bims-imicid 2025-10-19 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–10–19
37 papers selected by
Dylan Ryan, University of Cambridge

Nutrient allocation fuels T cell-mediated immunity.
Ubiquitination in macrophage plasticity: from inflammatory to immunometabolic pathways.
Metabolic Reprogramming and CD8+ T-Cell Exhaustion During Chronic HBV Infection.
Succinate in innate immunity: linking metabolic reprogramming to immune modulation.
CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.
Glutaminase activity maintains NK cell cytotoxicity through metabolic regulation of effector function.
The critical role of methylenetetrahydrofolate dehydrogenases in immune regulation and auto-immunity.
Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation.
Differential bioenergetic profile of human glioblastoma following transplantation of myocyte-derived mitochondria.
Lactate Secretion by Monocytes as a Determinant of Innate Immune Cell Fitness in Healthy Elderly.
Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression.
Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy.
Short-Chain Fatty Acid Sodium Butyrate Suppresses Protective Humoral Immunity by Inhibiting Follicular T Helper Cell Differentiation.
Amino acid and cholesterol metabolism in innate immunity.
A high-calorie diet exacerbates lipopolysaccharide-induced pneumonia by promoting acetate-mediated macrophage polarization via the HDAC9/10-HIF-1α-glycolysis axis.
dsHMGB1, released from IL-17A-induced pyroptotic prostate epithelial cells, drives M1 polarization by promoting Pfkp-mediated glycolysis via Jak2/Stat1 transcription in experimental autoimmune prostatitis.
Metabolites in the extracellular tumor microenvironment and the shaping of macrophage function.
Backtracking metabolic dynamics in single cells predicts bacterial replication in human macrophages.
Chronic HBV infection impairs the glucose metabolism and effector function of NK cells via HBsAg/IL-15/mTOR axis.
Role of macrophage PKM2 in inflammation and tumor progression and its targeted therapy.
HIF-1-mediated macrophage metabolic reprogramming promotes AKI to CKD transition.
Glutamine alleviates immunosuppression in polymicrobial sepsis by augmenting bacterial phagocytosis through sustaining the GFAT-DRP1 dependent mitochondrial calcium dynamics.
Zinc Promotes Mitochondrial Health Through PGC-1alpha Enhancing Bacterial Clearance in Macrophages Infected with Mycobacterium avium Complex.
Gut microbiota butyrate mediated RUNX3 promotes Nr4a1highZFP36highresident macrophages via NR4A1/ERK1/2 MAPK to maintain gut homeostasis.
Echinocystic acid in Momordica charantia L. exosome-like nanovesicles attenuates dengue virus-induced vascular leakage associated inflammatory mediators through macrophage metabolic reprogramming and HIF-1α/p300-CBP interaction.
Glycolysis inhibition restores immune sensitivity in GSNOR-deficient colorectal cancer.
Mitochondria-Targeted Nanoformulations: New Therapeutic Strategies and Opportunities for Cancer Immunotherapy.
Microbiome and Metabolic Immune Mechanisms in Sepsis-Associated Encephalopathy.
Conversations at the interface of metabolism and immunity.
Itaconate regulates PANoptosis in splenocytes to alleviate sepsis-induced multiple organ dysfunction syndrome.
IDO-Mediated Immune and Metabolic Dysregulation in Schwann Cells Exposed to Mycobacterium leprae.
Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis.
TCR signal-enhancing mutation alters lipid metabolism of thymocytes and impairs antitumor immunity of mature T cells.
Gut microbiota and metabolism in systemic lupus erythematosus: from dysbiosis to targeted interventions.
Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.
Claudin-7 deficiency induces metabolic reprogramming of neutrophils in the colorectal cancer microenvironment.
Adenosine metabolic clearance maintains liver homeostasis by licensing arginine methylation of RIPK1.

Cell Metab. 2025 Oct 15. pii: S1550-4131(25)00393-6. [Epub ahead of print]

Nutrient allocation fuels T cell-mediated immunity.

Joseph Longo, McLane J Watson, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

  T cell activation and function are intricately linked to metabolic reprogramming. The classic view of T cell metabolic reprogramming centers on glucose as the dominant bioenergetic fuel, where T cell receptor (TCR) stimulation promotes a metabolic switch from relying primarily on oxidative phosphorylation (OXPHOS) for energy production to aerobic glycolysis (i.e., the Warburg effect). More recently, studies have revealed this classic model to be overly simplistic. Activated T cells run both glycolysis and OXPHOS programs concurrently, allocating diverse nutrient sources toward distinct biosynthetic and bioenergetic fates. Moreover, studies of T cell metabolism in vivo and ex vivo highlight that physiologic nutrient availability influences how glucose is allocated by T cells to fuel both optimal proliferation and effector function. Here, we summarize recent advancements that support a revised model of effector T cell metabolism, where strategic nutrient allocation fuels optimal T cell-mediated immunity.

Keywords:  T cells; adaptive immunity; effector function; glucose; immunometabolism; nutrient allocation

DOI:  https://doi.org/10.1016/j.cmet.2025.09.008
Front Immunol. 2025 ;16 1621328

Ubiquitination in macrophage plasticity: from inflammatory to immunometabolic pathways.

Jianing Liu, Magdalena Paolino.

  Macrophages are highly plastic innate immune cells whose polarization and effector functions are tightly linked to their metabolic programs. Ubiquitination, the post-translational modification that attaches ubiquitin chains to target proteins, plays a crucial role in regulating macrophage immunometabolism and phenotype transitions. In this mini-review, we summarize the current understanding of ubiquitin-dependent mechanisms that modulate macrophage polarization. We discuss how E3 ubiquitin ligases and deubiquitinases regulate key metabolic and signaling pathways, balancing pro-inflammatory and immunosuppressive states. Additionally, we describe the pathophysiological consequences of dysregulated ubiquitin-dependent control of macrophage polarization and its implications for disease. These insights underscore the importance of ubiquitination as a central modulator of macrophage function and its potential as a therapeutic target for controlling immunity in infections, inflammation, and cancer.

Keywords:  immunometabolism; inflammation; macrophage; polarization; ubiquitination

DOI:  https://doi.org/10.3389/fimmu.2025.1621328
Liver Int. 2025 Nov;45(11): e70402

Metabolic Reprogramming and CD8+ T-Cell Exhaustion During Chronic HBV Infection.

Haohao Li, Weiwei Mu, Alison Zhao, Su Xiao, Chenxin Huo, Huajun Zhao, Hongchun Wang, Ronghui Li, Qiuju Han.

  HBV is an enveloped DNA virus that exclusively infects hepatocytes of humans and some non-human primates. During its viral life cycle, HBV and its structural components can directly regulate the metabolism of hepatocytes, which may reshape the liver immune microenvironment. CD8+ T-cells, well known as cytotoxic T lymphocytes for their antiviral immunity, can undergo metabolic reprogramming during chronic HBV infection. Increasing evidence demonstrates that metabolic reprogramming promotes T-cell exhaustion, which is a hallmark of HBV infection. Additionally, complicated metabolites (e.g., glucose, lipids, amino acids and nucleic acids) secreted from hepatocytes or T-cells contribute to the communication between these two cell types, which may facilitate HBV infection and hinder antiviral immune response. In recent years, supplementation of certain specific metabolic substrates or targeting metabolic enzyme genes has been reported to mitigate HBV replication and induce antiviral immune response, holding promise as effective strategies for curing chronic HBV infection. This review provides a thorough overview of recent advances in the metabolic characteristics of hepatocytes and T-cells during HBV infection, discusses the relationship between CD8+ T-cell exhaustion and metabolic reprogramming, and emphasises the therapeutic potential of metabolic approaches in the HBV clinical landscape.

Keywords:  CD8+ T‐cells; chronic hepatitis B; hepatocytes; immunometabolism; metabolic reprogramming

DOI:  https://doi.org/10.1111/liv.70402
Front Immunol. 2025 ;16 1661948

Succinate in innate immunity: linking metabolic reprogramming to immune modulation.

Reham Atallah, Juergen Gindlhuber, Akos Heinemann.

  Succinate is an essential metabolite in the tricarboxylic acid (TCA) cycle. In mitochondria, succinate holds a unique position connecting the TCA cycle and the electron transport chain (ETC), thereby providing a shortcut path for adenosine triphosphate (ATP) production. Beyond this fundamental role in cellular metabolism, succinate is increasingly acknowledged as a key modulator of immune cell function. Production of reactive oxygen species (ROS), hypoxia-inducible factor-1α (HIF-1α) stabilization, protein succinylation and cell-cell communication mediated by succinate receptor 1 (SUCNR1) are traits induced by succinate. During inflammation, succinate plays key dual roles, culminating in either pro- or anti-inflammatory effects that are tissue- and context-dependent. In this review, we provide a succinct overview focusing on the regulatory role of succinate in innate immune cells, highlighting involved mechanisms and research gaps that represent promising targets for future study.

Keywords:  hypoxia-inducible factor-1α (HIF-1α); inflammation; innate immune cells; reactive oxygen species (ROS); succinate; succinate dehydrogenase (SDH); succinate receptor 1 (SUCNR1); succinylation

DOI:  https://doi.org/10.3389/fimmu.2025.1661948
Cell Rep. 2025 Oct 13. pii: S2211-1247(25)01183-0. [Epub ahead of print]44(10): 116412

CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms.

Alison Galloway, Katarzyna Knop, Carolina Gomez-Moreira, Vanessa Xavier, Sarah Thomson, Harunori Yoshikawa, Olga Suska, Radoslaw Lukoszek, Aneesa Kaskar, Angus I Lamond, Thomas MacVicar, Victoria H Cowling.

  During T cell activation, mitochondrial biogenesis and cellular metabolism are altered to meet the elevated energy demands of protein synthesis, rapid proliferation, and effector T cell function. The mechanisms coupling mitochondrial dynamics to T cell status are unclear. Here, we report that RNA cap methyltransferase 1 (CMTR1) is induced in activated T cells, methylating the first nucleotide on mRNA and U2 small nuclear RNA (snRNA), a component of the spliceosome. Using transcriptomic analyses, we identify a functional splicing module regulating mitochondrial dynamics in T cells, which alters the isoforms of proteins controlling mitochondrial fission and fusion. Through epitranscriptomic control of U2 snRNA and splicing, CMTR1 directs protein isoform selection during T cell activation to promote the development of longer mitochondria with increased respiratory capacity. Thus, CMTR1 upregulation supports the energetic demands of T cell activation, survival, and immune responses.

Keywords:  CMTR1; CP: Immunology; CP: Metabolism; MFF; RNA cap; RNA methylation; T cell; T lymphocyte; metabolism; mitochondria; snRNA; splicing

DOI:  https://doi.org/10.1016/j.celrep.2025.116412
J Inflamm (Lond). 2025 Oct 14. 22(1): 45

Glutaminase activity maintains NK cell cytotoxicity through metabolic regulation of effector function.

M Jedlička, T Feglarová, V Švubová, E Mašínová, V Graman, K Kuglerová, J Szabová, F Jahan, M Korhonen, K Kuželová, M Hortová-Kohoutková, J Frič.

   BACKGROUND: Natural killer (NK) cells are responsible for monitoring and eliminating malignant or virus-infected cells. To become activated, NK cells must upregulate oxidative phosphorylation and glycolysis to meet the high energetic demands associated with cytotoxic and effector functions. While glutamine can also fuel the tricarboxylic acid cycle through its conversion to alpha-ketoglutarate, the precise role of this pathway in NK-cell cytotoxic activity is unclear.
RESULTS: To investigate NK-cell dependency on glutamine, we selectively inhibited kidney-type glutaminase to prevent glutamine metabolism. We analysed the metabolism and cytotoxicity of expanded primary NK cells, treated or not with glutaminase inhibitor. Glutaminase inhibition significantly reduced oxidative phosphorylation and led to a significant decrease in NK cell cytotoxic function. Furthermore, glutaminase inhibition reduced protein synthesis in activated NK cells. Meanwhile, supplementation with alpha-ketoglutarate rescued both the metabolic and cytotoxic capacities of primary expanded NK cells.
CONCLUSIONS: Our findings highlight the importance of glutaminase activity in supporting NK cell respiratory metabolism and cytotoxic function, and the need for caution when combining glutaminase inhibitors with NK cell-based therapies.

Keywords:  Alpha-ketoglutarate; Cell cytotoxicity; Glutaminase; Immunometabolism; Natural killer cell

DOI:  https://doi.org/10.1186/s12950-025-00470-w
J Inflamm (Lond). 2025 Oct 14. 22(1): 44

The critical role of methylenetetrahydrofolate dehydrogenases in immune regulation and auto-immunity.

Peter Bunyard, Marina Makrecka-Kuka.



Keywords:  1-carbon metabolism; Immunometabolism; Inflammation; Metabolites

DOI:  https://doi.org/10.1186/s12950-025-00469-3
Nat Aging. 2025 Oct 17.

Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation.

David Ezuz, Heba Ombashe, Lana Watad, Akmaral Rakhymzhanova, Satyarth Pandey, Orna Atar, Esther G Meyron-Holtz, Noga Ron-Harel.

Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with immune and stromal cells. Here we found that splenic T cells exhibit greater functional decline than lymph node T cells within the same aged mouse, prompting investigation into how the aged spleen contributes to T cell aging. Proteomic analysis revealed increased expression of heme detoxification in aged spleen-derived lymphocytes. Exposure to the heme- and iron-rich aged splenic microenvironment induced aging phenotypes in young T cells, including reduced proliferation and CD39 upregulation. T cells survived this hostile niche by maintaining a low labile iron pool, at least in part, via IRP2 downregulation to resist ferroptosis but failed to induce sufficient iron uptake for activation. Iron supplementation enhanced antigen-specific T cell responses in aged mice. This study identifies the aged spleen as a source of hemolytic signals that systemically impair T cell function, underscoring a trade-off between T cell survival and function and implicating iron metabolism in immune aging.

DOI: https://doi.org/10.1038/s43587-025-00981-4
PLoS One. 2025 ;20(10): e0330322

Differential bioenergetic profile of human glioblastoma following transplantation of myocyte-derived mitochondria.

Kent L Marshall, Ethan Meadows, Alan Mizener, John M Hollander, Christopher P Cifarelli.

Glioblastoma (GBM) exhibits profound plasticity, enabling adaptation to fluctuating microenvironmental stressors such as hypoxia and nutrient deprivation. However, this metabolic rewiring also creates subtype-specific vulnerabilities that may be exploited therapeutically. Here, we investigate whether mitochondrial transplantation using non-neoplastic, human myocyte-derived mitochondria alters the metabolic architecture of GBM cells and modulates their response to ionizing radiation. Using a cell-penetrating peptide-mediated delivery system, we successfully introduced mitochondria into two mesenchymal-subtype GBM cell lines, U3035 and U3046. Transplanted cells exhibited enhanced mitochondrial polarization and respiratory function, particularly in the metabolically flexible U3035 line. Bioenergetic profiling revealed significant increases in basal respiration, spare respiratory capacity, and glycolytic reserve in U3035 cells post-transplantation, whereas U3046 cells showed minimal bioenergetic augmentation. Transcriptomic analyses using oxidative phosphorylation (OXPHOS) and glycolysis gene sets confirmed these functional findings. At baseline, U3035 cells expressed high levels of both glycolytic and OXPHOS genes, while U3046 cells were metabolically suppressed. Following radiation, U3035 cells downregulated key OXPHOS and glycolysis genes, suggesting metabolic collapse. In contrast, U3046 cells transcriptionally upregulated both pathways, indicating compensatory adaptation. These results identify and establish mitochondrial transplantation as a metabolic priming strategy that sensitizes adaptable GBM subtypes like U3035 to therapeutic stress by inducing bioenergetic overextension. Conversely, rigid subtypes like U3046 may require inhibition of post-radiation metabolic compensation for effective targeting. Our findings support a novel stratified approach to GBM treatment which integrates metabolic subtype profiling with bioenergetic modulation.

DOI: https://doi.org/10.1371/journal.pone.0330322
Aging Cell. 2025 Oct 13. e70220

Lactate Secretion by Monocytes as a Determinant of Innate Immune Cell Fitness in Healthy Elderly.

Lisa Smeehuijzen, Frank Vrieling, Jenny Jansen, Hendrik J P van der Zande, Thomas M Houslay, Gabriele Gross, Janna A van Diepen, Lydia A Afman, Rinke Stienstra.

Immune cell metabolism is increasingly recognized as an important regulator of immune function, but its role in age-related immune dysfunction, chronic inflammation, and cardiometabolic complications in humans remains incompletely understood. This study investigated the impact of aging on monocyte metabolic and functional signatures in a healthy elderly population. We aimed to leverage these immunometabolic signatures to identify healthy elderly individuals with reduced immune cell fitness and, therefore, potentially at a higher risk for age-related complications. We characterized lactate and cytokine secretion, phagocytic capacity, and glycolytic and oxidative metabolic responses in monocytes from 103 elderly individuals and included 52 young adults as a reference group with healthy immune responses. We observed strong similarities in monocyte functional and metabolic signatures between young adults and elderly individuals. However, monocytes from the elderly secreted significantly more cytokines and displayed more ATP-linked respiration and a reduced proton leak compared to young adults. These significant differences were driven by a subgroup within the elderly population characterized by higher monocyte lactate secretion compared to the remainder of the elderly and young adults and were therefore classified as "immune-unfit". The immune-unfit elderly exhibited "hyperactive" monocytes, evidenced by significantly higher metabolic and functional signatures. Interestingly, compared to immune-fit individuals, immune-unfit elderly individuals had significantly elevated levels of circulating vascular endothelial growth factor and low-density lipoprotein cholesterol. Hence, we propose lactate secretion from monocytes as a parameter to classify "immune-unfit" elderly individuals with divergent immunometabolic properties of monocytes that could reflect increased susceptibility to age-related cardiometabolic complications. Trial Registration: NCT05940337.

DOI: https://doi.org/10.1111/acel.70220
Biochim Biophys Acta Rev Cancer. 2025 Oct 10. pii: S0304-419X(25)00213-6. [Epub ahead of print]1880(6): 189471

Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression.

Sayak Ghosh, Rittick Dutta, Devyani Goswami, Debapriya Ghatak, Rudranil De.

  Mitochondria in natural killer (NK) cells orchestrate a dynamic interplay between energy production and immune regulation, placing them at the forefront of oncogenesis and tumor microenvironment (TME) infiltration. This review unravels the intricate disruptions in mitochondrial dynamics-fission, fusion, and biogenesis-that hypoxia imposes within the TME, culminating in impaired NK cell functionality. Hypoxia-driven mitochondrial fragmentation, mediated by HIF-1α and mTOR-Drp1 signaling, cripples NK cell cytotoxicity, proliferation, and maturation, while elevated ROS levels and metabolic reprogramming bolster tumor immune evasion. The metabolic landscape of the TME adds another layer of complexity, with amino acid depletion significantly hindering NK cell performance. Arginine and leucine deficiencies suppress proliferation and mTOR activation, whereas disrupted glutamine metabolism impairs cMyc-driven metabolic adaptation. Additionally, immunosuppressive catabolites like nitric oxide and L-kynurenine exacerbate NK cell dysfunction by curbing cytokine production and receptor expression. Targeting these metabolic vulnerabilities offers a promising strategy; specifically, interventions aimed at amino acid pathways could simultaneously restrict nutrient availability within the tumor microenvironment and preserve NK cell functionalities. Emerging strategies spotlight the potential of NK cells to induce autophagic death in hypoxic cancer cells, a mechanism that could restore their cytotoxic potential. Furthermore, immune checkpoint pathways, such as PD-1 and CTLA-4, amplify mitochondrial dysfunction, underscoring their therapeutic significance. By addressing hypoxia, metabolic dysregulation, and mitochondrial reprogramming, this review illuminates actionable strategies to reinvigorate NK cell-mediated antitumor responses and pave the way for transformative cancer therapies.

Keywords:  Cancer; Glutamine; Hypoxia; Immunometabolism; Mitochondria; Natural killer (NK) cells

DOI:  https://doi.org/10.1016/j.bbcan.2025.189471
Nat Commun. 2025 Oct 14. 16(1): 9117

Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy.

Fei Fang, Erxiang Wang, Hanqiao Yang, Ting Zhao, Qiwei Wang, Zhen Zhang, Yang Song, Xiaoheng Liu.

Disruption in the dynamic stability of macrophage pro/anti-inflammatory phenotypes within plaques significantly impacts chronic vascular inflammation and exacerbates atherosclerosis. Reprogramming macrophages from pro-inflammatory to anti-inflammatory phenotype mitigates atherosclerosis progression. However, chronic inflammatory stimulation induces a closed chromatin state in atherosclerotic macrophages, inhibiting their phenotype reprogramming. This study demonstrates that restoring mitochondrial respiration increases histone acetylation (AcH3) and enhances chromatin accessibility in atherosclerotic macrophages, restarting macrophage phenotype reprogramming. Additionally, we identified that miR-10a can facilitate mitochondrial respiration and reorganize macrophage reprogramming. To optimize delivery, prolong circulation time, and target pro-inflammatory macrophages, we developed red blood cell membrane-modified liposome nanoparticles (miR-10a@H-MNP) to deliver miR-10a. Hyaluronic acid was conjugated to the liposomes to specifically target pro-inflammatory macrophages in plaque. Intravenous administration of miR-10a@H-MNP significantly alleviated atherosclerosis progression in male mice. Thus, the epigenomic priming approach developed here effectively triggers macrophage reprogramming in atherosclerosis, presenting a promising metabolically based epigenetic modulation method for plaque clearance.

DOI: https://doi.org/10.1038/s41467-025-64201-8
Eur J Immunol. 2025 Oct;55(10): e70076

Short-Chain Fatty Acid Sodium Butyrate Suppresses Protective Humoral Immunity by Inhibiting Follicular T Helper Cell Differentiation.

Bhushan Nikam, Someshwar Nath Jha, Yatish Thakare, Poonam Coshic, Nimesh Gupta.

  The gut microbiome and its metabolites are critical regulators of intestinal homeostasis, with emerging evidence highlighting their influence on humoral immune responses and vaccine efficacy. The development of effective humoral immunity depends on the magnitude and quality of germinal centers (GCs), which are driven by follicular T helper (Tfh) cells. Here, we investigate the role of short-chain fatty acids (SCFAs) in shaping humoral immunity, with a particular focus on Tfh cells. In ex vivo assays, we found that sodium butyrate, not sodium acetate or sodium propionate, directly suppresses Tfh cells differentiation and helper functions. Using antigen-specific and influenza virus infection models, we further demonstrate that sodium butyrate impairs Tfh cell differentiation, leading to diminished GC B cell responses and compromised humoral immunity during systemic infection. Notably, mice treated with sodium butyrate succumbed to virus infection, underscoring its effect on impairing protective immunity. Mechanistically, our findings reveal that sodium butyrate mediates these suppressive effects on Tfh cells via histone deacetylase (HDAC) inhibition. Together, our findings establish sodium butyrate as a negative regulator of humoral immunity by directly suppressing the Tfh-cell differentiation and Tfh-derived GC responses. These insights provide a mechanistic link between gut microbiome-derived metabolites and humoral immunity, with potential implications for vaccine efficacy and therapeutic interventions.

Keywords:  follicular T helper (Tfh) cells; germinal centers (GCs); gut–immune axis; humoral immunity; influenza infection; protective immunity; short‐chain fatty acids (SCFAs); sodium butyrate

DOI:  https://doi.org/10.1002/eji.70076
Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00779-8. [Epub ahead of print]85(20): 3760-3778

Amino acid and cholesterol metabolism in innate immunity.

Weiyun Li, Miao Jin, Hongye Li, Ruiyue Zhong, Zhaoheng Lin, Miao Shen, Hongyan Wang.

Innate immune cells not only serve as the first line of defense against pathogen invasion but also play essential roles in the immune regulatory function of various diseases. Distinct innate immune cells and their subtypes exhibit unique metabolic profiles, and their activation, differentiation, and effector functions are tightly governed by a complex regulatory network involving both intracellular metabolism and metabolites derived from the surrounding microenvironment. Cholesterol and amino acids function not only as structural constituents of membranes and proteins but also as signaling mediators that fine-tune immune cell activity. Importantly, their metabolic pathways are tightly interconnected. This review focuses on amino acid and cholesterol metabolism, offering comprehensive insights into how these metabolic processes shape innate immune cell function during homeostasis or pathological conditions. We further discuss emerging metabolic targets and therapeutic strategies aimed at modulating innate immunity in the context of immune-related diseases.

DOI: https://doi.org/10.1016/j.molcel.2025.09.019
Front Immunol. 2025 ;16 1614768

A high-calorie diet exacerbates lipopolysaccharide-induced pneumonia by promoting acetate-mediated macrophage polarization via the HDAC9/10-HIF-1α-glycolysis axis.

Qianqian Li, Hui Liu, Chen Bai, Lin Jiang, Chen Su, Xueying Qin, Tiegang Liu, Xiaohong Gu.

  Lung macrophage polarization imbalance is an important cause of aggravated pulmonary inflammation. The gut microbiota metabolites short-chain fatty acids (SCFAs) are an important regulator of macrophage polarization. A high-calorie diet has been shown to aggravate pneumonia and delay recovery, especially in children. However, the underlying mechanisms remain unclear. Our previous studies showed that a high-calorie diet can disrupt the gut microbiota structure and SCFA metabolism to aggravate LPS-induced lung inflammatory damage in juvenile rats. In this study, we investigated whether pneumonia aggravated owing to a high-calorie diet is associated with SCFA-driven macrophage phenotype changes in distal lung tissues and related mechanisms. Our data revealed that a high-calorie diet significantly aggravated pulmonary inflammatory injury in juvenile mice with LPS-induced pneumonia and also increased lung tissue M1-like (CD206-CD86+)/M2-like (CD206+CD86-) macrophage polarization imbalance. We found that a high-calorie diet decreased SCFA levels in mouse stool, serum, and lung tissues, which was most pronounced for acetate. Furthermore, we found that acetate reduction mediated by a high-calorie diet exacerbated M1-like (CD206⁻CD86⁺)/M2-like (CD206⁺CD86⁻) macrophage polarization imbalance in the lung tissue of pneumonia model mice and was associated with inhibiting histone deacetylase (HDAC), rather than G-protein-coupled receptor 43 (GPR43) signaling. More critically, we found that acetate supplementation had the most significant impact on HDAC9 and HDAC10 in the lung macrophages of pneumonia model mice fed a high-calorie diet. Furthermore, overexpression of Hdac9 and Hdac10 significantly attenuated the improvement effects of acetate on lung tissue M1-like (CD206-CD86+)/M2-like (CD206+CD86-) macrophage polarization in pneumonia model mice fed a high-calorie diet, and this mechanism was associated with the HIF-1α-glycolysis axis. Taken together, we demonstrated that a high-calorie diet could cause acetate levels to decrease in mice with LPS-induced pneumonia. This decrease in acetate was associated with a diminished inhibitory effect on HDAC9/10, potentially contributing to upregulation of HIF-1α expression and increased glycolysis. These changes may be linked to an imbalance in M1-like (CD206-CD86+)/M2-like (CD206+CD86-) macrophage polarization and aggravate lung tissue inflammatory injury. Our findings show that acetate supplementation may be a potential treatment strategy to prevent and treat pneumonia and other infectious diseases.

Keywords:  glycolysis; high-calorie diet; hypoxia inducible factor-1α; macrophage; pneumonia

DOI:  https://doi.org/10.3389/fimmu.2025.1614768
Int J Biol Sci. 2025 ;21(13): 5725-5743

dsHMGB1, released from IL-17A-induced pyroptotic prostate epithelial cells, drives M1 polarization by promoting Pfkp-mediated glycolysis via Jak2/Stat1 transcription in experimental autoimmune prostatitis.

Wenming Ma, Yi Zhang, Wenlong Xu, Yongtao Hu, Weikang Wu, Lei Chen, Li Zhang, Hexi Du, Jialin Meng, Jing Chen, Chaozhao Liang.

  Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological disorder in males, characterized by an unknown mechanism and limited therapeutic efficacy. The involvement of high mobility group box 1 (HMGB1)-mediated macrophage polarization has been extensively explored in various immune-inflammatory conditions; however, its potential role in CP/CPPS has not yet been examined. Method: In experimental autoimmune prostatitis (EAP) mouse model, with various treatments including anti-IL-17A, Bz-ATP, or glycyrrhizic acid (GA, a HMGB1 inhibitor). In vitro, prostate epithelial cells (PECs) and immortalized bone marrow-derived macrophages (iBMDM) were treated with IL-17A, disulfide HMGB1 (dsHMGB1), or fludarabine (Flu, a Stat1 inhibitor). Histological analysis, immunofluorescence, TUNEL, ELISA, reactive oxygen species detection, glucose uptake, lactate assays, flow cytometry, western blot, proteome sequence, differential gene analysis, RT-qPCR, ChIP-qPCR, and dual-luciferase assay, etc. were used for the detection of phenotypes and exploration of mechanisms. Results: We confirmed that IL-17A could induce pyroptosis in PECs and release dsHMGB1 in vitro, the similar function presented in vivo as well, and can be reversed by Bz-ATP. Additionally, dsHMGB1 enhances glycolytic metabolism via the Jak2/Stat1 pathway, thereby promoting polarization of M1 macrophage. Pfkp, a rate-limiting enzyme involved in glycolysis, plays a critical role in this metabolic shift. ChIP-qPCR and luciferase assays demonstrated that Stat1 can transcriptionally regulate Pfkp. In the rescue experiments, we also demonstrated that GA and Flu could potentially be the therapeutic options for CP/CPPS. Conclusions: IL-17A-mediated pyroptosis in prostate epithelial cells triggers the release of dsHMGB1, which transcriptional regulates the key glycolytic enzyme Pfkp through the Jak2/Stat1 transcription to promote the M1 polarization of macrophages. Targeting dsHMGB1 or Stat1 could be potential therapeutic strategies for managing CP/CPPS by regulating M1 macrophage polarization and reducing inflammatory cytokines.

Keywords:  CP/CPPS; Jak2/Stat1; M1 polarization; dsHMGB1; glycolysis

DOI:  https://doi.org/10.7150/ijbs.113908
Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00776-2. [Epub ahead of print]85(20): 3779-3792

Metabolites in the extracellular tumor microenvironment and the shaping of macrophage function.

Sara Lamorte, Matthew Bianca, Zhe Qi Liu, Tracy L McGaha.

  It has been a century since it was discovered that cancer cells have a distorted metabolism compared to healthy cells and tissues. It is now universally accepted that the abnormal metabolic state of cancers is essential for proliferation and survival in the harsh environment of most solid tumors. However, the impact of the altered metabolite pools generated from this rewiring is complex and has been challenging to functionally disentangle. Macrophages are innate immune cells and a major cellular constituent of the tumor microenvironment (TME). Macrophages are functionally plastic and highly sensitive to changes in metabolite exposure, with the potential to change the TME in a profound, disease-altering fashion. However, it was not until the recent advent of sensitive, high-dimensional analysis that the impact of metabolites on tumor macrophage diversity and function was fully appreciated. In this review, we discuss recent developments in our knowledge of how altered metabolites, resulting from metabolic reprogramming in the TME, influence macrophage phenotype and the implications for tumor development and progression. Furthermore, we examine emerging therapeutic strategies aimed at targeting tumor-metabolite crosstalk to improve disease outcomes.

Keywords:  immunity; macrophage; metabolism; metabolites; tumor microenvironment

DOI:  https://doi.org/10.1016/j.molcel.2025.09.016
Nat Commun. 2025 Oct 16. 16(1): 9189

Backtracking metabolic dynamics in single cells predicts bacterial replication in human macrophages.

Mariatou Dramé, Francisco-Javier Garcia-Rodriguez, Dmitry Ershov, Jessica E Martyn, Jean-Yves Tinevez, Carmen Buchrieser, Pedro Escoll.

Accurately tracking dynamic state transitions is crucial for modeling and predicting biological outcomes, as it captures heterogeneity of cellular responses. To build a model to predict bacterial infection in single cells, we have monitored in parallel infection progression and metabolic parameters in thousands of human primary macrophages infected with the intracellular pathogen Legionella pneumophila. By combining live-cell imaging with a tool for classifying cells based on infection outcomes, we were able to trace the specific evolution of metabolic parameters linked to distinct outcomes, such as bacterial replication or cell death. Our findings revealed that early changes in mitochondrial membrane potential (Δψm) and in the production of mitochondrial Reactive Oxygen Species (mROS) are associated with macrophages that will later support bacterial growth. We used these data to train an explainable machine-learning model and achieved 83% accuracy in predicting L. pneumophila replication in single, infected cells before bacterial replication starts. Our results highlight backtracking as a valuable tool to gain new insights in host-pathogen interactions and identify early mitochondrial alterations as key predictive markers of success of bacterial infection.

DOI: https://doi.org/10.1038/s41467-025-64225-0
Cell Death Dis. 2025 Oct 13. 16(1): 721

Chronic HBV infection impairs the glucose metabolism and effector function of NK cells via HBsAg/IL-15/mTOR axis.

Yating Yu, Zixuan Wang, Ailu Yang, Yucan Wang, Cuiping Bao, Li Zhuo, Qiuju Han, Huajun Zhao, Jian Zhang.

Natural killer (NK) cell function is impaired in patients with chronic hepatitis B (CHB) infection; however, the underlying mechanisms are not fully understood. Here, we collected the blood samples from healthy donors (HDs) and patients with CHB, and then analyzed the characteristics of NK cells by RNA-seq analysis, flow cytometry, Seahorse assay. HBV-carrier mice were used to confirm the findings in vivo. We found that the dysfunction of NK cells in peripheral blood of patients with CHB was associated with the disturbance of glycolysis. Further investigation showed chronic HBV infection impaired the activation of mammalian target of rapamycin (mTOR) in NK cells, resulting in decreased expression of molecules involved in glycolysis, including HIF-1α and GLUT1. Mechanistically, we found that HBsAg suppressed IL-15-triggered mTOR activity by competitively binding to the IL-15 receptor β (IL-15Rβ, CD122) on NK cells, leading to the decreased expression of HIF-1α and its downstream genes. Significantly, HBsAg neutralizing antibody intravenous injection or mTOR agonist MHY1485 intraperitoneal injection restored the IL-15/mTOR signaling in NK cells of HBV-carrier mice, resulting in NK cell activation and HBV clearance. Further, transferring MHY1485-pretreated NK cells isolated from HBV-carrier mice displayed augmented anti-HBV effects in recipient HBV-carrier mice. These findings reveal a new mechanism by which chronic HBV infection induces NK cell dysfunction, and highlight the potential of mTOR activation and HBsAg clearance as therapeutic strategies for CHB treatment via recovering NK cell immune functions.

DOI: https://doi.org/10.1038/s41419-025-08069-y
Biochim Biophys Acta Rev Cancer. 2025 Oct 14. pii: S0304-419X(25)00220-3. [Epub ahead of print] 189478

Role of macrophage PKM2 in inflammation and tumor progression and its targeted therapy.

Yafei Li, Lingao Zhu, Lu Liu, Bo Li.

  Macrophages play a dual role of promoting or inhibiting in inflammation and tumor progression, highly dependent on the dynamic changes of M1/M2 polarization. In inflammation, M1/M2 polarization balance determines the outbreak of inflammation or tissue repair. In the tumor microenvironment, M1 tumor-associated macrophages (TAMs) exert both anti-tumor and pro-tumor effects, while M2 TAMs promote tumor progression. PKM2 regulates the M1/M2 polarization and cytokine secretion of macrophages through the pyruvate kinase activity of tetramers as well as the protein kinase activity and transcriptional co-activator function of dimers. This review summarizes the role and molecular mechanism of macrophage PKM2 in inflammation and tumor progression，highlighting its potential as a therapeutic target in inflammatory diseases and cancers. Macrophage PKM2 plays a promoting role in inflammation and tumor progression due to its dual regulatory characteristics of metabolism and immunity. It can not only meet the energy demands of macrophages through glycolytic metabolism, but also affect the immune response through enzyme activity-dependent and non-dependent mechanisms. The non-enzyme activity-dependent mechanism by which PKM2 regulates immune responses serves as a bridge connecting cellular metabolism and immune responses. The unresolved issues include the functional heterogeneity of macrophage PKM2 across different macrophage subtypes, its specific roles in lipid and amino acid metabolism, its contribution to tumor microenvironmental metabolic reprogramming, and PKM2-mediated interactions of macrophages with other cells.

Keywords:  PKM2; inflammation; macrophage; targeted therapy; tumor

DOI:  https://doi.org/10.1016/j.bbcan.2025.189478
Int J Biol Sci. 2025 ;21(13): 5936-5955

HIF-1-mediated macrophage metabolic reprogramming promotes AKI to CKD transition.

Hong Ding, Yan Zhou, Ren-He Zhu, Shu Yu, Ai-Qing Zhang, Hong Liu, Jia-Ling Ji, Zuo-Lin Li.

  Macrophage is educated by the tubule epithelial cell with maladaptive repair during the renal maladaptive repair, which is one of the most important characteristic features in acute kidney injury (AKI) to chronic kidney disease (CKD) transition. However, the underlying mechanism of orchestrating characterization of macrophage in renal maladaptive repair remains largely unclear. Accordingly, we found that pro-inflammatory macrophage educated by tubule epithelial cell with maladaptive repair was the primary contributor to the renal maladaptive repair in AKI to CKD transition, because macrophages depletion significantly attenuated tubulointerstitial fibrosis. Meanwhile, we found that glycolysis was essential for maintaining pro-inflammatory macrophage phenotype. Further, we demonstrated that HIF-1α played a crucial role in macrophage glycolysis as myeloid HIF-1α knockout alleviated tubulointerstitial fibrosis and AKI to CKD transition in vivo. Mechanistically, NF-κB directly binds to the HIF-1α promoter, boosting its transcription and significantly contributing to tubulointerstitial fibrosis in the AKI to CKD transition. Blockage of NF-κB ameliorated the CKD progression following AKI in vivo. Taken together, our studies provide a novel paradigm in which pro-inflammatory macrophage orchestrates renal maladaptive repair, contributing to the AKI to CKD transition. Blockade of NF-κB-HIF-1 signaling-mediated macrophage metabolic reprogramming may provide attractive strategy for pharmacologic therapy of the AKI to CKD transition.

Keywords:  NF-κB; acute kidney injury; chronic kidney disease; hypoxia-inducible factor-1; macrophage; metabolic reprogramming

DOI:  https://doi.org/10.7150/ijbs.111238
Clin Sci (Lond). 2025 Oct 08. pii: CS20256651. [Epub ahead of print]

Glutamine alleviates immunosuppression in polymicrobial sepsis by augmenting bacterial phagocytosis through sustaining the GFAT-DRP1 dependent mitochondrial calcium dynamics.

Yuanfeng Zhu, Xiaoli Chen, Lin Xia, Shijun Fan, Qian Chen, Yan Wei, Yongling Lu, Xin Liu, Xi Peng.

  Sepsis triggers impaired macrophage bacterial phagocytosis, rendering the host more vulnerable to secondary infections, a manifestation termed sepsis-associated immunosuppression. Glutamine is a vital nutrient in critical illness that not only supports energy production and biomass synthesis but also potentially exerts immunomodulatory effects. The aim of this study was to investigate whether supplementation of glutamine modulates macrophage phagocytosis and mitigates sepsis-induced immunosuppression. Using a murine model of polymicrobial sepsis, we evaluated the effects of glutamine supplementation on bacterial load, cytokine production, and survival. In multiple in vitro assays, we employed molecular and pharmacological approaches to dissect glutamine-dependent signaling pathways in recovering the immunosuppressive macrophages. We found that glutamine deficiency impaired macrophage phagocytosis and exacerbated sepsis-induced immunosuppression. In contrast, exogenous glutamine supplementation restored macrophage function and improved survival in septic mice-effects that were abolished upon macrophage depletion. Mechanistically, glutamine promoted glutamine-fructose-6-phosphate transaminase (GFAT)-dependent protein O-GlcNAcylation, leading to dynamin-related protein 1 (DRP1) oligomerization. Concurrently, glutamine activated a GFAT-mediated, CDK1-dependent pathway that induced DRP1 phosphorylation at Ser616 irrelevant of O-GlcNAcylation. These effects enhanced DRP1-mediated mitochondrial fission, increased mitochondrial calcium efflux, and sustained cytosolic calcium levels essential for phagocytosis. In conclusion, our study demonstrates that glutamine strengthens macrophage phagocytosis and alleviates immunosuppression in sepsis through a dual GFAT-DRP1 mechanism coordinating mitochondrial dynamics and calcium signaling, highlighting the GFAT-DRP1-calcium axis as a potential therapeutic target for treating sepsis-induced immunosuppression.

Keywords:  DRP1; GFAT; glutamine; immunosuppression; mitochondrial; phagocytosis; sepsis

DOI:  https://doi.org/10.1042/CS20256651
Int J Mol Sci. 2025 Sep 23. pii: 9270. [Epub ahead of print]26(19):

Zinc Promotes Mitochondrial Health Through PGC-1alpha Enhancing Bacterial Clearance in Macrophages Infected with Mycobacterium avium Complex.

Ruxana T Sadikot, Prabagaran Narayanasamy, Zhihong Yuan, Deandra Smith, Daren L Knoell.

  Mitochondria are increasingly recognized as important contributors to immune function, in addition to energy production. They exert this influence through modulation of various signaling pathways that regulate cellular metabolism and immune function in response to pathogens. Peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PGC-1α) is the primary transcription factor and regulator involved in mitochondrial biogenesis. Long known to be involved in immune function, zinc (Zn) is also required for proper mitochondrial function. It is increasingly recognized that many cellular immunometabolic activities are also Zn-dependent. Taken together, we investigated the role of Zn deficiency, both dietary and genetically induced, and Zn supplementation in PGC-1α-mediated macrophage mitochondrial biogenesis and immune function following infection with Mycobacterium avium complex (MAC). Our novel findings show that Zn is an important regulator of PGC-1α, TFAM and mitochondrial biogenesis, leading to enhanced bacterial phagocytosis and bacterial killing in macrophages. Mechanistically, we show that the Zn importer ZIP8 (Zrt/Irt-like protein) orchestrates Zn-mediated effects on PGC-1α and mitochondrial function. Taken together, defective Zn biodistribution may increase susceptibility to infection, whereas Zn supplementation may provide a tractable host-directed therapy to enhance the innate immune response in patients vulnerable to MAC infection.

Keywords:  Mycobacterium avium; biogenesis; macrophages; mitochondria dysfunction; zinc

DOI:  https://doi.org/10.3390/ijms26199270
Gut Microbes. 2025 Dec 31. 17(1): 2569741

Gut microbiota butyrate mediated RUNX3 promotes Nr4a1highZFP36highresident macrophages via NR4A1/ERK1/2 MAPK to maintain gut homeostasis.

Yunhuan Gao, Yi Shi, Ningning Zhu, Yang Hao, Juanjuan Wang, Yuan Zhang, Rongcun Yang.

  Gut homeostasis is critical for systemic health, and its disruption is implicated in various diseases, including metabolic disorders. Gut-resident macrophages play a pivotal role in maintaining intestinal homeostasis, yet the mechanisms underlying their differentiation and function remain incompletely understood. Using single-cell RNA sequencing (scRNA-seq), we found a key regulatory axis in which gut microbiota-derived butyrate induces the differentiation of Nr4a1highZFP36high resident macrophages via RUNX3 to sustain gut homeostasis. Butyrate could upregulate RUNX3 expression in gut-resident macrophages through lncRNA lncLy6c-mediated H3K4me3 modification. Genetic ablation of RUNX3 in myeloid cells of RUNX3fl/fl-Lyz2-Cre mice led to a marked reduction in resident macrophages and increased susceptibility to DSS-induced colitis. RUNX3-mediated resident macrophages exhibited elevated ZFP36 expression alongside suppressed pro-inflammatory cytokines and chemokines. Further mechanistic studies revealed that RUNX3 drives the differentiation of Nr4a1highZFP36high resident macrophages via the Nr4a1-dependent activation of the ERK1/2 MAPK pathway. Consistently, high expression levels of RUNX3, Nr4a1, and ZFP36 were observed in colon-resident macrophages from healthy human donors. Collectively, our findings demonstrate that butyrate-RUNX3 signaling orchestrates the differentiation of Nr4a1highZFP36high resident macrophages through the Nr4a1/ERK1/2 MAPK pathway, thereby safeguarding gut homeostasis.

Keywords:  Gut microbe; Nr4a1; RUNX3; ZFP36; resident macrophage

DOI:  https://doi.org/10.1080/19490976.2025.2569741
Front Med (Lausanne). 2025 ;12 1653689

Echinocystic acid in Momordica charantia L. exosome-like nanovesicles attenuates dengue virus-induced vascular leakage associated inflammatory mediators through macrophage metabolic reprogramming and HIF-1α/p300-CBP interaction.

Honglin Liu, Juan He, Lili Xu, Yingxuan Chen, Xiaoni Wang, Xiaoni Pang, Haihui Yang, Lianhui Liang, Shuwen Chen, Shuli Li.

   Introduction: Dengue virus (DENV) infection can progress to severe dengue hemorrhagic fever and shock syndrome, characterized by vascular leakage with high mortality. This endothelial dysfunction is primarily driven by excessive inflammatory activation of monocytes and macrophages. While Momordica charantia L. is known for its broad bioactive properties, its potential role in mitigating dengue-induced immunopathology remains unexplored.
Methods: We investigated the effects of exosome-like nanoparticles derived from Momordica charantia L. (MC-ELNs) and their highly abundant constituent, echinocystic acid (EA), on DENV-induced macrophage inflammation and endothelial dysfunction. The mechanism focused on the HIF-1α-p300/CBP transcriptional complex.
Results: MC-ELNs and EA significantly alleviated DENV-induced macrophage inflammation without affecting HIF-1α expression or nuclear translocation. They shifted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, downregulated glycolytic enzymes (HK2, PFKL, PKM1, LDHA), suppressed phagocytosis, reduced secretion of endothelial damage-associated mediators (IL-1β, IL-6, TNF-α, MMP-9), and enhanced IL-10 production. Mechanistically, both interventions inhibited the interaction between HIF-1α and p300/CBP, thereby decoupling inflammatory activation from metabolic reprogramming.
Discussion: These findings reveal a novel host-directed therapeutic strategy against severe dengue by targeting the HIF-1α-p300/CBP complex. The study highlights the potential of plant-derived nanovesicles and their bioactive components, such as MC-ELNs and EA, in treating inflammatory vascular diseases.

Keywords:  Momordica charantia L.; dengue; echinocystic acid; macrophage; nanovesicles

DOI:  https://doi.org/10.3389/fmed.2025.1653689
Lab Invest. 2025 Oct 11. pii: S0023-6837(25)00160-6. [Epub ahead of print] 104250

Glycolysis inhibition restores immune sensitivity in GSNOR-deficient colorectal cancer.

Ana Mantrana, María Teresa Sánchez-Montero, Carmen Navarrete-Sirvent, Nerea Herrera-Casanova, Rafael Mena-Osuna, Aurora Rivas-Crespo, Alejandra Díaz-Chacón, Virginia Ávila-Oca, Marta Toledano-Fonseca, María Victoria García-Ortíz, Rafael González-Fernández, María Auxiliadora Gómez-España, Carlos Villar, Francisco Javier Medina-Fernández, Enrique Aranda, Silvia Guil-Luna, Antonio Rodríguez-Ariza.

  S-nitrosoglutathione reductase (GSNOR) is increasingly recognized as a tumor suppressor, and we have recently reported that its deficiency drives an aggressive and immune-evasive phenotype in colorectal cancer (CRC). However, the mechanisms linking GSNOR loss to immune escape remain incompletely understood. In this study, we uncover a previously unrecognized connection between metabolic reprogramming and immune escape in GSNOR-deficient CRC and identifies a therapeutic vulnerability that can be exploited to restore immune responsiveness. Comprehensive analysis of 137 clinical CRC samples revealed that GSNOR-deficient tumors exhibit high-grade tumor budding, an established marker of poor prognosis, and reduced CD4+ and CD8+ T-cell infiltration, consistent with an immunosuppressive tumor microenvironment. Integrating transcriptomic, immunohistochemical, and single-cell RNA-seq data, we demonstrate that GSNOR-deficient tumors undergo a striking metabolic reprogramming toward glycolytic dependence, with elevated lactate production contributing to T-cell exclusion. Based on these findings, we show that pharmacologic glycolysis inhibition with 2-deoxyglucose (2-DG) reverses immune resistance in GSNOR-KO models, enhancing CD8+ T-cell infiltration and sensitizing tumors to anti-PD-1 therapy both in vitro and in vivo. Notably, this is the first demonstration that metabolic intervention can restore immune sensitivity in GSNOR-deficient CRC. Our results identify GSNOR expression as a predictive biomarker for metabolic-immune combinatorial strategies and support the clinical translation of 2-DG plus anti-PD-1 as a precision immunotherapy approach for this high-risk CRC phenotype.

Keywords:  2-deoxyglucose; GSNOR; S-nitrosylation; colorectal cancer; immunotherapy; metabolism

DOI:  https://doi.org/10.1016/j.labinv.2025.104250
Curr Drug Targets. 2025 Oct 14.

Mitochondria-Targeted Nanoformulations: New Therapeutic Strategies and Opportunities for Cancer Immunotherapy.

Jia Cai, Hongwu Huang, Bingcong Peng, Jiasi Tang, Dongxiu He.

   INTRODUCTION: Immunotherapy has revolutionized cancer treatment, however, its effectiveness remains limited by weak tumor immunogenicity and immunosuppressive microenvironments. Mitochondria have emerged as a strategic therapeutic target, given their central role in regulating immune cell activation, proliferation, and function through metabolic reprogramming and signaling pathway modulation. Mitochondria-targeted nanoformulations offer a promising approach to amplify anti-tumor immunity by enhancing immune responses at the cellular and molecular levels.
METHODS: We searched the PubMed and Web of Science databases using keywords and combinations related to mitochondrial targeting, cancer, immunotherapy, and nanoformulations. The primary search timeframe focused on the last five years. The literature screening process mainly involved an initial screening based on titles and abstracts, followed by a full-text screening.
RESULTS: Mitochondria critically govern anti-tumor immunity by controlling the activation and function of immune cells, modulating immune signaling pathways, and adjusting mitochondrial dynamics and metabolism. Recent advancements in mitochondria-targeted nanoformulations have shown potential to enhance immunity by inducing immunogenic cell death (ICD), regulating mitochondrial dynamics and metabolism, and activating key immune pathways.
DISCUSSION: Mitochondrial-targeted is a novel strategy for activating anti-tumor immunity. Despite promising preclinical results, clinical translation remains unrealized. Future research must prioritize integrating basic and clinical studies to advance mitochondrial immunomodulation from bench to bedside.
CONCLUSION: Although preclinical studies demonstrate the promise of mitochondria-targeted nanoformulations, clinical translation remains unrealized. Advances in nanotechnology, immunometabolism, and AI-driven drug design hold immense potential to overcome current barriers, particularly in solid tumors. Future efforts may establish mitochondrial immunomodulation as a transformative strategy in oncology.

Keywords:  Cancer; immunotherapy; mitochondria; mitochondria-targeted.; nanoformulations; targeted therapy

DOI:  https://doi.org/10.2174/0113894501397738250919154624
J Intensive Care Med. 2025 Oct 15. 8850666251385540

Microbiome and Metabolic Immune Mechanisms in Sepsis-Associated Encephalopathy.

Zhai Nan.

  Sepsis associated encephalopathy (SAE) is common in patients with sepsis, and the occurrence of SAE often indicated adverse outcomes. In recent years, the imbalance of the intestinal microbiota and metabolites have been found to be related to the occurrence of SAE, and this regulation is often accompanied by the activation of the immune system. Possible mechanism still needs to be clarified. Intestinal flora disturbances and altered metabolic profiles are often accompanied by changes in the levels of small molecule metabolites, some of which are critical for the maintenance of brain functional homeostasis, such as short-chain fatty acids (SCFAs). These changes further affect the permeability of the blood-brain barrier and the activation of the central and peripheral immune system, and finally promote the release of inflammatory cytokines and the activation of immune cells. Targeting intestinal microbiota profile, small molecule metabolite, or neurostimulation regulation may be potential therapeutic methods for SAE, such as amino acid supplements, microbiota transplantation, or other metabolite level regulation drugs. Our review will summarize the intestinal flora disturbances, metabolic profiles, neuro-immunoinflammatory changes and related possible drug intervention. These findings may provide the possibility for further exploration of the mechanisms and treatment methods of SAE.

Keywords:  intestinal flora disturbances; metabolite; neuro-inflammation; sepsis associated encephalopathy

DOI:  https://doi.org/10.1177/08850666251385540
Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00784-1. [Epub ahead of print]85(20): 3730-3733

Conversations at the interface of metabolism and immunity.

Russell G Jones, M Celeste Simon, Cheng-Chin Kuo, Xinjian Li, Ping-Chih Ho.

The developing field of immunometabolism showcases how molecular insights inform on cellular-level responses to both internal context and environmental stimuli. For our focus issue on innate immunity, we spoke with researchers about the new doors they see opening in this area, from molecular crosstalk to therapeutic potential.

DOI: https://doi.org/10.1016/j.molcel.2025.09.024
Eur J Pharmacol. 2025 Oct 11. pii: S0014-2999(25)00996-3. [Epub ahead of print]1007 178242

Itaconate regulates PANoptosis in splenocytes to alleviate sepsis-induced multiple organ dysfunction syndrome.

De-Peng Lu, Lin-Zhi Lu, Li-Ao Zhang, Wei-Jia Zhai, Qing-Li Luo, Zhen-Xing Cheng, Xi Chen.

  Sepsis is a life-threatening condition triggered by infection and frequently progresses to multiple organ dysfunction syndrome (MODS). Its complex pathophysiology poses significant challenges for effective treatment. Itaconic acid, a key metabolic intermediate, has been recognized for its anti-inflammatory and immunomodulatory properties. Notably, elevated levels of extracellular circulating histones have been detected in the bloodstream of septic patients, and animal models further confirm that circulating histones play a critical role in driving multi-organ injury. This study was developed to investigate the therapeutic potential of itaconate in sepsis-induced MODS and elucidates its underlying molecular mechanisms. Using a sepsis mouse model, the spleen was identified as the primary source of circulating histones in sepsis. Itaconate intervention in septic mice effectively suppressed splenic cell PANoptosis and reduced histone release by modulating iNOS expression, thereby improving survival rates and alleviating multi-organ damage. In parallel, cellular experiments using primary splenic cells further confirmed that itaconate mitigates PANoptosis and decreases circulating histone production through a similar pathway. These findings suggest that itaconate represents a promising therapeutic strategy for sepsis and its complications. Moreover, this study highlights the critical role of splenocyte PANoptosis in histone release, establishing itaconate as a potential candidate for histone-targeted therapy in sepsis.

Keywords:  Circulating histones; PANoptosis; Sepsis; Spleen; iNOS

DOI:  https://doi.org/10.1016/j.ejphar.2025.178242
Cells. 2025 Oct 03. pii: 1550. [Epub ahead of print]14(19):

IDO-Mediated Immune and Metabolic Dysregulation in Schwann Cells Exposed to Mycobacterium leprae.

Atta Ur Rahman, Raíssa Couto Santana, Mylena Masseno de Pinho Pereira, Claudia Luciana Dos Santos Moura, Débora Santos da Silva, Otto Castro Araujo, Thyago Leal-Calvo, Isabela Espasandin, Tatiana Pereira da Silva, Euzenir Nunes Sarno, Bruno Jorge de Andrade Silva, Rubem Sadok Figueiredo Menna-Barreto, Márcia Maria Jardim, Cristiana Santos de Macedo, Flávio Alves Lara, Roberta Olmo Pinheiro.

  Leprosy is a chronic infectious disease that targets the peripheral nervous system, leading to peripheral neuropathy. Mycobacterium leprae primarily infects Schwann cells, adipocytes, and macrophages, altering their metabolism and gene expression. This study investigates the metabolic interaction between M. leprae and Schwann cells, with a focus on indoleamine 2,3-dioxygenase (IDO), a key enzyme in tryptophan catabolism via the kynurenine pathway. We found that M. leprae induces IDO expression in Schwann cells, suggesting a role in immune modulation and neuropathy. Inhibition of IDO with 1-methyl-L-tryptophan (1-MT) reduced Schwann cell viability and metabolic activity in response to M. leprae. After 24 h of infection, M. leprae impaired mitochondrial membrane potential, although no significant changes in autophagy or mitochondrial ultrastructure were observed by electron microscopy. Interestingly, IDO1 inhibition upregulated the expression of antioxidant genes, including GPX4, NFE2L2, and HMOX1. In conclusion, these findings highlight a central role for IDO in shaping the metabolic and immunological response of Schwann cells to M. leprae infection. IDO induction contributes to immune regulation and cellular stress, while its inhibition disrupts cell viability and promotes antioxidant gene expression. These results position IDO as a potential therapeutic target for modulating host-pathogen interactions and mitigating nerve damage in leprosy.

Keywords:  Indoleamine 2,3 Dioxygenase (IDO); Mycobacterium leprae; Schwann cells; kynurenine pathway

DOI:  https://doi.org/10.3390/cells14191550
Neuron. 2025 Oct 10. pii: S0896-6273(25)00710-X. [Epub ahead of print]

Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis.

Bongsoo Park, Alexandra M Nicaise, Dimitrios Tsitsipatis, Liviu Pirvan, Daniel Zucha, Andi Munteanu, Pranathi Prasad, Miguel Larraz Lopez De Novales, Cristian Bulgaru, Rafael Kollyfas, Julia Whitten, Cory M Willis, Luka Culig, Joseph Llewellyn, Rosana-Bristena Ionescu, Magdy Mekdad, Madalena B C Simões-Abade, Grzegorz Krzak, Jinshui Fan, Supriyo De, Matthew O Ellis, Marta Suarez Cubero, Angeliki Spathopoulou, Luca Peruzzotti-Jametti, Tommaso Leonardi, Gabriel Balmus, Frank Edenhofer, Myriam Gorospe, Lukas Valihrach, Irina Mohorianu, Stefano Pluchino, Isabel Beerman.

  Progressive multiple sclerosis (PMS) involves a persistent, maladaptive inflammatory process with numerous cellular drivers. We generated induced neural stem cells (iNSCs) from patient fibroblasts through a direct reprogramming protocol that preserved their epigenome, which revealed a PMS-specific hypomethylation of lipid metabolism and interferon (IFN) signaling genes. Single-cell multi-omics uncovered a novel, disease-associated radial glia-like cell (DARG) subpopulation in PMS cell lines exhibiting senescence and potent IFN responsiveness driven by specific transcription factors. Functionally, PMS iNSCs induced paracrine senescence and inflammation onto control cells, which was inhibited upon senolytic treatment. We identified in PMS brains a distinct population of senescent, IFN-responsive DARGs that developmentally aligned with the trajectories of iNSCs in vitro and spatially associated with inflammatory glia in chronically active lesions. DARGs may sustain smoldering inflammation, unveiling a previously unrecognized cellular axis that could underpin mechanisms in neurodegeneration. This discovery offers novel insights into disease mechanisms and highlights potential therapeutic targets.

Keywords:  cellular senescence; epigenetic dysregulation; interferon response; neural stem cells; neurodegeneration; progressive multiple sclerosis; radial glia-like cells; single-cell multi-omics; spatial transcriptomics; transcriptomic signatures

DOI:  https://doi.org/10.1016/j.neuron.2025.09.022
Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2507154122

TCR signal-enhancing mutation alters lipid metabolism of thymocytes and impairs antitumor immunity of mature T cells.

Wenhua Liang, Yuge Liang, Mingzhu Yu, Chenshuang Ji, Feng Wang.

  The T cell receptor (TCR), a master regulator of adaptive immunity, serves as a molecular transducer that converts antigen recognition into precisely modulated intracellular signals, orchestrating both T cell development and effector functions. In this study, we leveraged a germline CD3εI173A mutation, a previously characterized alteration that amplifies TCR signaling through the disruption of inhibitory lipid interactions, to dissect how thymocyte-intrinsic TCR signaling amplification influences the fate of mature T cells. Remarkably, thymic double-positive cells in CD3εI173A mice with altered TCR repertoires demonstrated a significant downregulation of the phosphatidylserine decarboxylase homolog gene AC149090.1. This modulation triggered a comprehensive rewiring of lipid metabolic pathways, establishing a systemic compensatory mechanism to counterbalance excessive TCR signaling. These metabolic adaptations culminated in functionally compromised mature T cells, characterized by diminished activation potential, reduced proliferative capacity, and impaired antitumor efficacy in CD3εI173A mice. Our results underscore the critical role of thymic TCR signaling in T cell development for sustaining immune homeostasis and orchestrating mature T cell functionality, unveiling the lipid metabolic plasticity during thymocyte development that acts as a critical regulatory checkpoint for maintaining immune homeostasis.

Keywords:  CD3ε mutation; TCR signaling; antitumor immunity; gain-of-function; lipid metabolism

DOI:  https://doi.org/10.1073/pnas.2507154122
Eur J Med Res. 2025 Oct 14. 30(1): 971

Gut microbiota and metabolism in systemic lupus erythematosus: from dysbiosis to targeted interventions.

Jing-He Zhu, Li-Pei Wu, Lin Deng, Su-Gang Zang, Xue-Bin Li, Xin Chen, Jian-Xiu Yu.

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multiorgan involvement, with pathogenesis closely linked to that of gut dysbiosis and metabolic disturbances. Studies indicate that SLE patients exhibit significantly reduced gut microbial diversity, increased abundance of pathogenic bacteria, and decreased beneficial bacteria. Dysbiosis exacerbates disease progression by disrupting the intestinal barrier, triggering autoimmune responses, and promoting proinflammatory cytokine release. Metabolomic analyses further reveal that SLE is associated with dysregulated amino acid metabolism, reduced short-chain fatty acids, and disrupted lipid homeostasis, which correlate with disease activity, renal injury, and increased atherosclerosis risk. Emerging microbiota-targeted interventions, such as fecal microbiota transplantation (FMT), probiotics/prebiotics, phage therapy, and dietary modifications, demonstrate promising therapeutic potential by restoring microbial balance, enhancing immune regulation, and improving metabolic homeostasis. This review systematically summarizes the alterations in gut microbiota and metabolism in SLE, their critical roles in disease progression, diagnosis, and pathogenesis, and explores the clinical value of microbial-targeted strategies in improving SLE outcomes.

Keywords:  Diagnosis and treatment; Gut microbiota; Metabolomics; Systemic lupus erythematosus; Therapeutic strategies

DOI:  https://doi.org/10.1186/s40001-025-03264-1
Nat Commun. 2025 Oct 15. 16(1): 9156

Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.

Ziying Xu, Sepideh Kiani Shabestari, Savannah Barannikov, Kevin F Bieniek, Mathew Blurton-Jones, Juan Pablo Palavicini, Xianlin Han.

Abnormal lipid metabolism is observed in Alzheimer's disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain's resident immune cells, influence lipid processing during AD. Here, we show that microglia-the brain's resident immune cells-selectively regulate lipid accumulation that associated with disease pathology in both AD mouse models and human postmortem brains. Using lipidomics and histological analysis, we identify a striking buildup of arachidonic acid-containing bis(monoacylglycero)phosphate in response to amyloid plaques, which depends on microglial activity and the AD risk gene GRN. In contrast, lysophosphatidylcholine and lysophosphatidylethanolamine accumulate independently of microglia, correlating instead with astrocyte activation and oxidative stress. These results connect dysregulated lipid metabolism in AD to distinct brain cell types and molecular pathways. Our findings highlight microglial lipid homeostasis as a potential therapeutic target for modifying disease progression in AD.

DOI: https://doi.org/10.1038/s41467-025-64161-z
Cell Death Dis. 2025 Oct 16. 16(1): 728

Claudin-7 deficiency induces metabolic reprogramming of neutrophils in the colorectal cancer microenvironment.

Xiaoqing Liang, Dajin Yuan, Songyun Zhao, Jianbo Zhou, Kun Wang, Xiaoli Liu, Yin Liu, Huimin Li, Mengdi Hao, Wenbin Huang, Wenjie Li, Lei Ding.

Neutrophils are integral components of the bone marrow and stromal cell network. They express the immune checkpoint molecule PD-L1 and can induce T cell exhaustion, thereby promoting immunosuppression. In this study, we investigated whether tumor-derived Cldn7 deficiency could recruit polymorphonuclear neutrophils (PMNs), induce their metabolic reprogramming, and consequently drive their transition toward a pro-tumor phenotype, leading to the establishment of an immunosuppressive tumor microenvironment (TME). Using single-cell RNA sequencing, clinical sample validation, and both in vivo and in vitro experiments, we found that Cldn7 deficiency in colorectal cancer (CRC) results in a tumor microenvironment characterized by significantly increased infiltration of CD11b⁺ Ly6G⁺ neutrophils. This is accompanied by neutrophil metabolic reprogramming that facilitates their phenotypic shift toward a tumor-promoting state, which in turn suppresses the cytotoxic function of CD8⁺ T cells and contributes to the formation of an immunosuppressive TME, thereby accelerating CRC progression. Mechanistically, Cldn7 deficiency indirectly activates the NF-κB signaling pathway, leading to elevated secretion of chemokines such as CXCL1 that are responsible for PMN recruitment. Inhibition of the NF-κB/CXCL1 axis reduces PMN infiltration, decreases PD-L1 expression on neutrophils, suppresses neutrophil glycolysis and histone lactylation, reverses the exhausted phenotype of CD8⁺ T cells, thereby mitigating the immunosuppressive microenvironment. Furthermore, overexpression of Cldn7 enhances the efficacy of immune checkpoint blockade (ICB) therapy.Collectively, our findings indicate that Cldn7 deficiency not only contributes to immune evasion and malignant progression in CRC but also plays a critical role in immune modulation. Targeting PMN metabolic reprogramming and immunosuppressive function associated with Cldn7 loss may offer a promising strategy to improve the therapeutic efficacy of immunotherapy in CRC.

DOI: https://doi.org/10.1038/s41419-025-08064-3
J Exp Med. 2026 Jan 05. pii: e20250603. [Epub ahead of print]223(1):

Adenosine metabolic clearance maintains liver homeostasis by licensing arginine methylation of RIPK1.

Ran Liu, Gengqiao Wang, Zhengting Jiang, Tianhao Zou, Chuanzheng Wang, Weimin Wang, Mao Cai, Shuhua Zhang, Guoliang Wang, Huan Cao, Di Zhang, Xueling Wang, Shenghe Deng, Tongxi Li, Jinyang Gu.

Tumor necrosis factor α (TNFα) maintains homeostasis through promoting cell survival or cell death; however, how this process is regulated by metabolic pathways remains largely unknown. Here, we identify adenosine kinase (ADK), the key enzyme for catalyzing the conversion of adenosine to AMP, as an endogenous suppressor of RIPK1 kinase. ADK-mediated adenosine metabolic clearance is a prerequisite for transmethylation reactions on various cellular targets. We found that ADK licenses constitutive R606 symmetric dimethylation in RIPK1 death domain (DD), which is catalyzed by protein arginine methyltransferase 5. Upon TNFα stimulation, DD-mediated RIPK1 dimerization is inhibited by R606 methylation, preventing RIPK1 kinase activation and keeping cell death in check. Both hepatocyte-specific ADK knockout and systemic ADK inhibition cause spontaneous RIPK1-driven hepatocyte death, which leads to hepatic homeostasis disruption. Furthermore, ADK is reduced in hepatic ischemia-reperfusion, aggravating hepatic injury during liver surgery. Thus, this study reveals a mechanism of adenosine metabolism-dependent homeostasis maintenance that is implicated in both physiological and pathological conditions.

DOI: https://doi.org/10.1084/jem.20250603