bims-imicid 2025-03-30 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–03–30
24 papers selected by
Dylan Ryan, University of Cambridge

Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research.
Metabolic control of microglia in health and disease.
Toll-like Receptor Activation Remodels the Polyamine and Tryptophan Metabolism in Porcine Macrophages.
Dual faces of itaconate and its derivatives: exploring diverse biological functions in immunity and infectious diseases.
Metabolic Adaptations Driving Innate Immune Memory: Mechanisms and Therapeutic Implications.
Enterovirus A71-induced glycolysis is essential for viral replication by activating PI3K/Akt pathway.
Itaconate: A Nexus Metabolite Fueling Leishmania Survival Through Lipid Metabolism Modulation.
The influence of fatty acid metabolism on T cell function in lung cancer.
Effect of Free Long-Chain Fatty Acids on Anagen Induction: Metabolic or Inflammatory Aspect?
The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function.
DHODH inhibition alters T cell metabolism limiting acute graft-versus-host disease while retaining graft-versus-leukemia response.
SIRT7 regulates T-cell antitumor immunity through modulation BCAA and fatty acid metabolism.
Metabolic Reprogramming in Response to Freund's Adjuvants: Insights from Serum Metabolomics.
SLC3A2-Mediated Lysine Uptake by Cancer Cells Restricts T cell Activity in Hepatocellular Carcinoma.
New insights into T cell metabolism in liver cancer: from mechanism to therapy.
Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice.
Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease.
Burning lactic acid: a road to revitalizing antitumor immunity.
Insights into the roles of macrophages in Klebsiella pneumoniae infections: a comprehensive review.
Arginine as host directed therapy in tuberculosis: insights from modulating arginine metabolism by supplementation and arginase inhibition.
Intestinal IL-25 prevents high-fat diet-induced obesity by modulating the cholesterol transporter NPC1L1 expression in the intestinal epithelial cells.
Metabolic profiling in experimental guinea pig models of bacterial and allergic inflammation.
Bilirubin metabolism in the liver orchestrates antiviral innate immunity in the body.
Pentose phosphate pathway metabolite restores T cell balance in SLE.

Mol Neurodegener. 2025 Mar 27. 20(1): 37

Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research.

Eun Sun Jung, Hayoung Choi, Inhee Mook-Jung.

  Alzheimer's disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play a central role. These immune cells undergo metabolic reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, and HIF-1α orchestrating these processes. Microglial metabolism adapts to environmental stimuli, shifting between oxidative phosphorylation and glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts as an energy sensor, coordinating lipid and glucose metabolism. TREM2 and APOE regulate microglial lipid homeostasis, influencing Aβ clearance and immune responses. LPL and ABCA7, both associated with AD risk, modulate lipid processing and cholesterol transport, linking lipid metabolism to neurodegeneration. PPARG further supports lipid metabolism by regulating microglial inflammatory responses. Amino acid metabolism also contributes to microglial function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked to AD pathology. Additionally, glucose-6-phosphate dehydrogenase regulates the pentose phosphate pathway, maintaining redox balance and immune activation. Dysregulated glucose and lipid metabolism, influenced by genetic variants such as APOE4, impair microglial responses and exacerbate AD progression. Recent findings highlight the interplay between metabolic regulators like REV-ERBα, which modulates lipid metabolism and inflammation, and Syk, which influences immune responses and Aβ clearance. These insights offer promising therapeutic targets, including strategies aimed at HIF-1α modulation, which could restore microglial function depending on disease stage. By integrating metabolic, immune, and genetic factors, this review underscores the importance of microglial immunometabolism in AD. Targeting key metabolic pathways could provide novel therapeutic strategies for mitigating neuroinflammation and restoring microglial function, ultimately paving the way for innovative treatments in neurodegenerative diseases.

Keywords:  APOE; Aβ; HIF; Hexokinase; Immunometabolism; Metabolic reprogramming; Microglia; Neuroinflammation; TREM2; Tau

DOI:  https://doi.org/10.1186/s13024-025-00825-0
Handb Clin Neurol. 2025 ;pii: B978-0-443-19104-6.00009-7. [Epub ahead of print]209 143-159

Metabolic control of microglia in health and disease.

Gloria Colombo, Katia Monsorno, Rosa C Paolicelli.

  Metabolic states within cells are tightly linked to functional outcomes and finely regulated by nutrient availability. A growing body of the literature supports the idea that various metabolites can influence cellular functions, such as cell differentiation, migration, and proliferation in different contexts, with ample evidence coming from the immune system. Additionally, certain functional programs can trigger significant metabolic changes within cells, which are crucial not only to meet high energy demands, but also to produce intermediate metabolites necessary to support specific tasks. Microglia, the resident innate immune cells of the central nervous system, are constantly active, surveying the brain parenchyma and providing support to neighboring cells in the brain. They exhibit high metabolic flexibility, capable of quickly undergoing metabolic reprogramming based on nutrient availability and functional requirements. In this chapter, we will discuss the major metabolic pathways within cells and provide examples of how relevant enzymes and metabolites can impact microglial function in physiologic and pathologic contexts.

Keywords:  Amino acids; CNS; Fatty acids; Glucose; Glycolysis; Immune function; Immunometabolism; Metabolism; Microglia; OXPHOS; TCA cycle

DOI:  https://doi.org/10.1016/B978-0-443-19104-6.00009-7
Metabolites. 2025 Mar 01. pii: 162. [Epub ahead of print]15(3):

Toll-like Receptor Activation Remodels the Polyamine and Tryptophan Metabolism in Porcine Macrophages.

Meimei Zhang, Lingfei Du, Yinhao Shen, Peng Bin.

  Background: The early nutritional metabolism of piglets is intimately associated with the regulation of immune function, and amino acids play a crucial role in modulating the fate and function of porcine immune cells, especially macrophages. However, the metabolic changes upon macrophage activation remain elusive. Methods: We established an in vitro activation model of porcine macrophages and investigated alterations in metabolites involved in polyamine and tryptophan metabolism upon activation by various toll-like receptor (TLR) activators. Results: TLR activation inhibits the production of spermine and alters the kynurenine pathway of the tryptophan metabolism toward the kynurenic acid biosynthesis. Specifically, TLR9 activation redirects the metabolic pathway of tryptophan toward kynurenic acid synthesis, which subsequently inhibits melatonin production via the protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP)/cAMP-responsive element-binding protein (CREB) signaling pathways. Conclusions: TLR activation reprograms the polyamine and tryptophan metabolism in porcine macrophages. Knowledge of the metabolic alterations in polyamine and tryptophan upon TLR activation in macrophages offers valuable insights and potential strategies for nutritional intervention to enhance piglet immunity.

Keywords:  Macrophage; TLRs; polyamine; tryptophan

DOI:  https://doi.org/10.3390/metabo15030162
Hum Mol Genet. 2025 Mar 26. pii: ddae177. [Epub ahead of print]

Dual faces of itaconate and its derivatives: exploring diverse biological functions in immunity and infectious diseases.

Cecilie Poulsen, Dominic G Roy, David Olagnier.

  The intersection of immunology and infectious diseases has been revolutionized by the emergence of immunometabolism, highlighting the critical role of metabolic processes in regulating immune responses. In recent years, itaconate alongside its derivatives dimethyl-itaconate (DMI) and 4-octyl-itaconate (4-OI), have received attention for their potent immunomodulatory and antimicrobial properties. This review examines the unique roles of itaconate and its derivatives in modulating immune functions and their implications in infectious diseases. We also explore their structural and functional discrepancies. Notably, while itaconate generally exhibits anti-inflammatory and antimicrobial effects, its derivatives may operate through distinct mechanisms, often exhibiting enhanced electrophilic properties. This review of recent research underscores the potential of itaconate and its derivatives as therapeutic agents, paving the way for future clinical applications in managing inflammation and infectious diseases.

Keywords:  antimicrobial activity; immunometabolism; inflammation; itaconate; itaconate derivatives

DOI:  https://doi.org/10.1093/hmg/ddae177
J Leukoc Biol. 2025 Mar 26. pii: qiaf037. [Epub ahead of print]

Metabolic Adaptations Driving Innate Immune Memory: Mechanisms and Therapeutic Implications.

Dan Hao, Margaret A McBride, Julia K Bohannon, Antonio Hernandez, Benjamin Klein, David L Williams, Edward R Sherwood.

  Immune memory is a hallmark of the adaptive immune system. However, recent research reveals that innate immune cells also retain memory of prior pathogen exposure that prompts enhanced responses to subsequent infections. This phenomenon is termed "innate immune memory" or "trained immunity." Notably, remodeling of cellular metabolism, which closely links to epigenetic reprogramming, is a prominent feature of innate immune memory. Adaptations in glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), glutaminolysis, and lipid synthesis pathways are critical for establishing innate immune memory. This review provides an overview of the current understanding of how metabolic adaptations drive innate immune memory. This understanding is fundamental to understanding innate immune system functions and advancing therapies against infectious diseases.

Keywords:  Innate immune memory; immune therapy; metabolism; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiaf037
Microb Pathog. 2025 Mar 22. pii: S0882-4010(25)00230-X. [Epub ahead of print]203 107505

Enterovirus A71-induced glycolysis is essential for viral replication by activating PI3K/Akt pathway.

Dan Li, Jing Yang, Yi Shen, Meng Su, Wenyi Ma, Wenping Guo, Jiangli Wang, Xiaohui Zou, Guangcheng Xie.

  Enterovirus A71 (EV-A71), an obligate intracellular acellular microbe, depends entirely on host cellular metabolism to accomplish viral replication. Glycolysis is a glucose metabolic pathway that generates adenosine triphosphate (ATP) and other intermediates that activate other metabolic pathways. However, the role of glycolysis in EV-A71 replication remains unknown. In this study, we systematically investigated the role and regulation of glycolysis in human tonsillar epithelial cells (HTECs) during EV-A71 infection. Concentration of glucose was decreased, the glucose-6-phosphate (G6P) level and lactate production were increased with upregulating the glucose transporter1 (Glut1) expression in EV-A71-infected HTECs. Moreover, cellular metabolism, including glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and cellular respiration were activated. PI3K/Akt pathway was also activated by EV-A71. Concentration of glucose was significantly increased but concentrations of G6P and lactate were significantly decreased along with decreased Glut1 protein level, and EV-A71 replication was also significantly suppressed when the glycolysis was inhibited by 2-deoxy-D-glucose (2DG) and sodium oxamate (Oxamate) treatments. A time-of-addition assay revealed that glycolysis regulated EV-A71 replication at the early (attachment/entry) and late (release) stages of the EV-A71 life cycle. Addition of glucose or lactate experiments showed too low or too high concentrations of glucose and excessive lactate impaired EV-A71 replication by decreasing Glut1 expression to inhibit glycolysis. Inhibition of oxidative phosphorylation (OXPHOS) also decreased EV-A71 replication. Finally, PI3K/Akt pathway inhibition severely reduced EV-A71 replication and G6P production. Therefore, these findings indicate that EV-A71 alters the host cellular metabolism to facilitate viral replication by exploiting glycolysis via the PI3K/Akt pathway, thereby providing a novel insight into the interaction between EV-A71 and host cells.

Keywords:  Cellular metabolism; Enterovirus A71; Glucose-6-phosphate; Glycolysis; PI3K/Akt pathway

DOI:  https://doi.org/10.1016/j.micpath.2025.107505
Microorganisms. 2025 Feb 27. pii: 531. [Epub ahead of print]13(3):

Itaconate: A Nexus Metabolite Fueling Leishmania Survival Through Lipid Metabolism Modulation.

Ayyoub Kihel, Hajar El Filaly, Dounia Darif, Aicha Assouab, Myriam Riyad, Imane Nait Irahal, Khadija Akarid.

  Leishmaniasis, caused by the Leishmania parasite, is a neglected public health issue. Leishmania mainly infects macrophages, where metabolic reprogramming shapes their plasticity (M1/M2), affecting the host's resistance or susceptibility to infection. The development of this infection is influenced by immune responses, with an excessive anti-inflammatory reaction linked to negative outcomes through the modulation of various mediators. Itaconate, produced by the Acod1 gene, is recognized for its anti-inflammatory effects, but its function in leishmaniasis is not well understood. This study aimed to investigate the potential role of itaconate in leishmaniasis. Using transcriptomic data from L. major-infected BMDMs, we assessed the expression dynamics of Il1b and Acod1 and performed pathway enrichment analysis to determine the profile of genes co-expressed with Acod1. Early Acod1 upregulation followed by later Il1b downregulation was noted, indicating a shift towards an anti-inflammatory response. Among the genes co-expressed with Acod1, Ldlr, Hadh, and Src are closely associated with lipid metabolism and the polarization of macrophages towards the M2 phenotype, thereby creating a favorable environment for the survival of Leishmania. Overall, these findings suggest that Acod1 and its co-expressed genes may affect the outcome of Leishmania infection by modulating host metabolism. Accordingly, targeting itaconate-associated pathways could provide a novel therapeutic strategy for leishmaniasis.

Keywords:  Acod1; Hadh; IL1b; Ldlr; Leishmania; M1/M2 macrophages; Src; itaconate

DOI:  https://doi.org/10.3390/microorganisms13030531
FEBS J. 2025 Mar 25.

The influence of fatty acid metabolism on T cell function in lung cancer.

Jessica Petiti, Ludovica Arpinati, Alessio Menga, Giovanna Carrà.

  The tumor microenvironment (TME) is a complex ecosystem, encompassing a variety of cellular and non-cellular elements surrounding and interacting with cancer cells, overall promoting tumor growth, immune evasion, and therapy resistance. In the context of solid tumors, factors, such as hypoxia, nutritional competition, increased stress responses, glucose demand, and PD-1 signals strongly influence metabolic alterations in the TME, highly contributing to the maintenance of a tumor-supportive and immune-suppressive milieu. Cancer cell-induced metabolic alterations partly result in an increased fatty acid (FA) metabolism within the TME, which strongly favors the recruitment of immune-suppressive M2 macrophages and myeloid-derived suppressor cells, crucial contributors to T-cell exhaustion, tumor exclusion, and decreased effector functions. The drastic pro-tumoral changes induced by the tumor metabolic rewiring result in signaling loops that support tumor progression and metastatic spreading, and negatively impact therapy efficacy. As tumor- and immune metabolism are increasingly gaining attention due to their potential therapeutic implications, we discuss the effects of altered lipid metabolism on tumor progression, immune response, and therapeutic efficacy in the context of lung cancer. In particular, we focus our analysis on the tumor-induced metabolic alterations experienced by T lymphocytes and the possible strategies to overcome immunotherapy resistance by targeting specific metabolic pathways in T cells.

Keywords:  T‐cell function; cancer metabolism; fatty acid metabolism; lung cancer

DOI:  https://doi.org/10.1111/febs.70081
Int J Mol Sci. 2025 Mar 13. pii: 2567. [Epub ahead of print]26(6):

Effect of Free Long-Chain Fatty Acids on Anagen Induction: Metabolic or Inflammatory Aspect?

Xiaowen Pan, Khava S Vishnyakova, Elina S Chermnykh, Maxim V Jasko, Alexander D Zhuravlev, Svetlana S Verkhova, Yegor S Chegodaev, Mikhail A Popov, Nikita G Nikiforov, Yegor E Yegorov.

  Hair growth is a highly complex process regulated at multiple levels, including molecular pathways, stem cell behavior, metabolic processes, and immune responses. The hair follicle exhibits metabolic compartmentalization, with some cells relying on glycolysis and others on oxidative phosphorylation. Interestingly, in mice, the onset of the anagen phase can be stimulated by locally suppressing oxidative phosphorylation in the skin. This study showed that topical application of palmitate or oleate accelerated the onset of anagen in mice, while lactate, the end product of glycolysis, delayed it. We also investigated the effects of fatty acids on cytokine production in various human cell cultures. Fatty acids did not induce a cytokine response in fibroblasts or keratinocytes but significantly affected monocytes. Specifically, palmitic acid induced the production of TNF-α, IL-8, and CCL2. Oleic acid, however, elicited almost no response. By comparing the "metabolic" and "inflammatory" hypotheses of anagen stimulation, the results of our study suggest that metabolic regulation holds significant promise for influencing hair growth.

Keywords:  free fatty acids; glycolysis; hair growth; inflammation; lactate; metabolic reprogramming

DOI:  https://doi.org/10.3390/ijms26062567
Cell Rep. 2025 Mar 21. pii: S2211-1247(25)00227-X. [Epub ahead of print]44(4): 115456

The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function.

Diogo Fonseca-Pereira, Sena Bae, Slater L Clay, Monia Michaud, Meghan H MacDonald, Jonathan N Glickman, Wendy S Garrett.

  Group 3 innate lymphoid cells (ILC3s) are tissue-resident cells that sense environmental cues, control infections, and promote tissue homeostasis at mucosal surfaces. The metabolic sensor liver kinase B1 (LKB1) integrates intracellular stress, metabolism, and mitochondrial function to promote the development and effector functions of a variety of immune cells; however, the role of LKB1 in ILC3 function was unknown. Here, we show that LKB1 is crucial for adult ILC3 homeostasis, cytokine production, and mitochondrial function. ILC3-specific LKB1 deletion resulted in a reduced number of ILC3s and interleukin-22 (IL-22) production. LKB1-deficient ILC3s had decreased survival, mitochondrial dysfunction, cytoplasmic lipid accumulation, and altered bioenergetics. Using LKB1 downstream kinase modulators, we found that LKB1 regulation of ILC3 survival and IL-22 production requires signaling through microtubule affinity-regulating kinases (MARKs). Mechanistically, LKB1 deficiency resulted in increased reactive oxygen species (ROS) production and NFAT2 and PD-1 expression. Our work reveals that metabolic regulation of enteric ILC3 function by an LKB1-dependent signaling network is crucial for intestinal immunity and tissue homeostasis.

Keywords:  CP: Immunology; CP: Metabolism; ILC3; LKB1; group 3 innate lymphoid cells; liver kinase B1; mitochondrial function

DOI:  https://doi.org/10.1016/j.celrep.2025.115456
J Immunol. 2025 Mar 22. pii: vkaf023. [Epub ahead of print]

DHODH inhibition alters T cell metabolism limiting acute graft-versus-host disease while retaining graft-versus-leukemia response.

Rathan Kumar, Kara M Braunreiter, Lotus Neidemire-Colley, Natalie Sell, Yandi Gao, Camryn Steere, Margot Weber, Dhruva Vanakeri, Eunice Choi, Hannah K Choe, Sandip Vibhute, Chad Bennett, Craig A Byersdorfer, Ola A Elgamal, Thomas E Goodwin, Erin K Hertlein, John C Byrd, Parvathi Ranganathan.

  Acute graft-versus-host disease (GVHD) is a donor T cell driven complication and the leading cause of non-relapse mortality in patients receiving an allogeneic hematopoietic cell transplantation (allo-HCT). Allogeneic donor T cells eradicate residual leukemia and prevent relapse via the graft-versus-leukemia (GVL) effect and are critical for responding against opportunistic infections post-transplant. Current regimens successful in preventing GVHD are broadly immunosuppressive and come at the cost of increased risk of relapse and/or infection. Therefore, there is an urgent need for new approaches that limit GVHD while retaining GVL responses. During GVHD, alloreactive T cells boost their energy production through oxidative phosphorylation (OXPHOS) and glycolysis, supporting heightened proliferation and pathogenicity against healthy host tissues. The enzyme dihydroorate dehydrogenase (DHODH), is essential for de novo pyrimidine biosynthesis and for maintaining mitochondrial membrane potential during OXPHOS. Having shown upregulation of DHODH messenger RNA and protein expression in activated human T cells, we evaluated DHODH inhibition, via a small molecule inhibitor HOSU-53, as a therapeutic approach for GVHD. Inhibiting DHODH significantly reduced oxidative metabolism in T cells both during and after activation, while selectively suppressing inflammatory cytokine production in de novo activated, but not previously activated, T cells. In a xenogeneic model, HOSU-53 treatment limited GVHD severity, decreased pathogenic Th1 and Th17 response, and preserved beneficial GVL effects. Altogether, we identify DHODH inhibition as an innovative treatment strategy in allo-HCT recipients to reduce GVHD severity and retain effective GVL response.

Keywords:  DHODH; GVHD; metabolism

DOI:  https://doi.org/10.1093/jimmun/vkaf023
Cell Death Differ. 2025 Mar 26.

SIRT7 regulates T-cell antitumor immunity through modulation BCAA and fatty acid metabolism.

Zuojian Hu, Yingji Chen, Jielin Lei, Ke Wang, Ziyue Pan, Lei Zhang, Xiayun Xu, Wenhui Li, Lianjun Zhang, Xue Qin, Ronghua Liu, Yiwei Chu, Chenji Wang, Hongxiu Yu.

SIRT7, one of the least studied members of the Sirtuins family, is an NAD+-dependent lysine deacetylase and desuccinylase. While previous studies using affinity enrichment and quantitative proteomics identified numerous lysine-deacetylated substrates of SIRT7, its lysine-desuccinylated substrates remain underexplored, limiting our understanding of its role in cellular homeostasis. Here, we demonstrated that SIRT7 is predominantly expressed in immune tissues, especially in adaptive immune cells, including T cells. Through proteomics, lysine succinylome, and acetylome analysis of spleen from wild-type (WT) and Sirt7-/- mice, we identified significant succinylation of proteins involved in the branched-chain amino acid (BCAA) catabolism pathway in Sirt7-/- mice. We further found that SIRT7 partially localizes to mitochondria, interacting with key enzymes of the BCAA catabolism pathway and promoting their desuccinylation. Sirt7 deficiency leads to enhanced BCAA catabolism, accumulation of acyl-CoA, and increased fatty acid (FA) synthesis. As T cells rely heavily on amino acid metabolism for activation, differentiation, and function, we investigated the impact of SIRT7 using a T cell-specific Sirt7 knockout mouse model (Sirt7fl/flCd4-Cre). Our results show that SIRT7 is crucial for T cell proliferation, activation, and antitumor function. Sirt7 deficiency in T cells results in the accumulation of BCAA metabolites and FAs, reduced cytotoxic cytokines secretion such as IFN-γ, and T cell exhaustion. Reducing BCAA levels with BT2, a BCKDK inhibitor, or BCAA-free treatment alleviated these effects, while FA treatment exacerbates them. Overall, our findings identify SIRT7 as a critical regulator linking BCAA and FA metabolism to T cell antitumor immunity, providing new insights into its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41418-025-01490-y
Microorganisms. 2025 Feb 22. pii: 492. [Epub ahead of print]13(3):

Metabolic Reprogramming in Response to Freund's Adjuvants: Insights from Serum Metabolomics.

Kiruthiga Mone, Eloy Jose Torres Garcia, Fatema Abdullatif, Mahima T Rasquinha, Meghna Sur, Mostafa Hanafy, Denise K Zinniel, Shraddha Singh, Raymond Thomas, Raul G Barletta, Teklab Gebregiworgis, Jay Reddy.

  Freund's adjuvants have been used in vaccine and autoimmune settings, and their effects can be overlapping or unique to each. While both incomplete Freund's adjuvants (IFA) and complete Freund's adjuvants (CFA) influence antibody and T cell responses, the robust T helper 1 cytokines induced by the mycobacterial components make CFA the powerful immunostimulating adjuvant. In these studies, the adjuvant effects are investigated in a select population of cells, and the changes, if any, with the metabolic alterations in the systemic compartment are unclear. We investigated whether the effects of IFA and CFA can be influenced by the metabolic shifts in mice immunized with saline, IFA, or CFA using Mycobacterium tuberculosis var. bovis Bacillus Calmette-Guérin (BCG) as a positive control. After seven days of immunization, we analyzed the serum metabolite profiles using liquid chromatography coupled with high-resolution mass spectrometry and multivariate statistical analysis to identify metabolic features between the groups. The data revealed that, in the scores space, the CFA and BCG groups were more closely aligned compared to the saline group, while the IFA group displayed an intermediate profile. Furthermore, comparisons between the CFA and BCG groups showed more significant perturbations in lipid and amino acid metabolism, particularly involving glycerophospholipids, cysteine, and aromatic amino acids. In contrast, comparisons between the BCG and IFA groups indicated a more pronounced disruption in central energy metabolism pathways, such as the citric acid cycle and pyruvate metabolism. Together, the data suggest that the serum metabolite profiles in response to IFA and CFA might play a role in modulating the immune responses.

Keywords:  adjuvants; biomarkers; immune regulation; immune response; immunometabolism; metabolites

DOI:  https://doi.org/10.3390/microorganisms13030492
Cancer Res. 2025 Mar 24.

SLC3A2-Mediated Lysine Uptake by Cancer Cells Restricts T cell Activity in Hepatocellular Carcinoma.

Yating Chang, Naizhen Wang, Shaopeng Li, Jiaqi Zhang, Yipeng Rao, Zilong Xu, Lu Li, Hongning Wu, Jun Chen, Yanhua Lin, Xiaoxuan Huang, Pingguo Liu, Jun Zhang, Yueting Liao, Chaolong Lin, Chenghao Huang, Ningshao Xia.

Abnormal amino acid metabolism supports cancer cell proliferation, invasion, and immune evasion in hepatocellular carcinoma (HCC). Previous research exploring amino acid metabolism in HCC has primarily focused on how metabolic reprogramming impacts tumor cells. Here, we focused on the role of amino acid metabolism dysregulation in the crosstalk between HCC and T cells. HCC cells disrupted lysine uptake in T cells, leading to impaired T cell immunity. Lysine deprivation decreased STAT3 levels in T cells, inhibiting T cell proliferation and effector function and ultimately promoting tumor progression. Mechanistically, HCC cells outcompeted T cells for lysine by expressing high levels of the lysine transporter SLC3A2. Clinically, elevated SLC3A2 expression correlated with poor survival and was linked to dysregulated T cell functional gene signatures in HCC patients. Furthermore, the multikinase inhibitor lenvatinib induced a c-Myc-SLC3A2 regulatory axis that limited the efficacy of lenvatinib treatment. Lysine supplementation enhanced tumor sensitivity to combined treatment with lenvatinib and anti-PD-1 immunotherapy. These findings suggest that lysine supplementation is a potential therapeutic strategy for treating HCC and enhancing the sensitivity of HCC to tyrosine kinase inhibitors and immune checkpoint blockade.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3180
Cell Death Discov. 2025 Mar 23. 11(1): 118

New insights into T cell metabolism in liver cancer: from mechanism to therapy.

Jie Xiao, Ting Liu, Fanxin Zeng, Jinhua Zhang.

Liver cancer is the sixth most common cancer worldwide and the third most common cause of cancer mortality. The development and progression of liver cancer and metastases is a multifaceted process involving numerous metabolic pathways. T cells have a protective role in the defense against cancer, and manipulating metabolic pathways in T cells can alter their antitumor activity. Furthermore, Liver cancer and T cell nutrition competition lead to T cell dysfunction through various molecular mechanisms. Some nanomaterials and drugs can improve T cell metabolism and promote the anti-liver cancer function of T cells. This review discusses the current literature regarding metabolic changes in liver cancer, the role of T cells in liver cancer, T cell metabolism in liver cancer, and targeted T cell metabolism therapy for liver cancer. The promise and challenges of studying target T cell metabolism for treating liver cancer are also addressed. Targeting T cell metabolism is a promising approach for treating liver cancer.

DOI: https://doi.org/10.1038/s41420-025-02397-w
Mol Metab. 2025 Mar 20. pii: S2212-8778(25)00035-3. [Epub ahead of print] 102128

Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice.

L Stilgenbauer, Q Chen, D Pungi, N James, H Jayarathne, L Koshko, S Scofield, K Zhang, M Sadagurski.

   BACKGROUND: Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive.
OBJECTIVES: To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction.
METHODS: Using novel conditional knockout mouse models (CX3CR1GFPΔIRE1 and TMEM119ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks.
RESULTS: Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression in vitro. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses.
CONCLUSIONS: Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases.

Keywords:  ER stress; Hypothalamic inflammation; Hypothalamus; Microglia; Neuroinflammation; UPR

DOI:  https://doi.org/10.1016/j.molmet.2025.102128
Metabolites. 2025 Mar 20. pii: 210. [Epub ahead of print]15(3):

Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease.

Yuechang Wang, Yonggang Zhang, Wei Wang, Yanmin Zhang, Xueqian Dong, Yang Liu.

  Tryptophan is an essential amino acid critical for human health. It plays a pivotal role in numerous physiological and biochemical processes through its metabolism. The kynurenine (KYN) pathway serves as the principal metabolic route for tryptophan, producing bioactive metabolites, including KYN, quinolinic acid, and 3-hydroxykynurenine. Numerous studies are actively investigating the relationship between tryptophan metabolism and physiological functions. These studies are highlighting the interactions among metabolites that may exert synergistic or antagonistic effects, such as neuroprotective or neurotoxic, and pro-oxidative or antioxidant activities. Minor disruptions in the homeostasis of these metabolites can result in immune dysregulation, contributing to a spectrum of diseases. These diseases include neurological disorders, mental illnesses, cardiovascular conditions, autoimmune diseases, and chronic kidney disease. Therefore, understanding the physiological roles of the KYN pathway metabolites is essential for elucidating the contribution of tryptophan metabolism to health regulation. The present review emphasizes the physiological roles of KYN pathway metabolites and their mechanisms in disease development, aiming to establish a theoretical basis for leveraging dietary nutrients to enhance human health.

Keywords:  kynurenine pathway; neurodevelopmental disorders; neurotoxicity; oxidative stress; tryptophan

DOI:  https://doi.org/10.3390/metabo15030210
Front Med. 2025 Mar 22.

Burning lactic acid: a road to revitalizing antitumor immunity.

Jingwei Ma, Liang Tang, Jingxuan Xiao, Ke Tang, Huafeng Zhang, Bo Huang.

  Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.

Keywords:  lactic acid; metabolism; tumor immunotherapy

DOI:  https://doi.org/10.1007/s11684-025-1126-6
Cell Mol Biol Lett. 2025 Mar 26. 30(1): 34

Insights into the roles of macrophages in Klebsiella pneumoniae infections: a comprehensive review.

Yangguang Li, Xuanheng Li, Wenqi Wu, Peizhao Liu, Juanhan Liu, Haiyang Jiang, Liting Deng, Chujun Ni, Xiuwen Wu, Yun Zhao, Jianan Ren.

  Klebsiella pneumoniae (KP) infections represent a significant global health challenge, characterized by severe inflammatory sequelae and escalating antimicrobial resistance. This comprehensive review elucidates the complex interplay between macrophages and KP, encompassing pathogen recognition mechanisms, macrophage activation states, cellular death pathways, and emerging immunotherapeutic strategies. We critically analyze current literature on macrophage pattern recognition receptor engagement with KP-associated molecular patterns. The review examines the spectrum of macrophage responses to KP infection, including classical M1 polarization and the newly described M(Kp) phenotype, alongside metabolic reprogramming events such as glycolytic enhancement and immune responsive gene 1 (IRG1)-itaconate upregulation. We systematically evaluate macrophage fate decisions in response to KP, including autophagy, apoptosis, pyroptosis, and necroptosis. Furthermore, we provide a critical assessment of potential future therapeutic modalities. Given the limitations of current treatment paradigms, elucidating macrophage-KP interactions is imperative. Insights gained from this analysis may inform the development of novel immunomodulatory approaches to augment conventional antimicrobial therapies, potentially transforming the clinical management of KP infections.

Keywords:   Klebsiella pneumoniae ; Cell death; Immunotherapy; Macrophage; PAMPs; PRRs

DOI:  https://doi.org/10.1186/s11658-025-00717-7
One Health Adv. 2025 ;3(1): 5

Arginine as host directed therapy in tuberculosis: insights from modulating arginine metabolism by supplementation and arginase inhibition.

Qingkui Jiang, Ranjeet Kumar, Yi Zhao, Selvakumar Subbian, Lanbo Shi.

  Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge. Arginine metabolism is central to immune responses, regulating nitric oxide (NO) production via inducible NO synthase (Nos2) and competing pathways mediated by arginases (Arg1 and Arg2). This study examines the impact of arginine supplementation and arginase inhibition during the acute phase of Mtb infection in mouse lungs, focusing on immune function, lung pathology, and mitochondrial function. Arginine supplementation enhanced Nos2 expression, promoted mitophagy, and supported angiogenesis and/or tissue repair by upregulating Vegfa. These mechanisms synergized to balance pro-inflammatory responses with tissue repair, improving immune defense while mitigating lung damage. In contrast, arginase inhibition disrupted Vegfa-mediated immune homeostasis, and impaired mitophagy, leading to exacerbated lung pathology. These findings underscore the complementary roles of Nos2 and arginase-mediated pathways in maintaining immune equilibrium during Mtb infection. Our results highlight arginine supplementation as a promising host-directed therapy for TB, capable of enhancing protective immunity and facilitating tissue repair. Conversely, caution is warranted for strategies targeting arginase due to potential adverse effects on inflammation resolution and mitochondrial quality control. Future studies should explore the long-term efficacy of arginine-based therapies and their integration with existing antibiotic regimens for optimal TB management.
Supplementary Information: The online version contains supplementary material available at 10.1186/s44280-025-00070-6.

Keywords:  Arginase; Arginine metabolsim; Cytokine network; Host directed therapy; Mitophagy; Mycobacterium tuberculosis

DOI:  https://doi.org/10.1186/s44280-025-00070-6
Sci Rep. 2025 Mar 26. 15(1): 10445

Intestinal IL-25 prevents high-fat diet-induced obesity by modulating the cholesterol transporter NPC1L1 expression in the intestinal epithelial cells.

Siranart Jeerawattanawart, Pornpimon Angkasekwinai.

  The intestine is essential for digestion and nutrient absorption, and its altered function contributes to metabolic dysregulation and obesity-induced intestinal inflammation. Intestinal immune responses have been associated with the regulation of metabolic dysfunction during obesity. Given that the epithelial cell-derived cytokine IL-25 has been demonstrated to regulate metabolic disorders, we sought to examine the role of intestinal IL-25 in modulating a high-fat diet (HFD)-induced obesity. We found that mice on a high-fat diet exhibited decreased IL-25 expression in the small intestine. Intestinal IL-25 mRNA levels displayed an inverse association with plasma triglycerides, total cholesterol, glucose levels, and the expression of the cholesterol transporter Npc1l1 in the intestine. In HFD-induced obesity, transgenic mice overexpressing IL-25 in the intestinal epithelial cells demonstrated diminished mRNA expression of intestinal genes related to glucose, cholesterol, and fat absorption, along with chylomicron production, while also systemically decreasing plasma glucose, total cholesterol, and triglyceride levels, fat accumulation, and weight gain. In vitro, IL-25 treatment of human intestinal Caco-2 cells directly decreased cholesterol uptake and downregulated the expression of NPC1L1 and its transcriptional regulator, SREBP2. These findings highlight IL-25 as a potential modulator in the intestine that regulates intestinal cholesterol absorption and systemic metabolism in obesity.

Keywords:  Cholesterol absorption; IL-25; Intestine; NPC1L1; Obesity

DOI:  https://doi.org/10.1038/s41598-025-95516-7
Metabolomics. 2025 Mar 23. 21(2): 43

Metabolic profiling in experimental guinea pig models of bacterial and allergic inflammation.

J Hanusrichterova, E Baranovicova, R Barosova, M Kolomaznik, P Mikolka, P Kosutova, D Mokra, J Mokry, A Calkovska.

   INTRODUCTION: Based on distinct triggers, bacterial and allergen-induced inflammatory reactions have different pathophysiology. Metabolomic analysis is high-throughput technique that can provide potential biomarkers to distinguish between these responses.
OBJECTIVES: In order to find out the metabolic profiles of two types of inflammation, metabolites were analysed in blood plasma and bronchoalveolar lavage fluid (BALF) of guinea pigs subjected to bacterial lipopolysaccharide (LPS) or allergen ovalbumin (OVA).
METHODS: Hydrogen-1 nuclear magnetic resonance (1H NMR) spectroscopy for metabolite analysis was performed in samples of blood plasma and BALF of guinea pigs.
RESULTS: Random forest algorithm built on combination of levels of circulating and BALF metabolites resulted in almost ideal discrimination between acute allergic and bacterial inflammation. The differences between inflammation triggered by LPS and OVA were manifested in shift in energy metabolism, metabolism of branched-chain amino acids (BCAAs)/branched-chain keto acids (BCKAs) with alterations in alanine and glutamine, which are linked with both, ammonia homeostasis as well as gluconeogenesis.
CONCLUSION: Distinct molecule nutrients are to be utilized during acute bacterial and allergic inflammatory response.

Keywords:  Allergy; Bacterial lipopolysaccharide; Inflammation; Metabolomics; Ovalbumin

DOI:  https://doi.org/10.1007/s11306-025-02239-x
Cell Rep. 2025 Mar 27. pii: S2211-1247(25)00252-9. [Epub ahead of print]44(4): 115481

Bilirubin metabolism in the liver orchestrates antiviral innate immunity in the body.

Qian Du, Wei He, Xiangjie Chen, Jin Liu, Mingcheng Guan, Yichang Chen, Meixia Chen, Yukang Yuan, Yibo Zuo, Ying Miao, Qin Wang, Haiyan Zhou, Yanli Liu, Jingting Jiang, Hui Zheng.

  Bilirubin metabolism crucially maintains normal liver function, but whether it contributes to antiviral immunity remains unknown. Here, we reveal that the liver bilirubin metabolic pathway facilitates antiviral innate immunity of the body. We discovered that viral infection upregulates uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression in the liver, which in turn stabilizes IRF3 proteins to promote type I interferon (IFN-I) production. Moreover, we found that serum unconjugated bilirubin (UCB), a unique physiological substrate of UGT1A1, can competitively inhibit the binding of IFN-I to IFN-I receptor 2 (IFNAR2), thus attenuating IFN-I-induced antiviral signaling of the body. Accordingly, effective bilirubin metabolism in the liver promotes antiviral immunity of the body by specifically employing liver UGT1A1-mediated enhancement of IFN-I production and reducing serum bilirubin-mediated inhibition of IFN-I signaling. This study uncovers the significance of bilirubin metabolism in antiviral innate immunity and demonstrates that conventional IFN-I therapy is less efficient for patients with hepatitis B virus (HBV) with high levels of bilirubin.

Keywords:  CP: Immunology; CP: Metabolism; HBV; IRF3; UGT1A1; bilirubin; innate immunity; interferon; metabolism; viral infection

DOI:  https://doi.org/10.1016/j.celrep.2025.115481
Nat Rev Rheumatol. 2025 Mar 24.

Pentose phosphate pathway metabolite restores T cell balance in SLE.

Maria Papatriantafyllou.

DOI: https://doi.org/10.1038/s41584-025-01238-5