bims-imicid 2025-06-08 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–06–08
twenty-two papers selected by
Dylan Ryan, University of Cambridge

Immunometabolism of regulatory T cells in cancer.
Metabolic reprogramming in viral infections: the interplay of glucose metabolism and immune responses.
Effector Tc17 cells resist shift from OXPHOS to aerobic glycolysis.
SIRT4 Controls Macrophage Function and Wound Healing through Control of Protein Itaconylation in Mice.
Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis.
Aromatic Microbial Metabolite Hippuric Acid Potentiates Pro-Inflammatory Responses in Macrophages through TLR-MyD88 Signaling and Lipid Remodeling.
Myoglobin expression improves T-cell metabolism and antitumor effector function.
Efflux of N1-acetylspermidine from hepatoma fosters macrophage-mediated immune suppression to dampen immunotherapeutic efficacy.
Pneumococcal H 2 O 2 Reshapes Mitochondrial Function and Reprograms Host Cell Metabolism.
Arginine metabolism supports metabolic reprogramming in trained immunity.
Interplay between inflammatory reflex and energetic metabolism in endotoxaemia: A role for haem oxygenase 1?
Metabolic modeling reveals a multi-level deregulation of host-microbiome metabolic networks in IBD.
Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells.
Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway.
Branched-chain ketoacid antioxidants mediate disease tolerance to sepsis.
Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics.
PGK1 phosphorylates NLRP3 and mediates inflammasome activation independent of its glycolytic activity.
Metabolic regulation of Th17 and Treg cell balance by the mTOR signaling.
Obesity-Derived Biomolecules Promote the Differentiation of THP1 Monocytes to Macrophages In Vitro.
Succinate drives gut inflammation by promoting FOXP3 degradation through a molecular switch.
Spatiotemporal Charging Single-Atom Nanozymes Activated Pyroptosis for Antitumor Immunotherapy via Bioorthogonal Disruption of Succination and Reinvigorating T Lymphocytes.
Elimination of intra-hepatocytic malaria parasites is driven by non-canonical autophagy but not nitric oxide production.

Oncogene. 2025 Jun 04.

Immunometabolism of regulatory T cells in cancer.

Jordy Saravia, Hongbo Chi.

Regulatory T (Treg) cells play critical roles in maintaining immune tolerance and tissue homeostasis, but impede anti-tumor immunity. Recent work has established how Treg cells metabolically adapt within the tumor microenvironment (TME), and these adaptations frequently provide a functional advantage over effector T cells. Further, enhanced Treg cell function in the TME may contribute to the limited efficacy of current immunotherapies, especially immune checkpoint blockade (ICB). Here, we review recent progress in understanding mechanisms of Treg cell heterogeneity and function in tumors, with a particular focus on cellular metabolism as an underlying factor by which Treg cells are uniquely poised to thrive in the TME and contribute to tumorigenesis. We describe how cellular metabolism and nutrient or metabolic communication shape Treg cell lineage identity and function in the TME. We also discuss the interplay between ICB and Treg cell metabolism and function, and highlight current strategies targeting Treg cell metabolism specifically in the TME. Understanding metabolic control of intratumoral Treg cells provides excellent opportunities to uncover new or combination therapies for cancer.

DOI: https://doi.org/10.1038/s41388-025-03458-1
Front Immunol. 2025 ;16 1578202

Metabolic reprogramming in viral infections: the interplay of glucose metabolism and immune responses.

Mahmoud Darweesh, Saeed Mohammadi, Mina Rahmati, Moosa Al-Hamadani, Ahmed Al-Harrasi.

  Metabolic reprogramming is an important player within the immune response to viral infections, allowing immune cells to fine-tune their energy production and biosynthetic requirements while it is actively working to restrict pathogen access to essential nutrients. Particularly, glucose metabolism, which appears to be one of the important regulators of immune function, affects immune cell activation, cytokine secretion, and pathogen restriction. This review explores the mechanisms of metabolic reprogramming during viral infections, with a specific emphasis on glucose metabolism. We discussed the key cytokines involved in orchestrating this metabolic process and the influence of pre-existing metabolic disorders on immune efficiency. Furthermore, we introduced emerging therapeutic strategies that target glucose metabolism to enhance antiviral immunity and improve disease outcomes. A deeper understanding of the interaction between metabolism and immunity could be promising for the development of novel immunometabolic targets against viral infections.

Keywords:  cytokines; diabetes; glucose metabolism; immune activation; immunometabolism; pathogen clearance; viral infections

DOI:  https://doi.org/10.3389/fimmu.2025.1578202
Front Immunol. 2025 ;16 1571221

Effector Tc17 cells resist shift from OXPHOS to aerobic glycolysis.

Reni John, Srinivasu Mudalagiriyappa, Nagabhushan Chandrashekar, Som G Nanjappa.

  IL-17A-expressing lymphocytes, including Tc17 cells, are instrumental in immunity, immunopathology, and autoimmunity. We have previously shown that experimental attenuated live fungal vaccine-induced Tc17 cells are stable, long-lived without plasticity, and necessary to mediate sterilizing immunity during CD4+ T cell deficiency, which poses higher susceptibility to fungal infections. Cell metabolism is integral for T cell homeostasis but the metabolic adaptations of Tc17 cells are poorly defined. In this study, we hypothesized that effector Tc17 cells adopt high energy-yielding metabolic pathways to form stable, long-lived memory cells in vivo. Using a mouse model of attenuated fungal vaccination, we found that effector Tc17 cells were metabolically highly active with higher proliferation and protein synthesis than IFNγ+ CD8+ T (Tc1) cells. Glucose was necessary for effector Tc17 cell expansion but with less dependency during the late expansion despite the active metabolism. Contrary to established dogma, we found that the effector Tc17 cells preferentially channeled the glucose to OXPHOS than glycolysis, which was correlated with higher mitochondrial mass and membrane potential. Inhibition of OXPHOS shrunk the Tc17 responses while sparing Tc1 cell responses. Tc17 cells actively relied on OXPHOS throughout the expansion period, resisting adaptation to aerobic glycolysis. Our data showed that the effector Tc17 cells predominantly utilize glucose for metabolism through OXPHOS rather than aerobic glycolysis. Our study has implications in vaccine design to enhance the efficacy and immunotherapeutics to modulate the immunity and autoimmunity.

Keywords:  CD8+ T cell; OXPHOS; T cell activation; Tc17 cell; antifungal; glycolysis; vaccine responses

DOI:  https://doi.org/10.3389/fimmu.2025.1571221
bioRxiv. 2025 May 13. pii: 2025.05.12.653532. [Epub ahead of print]

SIRT4 Controls Macrophage Function and Wound Healing through Control of Protein Itaconylation in Mice.

Kristin A Anderson, Beverly deSouza, Pol Castellano-Escuder, Zhihong Lin, Olga R Ilkayeva, Michael J Muehlbauer, Paul A Grimsrud, Matthew D Hirschey.

Proper regulation of inflammatory responses is essential for organismal health. Dysregulation can lead to accelerated development of the diseases of aging and the aging process itself. Here, we identify a novel enzymatic activity of the mitochondrial sirtuin SIRT4 as a lysine deitaconylase that regulates macrophage inflammatory responses. Itaconate is a metabolite abundantly produced in activated macrophages. We find it forms a protein modification called lysine itaconylation. Using biochemical and proteomics approaches, we demonstrate that SIRT4 efficiently removes this modification from target proteins both in vitro and in vivo . In macrophages, elevated protein itaconylation increases upon LPS stimulation, coinciding with elevated SIRT4 expression. SIRT4-deficient macrophages exhibit significantly increased IL-1β production in response to LPS stimulation. This phenotype is intrinsic to macrophages, as demonstrated by both lentiviral over-expression and acute SIRT4 knockdown models. Mechanistically, we identify key enzymes in branched-chain amino acid (BCAA) metabolism as targets of hyperitaconylation in SIRT4-deficient macrophages. The BCKDH complex component dihydrolipoamide branched chain transacylase E2 (DBT) is hyperitaconylated and has reduced BCKDH activity in SIRT4KO macrophages. Physiologically, SIRT4-deficient mice exhibit significantly delayed wound healing, demonstrating a consequence of dysregulated macrophage function. Our data reveal a novel protein modification pathway in immune cells and establish SIRT4 as a critical regulator at the intersection of metabolism and inflammation. These findings have implications for understanding immune dysregulation in aging and metabolic disease.

DOI: https://doi.org/10.1101/2025.05.12.653532
FASEB J. 2025 Jun 15. 39(11): e70665

Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis.

Huizhen Lin, Jingwen Qi, Siwei Lin, Mengnan Lin, Zijie Chen, Yunhui Guo, Xin Zhang, Qi-Long Wang, Ting Cai, Wei Yang, Xiaojun Zheng.

  Metabolic dysfunction-associated steatohepatitis (MASH) is a manifestation of systemic metabolic disease defined by abnormal lipid metabolism and causes liver disease. Inflammation driven by immune cells has been linked to liver damage, fibrosis, and the progression of MASH. Here, single-cell transcriptome analysis disclosed the increasing hepatic infiltration of CD8+ T cells in a murine methionine- and choline-deficient (MCD) diet-induced MASH model. Simvastatin alleviated the progression of MCD-diet-induced MASH, accompanied by the decreased infiltration of T cells. Depletion of CD8+ T cells also improved MASH progression. It is widely recognized that cholesterol plays an indispensable role in tuning the activation and function of CD8+ T cells. We found that specific inhibition of cholesterol synthesis in T cells significantly reduced MCD-induced hepatic steatosis, damage, inflammation, and concurrently lowered the accumulation of T cells and macrophages in the liver. Mechanistic studies revealed that MCD-induced hepatic oxidative stress was reduced by inhibiting T-cell cholesterol metabolism. Simvastatin ameliorated MASH in mice, at least in part through inhibiting the infiltration and effector function of CD8+ T cells. Collectively, our findings provide compelling evidence that pharmacological modulation of T-cell cholesterol metabolism may represent a promising therapeutic approach in the treatment of MASH.

Keywords:  T cells; cholesterol; metabolic dysfunction‐associated steatohepatitis; oxidative stress; simvastatin

DOI:  https://doi.org/10.1096/fj.202500115R
bioRxiv. 2025 May 23. pii: 2025.05.19.654724. [Epub ahead of print]

Aromatic Microbial Metabolite Hippuric Acid Potentiates Pro-Inflammatory Responses in Macrophages through TLR-MyD88 Signaling and Lipid Remodeling.

Gauri Mirji, Sajad Ahmad Bhat, Mohamed El Sayed, Sarah Kim Reiser, Siva Pushpa Gavara, Ying Ye, Taito Miyamoto, Qin Liu, Aaron R Goldman, Andrew Kossenkov, Nan Zhang, Rahul S Shinde.

The gut microbiome generates a diverse array of metabolites that actively shape host immunity, yet the pro-inflammatory potential of microbial metabolites remains poorly understood. In this study, we identified hippuric acid, an aromatic gut microbe-derived metabolite, as a potent enhancer of pro-inflammatory responses using a murine bacterial infection model and a non-targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics. Administering hippuric acid intraperitoneally in murine models of Escherichia coli infection or LPS-induced inflammation significantly heightened pro-inflammatory responses and innate immune cell activation. In vitro , hippuric acid selectively potentiated M1-like macrophage polarization (LPS + IFNγ) but had no effect on M2-like polarization (IL-4). Hippuric acid further enhanced responses to diverse MyD88-dependent TLR ligands, but not TRIF-dependent TLR3, implicating a possible mechanism of action via activation of TLR-MyD88 signaling. Genetic deletion of MyD88 abrogated the pro-inflammatory effects of hippuric acid both in vitro and in vivo , confirming its dependence on the MyD88 pathway. Transcriptomic and lipidomic analyses revealed that hippuric acid promoted cholesterol biosynthesis and lipid accumulation, linking microbial metabolism to lipid-driven immune activation. Notably, hippuric acid similarly enhanced pro-inflammatory responses in human macrophages, and its elevated levels correlated with increased sepsis mortality, highlighting its potential clinical relevance. These findings establish hippuric acid as a previously unrecognized microbial-derived inflammatory modulator, bridging gut microbial metabolism, lipid remodeling, and innate immune signaling, and offer new insights into its role in infection and inflammation.

DOI: https://doi.org/10.1101/2025.05.19.654724
J Immunother Cancer. 2025 Jun 03. pii: e011503. [Epub ahead of print]13(6):

Myoglobin expression improves T-cell metabolism and antitumor effector function.

Julia Werner, Haifeng C Xu, Georgios Theodorakis, Ichiro Katahira, Mitrajit Ghosh, Michal Gorzkiewicz, Luisa de Sousa Santos, Ann Kathrin Bergmann, Max Anstötz, Anne Busch, Diran Herebian, Sascha Dietrich, Carsten Berndt, Ertan Mayatepek, Aleksandra A Pandyra, Dirk Brenner, Philipp A Lang.

   BACKGROUND: The tumor microenvironment is frequently hypoxic and characterized by a scarcity of nutritional resources including a shortage of glucose. As effector T cells have high energy demands, tumor metabolism can contribute to T-cell dysfunction and exhaustion.
METHODS: In this study, we determined hypoxia in spleen and tumor tissue from tumor-bearing C57BL/6J mice using reverse transcription polymerase chain reaction (RT-PCR), histology and flow cytometry. Next, CD8+ T cells isolated from C57BL6J mice or P14+ mice were transduced with Thy1.1 (Control) or Thy1.1-Myoglobin (Mb) packaged retrovirus. Expression of Mb was confirmed with RT-PCR and western blot. Cellular metabolism was determined by flow cytometry, transmission electron microscopy, focused ion beam scanning electron microscopy, Seahorse, metabolomics and luminescence assays. Mb expressing or control P14+ or OT-I+ T cells were transferred in B16F10-gp33 or MC38-ova tumor-bearing mice respectively and analyzed using flow cytometry and histology. B16F10-gp33 tumor-bearing mice were additionally treated with anti-programmed cell death protein-1 (PD-1) checkpoint inhibitor.
RESULTS: Here we demonstrate that expression of the oxygen-binding protein myoglobin in T cells can boost their mitochondrial and glycolytic metabolic functions. Metabolites and tricarboxylic acid compounds were highly increased in the presence of myoglobin (Mb), which was associated with increased ATP levels. Mb-expressing T cells exhibited low expression of hypoxia-inducible factor-1α after activation and during infiltration into the tumor microenvironment (TME). Accordingly, Mb expression increased effector T-cell function against tumor cells in vitro with concomitant reductions in superoxide levels. Following adoptive transfer into tumor-bearing mice, Mb expression facilitated increased infiltration into the TME. Although T cells expressing Mb exhibited increased expression of effector cytokines, PD-1 was still detected and targetable by anti-PD-1 monoclonal antibodies, which in combination with transfer of Mb-expressing T cells demonstrated maximal efficacy in delaying tumor growth.
CONCLUSION: Taken together, we show that expression of Mb in T cells can increase their metabolism, infiltration into the tumor tissue, and effector function against cancer cells.

Keywords:  Adoptive cell therapy - ACT; Colon Cancer; Immune Checkpoint Inhibitor

DOI:  https://doi.org/10.1136/jitc-2025-011503
Immunity. 2025 May 27. pii: S1074-7613(25)00227-4. [Epub ahead of print]

Efflux of N1-acetylspermidine from hepatoma fosters macrophage-mediated immune suppression to dampen immunotherapeutic efficacy.

Zheng-Yu Liu, Cai-Yuan Wu, Rui-Qi Wu, Jun-Cheng Wang, Chun-Xiang Huang, Xu-Yan Wang, Yaojun Zhang, Limin Zheng, Yun Chen, Xiang-Ming Lao, Dong-Ping Chen, Dong-Ming Kuang.

  Metabolic reprogramming is a hallmark of tumor progression. Here, we examined the metabolic profile of hepatocellular carcinoma (HCC), a disease that responds poorly to immune checkpoint blockade (ICB). Polyamine metabolism increased in HCC samples. Of the polyamine spectrum analyzed, N1-acetylspermidine (N1-Ac-Spd) accumulated in HCC tissue as compared with nontumoral liver tissue and was elevated in paired plasma. Injection of N1-Ac-Spd promoted tumor progression in preclinical models and compromised the efficacy of ICB. Inflammatory macrophages increased expression of the spermidine/spermine N1-acetyltransferase 1, SAT1, in hepatoma cells, leading to increased N1-Ac-Spd efflux via the polyamine transporter protein SLC3A2. Mechanistically, N1-Ac-Spd efflux activated SRC signaling in a charge-dependent manner, which in turn induced CCL1+ macrophage polarization, the recruitment of CCR8+ regulatory T cells, and an immunosuppressive tumor microenvironment (TME). In vivo interventions targeting SLC3A2, SAT1, or CCL1 enhanced the antitumor effects of ICB therapy. Our findings provide insight into the mechanisms whereby metabolic reprogramming fosters an immunosuppressive TME, with implications for the treatment of HCC.

Keywords:  N1-acetylspermidine; hepatocellular carcinoma; immune privilege; immunotherapy; inflammatory macrophages; polyamine metabolism; regulatory T cells

DOI:  https://doi.org/10.1016/j.immuni.2025.05.006
bioRxiv. 2025 May 22. pii: 2025.05.22.655446. [Epub ahead of print]

Pneumococcal H 2 O 2 Reshapes Mitochondrial Function and Reprograms Host Cell Metabolism.

Anna Scasny, Babek Alibayov, Ngoc Hoang, Ana G Jop Vidal, Kenichi Takeshita, Eva Bengten, Antonino Baez, Wei Li, Jonathan Hosler, Kurt Warncke, Kristin Edwards, Jorge E Vidal.

Streptococcus pneumoniae (Spn) is a primary cause of pneumonia, induces acute lung parenchymal infection, damaging through a unique metabolic pathway that generates hydrogen peroxide (H 2 O 2 ) as a byproduct. This study reveals that Spn-derived H 2 O 2 , primarily produced by pyruvate oxidase (SpxB), inhibits the tricarboxylic acid (TCA) cycle in lung epithelial cells by targeting aconitase, glutamate dehydrogenase, and α-ketoglutarate dehydrogenase. This inhibition leads to citrate accumulation and reduced NADH production for oxidative phosphorylation, while RNA sequencing shows SpxB-dependent upregulation of glycolytic genes (e.g., HK2, PFKP), limiting pyruvate entry into the TCA cycle. Consequently, glucose consumption and lactate/acetate production increase, resembling a Warburg-like metabolic shift that supports bacterial survival. Despite TCA cycle suppression, mitochondrial membrane potential remains largely unaffected, with minimal apoptosis induced by Spn-mediated stress. These findings elucidate a novel mechanism by which Spn manipulates host metabolism to facilitate infection, highlighting potential therapeutic targets for pneumococcal diseases.
Highlights: Spn-derived SpxB-generated H 2 O 2 directly inhibits TCA cycle enzymes ACO2, GDH, and OGDHC. Spn-H 2 O 2 disrupts mitochondrial respiration, increases citrate levels, and enhances glucose consumption with elevated lactate and acetate production. SpxB-dependent H 2 O 2 induces transcriptional dysregulation, upregulating HK2 and PFKP while reducing pyruvate entry into the TCA cycle. H 2 O 2 -mediated reprogramming shifts host cells to a Warburg-like metabolic phenotype. Spn-H 2 O 2 triggers limited apoptosis and maintains mitochondrial membrane potential, supporting bacterial survival.
Graphical abstract:

DOI: https://doi.org/10.1101/2025.05.22.655446
J Leukoc Biol. 2025 Jun 04. pii: qiaf080. [Epub ahead of print]

Arginine metabolism supports metabolic reprogramming in trained immunity.

Laura M Merlo Pich, Athanasios Ziogas, Anaisa V Ferreira, Nicholas Sumpter, Andrei Sarlea, Sarantos Kostidis, Leo A B Joosten, Mihai G Netea.

  Trained immunity, also termed innate immune memory, is supported by metabolic rewiring of innate immune cells, altering their bioenergetic profile and ultimately their functions. While amino acids such as arginine are known to possess immunomodulatory properties, their role in trained immunity remains largely unexplored. Primary human monocytes were trained with β-glucan in a medium enriched with or deprived of arginine or supplemented with an arginase inhibitor. After a resting period, trained cells were restimulated with LPS. Arginine deprivation or arginase inhibition during β-glucan-training impaired the amplification of IL-6 and TNF cytokine response to LPS, while they did not affect the cells' phagocytotic capacity. Arginine deprivation also significantly reduced the oxygen consumption rate of trained cells, without affecting glycolysis. Genetic studies revealed polymorphisms near genes coding for arginine-metabolizing enzymes modulated induction of trained immunity, highlighting the role of arginine-derived metabolites in trained immunity. These findings demonstrate that arginine and its metabolites are involved in the induction of trained immunity. Understanding metabolic mechanisms involved in trained immunity could provide insights into new therapeutic strategies for harnessing arginine deprivation to modulate inflammatory disorders.

Keywords:  arginine; metabolism; monocytes; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiaf080
Br J Pharmacol. 2025 Jun 02.

Interplay between inflammatory reflex and energetic metabolism in endotoxaemia: A role for haem oxygenase 1?

Evelin C Cárnio, Luiz G S Branco, Fernanda Brognara, Patrícia Passaglia, Roberta Foresti, Roberto Motterlini.

  Inflammation is vital for defence against injury and infection, but excessive inflammation can lead to tissue damage and disease. The central nervous system (CNS) helps regulate immune responses through neuroendocrine pathways, such as the hypothalamic-pituitary-adrenal axis and the anti-inflammatory reflex, which limit systemic inflammation. Immune responses require significant metabolic energy and the liver adapts by increasing glucose production and mobilizing fatty acids. This immune-metabolic coordination is mediated by cytokines and metabolic regulators. This review explores how the anti-inflammatory reflex modulates the interplay between inflammation and metabolism during endotoxaemia, with a focus on the haem oxygenase 1/carbon monoxide (HO1/CO) pathway. Carbon monoxide, a byproduct of HO1 activity, acts as a key signalling molecule that reduces inflammation, supports mitochondrial function and protects tissues. Understanding this pathway provides new insights into potential therapeutic strategies for treating inflammatory and metabolic disorders by targeting neuroimmune-metabolic communication networks.

Keywords:  carbon monoxide; carotid body; endotoxaemia; fever and hypothermia; lipopolysaccharide; systemic inflammation

DOI:  https://doi.org/10.1111/bph.70093
Nat Commun. 2025 Jun 02. 16(1): 5120

Metabolic modeling reveals a multi-level deregulation of host-microbiome metabolic networks in IBD.

Jan Taubenheim, A Samer Kadibalban, Johannes Zimmermann, Claudia Taubenheim, Florian Tran, Philip Rosenstiel, Konrad Aden, Christoph Kaleta.

Inflammatory bowel diseases (IBDs) are chronic disorders involving dysregulated immune responses. Despite the role of disrupted host-microbial interaction in the pathophysiology of IBD, the underlying metabolic principles are not fully understood. We densely profiled microbiome, transcriptome and metabolome signatures from longitudinal IBD cohorts before and after advanced drug therapy initiation and reconstructed metabolic models of the gut microbiome and the host intestine to study host-microbiome metabolic cross-talk in the context of inflammation. Here, we identified concomitant changes in metabolic activity across data layers involving NAD, amino acid, one-carbon and phospholipid metabolism. In particular on the host level, elevated tryptophan catabolism depleted circulating tryptophan, thereby impairing NAD biosynthesis. Reduced host transamination reactions disrupted nitrogen homeostasis and polyamine/glutathione metabolism. The suppressed one-carbon cycle in patient tissues altered phospholipid profiles due to limited choline availability. Simultaneously, microbiome metabolic shifts in NAD, amino acid and polyamine metabolism exacerbated these host metabolic imbalances. Leveraging host and microbe metabolic models, we predicted dietary interventions remodeling the microbiome to restore metabolic homeostasis, suggesting novel therapeutic strategies for IBD.

DOI: https://doi.org/10.1038/s41467-025-60233-2
Nat Cell Biol. 2025 Jun 03.

Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells.

Jie Wan, Jian-Hong Shi, Min Shi, Haiyan Huang, Zhen Zhang, Wenyan Li, Chenyue Guo, Rujuan Bao, Xiaoyan Yu, Qiaoqiao Han, Xian Du, Song Li, Youqiong Ye, Xingang Cui, Xia Li, Jing-Hua Li, Qiang Zou.

The aberrant accumulation of intracellular disulfides promotes cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8+ T cell function remains unknown. Here we demonstrate that lactate dehydrogenase B (LDHB) facilitates intratumoural CD8+ T cell disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8+ T cells induces disulfidptosis, which plays critical roles in the development of exhausted CD8+ T cells. LDHB restricts glucose-6-phosphate dehydrogenase (G6PD) activity in exhausted CD8+ T cells by interacting with G6PD, causing NADPH depletion and consequently triggering disulfidptosis. Accordingly, the loss of LDHB in T cells prevents disulfidptosis-dependent CD8+ T cell exhaustion and improves antitumour immunity. Mechanistically, STAT3 directs LDHB expression to limit G6PD activity and mediate disulfidptosis in exhausted CD8+ T cells. Our results highlight the distinct roles of disulfidptosis and ferroptosis in driving CD8+ T cell exhaustion and suggest a potential therapeutic strategy to target LDHB in cancer immunotherapy.

DOI: https://doi.org/10.1038/s41556-025-01673-2
Cell Host Microbe. 2025 May 26. pii: S1931-3128(25)00186-6. [Epub ahead of print]

Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway.

Eric M Brown, Emily R Temple, Sarah Jeanfavre, Julian Avila-Pacheco, Noel Taylor, Kai Liu, Phuong N U Nguyen, Ahmed M T Mohamed, Panhasith Ung, Rebecca A Walker, Daniel B Graham, Clary B Clish, Ramnik J Xavier.

  Sphingolipids derived from Bacteroides species are associated with changes in host inflammation and metabolic syndrome; however, the signaling mechanisms within host cells are unknown. We utilize outer membrane vesicles (OMVs) from wild-type and sphingolipid-deficient Bacteroides strains to understand how these lipids modulate host inflammation. Characterization of the lipidome of B. thetaiotaomicron OMVs revealed enrichment of dihydroceramide phosphoethanolamine (CerPE). OMVs deliver bacterial sphingolipids into host dendritic and epithelial cells, where a subset of lipids, including CerPE, stably persist. Similarly, B. thetaiotaomicron colonization results in sphingolipid persistence in murine tissues and host lipidome alterations that are not observed with the sphingolipid-deficient strain. OMVs induce a potent, sphingolipid-dependent interleukin-10 (IL-10) anti-inflammatory response in dendritic cells, which depends on mevalonate pathway activation. Adding a CerPE fraction to sphingolipid-deficient OMVs rescued IL-10 secretion, similarly dependent on mevalonate pathway activation. These data highlight the essential roles of sphingolipids in stimulating anti-inflammatory responses mediated by mevalonate pathway induction.

Keywords:  Bacteroides; CerPE; IL-10; OMVs; anti-inflammatory signaling; dendritic cells; immunometabolism; mevalonate pathway; microbiome; outer membrane vesicles; sphingolipids

DOI:  https://doi.org/10.1016/j.chom.2025.05.007
bioRxiv. 2025 May 22. pii: 2025.05.22.654748. [Epub ahead of print]

Branched-chain ketoacid antioxidants mediate disease tolerance to sepsis.

Aditya Misra, Efi M Weitman, Michal Weitman, Jeannette R Brook, Joseph M Rone, Boryana Petrova, Randall T Mertens, Narae Hwang, Katherin Zambrano Vera, Mark A Perrella, Rebecca M Baron, Naama Kanarek, Roni Nowarski.

Metabolic adaptation is crucial for surviving systemic infection and withstanding the pathological host response to infection known as sepsis. The liver orchestrates key metabolic adaptation programs that enable disease tolerance in sepsis, yet the impact of liver metabolites on sepsis susceptibility is not well understood. By broadly profiling liver metabolite landscapes in mice surviving or succumbing to bacterial sepsis, we found that dysregulation of the branched-chain amino acid metabolite family is associated with sepsis non-survival. Administration of branched-chain ketoacids (BCKAs) during Klebsiella pneumoniae -induced sepsis in mice enhanced survival, yet not through enhanced bacterial clearance or BCKA catabolism. Instead, BCKAs served as antioxidants by directly neutralizing hydrogen peroxide, preventing tissue lipid peroxidation. Targeted metabolomics in sepsis patients revealed low BCKA abundance as an early prognostic biomarker of sepsis non-survival. Our results identify BCKAs as a systemic shield against oxidative damage and highlight new metabolite targets to enhance disease tolerance to sepsis.

DOI: https://doi.org/10.1101/2025.05.22.654748
Nat Commun. 2025 May 31. 16(1): 5059

Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics.

Yang Gao, Mingdu Luo, Hongmiao Wang, Zhiwei Zhou, Yandong Yin, Ruohong Wang, Beizi Xing, Xiaohua Yang, Yuping Cai, Zheng-Jiang Zhu.

Metabolic reactions play important roles in organisms such as providing energy, transmitting signals, and synthesizing biomacromolecules. Charting unknown metabolic reactions in cells is hindered by limited technologies, restricting the holistic understanding of cellular metabolism. Using mass spectrometry-resolved stable-isotope tracing metabolomics, we develop an isotopologue similarity networking strategy, namely IsoNet, to effectively deduce previously unknown metabolic reactions. The strategy uncovers ~300 previously unknown metabolic reactions in living cells and mice. Specifically, we elaborately chart the metabolic reaction network related to glutathione, unveiling three previously unreported reactions nestled within glutathione metabolism. Among these, a transsulfuration reaction, synthesizing γ-glutamyl-seryl-glycine directly from glutathione, underscores the role of glutathione as a sulfur donor. Functional metabolomics studies systematically characterize biochemical effects of previously unknown reactions in glutathione metabolism, showcasing their diverse functions in regulating cellular metabolism. Overall, these newly uncovered metabolic reactions fill gaps in the metabolic network maps, facilitating exploration of uncharted territories in cellular biochemistry.

DOI: https://doi.org/10.1038/s41467-025-60258-7
Cell Rep. 2025 Jun 04. pii: S2211-1247(25)00556-X. [Epub ahead of print]44(6): 115785

PGK1 phosphorylates NLRP3 and mediates inflammasome activation independent of its glycolytic activity.

Zemeng Ma, Yuxuan Wu, Zebing Rao, Chenhua Han, Naishuang Sun, Jinzhou Li, Qiang Zeng, Zaikui Zhang, Ding Ding, Jiajun Qiao, Wenjing Li, Yifeng Fang, Shuo Yang, Jiahuang Li, Jing Zhang, Yunzi Chen.

  Glycolysis is a critical player in the inflammatory response. Phosphoglycerate kinase 1 (PGK1) is an essential enzyme in the glycolysis pathway. However, little is known about its role in inflammatory response. In this study, we report PGK1 as a kinase that directly regulates NLRP3 inflammasome activation in response to lipopolysaccharide (LPS) stimulation via non-glycolytic function. We identified a novel phosphorylation modification of PGK1 at S271, mediated by protein kinase CK2. Importantly, phosphorylation at S271 serves as a molecular switch that activates PGK1's kinase function, activating it to phosphorylate NLRP3. This PGK1-mediated phosphorylation at S448/S449 of NLRP3 subsequently recruits USP14 to facilitate NLRP3 deubiquitination, thereby promoting NLRP3 inflammasome activation. Using PGK1S271A/S271A transgenic mouse model, we further demonstrated that blocking S271 phosphorylation conferred significant protection against LPS-induced endotoxemia and alum-induced peritonitis. Our findings reveal a novel regulatory role of PGK1 in inflammation and provide potential therapeutic strategies for NLRP3-driven diseases.

Keywords:  CK2; CP: Immunology; CP: Metabolism; NLRP3; PGK1; USP14; inflammasome; phosphorylation

DOI:  https://doi.org/10.1016/j.celrep.2025.115785
Metabol Open. 2025 Jun;26 100369

Metabolic regulation of Th17 and Treg cell balance by the mTOR signaling.

Zhengzheng Wang, Zhen Xu, Ming Zong, Lieying Fan.

  The balance between T helper type 17 (Th17) and regulatory T (Treg) cells is crucial for maintaining immune homeostasis. The breakdown of this equilibrium is strongly associated with autoimmune disorders, though the regulatory mechanism of the Th17/Treg plasticity is less well demonstrated. The glycolytic metabolism plays a vital role in regulating the Th17/Treg cell differentiation. The review addressed the importance of mammalian target of rapamycin (mTOR) signaling in the glycolysis pathway attributed to Th17/Treg cell balance and consequence. Notably, we discuss the consequences of its equilibrium that lead to various autoimmune diseases, which might provide a new insight into the potentially therapeutic drug target for autoimmune disorders.

Keywords:  Autoimmune disorders; Balance; Metabolism; Th17; Treg; mTOR

DOI:  https://doi.org/10.1016/j.metop.2025.100369
Front Biosci (Landmark Ed). 2025 May 23. 30(5): 36637

Obesity-Derived Biomolecules Promote the Differentiation of THP1 Monocytes to Macrophages In Vitro.

Luis I Terrazas, Valeria Gutiérrez-Almaraz, Valentina García-Garay, Victoria Hernández-Gómez, Nohemí Salinas-Jazmín, Mónica Graciela Mendoza-Rodríguez, Jonadab Efraín Olguín.

   BACKGROUND: It is well known that the microenvironment in which an immune response develops, generally pro-inflammatory or immunosuppressive, along with other overproduced biomolecules recognized by pattern recognition receptors, may promote the stimulation and differentiation of monocytes into macrophages with effector functions. Low-density lipoprotein (LDL) plays a fundamental role in cholesterol transport. By contrast, its oxidized form (ox-LDL), which is overexpressed in conditions of obesity and chronic low-grade inflammation, has been associated with cardiovascular diseases. Depending on the microenvironmental context, prostaglandin E2 (PGE2) participates in various scenarios such as inflammation, anti-inflammation, and homeostasis. Therefore, obesity-derived biomolecules such as LDL, ox-LDL, and PGE2 could induce the differentiation of immune cells into effector populations with either pro-inflammatory or immunosuppressive profiles.
METHODS: In the present work, we studied the effects of LDL, ox-LDL, and PGE2 on the differentiation of the human THP1 monocytic cell line into macrophages under two different protocols, analyzing several activation markers associated with either pro-inflammatory M1 or anti-inflammatory M2 profiles by flow cytometry and quantitative PCR (qPCR).
RESULTS: Our data suggest that native LDL induces the differentiation of human THP1 monocytes into M1 macrophages even more efficiently than classic phorbol 12-myristate 13-acetate (PMA) stimulation, whereas ox-LDL and PGE2 induce the expression of activation markers similarly to interferon gamma or interleukin 4 during PMA preactivation of macrophages.
CONCLUSIONS: The results of this study add evidence to the role of obesity-derived biomolecules as non-canonical differentiation stimuli in macrophages, which could be relevant in contexts where these biomolecules are chronically overproduced, such as obesity, low-grade inflammation, type 2 diabetes, and cancer.

Keywords:  activation profile; flow cytometry; immune response; low-density lipoprotein (LDL); macrophages; monocytes; oxidized LDL; prostaglandin E2

DOI:  https://doi.org/10.31083/FBL36637
Nat Immunol. 2025 Jun;26(6): 866-880

Succinate drives gut inflammation by promoting FOXP3 degradation through a molecular switch.

Hai Wang, Danqing Hu, Yang Cheng, Qiong Gao, Kun Liu, Nikita L Mani, Amy Y Tang, Radhika Iyer, Beixue Gao, Leyu Sun, Qi Zhou, Qin Yu, Samuel E Weinberg, Xiaoyu Zhang, Yingzi Cong, Parambir S Dulai, Yana Zhang, Zheng Liu, Deyu Fang.

Succinate levels are increased in inflammatory bowel disease (IBD), but its role in disease pathogenicity remains unknown. Here we showed that succinate promoted colitis in mice by reducing the expression of FOXP3 and increasing the expression of interleukin-17 in regulatory T (Treg) cells. Succinate selectively reduced the expression of 2-oxoglutarate dehydrogenase complex (OGDHc), the enzyme for succinyl-CoA synthesis, which in turn reduced FOXP3 succinylation and made FOXP3 lysine residues available for ubiquitination and FOXP3 protein degradation. Genetic deletion of Dlst, a member of OGDHc, in Treg cells led to reduced expression of FOXP3, impaired Treg cells function and severe gut inflammation. Restoring FOXP3 expression fully rescued the immune suppressive functions of Dlst-deficient Treg cells. In individuals with IBD, FOXP3 and OGDHc levels were reduced in Treg cells and negatively correlated with succinate levels and inflammation severity. This study identifies succinate as a pathogenic factor in IBD, uncovering a succinate-driven molecular switch that regulates FOXP3 stability and Treg cells function during inflammation.

DOI: https://doi.org/10.1038/s41590-025-02166-y
Adv Mater. 2025 Jun 04. e2502940

Spatiotemporal Charging Single-Atom Nanozymes Activated Pyroptosis for Antitumor Immunotherapy via Bioorthogonal Disruption of Succination and Reinvigorating T Lymphocytes.

Rui Niu, Bin Zhang, Yang Liu, Bo Xu, Ruiping Deng, Shuyan Song, Kai Liu, Yinghui Wang, Hongjie Zhang.

  Pyroptosis can trigger strong immunogenic cell death (ICD) of tumor cells for antitumor immunotherapy. However, metabolic disorders of fumarate in the tumor microenvironment (TME) can significantly reduce the pyroptosis rate and render T lymphocytes dysfunctional. Here, the ultrasound (US)-driven piezoelectric charges assisted Fe-based SAzyme (BFTM) with co-loaded triphenylphosphonium (TPP) and methyl (Z)-4-(chloro(2-phenylhydrazono)methyl)benzoate (MMB, a bioorthogonal reagent of fumarate) for activating pyroptosis and regulating fumarate metabolism is developed. Positive and negative charges generated by barium titanate (BTO) regulate the electron cloud density of single-Fe atom, endowing the BFTM with efficient reactive oxygen species (ROS) production ability for triggering caspase-1 related gasdermin D (GSDMD) mediated pyroptosis. Meanwhile, the consumption of intracellular fumarate through bioorthogonal reaction not only prevented the succinate of cysteines in GSDMD, causing it to be activated and oligomerized by caspase-1 to enhance pyroptosis but also restored the phosphorylation of ZAP70 to normalize the T cell receptor (TCR) signaling pathways for reinvigorating CD8+ T cells. In short, US-driven BFTM as a pyroptosis initiator and metabolism immune activator significantly enhances antitumor immunotherapy effects via ROS storms, fumarate depletion, triggering pyroptosis, and reinvigorating T lymphocytes.

Keywords:  antitumor immunotherapy; fumarate metabolism; pyroptosis; reactive oxygen species; single‐atom nanozyme

DOI:  https://doi.org/10.1002/adma.202502940
iScience. 2025 Apr 18. 28(4): 112052

Elimination of intra-hepatocytic malaria parasites is driven by non-canonical autophagy but not nitric oxide production.

Antonino Schepis, Jonas E Mertens, Patrick Lewis, Hardik Patel, Noah Stegman, Laura Reynolds, Nana K Minkah, Stefan H I Kappe.

  Elimination of the malaria parasite intra-hepatocytic liver stages (LS) by innate and adaptive immune cells requires interferon gamma (IFN-γ). The current view in the field posits that IFN-γ-mediated elimination of LS is executed by the induction of intra-hepatocytic nitric oxide (NO). Here, we refute this view and instead show that IFN-γ-driven induction of non-canonical autophagy via gamma-aminobutyric acid receptor-associated proteins (GABARAPs) has a critical functional role in IFN-γ-mediated elimination of LS. Furthermore, mediators of lysosomal maturation and fusion also have important functions in this process. Recruitment of GABARAPs to the LS parasitophorous vacuole (PV) compartment likely promotes the fusion of the PV membrane with lysosomes, thereby leading to elimination of intra-hepatocytic parasites. In contrast, LC3 has an infection-supportive function by protecting LS from GABARAP-mediated elimination. We also found an important role of the reactive oxygen species (ROS)-inducing protein NOX2, indicating a two-pronged host response drives LS elimination.

Keywords:  Cell biology; Microbiology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112052