bims-imicid 2026-01-04 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–01–04
39 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Metabolic regulation of regulatory T cells: mechanisms, heterogeneity, and implications in disease.
Regulatory T Cell Metabolism in Cancer.
TRP channels at the crossroads of metabolism and immunity: ion-metabolite coupling in inflammation and disease.
Editorial: Exploring immunometabolism: metabolic pathway and immune response in sepsis.
Aromatic microbial metabolite hippuric acid enhances inflammatory responses in macrophages via TLR-MyD88 signaling and lipid remodeling.
Mapping metabolic dependences and capacities using ATP as a biomarker.
Altered B cell metabolic pathways characterize type 1 diabetes progression.
Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.
Metabolic reprogramming as a therapeutic target for modulating the Th17/Treg balance in autoimmune diseases: a comprehensive review.
Taurine Attenuates M1 Macrophage Polarization and IL-1β Production by Suppressing the JAK1/2-STAT1 Pathway via Metabolic Reprogramming.
Metabolomic profiling reveals the potential of fatty acids as regulators of exhausted CD8 T cells during chronic viral infection.
Pp6-Pfkfb1 axis modulates intracellular bacterial proliferation by orchestrating host-pathogen metabolic crosstalk.
Beyond Bulk Metabolomics: Emerging Technologies for Defining Cell-Type Specific Metabolic Pathways in Health and Disease.
Assessing Intracellular Metabolism of Immune Cells In Situ in Live Zebrafish Larvae by Autofluorescence Lifetime Imaging Microscopy of NAD(P)H and FAD.
Autophagic regulation of CD8+ T cell metabolic reprogramming defines acute and latent phases of cytomegalovirus infection in vivo.
Kupffer cells control neonatal hepatic metabolism via Igf1 signaling.
High potassium enhances the immunosuppressive function of myeloid-derived suppressor cells via Kir4.1-dependent metabolic reprogramming and promotes tumor immune escape.
Targeting Atherosclerosis: Cholesterol-Lowering Therapies with a New Immunometabolic Dress for an Old Disease.
Shikonin alleviates rotenone-induced Parkinson's disease neuroinflammation by targeting PKM2-mediated glycolytic MG-Hs production.
Age-dependent reprogramming of vascular metabolism compromises endothelial resilience to inflammation-induced endothelial dysfunction.
Dimethyl itaconate suppresses dendritic cell and CD8+ T cell responses to halt vitiligo.
Nanomedicine-mediated modulation of tumor metabolism for enhanced immunotherapy.
3'UTR-derived small RNA couples acid resistance to metabolic reprogramming of Salmonella within macrophages.
L-lactic acid enhances type I interferon immune response and inhibits virus infection by promoting IRF9 L-lactylation.
Macrophage adaptation to hypoxia: metabolism, migration, and phagocytosis.
Neutrophil glycolysis mediates colitis-induced exacerbation of Alzheimer's disease.
Gut microbiome-derived propionate reprograms alveolar macrophages metabolically and regulates lung injury responses in mice.
Lactate-Mediated Epigenetic and Immunometabolic Reprogramming in Glioma: An Emerging Axis Linking Metabolism to Tumor Progression.
Arachidonic acid reverses microplastic-induced macrophage dysfunction in teleost fish.
Myeloid-Derived CD38 Mediates Age-Related Endometrial Aging Through NAD+ Depletion.
Pioglitazone Modulates p65-Mediated Mitochondrial Bioenergetics: Implications for Acetaldehyde-Induced HIV Replication in Alveolar Macrophages.
Unraveling the RKIP-YY1 axis: immune crosstalk in the pathogenesis of metabolic disorders.
Mitochondrial calcium shapes B cell signaling and mitochondrial function.
Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8 + T cell-macrophage interactions.
Glutamine metabolites promote the progression of cervical cancer by inducing M2 macrophage polarization.
Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.
CD5L Inhibits Allergic Airway Inflammation by Lysophosphatidylcholine-Induced ILC2 Apoptosis.
Galectin-3 exacerbates autoimmune diabetes by limiting regulatory T cell differentiation and function.
Invited: Longitudinal assessment of diets with varying carbohydrate-to-fat ratios and fiber supplementation on immunometabolic markers, liver function, and gut microbiome.

Front Immunol. 2025 ;16 1729690

Metabolic regulation of regulatory T cells: mechanisms, heterogeneity, and implications in disease.

Feven Getachew, Junhui Hu, Mehdi Benamar.

  Regulatory T (Treg) cells are essential for maintaining immune tolerance, preventing autoimmune responses, and supporting tissue repair. Tregs employ a flexible and diverse metabolic program that includes glycolysis, oxidative phosphorylation (OXPHOS), fatty acid oxidation, and lipid metabolism compared to conventional T cells, which largely rely on glycolysis to fuel their proliferation and function. This flexibility allows Tregs to adapt in different tissue environments while sustaining their suppressive activity. Thymic-derived (tTregs), peripheral (pTregs), and induced (iTregs) exhibit distinct metabolic profiles that influence their stability, proliferation, and suppressive capacity. These metabolic pathways are controlled by key regulators such as mTOR, LKB1, and Foxp3, while environmental cues, including nutrient availability, hypoxia, and microbiota-derived metabolites, further shape Treg function. Dysregulation of these pathways can compromise tolerance and contribute to immune-mediated diseases, chronic infections, cancer, and metabolic disorders. In this mini review, we summarize recent insights into the heterogeneity of Treg metabolism, highlighting how metabolic reprogramming underpins their immunoregulatory roles. We also explore therapeutic opportunities for targeting Treg metabolism and discuss future directions leveraging single-cell and spatial technologies to map context-specific metabolic programs in vivo.

Keywords:  Foxp3; diseases; immune tolerance; metabolism; regulatory T cells

DOI:  https://doi.org/10.3389/fimmu.2025.1729690
Immunology. 2025 Dec 28.

Regulatory T Cell Metabolism in Cancer.

Keywan Mortezaee.

  Regulatory T cells (Tregs) display metabolic fitness to adopt tumour microenvironment (TME), characterized by hypoxia, acidity and metabolic depletion/competition, in order to impair anti-tumour immunity and allow metastasis. Tregs and other TME immune cells interact metabolically, with glycolysis supporting proliferation of Tregs along with cancer cells and CD8+ T cells and a basal oxidative phosphorylation (OXPHOS) promoting Treg and CD8+ T cell activity. Lactate is a glycolysis byproduct that its accumulation creates acidosis within TME, and its uptake provides a fuel source for Treg activity and fosters their persistence in the hypoxic TME. Itaconate and hypoxic TME increase succinate accumulation, but they take complex roles on Tregs and T cells. Hypoxia and hypoxia inducible factor-1 (HIF-1) activity induce lactate release and Treg recruitment/accumulation via stimulating glycolysis path and extracellular adenosine aggregation. Knockout of HIF-1α although reduces lactate, it secondarily induces OXPHOS to fulfil Treg immunosuppressive function. FOXP3 is stabilized by mitochondrial transcription factor A (Tfam) and induces Treg CD36 and OXPHOS, which can be disturbed by nucleus accumbens-associated protein 1 (NAC1). Liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) although induce FOXP3 stability and OXPHOS in Tregs, their activities downregulate programmed death-1 (PD-1) in such cells. OXPHOS augmentation (by α-ketoglutarate [αKG]) or suppression (by metformin) disrupt Treg metabolism. Finally, indoleamine 2,3-dioxygenase (IDO) seems to affect Tregs and can be a promising target in advanced immunotherapy naïve cancer patients. The focus of this review is to describe Treg metabolic regulators/connectome and opportunities they bring about in cancer therapy.

Keywords:  adenosine; aryl hydrocarbon receptor (AHR); glycolysis; hypoxia inducible factor (HIF); lactate; liver kinase B1 (LKB1); metformin; oxidative phosphorylation (OXPHOS); regulatory T cell (Treg); α‐Ketoglutarate (αKG)

DOI:  https://doi.org/10.1111/imm.70096
Metabolism. 2025 Dec 29. pii: S0026-0495(25)00356-7. [Epub ahead of print] 156486

TRP channels at the crossroads of metabolism and immunity: ion-metabolite coupling in inflammation and disease.

De-Hua Liao, Shi-Long Jiang, Ting Wu, Zeng Cao, Ze-Wu Zhu, Nayiyuan Wu, Xiu Zhang, Ming-Hui Long, Jing Wang, Zhi-Bin Wang.

  Transient receptor potential (TRP) channels are not only multimodal ion sensors but also couplers between metabolic states and immune responses. TRP gating is controlled by lipid signaling (PIP2, DAG, cholesterol), redox/energy cues (NAD+/ADPR/ROS, ATP/AMP), and metabolite-derived signals (pH/lactate, bile acids, endocannabinoids, eicosanoids, SCFAs). In turn, TRP-driven Ca2+ signaling reprograms AMPK-mTORC1, glycolysis/OXPHOS, FAO, and glutaminolysis, thereby reshaping the metabolic programs and effector functions of T/B cells, macrophages, NK/DCs. In gut, skin, and arthritis, microbiota-metabolite-TRP axes dictate inflammatory phenotypes; within tumors, lactate, adenosine, and kynurenine modulate TRPs in cancer and immune infiltrates. In this study, we synthesize TRP metabolic sensing mechanisms, immunometabolic reprogramming, and pharmacological opportunities, highlighting synergistic strategies combining metabolic interventions with TRP modulation for precision management of inflammation-related diseases.

Keywords:  Immune response; Immunometabolism; Inflammation; Metabolic reprogramming; Metabolites; TRP channels

DOI:  https://doi.org/10.1016/j.metabol.2025.156486
Front Med (Lausanne). 2025 ;12 1758108

Editorial: Exploring immunometabolism: metabolic pathway and immune response in sepsis.

Yuan Yuan, Lulong Bo, Ruoxi Zhang, Feng Chen.



Keywords:  editorial; immune response; immunometabolism; metabolic pathway; sepsis

DOI:  https://doi.org/10.3389/fmed.2025.1758108
Cell Rep. 2025 Dec 30. pii: S2211-1247(25)01521-9. [Epub ahead of print]45(1): 116749

Aromatic microbial metabolite hippuric acid enhances inflammatory responses in macrophages via TLR-MyD88 signaling and lipid remodeling.

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

  The gut microbiome produces diverse metabolites shaping immunity, yet their pro-inflammatory potential remains unclear. Using untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics, we identified hippuric acid-an aromatic, microbe-derived metabolite-as a potent enhancer of inflammatory responses during Escherichia coli infection. Hippuric acid administration heightened inflammation, activated innate immune cells, and reduced survival in infected mice. In vitro, hippuric acid selectively potentiated M1-like (lipopolysaccharide [LPS] or LPS+interferon gamma [IFNγ]) macrophage pro-inflammatory responses but had no effect on M2-like (interleukin [IL]-4) polarization. It enhanced responses to myeloid differentiation primary response 88 (MyD88)-dependent Toll-like receptor (TLR) ligands but not TRIF-, STING-, or NOD2-mediated stimuli. Genetic deletion of MyD88 abolished hippuric-acid-induced pro-inflammatory responses. Transcriptomic and lipidomic analyses revealed increased cholesterol biosynthesis and lipid accumulation, while reducing cellular cholesterol blunted the pro-inflammatory effects of hippuric acid. Notably, hippuric acid also enhanced pro-inflammatory responses in human macrophages, and its elevated levels correlated with sepsis mortality, linking microbial metabolism, lipid remodeling, and innate immunity.

Keywords:  CP: immunology; CP: metabolism; TLR-MyD88 signaling; biomarker; cholesterol biosynthesis; hippuric acid; inflammation and infection; lipid remodeling; macrophage polarization; macrophages; microbial metabolite; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2025.116749
Res Sq. 2025 Apr 23. pii: rs.3.rs-4836421. [Epub ahead of print]

Mapping metabolic dependences and capacities using ATP as a biomarker.

Peter McGuire, Jose Marin, Amanda Fuchs, Tatiana Tarasenko, Emily Warren, Martha Kirby, Stacie Anderson, Eliza Gordon-Lipkin, Shannon Kruk, A West.

Metabolic dependences highlight a cell's reliance on specific pathways to meet its bioenergetic needs, with these pathways being interrogated using chemical inhibitors to assess their significance. While surrogate markers of bioenergetics (e.g., oxygen consumption) have yielded important insights, we asked whether metabolic dependences could be defined using ATP as a biomarker. To address this gap, we developed Mitochondrial/Energy Flow Cytometry (MitE-Flo), a method that evaluates the contributions of glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) to cellular ATP content. In models of mitochondrial disease due to complex I or complex IV deficiency, we identified impaired OXPHOS with a compensatory shift to glycolysis. To define the utility of ATP monitoring in immunometabolism research, we analyzed previously inaccessible cell populations: light zone (LZ) and dark zone (DZ) germinal center (GC) B cells. Highly proliferative DZ B cells exhibited elevated ATP levels and a preference for FAO and OXPHOS over glycolysis, with uniform increased activity across ETC complexes. In contrast, less proliferative LZ B cells showed lower ATP levels and an equal reliance on glycolysis and OXPHOS. Using ATP as a biomarker to define metabolic dependences provides valuable insights into disease states and elusive immune cell subtypes, thereby enhancing the metabolism research toolkit.

DOI: https://doi.org/10.21203/rs.3.rs-4836421/v2
J Immunol. 2025 Dec 27. pii: vkaf330. [Epub ahead of print]

Altered B cell metabolic pathways characterize type 1 diabetes progression.

Holly Conway, Jessica Bernard, Rachel Ramos, Sama Zahran, Dianna L Perez, Mugtaba Swar-Eldahab, Jon Piganelli, Carmella Evans-Molina, Jamie L Felton.

  Type 1 diabetes (T1D) results from immune-mediated destruction of pancreatic beta cells. B cells serve as critical antigen-presenting cells whose autoreactive specificities drive disease progression. Conversely, IL-10 producing regulatory B cells (Bregs) exert immunosuppressive functions and have been shown to protect against autoimmunity in mouse models of rheumatoid arthritis and multiple sclerosis, where microenvironmental cues promote their differentiation. In particular, signaling through hypoxia-inducible factor 1α (HIF-1α) induces glycolytic flux that supports Breg expansion. Defects in Breg development and function have been identified in both human T1D and the non-obese diabetic (NOD) mouse, but whether these impairments reflect intrinsic B-cell abnormalities or microenvironmental changes associated with hyperglycemia and inflammation remains unclear. Moreover, the mechanisms by which B cells suppress pathogenic T-cell responses likely vary across disease states. Here, we examine how B cell differentiation, metabolism, and HIF-1α signaling interact to shape immune regulation in autoimmune diabetes. We show that B cells undergo dynamic metabolic remodeling during disease progression. B cells from NOD mice are characterized by exaggerated glucose uptake and elevated IL-10 expression compared with non-autoimmune B6 B cells, despite reduced HIF-1α levels and attenuated induction of HIF-dependent glycolytic genes. These findings indicate that HIF-1α plays a diminished role in controlling IL-10 production in NOD B cells and that IL-10 alone is insufficient to maintain immune tolerance. Together, our results highlight how genetic and microenvironmental factors reprogram B cell metabolism and underscore the need to explore IL-10 independent pathways and B-cell extrinsic mechanisms when developing immunomodulatory therapies for T1D.

Keywords:  B cell; hypoxia; immunometabolism; type 1 diabetes

DOI:  https://doi.org/10.1093/jimmun/vkaf330
Pharmaceutics. 2025 Nov 26. pii: 1520. [Epub ahead of print]17(12):

Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.

Alex Wade Song, Xiaotong Song.

  Background/Objectives: Chimeric antigen receptor (CAR) T cells have shown remarkable clinical success in certain blood cancers but remain largely ineffective in solid tumors. A major reason for this limitation is the hostile tumor microenvironment, which restricts oxygen and nutrients while producing toxic metabolites that suppress immune cell activity. This review aims to examine how targeted metabolic reprogramming can overcome these barriers and improve CAR T cell performance. Methods: We evaluated preclinical and translational studies that focused on engineering CAR T cells to resist hypoxia, improve nutrient utilization, reduce metabolic exhaustion, and counteract suppressive metabolites in solid tumors. Results: Emerging strategies include engineering resistance to low oxygen and high lactate, enhancing nutrient uptake through transporter overexpression, and blocking inhibitory pathways such as those driven by adenosine. These approaches improve CAR T cell persistence, memory formation, and cytotoxic function in challenging tumor environments. Conclusions: Integrating metabolic reprogramming with conventional CAR design is essential to unlock the full potential of CAR T therapy against solid tumors. Continued innovation in this area will be critical for translating laboratory advances into effective clinical treatments.

Keywords:  CAR T cells; adenosine; hypoxia; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/pharmaceutics17121520
Front Immunol. 2025 ;16 1687755

Metabolic reprogramming as a therapeutic target for modulating the Th17/Treg balance in autoimmune diseases: a comprehensive review.

Yuehong Hu, Qihan Zhao, Haoran Dai, Yadi Wu, Xinyue Tang, Naiqian Zhang, Hanxue Jiang, Hongliang Rui, Baoli Liu.

  The dynamic balance between T helper 17 (Th17) cells and regulatory T (Treg) is the cornerstone of immune homeostasis. Disruption of this equilibrium is closely associated with various autoimmune diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS), and inflammatory bowel disease (IBD). Studies have revealed that metabolic reprogramming, mediated by key metabolic enzymes (including mTOR, HIF-1α, and AMPK) and pathways (such as glycolysis and lipid metabolism), acts as a major regulator of Th17/Treg differentiation and function owing to their distinct metabolic profiles. Metabolic dysregulation may exacerbate immune imbalance by altering the cellular differentiation trajectories and functional states. Although targeting metabolic pathways shows therapeutic promise, current intervention strategies face challenges in terms of specificity and safety. This review systematically combs the mechanisms by which metabolic reprogramming influences the differentiation and function of Th17/Treg cells, as well as the metabolic changes in immune cells of inflammation-related autoimmune diseases. It outlines the progress of the latest metabolism-targeted strategies and focuses on discussing the challenges and prospects regarding the specificity and safety of metabolic interventions.

Keywords:  Th17/Treg balance; autoimmune diseases; immunometabolism; mTOR; therapeutic target

DOI:  https://doi.org/10.3389/fimmu.2025.1687755
Biology (Basel). 2025 Dec 06. pii: 1751. [Epub ahead of print]14(12):

Taurine Attenuates M1 Macrophage Polarization and IL-1β Production by Suppressing the JAK1/2-STAT1 Pathway via Metabolic Reprogramming.

Zi'an Zhang, Danyue Li, Suhui He, Weilv Xu, Qian Lv, Yumeng Wang, Jinxia Xu, Zexu Yu, Shiyang Liu, Yuanxiang Ge, Fushan Shi, Yuqi Yan.

  Dysregulated macrophage polarization is associated with various diseases, including sepsis, atherosclerosis, and fibrotic diseases. While taurine is known to exert immunomodulatory effects, its mechanism in regulating M1 macrophage polarization and interleukin-1β (IL-1β) production remains incompletely understood. This study aimed to elucidate the role of taurine in modulating macrophage immunometabolism and inflammatory signaling. Using thioglycolate-elicited peritoneal macrophages and macrophage cell lines, we assessed taurine's impact on lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced M1 polarization through metabolomics and a range of molecular biology techniques. Pharmacological manipulation of the JAK1/2-STAT1 pathway and an LPS-induced murine sepsis model were used for mechanistic and therapeutic validation. Our results demonstrate that taurine significantly suppressed M1 polarization. Metabolomic profiling uniquely identified a marked increase in intracellular spermine as a key metabolic alteration induced by taurine. This increased spermine subsequently inhibited JAK1/2-STAT1 activation, leading to reduced IL-1β release. In mice, taurine alleviated systemic inflammation, reduced pathological damage in multiple organs, and decreased intestinal M1 macrophage infiltration. These findings establish a novel mechanism where taurine attenuates M1 polarization and IL-1β production through metabolically driven spermine accumulation and subsequent JAK1/2-STAT1 suppression, highlighting its therapeutic potential for inflammatory diseases.

Keywords:  immunometabolism; macrophage; sepsis; spermine; taurine

DOI:  https://doi.org/10.3390/biology14121751
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2419820122

Metabolomic profiling reveals the potential of fatty acids as regulators of exhausted CD8 T cells during chronic viral infection.

Katelynn R Kazane, Lara Labarta-Bajo, Dina R Zangwill, Kalle Liimatta, Fernando Vargas, Kelly C Weldon, Pieter C Dorrestein, Elina I Zúñiga.

  Chronic infections induce CD8 T cell exhaustion, marked by impaired effector function. While intrinsic drivers are well studied, the role of the surrounding metabolic environment in shaping exhausted CD8 T cells (Tex) is less understood. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model, we investigated systemic metabolite changes following acute vs. chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the early phase of the sustained infection. This included nutrient changes that were partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acids (FA) and acylcarnitines during the first week after chronic infection. Consistently, virus-specific CD8 T cells from chronic infection exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly the stem-like Tex (TexSTEM), which generates TexINT that directly limit viral replication. Notably, only TexSTEM increased oxidative metabolism upon ex vivo FA exposure, while short-term administration of FA during late chronic infection exclusively increased TexSTEM and their mitochondrial potential. The last-mentioned treatment also led to reduced TexINT and enhanced PD-1 across all Tex subsets, which coincided with compromised viral control. Our study offers a valuable resource for investigating the regulatory role of specific metabolites during acute and chronic viral infections and highlights the potential of FA to fine-tune Tex subsets during protracted infections.

Keywords:  CD8 T cell exhaustion; fatty acids; metabolomics; stem-like cells; viral infection

DOI:  https://doi.org/10.1073/pnas.2419820122
PLoS Pathog. 2025 Dec 31. 21(12): e1013304

Pp6-Pfkfb1 axis modulates intracellular bacterial proliferation by orchestrating host-pathogen metabolic crosstalk.

Li Fan, Yang Sun, Fangzhou Lou, Zilong Fang, Wengxiang Ding, Xiangxiao Li, Yan Li, Qingqing Shen, Siyu Deng, Jihuan Liang, Fengjiao Zhang, Sibei Tang, Zhikai Wang, Xiaojie Cai, Jiajia Tong, Zhenyao Xu, Jing Zou, Qing Yang, Honglin Wang.

Intracellular bacterial pathogens exhibit heterogeneous replication rates within host macrophages, but the mechanisms by which they manipulate host factors for survival remain incompletely understood. Using a fluorescence-dilution reporter system in Salmonella Typhimurium (Salmonella)-infected macrophages, we found that Protein Phosphatase 6 (Pp6) was downregulated in macrophages harboring growing bacteria. Conditional knockout of Pp6 elevated host susceptibility to Salmonella-mediated lethality due to compromised antimicrobial defenses. MicroRNA-31 (miR-31) was identified as a negative regulator of Pp6, and its conditional ablation enhanced bacterial clearance. Yeast two-hybrid screening identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 (Pfkfb1), a metabolic regulator, as a substrate of Pp6. Pp6 deficiency resulted in significantly elevated expression of Pfkfb1, which was highly expressed in macrophages containing replicating Salmonella. Pfkfb1 deletion restricted bacterial proliferation by promoting nitric oxide (NO) production while concurrently suppressing arginase-1 (Arg-1) expression and impairing arginine metabolism in macrophages. Collectively, these results establish the Pp6-Pfkfb1 axis as a key regulator of host metabolic adaptation and intracellular bacterial survival, offering potential therapeutic targets against multidrug-resistant pathogens.

DOI: https://doi.org/10.1371/journal.ppat.1013304
Biomolecules. 2025 Dec 02. pii: 1687. [Epub ahead of print]15(12):

Beyond Bulk Metabolomics: Emerging Technologies for Defining Cell-Type Specific Metabolic Pathways in Health and Disease.

Yichen Gong, Samuel Weinberg.

  While metabolomics has emerged as a powerful tool for discovering disease biomarkers, the clinical utility of plasma or tissue metabolite profiles remains limited due to metabolic heterogeneity and flexibility across cell types. Traditional bulk metabolomics fails to capture the distinct metabolic programs operating within rare cell populations that often drive disease pathogenesis. This review examines cutting-edge approaches that overcome these limitations by characterizing metabolism at single-cell and cell-type-specific resolution, with particular emphasis on rare immune cell populations as a proof of concept. We discuss how the integration of flow cytometric metabolic profiling, molecular techniques, advanced metabolomics platforms, and computational modeling enables unprecedented insight into cell-intrinsic metabolic states within physiological contexts. We critically evaluate how these technologies reveal metabolic plasticity that confounds bulk measurements while identifying cell-type-specific metabolic vulnerabilities. Finally, we address the crucial challenge of establishing causality in metabolic pathways, a prerequisite for translating metabolomic discoveries into clinically actionable interventions. By moving beyond descriptive metabolomics toward a mechanistic understanding of cell-type-specific metabolism, these approaches promise to deliver the precision required for effective metabolic targeting in disease.

Keywords:  CRISPR screening; LC-MS HILIC; immunometabolism; rare immune cell metabolomics; single-cell metabolic profiling

DOI:  https://doi.org/10.3390/biom15121687
Methods Mol Biol. 2026 ;2983 169-192

Assessing Intracellular Metabolism of Immune Cells In Situ in Live Zebrafish Larvae by Autofluorescence Lifetime Imaging Microscopy of NAD(P)H and FAD.

Rupsa Datta, Melissa C Skala, Veronika Miskolci.

  Understanding the dynamic changes in the intracellular metabolism of immune cells has become fundamental to understanding the regulation of their effector functions. Optical metabolic imaging, consisting of optical redox ratio and fluorescence lifetime imaging microscopy of endogenous coenzymes NAD(P)H and FAD, offers a label-free and non-invasive approach to assess intracellular metabolism at the single-cell level. The major advantage of optical metabolic imaging is that it can assess heterogeneity in the sample with spatiotemporal resolution. While this approach has been mainly used to perform metabolic imaging on in vitro samples, studies have demonstrated that it also performs well in live, intact animals, and is sensitive to dynamic changes in immune cell activation. This chapter describes protocols for performing optical metabolic imaging of innate immune cells at the caudal fin wound microenvironment of larval zebrafish following sterile injuries. However, the protocol can be readily applied to other cell types and in different biological contexts.

Keywords:  FAD; FLIM ; Immune cells; Metabolism; NAD(P)H; Optical metabolic imaging; Zebrafish

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_16
Front Cell Infect Microbiol. 2025 ;15 1673229

Autophagic regulation of CD8+ T cell metabolic reprogramming defines acute and latent phases of cytomegalovirus infection in vivo.

Hui Liu, Xiaobing Liu, Wai Ho Oscar Yeung, Jiang Liu, Kevin Tak Pan Ng, Kwan Man.

  Understanding the immunoregulatory mechanism during cytomegalovirus (CMV) infection may help to combat CMV reactivation in immunocompromised or immunosuppressed individuals. Here we developed a CMV infection model in immunocompetent Sprague Dawley (SD) rats with Priscott strain and explored the cross-talk between autophagic dynamics and metabolism alterations in CD8+ T cells post infection. We previously found that primary CMV infection induced a remarkable increase of CD8+ T cells which reached the peak around week 3 and returned to pre-inoculation status since week 6 post viral infection. In this study, our results demonstrated that the autophagic activity of CD8+ T cells was augmented at week 3 while decreased at week 6, which was closely associated with the up- (week 3 and 4) or down-regulation (since week 6) of metabolic markers ENTPD1 and SLC27A2. Furthermore, the in vitro study showed that the levels of these metabolic markers in rat splenocytes were modulated by autophagy inhibitors and enhancers. Our study indicated that the dynamic alterations of autophagy exerted a critical role in regulating the metabolic adaptation of CD8+ T cells during CMV infection process, and provides an ideal animal model for further research on the pathological mechanisms based on CMV latency.

Keywords:  CD8+ T cells; autophagic dynamics; cytomegalovirus; metabolism; sprague-dawley rats

DOI:  https://doi.org/10.3389/fcimb.2025.1673229
Development. 2025 Dec 29. pii: dev.204962. [Epub ahead of print]

Kupffer cells control neonatal hepatic metabolism via Igf1 signaling.

Nikola Makdissi, Daria Hirschmann, Aleksej Frolov, Inaam Sado, Bastian Bennühr, Fabian Nikolka, Jingyuan Cheng, Nelli Blank-Stein, Maria Francesca Viola, Mohamed Yaghmour, Philipp Arnold, Lorenzo Bonaguro, Matthias Becker, Christoph Thiele, Felix Meissner, Karsten Hiller, Marc D Beyer, Elvira Mass.

  During perinatal development, liver metabolism is tightly regulated to ensure energy supply for the newborn. Before birth, glycogen is stored in hepatocytes and later metabolized to glucose, meeting neonatal energy demands. Shortly after birth, lipogenesis begins, driven by transcriptional activation of enzymes involved in fatty acid oxidation. These processes are thought to be largely regulated by systemic insulin and glucagon levels. However, the role of liver-derived local factors in neonatal hepatocyte metabolism remains unexplored. Kupffer cells (KCs), the liver's resident macrophages, colonize the fetal liver early in embryogenesis and support liver metabolism in adulthood. Yet, whether KCs influence neonatal hepatocyte metabolism is unknown. Using conditional knockout mouse models targeting macrophages, we demonstrate that yolk sac-derived KCs play a critical role in hepatocyte glycogen storage and function by regulating the tricarboxylic acid cycle, a role monocyte-derived KC-like cells cannot substitute. Newborn pups lacking yolk sac-derived KCs mobilize glycogen more rapidly, a process in part regulated by insulin-like growth factor 1 (Igf1) production. Our findings identify KCs as major source of Igf1, with local production essential for balanced hepatocyte metabolism at birth.

Keywords:  Hepatocytes; Igf1; Kupffer cell; Liver development; Macrophage

DOI:  https://doi.org/10.1242/dev.204962
Int J Cancer. 2025 Dec 29.

High potassium enhances the immunosuppressive function of myeloid-derived suppressor cells via Kir4.1-dependent metabolic reprogramming and promotes tumor immune escape.

Zhiqi Xie, Jiayi Liu, Ying Chen, Kexin Wang, Ziyi Hong, Yanjie Li, Luqiong Liang, Jinglu Bi, Yuanzhen Jin, Weida Shen, Masashi Tachibana, Zeren Shen, Jinjin Shao.

  Despite advances in cancer immunotherapy, low response rates remain a critical clinical challenge. Myeloid-derived suppressor cells (MDSCs) drive tumor immune evasion by directly suppressing antitumor immunity, positioning them as prime therapeutic targets to improve immunotherapy efficacy. While dysregulated ionic microenvironments, particularly elevated potassium, are emerging as broad-spectrum immunomodulators, the role of high potassium in regulating MDSC function remains poorly understood. Here, we demonstrate that elevated extracellular potassium reprograms MDSC differentiation toward an immunosuppressive phenotype via the activation of the inwardly rectifying potassium channel Kir4.1. Mechanistically, Kir4.1 triggers metabolic rewiring by upregulating fatty acid-binding protein 3, thereby enhancing fatty acid uptake and oxidation to fuel the production of immunosuppressive molecules. In preclinical models, pharmacological inhibition of Kir4.1 with VU0134992 reversed MDSC-mediated T cell suppression, remodeled the tumor microenvironment, and synergized with anti-PD-1 therapy to achieve superior antitumor responses. Clinically, elevated Kir4.1 expression in tumor-infiltrating MDSCs correlates with an adverse prognosis in patients with lung and gastric cancer. Our study establishes Kir4.1 as a critical metabolic regulator governing MDSC functionality and proposes targeting potassium signaling as a strategy to overcome resistance to cancer immunotherapies.

Keywords:  Kir4.1; high potassium; immunotherapy; metabolic; myeloid‐derived suppressor cells

DOI:  https://doi.org/10.1002/ijc.70313
J Clin Med. 2025 Dec 11. pii: 8777. [Epub ahead of print]14(24):

Targeting Atherosclerosis: Cholesterol-Lowering Therapies with a New Immunometabolic Dress for an Old Disease.

Josep Julve, Ricardo Rodriguez-Calvo, Bertrand Perret, Laurent O Martinez, Didac Mauricio.

  Atherosclerotic cardiovascular disease (ASCVD) persists as the foremost cause of global morbidity and mortality. Central to its pathogenesis, atherosclerosis emerges as a chronic inflammatory disorder fueled by the intricate interplay between dysregulated lipid metabolism and immune cell activation. Recent insights reveal that inflammatory cues within atherosclerotic plaques or ischemic tissues orchestrate metabolic reprogramming in immune cells, thereby modulating disease trajectories. While cholesterol-lowering agents such as statins and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have long been recognized for their lipid-modulating properties, accumulating evidence now underscores their pleiotropic anti-inflammatory effects mediated through immune cell modulation. For instance, recent clinical observations reveal that PCSK9 inhibitors not only substantially reduce low-density lipoprotein cholesterol (LDL-C) and triglycerides but also appear to reduce advanced glycoprotein signals, emerging composite biomarkers of systemic inflammation. This highlights a novel and more nuanced dimension of inflammation modulation by PCSK9 inhibitors, although current evidence remains limited and requires further confirmation. Moreover, this dual immune-metabolic influence reshapes our understanding of therapeutic mechanisms and calls for a reassessment of treatment paradigms in ASCVD management. Here, we present a synthesis of current findings that emphasize how both established and novel therapies transcend lipid-lowering to exert profound immunomodulatory actions, offering promising avenues to attenuate cardiovascular disease progression through integrated metabolic and inflammatory control.

Keywords:  PCSK9; cardiovascular disease; clinical studies; diabetes; glycoproteins; immune cells; inflammation; lipids; lipoprotein metabolism; plaque; statins

DOI:  https://doi.org/10.3390/jcm14248777
Cell Commun Signal. 2025 Dec 29. 23(1): 537

Shikonin alleviates rotenone-induced Parkinson's disease neuroinflammation by targeting PKM2-mediated glycolytic MG-Hs production.

Ya Zhao, Dan Wang, Dan Mu, Lang Qu, Rong Li.

   BACKGROUND: In Parkinson's disease (PD), microglial activation is driven by metabolic reprogramming toward aerobic glycolysis, a shift regulated by pyruvate kinase M2 (PKM2). While the environmental toxin rotenone is a recognized PD risk factor, the precise glycolytic mechanism linking it to microglial neuroinflammation remains unclear, and the therapeutic potential of targeting this axis is largely unexplored.
PURPOSE: We sought to elucidate the specific glycolytic pathway by which rotenone induces microglial activation and to investigate whether shikonin, a natural PKM2 inhibitor, could attenuate neuroinflammation by targeting this metabolic mechanism.
METHODS: Using rotenone (250 nM)-treated BV2 microglia, we assessed glycolytic function (lactate production, glucose consumption) and quantified the formation of methylglyoxal-derived hydroimidazolones (MG-Hs), key pro-inflammatory glycation adducts. NF-κB pathway activation and inflammatory cytokine release were evaluated. The inhibitory effects of shikonin on this cascade were systematically examined.
RESULTS: We identified a novel mechanistic pathway: rotenone promotes PKM2-mediated glycolytic flux, leading to accumulation of the cytotoxic metabolite methylglyoxal (MG) and its derived MG-Hs. These MG-Hs function as critical signaling mediators that directly activate the NF-κB pathway, fueling neuroinflammation. Shikonin effectively disrupted this cascade at its source by inhibiting PKM2, thereby normalizing glycolytic activity, reducing MG-Hs formation, and subsequently suppressing NF-κB activation and the release of pro-inflammatory factors.
CONCLUSION: This study delineates a complete PKM2-glycolysis-MG-Hs-NF-κB axis as a fundamental mechanism in rotenone-induced neuroinflammation. Our results provide compelling preclinical evidence that shikonin exerts its neuroprotective effects by specifically targeting this metabolic-inflammatory pathway, positioning it as a highly promising disease-modifying therapeutic candidate for PD.

Keywords:  Glycolysis; Microglial activation; Neuroinflammation; Pyruvate kinase M2; Shikonin

DOI:  https://doi.org/10.1186/s12964-025-02542-z
Free Radic Biol Med. 2025 Dec 26. pii: S0891-5849(25)01463-7. [Epub ahead of print]

Age-dependent reprogramming of vascular metabolism compromises endothelial resilience to inflammation-induced endothelial dysfunction.

Agnieszka Karaś, Elżbieta Buczek, Janusz Pyka, Isabelly Annunciato, Barbara Kutryb-Zając, Agata Jędrzejewska, Klaudia Stawarska, Anna Bar, Anna Kurpińska, Anni I Nieminen, Csaba Szabo, Patrycja Kaczara, Stefan Chłopicki.

Endothelial dysfunction is a hallmark of vascular inflammation and aging. However, the role of cellular bioenergetics in the age-dependent resilience of endothelial function to inflammation has not yet been characterized. Therefore, the aim of this study was to determine whether IL-1β-induced inflammation differentially influences vascular metabolism and endothelial function in the isolated aorta of aged mice compared to young mice. Aorta from young (3-8 months) and old (22-28 months) C57BL/6 mice was isolated and subjected to ex vivo analysis of endothelial function using wire myography and vascular NO production by electron paramagnetic resonance spectroscopy (EPR). Cellular bioenergetics was assessed with the Seahorse extracellular flux analyzer for the measurement of mitochondrial respiration and glycolysis. 13C-glucose flux and high-energy phosphates were measured by liquid chromatography-tandem mass spectrometry and HPLC, respectively. IL-1β-induced impairment of endothelium-dependent relaxation was more severe in old mice. In young mice, IL-1β triggered metabolic activation characterized by increased mitochondrial respiration, glycolysis, and tricarboxylic acid cycle (TCA) activity. In contrast, in the aorta of aged mice, a blunted metabolic response was observed with a shift to the pentose phosphate pathway (PPP). Pharmacological inhibition of PPP restored endothelial function in the aorta of old but not young mice in the presence of IL-1β, indicating a maladaptive role of PPP hyperactivation in the ageing vasculature. In the aorta of aged mice, pyruvate oxidation and metabolic flux into TCA were impaired in response to IL-1β, with a concomitant activation of anaplerotic pyruvate-derived carbon influx into TCA and the malate-aspartate shuttle. Furthermore, using specific pharmacological inhibitors of oxidative phosphorylation and glycolysis, we demonstrated that mitochondrial respiration, but not glycolysis, was required for NO-dependent vasodilation in the aorta. In conclusion, our findings reveal that age-dependent metabolic reprogramming drives distinct vascular metabolic responses to IL-1β-induced inflammation, contributing to greater susceptibility of aged vessels to endothelial dysfunction.

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.12.046
BMC Med. 2025 Dec 29. 23(1): 698

Dimethyl itaconate suppresses dendritic cell and CD8+ T cell responses to halt vitiligo.

Yinghan Wang, Yuhan Chen, Jingjing Ma, Linxuan Wu, Pan Kang, Jianru Chen, Pengran Du, Wei Wu, Xinju Wang, Kaiqiao He, Yuqi Yang, Sen Guo, Weinan Guo, Ling Liu, Zhe Jian, Tianwen Gao, Shuli Li, Chunying Li.

   BACKGROUND: Although dendritic cell (DC)- and CD8+ T cell-mediated autoimmunity is critical for destroying melanocytes in vitiligo, treatment options remain limited by the absence of therapies that cotarget both cell types.
METHODS: We first evaluated the association between the immunoregulatory metabolite itaconate and disease development, by determining human vitiligo serum itaconate levels and monitoring depigmentation progression in Acod1 knockout (KO) mice with endogenous itaconate deficiency. We further evaluated the therapeutic efficacy of the itaconate derivative, dimethyl itaconate (DI) in mice and assessed its effects on cutaneous infiltration and the functional properties of DCs and CD8+ T cells in vivo and ex vivo. The gene signatures and signaling pathways involved in DI-treated CD8+ T cells were also assessed.
RESULTS: We observed an elevation of circulating itaconate in vitiligo patients, whereas itaconate deficiency accelerated depigmentation in Acod1 KO mice after vitiligo induction. The administration of DI halted vitiligo development and promoted repigmentation, with elevated circulating itaconate levels, increased melanocyte counts, and decreased cutaneous CD8+ T cell densities. Mechanistically, DI dampened CD8+ T cell activation (CD69), effector function (Interferon-γ, IFN-γ), cytotoxicity (Gzmb), proliferation, and proinflammatory gene expression (Csf1, Ifitm1, CD49a, NKG2D, and NKG2A), partly by suppressing the Janus kinase (JAK)‒STAT pathway. Moreover, DI-treated mice exhibited reduced cutaneous DC infiltration, as well as fewer DCs with mature and migratory phenotypes.
CONCLUSIONS: Our findings identify DI as a metabolite-derived small molecule that protects against autoimmune injury by cotargeting DC and CD8+ T cell responses, thereby demonstrating a promising therapeutic strategy and providing a foundation for treating vitiligo and other cell-specific autoimmune diseases.

Keywords:  Autoimmune disease; CD8+ T cell; Dendritic cell; Dimethyl itaconate; JAK-STAT pathway; Vitiligo

DOI:  https://doi.org/10.1186/s12916-025-04512-1
J Control Release. 2025 Dec 30. pii: S0168-3659(25)01201-5. [Epub ahead of print] 114587

Nanomedicine-mediated modulation of tumor metabolism for enhanced immunotherapy.

Yanjun Liu, Dongqi Sun, Wenshi Li, Zhixiao Zhang, Ce Li, Xiaofang Che, Shenwu Zhang.

  Immunotherapy has emerged as a transformative approach in cancer treatment. However, its efficacy remains limited in many cases. A key factor contributing to this limitation is metabolic reprogramming within the tumor microenvironment (TME), which suppresses immune cell function and promotes tumor progression. Recently, nanotechnology-based approaches have opened new ways to modulate tumor metabolism and enhance immunotherapy. This review outlines nanoscale strategies aimed at reprogramming tumor metabolism to potentiate antitumor immunity. We begin by discussing the rational design of immune-metabolic nanoregulators, along with key immunometabolic pathways and their regulatory mechanisms. Next, nanotechnology strategies for targeted metabolic intervention at the cellular and microbial levels, as well as the metabolic characteristics of TME are systematically summarized. Furthermore, we highlight recent advances in nanomedicine-based metabolic regulators and evaluate their potential for clinical translation, addressing both opportunities and challenges.

Keywords:  Cancer immunotherapy; Metabolism regulation; Nanotherapeutics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jconrel.2025.114587
Nucleic Acids Res. 2025 Nov 26. pii: gkaf1371. [Epub ahead of print]53(22):

3'UTR-derived small RNA couples acid resistance to metabolic reprogramming of Salmonella within macrophages.

Takeshi Kanda, Fang Liu, Hoda Kooshapour, Sarah Reichardt, Maolin Wang, Philippe Icyishaka, Nozomu Obana, Alexander J Westermann, Yanjie Chao, Masatoshi Miyakoshi.

Acid resistance is crucial for enterobacteria to withstand host acidic environments during infection, including the gastrointestinal tract and macrophage phagosomes. A key acid resistance mechanism of the facultative intracellular pathogen Salmonella is the expression of the arginine decarboxylase AdiA. While AdiA confers acid resistance via an H+-consuming reaction, we discover that the 3'-untranslated region (UTR) of adiA mRNA is processed by RNase E into a regulatory small RNA, AdiZ. Through RNA-RNA interactome profiling and transcriptomic analysis, followed by in vitro structural probing and in vivo validations, we demonstrate that AdiZ directly base-pairs with and negatively regulates ptsG, pykF, and dmsA mRNAs involved in glucose uptake, glycolysis, and anaerobic respiration, respectively. Intriguingly, AdiZ is induced and facilitates Salmonella survival within macrophages, where acidic and hypoxic stresses prevail. Thus, simultaneous expression of AdiA and AdiZ from a single mRNA ties arginine-dependent acid resistance to metabolic reprogramming of Salmonella in the host intracellular niches.

DOI: https://doi.org/10.1093/nar/gkaf1371
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2521070123

L-lactic acid enhances type I interferon immune response and inhibits virus infection by promoting IRF9 L-lactylation.

Ying Miao, Qun Cui, Tingting Zhang, Renxia Zhang, Qian Zhao, Haiyan Zhou, Yibo Zuo, Qin Wang, Yuerong Zhang, Zhijin Zheng, Wei He, Chunyan Liu, Yukang Yuan, Hui Zheng.

  Lysine lactylation is a crucial posttranslational modification (PTM) that regulates protein function. Here, this study revealed that L-lactic acid promotes host immune response and inhibits viral infection by inducing Interferon Regulatory Factor 9 (IRF9) L-lactylation. We first found L-lactylation modification (L-Kla) of IRF9 mediated by AARS1. Further studies demonstrated that IRF9 L-lactylation potentiates type I interferon (IFN-I) signaling by promoting IRF9-STAT2 interaction, thereby boosting antiviral immune response. Intriguingly, L-lactic acid exhibits dual effects on viral infection: L-lactic acid exhibits antiviral effects at physiological and moderately elevated levels but proviral effects at high levels. Furthermore, we found that the viruses can achieve immune evasion by promoting SIRT1-mediated delactylation of IRF9. Interestingly, we uncovered that metformin promotes IRF9 L-lactylation by both accumulating lactic acid and disrupting virus-induced IRF9-SIRT1 interaction. These findings renew the understanding of the roles of lactic acid in antiviral immune response and determine metformin's immunomodulatory effects on antiviral immunity through regulating IRF9 L-lactylation.

Keywords:  IRF9; L-lactic acid; antiviral immunity; lysine lactylation; metformin

DOI:  https://doi.org/10.1073/pnas.2521070123
Front Cell Infect Microbiol. 2025 ;15 1706664

Macrophage adaptation to hypoxia: metabolism, migration, and phagocytosis.

Lu Yuan, Tiemen Mellema, Gésinda I Geertsema-Doornbusch, Henny C van der Mei.

   Background: Hypoxia is a hallmark of many diseases, including periodontitis, where it influences the immune cell behavior. In low-oxygen conditions, macrophages shift toward glycolytic metabolism, altering their phenotype and function, However, it remains unclear how these functional changes affect the interaction between macrophages and oral bacteria in the hypoxic environment of infectious tissue.
Methods: In this study, which focused on periodontitis, we addressed this gap by investigating how a physiologically relevant low oxygen tension (2% O2) compared with normoxia (20% O2) modulates the metabolism, morphology, migration, and interaction of macrophages with both commensal and pathogenic oral bacteria.
Results: Hypoxia activated the hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway, induced glycolytic metabolism, reduced proliferation, and led to a rounded morphology with amoeboid migration characteristics. Despite reduced mobility, hypoxic macrophages maintained their phagocytic capacity and effectively limited the intracellular proliferation of Streptococcus oralis and Porphyromonas gingivalis. Hypoxia also altered the cytokine profiles, with increased interleukin-1 beta (IL-1β) and IL-10, reduced tumor necrosis factor alpha (TNF-α), and enhanced reactive oxygen species production.
Conclusion: These findings highlight the plasticity of macrophages in adapting to low-oxygen environments and underscore their potential role in host defense and inflammation resolution in periodontal disease. The modulation of these responses may inform novel therapeutic approaches targeting hypoxia-associated immune dysfunction.

Keywords:  bacteria; host-pathogen interaction; inflammation; oxidative stress; periodontitis

DOI:  https://doi.org/10.3389/fcimb.2025.1706664
Int Immunopharmacol. 2025 Dec 30. pii: S1567-5769(25)02116-2. [Epub ahead of print]171 116127

Neutrophil glycolysis mediates colitis-induced exacerbation of Alzheimer's disease.

Boyuan Tan, Jingjing Zhang, Kaikai Dong, Zhe Li, Xinyue Yu, Sophia W Zhang, Lin Luo, Wenjuan Yao, Feng Wu.

  Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-β (Aβ) deposition, synaptic dysfunction, and progressive cognitive decline. Emerging evidence suggests that peripheral inflammation, particularly intestinal inflammation, can aggravate AD pathology through the gut-brain axis. As key mediators of intestinal inflammation and systemic immune activation, neutrophils have emerged as critical contributors to AD progression. In this study, we investigated how dextran sulfate sodium (DSS)-induced colitis influences Aβ pathology and synaptic integrity in 5 × FAD mice, focusing on the role of neutrophil glycolysis and neutrophil elastase (NE) activation. DSS-induced colitis significantly exacerbated AD-like pathology, as evidenced by pronounced body-weight loss, colon shortening, increased brain neutrophil infiltration, and elevated NE expression in the hippocampus, accompanied by enhanced Aβ plaque burden and reduced dendritic spine density. These findings indicate that DSS-triggered peripheral inflammation promotes central immune activation and accelerates Aβ pathology via metabolic reprogramming of neutrophils. Administration of the glycolytic inhibitor PFK-158 effectively suppressed NE expression and mitigated Aβ accumulation. Peripheral injection of PFK-158 attenuated neuroinflammation and partially restored dendritic structure, while intracerebroventricular infusion directly inhibited central neutrophil activation and improved hippocampal synaptic transmission, as reflected by enhanced field excitatory postsynaptic potentials (fEPSPs) and long-term potentiation (LTP). Collectively, these results demonstrate that DSS-induced colitis aggravates AD pathology by enhancing neutrophil glycolysis and NE release, linking peripheral metabolic inflammation to central neurodegeneration. Targeting neutrophil glycolytic activation with PFK-158 represents a promising therapeutic strategy to disrupt gut-brain inflammatory crosstalk and slow AD progression.

Keywords:  Alzheimer's disease; Glycolysis; Gut–brain axis; Neutrophil; Neutrophil elastase; PFK-158

DOI:  https://doi.org/10.1016/j.intimp.2025.116127
Gut Microbes. 2026 Dec 31. 18(1): 2606486

Gut microbiome-derived propionate reprograms alveolar macrophages metabolically and regulates lung injury responses in mice.

Daisuke Maruyama, Xiaoli Tian, Thien N M Doan, Wen-I Liao, Tomohiro Chaki, Hiroki Taenaka, Mazharul Maishan, Michael A Matthay, Arun Prakash.

  Responses to lung injury can vary between individuals with the diet and gut microbiome representing two underappreciated sources for this variability. The gut microbiome can influence lung injury outcomes through the gut‒lung axis, but exactly how diet and its effects on the microbiota are involved remains unclear. We hypothesized that dietary fiber interventions would favor the presence of short-chain fatty acid (SCFA)-producing fermentative bacteria presence in the gut microbiome, thereby influencing the resting lung immunometabolic tone as well as influencing downstream responses to lung injury and infection. To test this hypothesis, we fed mice fiber-rich (FR) and fiber-free (FF) diets, and observed changes in the steady-state transcriptional programming of alveolar macrophages (AM). Next, we examined the effects of the FR and FF diets on murine responses to sterile and infectious lung injury in vivo while simultaneously profiling the gut microbiota and SCFA levels transmitted along the gut‒lung axis. Finally, we validated our in vivo observations with mechanistic studies of the metabolic, signaling, and chromatin-modifying effects of specific SCFAs on lung AM ex vivo and in vitro. Overall, our fiber-rich diet reprogrammed AMs and attenuated lung inflammation after sterile injury while exacerbating lung infection. This effect of FR diets could be transferred to germ-free (GF) mice by fecal microbiome transplantation (FMT) and depended on the ability of the microbiota to produce propionate. Mechanistically, SCFAs altered the metabolic programming of AMs and lung tissue ex vivo without a clear role for free fatty acid receptors (FFAR) or chromatin remodeling. These findings demonstrate that the gut‒lung axis can regulate resting lung metabolic tone through dietary fiber intake and the enrichment of SCFA-producing gut bacteria, as well as influence sterile and non-sterile lung injury responses. These results provide evidence to support the development of therapeutic dietary interventions to preserve or enhance specific aspects of host pulmonary immunity.

Keywords:  FFAR; Gut-lung axis; SCFA; gut microbiome; immunometabolic tone; lung immune tone; lung injury; lung metabolic tone; metabolites; propionate

DOI:  https://doi.org/10.1080/19490976.2025.2606486
Biomedicines. 2025 Dec 11. pii: 3041. [Epub ahead of print]13(12):

Lactate-Mediated Epigenetic and Immunometabolic Reprogramming in Glioma: An Emerging Axis Linking Metabolism to Tumor Progression.

Xinyi Xie, Wenjing Zhou, Yin Ku, Shasha Li, Yunhao Yang, Xiaohu Hao, Yaohui Chen.

  Background: Among primary malignant brain tumors in adults, glioblastoma is the most common and the most aggressive, characterized by profound metabolic reprogramming. This metabolic shift is essential for sustaining relentless proliferation and adapting to the challenging tumor microenvironment (TME). Central to this adaptation in glioma is the Warburg effect, which leads to excessive lactate production and accumulation, even in the presence of oxygen. This metabolic divergence significantly impacts the tumor immune microenvironment, promoting the recruitment of immunosuppressive cells and weakening the anti-tumor immune response. Core Content: This review provides a comprehensive analysis of the multifaceted roles of lactate in IDHwt glioma pathogenesis. It explores how lactate serves as a critical nexus connecting aberrant metabolism, epigenetic reprogramming (notably via histone lactylation), and immune evasion. The review delves into the molecular mechanisms by which lactate, particularly through the post-translational modification known as lactylation, directly modulates the epigenetic landscape to promote oncogene expression. Furthermore, it examines lactate's role in acidifying the TME, promoting the immunosuppressive M2 polarization of glioma-associated macrophages (GAMs), and inhibiting the cytotoxic activity of T lymphocytes. Conclusions: This "lactate-centric" framework provides a unifying model that links metabolic dysregulation directly to malignant progression and therapeutic resistance (e.g., to TMZ). By elucidating this metabolic-epigenetic-immune axis, the review highlights a critical dependency that fuels glioma aggression. Finally, it discusses emerging therapeutic strategies aimed at targeting lactate production (LDHAi), transport (MCTi), and downstream epigenetic signaling (HDACi/p300i), offering novel avenues for integrative immunometabolic therapy.

Keywords:  gliomas; immune microenvironment; lactate metabolism; lactylation; metabolic reprogramming

DOI:  https://doi.org/10.3390/biomedicines13123041
J Hazard Mater. 2025 Dec 22. pii: S0304-3894(25)03830-0. [Epub ahead of print]501 140909

Arachidonic acid reverses microplastic-induced macrophage dysfunction in teleost fish.

Yun-Chao Cao, Yu-Qing Zhou, Jia-Yao Wu, Hetron Mweemba Munang'andu, Bo Peng.

  Microplastic pollution poses a significant threat to aquaculture by compromising fish immunity, particularly macrophage function. This study investigated the impact of polystyrene microplastics (PS) on Nile tilapia (Oreochromis niloticus) macrophages and explored metabolic interventions to reverse PS-induced damage. PS exposure increased tilapia susceptibility to Streptococcus agalactiae infection, reducing fish survival. PS accumulated in head kidney macrophages, impairing phagocytosis, altering cytokine expression, elevating oxidative stress and malondialdehyde levels, and suppressing T-cell proliferation. Transcriptomics revealed PS dysregulated lysosomal pathways, reducing lysosomal membrane permeability and bacterial killing capacity. Metabolomic screening identified arachidonic acid (AA) as the most significantly suppressed metabolite in PS-exposed macrophages. Exogenous AA administration restored macrophage function including phagocytosis, cytokine expression, oxidative stress, enhanced lysosomal integrity, improved bactericidal activity, and increased survival during S. agalactiae challenge in PS-exposed fish. AA also reversed PS-induced transcriptional dysregulation of lysosomal genes. These results demonstrate that AA rectifies PS-induced macrophage dysfunction and lysosomal impairment, supporting its potential as a dietary supplement to mitigate microplastic immunotoxicity in aquaculture.

Keywords:  Arachidonic acid; Lysosome; Macrophage; Microplastic; Polystyrene microplastics; Tilapia

DOI:  https://doi.org/10.1016/j.jhazmat.2025.140909
Aging Cell. 2026 Jan;25(1): e70356

Myeloid-Derived CD38 Mediates Age-Related Endometrial Aging Through NAD+ Depletion.

Lun Hua, Luting Liu, Dengfeng Gao, Lulu Ma, Xianyang Jin, Liuyong Lu, Shangbo Tian, Xuemei Jiang, Chao Jin, Bin Feng, Lianqiang Che, Shengyu Xu, Yan Lin, Long Jin, Yong Zhuo, Mingzhou Li, De Wu.

  Against the backdrop of the global trend toward delayed childbearing, elucidating the mechanisms underlying uterine aging has emerged as a critical biomedical priority for addressing age-related implantation failure. Through unbiased global metabolomic profiling of peri-implantation uteri across different ages in mice, we identified nicotinamide adenine dinucleotide (NAD+) depletion as a hallmark metabolic feature of endometrial aging. Single-cell RNA sequencing further revealed an expansion of senescent stromal cell populations, which was accompanied by a decline in NAD+ levels. Supplementation with NAD+ precursors alleviated age-related stromal senescence and endometrial dysfunction, thereby restoring the uterus' implantation competence. Mechanically, we demonstrate that CD38 derived from myeloid serves as a principal driver of uterine NAD+ depletion; this process accelerates stromal senescence and impairs uterine receptivity. These findings establish CD38 as a central physiological integrator that links NAD+ metabolism to uterine function and highlight it as a promising target for rejuvenation strategies aimed at improving reproductive outcomes in women of advanced maternal age.

Keywords:  CD38; NAD+; endometrial aging; macrophage

DOI:  https://doi.org/10.1111/acel.70356
Biomolecules. 2025 Dec 13. pii: 1737. [Epub ahead of print]15(12):

Pioglitazone Modulates p65-Mediated Mitochondrial Bioenergetics: Implications for Acetaldehyde-Induced HIV Replication in Alveolar Macrophages.

Moses New-Aaron, Sarah Chang, Xian Fan, Ashish Mehta, Sara C Auld, Bashar S Staitieh, Michael Koval, Samantha M Yeligar.

  Alcohol misuse is twice as prevalent among people living with HIV (PWH), and this increases the risk of pulmonary complications even in those receiving antiretroviral therapy. Our prior work showed that the alcohol metabolite, acetaldehyde, activates nuclear factor kappa B p65 (p65), leading to HIV replication and interleukin (IL)-1β activation in alveolar macrophages (AMs). Since the aforementioned processes are energy-demanding, which conversely impair mitochondrial functions, we hypothesized that acetaldehyde-induced p65 drives AMs to a mitochondrial hyperactive state to promote HIV replication and IL-1β release and induces oxidative stress and mitochondrial dysfunction. Since we found pioglitazone (PIO) to be a negative regulator of p65, we postulate that PIO suppresses HIV replication and IL-1β activation in AMs by restricting p65-induced mitochondrial hyperactivation. Murine AMs were exposed to acetaldehyde via the acetaldehyde generating system (AGS) and infected in vitro with EcoHIV, a chimeric ecotropic HIV construct. AGS + EcoHIV activated p65, resulting in enhanced ATP-linked mitochondrial respiration, proton leak, non-mitochondrial respiration and the generation of reactive oxygen species (ROS) in AMs. Inhibition of mitochondrial ATP synthesis with low-dose oligomycin attenuated AGS-induced HIV replication and AGS + EcoHIV-induced IL-1β release from AMs. PIO treatment, which attenuated AGS-induced p65 activation, suppressed proton leak, non-mitochondrial oxygen consumption, ROS, and IL-1β and p24 release. While p65-induced mitochondrial hyperactivation represents AMs' adaptive response to the energy demands imposed by HIV replication and proinflammatory activation when exposed to acetaldehyde, PIO treatment may offer a novel therapeutic strategy to restore adequate mitochondrial bioenergetics in the AMs of PWH who misuse alcohol.

Keywords:  EcoHIV; acetaldehyde generating system; alcohol; alveolar macrophages; inflammation; mitochondrial hyperactivation; nuclear factor kappa B p65; pioglitazone

DOI:  https://doi.org/10.3390/biom15121737
Front Immunol. 2025 ;16 1675699

Unraveling the RKIP-YY1 axis: immune crosstalk in the pathogenesis of metabolic disorders.

Fawaz Alzaid, Hossein Arefanian, Fatemah Bahman, Shaima Albeloushi, Ghadeer Alhamar, Anwar Mohammad, Amal Hasan, Ashraf Al Madhoun, Rasheed Ahmad, Fahd Al-Mulla.

  Metabolic diseases, including obesity, type 2 diabetes, and cardiovascular disorders, are increasingly recognized as chronic inflammatory conditions driven by dysregulated immune-metabolic interactions. Two pivotal regulators of this crosstalk are Raf kinase inhibitor protein (RKIP) and the transcription factor Yin Yang 1 (YY1), which coordinate inflammatory signaling and metabolic stress responses across multiple tissues. RKIP exerts protective, anti-inflammatory effects by antagonizing the MAPK and NF-κB pathways, thereby preserving tissue homeostasis under metabolic stress. In contrast, YY1 acts as a context-dependent transcriptional regulator that promotes inflammatory gene programs, contributes to maladaptive immune cell differentiation, and exacerbates metabolic dysfunction. Notably, RKIP and YY1 are reciprocally regulated: RKIP suppresses YY1 expression via NF-κB inhibition, whereas YY1 represses RKIP transcription through a Snail-dependent feedback loop. In metabolic disease states, this balance is disrupted, RKIP is downregulated, and YY1 is upregulated, leading to heightened immune activation, cytokine production, and tissue damage. Therefore, we propose that RKIP and YY1 represent two opposing yet dynamically coordinated regulators of immunometabolic balance, functioning as a molecular rheostat that determines whether immune responses shift toward inflammation or resolution under metabolic stress. This review synthesizes current insights into the molecular structures, signaling pathways, and tissue-specific functions of RKIP and YY1, emphasizing their interplay in shaping immune responses in metabolic disorders. We further discuss emerging therapeutic approaches aimed at restoring RKIP-YY1 homeostasis to mitigate chronic inflammation and metabolic pathology.

Keywords:  RKIP; YY1; immunity; inflammation; metabolic disease

DOI:  https://doi.org/10.3389/fimmu.2025.1675699
Front Immunol. 2025 ;16 1710128

Mitochondrial calcium shapes B cell signaling and mitochondrial function.

Hakan Taskiran, Elena Czeslik, Leonhard Stark, Kathrin Kläsener, Theresa Elisa Schnalzger, Jürgen Ruland, Michael Reth, Julia Jellusova.

   Introduction: Calcium (Ca2+) signaling plays a pivotal role in determining B cell fate, shaping processes such as activation, differentiation, anergy or apoptosis. Upon B cell antigen receptor activation, Ca2+ is rapidly mobilized from the endoplasmic reticulum and supplemented by Ca2+ influx from the extracellular space, ultimately driving activation of various signaling pathways required for appropriate B cell responses. Although mitochondria also harbor significant levels of Ca2+, how mitochondrial Ca2+ dynamics are regulated in B cells in response to activation or other cues remains unknown, as do the functional consequences of altered mitochondrial Ca2+ levels.
Methods: Chemical dyes as well as a genetically encoded Ca2+ sensor with a mitochondrial targeting sequence were used to study mitochondrial Ca2+ dynamics in response to various stimuli. Proximity ligation assays were performed to assess interaction between mitochondria and the endoplasmic reticulum. Primary mouse B cells and the Burkitt lymphoma cell line Ramos were used to study functional consequences of the loss of the Mitochondrial Calcium Uniporter.
Results: Here, we show that mitochondrial Ca2+ levels dynamically respond to cell activation, stress and metabolic cues and that mitochondrial Ca2+ uptake is largely dependent on the Mitochondrial Calcium Uniporter. Reduced mitochondrial Ca2+ uptake has a negative impact on mitochondrial activity and also affects cell signaling. These findings demonstrate that changes in mitochondrial Ca2+ contribute to shaping functional B cell responses.
Discussion: The spatial and temporal dynamics of Ca2+ accumulation within distinct subcellular compartments, particularly the cytosol, endoplasmic reticulum and mitochondria, are essential for translating extracellular and intracellular signals into specific cellular outcomes. Our study provides new insights into the regulation of Ca2+ homeostasis in B cells.

Keywords:  B lymphocyte; calcium; metabolism; mitochondria; signaling

DOI:  https://doi.org/10.3389/fimmu.2025.1710128
bioRxiv. 2025 Oct 04. pii: 2025.10.02.680083. [Epub ahead of print]

Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8 + T cell-macrophage interactions.

Erin F McCaffrey, Alea C Delmastro, Bindu Singh, Annu Devi, Nadia A Golden, Shabaana A Khader, Michael Angelo, Deepak Kaushal, Smriti Mehra.

Granulomas, the hallmark of tuberculosis (TB) disease, can both restrict Mycobacterium tuberculosis (Mtb) dissemination and impede its clearance. Recent studies indicate that indoleamine 2,3-dioxygenase (IDO1), an immunosuppressive metabolic enzyme, limits infiltration of activated T cells and can contribute to TB disease progression. Treatment with 1-methyl-D-tryptophan (D-1MT), a small molecule inhibitor that restores mTOR signaling, has been shown to improve immune responses Mtb -infected rhesus macaques. Here, we investigated the impact of D-1MT treatment on TB granuloma architecture using 30-plex high-dimensional issue imaging in rhesus macaques. By spatially mapping 13 distinct cell populations, we found D-1MT treatment corresponded with significantly increased infiltration CD8 + T cells into granulomas compared to untreated controls. Notably, these CD8 + T cells expressed markers of cell proliferation and cytotoxicity. D-1MT enhanced CD8 + T cell infiltration throughout the granuloma, with particularly pronounced effects in the myeloid core, where we observed significantly enhanced spatial interactions between macrophages and CD8 + , but not CD4 + T cells. Our results demonstrate that: (i) effective intra-granulomatous Mtb control is associated with the close spatial proximity between CD8 + T cells and macrophages, a feature less abundant in uncontrolled pulmonary TB; (ii) IDO1 induction blocks CD8 + T cell infiltration and reduces T cell activation and proliferation; and (iii) therapeutic strategies, including D-1MT, that improve intra-granulomatous killing hold strong translational potential.
Significance statement: Our understanding of immune mechanisms within the TB granuloma has advanced greatly with the advent of high-resolution single cell multiplexed imaging. Using such imaging, we show that TB granulomas in rhesus macaques, a highly translational model of human TB pathology, are characterized by IDO1-mediated immunoregulation. Early pharmacologic restoration of mTOR signaling via D-1MT treatment can reduce IDO1 enzymatic activity and facilitate the recruitment and function of CD8 + T cells within the granulomas. These findings reveal specific mechanisms exploited by Mtb to maintain intra-granuloma persistence and underscore immune responses. Future vaccine and therapeutic design should consider these immunoregulatory features to achieve better control of Mtb infection.

DOI: https://doi.org/10.1101/2025.10.02.680083
Pathol Res Pract. 2025 Dec 29. pii: S0344-0338(25)00541-2. [Epub ahead of print]278 156348

Glutamine metabolites promote the progression of cervical cancer by inducing M2 macrophage polarization.

Tingting Liu, Lanyue Zhang, Yang Li, Wenxin Liao, Juexiao Deng, Hua Liang, Fujin Shen.

   BACKGROUND: Tumour-associated macrophages (TAMs) within the tumour microenvironment play crucial roles in tumour initiation, invasion, and metastasis. While glutamine synthetase (GS) is expressed predominantly in the tumour stroma, particularly in TAMs, the role of glutamine metabolism in regulating TAM polarization and function in cervical cancer (CC) remains poorly understood. This study aims to clarify this role and its implications for cancer progression.
METHODS: CD68 and GS expression in cervical tissues was detected using immunofluorescence staining. The effects of glutamine metabolism on TAM polarization were investigated via RTqPCR, flow cytometry, Western blotting and NAA treatment analyses. CCK8, colony formation, and Transwell assays were conducted to determine the effects of MSO-treated macrophages on tumour cell proliferation, migration, and invasion.
RESULTS: We observed a significant increase in GS expression in TAMs within cervical cancer (CC) tissues, particularly in M2-like TAMs. Glutamine synthesized by TAMs with high GS expression was found to increase the proliferation, migration, and invasion of CC cells. Inhibition of GS in TAMs notably reduced their tumour-promoting effects. Additionally, the byproducts of glutamine metabolism in CC cells contributed to the polarization of TAMs towards the M2 phenotype. This polarization was completely abrogated when SNAT1, a key glutamine transporter, was inhibited in CC cells.
CONCLUSIONS: Our findings demonstrate that glutamine synthesized by TAMs with high GS expression promotes tumour progression in CC. Furthermore, glutamine byproducts produced by CC cells induce TAM polarization towards the M2 phenotype, suggesting crucial metabolic crosstalk between tumour cells and macrophages that supports tumour progression. These results highlight the potential of targeting glutamine metabolism to modulate TAM function and inhibit tumour growth.

Keywords:  Cervical cancer; GS; Glutamine; M2 polarization; Tumour-associated macrophages

DOI:  https://doi.org/10.1016/j.prp.2025.156348
Cell Metab. 2025 Dec 29. pii: S1550-4131(25)00530-3. [Epub ahead of print]

Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.

Jianbiao Xiao, Zhiyang Li, Yi Ding, Kejin Zhu, Zhihao Zheng, Yaowei Zhang, Jiawen Weng, Feifei Wang, Yuqin Zhang, Sisi Zeng, Minxing Qiu, Zhaowen Zhang, Zhizhang Wang, Li Liang.

  Immune checkpoint blockade (ICB) faces limitations owing to high cost and restricted efficacy. This study identifies SNX17 as a key mediator of ICB resistance. Elevated SNX17 correlates with poor anti-PD-1 response in humans and mice. SNX17 deletion in tumor cells inhibits tumor growth via CD8+ T cell-dependent mechanisms. SNX17 reduces uridine in the tumor microenvironment (TME), suppressing IFN-γ and upregulating PD1 in CD8+ T cells. Exogenous uridine shows antitumor efficacy comparable to anti-PD-1/PD-L1 in low-SNX17 tumors and overcomes resistance in high-SNX17 models. Uridine enhances CD8+ T cell function by promoting CD45 N-glycosylation and LCK phosphorylation. Mechanistically, SNX17 stabilizes RUNX2, promoting UPP1 transcription and uridine degradation in the TME. These findings position SNX17 as an ICB response biomarker and nominate uridine as a cost-effective immunotherapeutic strategy.

Keywords:  CD8+ T cell; N-glycosylation; SNX17; UPP1; checkpoint blockade; immunotherapy resistance; uridine

DOI:  https://doi.org/10.1016/j.cmet.2025.11.016
Antioxid Redox Signal. 2025 Dec 16.

CD5L Inhibits Allergic Airway Inflammation by Lysophosphatidylcholine-Induced ILC2 Apoptosis.

Yan Wang, Te Chen, Yaqi Qin, Meilian Lin, Shifei Yao, Xiaoyu Sun, Yanjun Jia, Xiaoliang Yang, Qingxiang Kong, Minghao Zhang, Xuemei Zhang, Yibing Yin, Wenchun Xu.

  Aims: Group 2 innate lymphoid cells (ILC2s) play key roles in allergic asthma development. We have previously discovered that CD5 antigen-like protein (CD5L) can inhibit allergic airway inflammation. In this study, we investigate the effect of CD5L on ILC2s and the underlying mechanism. Results: Our findings demonstrated that CD5L suppresses allergic airway inflammation by inhibiting ILC2s. CD5L inhibited NF-κB, MAPK, and PI3K-AKT pathways in ILC2s, thus reducing interleukin (IL)-5 and IL-13 production. CD5L increased the level of lysophosphatidylcholine (lysoPC) in ILC2s through the transforming growth factor beta (TGF-β) signaling pathway. The elevated lysoPC further induced reactive oxygen species (ROS) production in ILC2s, and the increased ROS fed back to increase the level of lysoPC. The accumulated ROS induced ILC2 apoptosis. The scavenger receptor CD36 mediated the inhibitory effect of CD5L on ILC2s and allergic airway inflammation. Finally, CD5L was shown to be potential therapeutic for allergic asthma. Innovation: This study is the first to demonstrate that CD5L suppresses allergic airway inflammation by inhibiting ILC2 responses. It is the initial discovery that CD5L promotes ILC2 apoptosis, whereas CD5L was previously recognized as an apoptosis inhibitor. The regulation of TGF-β signaling pathway on lysoPC is demonstrated for the first time. Conclusion: This study demonstrated that CD5L inhibits ILC2 activation and induces ILC2 apoptosis, thereby suppressing allergic airway inflammation. CD5L can serve as a novel therapeutic strategy for allergic asthma. Antioxid. Redox Signal. 00, 000-000.

Keywords:  CD5 antigen-like protein; asthma; group 2 innate lymphoid cells; lipid metabolism; lysophosphatidylcholine; oxidative stress

DOI:  https://doi.org/10.1177/15230864251406294
Sci Adv. 2026 Jan 02. 12(1): eadz7916

Galectin-3 exacerbates autoimmune diabetes by limiting regulatory T cell differentiation and function.

Lingxiang Xie, Rong Zhang, Hailan Zou, Jingyi Hu, Jiangming Deng, Jin Ding, Long Liu, Qiuqiu Lin, Bin Zhao, Aimin Xu, Zhiguang Zhou, Yang Xiao.

Galectin-3, a β-galactoside-binding lectin, has been implicated in several inflammatory and autoimmune diseases. However, the significance of circulating Galectin-3 in type 1 diabetes (T1D) remains unclear. Here, we report that compared to healthy controls, patients with T1D and their first-degree relatives (FDRs) exhibited significantly increased serum Galectin-3 levels primarily produced and secreted by monocytes/macrophages. Pharmacological inhibition (TD139) as well as knockout of Galectin-3 gene both attenuated Galectin-3-mediated suppression of regulatory T cells (Treg cells) and protected from insulitis and diabetes onset in NOD mice. Mechanistically, Galectin-3 bound to and activated lymphocyte activation gene 3 (LAG3), a receptor expressed on activated T cells, subsequently suppressing the MEK/ERK signaling pathway and thereby hindering Treg cell differentiation and function. In summary, our study identifies Galectin-3 as a potential biomarker for T1D and suggests that TD139 holds promise as a therapeutic candidate for patients with T1D and high serum Galectin-3 levels.

DOI: https://doi.org/10.1126/sciadv.adz7916
J Nutr. 2025 Dec 31. pii: S0022-3166(25)00791-6. [Epub ahead of print] 101285

Invited: Longitudinal assessment of diets with varying carbohydrate-to-fat ratios and fiber supplementation on immunometabolic markers, liver function, and gut microbiome.

Umesh K Goand, Devendra Paudel, Anthony M Koehle, Fuhua Hao, Loi V Nguyen, Gopi Yalavarthi, Sangshan Tian, Sumudu Rajakaruna, Chloé E M Robert, Inês V da Silva, Benoit Chassaing, Andrew D Patterson, Rita Castro, Vishal Singh.

  The proportions of macronutrients and fiber in the diet influence host metabolism and the development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear how early shifts in immune, metabolic and liver function markers occur upon consuming diets with markedly different proportions of carbohydrates and fats such as the ketogenic diet (KD) and the high-carbohydrate diet (HCD) and whether these diets exert differential effects on these markers under lean and obese conditions. Moreover, the potential for prebiotic fiber supplementation to alter or mitigate the metabolic consequences of the KD has not been established. To address these questions, we conducted longitudinal assessments at 2-, 4-, 8-, and 16-weeks post-intervention in lean C57BL/6 mice, which revealed that diets rich in fat (high fat (HFD) and KD) induced obesity and hyperglycemia compared to the baseline chow diet. KD resulted in nutritional ketosis as early as two-weeks post-feeding; however, it impaired metabolic and liver function starting from week 2. Following the 16-week intervention, we observed that the fat-rich diets (HFD & KD), but not the HCD, promoted hepatic steatosis, inflammation, and fibrosis, as assessed by 1H-NMR, quantitative PCR, and histology, respectively. Next, we found that incorporating inulin into the KD (KD-F) partly mitigated the adverse immunometabolic effects of the KD. In the HFD-induced obesity cohort, intervention with HCD and KD-F improved immunometabolic and liver function markers. The HCD showed the most pronounced benefits as early as two weeks following the diet switch. Microbiome analysis revealed reduced bacterial richness across all experimental diets (HCD, KD, and KD-F) compared to standard chow. Collectively, the present study highlights that high fat intake, but not high-carbohydrate consumption negatively impacts metabolic and liver health in lean mice. The incorporation of dietary fiber into a KD may enhance its metabolic effects while preserving the therapeutic benefits of ketogenesis.

Keywords:  Grain-based diet; High carbohydrate diet; Ketogenic diet; Prebiotic fiber; Steatohepatitis

DOI:  https://doi.org/10.1016/j.tjnut.2025.101285