bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–06–22
39 papers selected by
Dylan Ryan, University of Cambridge
  1. Immunometabolism in systemic lupus erythematosus.
  2. Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury.
  3. Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
  4. The role of immune cells glycolysis in neuroinflammation secondary to intracerebral hemorrhage.
  5. ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.
  6. Aerobic Exercise Pretreatment Mitigates Acute Lung Injury through Metabolic Reprogramming, Anti-inflammatory Modulation, and 6-Keto-Prostaglandin F1α Regulation.
  7. LKB1 regulates ILC3 postnatal development and effector function through metabolic programming.
  8. p67phox/NOX2 inhibits psoriasis by regulating the HIF-1α-glycolysis axis via p53-AMPK in keratinocytes.
  9. Salmonella exploits host- and bacterial-derived β-alanine for replication inside host macrophages.
  10. Uncovering metabolic pathways in human alveolar macrophages in response to lipopolysaccharide.
  11. Cholesterol metabolism reprogramming in multiple myeloma: examining its specificity and impact on the immune microenvironment.
  12. NDRG1-Driven Lactate Accumulation Promotes Lung Adenocarcinoma Progression Through the Induction of an Immunosuppressive Microenvironment.
  13. Enhanced mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from young children with overweight/obesity and insulin resistance.
  14. Kupffer cell programming by maternal obesity triggers fatty liver disease.
  15. Landscape of targets within nucleoside metabolism for the modification of immune responses.
  16. SAM cycle and adenosine at the heart of immune conversations.
  17. Microglia energy metabolism: A new perspective on Alzheimer's disease treatment.
  18. Cysteine Signalling in Plant Pathogen Response.
  19. Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection.
  20. Coordinated modulation of glucose metabolism and immunity via metal-drug nanovesicles for hepatocellular carcinoma therapy.
  21. Chronic Cellular NAD Depletion Activates a Viral Infection-Like Interferon Response Through Mitochondrial DNA Leakage.
  22. Enhanced resistance to Listeria infection in mice surviving sepsis: the role of lipid metabolism and myeloid cell reprogramming.
  23. Targeting glutamine metabolism in CD4+ T-cell-mediated autoimmune diseases.
  24. The crosstalk between immune activation and metabolism in heart failure. A scientific statement of the Heart Failure Association of the ESC.
  25. Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
  26. E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1.
  27. Iron and the immune system.
  28. Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise.
  29. Fructose intake enhances lipoteichoic acid-mediated immune response in monocytes of healthy humans.
  30. Breaking the psoriasis pathological signaling cycle: A novel nanomedicine strategy targeting metabolism and oxidative stress.
  31. Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
  32. Investigation of Protein Fatty Acylation in Virus-Host Interaction.
  33. Boosting mRNA cancer vaccine efficacy via targeting Irg1 on macrophages in lymph nodes.
  34. Hexokinase-2 as a Therapeutic Target: Alleviating Herpes Simplex Keratitis Through Metabolic Reprogramming.
  35. Spermidine is a key polyamine required by intracellular parasites for survival within host erythrocytes.
  36. Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.
  37. Thyrotropin exacerbates insulin resistance by triggering macrophage inflammation in subclinical hypothyroidism.
  38. TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation.
  39. Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
  1. Nat Rev Rheumatol. 2025 Jun 16.
    Immunometabolism in systemic lupus erythematosus.
    Eduardo Patiño-Martinez, Mariana J Kaplan.
      Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by chronic inflammation, tissue damage, accelerated cardiovascular disease and the synthesis of autoantibodies that target nucleic acids and nuclear protein complexes. Emerging evidence underscores the key role of immune metabolic dysregulation in SLE, revealing how metabolic reprogramming during immune cell activation influences disease development and progression. Alterations in key metabolic pathways such as glycolysis and oxidative phosphorylation profoundly affect the activation, differentiation and function of B and T cells, monocytes, neutrophils and other immune cells, driving inflammation and tissue injury. This Review synthesizes current findings on immune cell metabolism in animal models of lupus and in patients with SLE, highlighting the interplay of metabolic disturbances, mitochondrial dysfunction and disease pathogenesis. Furthermore, it explores the potential of targeting metabolic pathways as therapeutic strategies to mitigate organ damage and improve outcomes in SLE.
    DOI:  https://doi.org/10.1038/s41584-025-01267-0
  2. Cell Metab. 2025 Jun 14. pii: S1550-4131(25)00268-2. [Epub ahead of print]
    Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury.
    Mengtian Shan, Song Zhang, Zhibing Luo, Shengjie Deng, Linyu Ran, Quan Zhou, Huimin Wan, Jihui Ye, Chenchen Qian, Ximin Fan, Yun Feng, David W Morse, Joerg Herrmann, Qiang Li, Zhongliang Guo, Feilong Wang.
      Itaconate is an anti-inflammatory metabolite with therapeutic potential in multiple inflammatory diseases. However, its immunomodulatory function has been mainly based on ex vivo-generated macrophages or cell lines, whereas its role in tissue-resident macrophages is still poorly understood. Here, we report that, in contrast to its effects on bone-marrow-derived macrophages (BMDMs), itaconate promotes the production of proinflammatory cytokines and augments the activation of the NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome in resident alveolar macrophages (AMs). Unlike native itaconate, the itaconate derivatives dimethyl itaconate (DI) and 4-octyl itaconate (4OI) suppress the inflammatory response in AMs. Notably, the intratracheal transfer of BMDMs reversed their responsiveness to itaconate, indicating an essential role of the alveolar microenvironment in shaping macrophage immunometabolism. We also demonstrate that itaconate promotes AM-mediated inflammatory responses in vivo and aggravates lung injury. Taken together, our study unexpectedly demonstrates a proinflammatory role of itaconate in tissue-resident AMs, suggesting that further investigations are needed before its clinical application.
    Keywords:  inflammatory responses; itaconate; macrophages; succinate dehydrogenase; the NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.012
  3. Nat Commun. 2025 Jun 20. 16(1): 5355
    Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
    Megan R Teh, Nancy Gudgeon, Joe N Frost, Linda V Sinclair, Alastair L Smith, Christopher L Millington, Barbara Kronsteiner, Jennie Roberts, Bryan P Marzullo, Hannah Murray, Alexandra E Preston, Victoria Stavrou, Jan Rehwinkel, Thomas A Milne, Daniel A Tennant, Susanna J Dunachie, Andrew E Armitage, Sarah Dimeloe, Hal Drakesmith.
      Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
    DOI:  https://doi.org/10.1038/s41467-025-60204-7
  4. Clin Immunol. 2025 Jun 14. pii: S1521-6616(25)00118-4. [Epub ahead of print]279 110543
    The role of immune cells glycolysis in neuroinflammation secondary to intracerebral hemorrhage.
    Baochun Luo, Sifan Liu, Lei Zheng, Baiwen Zhang, Yaxin Shang, Tong Shang, Jia Zheng, Binglin Kuang, Wei Zou.
      Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke, making the effective prevention and treatment of inflammatory secondary injury crucial. Recently, the role of immune cell metabolism in ICH has gained attention, particularly the regulatory mechanisms of glycolytic reprogramming in neuroinflammation. This review explores how glycolysis activation in peripheral immune cells (including neutrophils, macrophages, T cells, and natural killer cells), central immune cells (microglia), and other glial cells (including astrocytes and oligodendrocytes) involved in immune regulation influences the inflammatory response following ICH. We analyze the metabolic shifts in glycolysis within these immune cells, highlighting its dual role in neuroinflammation: glycolysis not only provides rapid energy to immune cells, which can either promote or inhibit inflammation, but lactate-a glycolysis byproduct-can modulate inflammatory damage by altering pH and immune cell function. Furthermore, we explore the therapeutic potential of targeting glycolysis in immune cells for neuroinflammation treatment. A deeper understanding of the glycolytic mechanism in ICH may facilitate the development of clinical therapeutic strategies targeting metabolism.
    Keywords:  Glycolysis; ICH; Immune cells; Lactate; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.clim.2025.110543
  5. Cell Rep. 2025 Jun 13. pii: S2211-1247(25)00622-9. [Epub ahead of print]44(6): 115851
    ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.
    Huiyan Ji, Wanwan Jiang, Juan Zhang, Mengdi Liu, Danhua Su, Jiaxin Lei, Lingyi Li, Ming Zheng, Ting Liu, Zhichun Liu, Qinghua Cao, Lin Xu, Sidong Xiong, Zhenke Wen.
      T cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), yet the underlying molecular mechanisms governing their fate remain elusive. Here, we identify cytosolic mitochondrial DNA (mtDNA) as an intrinsic trigger for driving effector T cell differentiation in patients with SLE. Specifically, accumulated cytosolic mtDNA is sensed by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which enhances the transcription of GLUT1 and glycolysis in SLE T cells. This metabolic shift reduces lipogenesis and depletes free fatty acids (FFAs), impairing the N-myristylation and lysosomal localization of AMP-activated protein kinase (AMPK). Inactive AMPK fails to restrain mammalian target of rapamycin complex 1 (mTORC1), leading to its hyperactivation and driving the mal-differentiation of effector T cells. Consequently, interventions targeting ENPP1, glycolysis, AMPK, and mTORC1 effectively inhibit the generation of immunoglobulin (Ig)G anti-double-stranded DNA (dsDNA) and the progression of lupus nephritis in humanized SLE chimeras. Overall, our findings uncover an mtDNA-ENPP1-metabolic axis that governs effector T cell fate in autoimmunity.
    Keywords:  AMPK; CP: Immunology; CP: Molecular biology; ENPP1; SLE; T cell; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.celrep.2025.115851
  6. Free Radic Biol Med. 2025 Jun 16. pii: S0891-5849(25)00773-7. [Epub ahead of print]
    Aerobic Exercise Pretreatment Mitigates Acute Lung Injury through Metabolic Reprogramming, Anti-inflammatory Modulation, and 6-Keto-Prostaglandin F1α Regulation.
    Xishuai Wang, Shunqiang Nong, Qibao Zheng, Congcong Zhao, Chao Yi, Simin Li, Lunan Zhao, Xiliang Kong, Yuehui Zhou, Depeng Dong, Weina Niu, Zhuo Chen, Cong Liu, Wei Zhao, Zhuo Sun, Jie Wei, Yang Lv, Lichang Yang, Xin Jin, Shanshan Cai, Di Wu, Fugao Jiang.
       OBJECTIVE: Although moderate physical exercise improves outcomes in pulmonary diseases such as acute lung injury (ALI), the underlying mechanisms, particularly those involving metabolic reprogramming, remain poorly defined. We investigated the impact of aerobic exercise (AE) pretreatment on metabolic pathways, inflammatory responses, and survival in ALI.
    METHODS: ALI model mice were induced through intratracheal lipopolysaccharide (LPS) after a 4-week AE protocol. Key assessments included histopathological evaluation, cytokine quantification, survival analysis, and serum metabolomic profiling.
    RESULTS: AE pretreatment significantly reduced mortality, attenuated lung damage, and suppressed neutrophil-driven inflammation. Mechanistically, AE restored LPS-induced metabolic dysregulation by normalizing ATP/ADP and NAD+/NADH ratios, phosphocreatine levels, and glucose-insulin homeostasis, in addition to decreasing lactate accumulation. Metabolomic analysis identified 991 differentially expressed metabolites (DEMs) between the Con and ALI groups, predominantly enriched in metabolic pathways, biosynthesis of unsaturated fatty acids, and linoleic acid metabolism, with arachidonic acid emerging as a critical upregulated hub node. In addition, 190 DEMs were identified between the AE+ALI and ALI groups, predominantly enriched in linoleic acid metabolism, metabolic pathways, and arachidonic acid metabolism, with linoleic acid and arachidonic acid emerging as critical upregulated hub nodes. AE pretreatment markedly suppressed the LPS-induced activation of the linoleic acid-arachidonic acid-6-keto-PGF1α signaling axis, which was aberrantly upregulated during ALI progression. Suppressing 6-keto-PGF1α activity using U51605 markedly alleviated the inflammatory response and tissue damage associated with ALI.
    CONCLUSIONS: AE pretreatment confers protection against ALI by orchestrating metabolic reprogramming to enhance anti-inflammatory responses. AE pretreatment attenuates LPS-induced ALI by reprogramming linoleic acid and arachidonic acid metabolism, thereby suppressing 6-keto-PGF1α biosynthesis. Pharmacological inhibition of 6-keto-PGF1α significantly alleviated ALI severity and mortality. These findings highlight AE as a preventive strategy and identify 6-keto-PGF1α as a therapeutic target for inflammatory lung injury.
    Keywords:  acute lung injury; aerobic exercise pretreatment; linoleic acid-arachidonic acid-6-keto-PGF1α signaling axis; metabolic reprogramming; metabolomics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.024
  7. Front Immunol. 2025 ;16 1587256
    LKB1 regulates ILC3 postnatal development and effector function through metabolic programming.
    Huasheng Zhang, Linfeng Zhao, Qingbing Zhang, Lin Hu, Xiaohui Su, Jiping Sun, Lei Shen.
       Introduction: Group 3 Innate Lymphoid Cells (ILC3s) are important for maintaining intestinal homeostasis and host defense. Emerging studies have shown that metabolic regulation plays a crucial role in regulating ILC3 activation and function. However, the role of Liver Kinase B1 (LKB1), a key metabolic regulator, in regulating ILC3 function and intestinal immunity remains poorly understood.
    Methods: To investigate the role of LKB1 in intestinal ILC3s, we generated LKB1 conditional knockout mice by crossing Rorc cre and Stk11 flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection model were used to determine the role of LKB1 in intestinal defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses.
    Results: In this study, we show that LKB1 is essential for ILC3 postnatal development, effector function, and intestinal immunity. LKB1-deficient mice exhibit a marked decrease in ILC3 number at 2 -3 weeks after birth. Ablation of LKB1 in ILC3s results in diminished IL-22 production and less protection against Citrobacter rodentium infection. Moreover, LKB1 deficiency leads to impaired cell metabolism, as indicated by reduced glycolysis and oxidative phosphorylation and less mitochondrial mass. Together, our data demonstrate that LKB1 promotes ILC3 postnatal development and effector function to maintain intestinal immune homeostasis.
    Discussion: Our findings reveal that LKB1 is a key regulator of intestinal ILC3 development, function, and metabolism, thereby linking metabolic control to intestinal immune homeostasis and offering potential therapeutic implications.
    Keywords:  Liver Kinase B1 (LKB1); group 3 innate lymphoid cells (ILC3s); inflammation; intestinal immune homeostasis; metabolic programming
    DOI:  https://doi.org/10.3389/fimmu.2025.1587256
  8. Free Radic Biol Med. 2025 Jun 16. pii: S0891-5849(25)00765-8. [Epub ahead of print]237 503-514
    p67phox/NOX2 inhibits psoriasis by regulating the HIF-1α-glycolysis axis via p53-AMPK in keratinocytes.
    Ang Li, Zhou Zhuang, Qingyue Xia, Xinzhu Zhou, Jungang Yang, Baoyi Liu, Xiaoyi Huang, Ke Xue, Xuejiao Song, Jingkai Xu, Yong Cui.
      Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation, oxidative stress, and metabolic reprogramming. While reactive oxygen species (ROS) are implicated in skin inflammation, their cellular sources and regulatory mechanisms in psoriatic pathophysiology remain poorly defined. Here, we identify p67phox/NOX2, a critical ROS-generating enzyme, as a key regulator of glucose metabolism in psoriatic keratinocytes. p67phox/NOX2 expression was significantly upregulated in psoriatic epidermis and positively correlated with glycolysis and JAK-STAT signaling signatures. p67phox knockdown in keratinocytes disrupted metabolic homeostasis, leading to AMPK inactivation, p53 suppression, and HIF-1α stabilization. These perturbations triggered increased lactate production, metabolic lactylation, and proinflammatory cytokine expression. In an imiquimod-induced murine psoriasis model, pharmacologic inhibition of NOX2 by GSK2795039 aggravated psoriasiform inflammation, whereas BML-111, a lipoxin A4 analog, alleviated pathology by restoring p67phox/NOX2 activity and metabolic balance. Together, NOX2-derived ROS function in the protective metabolism of epidermal inflammation, and that therapeutic activation, rather than inhibition, of NOX2 may represent a novel strategy for the treatment of psoriasis.
    Keywords:  Glycolysis; HIF-1α; Inflammation; NOX2; Psoriasis; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.016
  9. Elife. 2025 Jun 19. pii: RP103714. [Epub ahead of print]13
    Salmonella exploits host- and bacterial-derived β-alanine for replication inside host macrophages.
    Shuai Ma, Bin Yang, Yuyang Sun, Xinyue Wang, Houliang Guo, Ruiying Liu, Ting Ye, Chenbo Kang, Jingnan Chen, Lingyan Jiang.
      Salmonella is a major foodborne pathogen that can effectively replicate inside host macrophages to establish life-threatening systemic infections. Salmonella must utilize diverse nutrients for growth in nutrient-poor macrophages, but which nutrients are required for intracellular Salmonella growth is largely unknown. Here, we found that either acquisition from the host or de novo synthesis of a nonprotein amino acid, β-alanine, is critical for Salmonella replication inside macrophages. The concentration of β-alanine is decreased in Salmonella-infected macrophages, while the addition of exogenous β-alanine enhances Salmonella replication in macrophages, suggesting that Salmonella can uptake host-derived β-alanine for intracellular growth. Moreover, the expression of panD, the rate-limiting gene required for β-alanine synthesis in Salmonella, is upregulated when Salmonella enters macrophages. Mutation of panD impaired Salmonella replication in macrophages and colonization in the mouse liver and spleen, indicating that de novo synthesis of β-alanine is essential for intracellular Salmonella growth and systemic infection. Additionally, we revealed that β-alanine influences Salmonella intracellular replication and in vivo virulence partially by increasing expression of the zinc transporter genes znuABC, which in turn facilitates the uptake of the essential micronutrient zinc by Salmonella. Taken together, these findings highlight the important role of β-alanine in the intracellular replication and virulence of Salmonella, and panD is a promising target for controlling systemic Salmonella infection.
    Keywords:  Salmonella; infectious disease; microbiology; replication in macrophage; virulence; zinc uptake; β-alanine
    DOI:  https://doi.org/10.7554/eLife.103714
  10. Clin Exp Immunol. 2025 Jun 14. pii: uxaf028. [Epub ahead of print]
    Uncovering metabolic pathways in human alveolar macrophages in response to lipopolysaccharide.
    Christine C A van Linge, Erik H A Michels, Liza Pereverzeva, Regina de Beer, Augustijn M Klarenbeek, Bauke V Schomakers, Michel van Weeghel, Riekelt H Houtkooper, W Joost Wiersinga, Peter I Bonta, Jouke T Annema, Tom van der Poll, Alex F de Vos.
       INTRODUCTION: Alveolar macrophages (AMs) play an essential role in maintaining homeostasis in the lung and in innate immunity for host defense. To fuel inflammatory responses, AMs do not rely on glycolysis, but require oxidative phosphorylation. However, which nutrients AMs use to fuel their energy demand during inflammatory responses, is still unknown. The present study aimed to determine the contribution of three key metabolic pathways; fatty acid oxidation, glutaminolysis, and glycogenolysis, to the inflammatory response of AMs.
    METHODS: Primary AMs were isolated from healthy human volunteers and stimulated with lipopolysaccharide (LPS). After 24 hours, cells were subjected to analyses of metabolic flux, expression of genes involved in these metabolic pathways, and inflammatory cytokine secretion in the presence of metabolic inhibitors.
    RESULTS: The results of our study show that human AMs display expression of genes involved in fatty acid and glutamine metabolism and are capable of metabolizing oleic acid and glutamine during homeostasis, but do not use these metabolites to fuel the production of inflammatory cytokines. We demonstrate that AMs, while residing in a glucose-deprived environment, contain glycogen and use glycogenolysis to fuel inflammatory cytokine secretion, as reflected by reduced TNF, IL-1βand IL-6 levels in supernatant of LPS-stimulated AMs treated with the glycogenolysis inhibitor CP316819. Moreover, AMs display marked expression of genes involved in glycogenesis, including FBP1 and GYS.
    CONCLUSION: Taken together, these results indicate that primary human AMs are equipped to use different nutrients to fuel their metabolic demands. Moreover, our findings suggest that glycogenolysis is critical for the inflammatory response of AMs.
    Keywords:  Cellular Immunology; Lipopolysaccharide; Macrophage; Metabolism
    DOI:  https://doi.org/10.1093/cei/uxaf028
  11. Am J Cancer Res. 2025 ;15(5): 2004-2021
    Cholesterol metabolism reprogramming in multiple myeloma: examining its specificity and impact on the immune microenvironment.
    Hongtao Teng, Feifei Wang, Hairui Liu, Xiaolei Zhang.
      Multiple myeloma (MM) represents a malignancy within the hematological system, in which the reprogramming of cholesterol metabolism plays a pivotal role in its pathogenesis. This review focuses on the specificity of cholesterol metabolism abnormalities in the diagnosis of MM and their implications for the immune microenvironment, aiming to provide new perspectives for both diagnosis and treatment of MM. The expression changes of cholesterol metabolism-related genes (CMGs), such as ANXA2 and CHKA, closely correlate with the prognosis of MM. These CMGs are linked not only to clinical parameters, including the number of transplants and the International Staging System, but also to tumor incidence, progression, and treatment resistance. Consequently, they offer new biological markers for both the prognosis assessment and therapeutic strategies for MM. In terms of the immune microenvironment, reprogramming of cholesterol metabolism significantly influences tumor-infiltrating immune cells (TIICs), including T lymphocytes, B lymphocytes, tumor-associated macrophages (TAMs), dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs). Moreover, the cholesterol metabolite 25-hydroxycholesterol (25-HC) enhances the activity of immunosuppressive macrophages by modulating lysosomal AMPK activation and metabolic reprogramming, thus presenting a new metabolic target for tumor immunotherapy. The regulatory effects of cholesterol metabolism on MDSCs are also noteworthy; these cells promote tumor progression by inhibiting T-cell responses. High-fat diets and obesity can induce the accumulation of MDSCs, where molecules involved in the cholesterol metabolic pathway, such as the synthase CYP27A1 for 27-hydroxycholesterol (27-HC), have been associated with poor prognoses in ovarian cancer. Genetic knockout of this enzyme significantly inhibits tumor progression. Regarding the diagnostic specificity of cholesterol metabolism abnormalities, these changes present novel biomarkers for the early diagnosis and therapeutic monitoring of MM. Analyzing the correlation between immune cell proportions in the tumor microenvironment and lipid metabolism genes has unveiled potential links between cholesterol metabolism and immune responses, paving the way for precision medicine in MM. Thus, the reprogramming of cholesterol metabolism in MM offers a multidimensional and interdisciplinary research avenue. Future studies need to delve deeper into the specific mechanisms through which cholesterol metabolism contributes to MM development and leverage these findings to formulate new therapeutic strategies, ultimately improving outcomes for MM patients.
    Keywords:  Multiple myeloma; cholesterol metabolism reprogramming; diagnostic specificity; immune microenvironment
    DOI:  https://doi.org/10.62347/CCCT1933
  12. Adv Sci (Weinh). 2025 Jun 20. e01238
    NDRG1-Driven Lactate Accumulation Promotes Lung Adenocarcinoma Progression Through the Induction of an Immunosuppressive Microenvironment.
    Gujie Wu, Hongxia Cheng, Jiacheng Yin, Yuansheng Zheng, Haochun Shi, Binyang Pan, Ming Li, Mengnan Zhao, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Guoshu Bi, Weigang Guo, Lin Wang, Yiwei Huang.
      Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, with the tumor microenvironment (TME) playing a critical role in its progression. Metabolic reprogramming, particularly lactate accumulation, drives immune suppression within the TME. Utilizing single-cell RNA sequencing (scRNA-seq) of 30 LUAD samples, genome-wide association studies (GWAS) involving 29,863 patients and 55,586 controls, and clinical data from 220 LUAD patients, we identified N-Myc downstream-regulated gene 1 (NDRG1) as a key pathogenic gene in LUAD, strongly associated with tumor progression and poor prognosis. Mechanistic studies revealed that NDRG1 stabilizes lactate dehydrogenase A (LDHA) by inhibiting its ubiquitination, thereby enhancing glycolysis and promoting lactate accumulation. This process fosters immune suppression by inducing M2 macrophage polarization, impairing CD8+ T cell function, and upregulating immunosuppressive genes. Furthermore, histone H3K18 lactylation in macrophages exacerbates this immunosuppressive state. Clinically, elevated NDRG1 expression correlates with increased PD-L1 levels, a higher abundance of immunosuppressive macrophages, and reduced CD8+ T cell infiltration, contributing to immunotherapy resistance. Conversely, low NDRG1 expression is associated with enhanced CD8+ T cell infiltration and improved therapeutic outcomes. Preclinical studies demonstrated targeting NDRG1 suppresses tumor growth, alleviates immune suppression, and boosts anti-PD-L1 efficacy. These findings establish NDRG1 as a critical LUAD regulator and a promising immunotherapy target.
    Keywords:  NDRG1; immunotherapy; lactylation; lung adenocarcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202501238
  13. Eur J Clin Invest. 2025 Jun 17. e70090
    Enhanced mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from young children with overweight/obesity and insulin resistance.
    Eugenia Carvalho, Reid D Landes, Matthew Cotter, Leanna M Delhey, Elisabet Børsheim, Shannon Rose.
       BACKGROUND: Studies implicating dysfunctional mitochondrial respiration in metabolic tissues in the development of insulin resistance in obesity have only included adults. Peripheral blood mononuclear cells (PBMCs) and platelets have been found to reflect systemic mitochondrial fitness and bioenergetic health. We sought to identify bioenergetic differences in PBMCs and platelets from children with obesity and insulin resistance and determine associations with whole-body metabolism and/or biomarkers of metabolic health and inflammation.
    METHODS: We stratified prepubertal children (ages 5-10 years) into three groups: normal weight insulin sensitive (N-IS; n = 20), overweight/obese insulin sensitive (O-IS; n = 28) and overweight/obese insulin resistant (O-IR; n = 17). We measured oxygen consumption rate and proton efflux rate in PBMCs and platelets. We estimated whole-body resting metabolic rate by bioimpedance and dietary fatty acid oxidation by oral deuterated palmitate and quantifying recovery of D2O in urine. We used ANOVA for comparisons among groups and Spearman correlations for associations between circulating cell bioenergetics and whole-body metabolism and biomarkers.
    RESULTS: O-IS and O-IR PBMCs exhibited increased maximal mitochondrial respiration and spare respiratory capacity compared to N-IS. Bioenergetics shifted towards glycolysis in O-IS PBMCs as compared to both N-IS and O-IR PBMCs. In platelets, glycolysis and ATP production rates were decreased in O-IR compared to O-IS children. PBMC respiration positively correlated with BMIz, HOMA-IR and fasting glucose and insulin, but negatively correlated with inflammatory cytokines. Dietary fatty acid oxidation was higher in O-IS compared to N-IS children and positively correlated with PBMC spare respiratory capacity. Resting metabolic rate correlated positively with several parameters of PBMC mitochondrial respiration.
    CONCLUSIONS: PBMCs from young children with overweight/obesity exhibit adaptations to the metabolic stressors associated with insulin resistance, and PBMC metabolism correlates well with whole-body metabolism.
    Keywords:  bioenergetics; circulating cells; inflammation; insulin resistance; metabolic health; paediatric obesity
    DOI:  https://doi.org/10.1111/eci.70090
  14. Nature. 2025 Jun 18.
    Kupffer cell programming by maternal obesity triggers fatty liver disease.
    Hao Huang, Nora R Balzer, Lea Seep, Iva Splichalova, Nelli Blank-Stein, Maria Francesca Viola, Eliana Franco Taveras, Kerim Acil, Diana Fink, Franzisca Petrovic, Nikola Makdissi, Seyhmus Bayar, Katharina Mauel, Carolin Radwaniak, Jelena Zurkovic, Amir H Kayvanjoo, Klaus Wunderling, Malin Jessen, Mohamed H Yaghmour, Lukas Kenner, Thomas Ulas, Stephan Grein, Joachim L Schultze, Charlotte L Scott, Martin Guilliams, Zhaoyuan Liu, Florent Ginhoux, Marc D Beyer, Christoph Thiele, Felix Meissner, Jan Hasenauer, Dagmar Wachten, Elvira Mass.
      Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis1. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions1-3. Throughout development and adulthood, KCs perform distinct core functions that are essential for liver and organismal homeostasis, including supporting fetal erythropoiesis, postnatal erythrocyte recycling and liver metabolism4. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs promote lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonate mice born to obese mothers, followed by replenishment with naive monocytes, rescues fatty liver disease. Furthermore, genetic ablation of the gene encoding hypoxia-inducible factor-α (HIF1α) in macrophages during gestation prevents the metabolic programming of KCs from oxidative phosphorylation to glycolysis, thereby averting the development of fatty liver disease. These results establish developmental perturbation of KC functions as a causal factor in fatty liver disease in adulthood and position fetal-derived macrophages as critical intergenerational messengers within the concept of developmental origins of health and diseases5.
    DOI:  https://doi.org/10.1038/s41586-025-09190-w
  15. Front Oncol. 2025 ;15 1483769
    Landscape of targets within nucleoside metabolism for the modification of immune responses.
    Ella M Dunderdale, Evan R Abt.
      Nucleoside metabolism regulates immune cell development and function, but the therapeutic implications of this link have yet to be fully realized. Evidence for the importance of nucleoside metabolism in immune system control was provided by observations of immunodeficiency and autoimmunity across patients with genetic errors that alter nucleoside synthesis or breakdown. Research over the past several decades has uncovered a multifaceted role for nucleosides in mediating immune responses that involves their function as metabolic precursors and as ligands for immune receptors. These findings prompted the development of treatments that block the production of the immunosuppressive nucleoside adenosine for cancer immunotherapy. Guanosine and pyrimidine nucleosides also mediate immune outcomes, and the key regulators of their metabolism are promising new targets to unleash anti-cancer immune responses or dampen autoimmune reactions. This review provides an overview of (i) recent research concerning the mechanisms underlying nucleoside-mediated immune regulation, (ii) the current landscape of therapeutic targets for immune modulation within nucleoside metabolism, and (iii) opportunities for developing improved preclinical models that recapitulate human nucleoside metabolism, which are needed to advance new metabolism-targeting therapies toward the clinic.
    Keywords:  autoimmune disease; cancer immunotherapy; immune activation; immuno-metabolism; metabolism; nucleotide metabolism
    DOI:  https://doi.org/10.3389/fonc.2025.1483769
  16. Trends Biochem Sci. 2025 Jun 17. pii: S0968-0004(25)00131-8. [Epub ahead of print]
    SAM cycle and adenosine at the heart of immune conversations.
    Sajad Ahmad Najar, Rahul Bohra, Tina Mukherjee.
      Recent work by Nedbalova et al. reframes the SAM transmethylation pathway as a biosensor and signaling hub, linking immune activation to systemic metabolic changes via adenosine export. Their compelling findings reveal a key mechanism by which immune cells influence organism-wide physiology beyond traditional methylation roles.
    Keywords:  SAM cycle; immuno-metabolism; infection; macrophages
    DOI:  https://doi.org/10.1016/j.tibs.2025.06.001
  17. J Neurol Sci. 2025 Jun 16. pii: S0022-510X(25)00202-3. [Epub ahead of print]475 123585
    Microglia energy metabolism: A new perspective on Alzheimer's disease treatment.
    Qing-Lin Wu, Xiong Yang, Jia-Xin Luo, Li Liu, Ya Zhou, Mei-Hong Lu.
      Alzheimer's disease (AD) is a progressive age-associated neurodegenerative disorder characterized by systemic cerebral metabolic disturbances. Neuroimaging and biochemical analyses reveal three hallmark features: decreased glucose utilization, mitochondrial bioenergetic deficits, and impaired energy homeostasis within hippocampal circuits. Emerging evidence highlights the pivotal role of microglia, the brain's specialized immune guardians, whose metabolic plasticity forms a self-reinforcing pathological cycle with AD progression. During early disease stages, oxidative phosphorylation (OXPHOS)-dependent M2 microglia mediate neuroprotective functions through efficient β-amyloid (Aβ) phagocytosis. However, progressive metabolic reprogramming drives a pathological shift toward glycolysis-dominant M1, characterized by heightened proinflammatory cytokine secretion and compromised clearance capacity. Notably, AD-associated pathological aggregates disrupt microglial metabolic adaptation, suppress mitophagy processes, and perpetuate sustained neuroinflammatory responses. The metabolic flexibility of microglia allows them to adapt to different energy demands. This study reviews the roles of major metabolic pathways and metabolic regulators of microglia in AD and the link between AD pathology and microglia energy metabolism, and describes the potential of relevant drugs and non-drug approaches in AD treatment, revealing metabolic regulation as a new target for AD therapy.
    Keywords:  Alzheimer's disease; Energy metabolism; Inflammatory; Microglia; Mitochondrial; Treatment
    DOI:  https://doi.org/10.1016/j.jns.2025.123585
  18. Plant Cell Environ. 2025 Jun 16.
    Cysteine Signalling in Plant Pathogen Response.
    Jannis Moormann, Björn Heinemann, Cecile Angermann, Anna Koprivova, Ute Armbruster, Stanislav Kopriva, Tatjana M Hildebrandt.
      The amino acid cysteine is the precursor for a wide range of sulfur-containing functional molecules in plants, including enzyme cofactors and defence compounds. Due to its redox active thiol group cysteine is highly reactive. Synthesis and degradation pathways are present in several subcellular compartments to adjust the intracellular cysteine concentration. However, stress conditions can lead to a transient increase in local cysteine levels. Here we investigate links between cysteine homeostasis and metabolic signalling in Arabidopsis thaliana. The systemic proteome response to cysteine feeding strongly suggests that Arabidopsis seedlings interpret accumulation of cysteine above a certain threshold as a signal for a biotic threat. Cysteine supplementation of Arabidopsis plants via the roots increases their resistance to the hemibiotrophic bacterium Pseudomonas syringae confirming the protective function of the cysteine induced defence pathways. Analysis of mutant plants reveals that the balance of cysteine synthesis between the cytosol and organelles is crucial during Arabidopsis immune response to Pseudomonas syringae. The induction profile of pathogen responsive proteins by cysteine provides insight into potential modes of action. Our results highlight the role of cysteine as a metabolic signal in the plant immune response and add evidence to the emerging concept of intracellular organelles as important players in plant stress signalling.
    Keywords:  amino acid metabolism; immunometabolism; infochemicals; mitochondria; proteomics; sulfur signalling
    DOI:  https://doi.org/10.1111/pce.70017
  19. J Neuroinflammation. 2025 Jun 14. 22(1): 157
    Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection.
    Satoshi Suyama, Sally Boxall, Benjamin Grace, Andrea Fořtová, Martina Pychova, Lenka Krbkova, Rupasri Mandal, David Wishart, Diane E Griffin, Daniel Růžek, Niluka Goonawardane.
       BACKGROUND: Tick-borne encephalitis virus (TBEV) is a significant threat to human health. The virus causes potentially fatal disease of the central nervous system (CNS), for which no treatments are available. TBEV infected individuals display a wide spectrum of neuronal disease, the determinants of which are undefined. Changes to host metabolism and virus-induced immunity have been postulated to contribute to the neuronal damage observed in infected individuals. In this study, we evaluated the cytokine, chemokine, and metabolic alterations in the cerebrospinal fluid (CSF) of symptomatic patients infected with TBEV presenting with meningitis or encephalitis. Our aim was to investigate the host immune and metabolic responses associated with specific TBEV infectious outcomes.
    METHODS: CSF samples of patients with meningitis (n = 27) or encephalitis (n = 25) were obtained upon consent from individuals hospitalised with confirmed TBEV infection in Brno. CSF from uninfected control patients was also collected for comparison (n = 12). A multiplex bead-based system was used to measure the levels of pro-inflammatory cytokines and chemokines. Untargeted metabolomics followed by bioinformatics and integrative omics were used to profile the levels of metabolites in the CSF. Human motor neurons (hMNs) were differentiated from induced pluripotent stem cells (iPSCs) and infected with the highly pathogenic TBEV-Hypr strain to profile the role(s) of identified metabolites during the virus lifecycle. Virus infection was quantified via plaque assay.
    RESULTS: Significant differences in proinflammatory cytokines (IFN-α2, TSLP, IL-1α, IL-1β, GM-CSF, IL-12p40, IL-15, and IL-18) and chemokines (IL-8, CCL20, and CXCL11) were detected between neurological-TBEV and control patients. A total of 32 CSF metabolites differed in TBE patients with meningitis and encephalitis. CSF S-Adenosylmethionine (SAM), Fructose 1,6-bisphosphate (FBP1) and Phosphoenolpyruvic acid (PEP) levels were 2.4-fold (range ≥ 2.3-≥3.2) higher in encephalitis patients compared to the meningitis group. CSF urocanic acid levels were significantly lower in patients with encephalitis compared to those with meningitis (p = 0.012209). Follow-up analyses showed fluctuations in the levels of O-phosphoethanolamine, succinic acid, and L-proline in the encephalitis group, and pyruvic acid in the meningitis group. TBEV-infection of hMNs increased the production of SAM, FBP1 and PEP in a time-dependent manner. Depletion of the metabolites with characterised pharmacological inhibitors led to a concentration-dependent attenuation of virus growth, validating the identified changes as key mediators of TBEV infection.
    CONCLUSIONS: Our findings reveal that the neurological disease outcome of TBEV infection is associated with specific and dynamic metabolic signatures in the cerebrospinal fluid. We describe a new in vitro model for in-depth studies of TBEV-induced neuropathogenesis, in which the depletion of identified metabolites limits virus infection. Collectively, this reveals new biomarkers that can differentiate and predict TBEV-associated neurological disease. Additionally, we have identified novel therapeutic targets with the potential to significantly improve patient outcomes and deepen our understanding of TBEV pathogenesis.
    Keywords:  Cerebrospinal fluid; Chemokines; Human motor neurons; Metabolomics; Neuroinflammation; Pro-inflammatory cytokines; Tick-borne encephalitis virus
    DOI:  https://doi.org/10.1186/s12974-025-03478-4
  20. J Control Release. 2025 Jun 12. pii: S0168-3659(25)00577-2. [Epub ahead of print] 113957
    Coordinated modulation of glucose metabolism and immunity via metal-drug nanovesicles for hepatocellular carcinoma therapy.
    Mengjie Kong, Liyan Qiu.
      A highly immunosuppressive microenvironment, along with disordered glucose metabolism, promotes immune evasion and compromises the effectiveness of cancer immunotherapy. To address these challenges, we developed a multifunctional C-B-M-Mn nanovesicle platform to disrupt tumor metabolism and enhance antitumor immunity. This system encapsulated BAY-876 (a Glut1 inhibitor) and MSA-2 (a STING agonist) in the nanovesicle membrane and incorporated Mn2+ through chelation with gallic acid-modified chitosan oligomers within the nanovesicle core. Under acidic tumor conditions, the surface potential of the nanovesicles shifted to positive charge, facilitating cellular uptake. Once internalized by tumor cells, C-B-M-Mn released its cargo in response to acidic pH and high esterase activity. Inhibiting BAY-876-mediated glycolysis increased reactive oxygen species (ROS) production and triggered the release of mitochondrial DNA, thereby priming the cGAS-STING signaling pathway. Mn2+ enhanced cGAS sensitivity, while MSA-2 further activated STING, promoting dendritic cell (DC) maturation and CD8+ T and natural killer (NK) cell recruitment. In addition, this metabolic blockade reduced PD-L1 expression levels and mitigated immune evasion. Additionally, Mn2+ provided MRI contrast enhancement, enabling simultaneous imaging and treatment. Collectively, these findings highlight the C-B-M-Mn platform as a promising strategy for integrated glucose metabolic inhibition and immunotherapeutic intervention to improve hepatocellular carcinoma (HCC) treatment.
    Keywords:  Hepatocellular carcinoma; Immunotherapy; Metabolic inhibition; Nanovesicle; cGAS–STING pathway
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113957
  21. Aging Cell. 2025 Jun 16. e70135
    Chronic Cellular NAD Depletion Activates a Viral Infection-Like Interferon Response Through Mitochondrial DNA Leakage.
    Claudia C S Chini, Laura Colman, Eduardo Palmieri, Jessica L Strange, Sonu Kashyap, Bing Han, Andres Benitez-Rosendo, Gina L Ciccio Lopez, Sara Peixoto Rabelo, Shreyartha Mukherjee, Gustavo H de Souza, John Varga, Ralph G Meyer, Mirella L Meyer-Ficca, Eduardo N Chini.
      Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in energy metabolism, DNA repair, and cellular signaling. While the effects of acute NAD depletion have been better characterized, the consequences of chronic NAD deficiency remain unclear. Here, we investigated the impact of chronic NAD depletion in cultured cells by removing the availability of nicotinamide (NAM), a key precursor for NAD synthesis, from the culture media. In NIH3T3 fibroblasts, NAM depletion caused a dramatic drop in intracellular NAD levels within 2 days. Remarkably, the cells remained viable even after 7-14 days of NAM depletion, despite NAD+ levels falling to less than 10% of control conditions. This chronic NAD depletion led to distinct metabolic alterations. Mitochondrial basal respiration remained unchanged, but cells exhibited reduced spare respiratory and maximal capacities, along with significantly impaired glycolysis. Notably, NAD depletion triggered an interferon-dependent inflammatory response, resembling viral infections. This was driven by cytosolic leakage of mitochondrial DNA (mtDNA) through voltage-dependent anion channel 1 (VDAC1), which activated the cGAS-STING signaling pathway. Inhibition of VDAC oligomerization with VBIT-4, STING signaling with H-151, or mtDNA depletion blocked the upregulation of interferon genes induced by NAM depletion. Similar interferon responses triggered by NAD depletion were observed in IMR90 human fibroblasts and HS5 stromal cells. Our findings reveal a novel link between chronic NAD deficiency, VDAC-mediated mtDNA release to the cytoplasm, and the activation of the inflammatory response, providing new insight into how NAD decline affects cellular metabolic and inflammatory processes.
    DOI:  https://doi.org/10.1111/acel.70135
  22. Front Pharmacol. 2025 ;16 1588987
    Enhanced resistance to Listeria infection in mice surviving sepsis: the role of lipid metabolism and myeloid cell reprogramming.
    Haruki Watanabe, Tengfei Song, Jaewoo Choi, Moses Lee, Kwangmin Choi, Junhwan Kim, Barbara Sherry, Betty Diamond, Yong-Rui Zou, Myoungsun Son.
       Introduction: Immune resilience is the capacity of the immune system to recover from sepsis-induced organ injury and reestablish host defense. While sepsis survivors are often viewed as immunocompromised, recent studies suggest that some may acquire adaptive immune traits that enhance resistance to secondary infections.
    Methods: We employed a murine cecal ligation and puncture (CLP) model to study polymicrobial sepsis and subsequent immune responses. Listeria monocytogenes was used as a model intracellular pathogen to assess immune protection. We analyzed myeloid cell phenotypes using single-cell RNA sequencing and evaluated lipid metabolic changes through quantitative RT-PCR, immunohistochemistry, serum cytokine assays, and plasma lipidomics.
    Results: Sepsis-surviving mice showed enhanced resistance to Listeria infection. Single-cell RNA sequencing revealed transcriptional reprogramming in splenic CD11b+Ly6Chigh myeloid cells, including downregulation of lipoprotein lipase and lipid efflux genes. CD11b+ myeloid cells exhibited increased lipid droplet accumulation, accompanied by elevated serum interferon-gamma (IFN-γ) levels. Plasma lipidomics identified systemic lipid remodeling, with increased phosphatidylserine and decreased phosphatidylinositol and phosphatidylglycerol levels.
    Discussion: Our findings suggest that sepsis survival induces lipid metabolic reprogramming in myeloid cells, contributing to enhanced immunity against intracellular pathogens. These insights reveal potential therapeutic targets within lipid metabolic pathways to improve host defense in sepsis survivors.
    Keywords:  Listeria monocytogenes; lipid droplets; lipid metabolism; lipidomics; myeloid cells; sepsis; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fphar.2025.1588987
  23. Immunol Cell Biol. 2025 Jun 18.
    Targeting glutamine metabolism in CD4+ T-cell-mediated autoimmune diseases.
    Zheng Li, ZeHong Su, ZhiMin Wu, LvHeng He, PingPing Hu, GaoJian Lian.
      CD4+ T cells play a vital role in the occurrence and development of autoimmune diseases (AID). The differentiation direction and function of CD4+ T cells are both regulated by metabolic reprogramming, which differs across various CD4+ T subsets. Glutamine (Gln), as an immunoregulatory nutrient, not only provides bioenergy and biosynthesis for the differentiation and effector function of CD4+ T cells but also regulates intracellular redox conditions and produces metabolic intermediates that are used for epigenetic modification of effector cell genes. Here, we review the metabolic characteristics of Gln in CD4+ T cells and its regulatory effects on CD4+ T-cell differentiation and function. We also summarize potential targets on Gln metabolism for AID therapy, including Gln transporters, Gls1, GSH synthesis and epigenetic modification. However, the primary challenge remains how to achieve cell type-specific metabolic inhibition in vivo. Therefore, future research should focus on developing selective and effective therapeutic agents that modulate Gln metabolism while minimizing cytotoxicity for AID treatment.
    Keywords:  autoimmune disease; epigenetic modification; glutamine; glutaminolysis; selective immunotherapy
    DOI:  https://doi.org/10.1111/imcb.70042
  24. Eur J Heart Fail. 2025 Jun 16.
    The crosstalk between immune activation and metabolism in heart failure. A scientific statement of the Heart Failure Association of the ESC.
    Gabriele Fragasso, Davide Stolfo, Markus S Anker, Antoni Bayes-Genis, Ovidiu Chioncel, Stephane Heymans, Pardeep S Jhund, Basil S Lewis, Gary D Lopaschuk, Lars H Lund, Arantxa Gonzalez, Matteo Pagnesi, Gabriele Giacomo Schiattarella, Carlo Gabriele Tocchetti, Peter van der Meer, Sophie Von Linthout, Sven Wassmann, B Daan Westenbrink, Marco Metra, Giuseppe M C Rosano, Gianluigi Savarese.
      A better understanding of additional mechanisms of heart failure (HF) progression may allow a different and more complete phenotyping of the disease and identification of novel therapeutic targets. Persistent latent myocardial inflammation/immune activation in HF may represent an attempt to restore tissue homeostasis in the failing heart, where cardiomyocytes and immune cells undergo metabolic reprogramming, which allows them to deal with decreased availability of nutrients and oxygen. This status can trigger a metabolic crosstalk between immune cells and cardiomyocytes which, depending on the outcome, can either perpetuate the maladaptive remodelling of the heart, or determine an adaptive response. Therefore, the interplay between immune activation and metabolism is gaining recognition as a potential therapeutic framework. On these premises, future studies addressing novel HF treatments should attempt to evaluate the potential therapeutic role of direct metabolic and immunological crosstalk modulation. The aim of the present scientific statement from the Heart Failure Association of the ESC is to summarize the current evidence for the connection between inflammatory and immune activation and metabolic adaptation in the onset and progression of HF, in order to promote future strategies for the development of targeted-disease preventive and therapeutic measures.
    Keywords:  Aging; Heart failure; Immunometabolism; Inflammation; Maladaptive; Myocardial Metabolism; Therapy
    DOI:  https://doi.org/10.1002/ejhf.3703
  25. Cell Commun Signal. 2025 Jun 19. 23(1): 290
    Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
    Xianhong Zhang, Yue Gao, Siyu Zhang, Yiqi Wang, Xinke Pei, Yufei Chen, Jinhui Zhang, Yichen Zhang, Yitian Du, Shauilin Hao, Yujiong Wang, Ting Ni.
      Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.
    Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Metabolic remodelling; Mitochondria
    DOI:  https://doi.org/10.1186/s12964-025-02308-7
  26. J Clin Invest. 2025 Jun 17. pii: e186509. [Epub ahead of print]
    E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1.
    Lei Cao, Jie Zhang, Liwen Yu, Wei Yang, Wenqian Qi, Ruiqing Ren, Yapeng Liu, Yonghao Hou, Yu Cao, Qian Li, Xiaohong Wang, Zhengguo Zhang, Bo Li, Wenhai Sui, Yun Zhang, Chengjiang Gao, Cheng Zhang, Meng Zhang.
      Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
    Keywords:  Atherosclerosis; Cardiology; Metabolism; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI186509
  27. Nat Rev Immunol. 2025 Jun 16.
    Iron and the immune system.
    Joe N Frost, Hal Drakesmith.
      Iron is a cofactor for hundreds of enzymes and biochemical processes that support cellular metabolism across the kingdoms of life. Because of this, the host and pathogen compete for iron as a vital resource. Moreover, research has shown that iron acquisition and iron trafficking have substantial effects on the immune system. This is especially important because iron-related disorders - both deficiency and overload - are common worldwide. In this Review, we describe how immune cells acquire and use iron, which branches of the immune system are most affected by iron and how changes in iron availability can affect infectious diseases, autoinflammatory disorders and antitumour immunity. We also discuss key unanswered questions and potential therapeutic opportunities to manipulate immunity by controlling iron trafficking.
    DOI:  https://doi.org/10.1038/s41577-025-01193-y
  28. Trends Endocrinol Metab. 2025 Jun 12. pii: S1043-2760(25)00119-5. [Epub ahead of print]
    Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise.
    Jin Ma, Annie Yujin Son, Youlim Son, Ping-Yuan Wang, Paul M Hwang.
      Exercise-induced inflammation is regarded as a response to muscle damage from mechanical stress, but controlled immune signaling can be beneficial by promoting metabolic adaptation which, for example, decreases obesity and lowers the risk of diabetes. In addition to oxidative metabolism, mitochondria play a central role in initiating innate immune signaling. We review recent work that has identified the cGAS-STING-NF-κB signaling pathway, activated by the downregulation of mitochondrial proteins CHCHD4 and TRIAP1, as mediating skeletal muscle adaptation to exercise training as well as potentially promoting cellular resilience to environmental stresses. Notably, CHCHD4 haploinsufficiency prevents obesity in aging mice; therefore, this innate immune signaling pathway could be targeted to achieve some of the health benefits of exercise.
    Keywords:  CHCHD4; TRIAP1; exercise; fiber type; innate immunity; metabolism; mtDNA; obesity
    DOI:  https://doi.org/10.1016/j.tem.2025.05.004
  29. Redox Biol. 2025 Jun 12. pii: S2213-2317(25)00242-3. [Epub ahead of print]85 103729
    Fructose intake enhances lipoteichoic acid-mediated immune response in monocytes of healthy humans.
    Raphaela Staltner, Katja Csarmann, Amelie Geyer, Anika Nier, Anja Baumann, Ina Bergheim.
      Metabolic diseases like type 2 diabetes are afflicted with higher rates of infections and longer, more complicated infection course as well as higher fatality rates. The impact of nutrition and specific nutrients like free fructose herein has not yet been fully understood. Here, we performed dietary intervention studies in healthy individuals and performed ex vivo experiments in isolated blood immune cells to assess the effects of dietary fructose intake on Gram-positive bacterial toxin induced immune responses. Acute and extended intake of fructose but not glucose was related with an induction of Toll like receptor 2 mRNA expression in monocytes and enhanced the LTA-dependent release of proinflammatory cytokines from monocytes. Blocking fructose metabolism and transcription factor SP1 attenuated the fructose-related induction of Toll like receptor 2 mRNA expression and augmentation of proinflammatory cytokine release further suggesting that fructose-dependent metabolic alterations are critical in enhancing immune responsiveness of humans after fructose consumption.
    Keywords:  Gram-positive bacteria; Ketohexokinase; Lipoteichoic acid; SP1; Sugar; Toll like receptor 2
    DOI:  https://doi.org/10.1016/j.redox.2025.103729
  30. Mater Today Bio. 2025 Jun;32 101887
    Breaking the psoriasis pathological signaling cycle: A novel nanomedicine strategy targeting metabolism and oxidative stress.
    Fugen Wu, Xing Xia, Yuqi Han, Zihao Huang, Yitianhe Xu, Zihao Tao, Yunzhi Wang, Dingchao Shen, Shengnan Song, Wanling Zhu, Ruijie Chen, Xianbao Shi, Xinyu Jiang, Longfa Kou.
      Psoriasis is a chronic skin disorder characterized by dysregulation of immune and epithelial cells, resulting in persistent symptoms such as erythema, scaling, and induration. The abnormal metabolism and increased oxidative stress in psoriasis lesions have been identified as key drivers in the pathogenesis of psoriasis, forming a positive feedback loop within psoriatic skin. Therefore, targeting this feedback loop through modulation of local metabolism and alleviation of oxidative stress could be a rational and promising therapeutic strategy for addressing psoriasis. Herein, we designed a carrier-free nanomedicine (BTN) incorporating bilirubin (BR) and triptolide (TPL) to specifically target two key pathological features of psoriasis: inflammation induced by enhanced reactive oxygen species (ROS) and aberrant proliferation/immune activation driven by heightened nutrient metabolism. In vitro studies demonstrated that BTN effectively improved the water solubility of BR and TPL while facilitating efficient drug delivery to inflammatory keratinocytes. Mechanistically, BTN was found to alleviate the inflammatory cascade caused by oxidative stress and inhibit the IL-23/IL-17 axis. Importantly, downregulation of HIF-1α in keratinocytes resulted in blocking glucose transportation via GLUT-1 as well as amino acid transportation via LAT1, ultimately impeding excessive proliferation by disrupting nutritional requirements. In an imiquimod-induced psoriasis model, BTN effectively permeated inflamed skin epithelium with long-term retention effect. As a multifunctional nanomedicine combining ROS scavenging properties with regulation of nutrition metabolism, BTN shows great promise for reducing inflammatory cell infiltration and suppressing keratinocyte proliferation. Our findings demonstrated the great potential of BTN in ameliorating psoriasis symptoms by restoring the metabolic imbalance and mitigating oxidative stress between the epithelial and immune compartments.
    Keywords:  Bilirubin; HIF-1α; Nanomedicine; Psoriasis; Triptolide
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101887
  31. Nat Immunol. 2025 Jun 17.
    Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
    Hongxu Xian, Kosuke Watari, Masafumi Ohira, Jonathan S Brito, Peng He, Janset Onyuru, Elina I Zuniga, Hal M Hoffman, Michael Karin.
      Stress-induced oxidized mitochondrial DNA (Ox-mtDNA) fragments enter the cytoplasm, activating the NLRP3 inflammasome and caspase-1 and enabling gasdermin-D-mediated circulatory release of mtDNA. Elevated amounts of circulating mtDNA, presumably oxidized, have been detected in older individuals and patients with metabolic or autoimmune disorders. Here we show that sustained Ox-mtDNA release, triggered by a prototypical NLRP3 inflammasome activator, induces autoantibody production and glomerulonephritis in mice. Similar autoimmune responses, dependent on plasmacytoid dendritic cells (pDCs) and follicular helper T (TFH) cells, are elicited by in vitro-generated Ox-mtDNA, but not by non-oxidized mtDNA. Although both mtDNA forms are internalized by pDCs and induce interferon-α, only Ox-mtDNA stimulates autocrine interleukin (IL)-1β signaling that induces co-stimulatory molecules and IL-21, which enable mouse and human pDCs to induce functional TFH differentiation, supportive of autoantibody production. These findings underscore the role of pDC-generated IL-1β in autoantibody production and highlight Ox-mtDNA as an important autoimmune trigger, suggesting potential therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41590-025-02179-7
  32. Methods Mol Biol. 2025 ;2940 1-9
    Investigation of Protein Fatty Acylation in Virus-Host Interaction.
    Dan Hou, Chunfu Zheng, Tao Yu.
      Fatty acylation has a critical impact on antiviral innate immunity. Fatty acylation of virus proteins affects virus virulence and invasion. In contrast, fatty acylation of host cell proteins regulates virus recognition and host-virus interactions, thus affecting antiviral immune responses. Therefore, an emerging need exists to investigate and understand the mechanism and function of protein fatty acylation in regulating antiviral innate immunity. Alkyne probe metabolic labeling and click chemistry assays with biotin-conjugated or fluorophore-conjugated azide provide a simple way to determine the potential fatty-acylated proteins in antiviral innate pathways. Here, we demonstrate comprehensive approaches to determine protein fatty acylation in virus-infected macrophages or protein-overexpressing HEK293T cells in the context of antiviral innate immunity.
    Keywords:  Antiviral innate immunity; Click chemistry; Fatty acylation; Metabolic labeling; Palmitoylation
    DOI:  https://doi.org/10.1007/978-1-0716-4615-1_1
  33. Theranostics. 2025 ;15(13): 6329-6346
    Boosting mRNA cancer vaccine efficacy via targeting Irg1 on macrophages in lymph nodes.
    Wenwen Wei, Xiao Yang, Yeshan Chen, Mengjie Che, Ying Ye, Yue Deng, Mengyao Su, Yajie Sun, Jingshu Meng, Yan Hu, Jiacheng Wang, Yijun Wang, Zishan Feng, Zhiyuan Zhou, Yan Li, Qian Li, Zhanjie Zhang, Bian Wu, Haibo Zhang, You Qin, Lu Wen, Chao Wan, Kunyu Yang.
      Rationale: mRNA cancer vaccines show great promise for tumor therapy, but the therapeutic efficacy is limited. Metabolites play critical roles in immunomodulation. However, their role in mRNA cancer vaccines remains poorly understood. Methods: Metabolome analysis and single-cell RNA sequence were performed to explore the most important metabolite and its source cell. B16-F10-OVA-bearing wide-type and Irg1-depleted C57BL/6 mice were treated with OVA-LNP, OVA&si-Irg1-LNP, or anti-PD-1 antibody to evaluate therapeutic efficacy. Flow cytometry analysis was used to examine the immune cells within the lymph nodes, spleens, and the tumor immune environment. Results: We found that macrophage-derived itaconate was increased markedly in activated ipsilateral lymph nodes after ovalbumin-encoding mRNA-lipid nanoparticle (OVA-LNP) injection, compared to homeostatic contralateral lymph nodes. Depleting the immune-responsive gene 1(Irg1), which encodes the itaconate-production enzyme aconitate decarboxylase (ACOD1), in macrophages improved dendritic cell antigen presentation and enhances T cell function. Combining Irg1 knockdown via small interfering RNA (siRNA) with OVA mRNA in LNPs augmented the therapeutic efficacy of mRNA cancer vaccines, both as monotherapy and in combination with an anti-programmed cell death-1 antibody. Conclusions: Our findings reveal a link between itaconate and mRNA cancer vaccines, suggesting that targeting Irg1 via siRNA-LNP could be a promising strategy to improve the therapeutic efficacy of mRNA cancer vaccines.
    Keywords:  DCs; anti-PD-1 antibody; mRNA cancer vaccines; macrophages; taconate
    DOI:  https://doi.org/10.7150/thno.110305
  34. Adv Sci (Weinh). 2025 Jun 20. e03690
    Hexokinase-2 as a Therapeutic Target: Alleviating Herpes Simplex Keratitis Through Metabolic Reprogramming.
    Dan Jiang, Yining Sun, Xintong Yu, Ruoqi Wang, Yuting Zhang, Jinjie Yu, Shuang Xie, Yujia Cai, Yuhong Luo, Wei Chen.
      Herpes simplex keratitis (HSK) is a leading infectious cause of blindness worldwide, with current therapies primarily targeting viral replication rather than addressing host-cell injury. RNA sequencing of corneal tissue from HSK patients and healthy donors identifies a metabolic shift from mitochondrial oxidative phosphorylation to aerobic glycolysis. Notably, hexokinase-2 (HK2), a pivotal glycolytic enzyme, exhibits the greatest up-regulation, coinciding with a marked reduction in the activity of mitochondrial respiratory chain complexes in HSK corneas. Pharmacological inhibition of HK2 with lonidamine in human corneal epithelial cells reduces herpes simplex virus type 1 (HSV-1) replication while preserving cell viability. In a murine model of HSK, topical lonidamine restored respiratory-chain activity, lowered viral load, and accelerated corneal re-epithelialization; its early therapeutic efficacy surpassed that of ganciclovir, and combination therapy conferred additive benefit. These findings identify HK2-driven glycolytic reprogramming as a pathogenic hallmark of HSK and demonstrate that metabolic targeting concurrently restricts viral propagation and promotes tissue regeneration. Thus, metabolic intervention has the potential to complement direct antiviral therapy and represents a promising, clinically translatable strategy to preserve vision in HSK.
    Keywords:  herpes simplex keratitis; hexokinase‐2; lonidamine; metabolism; regeneration
    DOI:  https://doi.org/10.1002/advs.202503690
  35. Sci Adv. 2025 Jun 20. 11(25): eadv2397
    Spermidine is a key polyamine required by intracellular parasites for survival within host erythrocytes.
    Pallavi Singh, Jae-Yeon Choi, Emmanuel Cornillot, Choukri Ben Mamoun.
      Intracellular parasites, including Babesia and Plasmodium, the agents of human babesiosis and malaria, depend on the salvage or de novo synthesis of critical nutrients for survival within human erythrocytes. Among these, polyamines play a pivotal role, but their specific requirements and molecular functions in intraerythrocytic parasites remain poorly understood. We identify spermidine as a key polyamine for Babesia duncani and Plasmodium falciparum for intraerythrocytic development. We demonstrate that spermidine is indispensable for regulating protein translation through hypusination of the eukaryotic translation initiation factor eIF5A, and its depletion leads to increased production of reactive oxygen species. Disruption of spermidine biosynthesis or its conversion from spermine results in parasite death. We also show that B. duncani and other Babesia species use an ancestral spermidine synthase-like enzyme, highlighting a distinct evolutionary adaptation from P. falciparum. Our results reveal the spermidine's dual role in oxidative stress defense and translation regulation, positioning spermidine biosynthesis as a critical vulnerability and a promising therapeutic target.
    DOI:  https://doi.org/10.1126/sciadv.adv2397
  36. J Clin Invest. 2025 Jun 19. pii: e181034. [Epub ahead of print]
    Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.
    Alice Horisberger, Alec Griffith, Joshua Keegan, Arnon Arazi, John Pulford, Ekaterina Murzin, Kaitlyn Howard, Brandon Hancock, Andrea Fava, Takanori Sasaki, Tusharkanti Ghosh, Jun Inamo, Rebecca Beuschel, Ye Cao, Katie Preisinger, Maria Gutierrez-Arcelus, Thomas M Eisenhaure, Joel Guthridge, Paul J Hoover, Maria Dall'Era, David Wofsy, Diane L Kamen, Kenneth C Kalunian, Richard Furie, Michael Belmont, Peter Izmirly, Robert Clancy, David Hildeman, E Steve Woodle, William Apruzzese, Maureen A McMahon, Jennifer Grossman, Jennifer L Barnas, Fernanda Payan-Schober, Mariko Ishimori, Michael Weisman, Matthias Kretzler, Celine C Berthier, Jeffrey B Hodgin, Dawit S Demeke, Chaim Putterman, Michael B Brenner, Jennifer H Anolik, Soumya Raychaudhuri, Nir Hacohen, Judith A James, Anne Davidson, Michelle A Petri, Jill P Buyon, Betty Diamond, Fan Zhang, James A Lederer, Deepak A Rao.
      Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified three immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells showed more active disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to five simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.
    Keywords:  Autoimmunity; Biomarkers; Immunology; Lupus
    DOI:  https://doi.org/10.1172/JCI181034
  37. Exp Mol Med. 2025 Jun 16.
    Thyrotropin exacerbates insulin resistance by triggering macrophage inflammation in subclinical hypothyroidism.
    Haihong Zhang, Zekun Zeng, Yan Liu, Wenfang Zheng, Jianling Wang, Yao Yao, Yanan Wang, Meiju Ji, Peng Hou.
      In subclinical hypothyroidism, the levels of serum thyroid-stimulating hormone (TSH) are positively correlated with insulin resistance; however, the precise mechanism is unclear. Except for thyroid follicular epithelial cells, macrophages express the highest levels of TSHR. Thus, we speculate that TSH may promote insulin resistance by triggering macrophage inflammation. Here we established a mouse model of TSH receptor (Tshr) myeloid-specific knockout (TshrMKO) and found that TshrMKO mice showed improvement on high-fat diet-induced obesity and insulin resistance compared with wild-type mice (Tshrf/f). In addition, TshrMKO mice exhibited decreased infiltration and M1 polarization of macrophages in liver, adipose and skeletal muscle. Co-culture experiments proved that Tshr-deficient macrophages decreased gluconeogenesis in hepatocytes but increased glucose uptake in adipocytes and skeletal muscle cells by improving the insulin signaling pathway. Mechanistically, increased TSH levels in subclinical hypothyroidism promoted the secretion of cytokines IL-1α, IL-1β and IL-6 by inducing macrophage M1 polarization, which upregulated EGR1 to transcriptionally activate LCN2 and SOCS3 in insulin target cells, thereby exacerbating insulin resistance. These effects could be reversed by IL-1 and IL-6 blockers IL-1RA and IL-6ST. Thus, we provided mechanistic insights into the predisposition to insulin resistance in subclinical hypothyroidism and revealed the role of TSH in metabolic disorders.
    DOI:  https://doi.org/10.1038/s12276-025-01478-1
  38. Nat Commun. 2025 Jun 19. 16(1): 5344
    TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation.
    Lena Lößlein, Mathias Linnerbauer, Finnja Zuber, Thanos Tsaktanis, Oliver Vandrey, Anne Peter, Franziska Panier, Julia Zissler, Vivienne Riekher, Tobias Bäuerle, Jannis Hanspach, Frederik B Laun, Lisa Nagel, Lisa Mészáros, Friederike Zunke, Jürgen Winkler, Ulrike J Naumann, Nora Schwingen, Emely Neumaier, Arthur Liesz, Francisco Quintana, Veit Rothhammer.
      After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.
    DOI:  https://doi.org/10.1038/s41467-025-60363-7
  39. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00580-7. [Epub ahead of print]44(6): 115809
    Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
    Jack H Howden, Hanna Hakansson, Manuela Nieto-Rostro, Robyn McAdam, Charles Arber, Nicholas J Brandon, Josef T Kittler.
      Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure to neuroinflammatory stimuli enhances PINK1/HK2-dependent mitophagy, providing neuroprotection. These findings contribute to our understanding of mitophagy mechanisms in astrocytes and underscore the importance of PINK1 in cellular health and function within the context of neurodegenerative diseases.
    Keywords:  CP: Metabolism; CP: Neuroscience; PINK1; Parkinson’s disease; astrocyte; hexokinase; inflammation; metabolism; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2025.115809
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒23 at 16:02.