bims-imicid 2025-06-15 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–06–15
37 papers selected by
Dylan Ryan, University of Cambridge

Immunometabolism at the Crossroads of Infection: Mechanistic and Systems-Level Perspectives from Host and Pathogen.
The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity.
Epigenetic Modulation by Lactylation in Sepsis: Linking Metabolism to Immune Dysfunction.
Cellular metabolism in Th9, Th17, and Treg cell differentiation.
Spermidine suppresses DC activation via eIF5A hypusination and metabolic adaptation.
Emerging advancements in metabolic properties of macrophages within disease microenvironment for immune therapy.
EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses.
Targeting tumor metabolism to augment CD8+ T cell anti-tumor immunity.
Targeting myeloid cell immunometabolism to improve current non-small cell lung cancer therapies.
Inflammatory macrophage-derived itaconate inhibits DNA demethylase TET2 to prevent excessive osteoclast activation in rheumatoid arthritis.
G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway.
Gut microbe-derived lactic acid optimizes host energy metabolism during starvation.
Integrated transcriptomic, metabolomic, and lipidomic analyses reveal a unique lipid profile of regulatory T cells upon activation.
Pentose phosphate pathway inhibition metabolically reprograms CD8+ T cells and disrupts CNS autoimmunity.
Aging-related dysregulation of energy metabolism and mitochondrial dynamics in microglia.
Hormetic elevation of taurine restrains inflammaging by deactivating the NLRP3 inflammasome.
TNFα impairs platelet function by inhibiting autophagy and disrupting metabolism via Syntaxin-17 downregulation.
PGC1α-mediated mitochondrial fitness promotes Treg cell differentiation.
Tolerance to Lung Infection in TWIK2 K + Efflux Mediated Macrophage Trained Immunity.
Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models.
Endosymbiont control through non-canonical immune signaling and gut metabolic remodeling.
Maternal vitamin D regulates the metabolic rearrangement of offspring CD4+ T cells in response to intestinal inflammation.
No (innate immune) training without lactate.
Targeting lactylation reinforces NK cell cytotoxicity within the tumor microenvironment.
Transcription factor IRF-5 regulates lipid metabolism and mitochondrial function in murine CD8+ T-cells during viral infection.
Radiation-induced upregulation of itaconate in macrophages promotes the radioresistance of non-small cell lung cancer by stabilizing NRF2 protein and suppressing immune response.
C1q reprograms innate immune memory.
A backhanded complement: Prostacyclin turns inflammation off from the inside out.
Early life high fructose impairs microglial phagocytosis and neurodevelopment.
Outer membrane vesicles derived from probiotic Escherichia coli Nissle 1917 promote metabolic remodeling and M1 polarization of RAW264.7 macrophages.
Glucose-1-phosphate promotes compartmentalization of glycogen with the pentose phosphate pathway in CD8+ memory T cells.
PDPK1 governs macrophage M2 polarization via hypoxia-driven CD47/AKT-glycolytic Axis in endometriosis.
The interplay between STING and metabolic reprogramming: From mechanisms to therapeutic strategies.
Helminth-induced prostaglandin signalling and dietary shifts in PUFA metabolism promote colitis-associated cancer.
OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis.
PCSK9 inhibition mitigates vulnerable plaque formation induced by hyperhomocysteinemia through regulating lipid metabolism and inflammation.
Serum metabolomics in women with major depressive disorder: Associations with mitochondrial function, inflammation, and oxidative stress.

ArXiv. 2025 Jun 02. pii: arXiv:2506.02236v1. [Epub ahead of print]

Immunometabolism at the Crossroads of Infection: Mechanistic and Systems-Level Perspectives from Host and Pathogen.

Sunayana Malla, Nabia Shahreen, Rajib Saha.

The emerging field of immunometabolism has underscored the central role of metabolic pathways in orchestrating immune cell function. Far from being passive background processes, metabolic activities actively regulate key immune responses. Fundamental pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation critically shape the behavior of immune cells, influencing macrophage polarization, T cell activation, and dendritic cell function. In this review, we synthesize recent advances in immunometabolism, with a focus on the metabolic mechanisms that govern the responses of both innate and adaptive immune cells to bacterial, viral, and fungal pathogens. Drawing on experimental, computational, and integrative methodologies, we highlight how metabolic reprogramming contributes to host defense in response to infection. These findings reveal new opportunities for therapeutic intervention, suggesting that modulation of metabolic pathways could enhance immune function and improve pathogen clearance.
Cell Rep. 2025 Jun 05. pii: S2211-1247(25)00570-4. [Epub ahead of print]44(6): 115799

The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity.

Chao Wang, Allon Wagner, Johannes Fessler, David DeTomaso, Sarah Zaghouani, Yulin Zhou, Kerry Pierce, Raymond A Sobel, Clary Clish, Nir Yosef, Vijay K Kuchroo.

  Glucose metabolism is a critical regulator of T cell function, largely thought to support their activation and effector differentiation. Here, we investigate how individual glycolytic reactions determine the pathogenicity of T helper 17 (Th17) cells using Compass, an algorithm we previously developed for inferring metabolic states from single-cell RNA sequencing. Surprisingly, Compass predicted that the metabolic shunt between 3-phosphoglycerate (3PG) and 2-phosphoglycerate (2PG) is inversely correlated with pathogenicity in Th17 cells. Indeed, perturbation of phosphoglycerate mutase (PGAM), the enzyme catalyzing 3PG to 2PG conversion, induces a pathogenic gene expression program by suppressing a gene module associated with the least pathogenic state of Th17 cells. Finally, PGAM inhibition in Th17 cells exacerbates neuroinflammation in the adoptive transfer model of experimental autoimmune encephalomyelitis, consistently with PGAM promoting the non-pathogenic phenotype of Th17 cells. Overall, our study identifies PGAM, contrary to other glycolytic enzymes, as a negative regulator of pathogenic Th17 cell differentiation.

Keywords:  CP: Immunology; CP: Metabolism; EGCG; PGAM; PGM; T helper 17; central carbon metabolism; epigallocatechin-3-gallate; glycolysis; immune metabolism; immunometabolism; phosphoglycerate mutase

DOI:  https://doi.org/10.1016/j.celrep.2025.115799
J Inflamm Res. 2025 ;18 7357-7367

Epigenetic Modulation by Lactylation in Sepsis: Linking Metabolism to Immune Dysfunction.

Yinghong Chen, Hanrong Hu, Congwei Wang, Junxuan Wu, Jie Zan, Yuntao Liu.

  Lactate, traditionally viewed as a metabolic byproduct, is now recognized as a key regulator of immune and epigenetic processes in sepsis. A recently discovered post-translational modification, lactylation, utilizes lactate as a substrate and plays a crucial role in cellular regulation. Accumulating evidence suggests that elevated lactate levels contribute to immune dysfunction in sepsis by modulating the activity of various immune cells. This modification links metabolic changes to immune regulation, making it a crucial factor in sepsis progression. Understanding how lactylation is altered in sepsis unveils critical links between immunometabolism, epigenetic regulation, and disease pathophysiology. These insights also highlight the interplay between metabolic and epigenetic reprogramming during septic progression. As a result, lactylation has emerged as a promising biomarker and potential therapeutic target in sepsis. This review aims to summarize the latest findings on lactate metabolism, lactylation modifications, and their immunometabolic implications in sepsis.

Keywords:  histone; lactate; lactylation; sepsis

DOI:  https://doi.org/10.2147/JIR.S522081
Int Immunol. 2025 Jun 09. pii: dxaf032. [Epub ahead of print]

Cellular metabolism in Th9, Th17, and Treg cell differentiation.

Toshio Kanno, Keiko Nakano, Yusuke Endo.

  CD4+ helper T (Th) cell subsets play an essential role in the regulation of adaptive immunity. Th9, Th17, and regulatory T (Treg) cells require transforming growth factor-beta (TGF-β) for their differentiation; however, their respective functions are highly distinct. Recent studies have highlighted the critical role of cellular metabolism in initiating clonal expansion and facilitating the effector differentiation of Th cells. Upon antigen exposure, naïve CD4+ T cells undergo metabolic reprogramming to fulfill their bioenergetic and biosynthetic demands. This process involves a shift from fatty acid oxidation to glycolysis, which ensures a sufficient energy supply for activation and proliferation. Lipid metabolism plays a pivotal role in modulating the differentiation and function of Th17, Treg, and Th9 cells. This review explores the influence of metabolic pathways on key transcription factors, including RORγt and SMADs, and emphasizes their regulatory roles in Th cell differentiation. Furthermore, it discusses emerging therapeutic strategies aimed at targeting cellular metabolism to address autoimmune and inflammatory diseases associated with these T cell subsets.

Keywords:  ACC1; Lipid metabolism; RORγt

DOI:  https://doi.org/10.1093/intimm/dxaf032
Discov Immunol. 2025 ;4(1): kyaf009

Spermidine suppresses DC activation via eIF5A hypusination and metabolic adaptation.

Gavin R Meehan, Utku Gunes, Larissa Camargo da Rosa, Hannah E Scales, George Finney, Ross Deehan, Sofia Sintoris, Aegli Athanasiadou, Jack Jones, Georgia Perona-Wright, James M Brewer.

   Introduction: Cell metabolism plays an important role in immune effector responses and through responding to metabolic signals, immune cells can adapt and regulate their function. Arginine metabolism in dendritic cells (DC) has been shown to reduce T cell activation; however, it is unclear how this immunosuppressive state is induced.
Method: To address this issue, we examined the immunomodulatory capacity of various metabolites from arginine metabolism.
Results: Through the use of a recently described DC:T cell interaction assay and flow cytometry we demonstrated that spermidine most significantly inhibited DC activation, preventing subsequent interactions with CD4 T cells. DC function could be restored by addition of inhibitors of spermidine metabolism via the eIF5A-hypusine axis, required for expression of some mitochondrial enzymes. We also demonstrated that the spermidine induced-immunosuppressive state protected DC against activation-induced loss of mitochondrial capacity for energy generation, which was also hypusination dependent.
Conclusion: Taken together, these data demonstrate that spermidine is the key immunomodulatory component downstream of arginine metabolism and that it mediates this effect by stimulating hypusination-dependent protection of OXPHOS in DC, which in turn results in a reduced ability of DC to activate and interact with T cells. This pathway may be utilized by the immune system to regulate excessive immune responses but could also be exploited by pathogens as a method of immune evasion.

Keywords:  dendritic cells; eIF5A; hypusination; immunosuppression; spermidine

DOI:  https://doi.org/10.1093/discim/kyaf009
J Innate Immun. 2025 Jun 11. 1-27

Emerging advancements in metabolic properties of macrophages within disease microenvironment for immune therapy.

Feng Zhao, Zhongyu Yue, Lijiaqi Zhang, Yujie Qi, Yunting Sun, Shuling Wang, Qingchang Tian.

BACKGROUND: As sentinel cells of innate immunity, macrophages exhibit microenvironment-driven functional plasticity critical for immune regulation and tissue homeostasis, yet maladaptive metabolic reprogramming-induced polarization dysregulation exacerbates disease progression by manifesting immune dysfunction Summary: This review systematically deciphers the metabolic signatures governing macrophage polarization - spanning amino acid metabolism, glycolytic flux, lipid dynamics, and iron homeostasis - while dissecting how pathological microenvironments (encompassing tumor niches, atherosclerotic plaques, and obese adipose tissue) co-opt these pathways to drive pathogenesis. Crucially, this analysis demonstrates that cellular metabolism dictates macrophage phenotypic/functional states across disease contexts, with comprehensive decoding of their metabolic networks emerging as imperative for developing next-generation immunotherapies.
KEY MESSAGES: Therapeutically, pathogenic polarization may be reversed through strategic interventions targeting metabolite-sensing receptors, pharmacologically blocking metabolic checkpoints, and reprogramming core metabolic modalities to restore immunoregulatory competence.

DOI: https://doi.org/10.1159/000546476
Cell Chem Biol. 2025 Jun 03. pii: S2451-9456(25)00168-0. [Epub ahead of print]

EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses.

Yuchen Zhang, Hongpeng Li, Yi Hao, Jiaqi Chen, Xing Chen, Hang Yin.

  Tumor associated macrophages (TAMs) exhibit a high capacity to take up glucose. However, how metabolic cues derived from glucose rewire TAMs remains unclear. Here, we report that glucose metabolism-driven protein O-GlcNAcylation increases in TAMs and shapes the differentiation and protumoral function of TAMs. Deficiency of O-GlcNAc transferase (OGT) in TAMs restricted tumor growth by reducing the proportion of C1QC+ F4/80+ TREM2+ MerTK+ TAMs as well as Trem2 expression, which in turn preserved the cytotoxic function of effector CD8+ T cells while exhibiting reduced features of exhaustion. Mechanistically, O-GlcNAc targeted the macrophage-specific transcription factor EGR2 to promote its transcriptional activity. Transcriptional profiling revealed that OGT increased EGR2-related motifs accessibility in TAMs. O-GlcNAcylation of EGR2 at serine 299 enhanced its binding to myeloid cell differentiation-associated genes, including Trem2, thus facilitating the protumoral function of TAMs in GM-CSF-sufficient tumor. Overall, our work defines a tumor-specific reprogramming of protumoral TAMs via O-GlcNAc-modified EGR2 transcriptional regulation.

Keywords:  CD8(+) T cells; EGR2; GM-CSF; TREM2; anti-tumor immunity; glucose metabolism; post-translational modification; protein O-GlcNAcylation; tumor associated macrophages; tumor microenvironment

DOI:  https://doi.org/10.1016/j.chembiol.2025.05.007
J Pharm Anal. 2025 May;15(5): 101150

Targeting tumor metabolism to augment CD8+ T cell anti-tumor immunity.

Huan Liu, Wenyong Yang, Jingwen Jiang.

  CD8+ T cell-based immune-therapeutics, including immune checkpoint inhibitors and adoptive cell therapies (tumor-infiltrating lymphocytes (TILs), T cell receptor-engineered T cells (TCR-T), chimeric antigen receptor T cells (CAR-T)), have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases. However, immunotherapy resistance and tumor insusceptibility frequently occur, leading to treatment failure. Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites, immune-inhibitory cytokines, and alteration of gene expression, which suppress the activity of immune cells, particularly CD8+ T cells to evade immune surveillance. Therefore, targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy. Here, we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming, focusing on the regulatory mechanisms underlying tumor cell glucose metabolism, amino acid metabolism, and lipid metabolism in influencing CD8+ T cells to provide promising metabolic targets or combinational strategies for immunotherapy.

Keywords:  CD8+ T cell; Immunotherapy; Metabolism reprogramming; TME; Tumor

DOI:  https://doi.org/10.1016/j.jpha.2024.101150
Pharmacol Ther. 2025 Jun 04. pii: S0163-7258(25)00105-6. [Epub ahead of print]273 108893

Targeting myeloid cell immunometabolism to improve current non-small cell lung cancer therapies.

Marah C Runtsch, Stefano Angiari, Julia Kargl.

  Although recent advancements in immunotherapy have improved clinical outcomes, non-small cell lung cancer (NSCLC) is still the deadliest cancer type, as current treatments fail in many patients. This highlights a need for continued studies on this complex and multifaceted malignancy. The lung tumor microenvironment (TME) is marked by an infiltration of innate immune cells of the myeloid lineage, including macrophages and neutrophils, which affect patient outcomes. These cells induce inflammation and functional responses that can both promote and inhibit tumor growth and progression, with these functions being directly linked to their intracellular metabolism. The lung TME provides a milieu of signals, including cytokines and metabolites, that induce metabolic reprogramming in tumor-associated myeloid cells. Here, we review the present understanding of tumor-associated myeloid cell metabolism specifically in the context of NSCLC. Recent studies demonstrated that some metabolic pathways have the potential to be manipulated pharmacologically to eliminate or reprogram pathogenic, pro-tumor, and/or immunosuppressive myeloid cells to anti-tumor states for NSCLC therapies. Therefore, we highlight and propose potential metabolic targets in these myeloid cells, focusing on macrophages and neutrophils. These cells have direct roles in affecting subsequent responses of adaptive cells and their cellular metabolism must be further investigated to identify potential pharmacologic therapeutic targets. Targeting myeloid cell metabolism in the TME may be used in combination with the current regimen of immune checkpoint inhibition (ICI) and chemotherapy to improve outcomes for lung cancer patients.

Keywords:  Immunometabolism; Immunotherapy; Lung cancer; Macrophage; Myeloid; NSCLC; Neutrophil

DOI:  https://doi.org/10.1016/j.pharmthera.2025.108893
Bone Res. 2025 Jun 11. 13(1): 60

Inflammatory macrophage-derived itaconate inhibits DNA demethylase TET2 to prevent excessive osteoclast activation in rheumatoid arthritis.

Kewei Rong, Dezheng Wang, Xiting Pu, Cheng Zhang, Pu Zhang, Xiankun Cao, Jinglin Zheng, Xiao Yang, Kexin Liu, Lei Shi, Yin Li, Peixiang Ma, Dan Ye, Jie Zhao, Pu Wang, An Qin.

Itaconate, a macrophage-specific anti-inflammatory metabolite, has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis. We found that itaconate is a TNF-α responsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts. In TNF-transgenic and Irg1-/- hybrid mice, a more severe bone destruction phenotype was observed. Administration of itaconate prevents excessive activation of osteoclasts by inhibiting Tet2 enzyme activity. Furthermore, exogenous administration of itaconate or its derivative, 4-octyl-itaconate, inhibits arthritis progression and mitigates bone destruction, offering a potential therapeutic strategy for rheumatoid arthritis. This study elucidates that TNF-α drives macrophage-derived itaconate production to epigenetically suppress osteoclast hyperactivation through Tet2 inhibition, establishing itaconate and its derivative OI as novel therapeutic agents against rheumatoid arthritis -associated bone destruction.

DOI: https://doi.org/10.1038/s41413-025-00437-w
bioRxiv. 2025 Jun 08. pii: 2025.06.06.658371. [Epub ahead of print]

G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway.

Esther Liu, Matthew Wright, Andrew O Kearney, Tiffany Caza, Johnson Y Yang, Valerie Garcia, Amal O Dadi, Shuta Ishibe, Navdeep S Chandel, Hanrui Zhang, Edouard Benjamin Thorp, Jennie Lin.

The G1 and G2 variants of the gene encoding Apolipoprotein L1 ( APOL1 ) increase risk for kidney disease and cardiometabolic traits. While previous studies have elucidated key mechanisms by which G1 and G2 APOL1 cause cellular inflammation and cytotoxicity, it remains unclear whether these mechanisms drive inflammation in G1 and G2 macrophages. In this study, we used mouse bone-marrow-derived macrophages and human induced pluripotent stem cell-derived macrophages to identify altered immune signaling and inflammatory activation caused by G1 and G2 APOL1 . We demonstrated that G1 and G2 APOL1 increased lipid accumulation, pro-inflammatory cytokine expression, and inflammasome signaling; this inflammatory response was sustained when treated with anti-inflammatory cytokines IL-4 and IL-10. Additionally, in G1 and G2 macrophages we observed increased mitochondrial size and elongation, oxidative phosphorylation, and glycolysis. Finally, we used unbiased metabolite analysis to identify an accumulation of polyamine spermidine and the enrichment of the spermidine synthesis pathway in G1 and G2 macrophages. When treated with polyamine inhibitor α-difluoromethylornithine (DFMO), lipid accumulation and inflammasome gene expression decreased in G1 and G2 macrophages. Together, these findings establish the pro-inflammatory effects of G1 and G2 APOL1 in macrophages and identify a novel pathway which ameliorates G1 and G2 effects on cellular inflammation.

DOI: https://doi.org/10.1101/2025.06.06.658371
bioRxiv. 2025 May 28. pii: 2025.05.27.656452. [Epub ahead of print]

Gut microbe-derived lactic acid optimizes host energy metabolism during starvation.

Jason William Millington, Jamie Alcira Lopez, Amin M Sajjadian, Robert J Scheffler, Brian C DeFelice, William Basil Ludington, Benjamin H Good, Lucy Erin O'Brien, Kerwyn Casey Huang.

Gut microbes convert dietary compounds into an array of metabolites that can directly provide energy to their host and indirectly impact host metabolism as systemic endocrine signals. Here, we show that gut microbe-derived metabolites can extend Drosophila melanogaster survival during starvation, despite minimal alteration of dietary energy intake. Combining survival assays with mathematical modeling and untargeted metabolomics, we identify a single, dominant mediator of starvation resilience: lactic acid produced by the commensal bacterium Lactiplantibacillus plantarum . We discover that the basis of starvation resilience is not catabolism of lactic acid using lactate dehydrogenase, but rather increased dietary energy yield through lactic acid-driven promotion of oxidative phosphorylation. Our findings emphasize the role of the microbiome as a source of endocrine cues coordinating host metabolism and underscore the potential of microbiome-derived metabolites as therapeutic molecules for manipulating metabolic health and preventing disease.

DOI: https://doi.org/10.1101/2025.05.27.656452
Immunobiology. 2025 Jun 07. pii: S0171-2985(25)00221-9. [Epub ahead of print]230(4): 153087

Integrated transcriptomic, metabolomic, and lipidomic analyses reveal a unique lipid profile of regulatory T cells upon activation.

Yohei Sato, Misa Yura, Alana Chandler, Yamato Hanawa, Akihito Tsubota.

  Regulatory T cells (Tregs) exhibit stable FOXP3 expression and regulate the immune response through suppressive activity. Their unique metabolic properties include increased glycolysis and oxidative phosphorylation. We combined transcriptomic, metabolomic, and lipidomic analyses to dissect the metabolic dynamics of Tregs upon activation. Combined metabolomic and lipidomic analyses showed that freshly isolated and activated Tregs had distinct metabolomic and lipidomic properties, respectively. Compared with activated effector T cells (Teffs), activated Tregs contained omega-3 long-chain polyunsaturated fatty acid (PUFA)-rich diglycerides and triglycerides. These were supported by transcriptomics data, showing upregulation of PPAR-alpha and PPAR-gamma. Compared with activated Teffs, activated Tregs exhibited greater ceramide production, consistent with the upregulation of ceramide synthase and sphingomyelin synthase. Confocal microscopy revealed that Tregs, in contrast to Teffs, were enriched in lysosomes and peroxisomes upon activation. Our data confirm the unique metabolic properties of Tregs, especially those characterized by omega-3 long-chain PUFA-rich triglycerides and ceramides, together with enriched lysosomes and peroxisomes, which correspond to metabolic alterations.

Keywords:  FOXP3; Lipidomics; Lysosome; Metabolomics; Omega-3 long-chain polyunsaturated fatty acids; PPAR-gamma; Peroxisome; RRAR-alpha; Regulatory T cells; Triglyceride

DOI:  https://doi.org/10.1016/j.imbio.2025.153087
JCI Insight. 2025 Jun 10. pii: e184240. [Epub ahead of print]

Pentose phosphate pathway inhibition metabolically reprograms CD8+ T cells and disrupts CNS autoimmunity.

Ethan M Grund, Benjamin Ds Clarkson, Susanna Pucci, Maria S Westphal, Carolina Muniz Partida, Sara A Muhammad, Charles L Howe.

  Multiple sclerosis is characterized by CNS infiltration of auto-reactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8+ anti-neural T cells in the irreversible neurodegeneration that underlies progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8+ T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8+ T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8+ T cell-mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer-based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8+ T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8+ T cell-mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8+ T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.

Keywords:  Autoimmune diseases; Autoimmunity; Glucose metabolism; Immunology; Multiple sclerosis; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.184240
J Clin Biochem Nutr. 2025 May;76(3): 239-244

Aging-related dysregulation of energy metabolism and mitochondrial dynamics in microglia.

Yoki Nakamura, Manaya Nakano, Kazue Hisaoka-Nakashima, Norimitsu Morioka.

  Microglia, the primary immune cells of the central nervous system, play a pivotal role in maintaining brain homeostasis. Recent studies have highlighted the involvement of microglial dysfunction in the pathogenesis of various age-related neurodegenerative diseases, such as Alzheimer's disease. Moreover, the metabolic state of microglia has emerged as a key factor in these diseases. Interestingly, aging and neurodegenerative diseases are associated with impaired mitochondrial function and a metabolic shift from oxidative phosphorylation to glycolysis in microglia. This metabolic shift may contribute to sustained microglial activation and neuroinflammation. Furthermore, the leakage of mitochondrial DNA into the cytoplasm, because of mitochondrial dysfunction, has been implicated in triggering inflammatory responses and disrupting brain function. This review summarizes recent advances in understanding the role of microglial metabolic shifts, particularly glycolysis, and mitochondrial dysfunction. It also explores the potential of targeting microglial metabolism, for instance by modulating mitophagy or intervening in specific metabolic pathways, as a novel therapeutic approach for changes in brain function and neurodegenerative diseases associated with aging.

Keywords:  Alzheimer’s disease; aging; glycolysis; microglia; mitochondria

DOI:  https://doi.org/10.3164/jcbn.24-202
bioRxiv. 2025 May 31. pii: 2025.05.27.656381. [Epub ahead of print]

Hormetic elevation of taurine restrains inflammaging by deactivating the NLRP3 inflammasome.

Chenyang Guan, Seungjin Ryu, Mingze Dong, Yun-Hee Youm, Subhasis Mohanty, Rae Maeda, Lucie Orliaguet, Hee-Hoon Kim, Tamara Dlugos, Steven R Smith, Eric Ravussin, Janset Onyuru, Andrew Wang, Albert C Shaw, Hal M Hoffman, Yuval Kluger, Yuki Sugiura, Vishwa Deep Dixit.

Taurine, the most abundant sulfonic amino acid in humans is largely obtained from diets rich in animal proteins. However, taurine is dietary non-essential because it can be synthesized from cysteine by activation of transsulfuration pathway (TSP) when food consumption is low or if the diet is predominantly plant based. The decline of taurine was proposed as the driver of aging through an undefined mechanism. Here, we found that mild food restriction in humans for one year that resulted in 14% reduction of calorie intake elevated the hypotaurine and taurine concentration in adipose tissue. Therefore, we investigated whether elevated taurine mimics caloric-restriction's beneficial effects on inflammation, a key mechanism of aging. Interestingly, aging increased the circulating and tissue concentrations of taurine suggesting that elevated taurine may serve as a hormetic stress response metabolite that regulates mechanism of age-related inflammation. The elevated taurine protected mice against mortality from sepsis and inhibited inflammasome-driven inflammation and gasdermin-D (GSDMD) mediated pyroptosis. Mechanistically, 'danger signals' including hypotonicity that activate NLRP3-inflammasome, caused upstream taurine efflux from macrophages, which triggered potassium (K + ) release and downstream canonical NLRP3 inflammasome assembly, caspase-1 activation, GSDMD cleavage and IL-1β and IL-18 secretion that was reversed by taurine restoration. Notably, taurine does not efflux from GSDMD pore and inhibited IL-1β from macrophages independently of known transporters SLC6A6 and SLC36A1. Increased taurine in old mice promotes healthspan by inducing anti-inflammatory pathways previously linked to youthfulness. These findings demonstrate that taurine is an upstream metabolic sensor of cellular perturbations that control NLRP3 inflammasome and lowers age-related inflammation.

DOI: https://doi.org/10.1101/2025.05.27.656381
J Clin Invest. 2025 Jun 10. pii: e186065. [Epub ahead of print]

TNFα impairs platelet function by inhibiting autophagy and disrupting metabolism via Syntaxin-17 downregulation.

Guadalupe Rojas-Sanchez, Jorge Calzada-Martinez, Brandon McMahon, Aaron C Petrey, Gabriela Dveksler, Gerardo P Espino-Solis, Orlando Esparza, Giovanny Hernandez, Dennis Le, Eric P Wartchow, Ken Jones, Lucas H Ting, Catherine Jankowski, Marguerite R Kelher, Marilyn Manco-Johnson, Marie L Feser, Kevin D Deane, Travis Nemkov, Angelo D'Alessandro, Andrew Thorburn, Paola Maycotte, José A López, Pavel Davizon-Castillo.

  Platelets play a dual role in hemostasis and inflammation-associated thrombosis and hemorrhage. While the mechanisms linking inflammation to platelet dysfunction remain poorly understood, our previous work demonstrated that TNFα alters mitochondrial mass, platelet activation, and autophagy-related pathways in megakaryocytes. Here, we hypothesized that TNFα impairs platelet function by disrupting autophagy, a process critical for mitochondrial health and cellular metabolism. Using human and murine models of TNFα-driven diseases, including myeloproliferative neoplasms and rheumatoid arthritis, we found that TNFα downregulates STX17, a key mediator of autophagosome-lysosome fusion. This disruption inhibited autophagy, leading to the accumulation of dysfunctional mitochondria and reduced mitochondrial respiration. These metabolic alterations compromised platelet-driven clot contraction, a process linked to thrombotic and hemorrhagic complications. Our findings reveal a mechanism by which TNFα disrupts hemostasis through autophagy inhibition, highlighting TNFα as a critical regulator of platelet metabolism and function. This study provides new insights into inflammation-associated pathologies and suggests autophagy-targeting strategies as potential therapeutic avenues to restore hemostatic balance.

Keywords:  Autophagy; Hematology; Metabolism; Mitochondria; Platelets

DOI:  https://doi.org/10.1172/JCI186065
Cell Immunol. 2025 May 30. pii: S0008-8749(25)00071-1. [Epub ahead of print]414 104985

PGC1α-mediated mitochondrial fitness promotes Treg cell differentiation.

Luis Eduardo Alves Damasceno, Gabriel Alberto de Carvalho Barbosa, Tim Sparwasser, Thiago Mattar Cunha, Fernando Queiroz Cunha, José Carlos Alves-Filho.

  Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance to self-antigens and suppression of excessive immune responses. They employ a distinct metabolic profile from other CD4 T cell subsets to support their differentiation and suppressive function, which is characterized by enhanced mitochondrial metabolism. Although PGC1α is considered a master regulator of mitochondrial biogenesis and function, its role in Treg cell differentiation remains unclear. Herein, we demonstrated that PGC1α is highly expressed in Treg cells compared to other CD4 T cell populations. Using a pharmacological approach, we found that its transcriptional activation in iTreg cells enhanced mitochondrial fitness, characterized by increased expression of mitochondrial genes, mitochondrial mass, and metabolic activity. Moreover, PGC1α activation enhanced both mouse and human iTreg cell differentiation, while its inhibition reduced this process. Therefore, our findings shed light on the potential role of PGC1α as a pharmacological target when manipulating Treg cells as a therapeutic strategy.

Keywords:  Mitochondria; PGC1α; T(reg) cell

DOI:  https://doi.org/10.1016/j.cellimm.2025.104985
bioRxiv. 2025 May 28. pii: 2025.05.25.655979. [Epub ahead of print]

Tolerance to Lung Infection in TWIK2 K + Efflux Mediated Macrophage Trained Immunity.

Josh Thompson, Yufan Li, Yuanling Song, Ki-Wook Kim, Asrar B Malik, Jingsong Xu.

Alveolar macrophages (AMφ) are essential for innate immune function in the lungs. It is now apparent that macrophages can be trained to become better at attacking infections. Although trained immunity is thought to result from metabolic and epigenetic reprogramming, the underlying mechanisms remain unclear. Here, we report that AMφ can be trained by extracellular ATP, which is ubiquitously released during inflammation. ATP ligates the canonical Purinergic Receptor 2 subtype X7 receptor (P2X7) to mediate endosomal Two-pore domain Weak Inwardly rectifying K + channel 2 (TWIK2) translocation into the plasma membrane (PM). This endows the cells to transit to a 'ready' state for microbial killing in two directions: first, K + efflux via PM-TWIK2 induces NLRP3 inflammasome activation, which further activates metabolic pathways; second, upon bacterial phagocytosis, PM-TWIK2 internalizes into phagosome membrane with proper topological orientation, where TWIK2 mediates K + influx into phagosomes to control pH and ionic strength favoring bacterial killing. Therefore, the enhanced association of TWIK2 in phagosomal and plasma membranes signaled by danger-associated molecular patterns (DAMPs), such as ATP, mediates trained immunity in AMφ and enhances the microbiocidal activity.

DOI: https://doi.org/10.1101/2025.05.25.655979
Front Immunol. 2025 ;16 1544973

Chitinase-1 inhibition attenuates metabolic dysregulation and restores homeostasis in MASH animal models.

Katarzyna Drzewicka, Katarzyna M Głuchowska, Michal Mlącki, Bartłomiej Hofman, Irina Tuszyńska, Tristram A J Ryan, Katarzyna Piwowar, Bartosz Wilczyński, Dorota Dymkowska, Marcin M Grzybowski, Barbara Dymek, Tomasz Rejczak, Kamil Lisiecki, Adam Gołębiowski, Adam Jagielski, Angelika Muchowicz, Dylan Ryan, Krzysztof Zabłocki, Luke A J O'Neill, Zbigniew Zasłona.

   Background: OATD-01 is a chitinase-1 (CHIT1) inhibitor, reducing inflammation and fibrosis in animal models where chronic inflammation leads to tissue remodeling. CHIT1, predominantly secreted by macrophages, is overexpressed in metabolic dysfunction-associated steatohepatitis (MASH).
Methods and results: In the study, we demonstrated the therapeutic efficacy of OATD-01 in two murine models (STAM, DIAMOND) and one rat model (CDHFD) of MASH. RNA-Seq analysis of livers obtained from CDHFD rat model revealed that OATD-01 reversed MASH-dysregulated genes. In addition to reducing inflammation and fibrosis observed in the rat model, RNA-Seq demonstrated that OATD-01 regulated key metabolic processes such as acetyl-CoA metabolism, triglyceride metabolism, cholesterol synthesis, cholesterol flux, and glycolysis. Using functional assay performed on bone marrow-derived macrophages (BMDMs) we demonstrated that both genetic and pharmacological inactivation of CHIT1 resulted in inhibition of glucose uptake. As a consequence, our data suggest decreased glycolysis, accompanied by increased ATP levels, lower citrate, and increased acetate levels, ultimately leading to a reduced IL-1β secretion in BMDMs.
Conclusions: These results revealed the key role for CHIT1 in regulating metabolism. OATD-01 is a macrophage modulator that can directly restore metabolic balance and consequently inhibit inflammation and fibrosis, supporting its use for MASH treatment.

Keywords:  MASH; OATD-01; chitinase 1; fibrosis; glycolysis; inflammation; macrophage; metabolism

DOI:  https://doi.org/10.3389/fimmu.2025.1544973
Cell Rep. 2025 Jun 06. pii: S2211-1247(25)00582-0. [Epub ahead of print]44(6): 115811

Endosymbiont control through non-canonical immune signaling and gut metabolic remodeling.

Sofie Burgmer, Fenja L Meyer Zu Altenschildesche, Akos Gyenis, Hyun Ju Lee, David Vilchez, Patrick Giavalisco, Arnaud Fichant, Mirka Uhlirova, Gilles Storelli.

  Animals coexist with bacteria and need to keep these microorganisms under tight control. To achieve such control, pattern recognition receptors (PRRs) sense bacterial cues and induce the production of antimicrobials. Here, we uncover a metabolic arm in the control of symbionts by PRRs. We show that, in Drosophila, the PRRs PGRP-LC and PGRP-LE act independently of canonical NF-κB signaling to repress essential metabolic functions in the gut, such as digestion and central carbon metabolism. This metabolic switch affects commensal populations and drastically reduces intestinal and systemic populations of the intracellular parasite Wolbachia. We propose that intestinal metabolic remodeling complements immune responses by imposing nutrient restriction on intracellular bacteria, whose lifestyle protects them from antimicrobials. Our findings reveal a role for PRRs in bacterial control beyond canonical immune pathways and provide insights into how microbial signals modulate symbiotic populations but also nutrition and metabolism in animals.

Keywords:  CP: Immunology; CP: Metabolism; Drosophila; IMD; PGRP-LC; PGRP-LE; Wolbachia; endosymbiont; gut microbiome; innate immunity; metabolism; symbiosis

DOI:  https://doi.org/10.1016/j.celrep.2025.115811
Cell Rep. 2025 Jun 12. pii: S2211-1247(25)00628-X. [Epub ahead of print]44(6): 115857

Maternal vitamin D regulates the metabolic rearrangement of offspring CD4+ T cells in response to intestinal inflammation.

Binjun Zhu, Jingwei Yang, Ruiling Fan, Haiyang Song, Lanlan Zhong, Tianli Zeng, Runmin Long, Xing Wan, Qingxi Li, Lei Liu, Jiang Xie.

  Children with autism spectrum disorders often have increased susceptibility to intestinal inflammation. However, the mechanisms and prevention of gastrointestinal immune dysfunction remain unclear. We demonstrate that maternal high vitamin D (VitD) level can rescue abnormal intestinal immune phenotypes in offspring that exhibit autism-like phenotypes due to exposure to maternal inflammation. Offspring exposed to dual insult of maternal inflammation and VitD deprivation show increased susceptibility to intestinal inflammation. Maternal high VitD level altered the metabolic patterns and chromatin accessibility of offspring CD4+ T cells and rescued the abnormal immune state of offspring induced by maternal immune activation (MIA). Additionally, MIA has long-term impacts on the immune phenotype of offspring in the second litter. Our findings suggest why exposure in utero to high inflammation and low maternal VitD levels increase the risk of inflammatory diseases in offspring.

Keywords:  CP: Immunology; CP: Metabolism; adaptive immune response; autism spectrum disorder; inflammatory bowel diseases; interferon-gamma; interleukin-17A; maternal immune activation; oxidative phosphorylation; pregnancy; vitamin D

DOI:  https://doi.org/10.1016/j.celrep.2025.115857
Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00448-4. [Epub ahead of print]85(11): 2065-2067

No (innate immune) training without lactate.

Jan Van den Bossche.

A recent study in Cell unveils lactate production and downstream histone lactylation as a new player in the induction of trained immunity.1 It provides insight into the intricate metabolic-epigenetic interplay that governs innate immune memory and offers a potential target to reverse maladaptive trained immunity in chronic inflammatory diseases.

DOI: https://doi.org/10.1016/j.molcel.2025.05.014
Nat Immunol. 2025 Jun 10.

Targeting lactylation reinforces NK cell cytotoxicity within the tumor microenvironment.

Jing Jin, Peidong Yan, Dongyao Wang, Lin Bai, Hao Liang, Xiaoyu Zhu, Huaiping Zhu, Chen Ding, Haiming Wei, Yi Wang.

Dysfunction of natural killer (NK) cells can be associated with tumor-derived lactate in the tumor microenvironment. Lactate-induced lysine lactylation (Kla) is a posttranslational modification, and strategies aimed at augmenting NK cell resistance to Kla might enhance cytotoxicity. Here we show that increased Kla levels in NK cells are accompanied by impaired nicotinamide adenine dinucleotide metabolism, fragmented mitochondria and reduced cytotoxicity. Supplementation with nicotinamide riboside (a nicotinamide adenine dinucleotide precursor) and honokiol (a SIRT3 activator) enhanced NK cell cytotoxicity by reducing cellular Kla levels. This combination restores antileukemic activity of NK cells in vivo and ex vivo by modulating Kla on ROCK1, thereby inhibiting ROCK1-DRP1 signaling to prevent mitochondrial fragmentation. Altogether, this study shows how lactylation can compromise NK cells and highlights this lactylation as a target for NK cell-based immunotherapy to enhance resilience to lactate in the tumor microenvironment.

DOI: https://doi.org/10.1038/s41590-025-02178-8
EMBO J. 2025 Jun 10.

Transcription factor IRF-5 regulates lipid metabolism and mitochondrial function in murine CD8+ T-cells during viral infection.

Linh Thuy Mai, Sharada Swaminathan, Trieu Hai Nguyen, Etienne Collette, Tania Charpentier, Liseth Carmona-Pérez, Hamza Loucif, Alain Lamarre, Krista M Heinonen, David Langlais, Jörg H Fritz, Simona Stäger.

  Exhaustion of CD8+ T-cells leads to their reduced immune functionality and is controlled by numerous transcription factors. Here we show that the transcription factor IRF-5 helps to limit functional exhaustion of murine CD8+ T-cells during the chronic stage of LCMV (CL13) viral infection. Our results suggest that T-cell inhibitory receptors and transcription factor TOX, which are implicated in dampening T-cell activation and promoting exhaustion, are upregulated in infected IRF-5-deficient CD8+ T-cells. In addition, these cells display a reduced capacity to produce cytokines and lower survival rates than wild-type cells. Our findings indicate that these effects are mediated by defective lipid metabolism, increased lipid peroxidation, enhanced mitochondrial ROS production, and reduced levels of oxidative phosphorylation in the absence of IRF-5. These results identify IRF-5 as an important regulator of lipid metabolism and mitochondrial function that protects CD8+ T-cells from functional exhaustion during the chronic stage of viral infection.

Keywords:  CD8 T Cells; Cell Exhaustion; IRF-5; Lipid Metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s44318-025-00485-2
Redox Biol. 2025 Jun 03. pii: S2213-2317(25)00224-1. [Epub ahead of print]85 103711

Radiation-induced upregulation of itaconate in macrophages promotes the radioresistance of non-small cell lung cancer by stabilizing NRF2 protein and suppressing immune response.

Mengjie Che, Wenwen Wei, Xiao Yang, Jinzi Liang, Yan Li, Ying Ye, Yajie Sun, Yan Hu, Zhanjie Zhang, You Qin, Jing Huang, Bian Wu, Haibo Zhang, Kunyu Yang, Chao Wan, Lu Wen.

  Radioresistance is one of the important reasons for local recurrence and distant metastasis in non-small cell lung cancer (NSCLC). Itaconate primarily functions as an anti-inflammatory metabolite in macrophages, however, its role in radiotherapy remains to be explored. In this study, we demonstrated that radiation significantly increases itaconate in the tumor microenvironment (TME), which is produced by macrophages. Mechanistically, the NF-κB signaling pathway is rapidly activated in macrophages, which enhances the binding of P65 to the Acod1 promoter region, leading to significantly increased secretion of itaconate. Excessive itaconate alleviates oxidative stress of NSCLC cell lines by stabilizing NRF2 protein. Notably, specifically knocking out Acod1 on myeloid cells enhances the activation of the tumor immune microenvironment in response to radiotherapy, particularly increasing the infiltration and activation of CD8+ T cells. Therefore, we propose that targeting Acod1 could be an effective strategy to improve radiosensitivity in NSCLC.

Keywords:  Itaconate; Macrophage; Radioresistance; Radiotherapy

DOI:  https://doi.org/10.1016/j.redox.2025.103711
Front Immunol. 2025 ;16 1515127

C1q reprograms innate immune memory.

Inge Jonkman, Maaike M E Jacobs, Yutaka Negishi, Julia I P van Heck, Vasiliki Matzaraki, Joost H A Martens, Marijke Baltissen, Michiel Vermeulen, Zahi A Fayad, Abraham J P Teunissen, Willem J M Mulder, Luuk B Hilbrands, Leo A B Joosten, Mihai G Netea, Musa M Mhlanga, Nils Rother, Raphaël Duivenvoorden.

  Innate immune memory, also called trained immunity, is a metabolic and epigenetically regulated process that enables innate immune cells to recalibrate their inflammatory reactivity in response to pathogenic or endogenous stimuli. In addition to its function in host defense, trained immunity contributes to diverse immune-mediated diseases. We discovered that complement component 1q (C1q) is an effective modulator of innate immune memory, potently suppressing the responsiveness of myeloid cells. We found that C1q leads to profound reprogramming of myeloid cell metabolism, particularly glycolysis, and exerts control over the transcriptional regulation of important metabolic and inflammatory genes. We corroborate our findings by identifying single-nucleotide polymorphisms close to the C1q gene that are linked to induction of trained immunity by Bacillus Calmette-Guérin (BCG) or beta-glucan in healthy peripheral blood mononuclear cells. Our results reveal an immunomodulatory role for C1q and provide evidence of a molecular interaction between the complement system and innate immune memory. These findings expand our understanding of innate immune memory.

Keywords:  C1q; complement; immunometabolism; innate immune memory; tolerance; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1515127
Immunity. 2025 Jun 10. pii: S1074-7613(25)00230-4. [Epub ahead of print]58(6): 1361-1363

A backhanded complement: Prostacyclin turns inflammation off from the inside out.

Samuel E J Preston, Russell G Jones.

To limit hyperactive T helper (Th)1-driven pathology, it is crucial that this T cell population contracts upon pathogen clearance. In this issue of Immunity, Rahman et al. define a complement-C5-mediated lipid-class-switch mechanism that regulates Th1 self-control. Following activation, enhanced cell-intrinsic prostacyclin (PGI2) signaling boosts interleukin (IL)-1R2 production to facilitate Th1 cell contraction.

DOI: https://doi.org/10.1016/j.immuni.2025.05.009
Nature. 2025 Jun 11.

Early life high fructose impairs microglial phagocytosis and neurodevelopment.

Zhaoquan Wang, Allie Lipshutz, Celia Martínez de la Torre, Alissa J Trzeciak, Zong-Lin Liu, Isabella C Miranda, Tomi Lazarov, Ana C Codo, Jesús E Romero-Pichardo, Achuth Nair, Tanya Schild, Waleska Saitz Rojas, Pedro H V Saavedra, Ann K Baako, Kelvin Fadojutimi, Michael S Downey, Frederic Geissmann, Giuseppe Faraco, Li Gan, Jon Iker Etchegaray, Christopher D Lucas, Marina Tanasova, Christopher N Parkhurst, Melody Y Zeng, Kayvan R Keshari, Justin S A Perry.

Despite the success of fructose as a low-cost food additive, epidemiological evidence suggests that high fructose consumption during pregnancy or adolescence is associated with disrupted neurodevelopment1-3. An essential step in appropriate mammalian neurodevelopment is the phagocytic elimination of newly formed neurons by microglia, the resident professional phagocyte of the central nervous system4. Whether high fructose consumption in early life affects microglial phagocytosis and whether this directly affects neurodevelopment remains unknown. Here we show that offspring born to female mice fed a high-fructose diet and neonates exposed to high fructose exhibit decreased phagocytic activity in vivo. Notably, deletion of the high-affinity fructose transporter GLUT5 (also known as SLC2A5) in neonatal microglia completely reversed microglia phagocytic dysfunction, suggesting that high fructose directly affects neonatal development by suppressing microglial phagocytosis. Mechanistically, we found that high-fructose treatment of mouse and human microglia suppresses phagocytosis capacity, which is rescued in GLUT5-deficient microglia. Additionally, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism to fructose 6-phosphate, rewiring microglial metabolism towards a hypo-phagocytic state in part by enforcing mitochondrial localization of the enzyme hexokinase 2. Mice exposed to high fructose as neonates develop anxiety-like behaviour as adolescents-an effect that is rescued in GLUT5-deficient mice. Our findings provide a mechanistic explanation for the epidemiological observation that high-fructose exposure during early life is associated with increased prevalence of adolescent anxiety disorders.

DOI: https://doi.org/10.1038/s41586-025-09098-5
Front Immunol. 2025 ;16 1501174

Outer membrane vesicles derived from probiotic Escherichia coli Nissle 1917 promote metabolic remodeling and M1 polarization of RAW264.7 macrophages.

DongXue Ma, YuXin Zhang, Jia Zhang, Jun Shi, ShanHu Gao, Fei Long, Xin Wang, XingYu Pu, Jiayao Sun, Shuang Liang, Richard D Cannon, Silas Villas-Boas, Ting-Li Han.

   Introduction: Escherichia coli Nissle 1917 (EcN) is one of the most extensively studied nonpathogenic Gram-negative probiotic strains worldwide. Recent research has highlighted the ability of EcN outer membrane vesicles (OMVs) to enhance the phagocytosis and proliferation of RAW264.7 macrophages. However, the impact of EcN-OMVs on M1/M2 polarization and metabolic modulation remains unknown.
Methods: In this study, we evaluated the metabolic effects of EcN-OMVs on RAW264.7 macrophage polarization using metabolomic, transcriptomic, and fluxomic approaches.
Reuslts: We found that the RAW264.7 macrophages phagocytosed EcN-OMVs, triggering upregulation of the HIF-1, mTORC1, and NF-κB signaling pathways. This metabolic reprogramming enhanced glycolysis, suppressed the TCA cycle, elevated intracellular reactive oxygen species (ROS), TNF-α, IL-6, IL-1β, ATP, and nitric oxide (NO) production, and promoted macrophage proliferation, migration, invasion, and M1-type polarization.
Discussion: In summary, this research establishes a theoretical foundation for utilizing probiotic OMVs in immunomodulatory therapeutic applications.

Keywords:  Escherichia coli Nissle 1917; fluxomics; macrophage polarization; metabolomics; outer membrane vesicles (OMVs)

DOI:  https://doi.org/10.3389/fimmu.2025.1501174
Mol Cell. 2025 Jun 03. pii: S1097-2765(25)00458-7. [Epub ahead of print]

Glucose-1-phosphate promotes compartmentalization of glycogen with the pentose phosphate pathway in CD8+ memory T cells.

Yabo Zhou, Chaoying Zhang, Lina He, Youli Kang, Dianheng Wang, Shujing Wang, Zheng Ling, Jie Chen, Nannan Zhou, Li Zhou, Zhenfeng Wang, Chaoqi Zhang, Ke Tang, Huafeng Zhang, Jingwei Ma, Bo Qin, Sheng Cui, Jiadi Lv, Bo Huang.

  Glucose-6-phosphate (G6P) is a key metabolic molecule that regulates reactive oxygen species (ROS) homeostasis by initiating the pentose phosphate pathway (PPP) to generate nicotinamide adenine dinucleotide phosohate (NADPH) that converts hydrogen peroxide (H2O2) to water by providing hydrogen. While both glucose phosphorylation and glycogenolysis result in G6P production, here we show that G6P derived from glycogenolysis, rather than glucose phosphorylation, flows to PPP for ROS clearance in CD8+ memory T (Tm) cells and inflammatory macrophages. Mechanistically, glycogenolysis-produced glucose-1-phosphate (G1P) allosterically induces G6P dehydrogenase (G6PD) binding to glycogen, which together undergo liquid-liquid phase separation (LLPS) and recruit PPP enzymes, resulting in a compartmentalized reaction cascade. Based on mechanistic elucidation, we demonstrated that G1P can act as an antitumor immunotherapeutic agent by modulating memory fitness and maintenance of tumor-reactive CD8+ T cells in mice. These findings revealed an unusual function of glycogen metabolism, which is of paramount importance in the regulation of PPP and redox homeostasis in cells.

Keywords:  CD8(+) T(m); G1P; G6PD; LLPS; PPP; ROS; compartmentalization; glycogen

DOI:  https://doi.org/10.1016/j.molcel.2025.05.019
Cell Signal. 2025 Jun 04. pii: S0898-6568(25)00337-7. [Epub ahead of print]134 111922

PDPK1 governs macrophage M2 polarization via hypoxia-driven CD47/AKT-glycolytic Axis in endometriosis.

Han Li, Xiaoshan Chai.

   BACKGROUND: Macrophage M2 polarization plays a critical role in the progression of endometriosis (EMS), and glycolysis has emerged as a potential therapeutic target. This study aimed to investigate the interplay between glycolytic signaling and macrophage M2 polarization in EMS.
METHODS: Clinical correlations were analyzed in ectopic endometrial tissues from EMS patients. Primary endometrial stromal cells (ESCs) and Ishikawa cells were cultured under hypoxic conditions, and their conditioned media were used to treat THP-1-derived macrophages. Mechanistic investigations were performed through PDPK1 knockdown, AKT/CD47 overexpression, and lactic acid (LA) supplementation, and the therapeutic potential was assessed in a mouse model of EMS treated with PDPK1, CD47, and LDHA inhibitors.
RESULTS: Ectopic EMS tissues exhibited increased infiltration of CD206+ M2 macrophages, which positively correlated with upregulation of CD47, PDPK1, and LDHA. Hypoxia enhanced the proliferation and migration of endometrial cells, accompanied by activation of the AKT/mTOR pathway and glycolytic reprogramming, as indicated by elevated glucose uptake, LA, and ATP production, and elevated expression of GLUT1, PDK1, and PKM2. Moreover, hypoxia promoted M2 polarization of THP-1-derived macrophages, evidenced by an increased CD206+ population, a disrupted M1/M2 ratio, reduced pro-inflammatory cytokines (IL-6, TNF-α), and elevated anti-inflammatory factors (IL-10, TGF-β). Silencing of PDPK1 attenuated hypoxia-induced AKT/mTOR activation and CD47/LDHA expression, thereby reducing glycolysis and M2 polarization. These effects were restored by AKT/CD47 overexpression or exogenous LA supplementation. In vivo, pharmacological inhibition of PDPK1, CD47, or LDHA significantly reduced lesion size, suppressed M2 macrophage infiltration, and promoted apoptosis.
CONCLUSION: PDPK1 promotes M2 polarization via CD47/AKT-LDHA-mediated glycolytic reprogramming, thereby exacerbating EMS progression. Targeting this glycolysis-immune axis could be a promising therapeutic strategy for EMS.

Keywords:  Endometriosis; Glycolysis; Macrophage polarization; PDPK1-CD47/AKT-LDHA axis

DOI:  https://doi.org/10.1016/j.cellsig.2025.111922
Int Immunopharmacol. 2025 Jun 05. pii: S1567-5769(25)00977-4. [Epub ahead of print]161 114987

The interplay between STING and metabolic reprogramming: From mechanisms to therapeutic strategies.

Lu Zhou, Yu-Han Wang, Lu Zhang.

  Stimulator of interferon genes (STING) is an intracellular sensor of cyclic dinucleotides involved in the innate immune response to pathogen- or self-derived DNA. Metabolic reprogramming regulates STING, and the interaction between STING and metabolism has been highlighted in recent studies. Given the strong association between STING-related metabolic dysregulation and the onset of diseases such as diabetes, liver diseases, and cardiovascular diseases, summarizing the relationship between STING and metabolism and identifying potential therapeutic targets seem particularly crucial. This review focuses on the mutual regulation of STING and metabolism, summarizes the regulatory effects of STING on glucose and lipid metabolism, and highlights the potential therapeutic roles of STING agonists and inhibitors in various metabolism-related diseases. More importantly, STING activation or function is influenced by the products or key enzymes involved in these metabolic reactions. The mechanisms of these regulatory pathways have been elucidated, and novel therapeutic approaches that target metabolic regulation to modulate the STING response have been proposed, thereby enhancing its downstream immune responses and promoting improved anti-tumor and antiviral effects in the body.

Keywords:  Glucose metabolism; Immune response; Lipid metabolism; Metabolic reprogramming; STING

DOI:  https://doi.org/10.1016/j.intimp.2025.114987
J Lipid Res. 2025 Jun 07. pii: S0022-2275(25)00097-5. [Epub ahead of print] 100837

Helminth-induced prostaglandin signalling and dietary shifts in PUFA metabolism promote colitis-associated cancer.

Katherine A Smith, Ella K Reed, Irina Guschina, Victoria J Tyrrell, Claire Butters, Matthew G Darby, Brunette Katsandegwaza, Alisha Chetty, William Gc Horsnell, Valerie B O'Donnell, Awen Gallimore.

  Oxylipins derived from dietary polyunsaturated fatty acids (PUFAs) are key determinants of intestinal health, homeostasis and inflammatory disorders, such as colitis-associated colorectal cancer (CAC). Previous research has independently linked a high dietary omega (ω)-6:ω-3 PUFA ratio, or intestinal helminth infection, to an increased risk of CAC. However, whether these two factors interact to exacerbate disease risk and whether oxylipins contribute to this is unknown. In this study, we report that infection with the helminth Heligmosomoides polygyrus bakeri (Hpb) exacerbates tumour formation when combined with a high ω-6:ω-3 PUFA ratio diet. Dietary increases in tumour burden correlated with heightened levels of arachidonic acid (AA) and AA-derived lipoxygenase (LOX) oxylipins in the colon, including the 12/15-LOX product 12-hydroxyeicosatetraenoic acid, prior to disease onset. Although helminth infection further increased the production of 12/15-LOX oxylipins and increased expression of Alox15, responsible for producing these metabolites, inhibition of cyclooxygenase-dependent prostaglandin production with aspirin prevented helminth-exacerbation of disease. Helminth-infected mice exhibited increased phosphorylation of β-catenin in the colon, which was inhibited by EP2 and 4 antagonists. Moreover, administration of an EP agonist increased tumour burden in naive mice fed a high ω-6:ω-3 PUFA ratio diet, to the levels seen in helminth-exacerbation of disease. These data suggest that dietary changes in fatty acid composition coordinate with helminth-induced activation of EP signalling to exacerbate tumour development.

Keywords:  Arachidonic acid; Cell signalling; Colon; Lipolysis and fatty acid metabolism; Lipoxygenase; Omega-3 fatty acids; Phospholipids/Metabolism; Prostaglandins

DOI:  https://doi.org/10.1016/j.jlr.2025.100837
J Neuroinflammation. 2025 Jun 11. 22(1): 154

OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis.

Guoqing Jing, Hailong Gong, Han Wang, Jing Zuo, Die Wu, Huifan Liu, Xing Wang, Min Yuan, Yun Xia, Tongtong Du, Wanhong Liu, Xiaojing Wu, Xuemin Song.

   BACKGROUND: Sepsis-associated encephalopathy (SAE), a life-threatening neurological complication of systemic infection, contributes substantially to sepsis-related mortality. Accumulating evidence demonstrates that microglia-driven neuroinflammation emerges as a central pathogenic mechanism underlying SAE. Here, we identify ovarian tumor deubiquitinase 1 (OTUD1) as a critical mediator of SAE pathogenesis. We demonstrate that OTUD1 promotes hexokinase 2 (HK2) dissociation from mitochondria via selective K63-linked deubiquitination, triggering microglia pyroptosis and neuroinflammation. Our findings address a key knowledge gap by elucidating the OTUD1-HK2 axis as a novel regulatory pathway in SAE, offering potential therapeutic targets to mitigate cognitive deficits in sepsis.
METHODS: Single-cell RNA sequencing was used to identify SAE-specific microglia subpopulations and analyze the expression of deubiquitinases within these subpopulations. OTUD1 knockout mice were generated to investigate the role of OTUD1 in SAE. Both wild-type and OTUD1 knockout mice were subjected to cecal ligation and puncture to induce SAE. In vitro, primary microglia and BV2 cells were treated with LPS and nigericin to simulate inflammatory conditions. Cognitive function of the mice was assessed through behavioral tests. Neuronal and synaptic damage were evaluated using HE and Nissl staining, as well as transmission electron microscopy. ELISA and qPCR were used to detect neuroinflammation. Western blot and immunofluorescence were employed to analyze protein expression. Molecular docking, 3D confocal microscopy, and co-immunoprecipitation were conducted to detect the interaction between OTUD1 and HK2. Finally, the correlation between OTUD1 and SAE was evaluated by analyzing clinical samples.
RESULTS: Through single-cell RNA seq and subpopulation analysis, we identified an SAE-associated microglia (SAM) subpopulation with high expression of pyroptosis-related genes. Deubiquitinase expression analysis showed significantly elevated OTUD1 expression in SAM. OTUD1 deficiency attenuated neural damage and cognitive dysfunction in SAE mice in vivo. Further experiments revealed that OTUD1 regulates pyroptosis in microglia, affecting the progression of SAE. Mechanistically, OTUD1 directly binds to the C-terminal domain of HK2 through its Ala-rich domain and selectively cleaves K63-linked polyubiquitin chains on HK2 to promote the dissociation of HK2 from mitochondria, thereby activating the NLRP3 inflammasome and pyroptosis.
CONCLUSIONS: In SAE, OTUD1 deubiquitinates HK2, promoting its dissociation from mitochondria, which triggers microglia pyroptosis, leading to neuronal damage and cognitive impairment.

Keywords:  HK2; Microglia; OTUD1; Pyroptosis; SAE

DOI:  https://doi.org/10.1186/s12974-025-03480-w
Biochem Pharmacol. 2025 Jun 04. pii: S0006-2952(25)00296-5. [Epub ahead of print]239 117031

PCSK9 inhibition mitigates vulnerable plaque formation induced by hyperhomocysteinemia through regulating lipid metabolism and inflammation.

Ping Jin, Juan Ma, Peng Wu, Ru Yan, Yitong Bian, Shaobin Jia, Qiangsun Zheng, Xueping Ma.

  Atherosclerosis (AS) is a persistent inflammatory disorder marked by vulnerable plaques, which increase the likelihood of cardiovascular incidents. This study explored the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the development of vulnerable plaques triggered by hyperhomocysteinemia (HHcy), with a focus on lipid metabolism, and inflammation. Apolipoprotein E knockout (ApoE-/-) mice were fed a methionine-rich diet to induce HHcy. PCSK9 inhibition via SBC-115076 significantly improved plaque stability. HHcy upregulated PCSK9 levels, and hinder cholesterol efflux by downregulating the ATP-binding cassette transporters ABCA1 and ABCG1. In contrast, no significant effects were noted on low-density lipoprotein receptor (LDLR), cluster of differentiation 36 (CD36), or scavenger receptor class B type I (SR-BI). Inhibition of PCSK9 led to the restoration of ABCA1 and ABCG1, thereby facilitating an increase in cholesterol efflux. Furthermore, PCSK9 inhibition reduced HHcy-induced increase of proinflammatory cytokines, including interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). In vitro, mouse peritoneal macrophages (MPMs) exposed to HHcy presented reduced ABCA1 and ABCG1, whereas LDLR, CD36, and SR-BI remained unaffected. PCSK9 knockout reversed these changes. Additionally, HHcy upregulated expression of proinflammatory cytokines, along with the activation of Toll-like receptor 4 (TLR4) /nuclear factor kappa B (NF-κB) pathway. PCSK9 inhibition reduced the production of these cytokines and mitigated the activation of the TLR4/NF-κB pathway, confirming its role in macrophage inflammation. These findings reveal that PCSK9 exacerbates HHcy-related AS by impairing cholesterol efflux and promoting inflammation. PCSK9 inhibitors may offer a dual therapeutic approach for stabilizing plaques and reducing cardiovascular risk in patients with HHcy.

Keywords:  Cholesterol efflux; Hyperhomocysteinemia; Inflammation; Macrophages; PCSK9; Vulnerable plaque

DOI:  https://doi.org/10.1016/j.bcp.2025.117031
Psychiatry Res. 2025 Jun 04. pii: S0165-1781(25)00217-3. [Epub ahead of print]351 116569

Serum metabolomics in women with major depressive disorder: Associations with mitochondrial function, inflammation, and oxidative stress.

Ellen Bisle, Sven-Bastiaan Haange, Roberto Rojas, Alexander Behnke, Alexander Karabatsiakis, Anja Gumpp, Matthias Mack, Rezan Nehir Mavioglu, Sabine Lutz-Bonengel, Ulrike Rolle-Kampczyk, Andreas Mielcarek, Martin von Bergen, Iris-Tatjana Kolassa.

  Despite intensified research, depression remains a mental disorder with an insufficiently understood pathophysiology. Clinically applicable biomarkers are lacking but are of highest interest, particularly for preventive and predictive measures. Here, we report combined findings on untargeted metabolomics, inflammation markers in serum, mitochondrial respiration in peripheral blood immune cells, and measures of oxidative stress, along with psychometric assessments in a female outpatient cohort (n = 19) compared to non-depressed female controls (n = 23). We used Weighted Correlation Network Analysis (WCNA) to identify metabolite clusters differentiating depressed and non-depressed individuals. Furthermore, WCNA revealed associations between biological parameters - previously associated with major depression - and the identified metabolite clusters. Including all identified metabolites, our results showed separation between participants with depression and non-depressed controls. WCNA identified ten metabolite clusters positively correlated with depression and one negatively correlated cluster. Several clusters indicated alterations in lipids and metabolites related to oxidative stress, mitochondrial function, and inflammation, underscoring the significance of inflammatory activity and oxidative stress in depression. Subsequent pathway analysis assigned the metabolites to sphingolipid, glycerophospholipid, and glycerolipid metabolism, highlighting potential targets for further research and intervention. This study supports the view of depression as a pathophysiological condition associated with alterations in several biological parameters and reinforces previous findings on the role of lipid metabolism in depression, alongside alterations in inflammatory activity and mitochondrial bioenergetics. The data also revealed correlations between bacterial and plant metabolites and MDD, suggesting impaired gut epithelial integrity in depression.

Keywords:  Inflammation; Major depressive disorder; Metabolome; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1016/j.psychres.2025.116569