed-forward cycle of immune activation and tissue remodeling. Systemic inputs, such as insulin-resistant adipose tissue and impaired clearance of dietary lipids and branched-chain amino acids, further contribute to liver injury. Together, these pathways establish a metabolically driven network linking nutrient excess to chronic liver inflammation and fibrosis. This Review outlines how coordinated disruptions in lipid metabolism and intercellular signaling drive MASH pathogenesis and provides a framework for understanding disease progression across tissue and cellular compartments.

DOI: https://doi.org/10.1172/JCI186420
bioRxiv. 2025 Sep 02. pii: 2025.08.28.672769. [Epub ahead of print]

Diacylglycerol metabolism drives host-pathogen responses during enteric infection in Drosophila.

Xiaotong Li, Mohamed Mlih, Jason Karpac.

Lipid metabolism is fundamental to cellular homeostasis, supporting energy storage, membrane architecture, and cellular signaling. Beyond these canonical roles, lipids have emerged as critical regulators of host immunity. Here, we define a lipid-driven mechanism that governs host-pathogen interactions by impacting pathogen clearance and thus infection outcomes. Exploiting Drosophila, we show that enteric infection triggers robust accumulation of neutral lipids, and specifically 1,2-diacylglycerols (DAGs), in the midgut. Disruption of DAG biosynthesis or lipid transport in midgut enterocytes (ECs) impairs lipid accumulation and reduces host survival. Conversely, dietary lipid supplementation enhances lipid storage and improves survival. Mechanistically, these lipid-dependent responses regulate defecation, thereby controlling bacterial clearance from the midgut. DAGs can act as signaling lipids that activate protein kinase C (PKC), and DAG accumulation in ECs correlates with elevated PKC activity and calcium signaling in midgut visceral muscle (VM), promoting VM contraction, midgut motility, and expulsion of pathogens via defecation. Together, our findings reveal a previously unrecognized role for DAG metabolism in shaping host defenses.

DOI: https://doi.org/10.1101/2025.08.28.672769
Front Med (Lausanne). 2025 ;12 1636699

Malignant epithelia cells-derived spermine induces APOE+ macrophages to suppress tumor immunity in adenocarcinoma of the esophagogastric junction.

Yan Zhang, Zhaoyang Liu, Huihui Sun, Zhenxiang Wang, Ye Chen, Zhiqian Hu, Xinxing Li, Kai Xu, Ying Chen, Yanping Xu, Chenfei Wang, Shuchang Xu.

   Background: Adenocarcinoma of the esophagogastric junction (AEG) is increasingly recognized as a distinct gastrointestinal tumor type with a poor prognosis. However, the mechanisms driving AEG progression, particularly the interplay between metabolic reprogramming and the immune microenvironment, remain poorly understood.
Methods: We integrated multi-omics to profile the tumor microenvironment and metabolic reprogramming of AEG. Tumor tissues and paired normal adjacent tissues from AEG patients were subjected to single-cell RNA sequencing (N=11), spatial transcriptomics (N=4), and metabolomics analysis (N=26). Molecular experiments and animal models were used for validation.
Results: Our analysis revealed an AEG-specific malignant subtype originating from the esophagogastric junction, characterized by heightened proliferation and poor differentiation. These malignant cells exhibited metabolic reprogramming marked by hyperactivation of the glutamine-arginine-spermine axis with concomitant spermine accumulation. Spermine was found to drive the polarization of tumor-associated macrophages into an APOE+ immunosuppressive phenotype, thereby modulating the tumor immune microenvironment. Mechanistically, spermine promoted the phosphorylation of STAT3, thereby enhancing its binding affinity to the APOE promoter region and leading to enhanced transcriptional activation of APOE.
Conclusion: This study identified AEG-like malignant cells as a high-risk subtype, revealed the metabolic-immune crosstalk driven by the spermine-STAT3-APOE axis in AEG progression, and provided potential targets for AEG metabolic intervention and immunotherapy.

Keywords:  adenocarcinoma of the esophagogastric junction; cancer metabolism; single-cell RNA sequencing; spatial transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.3389/fmed.2025.1636699
Cell Host Microbe. 2025 Sep 18. pii: S1931-3128(25)00337-3. [Epub ahead of print]

Long-chain unsaturated fatty acids released during immune responses stimulate host-microbe trans-kingdom communication.

Aleksander Czauderna, Grishma Kulkarni, Niccolò Bianchi, Liqing Cheng, Marissa Sim, Nicola R Realini, Joanna Gach, Aurelie Caillon, Joachim Kloehn, Gérard Lambeau, Annika Hausmann, Stefano Serra, Matthew T Sorbara, Simone Becattini.

  Immune responses can significantly alter the structure and function of the gut microbiota, leading to rapid transcriptional and metabolic shifts in commensal microbes. However, the host mediators involved in this process and their effects on bacteria remain poorly elucidated. Here, using a flagellin injection model to induce immune activation, we identified unsaturated long-chain fatty acids (uLCFAs) as broad modulators that are released into the gut lumen and alter bacterial gene expression. Luminal release of uLCFAs is partially mediated by host phospholipases, including PLA2G5. In response to uLCFAs, commensals such as Blautia trigger the expression of ohyA, encoding oleate hydratase, which converts toxic uLCFAs to non-toxic hydroxy fatty acids with immunomodulatory properties. Remarkably, oral administration of uLCFAs to mice replicates many of the bacterial transcriptional changes induced by flagellin. This molecular loop underscores the sophisticated interactions between host and microbiota and sheds light on how immune responses affect gut commensal functions.

Keywords:  Blautia; immune responses; long-chain unsaturated fatty acids; microbiota; oleate hydratase; transcriptomics

DOI:  https://doi.org/10.1016/j.chom.2025.08.011
J Immunol. 2025 Sep 16. pii: vkaf197. [Epub ahead of print]

Non-hematopoietic tryptophan metabolism is a driver of ineffective T cell responses during secondary pulmonary bacterial infection.

Lydia M Roberts, Leanne Arakkal, Tara Wehrly, Claire Poore Fonseka, Pavlina Laskova, Benjamin Schwarz, Eric Bohrnsen, Ronald Germain, Catharine M Bosio, Emily Speranza.

  Pulmonary infections often fail to produce long-lived immune memory and the underlying mechanism(s) for this are unclear. Given the complex interactions between cells within the lung, we predicted intrinsic and extrinsic factors contribute to development of poor memory immune responses. To identify these factors, we used a multiomics approach to determine host-driven responses that undermine or support development of effective immune responses in two mouse models of pulmonary bacterial infections. Single cell RNA analysis and spatial imaging of the lung revealed that, in contrast to Bordetella pertussis driven immunity, subpar responses following Francisella tularensis infection were associated with the inability of T cells to readily proliferate upon re-challenge and absence of formation of iBALT. Further, we also identified that these features were partially a consequence of IFN-γ driven reprogramming of endothelial cells resulting in expression of IDO1 and dysregulated tryptophan metabolism. Interestingly, IDO1 expression and imbalanced tryptophan persisted even after clearance of the primary infection. The importance of expression of IDO1 was confirmed using IDO1 knock out mice. Specifically, these animals could withstand higher doses of the initial infection and developed significantly larger pools of functional T cells compared to wild type controls. Together, these results demonstrate critical crosstalk among cells in the lung that influences spatial organization of immune cells which affects the ability to develop effective memory immune responses against secondary bacterial infection. Our data also underscores the challenge of utilizing a live vaccine strategy against tularemia and the necessity for identifying novel, acellular vaccine candidates.

Keywords:  T cell; bacteria; lung; metabolism

DOI:  https://doi.org/10.1093/jimmun/vkaf197
Semin Oncol. 2025 Sep 12. pii: S0093-7754(25)00105-8. [Epub ahead of print]52(6): 152413

Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond.

Chou-Yi Hsu, Yasmeen Kateb Ahmed, Shaker Mohammed, Mohammad A Alghamdi, Hasan S Al-Ghamdi, Jaafaru Sani Mohammed, Mohammed Abed Jawad, Salim B Alsaadi.

  Melanoma is a particularly aggressive type of skin cancer due to its rapid growth and capacity to metastasize. There is substantial metabolic reprogramming in melanoma that is linked to its malignant characteristics, including therapeutic resistance. This review intended to provide a detailed overview of the central metabolic pathways reprogrammed in melanoma, including the Warburg effect and the complex interactions between glycolysis and oxidative phosphorylation, which ultimately influence energy production, biosynthesis, and adaptation to the tumor microenvironment. We also discuss the molecular pathways that regulate these metabolic pathways and the effect these metabolic processes have on crucial elements of melanoma progression, including invasion, metastasis, and survival during nutrient deprivation and hypoxia. Furthermore, we discuss the importance of metabolism beyond glucose, including glutamine metabolism, changes in lipid metabolism, and alterations in one-carbon and nucleotide biosynthesis, as well as mechanisms critical for the proliferation and survival of melanoma cells. An emphasis is placed on the active metabolic crosstalk between melanoma cells and the immune system within the tumor microenvironment, where melanoma cells utilize nutrient competition and the production of immunosuppressive metabolites to alter and block the function of anti-tumor immune cells, thereby facilitating immune evasion and therapy resistance. Lastly, we critically assess developments targeting melanoma metabolism, including pharmacological inhibition of key metabolic enzymes and pathways, as well as metabolic modulation to enhance the efficacy of conventional and immunotherapies. Although promising, this area is complex and subject to contextual effects and metabolic heterogeneity, indicating that we still have a way to go in annotating robust and clinically relevant metabolic targets. We sought to consolidate current knowledge about melanoma metabolism and highlight the challenges, future directions, and complexity of a potential therapeutic vulnerability in the rapidly evolving field of cancer research.

Keywords:  Bioenergetics; Melanoma; Metabolism; Pathogenesis; Therapy

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152413
Front Immunol. 2025 ;16 1588019

PKM2 orchestrates tumor progression via metabolic reprogramming and MDSCs-mediated immune suppression in the tumor microenvironment.

Wenxi Liu, Jiaqi Wu, Xinran Zhang, Yanhua Zhang, Xianqin Zeng, Xiaochun Peng.

  The tumor microenvironment (TME) is a complex system, in which the energy metabolism of tumor cells plays a key role in the occurrence, development and metastasis of tumors. In the TME, the energy supply of tumor cells mainly comes from glycolysis. This metabolic reprogramming phenomenon is usually called the Warburg effect. Despite the abundance of oxygen, tumor cells still preferentially utilize the glycolytic pathway to meet their bioenergetic demands. Pyruvate kinase (PK), as a key enzyme in glycolysis, plays an important role in the regulation of energy metabolism in tumor cells. Among them, pyruvate kinase M2 (PKM2) is highly expressed in tumors and promotes the release of cytokines by tumor cells, thereby recruiting myeloid-derived suppressor cells (MDSCs). These cytokines bind to the surface receptors of MDSCs, activate related signaling pathways, and up-regulate the expression of cathepsin cysteine proteases. This process subsequently inhibits the activity of T cells, thereby affecting tumor development.

Keywords:  T cell; cathepsins; cysteinecathepsins; glycolysis; myeloid-derived suppressor cells; pyruvate kinase M2 type; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1588019
Metabolism. 2025 Sep 17. pii: S0026-0495(25)00258-6. [Epub ahead of print] 156389

Sepsis-induced lipid droplet accumulation enhances antibacterial innate immunity through mechanisms dependent on DGAT-1 and interferon-beta.

Filipe S Pereira-Dutra, Julia Cunha Santos, Ellen Kiarely Souza, Rodrigo Vieira Savi, Tamyris S Souza, Helen Gil, Hugo Espinheira-Silva, Felipe Ferraro-Moreira, Guilherme Iack, Tamires Cunha-Fernandes, Tathiany Igreja-Silva, Lohanna Palhinha, Mariana Macedo Campos, Ester Fernanda Terra Souza, Amanda França Cordeiro, Pablo Andrade-Dos-Santos, Douglas Mathias Oliveira, Vinicius Soares Cardoso, Matheus A Rajão, Livia Teixeira, Luciana Souza-Moreira, Maria Fernanda Souza Costa, Patrícia Alves Reis, Patrícia T Bozza.

  Lipid droplets (LDs) are lipid-rich organelles recognized as central players in lipid homeostasis, signaling, and inflammation. While their functions in inflammation are well-documented, the mechanisms of LDs in antibacterial immunity and infection resistance remain less understood. Our results show that E. coli-infection trigger immunometabolic reprogramming and LD accumulation in macrophages. Moreover, purified LDs from LPS-stimulated and E. coli-infected macrophages exhibited direct E. coli anti-bacterial activity. Pharmacological inhibition or genetic knockdown of DGAT1, a key enzyme in triglyceride synthesis, reduced LD formation, bacterial clearance, and pro-inflammatory responses (nitric oxide, PGE2, CCL2, IL-6). Notably, DGAT1 inhibition impaired the expression of IFN-β and several interferon-stimulated genes (ISGs), including viperin, iNOS, cathelicidin and IGTP, in E. coli-infected macrophages. In a cecal-ligation and puncture model of sepsis in C57BL/6 mice, DGAT1 inhibition reduced sepsis-induced LD accumulation in peritoneal cells and decreased levels of IFN-β, CCL2, nitric oxide, and lipid mediators (PGE2, LTB4, and RvD1). Furthermore, DGAT1 inhibition accelerated sepsis-related mortality, coinciding with elevated bacterial loads in the peritoneum and bloodstream at 6- and 24-h post-sepsis. Our results demonstrate that LDs are critical regulators of innate immunity infection resistance, contributing to both bacterial clearance and the coordination of a protective proinflammatory response during sepsis through mechanisms dependent on DGAT-1 and Type I IFN.

Keywords:  Immunometabolism; Lipid droplets; Lipid metabolism; Resistence to infection

DOI:  https://doi.org/10.1016/j.metabol.2025.156389