bims-imicid 2025-10-12 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–10–12
29 papers selected by
Dylan Ryan, University of Cambridge

Dexamethasone inhibits Mycobacterium tuberculosis-induced glycolysis but preserves antimicrobial function in primary human macrophages.
Deciphering metabolic reprogramming of immune cells within the tumor microenvironment.
Metabolic regulation of immune memory and function of microglia.
TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
Microbial metabolites and their influence on the tumor microenvironment.
Multifaceted mitochondria in innate immunity.
Spermidine enhances macrophages anti-inflammatory and regenerative functions by improving mitochondrial fitness.
Enterobacteriaceae-derived cadaverine manipulates gut macrophage metabolism.
Targeting complex IV to alter the tumor microenvironment and boost macrophage antitumor immunity.
Songorine protects cartilage in osteoarthritis by targeting PFKFB3 to disrupt the glycolysis-inflammation positive feedback loop.
Protocol for measuring cellular energetics through noncanonical amino acid tagging in human peripheral blood and murine tissue immune cells.
Mito-Specific "Trojan Horse" Nanotherapy: Synergistic Antitumor Immunotherapy via Dual Modulation Mitochondrial Metabolism and Glycolysis.
Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.
Purin Metabolism Is Crucial for Regulatory T Cell Stability and Function.
Immunometabolism: crosstalk with tumor metabolism and implications for cancer immunotherapy.
Chlamydia trachomatis disrupts host metabolism in primary cervical epithelial cells.
Dynamic changes in neutrophil activation and metabolic profile during pregnancy are associated with gingival inflammation.
Time-restricted feeding provides limited microglial immunometabolic improvements in diet-induced obese rats.
T cell cholesterol transport links intestinal immune responses to dietary lipid absorption.
Mycobacterium tuberculosis-derived linoleic acid increases regulatory T cell function to promote bacterial survival within macrophages.
Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.
Faithful modeling of terminal CD8+T cell dysfunction and epigenetic stabilization in vitro.
Fatty acid synthase-mediated lipid droplet formation enhances macrophage killing of Staphylococcus aureus.
ABHD6 suppression attenuates pro-inflammatory responses in mice and promotes anti-inflammatory polarization of macrophages during endotoxin stress.
The influence of Pseudomonas aeruginosa infection on the airway metabolome.
Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.
PDK4-driven lactate accumulation facilitates LPCAT2 lactylation to exacerbate sepsis-induced acute lung injury.
Histone lactylation promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies.
Mitochondrial respiratory chain regulates HBV clearance through dual modulation of lysosomal acidification.

Sci Rep. 2025 Oct 09. 15(1): 34310

Dexamethasone inhibits Mycobacterium tuberculosis-induced glycolysis but preserves antimicrobial function in primary human macrophages.

Lorraine Thong, Olivia Sandby Thomas, Oisin Ó Gallchobhair, Emily Duffin, Anjali S Yennemadi, Gina Leisching, Dearbhla M Murphy, Parthiban Nadarajan, Finbarr O'Connell, Mary P O'Sullivan, Sharee A Basdeo, Donal J Cox, Joseph Keane.

  Glucocorticoids (GC) are useful adjunctive host directed therapies (HDT) for sub-types of tuberculosis (TB). Macrophages play a central role in controlling Mycobacterium tuberculosis (Mtb) infection, relying on glycolytic reprogramming to support an effective host defence, yet the influence of GC on these important phagocytes is poorly understood. Here, we examined the impact of dexamethasone on metabolic and functional responses of primary human airway macrophages (AM) from bronchoalveolar lavage fluid and monocyte-derived macrophages (MDM). We found that dexamethasone significantly reduced basal and compensatory glycolysis in both AM and MDM, and decreased expression of the glycolytic enzyme PFKFB3. Oxidative metabolism was lower in dexamethasone AM but not MDM, indicating different specific metabolic sensitivity of macrophages. Dexamethasone also inhibited the glycolytic response to Mtb and reduced secretion of IL-1β, TNF, IL-6, IL-8, and IL-10. Dexamethasone-treated macrophages showed enhanced survival following Mtb infection and these cells had a significant reduction in bacterial burden. This antimicrobial effect was impaired when macrophages were pre-treated with bafilomycin A1, implicating that phagosomal acidification may at least in part mediate dexamethasone-induced bacterial control. Collectively, these findings demonstrate that dexamethasone reprograms human macrophage metabolism toward a less glycolytic state while preserving their ability to limit Mtb growth. These results may provide a basis for the clinical benefit of GC in some TB presentations and support the development of targeting GC therapies to macrophages, thereby mitigating inflammation without compromising host antimicrobial defence.

Keywords:  Glycolysis; Human alveolar macrophage; Immunometabolism; Mycobacterium tuberculosis; Oxidative phosphorylation; Steroid

DOI:  https://doi.org/10.1038/s41598-025-20188-2
J Transl Med. 2025 Oct 06. 23(1): 1055

Deciphering metabolic reprogramming of immune cells within the tumor microenvironment.

Yinping Wang, Weijie Chen, Zida Wang, Siwen Cai, Xinnan Zhao, Jingsi Jin, Ting Gao, Junwen Qu.

   BACKGROUND: Immunometabolic adaptations may induce tumor immune escape and immunotherapeutic resistance, representing crucial mechanisms in cancer progression. Understanding the metabolic rewiring of tumor-infiltrating immune cells as tumors advance could enhance current immune-oncology treatments.
METHODS: In this study, we investigated metabolic heterogeneity in immune cells within both tumor and adjacent normal tissue using single-cell transcriptome profiling of colon cancer. We also utilized the MC38 colorectal cancer model, a commonly employed mouse tumor model, to assess the metabolic atlas of major immune cell populations in tumor and normal tissue.
RESULTS: We examined the immunometabolic features in tumor tissue and adjacent normal tissue using public single-cell transcriptomic datasets of colorectal cancer (CRC) patients, in which myeloid cells showed dominant metabolic activity. Using a mouse tumor model, we demonstrated distinct metabolic reprogramming of major immune cell types in tumor compared to normal tissue. Specifically, we observed increased glucose and lipid uptake, along with abundant lipid accumulation in tumor-infiltrating myeloid cells, particularly macrophages. Additionally, we identified diverse mitochondrial fitness and oxidative stress levels within the tumor immune microenvironment. Macrophages exhibited metabolic fitness, CD8+ T cells displayed mitochondrial depolarization, and neutrophils showed high oxidative stress. Furthermore, we investigated immunometabolic dynamics and observed augmented metabolic activity in immune cells infiltrating progressive and late stages of tumor development. Notably, intratumoral macrophages exhibited metabolic heterogeneity, characterized by robust lipid uptake and synthesis, which correlated with a pro-tumor phenotype and poor clinical outcomes.
CONCLUSION: Overall, our study unveils the heterogeneity and dynamics of metabolic properties in immune cells within the tumor microenvironment. These findings provide insights for developing therapeutic strategies that target metabolism to enhance antitumor immunity.

Keywords:  Colon cancer; Immune metabolism; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1186/s12967-025-07069-y
Elife. 2025 Oct 10. pii: e107552. [Epub ahead of print]14

Metabolic regulation of immune memory and function of microglia.

Nikolaos Nirakis, Sofia Dimothyra, Eleftheria Karadima, Vasileia Ismini Alexaki.

  Innate immune cells possess memory-like properties. Exposure to infections or sterile inflammation can prime them, leading to either exacerbated inflammatory responses, a process called trained immunity, or reduced responsiveness to pro-inflammatory signals, a process termed immune tolerance. Microglia, the resident innate immune cells of the central nervous system, are central players in neurodegenerative diseases. Characterizing trained immunity and tolerance in microglia is necessary for a better understanding of neurodegenerative diseases. Cell metabolic processes orchestrate microglia inflammatory responses and promote epigenetic changes shaping immune memory in microglia. Here, we review current knowledge on the role of cell metabolic pathways in microglia innate immune memory formation, focusing on glucose, glutamine, and lipid metabolism. Moreover, we address the significance of microglial immune memory in disease pathology and discuss the potential of therapeutic targeting of cell metabolic pathways in neurodegenerative disorders.

Keywords:  cell metabolism; immunology; inflammation; microglia; tolerance; training

DOI:  https://doi.org/10.7554/eLife.107552
Sci Adv. 2025 Oct 10. 11(41): eadw4153

TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.

Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Biaoxin Chai, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.

Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.

DOI: https://doi.org/10.1126/sciadv.adw4153
Front Immunol. 2025 ;16 1675677

Microbial metabolites and their influence on the tumor microenvironment.

Huanglin Duan, Baisheng Xu, Peiyue Luo, Tao Chen, Jun Zou.

  While tumor immunotherapy has achieved remarkable progress in many hematological malignancies, its efficacy remains limited by key challenges, including the immunosuppressive microenvironment of solid tumors, metabolic abnormalities, and drug resistance. As a central mechanism underlying impaired immune function, metabolic reprogramming of immune cells has emerged as a pivotal focus for unraveling tumor immune evasion and therapeutic resistance. Advances in metagenomics have highlighted the significance of the human commensal microbiome as a 'second genome.' Microbial metabolites, whether circulating systemically or accumulating locally, serve as key messengers linking the microbiota to tumor immunometabolism. This review comprehensively examines the regulatory roles and metabolic mechanisms through which microbial metabolites-including short-chain fatty acids (SCFAs), bile acids, tryptophan metabolites, and lipopolysaccharides (LPS)-modulate tumor immunity and immunotherapeutic responses via immune cell metabolism. These metabolites shape the tumor immune microenvironment and influence immunotherapeutic efficacy by reprogramming immune cell metabolic and biosynthetic pathways. This review underscores the central regulatory role of microbial metabolites as the 'second genome' in tumor immunometabolism, offering a theoretical foundation and potential targets to elucidate mechanisms of immunotherapeutic resistance and advance microbiota metabolism-based precision interventions.

Keywords:  immunometabolism; immunotherapy; microbial metabolites; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1675677
NPJ Metab Health Dis. 2024 May 27. 2(1): 6

Multifaceted mitochondria in innate immunity.

Eloïse Marques, Robbin Kramer, Dylan G Ryan.

The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

DOI: https://doi.org/10.1038/s44324-024-00008-3
Phytomedicine. 2025 Oct 02. pii: S0944-7113(25)00987-0. [Epub ahead of print]148 157349

Spermidine enhances macrophages anti-inflammatory and regenerative functions by improving mitochondrial fitness.

Rui Liu, Lijuan Cao, Yipeng Zhou, Yanan Li, Tingting Wang, Zhenzhen Meng, Tingting Yang, Chao Feng, Qian Yang, Xiaojie Liu, Yongjing Chen, Massimiliano Agostini, Peishan Li, Gerry Melino, Ying Wang, Changshun Shao, Yufang Shi.

   BACKGROUND: Liver fibrosis is an aberrant wound-healing process in response to chronic hepatic injury. Functional plasticity of macrophages is crucial in this pathological process. How the pro-fibrotic function of macrophages is sustained metabolically and whether it can be targeted for therapy remain to be explored.
PURPOSE: This study investigates the impact of spermidine, a natural polyamine, on macrophage function and its potential in treating hepatic fibrosis.
METHODS: Chronic liver disease datasets and single-cell RNA sequencing (scRNA-seq) data were analyzed for the characteristics of spermidine metabolism in hepatic macrophage function and liver fibrosis. Mice undergoing liver fibrosis caused by carbon tetrachloride (CCl4) were treated with spermidine through daily drinking water. Macrophage-specific PGC1α knockout mice were used to determine the requirement of mitochondrial fitness in the anti-fibrotic function of macrophages. Furthermore, spermidine-treated macrophages were adoptively transferred to mice with liver fibrosis to test their therapeutic potential.
RESULTS: Analysis of chronic liver disease datasets revealed a dysregulated polyamine metabolism in diseased liver tissues, particularly in distinct subsets of macrophages. Spermidine supplementation protected mice from CCl4-induced liver fibrosis through endowing macrophages a persistent anti-inflammatory and pro-resolving function that is characterized by elevated matrix metalloproteinase expression and enhanced mitochondrial function. Spermidine-treated macrophages (SPDMs) exhibited increased mitochondrial mass, augmented oxidative phosphorylation, and altered fatty acid metabolism. The markers characteristic of tolerogenic and liver-regenerative macrophages were upregulated in SPDMs in a manner dependent on peroxisome proliferator-activated receptor-γ coactivator (PGC) -1α, a key regulator of mitochondrial homeostasis. Interestingly, oleate generated by stearoyl-CoA desaturase 1 (SCD1) was essential for SPDMs to acquire the increased mitochondrial fitness. Notably, adoptive transfer of SPDMs to fibrotic mice significantly attenuated disease progression. The anti-fibrotic effect was compromised in mice with myeloid cell-specific deletion of PGC1α, highlighting the importance of mitochondrial biogenesis in mediating macrophage phenotype plasticity.
CONCLUSIONS: Our study implicates dysregulation of spermidine metabolism in hepatic macrophages in the development of chronic liver diseases. We demonstrated an anti-fibrotic function of spermidine that is attributed to its action on macrophages. PGC1α-mediated mitochondrial fitness is required for spermidine to confer macrophages an enhanced anti-inflammatory and anti-fibrotic capacity. Meanwhile, we provide novel insights into the role of fatty acid metabolism in modifying the biological function of macrophages. This study opens new avenues for treating fibrotic diseases by targeting macrophage plasticity through spermidine-mediated metabolic reprogramming and demonstrate the potential of spermidine-trained macrophages as approaches for inflammatory and fibrotic conditions.

Keywords:  Liver fibrosis; Macrophages; Metabolism; Peroxisome proliferator-activated receptor-γ coactivator -1α; Spermidine; Stearoyl-coa desaturase 1

DOI:  https://doi.org/10.1016/j.phymed.2025.157349
Nat Rev Immunol. 2025 Oct 07.

Enterobacteriaceae-derived cadaverine manipulates gut macrophage metabolism.

Alexandra Flemming.

DOI: https://doi.org/10.1038/s41577-025-01234-6
Life Metab. 2025 Dec;4(6): loaf032

Targeting complex IV to alter the tumor microenvironment and boost macrophage antitumor immunity.

Thomas Pfefer, Luke A J O'Neill.

Clark et al. showcase that interferons (IFNs) trigger a functional reprogramming of tumor-associated macrophages (TAMs) by downregulating NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4), a key subunit of mitochondrial complex Ⅳ. This drives a transition from protumor TAMs to antitumor IFN-associated TAMs (IFN-TAMs) through activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This mechanism can be leveraged to boost antitumor immunity and improve responses to immune checkpoint blockade.

DOI: https://doi.org/10.1093/lifemeta/loaf032
Phytomedicine. 2025 Sep 19. pii: S0944-7113(25)00925-0. [Epub ahead of print]148 157286

Songorine protects cartilage in osteoarthritis by targeting PFKFB3 to disrupt the glycolysis-inflammation positive feedback loop.

Xixi He, Qiongqian Xu, Kai Qiu, Zhao Tian, Dong Sun, Jichang Han, Chuncan Ma, Xue Ren, Dongming Wang, Jian Wang, Aiwu Li.

   BACKGROUND: Metabolic reprogramming has recently been recognized as a critical driver in the development and progression of osteoarthritis (OA). While Songorine has been shown to modulate macrophage metabolism, its direct effects on chondrocyte metabolism and inflammation remain poorly understood.
PURPOSE: This study set out to explore how Songorine regulates glycolysis-driven inflammation in OA chondrocytes and to elucidate a novel mechanism linking metabolic reprogramming, histone lactylation, and inflammatory signaling.
STUDY DESIGN: We utilized both in vivo OA rat models and in vitro IL-1β-induced chondrocyte inflammation models to assess Songorine's metabolic and anti-inflammatory effects.
METHODS: Histological and biochemical analyses were performed on OA rat joints to evaluate cartilage degeneration, metabolic alterations, and inflammatory markers. RNA sequencing, ¹³C-glucose metabolic flux assays, and Seahorse extracellular flux analysis were used to characterize glycolytic activity. Histone lactylation levels were assessed by immunoblotting and CUT&Tag. The binding between Songorine and PFKFB3 was evaluated by molecular docking and surface plasmon resonance (SPR).
RESULTS: OA cartilage exhibited elevated glycolysis and inflammation, while Songorine treatment significantly restored metabolic homeostasis and alleviated inflammation. In IL-1β-stimulated chondrocytes, Songorine suppressed glycolytic flux, reduced lactate production and histone H4K12 lactylation. Lactate-induced H4K12 lactylation promoted the transcription of pro-inflammatory genes and reinforced a PFKFB3-mediated positive feedback loop that sustained glycolysis and inflammation. SPR confirmed that Songorine directly binds to and inhibits PFKFB3, thereby disrupting this loop.
CONCLUSION: Songorine protects cartilage by directly targeting PFKFB3, thereby limiting glycolytic-driven lactate production, histone lactylation, and downstream inflammatory signaling. These findings uncover a novel glycolysis-lactylation-inflammation axis in OA and support Songorine as a promising metabolic modulator for OA therapy.

Keywords:  Glycolysis; Lactylation; Metabolic inflammation; Osteoarthritis; PFKFB3; Songorine

DOI:  https://doi.org/10.1016/j.phymed.2025.157286
STAR Protoc. 2025 Oct 08. pii: S2666-1667(25)00540-4. [Epub ahead of print]6(4): 104134

Protocol for measuring cellular energetics through noncanonical amino acid tagging in human peripheral blood and murine tissue immune cells.

Frank Vrieling, Hendrik J P van der Zande, Manon Dumont, Rinke Stienstra.

  Cellular metabolism dictates immune cell function, yet we lack tools to functionally profile immunometabolism in low-yield, complex samples. We present a flow cytometry-based protocol for measuring cellular energetics through noncanonical amino acid tagging (CENCAT) in human peripheral blood and murine tissue immune cells. We describe steps for sample preparation, metabolic inhibition, protein synthesis analysis using click chemistry, immunophenotyping, and calculation of metabolic dependencies. For complete details on the use and execution of this protocol, please refer to Vrieling et al.1.

Keywords:  Cell Biology; Cell culture; Cell isolation; Flow Cytometry; Immunology; Metabolism; Molecular Biology; Molecular/Chemical Probes

DOI:  https://doi.org/10.1016/j.xpro.2025.104134
ACS Nano. 2025 Oct 07.

Mito-Specific "Trojan Horse" Nanotherapy: Synergistic Antitumor Immunotherapy via Dual Modulation Mitochondrial Metabolism and Glycolysis.

Jingjing Yang, Mingyang Li, Zhao Wei, Jin Qian, Maoquan Chu, Zhe Qiang, Jie Ren.

  Metabolic reprogramming enables tumor cells to survive and proliferate in a nutrient-deficient environment. However, the immunosuppressive tumor microenvironment caused by metabolic reprogramming is often overlooked in current metabolism interventions. Herein, we developed a mito-specific "Trojan Horse" nanoplatform (2-pN@LNPs) coloaded with Niclosamide (Nic) and 2-deoxy-d-glucose (2-DG) to attack key metabolism pathways and synergistically ignite pyroptosis for restoring antitumor immunity. 2-pN@LNPs promoted proton influx across the inner mitochondrial membrane and caused oxidative phosphorylation (OXPHOS) into a futile cycle. Furthermore, 2-pN@LNPs exploited the increased glucose demand to deliver the glycolysis inhibitor 2-DG, causing metabolic network collapse. Both cell and three-dimensional multicellular tumor spheroid results demonstrated superior synergistic metabolic intervention efficacy. The multipath metabolism deprivation leads to irreversible mitochondrial dysfunction, followed by excessive reactive oxygen species accumulation, severe adenosine triphosphate loss, and ultimately exerted a pyroptosis-like micromorphology. Moreover, the synergistic treatment regimen can promote cytotoxic and helper T cells (CD8+/CD4+ T cells) recruitment and M1-type macrophage polarization, facilitating the establishment of a boost in immunological memory to prevent recurrence and metastasis. Overall, this work provides a robust strategy targeting metabolism through mitochondrial uncoupling and glycolysis inhibition, which can effectively improve the antitumor effect, inhibit lung metastasis, and help modulate antitumor immunity.

Keywords:  antitumor immunity; glycolysis inhibition; metabolic reprogramming; mitochondrial uncoupling; mitochondrial-targeted therapy

DOI:  https://doi.org/10.1021/acsnano.5c08486
Cell Host Microbe. 2025 Oct 08. pii: S1931-3128(25)00363-4. [Epub ahead of print]33(10): 1645-1647

Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.

Evie R Hodgson, Diana Stojanovski.

In a recent Science paper, Medeiros et al. describe how infected cells use mitochondria as metabolic guardians, outcompeting Toxoplasma parasites for folate, an essential vitamin for DNA synthesis. This metabolic immunity strategy transforms the cell's powerhouse to an active defender, sequestering nutrients away from invaders in a metabolic tug-of-war.

DOI: https://doi.org/10.1016/j.chom.2025.09.002
Eur J Immunol. 2025 Oct;55(10): e70070

Purin Metabolism Is Crucial for Regulatory T Cell Stability and Function.

Young S Lee, Marina W Shirkey, Vikas Saxena, Dejun Kong, Bing Ma, Reza Abdi, Jonathan S Bromberg.

  Cellular metabolism intricately directs the differentiation, stability, and function of regulatory T cells (Tregs), which are pivotal in immune regulation. Metabolic reprogramming enables Tregs to adapt to diverse tissue environments; however, it can also disturb immune equilibrium, driving their conversion into unfavorable states like exTregs that hinder regulation in autoimmunity and transplantation. Purine metabolism has emerged as a critical but underexplored regulator of Treg biology. Beyond their traditional roles in nucleotide synthesis and energy balance, purine metabolites also serve as potent second messengers shaping Treg phenotype, suppressive capacity, and adaptability in inflammatory, autoimmune, and transplant environments. Extracellular ATP promotes inflammation, while adenosine supports Treg-mediated immunosuppression, highlighting a dual and context-dependent nature of purinergic signaling. This review outlines current findings on intracellular and extracellular purine metabolism in Tregs, emphasizing key enzymes and purinergic receptors that sustain Treg phenotype and resilience. It discusses disruptions in purine signaling compromising Treg functions, identifies knowledge gaps, and proposes future research directions for potential therapeutic strategies in immune-related ailments.

Keywords:  Treg stability; exTregs; purine metabolism; purinergic receptors; regulatory T cells (Tregs)

DOI:  https://doi.org/10.1002/eji.70070
Mol Cancer. 2025 Oct 08. 24(1): 249

Immunometabolism: crosstalk with tumor metabolism and implications for cancer immunotherapy.

Huiru Zhang, Jialiang Fan, Deyang Kong, Yu Sun, Qi Zhang, Renshen Xiang, Shuaibing Lu, Wenjing Yang, Lin Feng, Haizeng Zhang.

  Immunometabolism has established a groundbreaking paradigm for cancer immunotherapy by decoding the intricate interaction networks between metabolic pathways and immune responses. This review comprehensively explores the metabolic reprogramming of immune cells in the tumor microenvironment, analyzes the roles of key metabolic pathways, enzymes, and metabolites in immune regulation, and unveils the intricate metabolic interactions between tumor and immune cells. Furthermore, we discuss how metabolic interventions can enhance antitumor immune responses and highlight the potential of immunometabolic checkpoints as therapeutic targets. Future research in immunometabolism will focus on the application of advanced technologies, the discovery of novel metabolic biomarkers, and metabolomics-driven personalized medicine to advance cancer diagnosis, treatment, and precision oncology.

Keywords:  Cancer therapy; Immunometabolic checkpoints; Immunometabolism; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02460-1
World J Microbiol Biotechnol. 2025 Oct 09. 41(10): 366

Chlamydia trachomatis disrupts host metabolism in primary cervical epithelial cells.

Heng Choon Cheong, Muhammad Ihsan Rommel, Yi Ying Cheok, Yee Teng Chan, Ting Fang Tang, Sofiah Sulaiman, Chung Yeng Looi, Bernard Arulanandam, Li-Yen Chang, Won Fen Wong.

  Chlamydia trachomatis is a major cause of bacterial sexually transmitted infections and reproductive complications. Despite progress in understanding C. trachomatis pathogenesis, studies using primary cells remain limited. Here, we investigated C. trachomatis infection of cervical epithelial cells and its impact on host cellular processes. Transcriptomic profiling show that C. trachomatis infection in cervical epithelial cells leads to significant changes in host cellular processes, including modulation of immune signaling, attenuation of DNA repair and proliferation-linked signaling pathways, as well as disruption of mitochondrial function. Mitochondrial substrate utilization assays revealed selective TCA cycle impairments. Our findings show that C. trachomatis infection is associated with marked changes of host cell metabolism and mitochondrial function. These findings suggest that metabolic rewiring in cervical epithelial cells may reflect a host defense strategy to restrict pathogen. Our results provide novel insights into the metabolic interplay between host and C. trachomatis and open avenues for future investigations into the consequences of metabolic remodeling during chlamydial infection.

Keywords:   Chlamydia trachomatis ; Mitochondria metabolism; Oxidative phosphorylation (OXPHOS); Primary cervical epithelial cells; Tricarboxylic Acid (TCA) cycle

DOI:  https://doi.org/10.1007/s11274-025-04584-4
Sci Rep. 2025 Oct 10. 15(1): 35510

Dynamic changes in neutrophil activation and metabolic profile during pregnancy are associated with gingival inflammation.

Guillermina Calo, Fátima Merech, Florencia Sabbione, Luciana D Eramo, Luciana Doga, Brenda Lara, Vanesa Hauk, Laura Gliosca, Sofía Novoa, Ariana Santillán, Pablo Fabiano, Rosanna Ramhorst, Aldo Squassi, Daiana Vota, Claudia Pérez Leirós.

  Neutrophils are key players in both periodontal and placental immunity, undergoing profound immunometabolic and functional changes during pregnancy. Their excessive activation has been linked to gestational complications. Gingivitis, and even more so periodontitis, the advanced stage of this condition, are chronic inflammatory diseases that frequently worsen during pregnancy and have been associated with adverse outcomes such as fetal growth restriction and placental dysfunction. Although bacterial dissemination and inflammation are thought to mediate this link, the underlying mechanisms remain poorly understood. How neutrophil activation and metabolism evolve throughout pregnancy-and how this relates to the exacerbation of periodontal inflammation-remains largely unexplored. We analyzed the immunometabolic and activation profiles of circulating neutrophils from pregnant women at 16-20 weeks and term, alongside their gingival inflammatory status. Our findings show that pregnancy reprograms neutrophil metabolism, promoting a progressive shift towards enhanced glucose utilization and increased lipid droplet accumulation at term. Basal reactive oxygen species production increased throughout pregnancy and correlated with gingival inflammation. Basal and PMA-induced neutrophil extracellular trap release also increased with gestation. Gingival crevicular fluid samples further stimulated neutrophil activation, particularly those enriched in P. gingivalis. These results reveal a dynamic immunometabolic rewiring in maternal circulating neutrophils throughout pregnancy, suggesting its modulatory role in the interplay between systemic immunity and oral inflammation.

Keywords:  Human neutrophils; Immunometabolism; Periodontal disease; Pregnancy

DOI:  https://doi.org/10.1038/s41598-025-19672-6
Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01151-9. [Epub ahead of print]44(10): 116380

Time-restricted feeding provides limited microglial immunometabolic improvements in diet-induced obese rats.

Han Jiao, Jarne Jermei, Xian Liang, Hendrik J P van der Zande, Frank Vrieling, Valentina Sophia Rumanova, Milan Dorscheidt, Anhui Wang, Ewout Foppen, Bob Ignacio, Dirk Jan Stenvers, Tiemin Liu, Kimberly Bonger, Rinke Stienstra, Zhi Zhang, Andries Kalsbeek, Chun-Xia Yi.

  Time-restricted eating has shown great promise for improving metabolic health in humans with obesity, but its mechanism is still not completely resolved. In this study, we investigated how time-restricted feeding (TRF) affects microglial immunometabolism using Wistar rats. High-fat diet (HFD)-fed animals became obese, but restricting food intake to the active phase reduced fat mass, reinforced the rhythmicity of the microglial transcriptome, and prevented an increase in hypothalamic microglial cell numbers. However, TRF failed to reverse HFD-induced microglial immune dysfunction and metabolic disturbances, including suppressed electron transport chain activity, increased lipid metabolism gene expression, and impaired metabolic flexibility. These findings suggest that obesity-driven microglial immunometabolic reprogramming persists despite TRF-induced weight loss and may contribute to obesogenic memory and weight regain after weight loss induced by dietary interventions.

Keywords:  CP: Immunology; CP: Metabolism; circadian rhythm; immunometabolism; microglia; obesity; time-restricted feeding

DOI:  https://doi.org/10.1016/j.celrep.2025.116380
Science. 2025 Oct 09. 390(6769): eadt4169

T cell cholesterol transport links intestinal immune responses to dietary lipid absorption.

Yajing Gao, John P Kennelly, Xu Xiao, Emily Whang, Alessandra Ferrari, Alexander H Bedard, Julia J Mack, Alexander Nguyen, Sonal Srikanth, Thomas Weston, Lauren F Uchiyama, Whitaker Cohn, Danielle H Cho, Min Sub Lee, Julian Whitelegge, Yousang Gwack, Stephen G Young, Steven J Bensinger, Peter Tontonoz.

The intrinsic pathways that control membrane organization in immune cells and their impact on cellular functions are poorly defined. We found that the nonvesicular cholesterol transporter Aster-A linked plasma membrane (PM) cholesterol availability in CD4 T cells to systemic metabolism. Aster-A was recruited to the PM during T cell receptor (TCR) activation, where it facilitated the removal of accessible cholesterol. Loss of Aster-A increased cholesterol accumulation in the PM, which enhanced TCR nanoclustering and signaling. Aster-A associated with stromal interaction molecule 1 (STIM1) and negatively regulated calcium (Ca2+) flux. Aster-A deficiency promoted CD4 T cells to acquire a T helper 17 (TH17) phenotype and stimulated interleukin-22 production, which reduced intestinal fat absorption and conferred resistance to diet-induced obesity. These findings delineate how immune cell membrane homeostasis links to systemic physiology.

DOI: https://doi.org/10.1126/science.adt4169
Nat Microbiol. 2025 Oct 10.

Mycobacterium tuberculosis-derived linoleic acid increases regulatory T cell function to promote bacterial survival within macrophages.

Hongyu Cheng, Shenzhi Li, Hongjie Liu, Meiyi Yan, Jingxiang Wang, Jingping Huang, Shanshan Liu, Yifan Yang, Xinyu Cao, Pengfei Cui, Yuanna Cheng, Zhonghua Liu, Jie Wang, Xiaochen Huang, Lin Wang, Lianhua Qin, Ruijuan Zheng, Carl G Feng, Qiang Zou, Yicheng Sun, Zhe Ji, Hua Yang, Baoxue Ge.

Regulatory T (Treg) cells expand during Mycobacterium tuberculosis (Mtb) infection and suppress T cell-mediated control. Whether Mtb actively contributes to this process is unclear. Here, using a genome-wide mutant library, we show that the expression of Mtb Rv1272c, an ATP-binding cassette transporter, increased under hypoxic conditions and promotes Mtb survival in vivo by increasing lecithin import, followed by the production and release of linoleic acid. Linoleic acid released by infected macrophages promoted surface trafficking of the immune checkpoint molecule cytotoxic T lymphocyte antigen 4 (CTLA-4) in Treg cells via the Ca²⁺ transporter ATP2a3. This in turn inhibited macrophage reactive oxygen species production and promoted Mtb survival inside macrophages. Rv1272c-induced linoleic acid further promoted Mtb immune evasion by increasing CTLA-4 surface trafficking on Treg cells in vivo. Mechanistically, linoleic acid interacts with ATP2a3 in Treg cells and promotes mitochondria-associated endoplasmic reticulum (ER) membrane formation. This facilitates ER-to-mitochondria Ca2+ transfer and depletion of Ca2+ in the ER, and triggers store-operated calcium entry, thus elevating cytosolic Ca2+ levels to increase Ca2+-dependent CTLA-4 surface trafficking in Treg cells. These findings reveal that Mtb can use a metabolite to manipulate host responses and promote its intracellular survival.

DOI: https://doi.org/10.1038/s41564-025-02140-2
Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01192-1. [Epub ahead of print]44(10): 116421

Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.

Lin Li, Yulan Chen, Yuanzhi Wang, Yuhui Dong, Haoran Wang, Ziyi Liu, Xin Ge, Puxiu Shen, Yue Li, Dingpu Liu, Xiangmei Zhou.

  Hexokinases (HKs) are essential enzymes in sugar metabolism, but their mitochondrial release also reflects cellular status in disease. Mycobacterium bovis (M. bovis), the causative agent of bovine and human tuberculosis, infects macrophages and induces mitophagy, yet the role of HKs in this process remains unclear. We find that M. bovis infection induces the release of HK2 from mitochondria, where it dissociates from voltage-dependent anion channel (VDAC). This dissociation promotes VDAC oligomerization, pore formation in the outer mitochondrial membrane, and mitochondrial damage. Damaged mitochondria subsequently undergo mitophagy, which enhances the intracellular survival of M. bovis. Consistent with this mechanism, we show that ESAT6-mediated phagosome membrane rupture is critical for HK2 release and subsequent mitochondrial events. Our study identifies a pathway by which M. bovis manipulates host cell processes to promote survival, providing insights into the host-pathogen interaction and potential avenues for tuberculosis prevention and therapy.

Keywords:  CP: Microbiology; Mycobacterium bovis; VDAC; autophagy; hexokinase; macrophage; mitochondria; mitophagy; tuberculosis

DOI:  https://doi.org/10.1016/j.celrep.2025.116421
JCI Insight. 2025 Oct 08. pii: e191220. [Epub ahead of print]10(19):

Faithful modeling of terminal CD8+T cell dysfunction and epigenetic stabilization in vitro.

Amir Yousif, Abbey A Saadey, Ava Lowin, Asmaa M Yousif, Ankita Saini, Madeline R Allison, Kelley Ptak, Eugene M Oltz, Hazem E Ghoneim.

  Epigenetic scarring of terminally dysfunctional (TDysf) CD8+ T cells hinders long-term protection and response to immune checkpoint blockade during chronic infections and cancer. We developed a faithful in vitro model for CD8+ T cell terminal dysfunction as a platform to advance T cell immunotherapy. Using TCR-transgenic CD8+ T cells, we found that 1-week peptide stimulation, mimicking conditions in previous models, failed to induce a stable exhaustion program. In contrast, prolonged stimulation for 2-3 weeks induced T cell dysfunction but triggered activation-induced cell death, precluding long-term investigation of exhaustion programs. To better mimic in vivo exhaustion, we provided post-effector, chronic TGF-β1 signals, enabling survival of chronically stimulated CD8+ T cells for over 3 weeks. These conditions induced a state of terminal dysfunction, marked by a stable loss of effector, cytotoxicity, and memory programs, along with mitochondrial stress and impaired protein translation. Importantly, transcriptomic and epigenetic analyses verified the development of terminal exhaustion-specific signatures in TDysf cells. Adoptive transfer of TDysf cells revealed their inability to recall effector functions or proliferate after acute lymphocytic choriomeningitis virus rechallenge. This tractable model system enables investigation of molecular pathways driving T cell terminal dysfunction and discovery of therapeutic targets for cancer or chronic infections.

Keywords:  Adaptive immunity; Cancer immunotherapy; Epigenetics; Immunology; Oncology

DOI:  https://doi.org/10.1172/jci.insight.191220
Cell Death Dis. 2025 Oct 07. 16(1): 715

Fatty acid synthase-mediated lipid droplet formation enhances macrophage killing of Staphylococcus aureus.

Yanping Wu, Jiaxin Shen, Shenwei Gao, Miao Li, Qingyu Weng, Kua Zheng, Chen Zhu, Zhongnan Qin, Jieyu Li, Jiafei Lou, Songmin Ying, Yinfang Wu, Zhihua Chen, Wen Li.

Macrophages play a critical role in defending against Staphylococcus aureus (S. aureus), a major human pathogen. Recently, there has been growing interest in the metabolic regulation of macrophage function; however, the specific role of lipid synthesis in macrophage activation remains poorly understood. This study demonstrates that fatty acid synthase (FASN), an enzyme integral to de novo lipogenesis, is significantly upregulated in macrophages during S. aureus infection. Notably, S. aureus engages in a functional interaction with proteasomes, inhibiting their activity through the PI3K/AKT/mTOR signaling pathway. This interaction results in reduced degradation of FASN, leading to elevated levels of this crucial enzyme. The increased expression of FASN is vital for macrophage-mediated pathogen clearance, as it facilitates the formation of lipid droplets (LDs), which in turn enhance the antimicrobial response against S. aureus, partly through the accumulation of the antimicrobial peptide CAMP. In a murine pneumonia model, deficiency of FASN correlates with increased bacterial burden, exacerbated lung inflammation, and a significant reduction in survival rates. Collectively, these findings underscore the essential role of FASN-mediated LD formation in macrophage activation and highlight potential therapeutic targets within the FASN and lipid metabolism pathways for the treatment of S. aureus pneumonia.

DOI: https://doi.org/10.1038/s41419-025-08044-7
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Oct 06. pii: S1388-1981(25)00102-7. [Epub ahead of print]1871(1): 159694

ABHD6 suppression attenuates pro-inflammatory responses in mice and promotes anti-inflammatory polarization of macrophages during endotoxin stress.

P Poursharifi, C Schmitt, I Chenier, Y H Leung, A K Oppong, Y Bai, L-L Klein, L Vilanou, A Al-Mass, R Lussier, M Abu-Farha, J Abubaker, F Al-Mulla, É Dumais, N Flamand, N Provost, C Bernard, P Delerive, M-L Peyot, S R M Madiraju, M Prentki.

  α/β-hydrolase domain-containing-6 (ABHD6) hydrolyzes various lipids, including monoacylglycerols (MAGs). Pharmacological inhibition of ABHD6 with WWL70 is anti-inflammatory in animal models. However, because of the multiple substrates of ABHD6 and the off-target effects of WWL70, the precise role of ABHD6 in inflammation remains to be clarified. Here, we investigated the role of ABHD6 in lipopolysaccharide (LPS)-mediated inflammatory response, employing a more specific ABHD6 inhibitor, KT203, and ABHD6-KO mice. ABHD6-KO mice showed lower susceptibility to LPS-mediated systemic endotoxemia. Inhibition by KT203 or deletion of ABHD6 in LPS-stressed macrophages reduced the pro-inflammatory and elevated the anti-inflammatory markers. In RAW 264.7 macrophages, KT203 reduced LPS-induced morphological changes, migration and cytokine release. In vivo, KT203 treatment of LPS-exposed wild-type mice markedly curtailed circulating TNF-α levels. Analysis of cellular and secreted bioactive lipids in the LPS-treated RAW 264.7 macrophages revealed that KT203 markedly elevated the levels of various lipid species, in particular secreted docosahexaenoic acid (DHA)-derived MAG (1/2-docosahexaenoylglycerol (DHG)) and DHA-containing N-acylethanolamines and oxylipins. We further observed that 1-DHG, 2-arachidonoylglycerol, docosahexaenoylethanolamide and 17-hydroxydocosahexaenoic acid showed anti-inflammatory effects and PPARα agonism in LPS-treated RAW 264.7 macrophages. The data suggest that ABHD6 suppression results in the accumulation of various bioactive lipids, in particular DHA-containing MAG, N-acylethanolamines and oxylipins, which activate PPARα signaling pathway to curtail the inflammatory response of macrophages to LPS. Overall, the findings provide evidence for a mechanism involving MAG and possibly other lipid species/PPARα signaling, for the anti-inflammatory effects of ABHD6 suppression during endotoxemia. Thus, the inhibition of ABHD6 is a promising approach to mitigate inflammation.

Keywords:  Inflammation; Lipidomics; PPARs; lipopolysaccharides; macrophages; α/β-hydrolase domain-containing-6

DOI:  https://doi.org/10.1016/j.bbalip.2025.159694
Microbiology (Reading). 2025 Oct;171(10):

The influence of Pseudomonas aeruginosa infection on the airway metabolome.

Angharad E Green, Dilem Ruhluel, Marie Phelan, Joanne L Fothergill, Daniel R Neill.

  Pseudomonas aeruginosa is an environmentally resilient bacterium and an important cause of both acute and chronic infections in people with impaired natural barriers or immunological defences. Chronic respiratory infection with P. aeruginosa is a major cause of morbidity and mortality in people with airway diseases, including cystic fibrosis (CF) and non-CF bronchiectasis. Chronic airway infection is characterized by periods of relative stability punctuated by pulmonary exacerbations, during which times rapid bacterial outgrowth necessitates intense antimicrobial chemotherapy. The periods of stable infection can be modelled in mice by nasal instillation of airway-adapted P. aeruginosa in saline, leading to prolonged colonization of both upper airway (sinus) and lower airway (lung) environments that is not associated with symptomatic disease. Here, we use NMR metabolomics to investigate the impact of P. aeruginosa colonization on the metabolic landscape of sinuses and lungs. Lung infection led to pronounced changes in the airway metabolome, with significant depletion of glucose and myo-inositol but enrichment of glutathione (GSH), relative to uninfected lungs. Changes in the sinuses were more subtle but could be identified through dimensionality reduction approaches. The NMR spectral peaks that discriminated between infected and uninfected sinuses in partial least squares discriminant analysis included those for lactate and choline but were mostly representative of yet unidentified metabolites. These data highlight the differential impact of infection on separate airway compartments and identify undefined metabolites undergoing pronounced abundance changes during infection.

Keywords:  NMR; Pseudomonas aeruginosa; metabolomics; respiratory infection

DOI:  https://doi.org/10.1099/mic.0.001617
Adv Sci (Weinh). 2025 Oct 06. e10270

Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.

De Xie, Qiuyang Zheng, Jiaming Lv, Qian Zhang, Zhiwei Cui, Shuai Huang, Wei Yu, Binyang Chen, Wanling Que, Shanpan Fu, Yuemei Xi, Jiayu Chen, Xueling Ye, Shuyi Chen, Hairong Zhao, Tetsuya Yamamoto, Hidenori Koyama, Xin Wang, Jidong Cheng.

  Epidemiological studies have linked uric acid (UA), the end product of purine metabolism in humans, with reduced Alzheimer's disease (AD) risk. Decreased serum UA levels are observed in AD patients versus age-matched controls, while upstream purine metabolites remained unchanged. In 5×FAD mice, two months of UA supplementation improved cognitive function and reduced amyloid plaque burden. Mechanistically, UA enhances microglial amyloid-β (Aβ) phagocytosis and induces transcriptional reprogramming in AD mouse microglia, characterized by upregulated phagocytic pathways and attenuated inflammatory responses. UA treatment restored the recycling of Aβ receptors CD36 and TREM2 in microglia, enhanced lysosomal biogenesis, and facilitated Aβ degradation. These findings identify UA as a critical endogenous modulator of microglial Aβ processing and suggest exploring UA supplementation as a therapeutic strategy for AD.

Keywords:  Alzheimer's disease; amyloid‐β; microglia; uric acid

DOI:  https://doi.org/10.1002/advs.202510270
Cell Death Differ. 2025 Oct 07.

PDK4-driven lactate accumulation facilitates LPCAT2 lactylation to exacerbate sepsis-induced acute lung injury.

Yifan Deng, Yuetan Qiu, Xiang Li, Ting Gong, Jinyan Guo, Haoxuan Liang, Ziyi Yuan, Ziqing Hei, Xuedi Zhang, Youtan Liu.

Elevated glycolysis in lung tissue is a hallmark of sepsis-induced acute lung injury (SI-ALI), yet the role of glycolytic reprogramming and lactate-derived protein modifications in damaging epithelial cells remains poorly understood. In this study, we reveal that PDK4-driven glycolytic reprogramming promotes excessive lactate production in lung tissue during SI-ALI. Mechanistically, AARS1 in epithelial cells selectively enhances lactylation modification at the K375 site of LPCAT2, which suppresses STAT1 acetylation and facilitates STAT1 phosphorylation, nuclear translocation, and transcriptional repression of SLC7A11. This cascade ultimately triggers epithelial cells ferroptosis. Pharmacological inhibition of PDK4 attenuates lactate accumulation and LPCAT2 lactylation, thereby restoring STAT1 acetylation and SLC7A11 expression. Furthermore, AARS1 knockdown or mutation of the LPCAT2-K375 lactylation site rescues STAT1-mediated SLC7A11 suppression and mitigates ferroptosis in vitro and septic mice. Our findings revealed that elevated expression of PDK4 is a critical factor contributing to the increased lactate production in lung tissue during sepsis, and established a novel LPCAT2-K375/STAT1/SLC7A11 axis driving epithelial cells ferroptosis in SI-ALI, highlighting the crosstalk between metabolic reprogramming, post-translational modifications (PTM), and ferroptosis. Targeting the PDK4 or LPCAT2 lactylation may offer therapeutic potential for SI-ALI. In sepsis-induced acute lung injury (SI-ALI), PDK4 hyperactivation drives excessive lactate production in epithelial cells, triggering AARS1/HDAC9-mediated LPCAT2 lactylation. This modification suppresses STAT1 acetylation while enhancing phosphorylation, driving its nuclear translocation and subsequent SLC7A11 transcriptional downregulation. The resultant glutathione synthesis deficiency promotes ferroptosis, exacerbating SI-ALI progression.

DOI: https://doi.org/10.1038/s41418-025-01585-6
Nat Commun. 2025 Oct 10. 16(1): 9034

Histone lactylation promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies.

Gan Wu, Chenglin Yang, Yuan Huang, Bin Liu, Haige Zhai, Zelin Cao, Siyue Lu, Jijian Ji, Xinyue Yin, Xianming Xin, Shengwei Jin, Youzhi Cai, Jianguang Wang.

Elevated lactate in the joint microenvironment of rheumatoid arthritis patients is crucial for disease progression, though the mechanism remains unclear. This study shows significantly increased global lactylation levels within fibroblast-like synoviocytes from RA patients compared to healthy controls, with lactylated proteins being enriched in histones. Furthermore, we find anti-lactylated histone autoantibodies present in RA patients that positively correlate with Disease Activity Score 28. Using CUT&Tag and RNA-seq, we identify NFATc2 as a key target gene regulated by histone H3 lysine 9 lactylation. Functional studies reveal that NFATc2 promotes migration of RA-FLSs. Additionally, using collagen antibody-induced arthritis and collagen-induced arthritis mouse models, we demonstrate that NFATc2 exacerbates RA disease progression through enhancing the cartilage invasive function of FLS. Here, we show that upregulated target gene NFATc2 by lactate-dependent histone lactylation, can be used as a potential therapeutic target for intervention, anti-lactylated histone autoantibodies is promising as a diagnostic marker for RA.

DOI: https://doi.org/10.1038/s41467-025-64096-5
Emerg Microbes Infect. 2025 Dec;14(1): 2563079

Mitochondrial respiratory chain regulates HBV clearance through dual modulation of lysosomal acidification.

Zhiqiang Wei, Yanying Yan, Lingzhu Zhao, Chen Li, Jinjin Qi, Dandan Chen, Xiuzhen Huang, Minwei Li, Zhengyun Xiao, Guohua Lou, Zhenggang Yang, Mengji Lu, Xueyu Wang, Min Zheng.

  Mitochondria are vital for maintaining cellular homeostasis. However, mitochondrial damage is evident in patients with chronic hepatitis B (CHB). The role of mitochondrial dysfunction in the persistence of viral replication remains unclear. Therefore, this study aims to investigate the impact of mitochondrial dysfunction on HBV replication and elucidate the underlying mechanisms. Both mitochondria and lysosomes were dysfunctional in HBV-replicating cells. Moreover, HBV replication inhibited mitochondrial respiratory chain both in vitro and in vivo. Moderate inhibition of mitochondrial respiratory complex I activity using rotenone (Rot) increased HBV replication and decreased autophagic degradation capacity in vitro and in vivo. Mechanistically, elevated mitochondrial reactive oxygen species (mtROS) levels by Rot treatment or SOD2 knockdown led to deteriorated lysosomal membrane permeabilization, which elevated lysosomal pH and promoted HBV replication. Conversely, scavenging mtROS with mitoquinone (mitoQ) and mitoTEMPO (mitoT) had the opposite effect. Additionally, mitochondrial dysfunction reduced mitochondrial ATP production and diminished mitochondria-lysosome contacts. Obstructing mitochondrial ATP synthesis with Oligomycin A treatment or disruption of mitochondria-lysosome contacts with vacuolar protein sorting 13 A (VPS13A) knockdown resulted in lysosomal alkalinization and increased HBV replication by inhibiting vacuolar (H+)-adenosine triphosphatase (v-ATPase) assembly in an mtROS-independent manner. Ultimately, inhibition of mitochondrial complex I facilitated HBV secretion by promoting endosomal trafficking of HBV components. In conclusion, mitochondrial function plays a crucial role in HBV autophagic degradation. HBV impairs mitochondrial function, leading to a reduction in the lysosomal degradation capacity, which may hinder effective clearance of the virus.

Keywords:  Lysosomal degradation; V-ATPase assembly; hepatitis B virus; lysosomal membrane permeabilization; mitochondira-lysosomal contacts; mitochondrial ATP synthesis; mtROS

DOI:  https://doi.org/10.1080/22221751.2025.2563079