bims-imicid 2025-06-29 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–06–29
28 papers selected by
Dylan Ryan, University of Cambridge

Metabolism and Immune Suppressive Response in Liver Cancer.
Immunometabolism in heart failure.
Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD.
The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion.
Therapeutic potential of NRF2 activating drug RTA-408 in suppressing T cell effector responses and inflammatory bowel disease.
RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation.
Methylglyoxal is an antibacterial effector produced by macrophages during infection.
Clostridium butyricum Ameliorates Atherosclerosis by Regulating Host Linoleic Acid Metabolism.
Functional characterisation of CD8+ T cells mobilised with acute supramaximal high-intensity interval exercise: implications for immune surveillance.
Virocell resource manipulation under nutrient limitation.
Recharging aged-CAR with NAD+ to boost immunotherapy.
HIV, Inflammation, and Immunometabolism: A Model of the Inflammatory Theory of Disease.
Mitochondrial Regulation of CD8⁺ T Cells: Mechanisms and Therapeutic Modulation.
Generation of Immune Modulating Small Metabolites-Metabokines-By Adult Schistosomes.
CypA inhibits respiratory syncytial virus (RSV) replication by suppressing glycolysis through the downregulation of PKM2 expression.
Itaconate and obesity-related hormones promote tumor progression - new insights on metabolic dysfunction in early-onset colon cancer.
Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.
5-Aminolevulinic Acid Phosphate as an Immune System Enhancer Along with Vaccination Against SARS-CoV-2 Virus Infection: An Open-Label, Randomized Pilot Study.
FXR inhibition functions as a checkpoint blockade of the pathogenic Tfh cell response in lupus.
Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro.
Exercise-induced metabolite Lac-Phe ameliorates colitis by inhibiting M1 macrophage polarization via the suppression of the NF-κB signaling pathway.
Metabolites as agents and targets for cancer immunotherapy.
Lysosomal zinc nanomodulation blocks macrophage pyroptosis for counteracting atherosclerosis progression.
Immunometabolic Regulation of Innate Immunity in Systemic Lupus Erythematosus.
Gut microbiome promotes succinate-induced ulcerative colitis by enhancing glycolysis through SUCNR1/NF-κB signaling pathway.
Fructose metabolism and its roles in metabolic diseases, inflammatory diseases, and cancer.
CD39 as a metabolic rheostat of immunoregulation.
FATS alleviates ulcerative colitis by inhibiting M1 macrophage polarization and aerobic glycolysis through promoting the ubiquitination-mediated degradation of HIF-1α.

Biomedicines. 2025 Jun 13. pii: 1461. [Epub ahead of print]13(6):

Metabolism and Immune Suppressive Response in Liver Cancer.

Patrizio Caini, Vinicio Carloni.

  Hepatocellular carcinoma (HCC) constitutes more than 90% of the primary tumor of the liver. Metabolic reprogramming is decisive in promoting HCC development. The new metabolic program drives the surrounding immune cells to an immune suppressive commitment, enabling tumor survival. The enhanced metabolic activity of cancer cells leads to competition for essential nutrients, depriving non-malignant cells of critical resources. Simultaneously, the accumulation of metabolic byproducts within the tumor microenvironment (TME) selectively favors innate immune responses while impairing adaptive immunity. Recent advances in cancer immunotherapy underscore the importance of targeting both immune cell function and metabolic pathways. In this context, reprogramming the metabolism of effector and regulatory immune cells represents a promising therapeutic avenue. This review focuses on a relatively underexplored aspect of liver cancer immunology, the immunosuppressive role of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) driven by metabolic alterations and how these mechanisms contribute to the suppression of effective anti-tumor immune responses.

Keywords:  epigenetics; glycolysis; hypoxia; macrophages; regulatory T cells

DOI:  https://doi.org/10.3390/biomedicines13061461
Nat Rev Cardiol. 2025 Jun 22.

Immunometabolism in heart failure.

Ioanna Andreadou, Alessandra Ghigo, Panagiota-Efstathia Nikolaou, Filip K Swirski, James T Thackeray, Gerd Heusch, Gemma Vilahur.

The interaction between inflammation and metabolism (immunometabolism) is a crucial factor in the pathophysiology of heart failure, whether the cardiac failure originates from ischaemic injury or systemic metabolic disorders, and whether it is associated with reduced or preserved ejection fraction. Ischaemia, metabolic stress and comorbidity-driven systemic inflammation attract innate and adaptive immune cells to the myocardium and induce their polarization towards pro-inflammatory or anti-inflammatory phenotypes through cell-intrinsic metabolic shifts involving oxidative phosphorylation and anaerobic glycolysis. These infiltrating immune cells modulate cardiac and systemic metabolism. The bidirectional metabolic crosstalk between immune cells and parenchymal and stromal cardiac cells contributes to adverse cardiac remodelling. In turn, ischaemic injury and deregulated metabolism stimulate bone marrow and extramedullary myelopoiesis, which increases immune cell recruitment and perpetuates a non-resolving chronic inflammatory state. Pharmacological interventions targeting metabolism have shown promise for improving outcomes in patients with heart failure, but immunomodulatory approaches face multiple challenges. Understanding the complex metabolic pathways and cell-cell interactions that regulate immunometabolism in heart failure is essential to identify new therapies that shift the balance from maladaptive to cardioprotective immune responses. In this Review, we provide a comprehensive overview of the intricate cellular and molecular mechanisms that govern immunometabolism in heart failure and discuss potential approaches to non-invasively monitor and treat patients with heart failure.

DOI: https://doi.org/10.1038/s41569-025-01165-8
J Hepatol. 2025 Jun 19. pii: S0168-8278(25)02273-1. [Epub ahead of print]

Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD.

Sebastian Deschler, Junika Pohl-Topcu, Lukas Ramsauer, Philippa Meiser, Sophia Erlacher, Robin P Schenk, H Carlo Maurer, Peng Shen, Juliane Kager, Joseph Zink, Karyna Pistrenko, Enric Redondo Monte, Julius Weber, Lena Wasmaier, Melanie Laschinger, Norbert Hüser, Fabian Geisler, Douglas Thorburn, Hanno Nieß, Gabriela M Wiedemann, Hans Zischka, Mathias Heikenwälder, Karin Kleigrewe, Carolin Mogler, Jan P Böttcher, Percy A Knolle, Roland M Schmid, Katrin Böttcher.

   BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells constitute a highly abundant innate-like T cell population in the human liver that is critical for immune surveillance of hepatic cancers but often dysfunctional in human hepatocellular carcinoma (HCC) for unclear reasons. Here, we sought to determine mechanisms that drive MAIT cells dysfunction in metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver disease predisposing patients for HCC development.
METHODS: We studied MAIT cell functionality, metabolism and anti-cancer activity directly ex vivo in patients with MASLD, as well as in co-culture models mimicking MASLD. (Single-cell) RNA sequencing was used for translation into clinical cohorts of patients with MASLD and MASLD-associated HCC.
RESULTS: We show that MAIT cells have lost their effector functions in patients with MASLD. We uncover that MAIT cell dysfunction is caused by MASLD-associated polyunsaturated fatty acids (PUFAs), which selectively accumulate in MAIT cells but not conventional CD8+ T cells or NK cells. Mechanistically, PUFAs drive MAIT cell dysfunction through intracellular formation of lipid peroxides that promote a state of 'metabolic exhaustion' characterised by compromised mitochondrial respiration and glycolysis in MAIT cells. Excessive signalling through this MASLD-PUFA-lipid peroxide axis results in MAIT cell death by ferroptosis. Interference with PUFA-induced lipid peroxide formation in MAIT cells reversed their metabolic exhaustion and prevented ferroptotic MAIT cell death, thereby restoring MAIT cell effector function and anti-cancer activity. In patients with HCC, high enrichment of the MAIT cell-PUFA gene signature linked to MAIT cell dysfunction was associated with poor survival.
CONCLUSIONS: Our findings uncover a novel immunometabolic axis that serves as a functional barrier for MAIT cell-mediated anti-cancer immunity and could be exploited for enhancement of immunotherapy. IMPACT AND IMPLICATIONS: ; This study identifies a novel immunometabolic axis by which polyunsaturated fatty acids (PUFAs) accumulating in MASLD liver tissue drive MAIT cell dysfunction through lipid peroxide-induced metabolic exhaustion and ferroptosis, thereby impairing their anti-tumour activity. These findings reveal how MASLD creates an immune-permissive environment that may facilitate HCC development and -progression. Targeting the PUFA-lipid peroxide axis could restore MAIT cell function and enhance current immunotherapeutic anti-cancer strategies.

Keywords:  HCC; MAIT cells; MASLD; ferroptosis; immunometabolism; lipid peroxidation

DOI:  https://doi.org/10.1016/j.jhep.2025.06.006
Nat Immunol. 2025 Jun 27.

The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion.

Michael S Dahabieh, Lisa M DeCamp, Brandon M Oswald, Susan M Kitchen-Goosen, Zhen Fu, Matthew Vos, Shelby E Compton, Joseph Longo, Nicole M Foy, Kelsey S Williams, Abigail E Ellis, Amy Johnson, Ibukunoluwa Sodiya, Michael Vincent, Hyoungjoo Lee, Chen Yao, Tuoqi Wu, Ryan D Sheldon, Connie M Krawczyk, Russell G Jones.

CD8+ T cell exhaustion (Tex) limits immune control of cancer, but the underlying molecular drivers are unclear. In the present study, we identified the prostaglandin I2 (prostacyclin) receptor PTGIR as a cell-intrinsic regulator of T cell exhaustion. Transcriptomic profiling of terminally exhausted (Ttex) CD8+ T cells revealed increased activation of the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response pathway. Enhancing NRF2 activity (by conditional deletion of Kelch-like ECH-associated protein 1 (KEAP1)) boosts glutathione production in CD8+ T cells but accelerates terminal exhaustion. NRF2 upregulates PTGIR expression in CD8+ T cells. Silencing PTGIR expression enhances T cell effector function (that is, interferon-γ and granzyme production) and limits Ttex cell development in chronic infection and cancer models. Mechanistically, PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of Tex cells. These findings identify PTGIR as a NRF2-dependent immune checkpoint that regulates balance between effector and exhausted CD8+ T cell states.

DOI: https://doi.org/10.1038/s41590-025-02185-9
J Immunol. 2025 Jun 16. pii: vkaf117. [Epub ahead of print]

Therapeutic potential of NRF2 activating drug RTA-408 in suppressing T cell effector responses and inflammatory bowel disease.

Debolina Dasgupta, Aprajita Tripathi, Rachel Griffard-Smith, Nandakumar Yellapu, Poojaben Dhorajiya, Kalyani Pyaram.

  RTA-408, also known as Omaveloxolone, is an FDA-approved drug for treating Friedrich's Ataxia, a neurological disorder. It is a triterpenoid compound that activates nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of cellular redox balance. In this study, we explored the impact of RTA-408 on T cells and evaluated its therapeutic potential in inflammatory bowel disease (IBD). In vitro activation of murine and human T cells in the presence of RTA-408 resulted in suppressed proliferation, reduced expression of IFN-γ, cytotoxic granules and IL-17, but enhanced frequency of Foxp3+ Treg cells. Treatment of Nrf2-deficient T cells with RTA-408 revealed that while the reduction in CD69 expression, IL-2, and IFN-γ levels is NRF2-dependent, the suppression of T cell proliferation and granzyme B/perforin expression occurs independently of NRF2. In vivo administration of RTA-408 alleviated the disease severity in DSS-induced colitis mice by decreasing colonic T cell counts and their inflammatory cytokine production. Additionally, ex vivo treatment of T cells from IBD patients with RTA-408 reduced their expansion and IL-17 expression. Transcriptomic and metabolic analyses revealed that RTA-408 reduces glycolysis and mitochondrial respiration in T cells and reprograms their metabolism towards pentose phosphate pathway and glutaminolysis. Our findings highlight the potential of RTA-408 as a modulator of T cell homeostasis, metabolism, and inflammation, supporting its repurposing for inflammatory diseases like IBD.

Keywords:  Nrf2 activating drugs; antioxidation; cytokines; immunometabolism; ulcerative colitis

DOI:  https://doi.org/10.1093/jimmun/vkaf117
Cell Metab. 2025 Jun 19. pii: S1550-4131(25)00294-3. [Epub ahead of print]

RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation.

Zezhao Chen, Xiaosong Gu, Hongbo Chen, Huijing Zhang, Jianping Liu, Xiaohua Yang, Yuping Cai, Mengmeng Zhang, Lingjie Yan, Yuanxin Yang, Bing Shan, Zheng-Jiang Zhu, Yixiao Zhang, Jinyang Gu, Daichao Xu.

  The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S-adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans-activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.

Keywords:  PRMT5; RIPK1; S-adenosylmethionine; TNF signaling; apoptosis; death domain; inflammation; methionine; methylation; one-carbon metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.05.014
Cell Host Microbe. 2025 Jun 13. pii: S1931-3128(25)00209-4. [Epub ahead of print]

Methylglyoxal is an antibacterial effector produced by macrophages during infection.

Andrea Anaya-Sanchez, Samuel B Berry, Scott Espich, Alex Zilinskas, Phuong M Tran, Carolina Agudelo, Helia Samani, K Heran Darwin, Daniel A Portnoy, Sarah A Stanley.

  Infected macrophages transition into aerobic glycolysis, a metabolic program crucial for controlling bacterial infection. However, antimicrobial mechanisms supported by aerobic glycolysis are unclear. Methylglyoxal is a highly toxic aldehyde that modifies proteins and DNA and is produced as a side product of glycolysis. We show that despite this toxicity, infected macrophages generate high levels of methylglyoxal during aerobic glycolysis while downregulating the detoxification system, including glyoxalase 1 (GLO1). Dampening methylglyoxal generation in mice resulted in enhanced survival of Listeria monocytogenes and Mycobacterium tuberculosis, whereas mice lacking Glo1 have increased methylglyoxal levels and improved infection control. Furthermore, bacteria unable to detoxify methylglyoxal (ΔgloA) exhibit attenuated virulence but are partially rescued in mice that cannot enter glycolysis and generate methylglyoxal. This loss of bacterial GloA results in up to a 1,000-fold greater genomic mutation frequency during infection. Collectively, these results suggest that methylglyoxal is an antimicrobial innate effector that defends against bacterial pathogens.

Keywords:  bacterial pathogens; glycolysis; innate immunity; methylglyoxal

DOI:  https://doi.org/10.1016/j.chom.2025.05.026
Microorganisms. 2025 May 27. pii: 1220. [Epub ahead of print]13(6):

Clostridium butyricum Ameliorates Atherosclerosis by Regulating Host Linoleic Acid Metabolism.

Chao Yin, Peizhi Fan, Xiangyu Mou, Wenjing Zhao.

  Dysbiosis of the gut microbiota is strongly implicated in atherosclerosis (AS), thus prompting microbial modulation to be explored as a therapeutic strategy. However, limited evidence exists for probiotic interventions capable of alleviating AS. Here, we focused on Clostridium butyricum (C. butyricum; CB), a probiotic known for its production of short-chain fatty acids (SCFAs). We found that administration of C. butyricum to high-fat diet (HFD)-fed Apoe deficient (Apoe-/-) mice reduced plaque area by improving blood lipid profiles, decreasing macrophage infiltration in the aortic roots, and lowering the levels of circulating pro-inflammatory monocytes and macrophages. By non-targeted serum metabolomics analysis, C. butyricum treatment significantly reduced the levels of both linoleic acid and its downstream metabolites. Collectively, these findings establish C. butyricum-mediated amelioration of AS through modulation of linoleic acid metabolism.

Keywords:  AS; Clostridium butyricum; inflammation; linoleic acid

DOI:  https://doi.org/10.3390/microorganisms13061220
Clin Transl Immunology. 2025 ;14(6): e70037

Functional characterisation of CD8+ T cells mobilised with acute supramaximal high-intensity interval exercise: implications for immune surveillance.

Anna Strömberg, Mirko Mandić, Brennan J Wadsworth, Sebastian Proschinger, Seher Alam, Lisa Mj Eriksson, Laura Barbieri, Eric Rullman, Helene Rundqvist.

   Objectives: The beneficial influence of exercise on outcomes such as infection control and cancer prevention has been attributed partly to the immune system response during physical exertion. CD8+ T cells play a crucial role in immune surveillance, and in this study, we performed an in-depth analysis of the impact of supramaximal high-intensity exercise (HIIT) on CD8+ T-cell dynamics and function, which are currently lacking in the literature.
Methods: CD8+ T cells obtained from healthy human subjects before and after 3 × 30 s of HIIT were analysed ex vivo for viability and expansion properties, metabolic function using SeaHorse, IFN-gamma release using EliSpot, phenotype using RNA-seq and flow cytometry, and cytotoxic capacity by co-culture with HEK293T cells.
Results: Exercise led to a threefold increase in CD8+ T-cell count, and CD8+ T cells obtained after exercise had a more cytotoxic profile. Post-exercise CD8+ T cells had a lower glycolytic capacity than pre-exercise cells, and incubation of pre-exercise CD8+ T cells with post-exercise serum replicated this metabolic shift, suggesting a systemic effect of exercise on CD8+ T-cell metabolism. Importantly, CD8+ T cells maintained their viability and expansion properties despite the metabolic challenges induced by exercise. Functionally, post-exercise CD8+ T cells showed increased release of IFN-gamma and an enhanced unspecific cell killing capacity as demonstrated by co-culture with the immortalised cell line HEK293T.
Conclusion: The pronounced increase in the total number of circulating CD8+ T-cells with an increased cytotoxic capacity suggests a potential improvement in immune surveillance after acute HIIT.

Keywords:  CD8+ T cells; cytotoxicity; exercise; flow cytometry; immune surveillance; metabolism

DOI:  https://doi.org/10.1002/cti2.70037
mSystems. 2025 Jun 24. e0052125

Virocell resource manipulation under nutrient limitation.

Morgan M Lindback, Cristina Howard-Varona, Jane Fudyma, Malak Tfaily, Matthew B Sullivan, Melissa B Duhaime.

  Virus-infected cells, called virocells, impact host metabolic functions, resources, and ecosystem processes, but the effects of nutrient limitation remain less well understood. Here, we leverage transcriptomic, proteomic, and endo- and exo-metabolomic data from two Pseudoalteromonas virocells independently infected by unrelated dsDNA viruses, PSA-HS2 (HS2-virocells) and PSA-HP1 (HP1-virocells), to examine how phosphate limitation affects virocell resource manipulation intra- and extracellularly. Intracellularly, we find that (i) HP1-virocells boost amino acid production toward the end of the infection cycle but deplete amino acid pools relative to HS2-virocells; (ii) both virocells dampen the production of de novo nucleotide synthesis proteins; (iii) HS2-virocells switch from de novo synthesis to recycling of phospholipids, whereas HP1-virocells decrease both activities; (iv) all cells (virocells and uninfected cells), but HP1-virocells especially, increase membrane fluidity; and (v) both virocells increase iron storage. Extracellularly, (i) polyphenols, a stress marker, increased in all cells, particularly in HP1-virocells, and (ii) only HP1-virocells showed elevated unsaturated hydrocarbons and oxygen-rich metabolites, which are likely byproducts of intracellular metabolic activity. These findings advance our understanding of how environmental conditions shape virocell activities in ecologically relevant nutrient-limited conditions and reveal distinct responses of virocells to infection by unrelated viruses.IMPORTANCEThis study addresses a knowledge gap in understanding how nutrient limitation shapes virus-infected bacterial cell (virocell) metabolism and its ecosystem footprints. Using multi-omics approaches, we examined how two different viruses (PSA-HP1 and PSA-HS2) independently infecting the same marine heterotrophic bacterium (Pseudoalteromonas) respond to phosphorus limitation. Building upon our previous work, we show how virocell metabolic reprogramming manipulates cellular resources and alters the extracellular environment. Intracellularly, while both virocells reprogram similar metabolic pathways, they manipulate key resources (nucleotides, amino acids, lipids, and iron) distinctly under nutrient limitation. Extracellularly, each virocell generates unique dissolved organic matter metabolites, with a differential expression of stress markers under phosphorus limitation, indicating environment-specific ecosystem footprints. These results provide fundamental insights into how virocell metabolic reprogramming and resource manipulation combine to produce ecosystem-scale metabolic outputs.

Keywords:  environment; microbe; multi-omics; phage; virocells

DOI:  https://doi.org/10.1128/msystems.00521-25
Trends Cancer. 2025 Jun 25. pii: S2405-8033(25)00152-9. [Epub ahead of print]

Recharging aged-CAR with NAD+ to boost immunotherapy.

Gaofeng Fan, Yuetong Wang, Ruoning Wang.

  Impaired cellular metabolism contributes to the age-related decline in T cell function, undermining the response to immunotherapy in older patients with cancer. In a recent study, Hope et al. report that a reduction in intracellular NAD+ levels compromises metabolic fitness and drives immunosenescence. Notably, restoring NAD+ levels can reverse age-related chimeric antigen receptor (CAR)-T deterioration, suggesting a promising 'metabolic immunotherapy' that widely benefits older patients with cancer.

Keywords:  CAR-T therapy; NAD(+); aging; metabolic immunotherapy

DOI:  https://doi.org/10.1016/j.trecan.2025.06.009
Viruses. 2025 Jun 11. pii: 839. [Epub ahead of print]17(6):

HIV, Inflammation, and Immunometabolism: A Model of the Inflammatory Theory of Disease.

Eman Teer, Nyasha C Mukonowenzou, M Faadiel Essop.

  Inflammation is a crucial component of the immune response essential for host defense and tissue repair. However, when the immune response becomes dysregulated, it can contribute to the pathogenesis of chronic diseases. While acute inflammation is a short-lived, protective response, chronic inflammation is sustained over time and can lead to immune dysfunction, tissue damage, and disease progression. The chronic inflammation theory of disease suggests that persistent immune activation/inflammation underlies both infectious and non-infectious conditions and serves as a unifying mechanism across distinct pathological states. In this review article, we argue that human immunodeficiency virus (HIV) infection represents a prime model for studying chronic inflammation, and that despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) exhibit persistent immune activation, systemic inflammation, and an increased risk of cardiovascular, metabolic, and neurodegenerative diseases. Here, the interplay between microbial translocation, immune dysregulation, and metabolic reprogramming fuels a state of chronic inflammation that accelerates disease progression beyond HIV itself. Key factors such as T-cell exhaustion, persistent monocyte/macrophage activation, and immunometabolic dysfunction contribute to such a sustained inflammatory state. This review explores the molecular and cellular mechanisms driving chronic inflammation in HIV infection with a focus on immunometabolism and its implications for broader inflammatory diseases. By understanding such pathways, we can identify novel therapeutic targets to mitigate inflammation-driven disease progression not only in HIV but across a spectrum of chronic inflammatory conditions.

Keywords:  HIV infection; chronic inflammation; immune activation; immunometabolism; inflammatory theory of disease; molecular mechanisms

DOI:  https://doi.org/10.3390/v17060839
Adv Sci (Weinh). 2025 Jun 23. e03095

Mitochondrial Regulation of CD8⁺ T Cells: Mechanisms and Therapeutic Modulation.

Xu Chen, Pei Lin, Ye Lu, Jiarong Zheng, Yunfan Lin, Zihao Zhou, Li Cui, Xinyuan Zhao.

  Mitochondria are integral to the regulation of CD8+ T cell function, critically influencing processes such as activation, differentiation, and long-term persistence during immune responses. Emerging evidence highlights the detrimental impact of mitochondrial dysfunction on CD8+ T cell activity, contributing to immune exhaustion and impairing both antitumor and antiviral immunity. This underscores the importance of understanding and modulating mitochondrial dynamics to optimize T cell-based immunotherapies. In this review, a comprehensive and in-depth analysis of the essential mitochondrial processes-including biogenesis, redox homeostasis, and metabolic reprogramming is provided-that govern CD8+ T cell function and are intricately linked to their therapeutic potential. The current strategies aimed at enhancing mitochondrial function in CD8+ T cells are also examined, focusing on both metabolic reprogramming and mitochondrial-targeted interventions. Despite these promising approaches, several significant challenges remain, such as achieving selective targeting, addressing mitochondrial plasticity, and mitigating off-target effects. Overcoming these obstacles will be crucial to improving the clinical efficacy and safety of mitochondrial modulation therapies. As the understanding of mitochondrial dynamics within CD8+ T cells continues to evolve, there is growing potential to leverage these insights to improve immune-based therapies across a range of diseases, including cancer and viral infections.

Keywords:  CD8⁺ T cells; T cell exhaustion; immunotherapy; metabolic reprogramming; mitochondrial dynamics

DOI:  https://doi.org/10.1002/advs.202503095
Pathogens. 2025 May 24. pii: 526. [Epub ahead of print]14(6):

Generation of Immune Modulating Small Metabolites-Metabokines-By Adult Schistosomes.

Patrick J Skelly, Akram A Da'dara.

  Schistosomes are intravascular parasitic worms that cause the debilitating tropical disease schistosomiasis, affecting >200 million people worldwide. How the worms survive within the body of immunocompetent hosts for many years is unclear. Here, using chromatography and mass spectrometry, we report on the ex vivo ability of adult Schistosoma mansoni worms to modulate the levels of 27 small molecule (often immunomodulatory) metabokines in murine plasma. Schistosomes significantly alter the relative amounts of most (16) of these molecules. Three (inosine, genistein, and glucose) are significantly decreased in the presence of the parasites. While levels of several immunomodulatory metabolites from the kynurenine pathway (kynurenine, kynurenic acid, and xanthurenic acid) remain unchanged, levels of anthranilate (an endogenous regulator of innate immunity) are significantly increased. Of particular interest are increases in levels of metabolites that are known to skew immune responses in a manner that is seen following natural schistosome infection, such as by promoting Th2 immunity (succinate), Treg generation (lactate) and M2 macrophage polarization (lactate and succinate). In addition, significant increases are also observed for 2-hydroxyglutarate, adenine, hypoxanthine, xanthine, myoinositol, betaine and N-acetylglucosamine. Each of these compounds can have immunosuppressive effects that could impact host immunological status and contribute to schistosome survival.

Keywords:  Schistosoma; blood fluke; immunomodulation; metabolomics; parasite

DOI:  https://doi.org/10.3390/pathogens14060526
J Virol. 2025 Jun 24. e0007425

CypA inhibits respiratory syncytial virus (RSV) replication by suppressing glycolysis through the downregulation of PKM2 expression.

Jing Zhang, Miao Li, Jing Cheng, Yutong Wang, Cuiqing Ma, Lizheng Yin, Jiachao Wang, Xue Gao, Wenzhang Liang, Lin Wei.

  The "Warburg effect," a type of metabolic reprogramming characterized by enhanced glycolysis even in the presence of oxygen, is frequently observed in tumor cells and has also been detected in cells infected with viruses. Our study demonstrated that respiratory syncytial virus (RSV) infection induced aerobic glycolysis both in vivo and in vitro. By utilizing the glycolysis agonist PS48 or inhibitor 2-DG, we ascertained that RSV can utilize glycolysis to promote its replication. Mechanistically, glycolysis may facilitate RSV replication by negatively regulating the IFNβ response. Additionally, we discovered a host molecule, namely CypA, that could downregulate glycolysis to combat RSV infection. CypA interacted with PKM2, a key enzyme of glycolysis, and reduced its expression. By overexpressing or knocking down CypA, we verified that CypA could inhibit aerobic glycolysis, enhance IFNβ production, and reduce RSV replication. Inhibiting the PPIase activity of CypA resulted in the disappearance of its function, indicating that CypA exerted its effects dependent on PPIase activity. Furthermore, we found that CypA has a synergistic effect with 2-DG and an antagonistic effect with PS48 on the IFNβ response, supporting the notion that CypA regulates IFNβ by inhibiting glycolysis. These results indicate that CypA may serve as a novel host factor in the regulation of glycolysis, the interferon response, and ultimately in resisting RSV infection.
IMPORTANCE: Viruses utilize the host's resources and energy to carry out essential life processes and achieve self-replication. In response, hosts have evolved a range of antagonistic mechanisms. Our study investigates how RSV employs glycolysis to benefit its replication, with a particular focus on the interaction between glycolysis and IFNβ regulation. Additionally, we explore how the host employs CypA to antagonize the virus's utilization of glycolysis, thereby inhibiting RSV replication. Our findings will contribute to the development of effective antiviral therapies targeting CypA.

Keywords:  CypA; IFNβ; PKM2; RSV; glycolysis; viral replication

DOI:  https://doi.org/10.1128/jvi.00074-25
Front Immunol. 2025 ;16 1572985

Itaconate and obesity-related hormones promote tumor progression - new insights on metabolic dysfunction in early-onset colon cancer.

Katharina M Scheurlen, Jacob Hallion, Dylan L Snook, Anne MacLeod, Robert J Beal, Mary A Parks, Andrew B Littlefield, Eliah Hiken, Adrian T Billeter, Jeannette Bensen, Jeremy T Gaskins, Julia Chariker, Eric C Rouchka, Susan Galandiuk.

   Introduction: Obesity is a strong risk factor for early-onset colon cancer (EOCC) and is associated with chronic inflammation largely mediated by macrophages. The macrophage-specific metabolite itaconate promotes growth in several types of cancer; however, its role in colon cancer (CC) is unknown. Here, we investigate a tumor promoting link between obesity-related hormones and itaconate within the NOTCH4-GATA4-IRG1 pathway in EOCC.
Methods: Patient tissue (n=20) was obtained and qRT-PCR, ELISA, and mass spectrometry were performed to evaluate IRG1 expression (Human Immune-Responsive Gene 1, encoding ACOD1), ACOD1 expression (Cis-aconitate decarboxylase 1, enzyme producing itaconate), and itaconate concentration in human CC versus EOCC. RNA sequencing data from 5 sources in the USA and Europe were obtained to perform IRG1-related differential expression analysis (n=178), IRG1-related survival analysis (n=185), and differential expression analysis and survival analysis related to genes of the NOTCH4-GATA4-IRG1 pathway (n=371). Furthermore, tumor versus normal colon was compared and the interaction of tissue with sex, age, and body mass index (BMI) was investigated. A coculture model using two CC cell lines (HT-29 and SW480) and THP-1 cell line-derived M0 and M2-like macrophages was used to evaluate NOTCH4-GATA4-IRG1 pathway-related gene expression following treatment with obesity-related hormones (leptin, adiponectin) and itaconate derivatives.
Results: Both ACOD1 and IRG1 expression were elevated in human CC tissue compared to adjacent normal colon tissue. Normal colon itaconate levels were higher in EOCC patients compared to that in older patients. Plasma itaconate levels in CC patients correlated with their BMI. Survival was decreased in IRG1-positive stage IV CC. IRG1-associated gene expression within the NOTCH4-GATA4-IRG1 pathway differed in CC versus normal colon tissue: GATA4, DLL4, VEGFA, and MAPK15 upregulation was associated with EOCC, while ABCG5 and GATA5 were downregulated in CCs and associated with higher BMI. Adiponectin and leptin treatment of macrophages cocultured with CC cells increased IRG1 expression.
Discussion: Obesity-related hormones can increase itaconate production in M2-like macrophages. IRG1 expression and the NOTCH4-GATA4-IRG1 pathway are associated with EOCC, BMI, and patient survival. As a macrophage metabolite affecting inflammation, itaconate may have a particular immunotherapeutic role in patients with EOCC.

Keywords:  early-onset colon cancer; immunology; macrophages; metabolism; obesity

DOI:  https://doi.org/10.3389/fimmu.2025.1572985
FASEB J. 2025 Jul 15. 39(13): e70774

Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.

Alice Scarpa, Yerin Jung, Arslan Hamid, Vasiliki Matzaraki, Tushar More, Alexander Heinz, Laszlo Groh, Siroon Bekkering, Karsten Hiller, Leo A B Joosten, Mihai G Netea, Katarzyna Placek, Niels P Riksen.

  Atherosclerosis is a chronic inflammatory disease of the arterial wall that causes cardiovascular disease. Monocyte-derived macrophages are an important contributor to atherogenesis. Monocytes can become primed for higher responsiveness to secondary, unrelated stimuli-a phenomenon known as trained immunity-a process driven by intracellular metabolic and epigenetic reprogramming. Oxidized low-density lipoprotein (oxLDL) induces trained immunity by enhancing glycolysis and oxidative phosphorylation (OXPHOS). Glutamine is known to enter the Krebs cycle through glutaminolysis where it can be used for ATP synthesis via OXPHOS. We therefore explored the role of the glutaminolysis pathway in oxLDL-induced trained immunity. Primary human monocytes from healthy donors were exposed to oxLDL for 24 h, followed by differentiation into macrophages over 6 days in culture medium. Thereafter, cytokine production capacity was assessed by stimulating them with Toll-like receptor agonist. Co-administration of the glutaminase inhibitor CB-839 during oxLDL exposure reduces glutamine anaplerosis. This prevented oxLDL-induced trained immunity, with diminished cytokine production capacity, associated with a reduced oxygen consumption rate (OCR), and glycolysis rate (ECAR). The role of glutaminolysis for induction of trained immunity was validated genetically, by showing significant associations between several single-nucleotide polymorphisms in genes related to glutaminolysis and ex vivo cytokine production in oxLDL-trained monocytes from 243 healthy volunteers. Finally, we identified a positive correlation between glutamate and Krebs cycle metabolites with inflammatory circulating biomarkers and monocyte counts in an independent cohort of 302 obese individuals. Altogether, these data suggest a crucial role of glutaminolysis in the establishment of oxLDL-induced trained immunity.

Keywords:  Krebs cycle; atherosclerosis; glutamine; glutaminolysis; oxLDL; trained immunity

DOI:  https://doi.org/10.1096/fj.202500802R
Life (Basel). 2025 Jun 13. pii: 953. [Epub ahead of print]15(6):

5-Aminolevulinic Acid Phosphate as an Immune System Enhancer Along with Vaccination Against SARS-CoV-2 Virus Infection: An Open-Label, Randomized Pilot Study.

Norbert Berenzen, Riyadh Rehani, Andrea Ebeling, Marcus Stocker, Motowo Nakajima.

  Previous studies have shown that 5-aminolevulinic acid phosphate together with sodium ferrous citrate, which is marketed as a food supplement, appears to be an important metabolic regulator in depleted T cell metabolism. Therefore, it was hypothesized that its administration in subjects vaccinated against COVID-19 could enhance their immune system. Therefore, the aim of our proof-of-concept study was to determine the safety (by adverse events monitoring) and the tolerability (by subject questionnaires) and to investigate immune-boosting properties (by Immunoglobulins) in which 200 subjects were randomized in a ratio of 1:1 within 2 arms. In the intervention arm, the study product was administered together with the vaccines Covishield or Covaxin, and up to 21 days thereafter with a 150 mg daily dose, whereas in the control arm, the subjects were vaccinated only. No safety issues were detected, and the evaluation of the subject questionnaires showed no limitation of the well-being, which confirms the excellent tolerability of 5-aminolevulinic acid phosphate with sodium ferrous citrate. Moreover, the 'Change in Immunoglobulin G levels', although statistically insignificant, showed strong signals of its immune supportive potential. However, further studies are recommended to verify the results.

Keywords:  5-ALA; 5-aminolevulinic acid; COVID-19; IgG; SARS-CoV-2; immune booster; vaccine

DOI:  https://doi.org/10.3390/life15060953
Cell Mol Immunol. 2025 Jun 25.

FXR inhibition functions as a checkpoint blockade of the pathogenic Tfh cell response in lupus.

Xiangyang Wang, Linsen Ye, Shanshan Liu, Yuhao Zheng, Lisi Zhu, Wenqian Huang, Jiawei Song, Jingxuan Shao, Fan Wu, Chunmin Zhang, Xiaomin Li, Shan Zeng, Youjun Xiao, Xiangyu Chen, Shunjun Fu, Lilin Ye, Jie Zhou, Yingjiao Cao.

  T follicular helper (Tfh) cells specialize in facilitating germinal center B-cell activation and high-affinity antibody generation, which are crucial in humoral immune responses. However, aberrant control of Tfh cells also contributes to the generation of self-reactive autoantibodies and promotes autoimmune diseases such as systemic lupus erythematosus (SLE). The mechanisms that control proper Tfh expansion remain unclear. Here, we show that farnesoid X receptor (FXR) is relatively upregulated in Tfh cells. Genetic deletion of Fxr restrains Tfh expansion both at steady state and in pristane-induced lupus. As a consequence of these defects, mice lacking Fxr manifested GC dysfunction and decreased plasma cell and autoantibody production, which alleviated nephritis progression in pristane-induced lupus. Mechanistically, FXR intrinsically regulates cholesterol homeostasis in Tfh cells, which subsequently controls Tfh cell proliferation. Preclinical treatment of wild-type (WT) mice with the clinically approved drug ursodeoxycholic acid (UDCA) to reduce FXR signaling mitigated lupus disease progression by repressing Tfh expansion, the GC reaction and autoantibody production. These findings provide a rationale for exploring FXR as a potential therapeutic target for SLE.

Keywords:  Cholesterol metabolism; Farnesoid X receptor (FXR); Follicular helper T cell (TFH); Systemic lupus erythematosus (SLE)

DOI:  https://doi.org/10.1038/s41423-025-01309-3
Cell Rep. 2025 Jun 25. pii: S2211-1247(25)00680-1. [Epub ahead of print]44(7): 115909

Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro.

Anna Podleśny-Drabiniok, Carmen Romero-Molina, Tulsi Patel, Wen Yi See, Yiyuan Liu, Edoardo Marcora, Alison M Goate.

  Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1 macrophages toward a transcriptional state reminiscent of disease-associated microglia and lipid-associated macrophages (LAM), collectively referred to as DLAM. Transcriptome profiling reveals gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing shows an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrate alterations in cell motility, phagocytosis, lysosomal activity, and metabolic profiles. These findings provide insights into cytokine-mediated reprogramming of macrophages toward disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.

Keywords:  Alzheimer’s disease; CP: Immunology; CP: Neuroscience; DAM; IL-4; LAM; THP-1 macrophages; disease-associated microglia; efferocytosis; lipid-associated macrophages

DOI:  https://doi.org/10.1016/j.celrep.2025.115909
Cell Mol Gastroenterol Hepatol. 2025 Jun 23. pii: S2352-345X(25)00099-2. [Epub ahead of print] 101558

Exercise-induced metabolite Lac-Phe ameliorates colitis by inhibiting M1 macrophage polarization via the suppression of the NF-κB signaling pathway.

Runfeng Yu, Chi Zhang, Ming Yuan, Shubiao Ye, Tuo Hu, Shaopeng Chen, Guanzhan Liang, Jiaqi Liu, Haoxian Ke, Junfeng Huang, Ping Lan, Xiaosheng He, Xianrui Wu.

   BACKGROUND AND AIMS: Although the anti-inflammatory benefits of exercise are well-documented, the specific mechanisms responsible for these advantages remain uncertain. N-lactoyl-phenylalanine (Lac-Phe), a major metabolite produced during exercise, is synthesized through the condensation of lactic acid and phenylalanine, catalyzed by the CNDP2. However, the potential anti-inflammatory properties of Lac-Phe remain poorly understood. This study aimed to investigate the anti-inflammatory effects of Lac-Phe in the context of inflammatory bowel disease (IBD) and to examine the underlying mechanisms.
METHODS: The levels of Lac-Phe were measured in both IBD patients and mice utilizing ELISA kits. The anti-inflammatory effects of Lac-Phe were demonstrated through colitis models. The impacts of Lac-Phe on macrophage polarization and the associated mechanisms were determined by flow cytometry, qPCR, RNA sequencing, Western blotting, and immunofluorescence.
RESULTS: Our study revealed a reduction in plasma Lac-Phe content in IBD patients, in conjunction with a decrease in the expression of CNDP2 in the colon, which exhibited a negative correlation with disease activity scores. Exercise mitigated DSS-induced colitis in mice by elevating plasma Lac-Phe levels and inhibiting the polarization of M1 macrophages. Mechanistically, Lac-Phe impedes the movement of p65 protein from the cytoplasm into the nucleus, consequently suppressing the activation of the NF-κB signaling pathway and macrophage M1 polarization. Furthermore, the supplementation of phenylalanine, a substrate of Lac-Phe, was observed to enhance the generation of Lac-Phe and to exert a protective effect in the murine colitis model.
CONCLUSION: Our results suggest that exercise can induce the production of Lac-Phe, which plays a preventive role against DSS-induced colitis in mice. Lac-Phe mitigates colitis through inhibition of the polarization of M1 macrophage. Adjusting macrophage polarization with Lac-Phe and phenylalanine supplementation may offer a potential therapeutic strategy for managing IBD.

Keywords:  Lac-Phe; exercise; inflammatory bowel disease; macrophage polarization

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101558
Nat Rev Drug Discov. 2025 Jun 26.

Metabolites as agents and targets for cancer immunotherapy.

Marcel P Trefny, Guido Kroemer, Laurence Zitvogel, Sebastian Kobold.

The depletion or accumulation of metabolites in the tumour microenvironment is one of the hallmarks of cancer, but targeting cancer cell metabolism therapeutically must also take into account the impact on metabolic pathways in immune cells. As we understand more about immunometabolism, opportunities arise for synergies between agents that modulate metabolism and immunotherapy. In this Review, we discuss the pivotal role of metabolic pathways in both cancer and immune cells in shaping the tumour microenvironment. We survey major anabolic and catabolic pathways and discuss how metabolic modulators and dietary nutrients can improve the anticancer immune response and overcome drug resistance mechanisms. Agents in the clinic include inhibitors of the adenosine and tryptophan pathways, and we discuss opportunities and challenges for successful drug development in the context of immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapies.

DOI: https://doi.org/10.1038/s41573-025-01227-z
Sci Adv. 2025 Jun 27. 11(26): eadu3919

Lysosomal zinc nanomodulation blocks macrophage pyroptosis for counteracting atherosclerosis progression.

Ruizhi Hu, Junchang Qin, Wei Feng, Xinran Song, Hui Huang, Chen Dai, Bo Zhang, Yu Chen.

Macrophage pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn2+ features the strongest anti-inflammatory performance by screening 10 representative metal ions, and the MTC1 agonists can trigger lysosomal Zn2+ release and inhibit pyroptosis in macrophages. Based on these findings, we further engineered a mucolipin TRP channel 1 (MTC1)-related therapeutic nanoplatform for endogenously triggering lysosomal zinc release to curb inflammation and block macrophage pyroptosis. This nanoplatform consists of mesoporous silica nanoparticles to deliver MTC1 agonists and carbon nanodots, which could synergistically exert antiatherosclerotic effect by scavenging toxic reactive oxygen species, inhibiting macrophage pyroptosis, modulating macrophage transition, and rebuilding atherosclerotic immune microenvironment. These findings demonstrate that macrophage pyroptosis can be efficiently blocked via leveraging self-lysosomal zinc pool, which provides the paradigm of lysosomal zinc modulation-involved nanotherapeutics for managing other inflammatory diseases.

DOI: https://doi.org/10.1126/sciadv.adu3919
Acta Med Okayama. 2025 Jun;79(3): 147-155

Immunometabolic Regulation of Innate Immunity in Systemic Lupus Erythematosus.

Haruki Watanabe, Yoshinori Matsumoto, Jun Wada.

  Pathogens or their components can induce long-lasting changes in the behavior of innate immune cells, a process analogous to "training" for future threats or environmental adaptation. However, such training can sometimes have unintended consequences, such as the development of autoimmunity. Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease characterized by the production of autoantibodies and progressive organ damage. Innate immunity plays a central role in its pathogenesis, contributing through impaired clearance of apoptotic cells, excessive type I interferon production, and dysregulated formation of neutrophil extracellular traps. Recent studies have revealed that metabolites and nucleic acids derived from mitochondria, a crucial energy production site, directly regulate type I interferon and anti-inflammatory cytokine production. These insights have fueled interest in targeting metabolic pathways as a novel therapeutic approach for SLE, offering promise for improving long-term patient outcomes.

Keywords:  innate immune memory; interferon; systemic lupus erythematosus; trained immunity; tricarboxylic acid cycle

DOI:  https://doi.org/10.18926/AMO/68722
Am J Physiol Cell Physiol. 2025 Jun 23.

Gut microbiome promotes succinate-induced ulcerative colitis by enhancing glycolysis through SUCNR1/NF-κB signaling pathway.

Long Huo, Qian Chen, Sailei Jia, Yuli Zhang, Lihui Wang, Xian Li, Zan Li, Boyun Sun, Jingyi Shan, Jiang Lin, Lili Yang, Hua Sui.

  Ulcerative colitis (UC) is a chronic recurrent inflammatory disease. Previous studies demonstrate that excessive accumulation of gut microbial metabolites, especially succinate increases the risk of disease progression. However, the role of succinate and its molecular mechanism has not been explored. We investigated the effects of succinate on colonic inflammation and intestinal microbiota, and their association with succinate receptor (SUCNR1) signaling in 3% dextran sodium sulfate (DSS) induced-acute UC in C57BL/6J mice. After treatment, fecal bacteria from UC mice were evaluated by 16S rRNA sequencing. Colon tissues and cell lysates were collected and prepared for histological evaluation, immunohistochemistry, Western blotting, and inflammatory activity cytokine analysis. It was found that Phascolarctobacterium spp. (P.bacterium), which consumed succinate, significantly decreased SUCNR1 expression, relieved colonic damage, reduced cytokine levels, and restored the integrity of the intestinal epithelial barrier in UC mice. In addition, the results of flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay indicated that succinate deficiency markedly suppressed secretion of proinflammatory cytokines (e.g, interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor-α). Moreover, SUCNR1 inhibitor (NF-56-EJ40) inhibited glycolysis of intestinal epithelial cells (IECs) in the co-culture system with Th17 cells, including downregulation of oxygen consumption rate (OCR) and increased extracellular acidification rate (ECAR) reflecting overall glycolytic flux, and regulated the expression of glycolysis-related proteins, such as GLUT1, HK-II, and LDHA. Collectively, our findings indicate that microbiota consumption of succinate can ameliorate DSS-induced UC through suppressing Th17, reducing IECs glycolysis, lowing the secretion of proinflammatory cytokines, maintaining epithelial barrier function, and improving dysbiosis.

Keywords:  Glycolysis; Gut microbial metabolites; Succinate; Th17 signaling; Ulcerative colitis

DOI:  https://doi.org/10.1152/ajpcell.00411.2025
Mol Biomed. 2025 Jun 23. 6(1): 43

Fructose metabolism and its roles in metabolic diseases, inflammatory diseases, and cancer.

Zhenhong Li, Xinzou Fan, Fan Gao, Shengguang Pan, Xiao Ma, Hao Cheng, Hiroko Nakatsukasa, Wei Zhang, Dunfang Zhang.

  Fructose, a prevalent hexose, has become a widely used food additive, with its usage rising significantly because of socio-economic advancements and shifts in human dietary habits. Excessive fructose intake has been implicated in obesity, cardiovascular disease, metabolic syndromes, inflammation, and cancer, among other disorders. This review discusses the absorption, distribution, and metabolism of fructose and the links between fructose metabolism and major metabolic pathways. The role of fructose in metabolic diseases, including metabolic dysfunction-associated fatty liver disease, hyperinsulinemia, and hyperuricemia, is also highlighted. Furthermore, the role of fructose in the development of chronic inflammation, including gut inflammation, liver inflammation, and neuroinflammation, is discussed. Lastly, in the context of cancer development, this review summarizes the dual role of fructose in tumors, both pro- and anti-tumor effects. Future studies on the role of fructose in cancer should focus on the complexity of physiological and pathological conditions, such as the specific tumor microenvironment and metabolic status. Fructose has been shown to induce metabolic reprogramming of multiple immune cells and increase pro-inflammatory immune responses; therefore, inhibiting or promoting its metabolism may regulate immune responses. And targeting fructose metabolism may be a promising approach to treating metabolic diseases, inflammation, and cancer.

Keywords:  Fructose; Fructose metabolism; Glycolysis; Inflammation; Tumor metabolism

DOI:  https://doi.org/10.1186/s43556-025-00287-2
Cell Mol Immunol. 2025 Jun 24.

CD39 as a metabolic rheostat of immunoregulation.

Vincenzo Barnaba, Silvano Sozzani.

DOI: https://doi.org/10.1038/s41423-025-01302-w
Biochem Pharmacol. 2025 Jun 19. pii: S0006-2952(25)00318-1. [Epub ahead of print] 117053

FATS alleviates ulcerative colitis by inhibiting M1 macrophage polarization and aerobic glycolysis through promoting the ubiquitination-mediated degradation of HIF-1α.

Yingdi Han, Jing Xun, Tian Li, Xiaolin Jiang, Bin Liu, Zhibo Hu, Huichao Yang, Qi Gao, Zhao Wu, Xueliang Wu, Aimin Zhang, Ximo Wang, Zhiyu Guan, Xiangyang Yu, Qi Zhang.

  Ulcerative colitis (UC) represents a challenging disorder characterized by a multifaceted pathogenesis. Macrophages, the predominant immune cell population in the intestinal milieu of individuals with UC, play a pivotal role in sustaining intestinal homeostasis. Common fragile sites (CFSs) are evolutionarily preserved genomic segments that exhibit a propensity for breakage and are present in all human beings. FATS (fragile site-associated tumor suppressor) is a novel CFS that functions as a tumor suppressor gene and an E3 ubiquitin ligase. But there are no studies on the regulation of inflammatory diseases by this gene. In this study, we used Fats whole-body knockout mice to construct DSS-induced UC model and elucidate the role of Fats in the progression of UC through immune regulation. We found that UC was more severe in Fats-/- mice than in WT control mice. The aggravation of UC observed in Fats-/- mice is contingent upon macrophage activity and corresponds with a phenotypic transition in colonic macrophages from an anti-inflammatory M2-like state to a pro-inflammatory M1-like state. In addition, co-IP (co-immunoprecipitation), PLA (Proximity ligation assay) and ubiquitylation experiments confirmed that Fats deficiency stabilizes the HIF-1α protein by reducing its degree of ubiquitination, which in turn heightens the expression of the transporters Glut1 and the enzymes Hk2 (hexokinase 2) and Ldha (lactate dehydrogenase) during glycolysis, thereby fostering macrophage polarization towards the M1 phenotype and exacerbating UC. Notably, inhibition of HIF-1α expression reversed the exacerbation of UC in Fats-/- mice. Collectively, these findings indicate that Fats plays a crucial role in modulating immune responses, positioning it as a potential therapeutic target in UC management.

Keywords:  Fats; Glycolysis; Macrophage; Ubiquitination; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.bcp.2025.117053