bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–09–14
forty-two papers selected by
Dylan Ryan, University of Cambridge
  1. Metabolites as regulators of autoimmune diseases.
  2. Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses.
  3. Immune Regulation of Itaconate and Its Derivatives in Liver Diseases.
  4. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
  5. Divergent metabolic rewiring shapes altered innate immunity.
  6. Fueling fibrosis: metabolic dysregulation in systemic sclerosis.
  7. Chitosan Oligosaccharide Attenuates Neuroinflammation by Regulating Microglial Immunometabolic Reprogramming via the mTOR Signaling Pathway.
  8. Beneficial effect of resveratrol on T cell oxidative metabolism and anti-tumor function is conditioned by prior in vivo T cell history.
  9. Metabolic and immunomodulatory control of type 2 diabetes via generating cellular itaconate reservoirs by inflammatory-targeting gene-therapy nanovesicles.
  10. A scoping review on the possible immunometabolic properties of the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid.
  11. Metabolic control of innate-like T cells.
  12. Aberrant Nutrient Metabolism in T Cells: Pathogenesis Insight and Therapeutic Target for Autoimmune Diseases.
  13. Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation.
  14. ADAM9 Promotes Glycolysis in Th17 Cells and Autoimmunity Through Activation of IGF-1 Signaling.
  15. Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.
  16. Phytochemical alkaloids orchestrate immunometabolism against viral infections.
  17. Macrophage metabolic reprogramming during dietary stress influences adult body size in Drosophila.
  18. Glycogen synthase kinase-3 is essential for Treg development and function.
  19. Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.
  20. TLR2 supports γδ T cell IL-17A response to ocular surface commensals by metabolic reprogramming.
  21. mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow.
  22. FABP5 in skin macrophages mediates saturated fat-induced IL-1β signaling in psoriatic inflammation.
  23. Multi-omic analysis reveals a key BCAT1 role in mTOR activation by B-cell receptor and TLR9.
  24. SAMHD1 promotes cardiac repair post myocardial infarction by targeting NR4a1 to regulate macrophage metabolic reprogramming.
  25. Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction-associated steatohepatitis.
  26. Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases.
  27. NAD Metabolism Regulates Proliferation of Macrophages in Atherosclerosis.
  28. Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism.
  29. TIM-3 ameliorates host responses to Salmonella infection by controlling iron driven CD4+ T cell differentiation and interleukin-10 formation.
  30. FABP4-dependent fatty acid oxidation-fueled mitochondrial ROS induces the mobilization of cellular iron and facilitates Trypanosoma cruzi proliferation in murine adipocytes.
  31. Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes.
  32. Gut microbe-derived metabolites drive psoriatic inflammation via modulation of skin Th17 cells.
  33. Nuclear glycine decarboxylase suppresses STAT1-dependent MHC-I and promotes cancer immune evasion.
  34. Macrophage metabolic rewiring rejuvenates muscle raman signatures and cellular remodeling during regrowth in aged mice.
  35. Lactate Metabolic Reprogramming Mediated by CircRNA-LDHA Complex Facilitates Innate Immune Evasion of Liver Cancer.
  36. Dietary supplementation of arachidonic acid promotes humoral immunity.
  37. Understanding the kinetics of macrophage uptake and the metabolic fate of iron-carbohydrate complexes used for iron deficiency anemia treatment.
  38. Multi-Omics and Clinical Validation Identify Key Glycolysis- and Immune-Related Genes in Sepsis.
  39. Novel bacterial strategy to hijack plant immunity through metabolic manipulation.
  40. Targeting the Immunometabolism Interface: A Novel Strategy for IPF Therapy.
  41. Lactate and Lactylation in Respiratory Diseases: from Molecular Mechanisms to Targeted Strategies.
  42. Altered T Lymphocytes Mitochondrial Function and Inflammatory Factors of Peripheral Blood in HIV Patients With Mycobacterial Infection.
  1. Front Immunol. 2025 ;16 1637436
    Metabolites as regulators of autoimmune diseases.
    Maria Tada, Michihito Kono.
      Immune cell metabolism is essential for regulating immune responses, including activation, differentiation, and function. Through glycolysis and oxidative phosphorylation (OXPHOS), metabolism supplies energy and key intermediates for cell growth and proliferation. Importantly, some metabolites generated during these processes act as signaling molecules that influence immune activity. Autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) involve multiple immune cell types, and recent research in immunometabolism has revealed that disrupted metabolic pathways in these cells contribute to disease progression. Effector T cells, for instance, undergo metabolic reprogramming, particularly increased glycolysis, to meet the demands of proliferation and function during autoimmune responses. Targeting metabolic enzymes has shown therapeutic potential. In addition, metabolites themselves, termed immunometabolites, can directly modulate immune responses. These include both intracellularly generated and secreted molecules. Itaconate is a key immunometabolite and is derived from the TCA cycle by aconitate decarboxylase 1 (ACOD1) in activated macrophages. It inhibits the NLRP3 inflammasome and pro-inflammatory cytokines, such as IL-1β and IL-6. Beyond macrophages, itaconate alters metabolism and epigenetics in T cells by reducing 2-hydroxyglutarate and the S-adenosyl-L-methionine (SAM)/S-adenosyl-L-homocysteine (SAH) ratio, thereby suppressing Th17 differentiation and enhancing Foxp3 expression in Tregs. Itaconate ameliorates disease in experimental autoimmune encephalomyelitis, RA, SLE, and others. It also exhibits antimicrobial effects by blocking bacterial isocitrate lyase and viral replication. Despite increasing interest, reviews focusing specifically on immunometabolites remain limited. This review highlights emerging insights into metabolites involved in glycolysis, the TCA cycle, glutaminolysis, one-carbon metabolism, and lipid metabolism that influence autoimmune pathophysiology.
    Keywords:  cellular metabolism; glutaminolysis; glycolysis; itaconate; metabolite
    DOI:  https://doi.org/10.3389/fimmu.2025.1637436
  2. Front Immunol. 2025 ;16 1568514
    Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses.
    Yazan Alwarawrah, Amanda G Nichols, Isha Patel, Andréa B Ball, Nancie J MacIver.
      Interleukin-6 (IL-6) is a multifunctional cytokine that plays important roles in inflammation. Several studies have shown that IL-6 regulates various aspects of T cell function, including the differentiation of CD4+ T cells into the pro-inflammatory Th17 subset. Given the tight link between T cell metabolism and function, and the role of IL-6 in regulating cellular metabolism across tissues, we investigated the role of IL-6 signaling in Th17 cell metabolism. Using T cell specific IL-6 receptor (IL-6R) conditional knockout mice and littermate controls, we found that IL-6R signaling regulates the proportions of CD4+ and CD8+ T cells and drives CD4+ T cell differentiation into Th17 cells. We also found that IL-6R signaling is required for Th17 cell glycolytic metabolism. In T cell-specific IL-6R knockout mice, Th17 cells had reduced glucose uptake and glycolysis, as well as decreased expression of key glycolytic enzymes, while showing increased basal oxygen consumption. However, we also found that IL-6R signaling enhanced oxidative capacity and mitochondrial coupling efficiency in Th17 T cells. Importantly, inhibition of lactate dehydrogenase using FX11 selectively impaired Th17 cell differentiation with minimal effects on Treg cells. These findings suggest that targeting metabolic pathways regulated by IL-6R signaling can selectively inhibit inflammatory Th17 responses, offering a potential strategy for controlling IL-6 mediated inflammation.
    Keywords:  T cells; Th17; cellular metabolism; glycolysis; immunometabolism; inflammation; interleukin-6 (IL-6)
    DOI:  https://doi.org/10.3389/fimmu.2025.1568514
  3. Mol Cell Biol. 2025 Sep 10. 1-18
    Immune Regulation of Itaconate and Its Derivatives in Liver Diseases.
    Tianning Ge, Yifei Zhang.
      Over the past few decades, liver disease has emerged as one of the leading causes of death worldwide. Liver injury is frequently associated with infections, alcohol consumption, or obesity, which trigger hepatic inflammation and ultimately lead to progressive fibrosis and carcinoma. Although various cell populations contribute to inflammatory and fibrogenic processes in the liver, macrophages serve as a pivotal mediator. Hepatic macrophages exhibit substantial heterogeneity and perform diverse functions that depend on the pathological microenvironment. The immune response gene 1 (IRG1), a critical metabolic regulatory gene, encodes the mitochondrial enzyme aconitate decarboxylase 1 (ACOD1), which influences macrophage functional polarization by promoting the synthesis of itaconate, a metabolite produced via a side pathway of the tricarboxylic acid (TCA) cycle. Increasing evidence indicates that itaconate and its derivatives exert immunomodulatory effects in processes such as oxidative stress, viral infection, inflammation, tumorigenesis, and wound healing, thereby demonstrating significant potential for treating liver disorders. In this review, we summarize the roles of itaconate and its derivatives in liver diseases and their underlying mechanisms, thereby providing insights into the therapeutic potential of targeting macrophages.
    Keywords:  IRG1; immunometabolism; itaconate; liver disease
    DOI:  https://doi.org/10.1080/10985549.2025.2553660
  4. Nat Metab. 2025 Sep 10.
    In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
    Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Mack B Reynolds, Emeline Joulia, Maureen L Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
    DOI:  https://doi.org/10.1038/s42255-025-01363-1
  5. Cell Immunol. 2025 Sep 06. pii: S0008-8749(25)00111-X. [Epub ahead of print]417 105025
    Divergent metabolic rewiring shapes altered innate immunity.
    Mohua Liu, Xiao Wang, Xiaoya Qu, Yao Wang, Xihui Shen, Lei Xu.
      Both trained immunity (TRIM) and endotoxin tolerance (ET) initiate similar metabolic reprogramming characterized by enhanced glycolysis following an initial stimulus. However, TRIM exhibited heightened immune activation upon restimulation, whereas ET showed suppressed innate immune response. This divergence is attributed to distinct metabolic intermediates accumulated after the initial stimulation. In TRIM, metabolites like fumarate and glutamine derivatives accumulate, reinforcing pro-inflammatory epigenetic modifications. Conversely, ET is characterized by increased itaconate and lactate levels, promoting anti-inflammatory epigenetic changes and metabolic paralysis. This review highlights metabolic intermediates as key regulators of innate immune fate decisions, presenting avenues for targeted immune modulation.
    Keywords:  Endotoxin tolerance (ET); Fumarate; Itaconate; Mevalonate pathway; Trained immunity (TRIM)
    DOI:  https://doi.org/10.1016/j.cellimm.2025.105025
  6. Curr Opin Rheumatol. 2025 Sep 15.
    Fueling fibrosis: metabolic dysregulation in systemic sclerosis.
    Katja Lakota, Nika Boštic, Blaž Burja.
       PURPOSE OF REVIEW: This review examines how metabolic reprogramming drives fibrosis and immune dysregulation in systemic sclerosis (SSc), emphasizing the role of nutrient-sensing and energy pathways in disease progression.
    RECENT FINDINGS: SSc is characterized by a shift from catabolic to anabolic metabolism, defined by reduced AMP-activated protein kinase (AMPK) and enhanced mechanistic target of rapamycin complex 1 (mTORC1) signaling. This promotes biosynthetic activity, with upregulated glycolysis supplying substrates for collagen production and supporting pro-inflammatory immune cell polarization. Remodeling of the tricarboxylic acid cycle yields key metabolites with extrametabolic roles. α-ketoglutarate (αKG) supports epigenetic regulation, collagen maturation, and AMPK activation, offering protective effects. In contrast, succinate and fumarate promote inflammation and fibrotic signaling. Despite increased anabolic activity, oxidative phosphorylation remains elevated in SSc fibroblasts, contributing to excess reactive oxygen species (ROS). Metabolomic analyses consistently show disrupted amino acid and lipid metabolism, including glutamine and tryptophan pathways, linked to immune activation and fibrogenesis. Single-cell transcriptomics reveal diverse fibroblast subtypes with distinct metabolic programs correlating with fibrosis severity.
    SUMMARY: SSc is characterized by a metabolic reprogramming that favors anabolic, profibrotic, and proinflammatory states. These interconnected metabolic shifts illustrate how central carbon and nutrient pathways not only sustain energy demands but also actively regulate profibrotic signaling, offering new therapeutic targets for modulating fibrosis.
    Keywords:  amino acids; anabolism; lipids; metabolism; systemic sclerosis
    DOI:  https://doi.org/10.1097/BOR.0000000000001123
  7. J Agric Food Chem. 2025 Sep 12.
    Chitosan Oligosaccharide Attenuates Neuroinflammation by Regulating Microglial Immunometabolic Reprogramming via the mTOR Signaling Pathway.
    Hongli Chen, Mingyang Cai, Yue He, Yaxuan Sun, Xueling Dai.
      Microglia, the primary immune cells in the central nervous system (CNS), undergo immunometabolic reprogramming under neuroinflammatory conditions. Chitosan oligosaccharide (COS) exhibits multiple biological activities, including anti-inflammatory and antioxidant effects, yet its influence on microglial metabolism remains unclear. Here, we demonstrate that lipopolysaccharide (LPS) triggers immunometabolic alterations in microglia via the mechanistic target of the rapamycin (mTOR) pathway. COS effectively normalized immunometabolism by modulating mTOR signaling, enhancing oxidative phosphorylation (OXPHOS), attenuating anaerobic glycolysis and pentose phosphate pathway (PPP) activation, promoting M2 polarization, and increasing adenosine triphosphate (ATP) production. In vivo, COS suppressed mTOR activation in the hippocampal and cortical regions, improved cognitive and spatial memory, and reduced neuronal damage in LPS-challenged mice. These findings suggest that COS modulates microglial immunometabolic reprogramming through mTOR signaling, thereby augmenting immune homeostasis and cognitive performance. In conclusion, our findings propose COS as a promising therapeutic candidate for the prevention and treatment of neuroinflammation-related disorders.
    Keywords:  M2 polarization; chitosan oligosaccharide (COS); immunometabolic reprogramming; mTOR signaling pathway; microglia; neuroinflammation; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.1021/acs.jafc.5c05010
  8. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101553
    Beneficial effect of resveratrol on T cell oxidative metabolism and anti-tumor function is conditioned by prior in vivo T cell history.
    Patricia Mercier-Letondal, Chrystel Marton, Bernard Royer, Paul Peixoto, Barbara Dehecq, Olivier Adotévi, Jeanne Galaine, Yann Godet.
      Despite the clinical success of redirected T cells in the setting of cancer adoptive cell immunotherapy, patients may exhibit resistance to treatment, resulting in uncontrolled disease and relapses. This phenomenon partly relies on impaired ex vivo-produced T cell metabolic fitness, including a decreased respiratory reserve, as well as a greater sensitivity to tumor-mediated metabolic stress. To improve the respiratory capacity of cultured T cells, we sought to target the nicotinamide adenine dinucleotide/sirtuine-1/reactive oxygen species (ROS) axis through supplementation of culture medium with resveratrol. Resveratrol-treated T cells display broader respiratory capacities, along with sustained ROS control ability. Strikingly, we reveal that the effect of resveratrol on T cells is restricted to cytomegalovirus (CMV)-exposed donors, a virus known to promote immune aging. Herein, CMV prior infection is associated with the influence of terminally differentiated T cells on the fate of companion T cell subsets. Moreover, beyond resveratrol's effect on redirected T cell metabolic features, it provides a functional anti-tumor advantage to these CMV-seropositive donor-derived T cells, in a third-generation CD123-specific chimeric antigen receptor-T cell in vitro model. This highlights the necessity to consider patient's intrinsic attributes, especially immune aging-related ones, when assessing new T cell production processes to improve clinical efficacy, pushing the limits of personalized medicine.
    Keywords:  T cell differentiation profile; T cell fitness; T cell metabolism; adoptive immunotherapy; cytomegalovirus; immune aging; nicotinamide adenine dinucleotide; redirected T cells; resveratrol
    DOI:  https://doi.org/10.1016/j.omtm.2025.101553
  9. Trends Biotechnol. 2025 Sep 08. pii: S0167-7799(25)00310-5. [Epub ahead of print]
    Metabolic and immunomodulatory control of type 2 diabetes via generating cellular itaconate reservoirs by inflammatory-targeting gene-therapy nanovesicles.
    An Lao, Weiqi Li, Yiting Sun, Yuting Cao, Yu Zhuang, Jianyong Wu, Dejian Li, Kaili Lin, Jing Mao, Jiaqiang Liu.
      Type 2 diabetes (T2D) is characterized by persistent and unresolved tissue inflammation caused by the infiltration and dysregulation of immune cells. Current therapeutics targeting inflammatory immune cells for T2D remain limited. In this study, we analyzed single cell RNA from metabolic organs in T2D, revealing increased macrophage accumulation and a pathogenic macrophage subpopulation defined as NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3)+ inflammatory and metabolically activated macrophages. To target these inflammatory cells, we developed nanovesicles encapsulating mitochondrial metabolic enzyme-related gene segments [immune-responsive gene 1 (IRG1)-overexpression plasmids] with cell membrane decoration. The nanovesicles functioned as cellular itaconate producers that elegantly circumvented the drug utilization barriers of a classic NLRP3 inhibitor and, as a mitochondria-reprograming system, mitigated fatty acid (FA)-associated metabolic dysfunction. The nanovesicles reversed inflammation, restored metabolic functions, and ameliorated obesity. Therefore, the metabolic and immunomodulatory functions of nanovesicles may offer translational opportunities for the prevention and treatment of T2D.
    Keywords:  NLRP3(+) macrophages; gene-therapy nanovesicles; inflammation; itaconate; mitochondrial metabolism; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.tibtech.2025.07.025
  10. Am J Clin Nutr. 2025 Sep 04. pii: S0002-9165(25)00516-7. [Epub ahead of print]
    A scoping review on the possible immunometabolic properties of the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid.
    Ole Bæk, Björn Klabunde, Tingting Wang, Klaus Bønnelykke, Jakob Stokholm, Nicklas Brustad, Duc Ninh Nguyen, Bo Chawes.
      Circulating levels of 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), a metabolite derived from dietary furan fatty acids primarily found in marine food sources, have long been recognized as biomarkers for fish intake. However, elevated CMPF levels are also observed in patients with type 2 diabetes or chronic kidney disease and in healthy people associated with a reduced infection risk, suggesting potential bioactive roles in metabolism and immune function. Yet, the possible causal mechanisms behind these associations are unknown. The aim of this scoping review, derived from human observations as well as in vivo and in vitro experimental studies, is to present the hypothesis that CMPF has immunometabolic properties by providing an overview of the determinants of circulating CMPF levels and presenting the studies suggesting its influence on cellular energy metabolism, particularly through enhancing lipid β-oxidation, potentially via activation of peroxisome proliferator-activated receptors (PPARs). CMPF notably affects hepatic metabolism by increasing mitochondrial fatty acid utilization and promoting the expression of hepatokines such as fibroblast growth factor 21, which may exert systemic metabolic and anti-inflammatory effects. Additionally, elevated CMPF levels have complex impacts on pancreatic function, potentially impairing insulin secretion and modifying glucose homeostasis. These metabolic alterations in liver and pancreas can indirectly influence immune responses, shaping energy metabolism within immune cells and enhance anti-inflammatory phenotypes. Moreover, CMPF may also directly influence immune cell metabolism and function through PPAR activation. Epidemiological evidence further supports that elevated CMPF levels are associated with reduced susceptibility to infections. Collectively, there is compelling evidence supporting the hypothesis that CMPF is a bioactive metabolite with systemic metabolic and immunomodulatory effects, warranting further in-depth investigation.
    Keywords:  CMPF; Diet; Fish oil; Immunity; Immunometabolism; Infection; Metabolism
    DOI:  https://doi.org/10.1016/j.ajcnut.2025.08.020
  11. Nat Rev Immunol. 2025 Sep 08.
    Metabolic control of innate-like T cells.
    Thomas Riffelmacher, Mitchell Kronenberg.
      Immunometabolism, the intersection of cellular metabolism and immune function, has revolutionized our understanding of T cell biology. Changes in cellular metabolism help guide the development of thymocytes and the transition of T cells from naive to effector, memory and tissue-resident states. Innate-like T cells are a unique group of T cells with special characteristics. They respond rapidly, reside mainly in tissues and express T cell receptors with limited diversity that recognize non-peptide antigens. This group includes invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and some populations of γδ T cells. Different subsets of innate-like T cells rely on specific metabolic pathways that influence their differentiation and function and distinguish them from conventional CD4+ and CD8+ T cells. Although there are differences between innate-like T cell types, they share metabolic and functional features. In this Review, we highlight recent research in this emerging field. Understanding how metabolic programmes differ between innate-like T cells and other T cells may open opportunities for tailoring innate-like T cell responses and adoptive T cell therapies for use in cancer, metabolic and autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41577-025-01219-5
  12. Eur J Immunol. 2025 Sep;55(9): e70059
    Aberrant Nutrient Metabolism in T Cells: Pathogenesis Insight and Therapeutic Target for Autoimmune Diseases.
    Shumei Cao, Jiao Jiang, Haoyuan Yin, Xiaoyu Su, Qilin Li, Junhui Wu, Wenrui Li, Lai Wang, Qianjin Lu.
      Abnormal T-cell activation and differentiation are pivotal in the pathogenesis of autoimmune disorders. Traditionally, T cell activation is orchestrated by three canonical signals: antigen recognition through the T-cell receptor (TCR) and major histocompatibility complex (MHC) interaction, co-stimulatory signals, and cytokine signaling. Recent studies have highlighted nutrients as a key fourth signal in modulating T cell immunity. T cell metabolism is integral to regulating cell proliferation, survival, and differentiation. Dysregulation of nutrient metabolism, including glucose, amino acids, and lipids, has been considered a crucial determinant of T cell activation, differentiation, and function, and may lead to the disease progression of autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). This review aims to elucidate the impact of T cell metabolic reprogramming on autoimmune disease development and explore potential therapeutic approaches targeting nutrient metabolism for treating autoimmune disorders.
    Keywords:  T cell; autoimmune disease; multiple sclerosis; nutrient metabolism; rheumatoid arthritis; systemic lupus erythematosus
    DOI:  https://doi.org/10.1002/eji.70059
  13. J Exp Med. 2025 Nov 03. pii: e20250185. [Epub ahead of print]222(11):
    Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation.
    Jinjin Xu, Lingjia Kong, Elizabeth A Creasey, Sneha Rath, Lei Deng, Julian Avila-Pacheco, Chenhao Li, Blayne A Oliver, Tyler T Dao, Angela R Shih, Mark J Daly, Alex K Shalek, Clary B Clish, Daniel B Graham, Jacques Deguine, Ramnik J Xavier.
      Genome-wide association studies (GWAS) have linked the locus encoding ankyrin repeat domain 55 (ANKRD55) with numerous autoimmune diseases; however, its biological function and role in inflammation are unclear. Here, we demonstrate that Ankrd55-deficient mice are protected from T cell-mediated colitis but are more susceptible to Citrobacter rodentium infection. Mechanistically, Ankrd55 deletion impairs CD4+ T cell proliferation and reduces effector cytokine production in T helper 17 (TH17) cells in a cell-intrinsic manner. ANKRD55 is associated with mitochondria, and its loss is associated with impaired mitochondrial respiration and activation of the LKB1 pathway. Consistently, IL-17 production can be rescued by the deletion of LKB1 in Ankrd55-deficient T cells. Altogether, our study implicates the protein ANKRD55 as a functional modulator of T cell metabolism that directly impacts TH17 responses, highlighting it as a potential target across multiple autoimmune diseases.
    DOI:  https://doi.org/10.1084/jem.20250185
  14. Arthritis Rheumatol. 2025 Jul 21.
    ADAM9 Promotes Glycolysis in Th17 Cells and Autoimmunity Through Activation of IGF-1 Signaling.
    Kohei Karino, Masataka Umeda, Theodoros Vichos, Wenliang Pan, Michihito Kono, Maria G Tsokos, George C Tsokos.
       OBJECTIVE: Interleukin-17-producing CD4+ Th17 cells contribute to the pathogenesis of autoimmune diseases, including crescentic glomerulonephritis. Although ADAM9 has been reported to contribute to organ inflammation, the mechanism remains poorly understood. The goal of the current study was to investigate how ADAM9 alters T cell metabolism to promote the generation of Th17 cell differentiation.
    METHODS: We induced antiglomerular basement membrane (anti-GBM) glomerulonephritis in Adam9+/+ and Adam9-/- mice using sheep anti-GBM IgG and compared disease severity. Glycolysis in Th17 cells was measured using a Seahorse XFp Extracellular Flux Analyzer (Agilent Technologies, Inc), and metabolomic analysis was conducted on Th17 cells from both Adam9+/+ and Adam9-/- mice. We measured the GLUT1 expression in Th17 cells from Adam9+/+ and Adam9-/- mice and insulin-like growth factor 1 (IGF-1)-treated Th17 cells. Finally, we assessed the protease activity of ADAM9 on IGF-binding protein 4 (IGFBP4).
    RESULTS: Mice deficient in ADAM9 had limited numbers of kidney-infiltrating CD4+ T cells and suffered reduced kidney damage and inflammation following the injection of sheep anti-GBM IgG. ADAM9 deficiency led to decreased GLUT1 expression and glycolysis in Th17 cells. Mechanistically, we found that ADAM9 cleaved IGFBP4 and enabled the release of IGF-1, which enhanced the expression of GLUT1 and promoted glycolysis.
    CONCLUSION: By cleaving IGFBP4, ADAM9 releases IGF-1, which in turn upregulates GLUT1 expression and promotes glycolysis in Th17 cells. These findings suggest that targeting ADAM9 or blocking IGF-1 should provide a therapeutic strategy for autoimmune diseases.
    DOI:  https://doi.org/10.1002/art.43313
  15. Sci Adv. 2025 Sep 12. 11(37): eadx6489
    Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.
    Gujie Wu, Xiaofei Fan, Lin Cheng, Zongwei Chen, Yanjun Yi, Jiaqi Liang, Xiaolong Huang, Na Yang, Jiacheng Yin, Weigang Guo, Yiwei Huang, Shanye Yin.
      The interplay between cellular metabolism and immune regulation is central to immune function and disease progression, revealing notable therapeutic opportunities. Upon activation, immune cells undergo metabolic reprogramming to meet heightened demands for energy and biosynthesis, reshaping regulatory networks across epigenomic, transcriptomic, and proteomic layers. Metabolite-derived posttranslational modifications (PTMs) serve as pivotal mechanisms integrating metabolic intermediates with immune signaling pathways. Beyond classical acetylation, diverse nonacetyl PTMs-including lactylation, succinylation, malonylation, palmitoylation, and myristoylation-modify histone and nonhistone proteins, regulating gene expression, protein stability, subcellular localization, enzymatic activity, and protein-protein interactions. Advances in mass spectrometry and bioinformatics now enable precise characterization of these PTMs, uncovering their broad roles in immune regulation. This review summarizes current progress in immunometabolism and explores future directions such as mechanistic studies, combination strategies, and clinical applications. Metabolite-driven PTMs critically connect metabolism to immune regulation, suggesting promising therapeutic approaches for cancer, autoimmune disorders, and inflammatory diseases.
    DOI:  https://doi.org/10.1126/sciadv.adx6489
  16. Natl Sci Rev. 2025 Sep;12(9): nwaf190
    Phytochemical alkaloids orchestrate immunometabolism against viral infections.
    Cuiqin Cheng, Yao Wang, Han Wang, Meiqi Zhang, Qiqi Li, Bing Xu, Lingdong Kong, Xia Liu, Yanli Yu, Yuting He, Yingjie Chu, Zhe Liu, Yuanyuan Qiao, Xinxin Yuan, Xin Jia, Anlong Xu.
      The role of cholesterol metabolism in antiviral immunity has been established, but if and how this cholesterol-mediated immunometabolism can be regulated by specific small molecules is of particular interest in the quest for novel antiviral therapeutics. Here, we first demonstrate that NPC1 is the key cholesterol transporter for suppressing viral replication by changing cholesterol metabolism and triggering the innate immune response via systemic analyses of all possible cholesterol transporters. We then use the Connectivity Map (CMap), a systematic methodology for identifying functional connections between genetic perturbations and drug actions, to screen NPC1 inhibitors, and found that bis-benzylisoquinoline alkaloids (BBAs) exhibit high efficacy in the inhibition of viral infections. Among all potent BBAs that we tested, tetrandrine (Tet) is the most effective, by directly binding to NPC1 and inducing lysosomal cholesterol accumulation in order to resist viral entries. Through the NPC1-STING interface mechanism, Tet further blocks STING lysosomal degradation which leads to boosting of the interferon-based antiviral response against multiple viruses both in vitro and in vivo. Therefore, BBAs represent very promising drug compounds for this newly discovered antiviral mechanism by targeting the NPC1-STING interface via cholesterol-mediated immunometabolism, which in turn disrupts the virus life cycle and boosts antiviral immunity.
    Keywords:  NPC1-STING interface; antiviral immunity; bis-benzylisoquinoline alkaloids; cholesterol metabolism; immunometabolism; virus
    DOI:  https://doi.org/10.1093/nsr/nwaf190
  17. EMBO Rep. 2025 Sep 09.
    Macrophage metabolic reprogramming during dietary stress influences adult body size in Drosophila.
    Anusree Mahanta, Sajad Ahmad Najar, Nivedita Hariharan, Ajit Bhowmick, Syed Iqra Rizvi, Manisha Goyal, Preethi Parupalli, Ramaswamy Subramanian, Angela Giangrande, Dasaradhi Palakodeti, Tina Mukherjee.
      Immune cells are increasingly recognized as nutrient sensors; however, their developmental role in regulating growth under homeostasis or dietary stress remains elusive. Here, we show that Drosophila larval macrophages, in response to excessive dietary sugar (HSD), reprogram their metabolic state by activating glycolysis, thereby enhancing TCA-cycle flux, and increasing lipogenesis-while concurrently maintaining a lipolytic state. Although this immune-metabolic configuration correlates with growth retardation under HSD, our genetic analyses reveal that enhanced lipogenesis supports growth, whereas glycolysis and lipolysis are growth-inhibitory. Notably, promoting immune-driven lipogenesis offsets early growth inhibition in imaginal discs caused by glycolytic and lipolytic immune-metabolic states. Our findings reveal a model of immune-metabolic imbalance, where growth-suppressive states (glycolysis, lipolysis) dominate over a growth-supportive lipogenic state, thereby impairing early organ size control and ultimately affecting adult size. Overall, this study provides important insights into dietary stress-induced immune-metabolic reprogramming and its link to organ size regulation and early developmental plasticity.
    Keywords:  Animal Growth; Dietary Stress; Glycolysis; Lipogenesis; Macrophages
    DOI:  https://doi.org/10.1038/s44319-025-00574-7
  18. Cell Rep. 2025 Sep 10. pii: S2211-1247(25)01027-7. [Epub ahead of print]44(9): 116256
    Glycogen synthase kinase-3 is essential for Treg development and function.
    Matheswaran Kandasamy, Hana F Andrew, Iwan G Raza, Robert Mitchell, Mariana Borsa, Salvatore Valvo, Mohammad Ali, Barbara Kronsteiner, Moustafa Attar, Alexander J Clarke.
      Tregs are critical regulators of the immune response, but the cellular and metabolic signaling pathways that control their development and homeostasis remain to be determined. We found that glycogen synthase kinase-3 (GSK3), a kinase that integrates signals from Akt and mTOR, was essential for Treg development, restraining fatal autoimmunity. Loss of Gsk3 led to metabolic rewiring in Tregs, with disordered nucleotide metabolism and activation of OxPhos. Acute deletion of Gsk3 did not affect Treg frequency or numbers but induced an effector gene expression program and led to the formation of populations with pro-inflammatory signatures. The acute loss of Gsk3 in Tregs profoundly enhanced anti-tumoral immune responses and suppressed tumor growth. Overall, we demonstrate that GSK3 critically regulates Treg homeostasis and anti-tumor immune responses.
    Keywords:  CP: Immunology; Tregs; metabolism; tumors
    DOI:  https://doi.org/10.1016/j.celrep.2025.116256
  19. Immunity. 2025 Sep 03. pii: S1074-7613(25)00371-1. [Epub ahead of print]
    Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.
    Dayana B Rivadeneira, Sanjana Thosar, Kevin Quann, William G Gunn, Victoria G Dean, Bingxian Xie, Angelina Parise, Andrew C McGovern, Kellie Spahr, Konstantinos Lontos, Ryan P Barnes, Marcel P Bruchez, Patricia L Opresko, Greg M Delgoffe.
      The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.
    Keywords:  DNA damage; ROS; T cell dysfunction; adoptive cell therapy; mitochondria; telomere; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2025.08.008
  20. J Exp Med. 2025 Nov 03. pii: e20251046. [Epub ahead of print]222(11):
    TLR2 supports γδ T cell IL-17A response to ocular surface commensals by metabolic reprogramming.
    Wenjie Zhu, Xiaoyan Xu, Vijayaraj Nagarajan, Jing Guo, Akriti Gupta, Zixuan Peng, Amy Zhang, Jie Liu, Mary J Mattapallil, Yingyos Jittayasothorn, Reiko Horai, Yasmine Belkaid, Michael G Constantinides, Anthony J St Leger, Rachel R Caspi.
      The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival γδ T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis (C. mast) elicits protective IL-17 responses from conjunctival Vγ4 T cells through a combination of γδ TCR ligation and IL-1 signaling. Here, we identify Vγ6 T cells as a major C. mast-responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that Vγ6 cells require both extrinsic (via dendritic cells) and intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes involved in fatty acid oxidation to support Il17a transcription. We identify a key transcription factor, IκBζ, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal γδ T cells.
    DOI:  https://doi.org/10.1084/jem.20251046
  21. Blood Adv. 2025 Sep 12. pii: bloodadvances.2025016439. [Epub ahead of print]
    mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow.
    Taylor Fulton-Ward, Nancy Gudgeon, Isaac Thirlwell, Emma Louise Bishop, Bryan Marzullo, Hannah Victoria Giles, Graham McIlroy, Paul Ferguson, Bhuvan Kishore, Kate Rogers, Nuri Nuri Alfasi, Timothy Wong, Satnam Aytain, Daniel A Tennant, Guy Pratt, Sarah Dimeloe.
      Novel therapies for multiple myeloma aim to engage anti-tumour functions of T cells. However, evidence indicates these functions are limited within the bone marrow environment. This is relatively hypoxic in health and studies indicate widespread hypoxia in multiple myeloma. In this study, CD8+ T cell responses to stimulation were assessed under hypoxia, which identified that activation, proliferation and interferon-gamma (IFN-γ) secretion were profoundly suppressed, whilst cytotoxicity and tumour necrosis factor-alpha (TNF-α) expression were unaffected. These changes occurred alongside decreased mTOR activity and expression of c-Myc, which drives T cell metabolic reprogramming upon stimulation. Consistently, hypoxic CD8+ T cells demonstrated decreased activation-induced glycolysis and mitochondrial glutamine oxidation. Mechanistically, this was linked to elevated BNIP3 expression under hypoxia and reciprocally decreased abundance of its interaction partner, Rheb, an important mTOR activator. Assessment of BCMAxCD3 bispecific antibody activity confirmed impaired capacity to elicit CD8+ T cell activation, IFN-γ expression, proliferation and altered memory differentiation under hypoxia, although initial target cell killing was unaffected. Finally, assessment of bone marrow CD8+ T cells from multiple myeloma patients identified decreased proliferation, c-Myc and Rheb expression compared to peripheral blood cells, alongside elevated BNIP3, confirming mechanistic features of hypoxic exposure in this environment. Taken together, the findings indicate potential for bone marrow hypoxia to influence efficacy of T cell-directed therapies for multiple myeloma.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016439
  22. Cell Rep. 2025 Sep 05. pii: S2211-1247(25)01025-3. [Epub ahead of print]44(9): 116254
    FABP5 in skin macrophages mediates saturated fat-induced IL-1β signaling in psoriatic inflammation.
    Jianyu Yu, Jiaqing Hao, Matthew S Yorek, Xingshan Jiang, Anthony Avellino, Shanshan Liu, Xiaochun Han, Jonathan Shilyansky, Zhaohua Wang, Yuhang Wang, Zizhen Kang, Ali Jabbari, Bing Li.
      High fat diet (HFD)-induced obesity increases the risk and severity of psoriasis. However, the immunoregulatory effects of different HFDs on psoriasis pathogenesis remains poorly understood. Here, mimicking human dietary fat profiles, four HFDs-saturated, monounsaturated, omega-6, and omega-3 fats-were designed and used to induce obesity in mice. Despite comparable obesity levels across groups, only the saturated HFD exacerbated imiquimod (IMQ)-induced psoriasis. This exacerbation correlated with elevated levels of IL-1β-producing macrophages, IL-17A-producing γδ T cells, and neutrophils within psoriatic lesions. Mechanistically, saturated fatty acids (FAs) promoted IL-1β/IL-17A signaling via fatty acid-binding protein 5 (FABP5)-mediated mitochondrial FA oxidation and extracellular ATP release in skin macrophages. Deletion of FABP5, either globally or specifically in macrophages, attenuated IL-1β/IL-17A signaling and alleviated IMQ-induced psoriasis. These findings identify FABP5 as a key mediator of saturated HFD-driven psoriasis via the IL-1β/IL-17 axis, offering insights into the interplay between dietary fats, obesity, and psoriasis.
    Keywords:  CP: Immunology; CP: Metabolism; FABP5; IL-17; IL-1β; macrophages; psoriasis; saturated fats
    DOI:  https://doi.org/10.1016/j.celrep.2025.116254
  23. J Clin Invest. 2025 Sep 09. pii: e186258. [Epub ahead of print]
    Multi-omic analysis reveals a key BCAT1 role in mTOR activation by B-cell receptor and TLR9.
    Rui Guo, Yizhe Sun, Matthew Y Lim, Hardik Shah, Joao A Paulo, Rahaman A Ahmed, Weixing Li, Yuchen Zhang, Haopeng Yang, Liang Wei Wang, Daniel Strebinger, Nicholas A Smith, Meng Li, Merrin Man Long Leong, Michael Lutchenkov, Jin-Hua Liang, Zhixuan Li, Yin Wang, Rishi Puri, Ari Melnick, Michael R Green, John M Asara, Adonia E Papathanassiu, Duane R Wesemann, Steven P Gygi, Vamsi K Mootha, Benjamin E Gewurz.
      B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states highly induced the transaminase branched chain amino acid transaminase 1 (BCAT1), which localized to lysosomal membranes to support branched chain amino acid synthesis and mechanistic target of rapamycin complex 1 (mTORC1) activation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes and identify BCAT1 as an activated B-cell therapeutic target.
    Keywords:  Adaptive immunity; Amino acid metabolism; Cell biology; Lymphomas; Metabolism
    DOI:  https://doi.org/10.1172/JCI186258
  24. J Adv Res. 2025 Sep 10. pii: S2090-1232(25)00701-5. [Epub ahead of print]
    SAMHD1 promotes cardiac repair post myocardial infarction by targeting NR4a1 to regulate macrophage metabolic reprogramming.
    Yu-Lan Ma, Hai-Yang Ni, Zhen Guo, Feng-Ming Guo, Ming-Yu Wang, Pan Wang, Yi-Peng Gao, Chun-Yan Kong, Qi-Zhu Tang.
       INTRODUCTION: Myocardial infarction (MI) is one of the leading causes of high mortality worldwide. Accumulating evidence suggests that macrophages emerge as the predominant immune population within the post-MI cardiac environment, serving as critical modulators that coordinate inflammatory cascades during myocardial repair.
    OBJECTIVES: The main objective of this study was to explore the effects of sterile alpha motif and HD domain-containing protein 1 (SAMHD1) on myocardial remodeling post-MI and to elucidate its potential mechanism. We used MI mouse model ligation of the left anterior descending coronary artery (LAD) to investigate the role of SAMHD1 in MI. To assess the role of SAMHD1 in MI, we generated both macrophage-specific knockout and overexpression mice. To investigate the mechanisms by which SAMHD1 regulates MI progression, we employed transcriptomics sequencing and nontargeted metabolomics.
    RESULTS: SAMHD1 was significantly upregulated in mouse cardiac macrophages on day 3 post-MI and was closely associated with immune responses. We found that SAMHD1 deficiency facilitated myocardial repair. We found that SAMHD1 deficiency confers cardioprotection through metabolic reprogramming mechanisms: increased mitochondrial oxidative phosphorylation capacity coupled with increased production of the anti-inflammatory metabolite itaconic acid and suppression of the pentose phosphate pathway and lactate biosynthesis. We found that these metabolic shifts facilitated macrophage differentiation by promoting a transition toward reparative macrophage populations. Furthermore, SAMHD1 deficiency drives macrophage phenotypic switching through the transcriptional suppression of NR4a1. More importantly, we have shown that SAMHD1 deficiency promotes the interaction between NR4a1 and Pparγ, which facilitates NR4a1 ubiquitination-dependent degradation.
    CONCLUSION: Our study revealed that macrophage-specific SAMHD1 deletion confers post-MI cardioprotection. More importantly, we demonstrated that NR4a1, a downstream target of SAMHD1, mediates the cardioprotective effects of SAMHD1 deficiency post-MI by regulating the remodeling of macrophage energy metabolism to promote the macrophage reparative phenotype.
    Keywords:  Macrophages; Metabolic reprogramming; Myocardial infarction; NR4a1; SAMHD1
    DOI:  https://doi.org/10.1016/j.jare.2025.09.018
  25. Sci Transl Med. 2025 Sep 10. 17(815): eadv2106
    Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction-associated steatohepatitis.
    Hongxue Shi, Xiaobo Wang, Christopher Sloas, Brennan Gerlach, Arif Yurdagul, Mary P Moore, Eui Jung Jung, Faridoddin Mirshahi, Luisa Ronzoni, Arun J Sanyal, Luca Valenti, Chyuan-Sheng Lin, James Montgomery, Bradley Zinker, Michael Klichinsky, Ira Tabas.
      Hepatocyte apoptosis is a key feature of metabolic dysfunction-associated steatohepatitis (MASH), but the fate of apoptotic hepatocytes in MASH is poorly understood. Here, we explore the hypotheses that clearance of dead hepatocytes by liver macrophages (efferocytosis) is impaired in MASH because of low expression of the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM4; gene Timd4) by MASH liver macrophages, which then drives liver fibrosis in MASH. We show that apoptotic hepatocytes accumulate in human and experimental MASH, using mice fed the fructose-palmitate-cholesterol (FPC) diet or the high-fat, choline-deficient amino acid-defined (HF-CDAA) diet. Apoptotic hepatocyte accumulation is associated with impaired efferocytosis and loss of TIM4. Administration of neutralizing anti-TIM4 antibodies or genetic deletion of Timd4 in Kupffer cells of FPC and HF-CDAA diet-fed mice decreased efferocytosis by liver macrophages, increased profibrotic activation of collagen-producing hepatic stellate cells (HSCs), and accelerated the progression to fibrotic MASH. Genetic restoration of macrophage Timd4 in FPC and HF-CDAA diet-fed MASH mice or cell therapy with TIM4+ macrophages enhanced apoptotic hepatocyte clearance and decreased HSC activation and liver fibrosis. Studies using an ex vivo macrophage HSC cross-talk model and the HF-CDAA MASH model revealed that inactivation of HSCs by efferocytosing macrophages involved macrophage reprogramming to secrete interleukin-10 (IL-10), which activated the IL-10 receptor on HSCs to dampen their profibrotic activation. These findings reveal a key process in the progression from hepatic steatosis to early MASH fibrosis and identify a mechanism-based therapeutic strategy to prevent fibrotic MASH progression.
    DOI:  https://doi.org/10.1126/scitranslmed.adv2106
  26. Trends Immunol. 2025 Sep 09. pii: S1471-4906(25)00201-7. [Epub ahead of print]
    Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases.
    Chun-Ting J Kwong, Mariana J Kaplan.
      Autoimmune diseases arise from genetic and environmental factors that disrupt immune tolerance. Recent studies highlight the role of myeloid cell immunometabolism, particularly mitochondrial dysfunction, in driving autoimmunity. Mitochondria regulate energy homeostasis and cell fate; their impairment leads to defective immune cell differentiation, abnormal effector activity, and chronic inflammation. We propose that chronic metabolic stress reprograms myeloid cells, fueling a vicious cycle of cell death and immune activation. Over time, this may induce several states of maladaptation in myeloid cells. Viewing autoimmune disease through a metabolic lens offers new insight into disease mechanisms and highlights potential therapeutic opportunities targeting mitochondrial function to restore immune balance.
    Keywords:  autoimmune diseases; mitochondrial dysfunction; myeloid cells
    DOI:  https://doi.org/10.1016/j.it.2025.08.003
  27. Arterioscler Thromb Vasc Biol. 2025 Sep 11.
    NAD Metabolism Regulates Proliferation of Macrophages in Atherosclerosis.
    Satyesh Sinha, Chantle R Swichkow, Lia Farahi, Miklós Péterfy, Calvin Pan, Zhiqiang Zhou, Marcus Seldin, Julia J Mack, Richard C Davis, Diana Shih, Aldons J Lusis.
       BACKGROUND: In genetic studies with the Hybrid Mouse Diversity Panel, we previously identified a chromosome 9 locus for atherosclerosis. We now identify NNMT (nicotinamide N-methyltransferase), an enzyme that degrades nicotinamide, as the causal gene in the locus and show that the underlying mechanism involves salvage of nicotinamide to nicotinamide adenine dinucleotide (NAD).
    METHODS: Gain/loss of function studies in macrophages were performed to examine the role of NAD levels in macrophage proliferation and apoptosis in atherosclerosis.
    RESULTS: Global inhibition of NNMT using an antisense oligonucleotide reduced atherosclerosis lesion area 5- to 10-fold in both male and female mice on a hyperlipidemic background. Selective inhibition of NNMT in liver and adipose, the major tissues expressing high levels of the enzyme, using siRNA, had little or no effect on atherosclerosis. Therefore, we hypothesized that levels of NAD in macrophages might contribute. This was confirmed by showing that transplantation with bone marrow from Nnmt knockout mice resulted in reduced lesional macrophage proliferation, increased macrophage apoptosis, and reduced atherosclerosis. Consistent with this conclusion, reduced expression of macrophage CD38, an enzyme that degrades NAD, reduced both macrophage proliferation and atherosclerosis. Moreover, cultured macrophages from heterozygous Nnmt knockout mice exhibited reduced proliferation, increased apoptosis, and an increased NAD/NADH ratio.
    CONCLUSIONS: These findings reveal a role for nicotinamide salvage and NAD turnover in macrophage proliferation and survival in the context of atherosclerosis.
    Keywords:  apoptosis; atherosclerosis; cell proliferation; macrophage; nicotinamide N-methyltransferase
    DOI:  https://doi.org/10.1161/ATVBAHA.125.323185
  28. Elife. 2025 Sep 08. pii: RP104138. [Epub ahead of print]14
    Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism.
    Mengyun Li, Huan Jin, Yongxiang Liu, Zining Wang, Lin Li, Tiantian Wang, Xiaojuan Wang, Hongxia Zhang, Bitao Huo, Tiantian Yu, Shoujie Wang, Wei Zhao, Jinyun Liu, Peng Huang, Jun Cui, Xiaojun Xia.
      Innate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by β-glucan. ATAC-seq and RNA-seq analysis reveal that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF, and NF-κB pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for S-adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions of Il6 and Tnf. Additionally, the tumor inhibition effect of β-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM levels through the mTOR-FOXO3-GNMT axis.
    Keywords:  Aurora kinase A; FOXO3; GNMT; S-adenosylmethionine; epigenetics; immunology; inflammation; mouse; trained immunity
    DOI:  https://doi.org/10.7554/eLife.104138
  29. EBioMedicine. 2025 Sep 11. pii: S2352-3964(25)00354-8. [Epub ahead of print]120 105910
    TIM-3 ameliorates host responses to Salmonella infection by controlling iron driven CD4+ T cell differentiation and interleukin-10 formation.
    Christa Pfeifhofer-Obermair, Natascha Brigo, Chiara Volani, Piotr Tymoszuk, Egon Demetz, Sabine Engl, Günter Weiss.
       BACKGROUND: Iron loading increases infection risk in being a nutrient for invading siderophilic bacteria and by modulating immune functions including the expression of the immune checkpoint regulator T-cell immunoglobulin-and-mucin-containing-domain-3 (TIM-3). TIM-3 affects specific immune cell functions including T-helper cell differentiation but also T cell dysfunction, and immune exhaustion. Given the prevalence of iron overload specifically in patients at higher risk for infection such as those suffering from hemo-oncological diseases, we investigated TIM-3's role in immune control of bacterial sepsis.
    METHODS: A sepsis model was employed in wildtype and Tim3-/- mice with transgenic expression of a functional natural resistance associated macrophage protein 1 (NRAMP1). This creates a chronic inflammation model with enhanced resistance to infections with Gram negative Salmonella typhimurium, enabling to study T cell immune responses over time.
    FINDINGS: Dietary iron supplementation reduced mouse survival, which was further exaggerated by TIM-3 deletion. This indicates that TIM-3 dependent immune regulation was essential for effective host defence against Salmonella. TIM-3 deletion increased the production of immune-deactivating interleukin (IL) -10 as a result of impaired interleukin-12 receptor (IL-12R)-dependent CD4+ cytotoxic T cell signalling and development which subsequently reduced the production of anti-microbial interferon gamma (IFNγ). Anti-IL-10 treatment in iron-loaded Tim3-/- mice improved Salmonella control and restored CD4+ T cell mediated IFNγ production.
    INTERPRETATION: Our study uncovers TIM-3 as a crucial regulator of T cell driven immune control of bacterial infection and identifies the underlying treatable pathways, which is of major importance to better combat infection related mortality in subjects with iron overload syndromes.
    FUNDING: Christian-Doppler-Society, FWF (I-3321, W-1253).
    Keywords:  CD4 T cells; IFNgamma; IL-10; Intracellular bacteria; Iron; TIM-3
    DOI:  https://doi.org/10.1016/j.ebiom.2025.105910
  30. mBio. 2025 Sep 08. e0218025
    FABP4-dependent fatty acid oxidation-fueled mitochondrial ROS induces the mobilization of cellular iron and facilitates Trypanosoma cruzi proliferation in murine adipocytes.
    Kazunari Ishii, Yusuke Kurihara, Michinobu Yoshimura, Nirwana Fitriani Walenna, Akinori Shimizu, Ryo Ozuru, Kenji Hiromatsu.
      Fatty acid-binding protein 4 (FABP4) is a cytosolic lipid chaperone predominantly expressed in adipocytes. It has been shown that Trypanosoma cruzi targets adipose tissues and resides in adipocytes. However, how T. cruzi manipulates adipocytes to redirect nutrients for its benefit remains unknown. Here, we uncover the role of FABP4 in facilitating T. cruzi infection in murine 3T3-L1 adipocytes. We demonstrate that pharmacological or genetic inhibition of FABP4, carnitine palmitoyltransferase I (CPT-1), or fatty acid oxidation (FAO) abrogates the intracellular growth of T. cruzi in adipocytes. We also found that inhibiting FABP4, CPT-1, or FAO eliminates the infection-induced elevation of mitochondrial and cellular reactive oxygen species (ROS) in adipocytes. Furthermore, T. cruzi infection-induced elevation of ROS in adipocytes increased the cytosolic Fe2+, which fueled T. cruzi proliferation. The treatment with antioxidants such as ROS scavenger N-acetyl cysteine (NAC) or mitochondrial ROS inhibitors MitoQ increased the expression level of mRNA for Ferroportin and Ferritin, leading to the decrease in cytosolic Fe2+ and the intracellular growth inhibition of T. cruzi in adipocytes. The addition of ferrous sulfate reversed the FABP4 inhibitor or antioxidant-induced decrease in adipocyte parasite burden. Our results demonstrate that T. cruzi exploits host FABP4 to facilitate fatty acid oxidation and elevate cellular ROS, increasing the labile iron pool for the intracellular replication of T. cruzi in adipocytes. These results highlight the therapeutic possibility of host FABP4 as a drug target for T. cruzi infection.IMPORTANCEPersistent infection with a protozoan parasite, Trypanosoma cruzi, causes Chagas disease. While it has been appreciated that adipose tissues are one of the sites of persistent infection, the mechanism of how the parasite survives in adipocytes remains to be established. Our study highlights FABP4, a key regulator of metabolic dysfunction and inflammation, as a therapeutic host target controlling T. cruzi infection in adipocytes. We uncover the importance of FABP4 for T. cruzi replication in mouse adipocytes through engagement with lipid droplet degradation and trafficking of liberated free fatty acids to the host cell's mitochondria, which are utilized for fatty acid oxidation (FAO). T. cruzi infection-induced FAO fuels reactive oxygen species, and the subsequent iron mobilization accelerates parasite replication. These results shed light on the mechanisms of T. cruzi persistent infection in adipocytes, raising the possibility of host FABP4 as a drug target for T. cruzi infection.
    Keywords:  FABP4; ROS; Trypanosoma cruzi; adipocyte; fatty acid oxidation; labile iron pool; mitochondria
    DOI:  https://doi.org/10.1128/mbio.02180-25
  31. Mol Med Rep. 2025 Dec;pii: 316. [Epub ahead of print]32(6):
    Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes.
    Jianping He, Chenxi Feng, Yaohan Xu, Yan Chen, Siji Chen, Jiang Zhu, Yinjing Song, Hao Cheng.
      Genital herpes (GH), which is primarily caused by herpes simplex virus type 2 (HSV‑2), is the leading cause of genital ulcers worldwide, and is characterized by recurring outbreaks of painful genital lesions. Despite the high prevalence of GH, the metabolic and transcriptomic mechanisms underlying disease recurrence remain poorly understood. Therefore, the present study aimed to identify metabolic alterations in patients with HSV‑2 GH via integrating transcriptomics, metabolomics and single‑cell RNA‑sequencing (scRNA‑seq) analyses. Non‑targeted metabolomics identified significant changes in pathways associated with glycerophospholipid metabolism, amino acid biosynthesis and cholesterol metabolism. In addition, RNA‑seq analysis revealed that genes associated with the alanine, aspartate and glutamate, and valine, leucine and isoleucine metabolism pathways were significantly upregulated in patients with recurrent HSV‑2 GH. Furthermore, scRNA‑seq data showed that IDH1 and ETNK1 were upregulated, mainly in dendritic cells (DCs), plasmacytoid DCs and monocytes derived from patients with GH. Notably, the expression levels of genes associated with oxidative phosphorylation, such as MT‑CYB and MT‑CO3, were significantly elevated across monocytes, T cells and B cells. Overall, the results of the current study suggested that metabolic reprogramming could occur in patients with recurrent HSV‑2 GH, thus providing potential biomarkers and therapeutic targets that could be involved in the future development of treatment approaches.
    Keywords:  RNA‑sequencing; genital herpes; glycerophospholipid metabolism; metabolomics; oxidative phosphorylation; single‑cell RNA-sequencing
    DOI:  https://doi.org/10.3892/mmr.2025.13681
  32. Immunity. 2025 Sep 09. pii: S1074-7613(25)00369-3. [Epub ahead of print]58(9): 2241-2255.e7
    Gut microbe-derived metabolites drive psoriatic inflammation via modulation of skin Th17 cells.
    Chenliang Wang, Shangzhi Dai, Shanshan Zhang, Zheyu Zheng, Zhixiao Zhou, Zhuojing Chen, Mingchao Wang, Yumei Gao, Yan Xin, Weihang Xiong, Sihan Xiong, Xiaowen Wang, Aiping Wang, Xueqiang Zhao, Hang Li, Xin Lin.
      The persistence of tissue-specific chronic inflammation results from an interplay of genetic and environmental factors. How these factors coordinate to sustain pathology in chronic conditions like psoriasis is not well resolved. Using a Card14E138A/+ murine model of psoriasis, we found that spontaneous skin inflammation reshaped not only the immune architecture in the skin but also systemic metabolites. We identified indole-producing microbiota in the gut-but not the skin-as drivers of psoriatic inflammation. Mechanistically, indole-producing intestinal microbes promoted host indoxyl sulfate (I3S) biosynthesis via a metabolic relay. I3S signaled through the aryl hydrocarbon receptor (AHR) in skin T helper (Th) 17 cells to modulate chromatin accessibility, which potentiated skin inflammation. In human psoriasis cohorts, serum I3S levels correlated with disease severity. In summary, our study uncovers a mechanistic link between gut microbial factors and skin inflammation, highlighting microbiota and metabolites as potential therapeutic targets for psoriasis.
    Keywords:  AHR; CARD14; Th17 cell; gut microbiota; gut-skin axis; indole pathway; indoxyl sulfate; metabolite; psoriasis; skin inflammation
    DOI:  https://doi.org/10.1016/j.immuni.2025.08.006
  33. EMBO J. 2025 Sep 08.
    Nuclear glycine decarboxylase suppresses STAT1-dependent MHC-I and promotes cancer immune evasion.
    Rui Liu, Hui-Fang Li, Qi Jiang, Jun-Ge Shi, Zi-Lun Ruan, Peng Ren, Yi-Nuo Li, Hong-Bing Shu, Shu Li.
      Inadequate antigen presentation by MHC-I in tumor microenvironment (TME) is a common immune escape mechanism. Here, we show that glycine decarboxylase (GLDC), a key enzyme in glycine metabolism, functions as an inhibitor of MHC-I expression in EGFR-activated tumor cells to induce immune escape by a mechanism independent of its enzymatic activity. Upon EGFR activation, GLDC is phosphorylated by SRC and subsequently translocated to the nucleus in human NSCLC cells. Nuclear GLDC sequesters STAT1 co-activator SMARCE1, inhibiting STAT1-dependent transcription of the inflammatory genes IRF1 and NLRC5. Further, GLDC recruits DNMT1 to the IRF1/NLRC5 promoter inducing DNA hypermethylation, suppressing transcription of downstream MHC-I genes. Inhibition of GLDC restores MHC-I levels in tumor cells, improves tumor-specific CD8+ T cells functions in the TME, and rescues anti-tumor effects of PD-1 blockade therapy in mice. Our findings reveal a non-enzymatic nuclear function for GLDC in the suppression of MHC-I antigen presentation, suggesting new strategies for ICB-based combination immunotherapy.
    Keywords:  EGFR Activation; GLDC; ICB Therapy; Immune Escape; MHC-I Antigen Presentation
    DOI:  https://doi.org/10.1038/s44318-025-00557-3
  34. JCI Insight. 2025 Sep 09. pii: e194303. [Epub ahead of print]
    Macrophage metabolic rewiring rejuvenates muscle raman signatures and cellular remodeling during regrowth in aged mice.
    Zachary J Fennel, Negar Kosari, Paul-Emile Bourrant, Elena M Yee, Robert J Castro, Anu S Kurian, Jonathan Palmer, Morgan Christensen, Katsuhiko Funai, Ryan M O'Connell, Anhong Zhou, Micah J Drummond.
      Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. Macrophage phenotype is metabolically controlled through TCA intermediate accumulation and activation of HIF1A. We hypothesized that transient hypoxia following disuse in old mice would enhance macrophage metabolic inflammatory function thereby improving muscle cellular remodeling and recovery. Old (20 months) and young adult mice (4 months) were exposed to acute (24h) normobaric hypoxia immediately following 14-days of hindlimb unloading and assessed during early re-ambulation (4- and 7-days) compared to age-matched controls. Treated aged mice had improved pro-inflammatory macrophage profiles, muscle cellular remodeling, and functional muscle recovery to the levels of young control mice. Likewise, young adult mice had enhanced muscle remodeling and functional recovery when treated with acute hypoxia. Treatment in aged mice restored the muscle molecular fingerprint and biochemical spectral patterns (Raman Spectroscopy) observed in young mice and strongly correlated to improved collagen remodeling. Finally, intramuscular delivery of hypoxia-treated macrophages recapitulated the muscle remodeling and recovery effects of whole-body hypoxic exposure in old mice. These results emphasize the role of pro-inflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.
    Keywords:  Aging; Fibrosis; Immunotherapy; Macrophages; Metabolism; Muscle biology
    DOI:  https://doi.org/10.1172/jci.insight.194303
  35. Adv Sci (Weinh). 2025 Sep 12. e09989
    Lactate Metabolic Reprogramming Mediated by CircRNA-LDHA Complex Facilitates Innate Immune Evasion of Liver Cancer.
    Hao Shen, Boqiang Liu, Jing He, Weijun Zhao, Weiqi Li, Lingfeng Ma, Lidan Hou, Yi Wang, Chenqi Jin, Yushun Chang, Jie Lin, Jia Zhao, Binghan Jin, Yuanshi Tian, Xiujun Cai, Liang Shi, Yifan Wang.
      Hepatocellular carcinoma (HCC) exhibits a distinctive metabolic profile that engenders a highly immunosuppressive tumor immune microenvironment, posing significant challenges for targeted therapy. Notably, natural killer (NK) cells, which are abundant in the liver and play a crucial role in innate immunity, are attracting growing attention in HCC immunotherapy. Previously, circular RNAs (circRNAs) have emerged as significant regulators in tumor development. Here, an in vitro NK-cell-driven tumor evolution model is innovatively established and a novel circRNA, circSMPD4 is identified, which induces lactate metabolic reprogramming in tumor, ultimately promoting immune evasion and metastasis. Lactate dehydrogenase A (LDHA), a main subunit of the critical enzyme in lactate metabolism, is identified as the core effector of circSMPD4's biological function. Mechanistically, circSMPD4 physically combines LDHA to reduce its acetylation levels via SIRT2-dependent deacetylation and thus preventing its degradation from chaperone-mediated autophagy-lysosome pathway. These findings unveil an oncogenic circRNA and elucidate a novel regulatory mechanism by which tumor cell metabolic reprogramming facilitates tumor immune evasion and tumor progression.
    Keywords:  circular RNA; immune evasion; lactate metabolism; liver cancer; natural killer cell; protein degradation
    DOI:  https://doi.org/10.1002/advs.202509989
  36. EMBO Mol Med. 2025 Sep 12.
    Dietary supplementation of arachidonic acid promotes humoral immunity.
    Shengyong Feng, Enhao Ma, Xiaona Na, Zongmei Wang, Wanbo Tai, Xinhui Bao, Mao Wang, Han Chang, Baolei Wu, Miaoxi Liu, Juzhen Li, Huicheng Shi, Celi Yang, Menglu Xi, Haibing Yang, Yuhan Li, Yibin Zhu, Penghua Wang, Ling Zhao, Ai Zhao, Gong Cheng.
      Vaccination offers the most effective protection against contagious infectious diseases primarily by inducing humoral immunity. Vaccination efficacy is influenced by various factors. We report that dietary administration of arachidonic acid (ARA) significantly boosts rabies vaccine-induced production of neutralizing antibodies and protection against lethal rabies virus (RABV) infection in mice. In human volunteers, oral supplementation of ARA accelerates the expression of neutralizing antibodies to the levels sufficient for protection against RABV as early as one week after primary immunization. Mechanistically, ARA is enriched in lymph nodes and metabolized into immune modulators there. One of the ARA metabolites, prostaglandin I2 (PGI2), via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) axis, upregulates the expression of costimulatory molecule CD86, and activates activation-induced cytidine deaminase (AID) in B cells. These results suggest that ARA can be a potent dietary adjuvant to foster germinal center (GC) B cell response and humoral immunity.
    Keywords:  Arachidonic Acid; Germinal Center Response; Humoral Immunity
    DOI:  https://doi.org/10.1038/s44321-025-00310-7
  37. J Control Release. 2025 Sep 05. pii: S0168-3659(25)00798-9. [Epub ahead of print] 114186
    Understanding the kinetics of macrophage uptake and the metabolic fate of iron-carbohydrate complexes used for iron deficiency anemia treatment.
    Stephanie Eitner, Vera M Kissling, Alexandra Rippl, Leonard Krupnik, Justus J Bürgi, Stefanie Gächter, Katharina Hast-Sribike, Alexander Gogos, Davide Bottone, Jonas Bossart, Rafael Riudavets Puig, Reinaldo Digigow, Amy E Alston, Beat Flühmann, Peter Wick, Vanesa Ayala-Nunez.
      Iron-carbohydrate complexes (ICCs) are widely used nanomedicines to treat iron deficiency anemia, yet their intracellular fate and the mechanisms of action underlying their differences in treatment outcomes remain poorly understood. Here, we thus performed a comprehensive dynamic characterization of two structurally distinct ICCs - iron sucrose (IS) and ferric carboxymaltose (FCM) - in primary human macrophages, key cells to the iron metabolism. By employing innovative correlative microscopy techniques, elemental analysis, and in vitro pharmacokinetic profiling, we demonstrate that the uptake, intracellular trafficking, and biodegradation of ICCs depend on their physicochemical properties. Specifically, IS is rapidly internalized and processed within endolysosomes, resulting in fast iron release and transient cytotoxicity. Conversely, FCM is sequestered in enlarged endosomes for an extended time before its biodegradation, a phenomenon we term the Hamster Effect, which leads to slower, more sustainable iron release. These results provide unprecedented insights into the metabolic fate of ICCs, enhancing our understanding of their different pharmacokinetic and pharmacodynamic profiles in vivo.
    Keywords:  Iron-carbohydrate complexes; Macrophages; Nanomedicines; iron deficiency anemia; iron metabolism
    DOI:  https://doi.org/10.1016/j.jconrel.2025.114186
  38. Int J Gen Med. 2025 ;18 5085-5103
    Multi-Omics and Clinical Validation Identify Key Glycolysis- and Immune-Related Genes in Sepsis.
    Hengjian Du, Xin Dai, Ting Zhang, Zhao Zhang, XiaoTao Xu, YaoXia Liu, Zhen Fan.
       Background: Sepsis is characterized by profound immune and metabolic perturbations, with glycolysis serving as a pivotal modulator of immune responses. However, the molecular mechanisms linking glycolytic reprogramming to immune dysfunction remain poorly defined.
    Methods: Transcriptomic profiles of sepsis were obtained from the Gene Expression Omnibus. Differentially expressed genes (DEGs) related to glycolysis were identified through a combination of ssGSEA, WGCNA and differential expression analysis. Hub genes were prioritized using Mendelian randomization and machine learning algorithms (LASSO, SVM-RFE, and Boruta), and validated in an independent dataset and by RT-qPCR in a clinical sepsis cohort. Immune cell infiltration was assessed using CIBERSORT to profile the immune landscape, and single-cell RNA sequencing (scRNA-seq) was employed to delineate the cell type-specific transcriptional profiles.
    Results: The ssGSEA scores derived from the glycolysis signature indicated a marked reduction in glycolytic activity associated with sepsis. By employing an integrative framework that includes WGCNA, differential expression analysis, Mendelian randomization, and machine learning algorithms, this study successfully identified five pivotal genes associated with glycolysis: DDX18, EIF3L, MAK16, THUMPD1, and ZNF260. The diminished expression of these genes was significantly correlated with immune remodeling, characterized by an increase in neutrophils and a decrease in lymphocytes. In a clinical sepsis cohort, RT-qPCR of peripheral blood, in conjunction with routine hematological profiling, validated their expression pattern and immune associations. Moreover, scRNA-seq facilitated a comprehensive characterization of these transcriptional alterations within distinct subsets of immune cells.
    Conclusion: This study identifies five glycolysis-related genes linked to immune remodeling in sepsis, revealing a metabolic-immune axis that may drives disease pathogenesis and offers promising targets for therapeutic intervention.
    Keywords:  Mendelian randomization; glycolysis; machine learning; sepsis; single-cell RNA sequencing
    DOI:  https://doi.org/10.2147/IJGM.S539158
  39. Dev Cell. 2025 Sep 08. pii: S1534-5807(25)00528-3. [Epub ahead of print]60(17): 2215-2217
    Novel bacterial strategy to hijack plant immunity through metabolic manipulation.
    Ran Lu, Elwira Smakowska-Luzan.
      In this issue of Developmental Cell, Yuan et al. explores how the pathogenic bacterium Pseudomonas syringae modulates plant metabolism, particularly through methylglyoxal (MG) accumulation, to suppress immune responses in Arabidopsis. By affecting key proteins TTM2 and CAT2, the pathogen reduces hydrogen peroxide levels, weakening plant defense mechanisms and promoting infection.
    DOI:  https://doi.org/10.1016/j.devcel.2025.08.008
  40. Pulm Pharmacol Ther. 2025 Sep 10. pii: S1094-5539(25)00051-3. [Epub ahead of print] 102394
    Targeting the Immunometabolism Interface: A Novel Strategy for IPF Therapy.
    Ganggang Li, Yuzhi Huo, Xiaochuan Pan, Nan Jia, Xuanyu Wu, Xinhui Wu, Fei Wang, Quanyu Du.
      Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by aberrant tissue remodeling and excessive deposition of extracellular matrix components. Emerging evidence underscores the critical role of the immunometabolism in the pathogenesis of IPF, highlighting how dysregulated metabolic pathways modulate immune responses and contribute to fibrotic progression. Key molecular regulators such as PPARG (peroxisome proliferator activated receptor gamma) and SPP1 (secreted phosphoprotein 1), along with signaling pathways including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and hypoxia-inducible factor 1-alpha (HIF-1α), orchestrate immune cell polarization, fibroblast activation, and extracellular matrix production. These insights reveal promising therapeutic targets at the intersection of metabolism and immunity. This review synthesizes current findings on immunometabolism interactions in IPF, emphasizing the potential of metabolic reprogramming and immune modulation as novel treatment strategies. Despite substantial advances, significant challenges persist in elucidating the precise mechanisms underlying these interactions and translating preclinical insights into effective clinical interventions. Future research should prioritize the identification of actionable metabolic biomarkers, refinement of molecular targets, and development of personalized therapeutic approaches. Addressing these gaps may pave the way for innovative therapies capable of halting or even reversing fibrosis, ultimately improving outcomes for patients with IPF.
    Keywords:  Fibrosis Pathogenesis; Idiopathic Pulmonary Fibrosis; Immunometabolism; Therapeutic Targets
    DOI:  https://doi.org/10.1016/j.pupt.2025.102394
  41. Lung. 2025 Sep 10. 203(1): 94
    Lactate and Lactylation in Respiratory Diseases: from Molecular Mechanisms to Targeted Strategies.
    Qi Jia, Quan Yuan, Xiangdong Chen, Zhiqiang Hu.
       INTRODUCTION: Lactate has emerged as a multifunctional signaling molecule regulating various physiological and pathological processes. Furthermore, lactylation, a newly identified posttranslational modification triggered by lactate accumulation, plays significant roles in human health and diseases. This study aims to investigate the roles of lactate/lactylation in respiratory diseases.
    METHODS: Comprehensive literature analysis was conducted using PubMed database, utilizing a range of keywords including "lactate", "lactylation", "lung", "pulmonary", and "disease".
    RESULTS: Emerging evidence indicates that increased glycolytic flux, resultant lactate accumulation, and elevated lactylation levels play key roles in the pathogenesis of respiratory diseases, including lung cancer, idiopathic pulmonary fibrosis (IPF), acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), and asthma. Under these conditions, the upregulation of glycolytic enzymes and increased lactate transport are observed. Elevated levels of lactate and lactylation profoundly influence multiple biological processes, such as inflammatory responses, immune cell activation, autophagy, ferroptosis, EMT, tumorigenesis, and fibrosis, and lactate/lactylation-targeted therapies have demonstrated therapeutic efficacy against diverse respiratory illnesses.
    CONCLUSIONS: Elevated levels of lactate and lactylation play key roles in the pathogenesis of various respiratory diseases, and lactate/lactylation-targeted therapies appear to be potential therapeutic strategies for these respiratory diseases.
    Keywords:  Fibrosis; Immune cell activation; Inflammatory response; Lactate; Lactylation; Respiratory diseases; Tumorigenesis
    DOI:  https://doi.org/10.1007/s00408-025-00848-w
  42. J Cell Mol Med. 2025 Sep;29(17): e70832
    Altered T Lymphocytes Mitochondrial Function and Inflammatory Factors of Peripheral Blood in HIV Patients With Mycobacterial Infection.
    Mengyan Wang, Xiaotian Dong, Hu Wan, Jinchuan Shi, Lu Hui, Wei Chen, Shourong Liu, Jun Yan.
      To characterise T-cell immunity and inflammatory profiles in HIV patients with mycobacterial co-infections. This study enrolled 41 HIV patients co-infected with Mycobacterium tuberculosis (HIV-TB, n = 27) or non-tuberculous mycobacteria (HIV-NTM, n = 14), along with 30 controls (20 HIV-monoinfected, 10 post-treatment) from a single centre. Flow cytometry quantified T-cell subsets (CD3 + CD4+, CD3 + CD8+, CD28+ subsets), mitochondrial parameters (mass [MM], low membrane potential [MMP-low%]) and cytokines (IFN-γ, IL-2/4/6/10/17A, TNF-α). Co-infected groups showed reduced T-cell counts versus HIV-monoinfected controls (p < 0.05). Elevated MMP-low% in CD3 + CD4+/CD28+ T cells indicated mitochondrial dysfunction in co-infected patients (p < 0.05). HIV-TB patients exhibited higher CD3 + CD4+/CD28+/CD8+ T-cell MM than HIV-NTM (p < 0.05), while HIV-NTM demonstrated greater MMP-low% (p < 0.05). Proinflammatory cytokines (IFN-γ, IL-6, IL-17A) inversely correlated with CD4+ counts and MM, but positively with CD8 + CD28+ MMP-low%. MMP-low% in CD3 + CD4 + CD28+ T cells and IL-2 differentiated IRIS/non-IRIS cases (p < 0.05), with combined AUC = 0.834 for IRIS prediction (p = 0.001). HIV/mycobacterial co-infection exacerbates T-cell depletion and mitochondrial dysfunction, with HIV-NTM showing more severe impairment. MMP-low% and IL-2 may serve as biomarkers for IRIS risk stratification.
    Keywords:  human immunodeficiency virus; inflammatory factors; low mitochondrial membrane potential; mitochondrial mass; tuberculosis
    DOI:  https://doi.org/10.1111/jcmm.70832
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