bims-imicid 2025-10-26 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–10–26
thirty-two papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Dysregulated immunometabolism in gut inflammation.
Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation.
Metabolic defense mediated by ACOD1/itaconate is crucial for mammary epithelial cells to resist Streptococcus uberis infection.
The Pathogenic Role of T Cell Metabolism and its Effect on Immune Senescence in Autoimmune Diseases and Infection.
Protective Role for Itaconate During Inhaled Allergen Challenge.
Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.
A non-canonical immunometabolic function of BRD3 during sepsis.
Glycolytic reprogramming during microglial polarization in neurological diseases.
Macrophage metabolism in inflammatory heart disease: new insights and therapeutic implications.
Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.
Cytochrome b5 reductase orchestrates IL-1β production in macrophages through FAD.
Kmo restricts Salmonella in a whole organism infection model by promoting macrophage lysosomal acidification through kainate receptor antagonism.
Modulation of Innate Immunity by Short-Chain Fatty Acids in Probiotic and Fecal Microbiota Transplantation Therapies for the Treatment of Colon Disorders.
Metabolic responses to Staphylococcus aureus airway infection.
Glutamate receptor-T cell receptor signaling potentiates full CD8+ T cell activation and effector function in tumor immunity.
IPA brews metabolic balance in gut immunity.
Glutamine synthetase loss in β-catenin-mutant hepatocellular carcinoma promotes tumor burden through macrophage metabolic reprogramming.
Phosphatidylcholine-bound palmitoleic acid: A bioactive key to unlocking macrophage anti-inflammatory functions.
Immunosenescence and metabolic reprogramming in MASLD: an age-dependent immunometabolic vicious cycle and therapeutic opportunities.
The effect of treatment with a non-ionic surfactant vesicular formulation of sodium stibogluconate on host immune responses and serum metabolites in a murine model of Leishmania donovani.
Small-molecule perturbation profiling reveals a mechanistic link between STING signaling and lipid metabolism in macrophages and dendritic cells.
HIVEP1 aggravates NASH by reprogramming polyamine metabolism in TH17 cells.
Immune and metabolic remodeling following bariatric surgery: Implications for targeted immunotherapy (Review).
Light Metabolically Reprograms CD8+ T Cells to Potentiate STING-Driven Tumor Eradication and Prevent Metastasis.
A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS.
Metabolic regulation of immunity in the tumor microenvironment.
Influenza virus infection reprograms cholesterol biosynthesis to facilitate virus replication by the TAK1-RORγ axis.
TREM2-Mediated Cholesterol Efflux in Macrophages Inhibits Anti-Tumor Immunity via Limitation of CD4+ T and NK Cells.
Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.
Magnetic resonance imaging quantifies causal body compartment effects on metabolic traits via immune phenotypes-a Mendelian randomisation study.
Butyrate suppresses mucosal inflammation in inflammatory bowel disease primarily through HDAC3 inhibition in monocytes and macrophages.
Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity.

Acta Biochim Biophys Sin (Shanghai). 2025 Oct 21.

Dysregulated immunometabolism in gut inflammation.

Mengqi Zheng, Qiuheng Tian, Jing Shen, Shiyang Li.

  Gut inflammatory diseases, including inflammatory bowel disease (IBD), infectious enteritis, and other inflammatory conditions, are among the most common non-neoplastic intestinal disorders. Their pathogenesis is often driven by an imbalance between pro-inflammatory and anti-inflammatory signals, with immune cells playing pivotal roles in maintaining this equilibrium. Immune cells in the gut exhibit complex, multifaceted functions: they eliminate pathogens, promote tissue repair, and counteract tumors, but excessive immune activation can exacerbate tissue damage and disease progression. Notably, metabolic reprogramming in inflammatory contexts serves as a key regulator of immune cell function and phenotypic switching. This includes alterations in cellular energy metabolism ( e. g., macrophage polarization via disrupted glycolysis or fatty acid oxidation) and the modulation of immune responses by microenvironmental metabolites ( e. g., bile acid-mediated Th17/Treg balance). While alterations in immune cell function and composition within the inflammatory milieu are well-established, the significance of disease-associated metabolic reprogramming-specifically how metabolism regulates immune cell function-has garnered increasing attention. This review explores how cellular metabolic reprogramming, changes in the metabolic microenvironment, and gut dysbiosis collectively influence the differentiation, proliferation, and function of immune cells in various intestinal inflammatory diseases, as well as their impact on disease progression.

Keywords:  immunometabolism; inflammation; intestinal disorder

DOI:  https://doi.org/10.3724/abbs.2025192
Nat Metab. 2025 Oct 21.

Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+ T cells to confer protection against intestinal inflammation.

Qing Li, Rodrigo de Oliveira Formiga, Virginie Puchois, Laura Creusot, Ahmad Haidar Ahmad, Salomé Amouyal, Márcio Augusto Campos-Ribeiro, Yining Zhao, Danielle M M Harris, Frederic Lasserre, Sandrine Ellero-Simatos, Hervé Guillou, Zhan Huang, Loic Brot, Yuhang Hu, Loic Chollet, Camille Danne, Cyril Scandola, Tatiana Ledent, Guillaume Chevreux, Rafael J Argüello, Marcelo De Carvalho Bittencourt, Jessica Bettinger, Maud D'Aveni-Piney, David Moulin, Stefan Schreiber, Konrad Aden, Nathalie Rolhion, Marie-Laure Michel, Timothy Wai, Harry Sokol.

The gut microbiota and its metabolites critically regulate immune cell phenotype, function and energy metabolism. We screened a collection of gut microbiota-related metabolites to identify modulators of mitochondrial metabolism in T cells. Here we show that indole-3-propionic acid (IPA) stimulates mitochondrial respiration of CD4+ T cells by increasing fatty acid oxidation (FAO) and amino acid oxidation (AAO), while inhibiting glycolytic capacity. IPA also impacts CD4+ T cell behaviour by inhibiting their differentiation to type 1 and type 17 helper T cell phenotypes. Mechanistically, the metabolic and immune effects of IPA are mediated by peroxisome proliferator-activated receptor-β/δ. The administration of IPA rescues mitochondria respiration in mice with gut bacteria depletion or colitis by enhancing FAO and AAO in colonic CD4+ T cells. Adoptive transfer experiments show that IPA acts on CD4+ T cells to exert its protective effect against inflammation. Collectively, our study reveals that the anti-inflammatory effects of IPA are mediated by metabolic reprogramming of CD4+ T cells toward the enhancement of mitochondrial respiration.

DOI: https://doi.org/10.1038/s42255-025-01396-6
Int Immunopharmacol. 2025 Oct 23. pii: S1567-5769(25)01712-6. [Epub ahead of print]167 115724

Metabolic defense mediated by ACOD1/itaconate is crucial for mammary epithelial cells to resist Streptococcus uberis infection.

Bo Yang, Shaodong Fu, Naiyan Sun, Huanhuan Wang, Yawei Qiu, Yuanyuan Xu, Jinqiu Zhang, Jinfeng Miao.

  Streptococcus uberis poses ongoing challenges to dairy production and public health security due to its ability to evade the immune system and its tendency to cause chronic mammary infections. Currently, strategies for controlling Streptococcus uberis infection remain inadequate, highlighting the targeting of host immunometabolism as a promising intervention measure. Itaconate, a key immunometabolic regulator, orchestrates diverse biological processes. Herein, we identified ACOD1/itaconate as an important endogenous defense molecule against Streptococcus uberis infection in mammary epithelial cells, mediated by activation of the KEAP1/Nrf2 signaling pathway. Specifically, Streptococcus uberis infection significantly up-regulated ACOD1 expression and induced intracellular itaconate accumulation. Overexpression of ACOD1 inhibited succinate dehydrogenase (SDH) activity and eliminated excess mitochondrial reactive oxygen species (mROS), thereby alleviating mitochondrial dysfunction and concomitantly enhancing cellular antioxidant defenses via up-regulation of HMOX1, NQO1, and SOD1. Furthermore, pretreatment of exogenous 4-octyl itaconate, a cell-permeable itaconate derivative, effectively alleviated the oxidative damage in mammary epithelial cells infected with Streptococcus uberis. Collectively, these findings position ACOD1/itaconate as a critical metabolic checkpoint in mammary epithelial cells during infection and highlight exogenous itaconate as a promising alternative for mastitis management.

Keywords:  ACOD1; Immunometabolism; Itaconate; Mitochondrial dysfunction; Oxidative damage; Streptococcus uberis

DOI:  https://doi.org/10.1016/j.intimp.2025.115724
Clin Rev Allergy Immunol. 2025 Oct 25. 68(1): 95

The Pathogenic Role of T Cell Metabolism and its Effect on Immune Senescence in Autoimmune Diseases and Infection.

Huan Yin, Suqing Zhou, Kai Shen, Hui Chen, Ming Yang, Yaxiong Deng, Christopher Chang, Haijing Wu.

  T cell metabolism constitutes a pivotal regulator of cellular states and disease progression. At the cellular level, the metabolic status of T cells directly governs their function and fate determination. Senescent T cells, for instance, exhibit fundamentally distinct metabolic signatures compared to effector T subsets, underscoring metabolic reprogramming as a critical mechanistic driver of T cell senescence. In pathological contexts, aberrant metabolic rewiring in T cells disrupts differentiation, function, and cellular survival, thereby contributing to disease onset and progression. Notably, the pathological accumulation of senescent T cells observed across chronic inflammatory and autoimmune diseases positions metabolism-driven T cell senescence as a key nexus linking metabolic dysregulation to clinical manifestations. Consequently, targeted modulation of T cell metabolism offers a dual therapeutic potential: direct intervention in cellular states (e.g., delaying senescent phenotypes) and synergistic amelioration of disease pathology through functional immune restoration. This Review summarizes the fundamental principles of T cell metabolic reprogramming, its causative role in propelling T cell senescence, and the dynamic interplay between metabolic dysfunction, T cell senescence, and disease pathogenesis. We specifically dissect these relationships in two immunologically divergent conditions-systemic lupus erythematosus (SLE, exemplifying hyperactive autoimmunity) and chronic infection (Chronic HIV infection, reflecting immune exhaustion)-to establish a mechanistic framework for developing metabolism-targeted immunotherapeutics that precisely restore T cell efficacy.

Keywords:  Autoimmune disease; Chronic infection; Metabolic reprogram; Senescent T cell; T cell

DOI:  https://doi.org/10.1007/s12016-025-09109-3
Allergy. 2025 Oct 24.

Protective Role for Itaconate During Inhaled Allergen Challenge.

Gesa J Albers, Patricia P Ogger, Christina Michalaki, Helen Stölting, Simone A Walker, Anna Caldwell, John M Halket, Kathryn Duvall, Atia Batool, Lisha Joshi, Helen O'Brien, Cormac McCarthy, Timothy Hinks, Gail M Gauvreau, Paul M O'Byrne, Clare M Lloyd, Adam J Byrne.

   BACKGROUND: Asthma is a chronic, heterogeneous disease characterised by airway remodelling, inflammation, and mucus production. Airway macrophages' functions are underpinned by changes in cellular metabolism. The TCA cycle-derived metabolite itaconic acid (whose synthesis is mediated by aconitate decarboxylase) is a master regulator of macrophage function; however, its role during inhaled allergen challenge is not clear. The objective of this study was to define the role of itaconate during inhaled allergen challenge.
METHODS: Sputum metabolite levels were measured in participants with mild allergic asthma undergoing allergen inhalation challenge, and in a second cohort, baseline levels in mild, moderate, and severe asthmatics. Airway inflammation, lung function, and bronchoalveolar lavage metabolite levels were assessed in wild-type and aconitate decarboxylase-deficient mice, or in mice treated with inhaled itaconate.
RESULTS: Allergen inhalation in mild asthmatics led to a significant reduction in sputum itaconate. We found no difference in baseline sputum itaconate levels when comparing healthy controls to mild, moderate, or severe asthmatics. Continuous exposure to aeroallergen in wild type and aconitate decarboxylase-deficient mice showed no change in disease phenotype after 48 h, 1, 3, or 5 weeks of allergen exposure. Treatment of house dust mite-exposed mice with inhaled itaconate reduced airway inflammation.
CONCLUSION: Levels of itaconate are altered after allergen challenge in mild asthmatics and in murine models of disease. Itaconate deficiency did not alter house dust mite-induced pathology at any of the timepoints tested; however, inhaled itaconate ameliorated inflammatory responses to inhaled allergen.

Keywords:  airway inflammation; allergen exposure; asthma; itaconate; macrophage metabolism

DOI:  https://doi.org/10.1111/all.70107
Sci Immunol. 2025 Oct 24. 10(112): eads9456

Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.

Jordy Saravia, Nicole M Chapman, Yu Sun, Xiaoxi Meng, Isabel Risch, Wei Li, Cliff Guy, Hao Shi, Haoran Hu, Yogesh Dhungana, Jia Li, Zhiyuan You, Anil Kc, Seon Ah Lim, Jana L Raynor, Sharad Shrestha, Erienne G Norton, Sarah E La Grange, Camenzind G Robinson, Peter Vogel, Hongbo Chi.

Immunotherapies targeting regulatory T (Treg) cells often trigger inflammation and autoimmunity. How Treg cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates Treg cell metabolic and functional fitness. Treg cell-specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of Treg cells with high mitochondrial metabolic and suppressive function. Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate-activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, Treg cell-specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency-associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient Treg cells were enriched in a terminal "metabolic quiescence reset" state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria-lysosome interplay control Treg cell differentiation and function.

DOI: https://doi.org/10.1126/sciimmunol.ads9456
Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00601-X. [Epub ahead of print]

A non-canonical immunometabolic function of BRD3 during sepsis.

Nian Wang, Jiao Liu, Runliu Wu, Feng Chen, Chunhua Yu, Herbert Zeh, Xianzhong Xiao, Haichao Wang, Timothy R Billiar, Ling Zeng, Jianxin Jiang, Daolin Tang, Rui Kang.

  Sepsis is a life-threatening condition characterized by a dysregulated host innate immune response to pathogen infection. Here, we identify a pathological role for bromodomain-containing 3 (BRD3) in driving septic shock by upregulating aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages via a non-canonical pathway. Mechanistically, lipopolysaccharide triggers an interaction between BRD3 and tripartite motif containing 21 (TRIM21), which activates CREB binding lysine acetyltransferase (CREBBP) via its E3 ligase activity, facilitating CREBBP's binding to and acetylation of cyclic adenosine monophophate (cAMP)-response-element-binding protein 1 (CREB1). BRD3 then recognizes and phosphorylates acetylated CREB1 at the transcription-activating site, thereby upregulating ACOD1 transcription. In four murine models of infection, myeloid-specific Brd3 deletion (Brd3Mye-/-) or pharmacological intervention using small-molecule inhibitor OTX015 confers significant protection, reducing systemic inflammation and organ injury, similar to the effects observed in Acod1Mye-/- mice. In patients with sepsis, elevated BRD3 levels correlate with accelerated inflammation, increased disease severity, and a greater risk of in-hospital death. These findings establish BRD3 as a potential therapeutic target for managing infection-associated immune dysregulation.

Keywords:  ACOD1; BRD3; immunometabolism; inflammation; itaconate; sepsis

DOI:  https://doi.org/10.1016/j.devcel.2025.09.016
Front Immunol. 2025 ;16 1648887

Glycolytic reprogramming during microglial polarization in neurological diseases.

Xiaoting Li, Congcong Fang, Yina Li, Xiaoxing Xiong, Xu Xu, Lijuan Gu.

   Background: Microglia, the resident immune cells of the central nervous system (CNS), play pivotal roles in the onset and progression of various neurological disorders. Owing to their remarkable plasticity, microglia can adopt diverse phenotypic states in response to distinct microenvironmental cues. Over the past decades, accumulating evidence has demonstrated that immune cell metabolism critically regulates their polarization and effector functions through a process termed metabolic reprogramming, in which glucose metabolism is particularly central. Glycolytic reprogramming underlies the entire polarization process, and elucidating its mechanisms may enable targeted modulation of microglial activity to mitigate their deleterious effects in CNS pathologies, thereby offering novel therapeutic avenues for these diseases.
Aim of the Review: This paper summarizes what is known about microglial polarization and glycolytic reprogramming and explores their important roles in the development of neurological diseases. The link between microglial metabolomics and epigenetics in neurological disorders requires further study.
Key Scientific Concepts of the Review: Microglia exhibit distinct phenotypic states at different stages of central nervous system (CNS) disorders, and these polarization processes are closely coupled with glucose metabolic reprogramming. Proinflammatory microglia predominantly rely on glycolysis, whereas reparative or anti-inflammatory phenotypes primarily utilize oxidative phosphorylation. Targeting glycolytic pathways to limit the polarization of microglia toward proinflammatory states has emerged as a promising therapeutic strategy for CNS diseases.

Keywords:  Warburg effect; glycolysis; lactylation; metabolic reprogramming; microglia; nervous system diseases

DOI:  https://doi.org/10.3389/fimmu.2025.1648887
Front Med (Lausanne). 2025 ;12 1664538

Macrophage metabolism in inflammatory heart disease: new insights and therapeutic implications.

Aocheng Xiang, Aie Chang, Jichang Zhou, Jin Jin, Xi Zhang, Qianyan Wang.

  Macrophages are essential immune cells involved in pathogen clearance, initiation and resolution of inflammation, and tissue repair across multiple organ systems. They exhibit remarkable phenotypic diversity, encompassing classical M1 and M2 subtypes-further subdivided into M2a, M2b, M2c, and M2d-as well as newly identified subsets such as Mreg, M4, Mox, and Mhem, each with distinct functional roles. Emerging evidence highlights cellular metabolism as a central regulator of macrophage phenotype and function. Distinct metabolic programs underpin the polarization of M1 and M2 macrophages in response to environmental cues, thereby critically influencing disease progression and tissue outcomes. Cardiovascular disease remains a leading cause of morbidity and mortality worldwide. In the heart, macrophages represent a dominant immune cell population and play integral roles in both pathological injury and tissue regeneration. This review provides a comprehensive overview of macrophage ontogeny, phenotypic heterogeneity, and metabolic reprogramming, with a particular focus on their roles in inflammatory heart diseases. We synthesize current findings on how metabolic pathways shape macrophage behavior and function within the cardiac microenvironment and discuss the therapeutic potential of targeting macrophage metabolism to modulate inflammation, promote repair, and improve clinical outcomes in cardiovascular disease.

Keywords:  disease; heart; immunometabolism; inflammatory; macrophage; metabolic; reprogramming; therapeutic targeting

DOI:  https://doi.org/10.3389/fmed.2025.1664538
Nat Commun. 2025 Oct 23. 16(1): 9370

Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.

Vikas Yadav, Sarthak Sahoo, Nitish Malhotra, Richa Mishra, Sreesa Sreedharan, Raju S Rajmani, Siva Shanmugam, Radha K Shandil, Shridhar Narayanan, Vivek V Thacker, Sunil Laxman, Mohit Kumar Jolly, Aswin Sai Narain Seshasayee, Amit Singh.

Effective clearance of Mycobacterium tuberculosis (Mtb) requires targeting drug-tolerant populations within host macrophages. Here, we show that macrophage metabolic states govern redox heterogeneity and drug response in intracellular Mtb. Using a redox-sensitive fluorescent reporter (Mrx1-roGFP2), flow cytometry, and transcriptomics, we found that macrophages with high oxidative phosphorylation (OXPHOS) and low glycolysis harbor reductive, drug-tolerant Mtb, whereas glycolytically active macrophages generate mitochondrial ROS via reverse electron transport, imposing oxidative stress on Mtb and enhancing drug efficacy. Computational and genetic analyses identified NRF2 as a key regulator linking host metabolism to bacterial redox state and drug tolerance. Pharmacological reprogramming of macrophages with the FDA-approved drug meclizine (MEC) shifted metabolism towards glycolysis, suppressed redox heterogeneity, and reduced Mtb drug tolerance in macrophages and mice. MEC exhibited no adverse interactions with frontline anti-TB drugs. These findings demonstrate the therapeutic potential of host metabolic reprogramming to overcome Mtb drug tolerance.

DOI: https://doi.org/10.1038/s41467-025-64407-w
Cell Death Dis. 2025 Oct 21. 16(1): 742

Cytochrome b5 reductase orchestrates IL-1β production in macrophages through FAD.

Jian Fu, Zhihua Liu, Hangchao Zhang, Xinmei Zhang, Shijie Liu, Xuehua Mei, Xiu Zeng, Wenkai Ren.

The cytochrome-b5 reductases (CYB5Rs) regulate cellular redox balance and contribute to the pathogenesis of inflammatory diseases. However, the roles of CYB5R5 in macrophages remain poorly understood and require further elucidation. In this study, we revealed that CYB5R5 orchestrates macrophage inflammation by inhibiting interleukin (IL)-1β production from M1 macrophages. Mechanistically, CYB5R5 enhances flavin adenine dinucleotide (FAD)-lysine demethylase1 (LSD1) signaling to regulate the histone demethylation of complement component 1, q subcomponent (C1q)-coding genes, thereby lowering NLRP3 inflammasome assembly. We also found that myeloid depletion of Cyb5r5 in mice exacerbates inflammatory responses in LPS-induced sepsis. This study reveals that CYB5R5 attenuates M1 macrophage polarization via metabolic and epigenetic reprogramming mechanism, thus providing potential therapeutic targets for macrophage-mediated inflammatory disorders.

DOI: https://doi.org/10.1038/s41419-025-08073-2
PLoS Pathog. 2025 Oct 23. 21(10): e1013273

Kmo restricts Salmonella in a whole organism infection model by promoting macrophage lysosomal acidification through kainate receptor antagonism.

Emily R Goering, Anne E Clatworthy, Margarita Parada-Kusz, Josephine Bagnall, Deborah T Hung.

The kynurenine pathway of tryptophan degradation has been implicated in various diseases including cancer, neurodegenerative disorders, and infectious diseases. A key branchpoint in this pathway is production of the metabolite 3-hydroxy-kynurenine (3-HK) by the enzyme kynurenine 3-monooxygenase (Kmo). We have previously reported that administration of exogenous 3-HK promotes survival of zebrafish larvae to Salmonella Typhimurium infection by restricting bacterial expansion via a systemic mechanism that targets kainate sensitive glutamate receptor (KAR) ion channels and that the endogenous production of 3-HK by Kmo is required for defense against systemic Salmonella infection. Here we show that endogenous 3-HK promotes lysosomal acidification to contribute to macrophage microbicidal activity, with its absence leading to increased host susceptibility to infection. Further, 3-HK promotes lysosomal acidification in a KAR-dependent manner. We thus reveal a novel link between KARs and macrophage lysosomal acidification, and a novel mechanism by which 3-HK promotes control of bacterial infection.

DOI: https://doi.org/10.1371/journal.ppat.1013273
Probiotics Antimicrob Proteins. 2025 Oct 22.

Modulation of Innate Immunity by Short-Chain Fatty Acids in Probiotic and Fecal Microbiota Transplantation Therapies for the Treatment of Colon Disorders.

Jayasree Saha, Ritobrata Goswami.

  Short-chain fatty acids (SCFAs) are produced by microbes in the gut from macronutrient fermentation. As the key bacterial metabolites, three SCFAs-acetate, propionate, and butyrate-are abundant in the gut and are presently linked to a number of homeostatic and pathophysiologic immune regulatory processes. The significance of these metabolites in the control of numerous immunological processes is currently being closely examined especially in gut immunity in gut-liver and gut-brain axes. Besides affecting cell metabolism and functions that confer immunity to the host, interestingly, SCFAs are currently in the spotlight for their role in innate immune cell maturation and differentiation having potential translational benefits. Dysbiosis in the gut leading to alterations of gut microbe population affects wide array of physiologic functions including both local and systemic immune regulation. Affecting millions worldwide, inflammatory bowel disease (IBD) and colorectal cancer (CRC) are the major gut diseases where the etiology can be partially attributed to gut dysbiosis and short-chain fatty acid alterations. We closely monitored the impact of intervention strategies of IBD and CRC by alteration of gut microbiota through probiotic administration and fecal microbiota transplantation on innate immunity. Although ongoing studies underscore the implications of these strategies in combatting gut inflammation but the importance of SCFA metabolism on innate immunity needs to be addressed. With the current narrative, we aim to connect the dots and find any missing links, between how probiotic administration and fecal microbiota transplantation as therapies impact gut inflammation via innate immune cell regulation through SCFAs as gut microbial metabolites.

Keywords:  Colon cancer; FMT; Gut microbiome; IBD; Innate immune cells; Probiotics; SCFAs

DOI:  https://doi.org/10.1007/s12602-025-10807-9
Am J Physiol Cell Physiol. 2025 Oct 21.

Metabolic responses to Staphylococcus aureus airway infection.

Dorothea Bünsow, Volker Winstel.

  Respiratory tract infections caused by antibiotic-resistant Staphylococcus aureus are often fatal and largely influenced by the pathogen's ability to overcome host immune defenses. Despite the importance of immune evasion, staphylococci along with their exoproducts are also known to modulate specific metabolic pathways within the respiratory epithelium and infection hot spot-infiltrating phagocytic cells, thereby impacting inflammatory and antimicrobial responses. Here, we briefly discuss how S. aureus induces disease-related metabolic alterations in professional and non-professional phagocytes during acute and chronic infections of the lung. Specifically, we focus on metabolic plasticity of airway epithelial cells and predominant phagocytes upon sensing of S. aureus, and further detail metabolic adaptation strategies of staphylococcal small colony variants that often cause persistent and hard-to-treat infections within the airways of individuals suffering from cystic fibrosis. In this context, we highlight how metabolic rerouting and buildup of specific bacterial metabolites including intermediates of the tricarboxylic acid cycle can shift the lifestyle of S. aureus toward sessility and intracellular persistence. Coupled with a section addressing the role of bacterial energy metabolism during S. aureus respiratory infections, these insights may aid in the design of novel anti-infective and immunometabolism-based therapeutic strategies.

Keywords:  Infection; Inflammation; Metabolism; Pneumonia; Staphylococcus aureus

DOI:  https://doi.org/10.1152/ajpcell.00612.2025
iScience. 2025 Oct 17. 28(10): 112772

Glutamate receptor-T cell receptor signaling potentiates full CD8+ T cell activation and effector function in tumor immunity.

Maria Teresa P de Aquino, Thomas W Hodo, Salvador González Ochoa, Roman V Uzhachenko, Muna A Mohammed, J Shawn Goodwin, Thanigaivelan Kanagasabai, Alla V Ivanova, Anil Shanker.

  Glutamate is best known as an excitatory neurotransmitter. However, its roles in T cell immunity remain underrecognized. We investigated the interplay between glutamate receptors (GluRs) and T cell receptors (TCRs) during CD8+ T cell activation. Our findings reveal that GluR expression in CD8+ T lymphocytes strongly correlates with the activation of TCR-CD28 signaling, enhancing their antitumor effector responses. Conversely, pharmacologic antagonism of GluRs in activated CD8+ T cells disrupts the colocalization of GluR with TCRVβ8.1, reduces the phosphorylation of TCR-signaling intermediates, alters calcium flux, and impairs the metabolic switch to glycolysis essential for T cell activation. Moreover, these disruptions blunt clonal proliferation and compromise the tumor-cytolytic capacity of CD8+ T cells. Thus, the glutamatergic system-via the GluR-TCR signaling complex-plays a critical amplifier role in activating CD8+ T cells and eliciting their full antitumor activity. This mechanistic insight reveals a previously underappreciated axis in T cell biology and opens avenues for immunotherapy regimens targeting GluR-TCR interactions to augment T cell-mediated responses in cancer and potentially other immunopathologies.
Video Abstract:

Keywords:  immune response; immunology

DOI:  https://doi.org/10.1016/j.isci.2025.112772
Nat Metab. 2025 Oct 21.

IPA brews metabolic balance in gut immunity.

Jacy Scott, Chaoran Li.

DOI: https://doi.org/10.1038/s42255-025-01401-y
Hepatology. 2025 Oct 23.

Glutamine synthetase loss in β-catenin-mutant hepatocellular carcinoma promotes tumor burden through macrophage metabolic reprogramming.

Evan R Delgado, Panari Patel, Junyan Tao, Yekaterina Krutsenko, Silvia Liu, Daniel Green, Raghad Alzubali, Brandon M Lehrich, Jai-Jun Liu, Tyler Yasaka, Minakshi Poddar, Sucha Singh, Vik Meadows, Aaron W Bell, Xin Chen, Aatur Singhi, Satdarshan P Monga.

   BACKGROUND AIMS: Activating β-catenin gene (CTNNB1) mutations are seen in 30% of all hepatocellular cancer (HCC). These tumors are a molecularly distinct subclass characterized in majority of cases by the presence of tumor-wide glutamine synthetase (GS), increased glutamine, mTOR activation, and susceptibility to mTOR inhibitors. Here, we investigate impact of GS loss from β-catenin-mutated HCCs.
APPROACH: TCGA was assessed for CTNNB1-mutated HCCs with differential Glul (encoding GS) expression for survival. Glul was conditionally deleted from hepatocytes and/or macrophages in HCCs co-expressing mutant-CTNNB1 (T41A) and mutant Nrf2 in mice. Macrophage depletion was also performed by Clodranate treatment. Tumors were characterized by histology and single cell spatial transcriptomics.
RESULTS: CTNNB1-mutated HCC patients with low Glul showed poor survival. β-Catenin-mutated HCCs lacking GS exhibited aggressive disease due to altered glutamate/glutamine availability, forcing metabolic adaptation through upregulation of macrophage Glul permitting mTOR activation and susceptibility to mTOR inhibitors, but switching macrophage function from immunosurveillance to immunosuppression. Glul loss from tumors did not interfere with β-catenin-dependent tumor zonation and responsiveness to β-catenin inhibition. Depleting macrophages using clodronate or conditionally deleting Glul from macrophages in GS-deficient, β-catenin-mutant HCCs, both decreased tumor burden and improved survival.
CONCLUSIONS: We demonstrate unique metabolic dependency of β-catenin-mutated HCCs on GS in tumor cells which is diverted to macrophages upon GS elimination in tumor cells. This adaptation alters macrophage metabolism and function leading to compromised immunosurveillance and greater tumor burden. Our study reveals a metabolic dynamic between HCC cells and macrophages with impact on tumor biology.

Keywords:  glutamine; hepatocellular carcinoma; immune microenvironment; macrophage; metabolic heterogeneity

DOI:  https://doi.org/10.1097/HEP.0000000000001591
Biomed Pharmacother. 2025 Oct 22. pii: S0753-3322(25)00846-7. [Epub ahead of print]192 118652

Phosphatidylcholine-bound palmitoleic acid: A bioactive key to unlocking macrophage anti-inflammatory functions.

Miguel A Bermúdez, Clara Meana, Alvaro Garrido, Alfonso Pérez-Encabo, María A Balboa, Jesús Balsinde.

  Inflammatory processes are central to the progression of numerous chronic conditions, including cardiovascular and metabolic disorders, with macrophages playing a pivotal role in these responses. Monounsaturated fatty acids, including palmitoleic acid (16:1 n - 7), have been implicated in modulating inflammation, yet their precise molecular mechanisms of action remain incompletely understood. Notably, in macrophages, 16:1 n - 7 is preferentially esterified into a specific phosphatidylcholine (PC) species, PC(16:0/16:1 n - 7), raising the possibility that its biological activity is governed by this lipid-bound form. Here, we demonstrate that the anti-inflammatory effects of 16:1 n - 7 in macrophages are mediated through its incorporation into this PC species. Using synthetic phospholipids and multiple activation stimuli, we show that PC(16:0/16:1 n - 7) directly regulates macrophage activation. It suppresses NF-κB signaling, reprograms gene expression, and promotes a shift toward an anti-inflammatory, M2-like phenotype that enhances phagocytic capacity. These effects are preserved in ether analogs resistant to phospholipase-mediated hydrolysis, confirming that the release of free 16:1 n - 7 is not required. These findings reveal a previously unrecognized lipid-driven mechanism of immunomodulation, in which specific structural features of PC(16:0/16:1 n - 7) confer intrinsic bioactivity. Our study broadens understanding of immunometabolic regulation by membrane phospholipids, and provides a mechanistic basis for the pharmacotherapeutic potential of defined lipid species in reprogramming macrophage function in inflammatory diseases.

Keywords:  Inflammation; Lipid signaling; Lipid-mediated immunomodulation; Macrophage activation; NF-κB signaling; Palmitoleic acid

DOI:  https://doi.org/10.1016/j.biopha.2025.118652
Front Cell Dev Biol. 2025 ;13 1650677

Immunosenescence and metabolic reprogramming in MASLD: an age-dependent immunometabolic vicious cycle and therapeutic opportunities.

Yuxin Xu, Qiuxiang Li, Xuehua Jiao.

  Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) poses a disproportionately severe burden on the aging population, with a heightened risk of progression to advanced fibrosis and cancer. While immunosenescence and metabolic reprogramming are recognized as key drivers, this review proposes an age-dependent immunometabolic vicious cycle as a critical integrative framework underlying MASLD progression. We hypothesize that at the core of this cycle lies mitochondrial dysfunction and reactive oxygen species (ROS) accumulation, which may initiate a self-amplifying loop: triggering NLRP3 inflammasome activation in Kupffer cells, promoting a context-dependent dysfunction of adaptive immunity. This includes driving CD8+ T cells toward exhaustion in advanced disease and disrupting regulatory T cell (Treg) function, which may range from loss of suppressive capacity to a pro-fibrotic phenotypic switch. Together, these alterations in T cell immunity create a permissive environment for unchecked inflammation and fibrosis. This cycle is further reinforced by gut-liver axis dysfunction. Critically, this framework reveals that overcoming the therapeutic bottleneck in age-associated MASLD necessitates a paradigm shift toward combination therapies that simultaneously target multiple nodes of the cycle.

Keywords:  combination therapy; immunosenescence; metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic reprogramming; mitochondrial dysfunction; vicious cycle

DOI:  https://doi.org/10.3389/fcell.2025.1650677
Front Immunol. 2025 ;16 1499513

The effect of treatment with a non-ionic surfactant vesicular formulation of sodium stibogluconate on host immune responses and serum metabolites in a murine model of Leishmania donovani.

Raphael Taiwo Aruleba, Bernard Ong'ondo Osero, Du Toit Loots, Laneke Luies, Zama Cele, Priscilla Abena Ankamaa Opare, Mari van Reenen, Frank Brombacher, Katharine C Carter, Ramona Hurdayal.

   Introduction: Visceral leishmaniasis (VL), caused by Leishmania donovani, is associated with parasite-induced immunological and physiological changes that ensure the survival of amastigotes within the host. Both the parasite and the host have nutritional requirements, and for auxotrophic Leishmania, dependence on the host to supply specific growth requirements is essential. This highlights an intricate link between host immunity and metabolism during VL. This study explores the interplay between the host metabolome and immune responses pre- and post-infection and treatment, aiming to identify early metabolite markers of therapeutic success against Leishmania.
Methods: BALB/c mice infected with L. donovani were divided into cured and non-cured groups based on treatment with a non-ionic surfactant vesicle formulation of sodium stibogluconate (300 mg Sbv/kg, SSG-NIV) or PBS vehicle control. Specific immune responses were determined at day 21 and day 60 post-infection, and serum metabolite levels was measured using untargeted GC×GC-TOFMS metabolomics.
Results and discussions: Treatment effectively reduced parasite loads, triggering heightened CD4+ and CD8+ T-cell responses at day 21, with increased IFN-γ, IL-12, and IL-4, and decreased IL-10 and TGF-β. Pre-treatment metabolomics analysis identified changes in glycolysis, fatty acid and amino acid metabolism 1-week PI, suggesting an increased Warburg effect to supplement parasite survival and initiation of immune responses. Valine, lactic acid, and glycerol-1-oleate were identified as markers of early infection. Treatment with SSG-NIV altered metabolism of major macromolecules and the TCA cycle relative to non-cured groups. Additionally, glycine and ribitol show promise as immune correlates for antiparasitic therapies. These findings highlight the diagnostic and prognostic potential of serum-derived metabolites in monitoring host immune responses to VL and treatment.

Keywords:  Leishmania donovani; chemotherapy; immunity; metabolomics; mouse

DOI:  https://doi.org/10.3389/fimmu.2025.1499513
Mol Immunol. 2025 Oct 17. pii: S0161-5890(25)00234-2. [Epub ahead of print]187 255-262

Small-molecule perturbation profiling reveals a mechanistic link between STING signaling and lipid metabolism in macrophages and dendritic cells.

Lilah Gmyrek, Jianan Zhang, Maria Andrade, Kathryn R Hillette, Xu Wu, Jin Mo Park.

  The DNA sensor cGAS and the signaling adaptor STING play a key role in the innate immune response to microbial and endogenous DNA in the cytoplasm. The cGAS-STING signaling pathway has evolved to promote immune defense and organismal fitness, yet its dysregulation can lead to chronic inflammation, autoimmunity, and neurodegeneration. Upon sensing double-stranded DNA, cGAS produces a cyclic dinucleotide second messenger that binds to STING in the endoplasmic reticulum. Ligand-bound STING translocates to the Golgi and activates a signaling cascade that results in interferon (IFN) gene transcription. These molecular events are mechanistically linked to intracellular lipid membrane dynamics and protein lipidation. To explore whether STING signaling is controlled by the availability and metabolic flux of cellular lipids, we screened small-molecule compounds targeting lipid metabolic pathways for their influence on STING agonist-responsive IFN induction. These screens identified inhibitors of the fatty acid synthase FAS and lipases as potent suppressors of STING signaling. An inhibitor of the cholesterol-esterifying enzyme SOAT1 enhanced STING-dependent IFN induction in mouse cells while attenuating it in human cells. From an analysis of STING sequences, we detected a difference in their lipid binding motifs that likely accounted for the species-specific effects of SOAT1 inhibition. Our findings reveal a connection between STING signaling and lipid metabolism and opportunities for expanding the toolbox for treating clinical conditions that arise from aberrant STING activity.

Keywords:  STING / Signaling / Lipid / Metabolism

DOI:  https://doi.org/10.1016/j.molimm.2025.09.010
Sci Transl Med. 2025 Oct 22. 17(821): eadn1150

HIVEP1 aggravates NASH by reprogramming polyamine metabolism in TH17 cells.

Yidan Ren, Xiaoyan Liu, Maoxiao Feng, Jianxiong Zhao, Yangmiao Duan, Guoying Dong, Huiru Gao, Xiaodong Hao, Qin Wang, Jiaying Yao, Zan Yuan, Xu Jing, Jing Wu, Yihai Cao, Yunshan Wang.

Nonalcoholic steatohepatitis (NASH) is a chronic, inflammatory form of nonalcoholic fatty liver disease (NAFLD) that frequently progresses to cirrhosis and hepatocellular carcinoma (HCC). However, the role of various immune cells in switching from NAFLD to NASH remains elusive. Here, we took an unbiased single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) approach to investigate the cellular composition, gene expression profiling, and causative roles of immune cells in NASH development. T helper 17 (TH17) cells were identified as the most abundant subpopulation of immune cells in mouse livers with NASH. Further analysis of scATAC-seq data and single-cell RNA sequencing (scRNA-seq) data from the GEO database showed that human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) is a critical transcription factor (TF) regulating TH17 cell differentiation and cytokine production. Specific knockout of Hivep1 in IL-17A+ and CD4+ T cells in mice showed impairment of TH17 cell differentiation and alleviation of NASH development. Mechanistically, HIVEP1 transcriptionally regulated ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine metabolism, to modulate TH17 cell differentiation and cytokine production. Consequently, pharmacological inhibition of ODC1 decreased cytokine production, alleviated inflammation, and prevented the NAFLD-to-NASH transition. Together, our findings elucidate the role of polyamine metabolism in TH17 cell-mediated NASH development and identify potential therapeutic targets for the effective treatment of NASH.

DOI: https://doi.org/10.1126/scitranslmed.adn1150
Int J Mol Med. 2026 Jan;pii: 5. [Epub ahead of print]57(1):

Immune and metabolic remodeling following bariatric surgery: Implications for targeted immunotherapy (Review).

Yiming Shao, Ke Song, Ruixin Yu, He Xiao, Chengjun Li, Yuling Deng, Yuan Zhang, Yixing Ren.

  Over the past few years, bariatric surgery has emerged as a potent remedy for obesity and its related metabolic issues, with its effects on peripheral immune cells garnering considerable attention. Obesity, recognized as a chronic metabolic condition, is intricately connected to dysfunctions spanning a range of immune cell types. Among peripheral immune cells, T cells, B cells and monocytes, obesity markedly alters their counts and functions, driving the inflammation and metabolic dysfunction characteristic of the condition. The modifications in these immune cell cohorts are inextricably intertwined with the augmentation of postoperative metabolic functions and have the potential to exert a salutary effect on complications associated with obesity. The present review primarily examined the latent influence of bariatric surgery on the number and function of peripheral immune cells, thereby offering novel perspectives and therapeutic targets for the immunotherapy of obesity.

Keywords:  bariatric surgery; inflammation; obesity; peripheral immune cells; targeted therapy

DOI:  https://doi.org/10.3892/ijmm.2025.5676
Adv Sci (Weinh). 2025 Oct 23. e15121

Light Metabolically Reprograms CD8+ T Cells to Potentiate STING-Driven Tumor Eradication and Prevent Metastasis.

Asmita Banstola, Shilin Gao, Zhengkung Zhang, Yan Dong, Prabhat Upadhyay, Quanwei Zhang, Yongli Li, Zuan-Tao Lin, Zhilong Wang, Mei X Wu.

  Immunotherapy remains ineffective in many solid tumors due to poor T-cell infiltration and a metabolically suppressive tumor microenvironment. A dual strategy combining low-level light (LLL) therapy with a nanoscale stimulator of interferon genes (STING) agonist formulation (nanoSTING@Mn) is presented to enhance immune activation and metabolic fitness for durable tumor immunity against T-cell lymphoma (EL4) model. NanoSTING@Mn, composed of ADU-S100 complexed with Mn2⁺ and encapsulated in biomimetic liposomes, potently activates the cGAS-STING pathway, induces a type I interferon response, and promotes lymphocyte infiltration. These monocytes polarize into M1 macrophages, suppressing regulatory T cells. Simultaneously, LLL photo-biomodulation reprograms mitochondrial metabolism in tumor-infiltrating CD8⁺ T and natural killer cells, restoring their durability and leading to complete local tumor eradication. This combination expands a distinct CD8⁺ T-cell subset with Tcf-1⁺ progenitor-exhausted features and elevated memory/effector gene expression, enhancing proliferation and cytotoxicity, as shown by single-cell RNA sequencing. Intranasal nanoSTING@Mn delivery mobilizes these LLL-revived T cells to the lung, where they differentiate into resident memory T cells and establish systemic antitumor immunity. Upon intravenous rechallenge, disseminated tumor cells are eliminated, preventing metastasis and ensuring long-term protection. This synergistic approach offers a scalable platform to boost immunotherapy efficacy and redefines immune-based metastasis prevention strategies.

Keywords:  cGAS–STING pathway; photo‐biomodulation; resident memory T cells; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202515121
Front Immunol. 2025 ;16 1652516

A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS.

Louise Nuyttens, Marah Heyerick, Maxime Roes, Elise Moens, Céline Van Dender, Charlotte Wallaeys, Tino Hochepied, Steven Timmermans, Jolien Vandewalle, Claude Libert.

  Tumor necrosis factor (TNF) causes a lethal systemic inflammatory response syndrome (SIRS) which is characterized by significant metabolic alterations. Based on liver RNA sequencing, we found that TNF impairs the malate-aspartate shuttle (MAS), an essential redox shuttle that transfers reducing equivalents across the inner mitochondrial membrane thereby recycling cytosolic NAD+. This downregulation of MAS genes in TNF-induced SIRS likely results from loss of HNF4α function, which appears to be the key transcription factor involved. Using Slc25a13-/- mice lacking citrin - a crucial MAS component - we demonstrate that MAS dysfunction exacerbates TNF-induced metabolic dysregulations and lethality. Disruptive NAD+ regeneration leads to diminished mitochondrial β-oxidation, leading to elevated levels of circulating free fatty acids (FFAs) and to hepatic lipid accumulation. Simultaneously, MAS dysfunction promotes glycolysis coupled to lactate production and reduces lactate-mediated gluconeogenesis, culminating in severe hyperlactatemia that triggers VEGF-induced vascular leakage. Overall, MAS dysfunction contributes to metabolic failure and lethality in TNF-induced SIRS, highlighting its potential as a promising, therapeutic target.

Keywords:  TNF-induced SIRS; carbohydrate metabolism; citrin; lipid metabolism; malate aspartate shuttle

DOI:  https://doi.org/10.3389/fimmu.2025.1652516
Cell Rep. 2025 Oct 22. pii: S2211-1247(25)01234-3. [Epub ahead of print]44(11): 116463

Metabolic regulation of immunity in the tumor microenvironment.

Shen Li, Yu Zhang, Huan Tong, Haozhen Sun, Hu Liao, Qingfang Li, Xuelei Ma.

  Metabolic-immune crosstalk in the tumor microenvironment (TME) is a critical driver of tumorigenesis, progression, and immune evasion. Tumor cells undergo profound metabolic reprogramming, causing nutrient competition, toxic metabolite accumulation, and the formation of cold niches that gradually exhaust effector immune cells. In contrast, immunosuppressive cells exhibit strong metabolic adaptability, reinforcing the suppressive milieu. Moreover, tertiary lymphoid structures provide nutrient- and oxygen-rich "moats" that sustain the functions of B and T cells. In addition, metabolic-immune interactions establish novel checkpoints through an "enzyme-metabolite-receptor" axis, which synergize with PD-1/CTLA-4 pathways to promote resistance to immune checkpoint inhibitors (ICIs). Although monotherapies with metabolic inhibitors have shown limited efficacy, their combination with ICIs is promising. Therefore, this review discusses the field from three perspectives: metabolic stress in the TME, immune cell adaptation, and targeting metabolic immune checkpoints in combination with immunotherapy.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2025.116463
PLoS Pathog. 2025 Oct 24. 21(10): e1013646

Influenza virus infection reprograms cholesterol biosynthesis to facilitate virus replication by the TAK1-RORγ axis.

Jingting Zhang, Ruixuan Cao, Yujie Wang, Yuling Sun, Xiaoyue Ji, Penggang Liu, Kaituo Liu, Jing Sun, Xiaojun Chen, Demin Cai, Pinghu Zhang, Xiaoquan Wang, Xiufan Liu, Xiulong Xu.

Infection and replication of enveloped viruses require host cells to supply substantial amounts of cellular cholesterol for processes such as binding, entry, trafficking, assembly, and budding. However, the mechanisms by which influenza A virus (IAV) regulates cholesterol biosynthesis remain poorly understood. In this study, we demonstrate that IAV infection induces the expression of the retinoic acid-related orphan receptor γ (RORγ), an orphan nuclear receptor, which cooperates with the sterol regulatory element-binding protein-2 (SREBP2) to regulate the expression of the 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase (HMGCR), a key enzyme in cholesterol biosynthesis. RORγ knockout and treatment with two RORγ inhibitors, XY018 and GSK805, suppress IAV-induced HMGCR expression, cholesterol biosynthesis, and viral replication. Notably, exogenous cholesterol rescues the inhibitory effect of XY018 on viral replication. Mechanistically, we show that IAV infection activates RORγ expression through the TGF-β-activated kinase 1 (TAK1) and its downstream kinases, the c-Jun N-terminal kinase (JNK) and the IκB kinase (IKK), which in turn activate AP1 and NF-κB. In vivo, RORγ knockout reduces IAV replication, alleviates body weight loss, and prolongs survival in infected mice. Furthermore, XY018 treatment reduces both viral replication and inflammation in the lungs of IAV-infected mice. Our findings provide novel mechanistic insights into how IAV infection upregulates cholesterol biosynthesis to facilitate viral replication.

DOI: https://doi.org/10.1371/journal.ppat.1013646
Adv Sci (Weinh). 2025 Oct 20. e06995

TREM2-Mediated Cholesterol Efflux in Macrophages Inhibits Anti-Tumor Immunity via Limitation of CD4+ T and NK Cells.

Yunhan Wang, Weina Yu, Xinxin Wang, Qitai Zhao, Qingyang Lei, Aitian Li, Shasha Liu, Tian Wang, Li Yang, Yi Zhang.

  Tumor-associated macrophages (TAMs) predominantly exert functions that facilitate tumor progression. Triggering receptor expressed on myeloid cell 2 (TREM2) is expressed in TAMs, playing a crucial role in mediating the immunosuppressive function of TAMs. The mechanisms by which TREM2+ TAMs promote tumor growth and inhibit anti-tumor immunity remain unclear. Through single-cell sequencing of tumor tissues derived from wild-type and Trem2 knockout mice bearing subcutaneous lung cancer, it is found that TREM2 deletion hindered tumor growth, with a notable increase in and improved functionality of CD4+ T and natural killer (NK) cells in the tumor microenvironment. TREM2 deficiency led to ATP-binding cassette transporter A1 (ABCA1) downregulation, causing cholesterol accumulation in TAMs and promoting a pro-inflammatory phenotype. This results in increased chemokine (C-X3-C motif) ligand 1 (CX3CL1) secretion of macrophages, recruiting more CD4+ T and NK cells to the tumor site, enhancing the anti-tumor response. After screening food and drug administration (FDA)-approved drugs, bortezomib and ataluren are found to effectively inhibit TREM2 expression in TAMs, indicating a potential therapeutic strategy against TREM2. This study elucidates the mechanism by which TREM2 shapes the immunosuppressive microenvironment and promotes tumorigenesis, highlighting TREM2 as a target for cancer immunotherapy.

Keywords:  CX3CL1; TREM2; anti‐tumor immunity; cholesterol; tumor microenvironment; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.202506995
Nat Metab. 2025 Oct 20.

Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.

Li Shen, Shenghao Wang, Chao Gao, Qin Li, Shuya Feng, Weiyan Sun, Xu Liu, Yiyi Ba, Yihui Chu, Yu Zhou, Junjie Pan, Hao Xu, Xu Zhang, Wenwei Zhu, Lunxiu Qin, Ming Lu.

Increased acetyl-coenzyme A (acetyl-CoA) generation facilitates cancer metastasis and represents a critical metabolic characteristic of metastatic cancers. To maintain high acetyl-CoA levels, cancer cells often enhance the uptake of acetate for acetyl-CoA biosynthesis. However, the microenvironmental source of acetate remains largely unknown. Here we demonstrate that acetate is secreted by tumour-associated macrophages (TAMs) and taken up by hepatocellular carcinoma (HCC) cells to support acetate accumulation. Mechanistically, HCC cell-derived lactate activates the lipid peroxidation-aldehyde dehydrogenase 2 (ALDH2) pathway in TAMs, which promotes the TAMs' acetate production and secretion. Inhibition of ALDH2 or of lipid peroxidation in TAMs abrogates acetate-induced migration of HCC cells in vitro. In an orthotopic HCC model involving male mice, genetic ablation of ALDH2 in TAMs reduces HCC cell acetate levels and HCC lung metastases. Collectively, our findings reveal a metabolic interaction between HCC cells and TAMs-involving lactate, lipid peroxidation and acetate-and position TAMs as an acetate reservoir that drives HCC metastasis.

DOI: https://doi.org/10.1038/s42255-025-01393-9
J Transl Med. 2025 Oct 22. 23(1): 1158

Magnetic resonance imaging quantifies causal body compartment effects on metabolic traits via immune phenotypes-a Mendelian randomisation study.

Di Zhang, Liang-Ping Li, Ying-Hui Zhang, Pu Wang, Lei Lei, Yun Hu, Chao Zhou, Shu-Shu Yang, Wei-Hui Liu, Xin-Yu Huang.

   BACKGROUND: Metabolic diseases, including type 2 diabetes (T2D), hypertension, hyperlipidemia and metabolic dysfunction-associated fatty liver disease (MAFLD), are globally prevalent. However, traditional measures, such as body mass index (BMI), fail to capture body composition heterogeneity to accurately predict metabolic diseases. Magnetic resonance imaging (MRI) provides a precise quantification of body composition; however, the causal links among these compartments, immune phenotypes, and metabolic traits remain unclear. This Mendelian randomisation (MR) study aimed to investigate the compartment-specific effects of MRI-derived body composition measures on metabolic diseases and assess the mediating role of immune phenotypes.
METHODS: Using a two-sample MR framework, genetic instruments for 10 MRI-assessed body composition traits were derived from GWAS data. The outcomes included metabolic diseases (T2D, MAFLD, and hypertension) and glycolipid metabolism traits. Mediation analysis integrated 731 immune cell types. Robustness was assessed using the MR-Egger, Weighted Median, and MR-PRESSO methods, addressing pleiotropy and heterogeneity.
RESULTS: Visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT) exerted strong causal effects on BMI (odds ratio [OR] = 1.136). The strongest causal effect on MAFLD risk was observed for liver proton density fat fraction (LPDFF) (OR = 1.833). VAT, weight-muscle ratio and ASAT positively influenced levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol, whereas they negatively influenced triglyceride levels. Immune phenotypes mediated 28 causal pathways: ectopic fat promoted pro-inflammatory immune profiles, transitional B cells and Memory-CD8+ T cells expanded positive correlation with BMI. CD14+ monocytes and CD16+ monocytes positively regulate Cholesterol and LDL-C levels, respectively.
CONCLUSION: Our study emphasised the correlation between MRI-derived body composition measures and metabolic diseases, particularly revealing VAT, subcutaneous adipose tissue, and liver proton density fat fraction as key causal drivers of metabolic diseases while uncovering the pivotal role of immune phenotypes in mediating these metabolic pathways. These findings support the integration of MRI-based body composition profiling into clinical screening for metabolic diseases of high-risk cohorts, and provide a novel theoretical foundation for immune-targeted therapies to combat metabolic dysregulation.

Keywords:  Immune phenotypes; MRI-profiled body composition; Mendelian randomisation; Metabolic diseases

DOI:  https://doi.org/10.1186/s12967-025-07241-4
FEBS J. 2025 Oct 19.

Butyrate suppresses mucosal inflammation in inflammatory bowel disease primarily through HDAC3 inhibition in monocytes and macrophages.

Daniela Parada-Venegas, Marjorie De la Fuente López, Karen Dubois-Camacho, Glauben Landskron, Tjasso Blokzijl, Héctor Molina, María-Celeste Casanova, Yingying Cui, Moting Liu, Antonio M Da Costa De Pina, Daniela Simian, María-Julieta González, Rinse K Weersma, Rodrigo Quera, Gerard Dijkstra, Klaas Nico Faber, Marcela A Hermoso.

  Butyrate-producing gut bacteria and luminal butyrate levels are reduced in Inflammatory Bowel Diseases (IBDs). Butyrate has anti-inflammatory properties through mechanisms not well-characterized in IBDs. Here, we determined the butyrate anti-inflammatory effect on primary IBD tissues and intestinal cell models to identify key target cells and pathway(s) involved. Cytokines, monocarboxylate transporter-1 (MCT1), G-protein-coupled receptor-109A (GPR109A), and histone deacetylase-3 (HDAC3) levels were analyzed in IBD and healthy tissues using cytometric bead arrays, RNA-seq analysis and immunofluorescence. Inflammatory markers and phagocytosis in butyrate-treated colonic organoids, primary monocytes or THP-1 macrophages, were assessed by qPCR, flow cytometry and amikacin protection assays, when relevant combined with GPR109A or HDAC3 antagonists. Butyrate suppressed TNF and IL-6 secretion by > 50% in ex vivo-cultured inflamed IBD biopsies. MCT1 expression was reduced in inflamed epithelium and cytokine-exposed organoids, while IL-18 was reduced 0.5-fold in organoids, and both were restored by butyrate, without suppressing pro-inflammatory gene expression. GPR109A and HDAC3 were elevated in IBD tissues and upregulated by butyrate in cultured mucosa. Butyrate also suppressed IL-6, TNF-α, CD40, and CD80 by > 50% and enhanced adherent-invasive Escherichia coli (AIEC) phagocytosis by 62% in monocytes/macrophages. Histone acetylation (H3K9ac) increased > 5-fold, mimicking the HDAC inhibitor SAHA. Contrary, specific GPR109A inhibition and gene G-protein-coupled receptor inhibition did not alter butyrate's effects. Butyrate restores MCT1 and IL-18 gene expression in inflamed epithelial cells, showing limited anti-inflammatory effects. Instead, butyrate targets HDAC3 in mononuclear cells, suppressing inflammation in IBD gut mucosa. The cell-type-specific effects of butyrate offer mechanistic insights that support its therapeutic relevance in IBDs.

Keywords:  butyrate; epithelial SLC16A1/MCT1; histone deacetylase (HDAC) inhibition; inflammatory bowel diseases (IBD); monocytes/macrophages

DOI:  https://doi.org/10.1111/febs.70289
Sci Immunol. 2025 Oct 24. 10(112): eadp0849

Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity.

Hiroyuki Yagyu, Masahiro Kiuchi, Atsushi Sasaki, Eisuke Itakura, Kota Kokubo, Chiaki Iwamura, Atsushi Onodera, Ami Aoki, Takahisa Hishiya, Kaori Tsuji, Takuto Hiramoto, Rie Shinmi, Yuri Sonobe, Takahiro Arano, Kanae Ohishi, Shigenori Baba, Junya Kurita, Tomohisa Iinuma, Syuji Yonekura, Yu Hara, Motoko Y Kimura, Shinichiro Motohashi, Damon J Tumes, Toyoyuki Hanazawa, Takeshi Kaneko, Toshinori Nakayama, Kiyoshi Hirahara.

A unique subpopulation of memory T helper 2 (TH2) cells expressing the interleukin-33 (IL-33) receptor ST2 drives allergic disease pathogenesis. However, the immunometabolic mechanisms that induce ST2hi memory TH2 cells remain unclear. We show using a mouse model of chronic allergic airway inflammation that long-chain unsaturated fatty acids (LC-UFAs) accumulate in the inflammatory milieu during chronic airway inflammation. Activated TH2 cells take up LC-UFAs, transiently store them in lipid droplets (LDs), and catabolize LDs through lipolysis and microlipophagy. LD catabolism regulated by adipose triglyceride lipase (ATGL) activates peroxisome proliferator-activated receptor γ (PPARγ). PPARγ then binds the Il1rl1 locus encoding ST2 and induces ST2hi effector and memory TH2 cells. In eosinophilic chronic rhinosinusitis, CD45RO+ CD4 T cells in nasal polyps exhibit microlipophagy and an accessible IL1RL1 enhancer, indicating that these mechanisms are conserved in humans. Thus, the storage and catabolism of inflammatory milieu-derived LC-UFAs direct pathogenic adaptive type 2 immunity, offering potential therapeutic strategies for persistent allergic inflammation.

DOI: https://doi.org/10.1126/sciimmunol.adp0849