bims-imicid 2025-08-17 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–08–17
33 papers selected by
Dylan Ryan, University of Cambridge

Species-specific serine metabolism differentially controls natural killer cell functions.
The diverse interaction of metabolism, immune response, and viral pathogens.
Mitochondrial Metabolism in T-Cell Exhaustion.
Recent advances in exercise immunometabolism: Immune cell bioenergetics, muscle-immune cell interactions, and potential dietary adjuvants.
Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
Altered glucose metabolism in B cells: Implications for the pathogenesis and treatment of autoimmune diseases.
Metabolic immune regulation of macrophages by melanized fungus Fonsecaea monophora.
Metabolic Adaptation via Glycolysis and Iron Acquisition Drives Klebsiella pneumoniae-Induced Intraocular Inflammation and Visual Impairment.
Pumilio2 deficiency promotes iron-dependent macrophage inflammation via TfR1 upregulation in lupus.
Metabolic Imprint of Poliovirus on Glioblastoma Cells and Its Role in Virus Replication and Cytopathic Activity.
Brucella abortus induces dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in infected macrophages via stress sensor IRE1α altering metabolic function.
Intronic miR-342 is a key regulator of cellular glycolysis in Foxp3+ regulatory CD4 T cells.
Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation.
Peroxisome proliferator-activated receptors in inflammatory bowel disease: linking immunometabolism, lipid signaling, and therapeutic potential.
CD31 regulates metabolic switch in Treg migration attenuates rheumatoid arthritis.
Gut microbial metabolites butyrate and acetate limit Zika virus replication and associated ocular manifestations via the G-protein coupled receptor 43/FFAR2.
Targeting Arginine Metabolism in Immune Cells for the Treatment of Pulmonary Inflammatory Diseases.
Metabolic imprinting drives epithelial memory during mucosal fungal infection.
Melatonin Modulates Glucose Metabolism Reprogramming via Targeting G6PD to Alleviate Lead-Induced Hepatocytes Pyroptosis in Common Carp (Cyprinus carpio L.).
Dysfunction and Metabolic Reprogramming of Gut Regulatory T Cells in HIV-Infected Immunological Non-Responders.
USP30 inhibition augments mitophagy to prevent T cell exhaustion.
Repurposing metabolic drugs as anti-inflammatory agents.
Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
Neutrophil TLR2 signaling promotes lipid accumulation and vascular plaque growth.
JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance.
Transcriptional Regulation of Microglial Metabolic and Activation States by P2RY12.
Decreased LONP1 expression exacerbates MASH-induced liver fibrosis via elevated orotic acid levels.
Protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages.
Mycobacterium tuberculosis curli pili facilitates pathogenicity by modulating central carbon metabolism.
TRPM8 modulation alters uptake of Transferrin-mediated Fe3+, mitochondrial Fe2+ and intracellular Ca2+-levels in microglia.
Dumping polyamines helps regulatory T cells "repair" a cancerous relationship.
Mitochondria protect against an intracellular pathogen by restricting access to folate.
Mitochondria hoard folate to starve a parasite.

Nat Metab. 2025 Aug 14.

Species-specific serine metabolism differentially controls natural killer cell functions.

Joey H Li, Qinyan Feng, Andréa B Ball, Cassidy D Lee, Michelle L Wallerius, Jan G Bormin, Edmund D Kapelczak, Wesley R Armstrong, Leen Hermans, Abigail Krall, Nedas Matulionis, Tara TeSlaa, Heather R Christofk, Ajit S Divakaruni, Timothy E O'Sullivan.

Immune cells undergo rapid metabolic reprogramming to fuel effector responses. However, whether the metabolic pathways that supply these functions differ between human and mouse immune cells is poorly understood. Using a comparative metabolomics approach, here we show both conserved and species-distinct metabolite alterations in cytokine-activated primary human and mouse natural killer (NK) cells. Activated human NK cells fail to perform de novo serine synthesis, resulting in broadly impaired effector functions when serine starved ex vivo or during in vivo dietary serine restriction, limiting their antitumour function. In contrast, activated mouse NK cells perform de novo serine synthesis to fuel one-carbon metabolism and proliferation, resulting in increased metabolic flexibility during ex vivo and dietary serine restriction. While NK cells from both species require one-carbon metabolism to proliferate and produce interferon-γ, GCLC-dependent glutathione synthesis tunes cytotoxic versus inflammatory function in human NK cells. Thus, activated NK cell functions display species-specific requirements for serine metabolism, and environmental serine availability dictates activated human NK cell functions.

DOI: https://doi.org/10.1038/s42255-025-01348-0
Front Immunol. 2025 ;16 1619926

The diverse interaction of metabolism, immune response, and viral pathogens.

Toshio Kanno, Keisuke Miyako, Yusuke Endo.

  During viral infections, both innate and adaptive immune responses are activated to establish host defense mechanisms. In innate immunity, the STING and MAVS pathways, which recognize viral genomes, play a central role in inducing type I interferons (IFN-I), a group of antiviral cytokines. Concurrently, adaptive immune responses, particularly those mediated by T cells, contribute to viral clearance and the establishment of immune memory through the recognition of viral antigens. Recently, numerous studies have highlighted the impact of alterations in lipid metabolism on host immune cells during viral infections. Because viruses lack the ability to synthesize their own lipid membranes, they rely on host lipid metabolic pathways to support their replication. In addition, IFN-I signaling has been shown to suppress the expression of lipid metabolic genes and promote the generation of antiviral lipids. Furthermore, following viral infection, both innate and adaptive immune cells rewire various metabolic pathways, including lipid metabolism, glycolysis, the tricarboxylic acid cycle, and amino acid metabolism, to mount effective antiviral responses. This review focuses on recent advances in our understanding of lipid metabolic reprogramming during viral infection at both the cellular and systemic levels, and how such metabolic changes shape and regulate immune responses.

Keywords:  SCD2; T cells; cGAS-STING; immunometabolism; lipid metabolism; pathogen nucleotide sensor; virus infections; virus lipid

DOI:  https://doi.org/10.3389/fimmu.2025.1619926
Int J Mol Sci. 2025 Jul 31. pii: 7400. [Epub ahead of print]26(15):

Mitochondrial Metabolism in T-Cell Exhaustion.

Fei Li, Yu Feng, Zesheng Yin, Yahong Wang.

  T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion.

Keywords:  T-cell exhaustion; metabolic reprogramming; metabolism; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.3390/ijms26157400
Curr Opin Clin Nutr Metab Care. 2025 Aug 12.

Recent advances in exercise immunometabolism: Immune cell bioenergetics, muscle-immune cell interactions, and potential dietary adjuvants.

Hashim Islam.

   PURPOSE OF REVIEW: Exercise profoundly alters immunological processes to improve overall health and immunity. The link between immune cell metabolism and function has prompted study of immune cell bioenergetics following acute exercise and the role of muscle-resident immune cells in training adaptations. This review highlights recent work in the area and discusses potential dietary approaches for boosting exercise-induced immunometabolic benefits.
RECENT FINDINGS: Human studies highlight the ability of exercise to alter immune cell bioenergetics, with some also reporting accompanying changes in immune cell function. Rodent studies involving moderate exercise report improved innate and adaptive immune cell phenotypes that are accompanied by increased mitochondrial size and bioenergetic function. Various muscle resident immune cell subpopulations including macrophages, mast cells, and regulatory T cells also appear to be involved in the adaptive responses to exercise. Fasting, exogenous ketones, and mitochondrial enhancing compounds (e.g., sulforaphane, urolithin A) could theoretically potentiate the immunometabolic benefits of exercise based on their independent effects, but evidence for combined interventions is currently lacking.
SUMMARY: Exercise and dietary manipulations that independently alter immunometabolic pathways could be combined to maximize associated health benefits. This may benefit those who cannot meet physical activity guidelines or want to maximize exercise adaptation.

Keywords:  fasting; immunology; inflammation; ketones; mitochondria

DOI:  https://doi.org/10.1097/MCO.0000000000001157
Immunity. 2025 Aug 09. pii: S1074-7613(25)00326-7. [Epub ahead of print]

Succinate preserves CD8+ T cell fitness to augment antitumor immunity.

Kaili Ma, Hongcheng Cheng, Lin Wang, Han Xiao, Fenghua Liu, Yu Yang, Zhen Xiao, Kun Tang, Shicheng Li, Gang Wang, Minmin Ge, Jiajia Wang, Xiaowei Liu, Hai-Xi Sun, Ziyi Luo, Zhimin Gu, Ping-Chih Ho, Guideng Li, Lianjun Zhang.

  Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8+ T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8+ T cell-mediated immune responses. Sustained succinate exposure promoted CD8+ T cell survival and facilitated the generation and maintenance of stem-like subpopulations. Mechanistically, succinate enhanced mitochondrial fitness through Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy and also promoted stemness-associated gene expression via epigenetic modulation. Succinate-conditioned CD8+ T cells displayed superior long-term persistence and tumor control capacity. Moreover, succinate enrichment signature correlates with favorable clinical outcomes in certain melanoma and gastric cancer patients receiving immune checkpoint blockade therapy. These findings reveal how succinate preserves T cell stemness and highlight the therapeutic potential of succinate supplementation for enhancing T cell immunotherapy efficacy.

Keywords:  SDHB-deficient tumor; T cell stemness; TCF-1; antitumor immune response; epigenetic reprogramming; exhaustion; immune checkpoint blockade; mitochondrial fitness; mitophagy; succinate

DOI:  https://doi.org/10.1016/j.immuni.2025.07.017
J Autoimmun. 2025 Aug 13. pii: S0896-8411(25)00117-9. [Epub ahead of print]156 103472

Altered glucose metabolism in B cells: Implications for the pathogenesis and treatment of autoimmune diseases.

Mengyu Zhu, Xiaolong Li, Kai Zhao, Zhiyan Huang, Ting Zhao.

   INTRODUCTION: Metabolic dysregulation in immune cells is increasingly recognized as a contributing factor in autoimmune diseases. B lymphocytes, which play key roles in immune tolerance and autoantibody production, show altered glucose metabolism. This review examines the role of glucose metabolism in B cell function and its potential impact on autoimmune pathogenesis.
METHODS: We reviewed evidence from animal and cell-based studies, together with available clinical findings, on glucose metabolic shifts in various B cell subsets-including naïve, activated, germinal center, plasma, and memory B cells-across major autoimmune diseases. Particular attention was given to glycolysis, oxidative phosphorylation (OXPHOS), and mTOR signaling pathways.
RESULTS: Evidence of altered B cell metabolism, especially increased glycolysis, is most extensively documented in systemic lupus erythematosus (SLE), with growing insights emerging in rheumatoid arthritis (RA), Sjögren's syndrome (SS), and type 1 diabetes (T1D). These metabolic changes are associated with B cell activation, autoantibody production, and broader immune modulation. While many findings are based on comparisons with healthy donors, the understanding of disease-specific metabolic patterns is progressively improving.
CONCLUSION: Altered glucose metabolism appears to be a common, though variable, feature of B cells in autoimmune diseases. Current data suggest distinct metabolic profiles in SLE, RA, SS, and T1D. Although much of the existing evidence is derived from in vitro and animal studies, ongoing research continues to refine our understanding. Further cross-disease comparative investigations-especially in RA, SS, and T1D-will be instrumental in delineating the unique metabolic adaptations underlying each condition.

Keywords:  B cell metabolism; Glycolysis; Rheumatoid arthritis; Sjögren's syndrome; Systemic lupus erythematosus; Type 1 diabetes

DOI:  https://doi.org/10.1016/j.jaut.2025.103472
J Mycol Med. 2025 Jul 28. pii: S1156-5233(25)00034-4. [Epub ahead of print]35(3): 101571

Metabolic immune regulation of macrophages by melanized fungus Fonsecaea monophora.

Qinling Pan, Tengteng Xin, Jing Zhang, Li Lin, Junmin Zhang.

   BACKGROUND: Glucose metabolism in the host is crucial during microbial infections. Here, we evaluated the effects of Fonsecaea monophora (F. monophora) wild strain and the pigment-knockout strain ΔpksA mutant on glucose metabolism and immune response of macrophages.
METHODS: Glucose consumption, lactate secretion, genes related to glucose metabolism, and pro-inflammatory cytokines were measured in mouse macrophage J774A.1 cells infected with F. monophora wild strain or ΔpksA. Notably, 2-deoxy-d-glucose (2-DG) and metformin (Glucophage) were used to inhibit glucose metabolism in macrophages.
RESULTS: The F. monophora wild strain significantly inhibited the glucose consumption level of macrophages or classically activated macrophages, and significantly inhibited the mRNA and protein levels of the tricarboxylic acid cycle gene IDH1 in macrophages. F. monophora wild strain inhibited the expression of the pro-inflammatory cytokine IL-1β in macrophages, and upregulated the expression of TNF and IL-6. Inhibition of glucose metabolism by 2-DG or metformin (Glucophage) affected the immune response of macrophages to F. monophora wild strain. The production of IL-1β in macrophages was significantly downregulated. Compared with the control group, ΔpksA did not change glucose utilization and IDH1 expression in macrophages. F. monophora wild strain inhibited IL-1β expression in macrophages, while ΔpksA promoted it.
CONCLUSION: Our results suggest that F. monophora wild strain reduces IL-1β expression by inhibiting the IDH1-related tricarboxylic acid cycle in macrophages. F. monophora melanin is a fungal virulence factor that inhibits glucose metabolism and regulates the immune response of macrophages.

Keywords:  Fonsecaea monophora; Glucose metabolism; IDH1; J774A.1 macrophage cells; Melanin

DOI:  https://doi.org/10.1016/j.mycmed.2025.101571
Res Microbiol. 2025 Aug 12. pii: S0923-2508(25)00056-7. [Epub ahead of print] 104321

Metabolic Adaptation via Glycolysis and Iron Acquisition Drives Klebsiella pneumoniae-Induced Intraocular Inflammation and Visual Impairment.

Ping Lu, Juan Xue, Xuemeng Ji.

  Klebsiella pneumoniae is a major cause of endogenous endophthalmitis, a rapidly progressing intraocular infection associated with severe inflammation and vision loss. The vitreous body presents a hypoxic and iron-restricted environment, yet the bacterial metabolic adaptations that enable persistence in this niche remain largely unknown. Here, we show that K. pneumoniae undergoes metabolic reprogramming to facilitate intraocular survival, characterized by enhanced glycolysis and siderophore-mediated iron acquisition. Proteomic profiling under vitreous-mimicking conditions revealed significant upregulation of PfkA, PykF, and EntB. Targeted deletion of these genes impaired bacterial growth under hypoxia and iron limitation, and significantly reduced intraocular colonization, proinflammatory cytokine production, and visual impairment in a murine model. Double mutants lacking both glycolytic and iron acquisition pathways were nearly avirulent. Correspondingly, infected eyes exhibited lower levels of lactate and iron, reflecting reduced bacterial metabolic activity. These findings establish glycolysis and iron acquisition as critical determinants of K. pneumoniae virulence in the eye and provide insight into the metabolic strategies underpinning bacterial persistence in nutrient-limited host environments.

Keywords:  Klebsiella pneumoniae; endophthalmitis; glycolysis; iron acquisition; metabolic reprogramming

DOI:  https://doi.org/10.1016/j.resmic.2025.104321
Free Radic Biol Med. 2025 Aug 07. pii: S0891-5849(25)00881-0. [Epub ahead of print]239 513-527

Pumilio2 deficiency promotes iron-dependent macrophage inflammation via TfR1 upregulation in lupus.

Xuefei Wang, Xiaoxiao Han, Ruizhi Feng, Wenlin Qiu, Lijuan Jiang, Xiaoru Duan, Guo-Min Deng.

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by persistent pathogenic IgG deposition, inflammation, and progressive organ damage. Despite its clinical importance, the mechanisms underlying sustained IgG-induced inflammation remain poorly understood, posing a major challenge for effective therapeutic intervention. Here, we identify Pumilio2 (Pum2), a post-transcriptional RNA-binding protein, as a crucial negative regulator of IgG-induced inflammation in lupus. Pum2 is consistently downregulated in SLE patient tissues and lupus-prone MRL/lpr mice. Using Pum2-deficient mice and MRL/lpr mice carrying Pum2 mutations generated via backcrossing, we demonstrate that Pum2 deficiency amplifies IgG-triggered immune activation, leading to aggravated tissue injury and accelerated disease progression. Mechanistically, loss of Pum2 in macrophages upregulates transferrin receptor 1 (TfR1), resulting in intracellular iron overload and enhanced proinflammatory responses upon IgG stimulation. Pharmacological inhibition of iron uptake or chelation effectively suppresses this inflammatory phenotype, revealing a functional Pum2-TfR1-iron axis linking RNA-level regulation to immune activation. Our findings establish Pum2 as a previously unrecognized checkpoint connecting post-transcriptional regulation, iron metabolism, and innate immunity in SLE. Targeting this pathway may offer a novel therapeutic strategy for mitigating persistent IgG-driven inflammation in lupus and related autoimmune diseases.

Keywords:  Inflammation; Iron metabolism; Lupus IgG; Post-transcriptional regulation; Systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.012
Int J Mol Sci. 2025 Jul 30. pii: 7346. [Epub ahead of print]26(15):

Metabolic Imprint of Poliovirus on Glioblastoma Cells and Its Role in Virus Replication and Cytopathic Activity.

Martin A Zenov, Dmitry V Yanvarev, Olga N Ivanova, Ekaterina A Denisova, Mikhail V Golikov, Artemy P Fedulov, Roman I Frykin, Viktoria A Sarkisova, Dmitry A Goldstein, Peter M Chumakov, Anastasia V Lipatova, Alexander V Ivanov.

  Poliovirus represents an oncolytic agent for human glioblastoma-one of the most aggressive types of cancer. Since interference of viruses with metabolic and redox pathways is often linked to their pathogenesis, drugs targeting metabolic enzymes are regarded as potential enhancers of oncolysis. Our goal was to reveal an imprint of poliovirus on the metabolism of glioblastoma cell lines and to assess the dependence of the virus on these pathways. Using GC-MS, HPLC, and Seahorse techniques, we show that poliovirus interferes with amino acid, purine and polyamine metabolism, mitochondrial respiration, and glycolysis. However, many of these changes are cell line- and culture medium-dependent. 2-Deoxyglucose, the pharmacologic inhibitor of glycolysis, was shown to enhance the cytopathic effect of poliovirus, pointing to its possible repurposing as an enhancer of oncolysis. Inhibitors of polyamine biosynthesis, pyruvate import into mitochondria, and fatty acid oxidation exhibited antiviral activity, albeit in a cell-dependent manner. We also demonstrate that poliovirus does not interfere with the production of superoxide anions or with levels of H2O2, showing an absence of oxidative stress during infection. Finally, we showed that a high rate of poliovirus replication is associated with fragmentation of the mitochondrial network, pointing to the significance of these organelles for the virus.

Keywords:  Plasmax; glioblastoma; metabolism; oncolytic viruses; poliovirus; polyamines; respiration; seahorse

DOI:  https://doi.org/10.3390/ijms26157346
J Immunol. 2025 Aug 14. pii: vkaf198. [Epub ahead of print]

Brucella abortus induces dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in infected macrophages via stress sensor IRE1α altering metabolic function.

Erika S Guimarães, Marco Túlio R Gomes, Pedro M Moraes-Vieira, Sergio C Oliveira.

  Brucella abortus exploits the endoplasmic reticulum as a site for replication, triggering the unfolded protein response (UPR). While various pathogens have developed strategies to manipulate mitochondrial dynamics, the mechanisms underlying bacterial infection and mitochondrial dynamics interactions remain poorly understood. Here, we demonstrate that B. abortus induces mitochondrial fragmentation via IRE1α. Our findings reveal that Brucella-induced mitochondrial fission is mediated by dynamin-related protein 1 (DRP1), a pivotal regulator of mitochondrial fission. Moreover, we have demonstrated that DRP1 is activated by the UPR. Brucella-induced fragmentation leads to mitochondrial energetic dysfunction, marked by impaired mitochondrial ATP production and compromised bioenergetic capacity. Furthermore, we reveal a novel role for DRP1 in regulating type I IFN production and signaling during B. abortus infection. Mechanistically, mitochondrial fission facilitates the release of mitochondrial DNA, a potent inducer of type I IFN responses. Despite its impact on mitochondrial function and IFN signaling, DRP1 does not influence the control of B. abortus infection. Our findings uncover a unique mechanism by which B. abortus-induced UPR triggers mitochondrial fragmentation affecting innate immune signaling and cellular metabolism.

Keywords:   Brucella abortus ; UPR; innate immunity; mitochondrial dysfunction

DOI:  https://doi.org/10.1093/jimmun/vkaf198
J Immunol. 2025 Aug 06. pii: vkaf181. [Epub ahead of print]

Intronic miR-342 is a key regulator of cellular glycolysis in Foxp3+ regulatory CD4 T cells.

Rongzhen Yu, Sohee Kim, Silei Li, Wenjing Yang, Giha Kim, Li-Fan Lu, Yingzi Cong, Dongkyun Kim, Booki Min.

  Foxp3+ regulatory T (Treg) cells are a subset of CD4 T cells that play a potent and indispensable role in regulating immunity and tolerance. The precise mechanisms by which Treg cells mediate such functions have extensively been explored, and there are many cellular and molecular factors that are instrumental for adequate Treg cell functions. microRNAs, small noncoding RNA molecules, are one of the factors capable of regulating Treg cell functions. In this study, we report that miR-342 is essential for Treg cells to mitigate autoimmune inflammation in the central nervous system and allergic airway inflammation in the lung. Utilizing novel mouse models with Treg cell-specific miR-342 deficiency or overexpression, we demonstrate that miR-342 expression in Treg cells, while dispensable for immune homeostasis at steady-state conditions, is necessary for Treg cells to control inflammatory responses. Mechanistically, we found that Treg cells deficient in miR-342 display dysregulated metabolic profiles, elevated glycolysis and decreased oxidative phosphorylation, a metabolic phenotype associated with functionally defective Treg cells. Interestingly, miR-342-dependent metabolic dysregulation was observed in Treg but not in T helper 1-type cells. In support, miR-342-mediated Rictor targeting was found in Treg but not in T helper 1-type cells. Last, Treg cells overexpressing miR-342 were able to effectively suppress ongoing autoimmune inflammation in an adoptive Treg transfer but not in active disease model. Collectively, our findings uncover that miR-342 may serve a key regulator specific for metabolism and functions in Treg cells.

Keywords:  Treg cells; glycolysis; metabolism; miRNA

DOI:  https://doi.org/10.1093/jimmun/vkaf181
Nat Commun. 2025 Aug 14. 16(1): 7564

Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation.

Yan Tao, Jinhao Zang, Tianci Wang, Peixuan Song, Zixin Zhou, Huijie Li, Yalin Wang, Yiyang Liu, Haipeng Jie, Mei Kuang, Hui Zhao, Fuwu Wang, Shen Dai, Chun Guo, Faliang Zhu, Haiting Mao, Fengming Liu, Lining Zhang, Qun Wang.

Morbid obesity induces adipose stem cell (ASC) shortage that impairs visceral adipose tissue (VAT) homeostasis. Macrophages cooperate with ASCs to regulate VAT metabolism, their impact on ASC shortage remains elusive. TNF-α-induced protein 8-like 2 (TIPE2) is an important regulator in immune cells, its expression in VAT macrophages and function in macrophage-ASC crosstalk are largely unknown. Here, TIPE2 loss in VAT macrophages promotes ASC ferroptosis to aggravate diet-induced obesity and metabolic disorders in male mice, which can be corrected by macrophage-specific TIPE2 restoration in VAT. Mechanistically, TIPE2-deficient macrophages propagate mitochondrial fragmentation and reduce delivery of exosomal ferritin toward ASCs, resulting in mitochondrial ROS and Fe2+ overload that dictates ASC ferroptosis. TIPE2 interacts with IP3R to constrain IP3R-Ca2+-Drp1 axis, thereby preventing excessive mitochondrial fission and enabling macrophages to protect against ASC ferroptosis. This study reveals distinct obesity-associated macrophages that dictate ASC ferroptosis, and proposes macrophage TIPE2 as therapeutic target for obesity-related diseases.

DOI: https://doi.org/10.1038/s41467-025-62690-1
Intest Res. 2025 Aug 11.

Peroxisome proliferator-activated receptors in inflammatory bowel disease: linking immunometabolism, lipid signaling, and therapeutic potential.

Kiandokht Bashiri, Mark C Mattar, Alireza Meighani, Andrew L Mason.

  Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis, is a chronic condition marked by immune dysregulation, genetic predisposition, and metabolic disturbances. Emerging evidence highlights the role of lipid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling in modulating immune responses in IBD. PPAR-γ and PPAR-α regulate macrophage polarization, T-cell differentiation, and epithelial barrier integrity, influencing disease severity and progression. Alterations in PPAR activity contribute to metabolic stress and inflammation, linking IBD pathophysiology to immunometabolism. Studies suggest that targeting PPARs may mitigate inflammation through modulation of cytokine production, immune cell function, and gut microbiota interactions. In this review, we focus specifically on CD and explore how PPAR signaling intersects with mesenteric adipose tissue dysfunction and microbial dysbiosis, 2 hallmark features of CD. PPAR agonists, already used in metabolic-inflammatory diseases such as metabolic-associated liver disease, have demonstrated antiinflammatory effects in experimental colitis models. Translating these findings into clinical applications could offer novel treatment strategies for CD. Future research should focus on clinical trials, genetic studies, and microbiota-targeted approaches to elucidate PPAR-driven mechanisms in CD pathogenesis. Understanding the interplay between PPARs, lipid metabolism, and immune responses may lead to innovative therapeutic strategies, improving disease management and patient outcomes.

Keywords:  Crohn disease; Immunometabolic phenomena; Inflammation; Lipid metabolism; Peroxisome proliferator-activated receptors

DOI:  https://doi.org/10.5217/ir.2025.00090
Clin Transl Med. 2025 Aug;15(8): e70441

CD31 regulates metabolic switch in Treg migration attenuates rheumatoid arthritis.

Meijun Liu, Wengqiong Huang, Xiaoli Chen, Zongzhen Meng, Jiawen Yang, Loiola Rodrigo Azevedo, Xiaojiao Zheng, Hao Shen, Wei Jia, Aiping Lyu, Kenneth Cp Cheung.

  CD31 (PECAM-1) plays a critical role in T cell migration, whilst its immunoreceptor tyrosine inhibitory motifs (ITIMs), Y663 and Y686, are recognised for their roles in endothelial function, the precise mechanism in regulating immune cell remains elusive. Here, we demonstrate that CD31 is essential for Treg migration. Upon ITIM engagement, CD31 activates and interacts with the protein tyrosine phosphatase SHP2. In vivo, CD31 Y663F gene transfer recapitulates the wild-type migration phenotype, driven by a metabolic switch to fructose utilisation under the regulation of the PFKFB3 gene. Conversely, the Y686F mutation impairs Tregs migration by disrupting both glycolysis and the switch to fructose metabolism, thus promoting the mitochondrial function via activation of the RNF111/OGT pathway. Our findings reveal a novel role for CD31 ITIMs in orchestrating a metabolic that is switch crucial for Treg migration. This understanding of CD31 polymorphisms and their impact on Treg migration offers potential therapeutic avenues for autoimmune diseases, particularly rheumatoid arthritis (RA). KEY POINTS: CD31 Y663F-mutant Tregs exhibit a glucose-to-fructose metabolic shift, characterised by reduced glucose uptake and enhanced fructose utilisation regulated by PFKFB3. CD31 Y686F mutation disrupts both glycolysis and fructose metabolism in Tregs, shifting energy production towards mitochondrial function via the RNF111/OGT pathway. These findings highlight a novel mechanism by which CD31 ITIMs control Treg migration, offering new therapeutic targets for autoimmune diseases such as RA.

Keywords:  CD31 ITIMs; PFKFB3; RNF111/OGT pathway; Tregs migration; metabolic switch

DOI:  https://doi.org/10.1002/ctm2.70441
bioRxiv. 2025 Jul 15. pii: 2025.07.15.664962. [Epub ahead of print]

Gut microbial metabolites butyrate and acetate limit Zika virus replication and associated ocular manifestations via the G-protein coupled receptor 43/FFAR2.

Nikhil Deshmukh, Prince Kumar, Lal Krishan Kumar, Vaishnavi Balendiran, Pawan Kumar Singh.

Short-chain fatty acids (SCFAs) are gut microbial metabolites produced by gut microbiota from dietary fiber. SCFAs have shown both pro- and anti-viral roles among different viruses, and are known to regulate immune functions during infections. However, their role against the Zika virus (ZIKV) in general and ocular infection, in particular, has never been investigated. In the present study, we aimed to examine the role of three SCFA derivatives: phenylbutyrate (PBA), sodium butyrate (NaB), and sodium acetate (NaAC), on ZIKV replication and associated ocular complications using primary human trabecular meshwork cells (HTMCs) and an IFNAR1-deficient mouse model of ocular infection. Our findings reveal that PBA and NaAc treatment dramatically suppressed the ZIKV replication in HTMCs. NaB showed a slightly less effect than PBA and NaAc. PBA and NaAc treatment significantly attenuated the ZIKV-induced inflammatory cytokine, interferons, and interferon-stimulated genes response via antagonizing the RIG-I/NFκB/MAPKs/STAT1-3 signaling pathways. We discovered that ZIKV induces the expression of free fatty acid receptor 2 (FFAR2)/ GPR43 in HTMCs, which is further potentiated by PBA/NaAc. Pharmacological inhibition of FFAR2 abrogated the protective abilities of PBA/NaAc and significantly increased viral replication. Blocking FFAR2 receptors promoted ZIKV-induced cell death, which was suppressed by PBA and NaAc. Mechanistically, butyrate and acetate inhibited ZIKV binding and cellular entry and inactivated the virus before internalization. PBA and NaAc treatment in mice attenuated the ZIKV-induced ocular manifestations (intraocular pressure, RPE/retinal atrophy, and anterior segment inflammation), which was abrogated by FFAR2 inhibition. Collectively, our findings indicate that SCFA treatment is an effective approach to limit ZIKV replication and associated ocular damage and may be worth exploring as a means to treat or prevent ZIKV-induced ocular complications in humans.
Importance: ZIKV is known to cause severe ocular manifestations in in-utero exposed infants; however, the molecular mechanisms of ZIKV-induced ocular complications remain unknown. SCFAs have demonstrated both pro- and anti-viral roles against different viruses; however, their role against ZIKV is unknown. We showed that SCFAs butyrate and acetate suppress ZIKV transmission and associated ocular complications. The anti-ZIKV activity of these SFACs is mediated via FFAR2, and pharmacological inhibition of FFAR2 promotes ZIKV-induced inflammatory and cell death responses, as well as ocular malformations.

DOI: https://doi.org/10.1101/2025.07.15.664962
Curr Allergy Asthma Rep. 2025 Aug 11. 25(1): 35

Targeting Arginine Metabolism in Immune Cells for the Treatment of Pulmonary Inflammatory Diseases.

Hangyu Li, Yuemei Liang, Jingyi Deng, Yisen Cheng, Su Chen, Xinlong Lian, Suidong Ouyang.

   PURPOSE OF REVIEW: This review aims to provide a comprehensive overview of the role of arginine and its metabolic pathways in regulating immune cell function, with a particular focus on their involvement in pulmonary inflammatory diseases. Additionally, it highlights recent advances in therapeutic strategies that target arginine metabolism as a potential therapeutic approach for the treatment of these conditions.
RECENT FINDINGS: Arginine is a conditionally essential amino acid that plays a pivotal role in numerous physiological processes, including immune regulation, tissue repair, airway tone modulation, and vasodilation. We found emerging evidence underscores that arginine metabolism is tightly controlled by various regulatory mechanisms, with two key enzymes-nitric oxide synthase (NOS) and arginase (ARG)-occupying central roles. These enzymes exert opposing yet coordinated effects within immune cells, contributing to the delicate balance between immune activation and resolution. Dysregulation of arginine metabolism has been implicated in the pathogenesis of several pulmonary inflammatory diseases, including respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. Aberrant arginine metabolic activity in immune cells promotes either excessive inflammation or impaired immune defense, depending on the context. Understanding the immunometabolic functions of arginine offers valuable insights into the mechanisms underlying pulmonary inflammatory diseases. Therapeutic modulation of the arginine metabolic pathway represents a promising strategy for controlling disease progression and improving clinical outcomes, paving the way for the development of novel targeted treatments.

Keywords:  Arginine metabolism. immune cells. pulmonary inflammatory diseases. therapeutic targets

DOI:  https://doi.org/10.1007/s11882-025-01216-7
bioRxiv. 2025 Jul 17. pii: 2025.07.11.664387. [Epub ahead of print]

Metabolic imprinting drives epithelial memory during mucosal fungal infection.

Jinendiran Sekar, Norma V Solis, Jian Miao, Nicolas Millet, Bryce Tom, Derek Quintanilla, Aize Pellon, David L Moyes, Joseph A Gogos, Harry B Rossiter, Scott G Filler, Mihai G Netea, Jennifer K Yee, Marc Swidergall.

Epithelial cells at barrier sites are emerging as active participants in innate immune memory, yet the underlying metabolic and epigenetic mechanisms remain unclear. Here, we uncover a previously unrecognized form of trained immunity in oral epithelial cells that enhances protection against fungal infection. Using a mouse model, we show that mucosal exposure to Candida albicans confers sustained protective memory that is independent of adaptive immunity and myeloid cells. Mechanistically, mucosal memory is driven by proline catabolism via proline dehydrogenase (Prodh) in epithelial cells, which sustains mitochondrial function, epigenetic remodeling, and promotes cytokine production upon secondary challenge. Unlike classical trained immunity in immune cells, epithelial memory is independent of glycolysis but partially sustained by fatty acid oxidation via carnitine palmitoyltransferase-I (CPT1). These findings uncover a distinct metabolic-epigenetic axis that underlines long-term epithelial memory in the oral mucosa and reveal novel non-hematopoietic mechanisms of mucosal defense against fungal pathogens.

DOI: https://doi.org/10.1101/2025.07.11.664387
Adv Sci (Weinh). 2025 Aug 11. e01041

Melatonin Modulates Glucose Metabolism Reprogramming via Targeting G6PD to Alleviate Lead-Induced Hepatocytes Pyroptosis in Common Carp (Cyprinus carpio L.).

Zhiying Miao, Xiaofeng Ji, Lai Wei, Zhiruo Miao, Shiwen Xu.

  Lead (Pb) is a prevalent toxic contaminant that accumulates in freshwater ecosystems, posing severe toxicity to non-target species such as fish and contributing to the pathogenesis of liver disease. Melatonin (Mel) is a well-known natural antioxidant that has been found to improve liver function through its potent anti-inflammatory properties. However, whether and how Mel alleviates Pb-triggered hepatotoxicity remains unclear. Mitochondria play a vital role in glucose metabolism, and glucose metabolic reprogramming is characterized by elevated glycolysis, resulting in lactate accumulation, which is a precursor for histone lactylation, an epigenetic modification. In this study, it is demonstrated that Pb triggers glucose metabolism reprogramming, resulting in lactate accumulation. Specifically, lactate links glycolysis and mitochondrial homeostasis via histone H3 lysine 18 lactylation (H3K18la), which modulates the activity of dynamin-related protein 1 (DRP1). Furthermore, DRP1 actively mediates mitochondrial fragmentation, thereby facilitating inflammatory signals derived from the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Additionally, the results first demonstrate that Mel redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) by targeting glucose-6-phosphate dehydrogenase (G6PD). In summary, Mel targets G6PD to suppress glycolysis-driven H3K18la and DRP1 transcription, thereby maintaining mitochondrial homeostasis to alleviate hepatocytes pyroptosis dependent on cGAS-STING pathway under Pb exposure.

Keywords:  glucose metabolism reprogramming; glucose‐6‐phosphate dehydrogenase; histone H3 lysine 18 lactylation; lead; melatonin

DOI:  https://doi.org/10.1002/advs.202501041
Cells. 2025 Jul 29. pii: 1164. [Epub ahead of print]14(15):

Dysfunction and Metabolic Reprogramming of Gut Regulatory T Cells in HIV-Infected Immunological Non-Responders.

Minrui Yu, Mengmeng Qu, Zerui Wang, Cheng Zhen, Baopeng Yang, Yi Zhang, Huihuang Huang, Chao Zhang, Jinwen Song, Xing Fan, Ruonan Xu, Yan-Mei Jiao, Fu-Sheng Wang.

  Disruption of the gut microenvironment is a hallmark of HIV infection, where regulatory T cells (Tregs) play a critical role in maintaining gut homeostasis. However, the mechanisms by which gut Tregs contribute to immune reconstitution failure in HIV-infected individuals remain poorly understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to analyze gut Treg populations across three cohorts: eight immunological responders (IRs), three immunological non-responders (INRs), and four HIV-negative controls (NCs). Our findings revealed that INRs exhibit an increased proportion of gut Tregs but with significant functional impairments, including reduced suppressive capacity and heightened apoptotic activity. Notably, these Tregs underwent metabolic reprogramming in INRs, marked by an upregulation of glycolysis-related genes and a downregulation of the oxidative phosphorylation (OXPHOS) pathway. Additionally, both the abundance of short-chain fatty acid (SCFA)-producing bacteria and SCFA concentrations were reduced in INRs. In vitro SCFA supplementation restored Treg function by enhancing suppressive capacity, reducing early apoptosis, and rebalancing cellular energy metabolism from glycolysis to OXPHOS. These findings provide a comprehensive characterization of gut Treg dysfunction in INRs and underscore the therapeutic potential of targeting gut Tregs through microbiota and metabolite supplementation to improve immune reconstitution in HIV-infected individuals.

Keywords:  HIV; SCFA; Tregs; gut; immunological non-responders; immunological responders

DOI:  https://doi.org/10.3390/cells14151164
Sci Adv. 2025 Aug 15. 11(33): eadv6902

USP30 inhibition augments mitophagy to prevent T cell exhaustion.

Ruohan Zhang, Fengxia Gao, Jianying Li, Jiacheng Jin, Kangxuan Chen, Samhita Chaudhuri, Zhiwei Liao, Tong Xiao, Yang Xu, Haitao Wen, Kai He, Zihai Li, Gang Xin, Nuo Sun.

The exhaustion of tumor-infiltrating CD8+ T cells poses a substantial challenge in cancer immunotherapy, with mitochondrial health essential for sustaining T cell functionality. Mitophagy, a critical process for mitochondrial quality control, is severely impaired in exhausted CD8+ T cells, yet the underlying mechanisms remain unclear. We identified ubiquitin-specific protease 30 (USP30), a mitochondrial deubiquitinase that inhibits mitophagy, as a key factor up-regulated in exhausted CD8+ T cells. Notably, prolonged antigen stimulation triggers the T cell receptor and nuclear factor of activated T cell 1 signaling, which drives the transcriptional up-regulation of USP30. Excitingly, our interventions targeting USP30 through genetic deletion or pharmacological inhibition effectively restored mitophagy, improved mitochondrial fitness, and rejuvenated CD8+ T cell effector functions. These interventions reinvigorated antitumor responses and markedly suppressed tumor growth. Our findings establish USP30 as a critical regulator of mitophagy and a promising therapeutic target for reversing T cell exhaustion and enhancing the efficacy of cancer immunotherapy.

DOI: https://doi.org/10.1126/sciadv.adv6902
Trends Endocrinol Metab. 2025 Aug 13. pii: S1043-2760(25)00149-3. [Epub ahead of print]

Repurposing metabolic drugs as anti-inflammatory agents.

Andrew E Hogan, Cian Davis, Benjamin J Jenkins, Nicholas Jones, Donal O'Shea.

  Dysregulation of bodyweight systemic metabolism is intrinsically linked to an inflammatory phenotype, with each underpinning the other. Over the past decade, new classes of drug, such as glucagon-like peptide-1 (GLP-1)-based therapies and sodium glucose co-transporter 2 (SGLT2) inhibitors, have entered the clinical management of bodyweight and metabolic disease with great success. With their expanded use, it is emerging that the benefits of these drugs extend beyond metabolic improvements into changes in chronic inflammation, potentially independent of those in metabolism. In this review, we discuss the impact of metabolic drugs on inflammatory comorbidities of metabolic disorders and beyond. We highlight the molecular mechanisms via which these drugs exert their anti-inflammatory actions and discuss their potential repurposing as direct anti-inflammatory agents.

Keywords:  SLGT2i; glucagon-like peptide-1; inflammation; obesity

DOI:  https://doi.org/10.1016/j.tem.2025.07.003
bioRxiv. 2025 Aug 06. pii: 2025.08.04.668533. [Epub ahead of print]

Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.

Manish Mishra, Hee-Hoon Kim, Yun-Hee Youm, Elsie Gonzalez-Hurtado, Konstantin Zaitsev, Tamara Dlugos, Irina Shchukina, Christy Gliniak, Eric Ravussin, Subhasis Mohanty, Albert C Shaw, Philipp E Scherer, Maxim N Artyomov, Vishwa Deep Dixit.

Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.

DOI: https://doi.org/10.1101/2025.08.04.668533
bioRxiv. 2025 Jul 14. pii: 2025.07.09.663961. [Epub ahead of print]

Neutrophil TLR2 signaling promotes lipid accumulation and vascular plaque growth.

Anudari Letian, Kyrlia Young, Anna Pi, Michelangelo Gonzatti, Regan Volk, Isha Sharma, Clayton Baker, Bérénice A Benayoun, Balyn W Zaro, Amber N Stratman, Emily L Goldberg.

Neutrophils are short-lived cells that are produced by the billions every day to circulate throughout the body and surveil all tissues. They are a key component of the innate immune system that play essential roles in antimicrobial immunity, but can also instigate sterile inflammatory diseases like gout and cancer. Immunometabolic paradigms that were developed by studying T cells and macrophages establish that cellular metabolic programming dictates immune function. Neutrophils have long been known as glucose-reliant and highly glycolytic. But surprising neutrophil heterogeneity has recently been described, and roles for lipids have been reported in both granulopoiesis and mature neutrophil effector function. Therefore, we set out to uncover how neutrophils acquire lipids from their environment and how this influences their functionality in the context of lipotoxicity. We found that neutrophils take up both free fatty acids and complex lipoproteins, but that their uptake is regulated through different signaling pathways. Neutrophil lipoprotein uptake is inducible by certain TLR2 signals, and this causes neutrophils to depolymerize their actin fibers and stop moving. Using a mouse model of atherosclerosis, we show that neutrophils in the plaque are lipid-laden and that neutrophil-deficient mice are protected from atherosclerotic plaque growth. Lipoprotein uptake causes neutrophils to recruit macrophages, conditional ablation of TLR2 on neutrophils prevents their lipid uptake and storage, and these mice are also protected against atherosclerosis. Our work highlights an important understudied role for lipids in neutrophil biology, and the importance of studying different lipid classes and different signaling pathways in neutrophils as compared to other myeloid populations.

DOI: https://doi.org/10.1101/2025.07.09.663961
Cells. 2025 Aug 02. pii: 1194. [Epub ahead of print]14(15):

JAK2/STAT3 Signaling in Myeloid Cells Contributes to Obesity-Induced Inflammation and Insulin Resistance.

Chunyan Zhang, Jieun Song, Wang Zhang, Rui Huang, Yi-Jia Li, Zhifang Zhang, Hong Xin, Qianqian Zhao, Wenzhao Li, Saul J Priceman, Jiehui Deng, Yong Liu, David Ann, Victoria Seewaldt, Hua Yu.

  Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance.

Keywords:  JAK2/STAT3; inflammation; insulin resistance; obesity

DOI:  https://doi.org/10.3390/cells14151194
Glia. 2025 Aug 15.

Transcriptional Regulation of Microglial Metabolic and Activation States by P2RY12.

Aida Oryza Lopez-Ortiz, Madison Doceti, JaQuinta Thomas, Abigayle Duffy, Morgan Coburn, Akhabue K Okojie, Audrey Lee, Elizabeth Aidita Sou, Alban Gaultier, Ukpong B Eyo.

  Microglia are the resident immune cells of the CNS. Under homeostatic conditions, microglia play critical roles in orchestrating synaptic pruning, debris clearance, and dead cell removal. In disease, they are powerful mediators of neuroinflammation, as they rapidly respond to injury or infection within the CNS by altering their morphology, proliferating, and releasing cytokines and other signaling molecules. Understanding the molecular pathways involved in microglial function is pivotal for advancing neurobiological research and developing effective strategies for CNS disorders. In this context, P2RY12 is a G protein-coupled receptor (GPCR) that is uniquely enriched in microglia in the parenchyma and a canonical marker of homeostatic, ramified microglia. However, P2RY12 is downregulated in activated microglia and in neurological conditions. The consequences of P2RY12 downregulation in disease-associated microglia and how they influence microglial activation remain poorly understood. In this study, we apply transcriptional and histological methods to explore the changes to microglia upon a genetic P2RY12 loss. Our findings reveal that P2RY12-deficient microglia experience alterations in distinct metabolic pathways while preserving overall homeostatic microglial transcriptional identity. Lack of P2RY12 alters signature genes involved in homeostatic iron metabolism. Importantly, the genes encoding proteins in the Glutathione Peroxidase 4 (Gpx4)-Glutathione (GSH) antioxidant pathway related to ferroptosis susceptibility are impaired upon microglial activation with lipopolysaccharide (LPS) treatment. These results highlight the critical role of P2RY12 in regulating microglial immune and metabolic transcriptional responses under both homeostatic and inflammatory conditions, providing insights into its involvement in CNS pathophysiology.

Keywords:  CNS homeostasis; LPS‐induced activation; P2RY12; disease‐associated microglia (DAM); ferroptosis; glutathione (GSH) antioxidant pathway; microglia; microglial metabolism; neuroinflammation; transcriptional regulation

DOI:  https://doi.org/10.1002/glia.70078
J Hepatol. 2025 Aug 08. pii: S0168-8278(25)02379-7. [Epub ahead of print]

Decreased LONP1 expression exacerbates MASH-induced liver fibrosis via elevated orotic acid levels.

Dengqiu Xu, Zehua Zhang, Ziqi Zhu, Wenjing Wei, Yipeng Bai, Wen Wang, Yong Zhu, Abudureyimu Alimujiang, Yuze Shi, Zhen Zhang, Zhijian Li, Pengkai Wu, Beicheng Sun.

   BACKGROUND & AIMS: Identifying the metabolic targets driving liver fibrosis in metabolic-dysfunction-associated steatohepatitis (MASH) is essential for developing effective preventive therapies. However, the metabolic pathways dysregulated in MASH and the underlying molecular mechanisms remain poorly understood. Lon peptidase 1 (LONP1), a mitochondrial protease, is known for its pivotal role in maintaining mitochondrial protein quality surveillance and performing highly regulated proteolytic reactions. This study aims to explore the precise mechanisms by which LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring in liver fibrosis.
METHODS: We used murine liver fibrosis models, a hepatocyte-specific LONP1 knockout mouse model, and liver biopsies from MASH patients. Transcriptomics, proteomics and metabolomics were used to identify the potential metabolites that promote MASH-induced liver fibrosis.
RESULTS: LONP1 expression was reduced in patients and mice with MASH. Hepatocyte-specific LONP1 deficiency results in dihydroorotate dehydrogenase (DHODH) accumulation, elevated orotic acid levels, and aggravated MASH-induced fibrosis. Conversely, the overexpression of LONP1 or the administration of a DHODH inhibitor reduced orotic acid levels and alleviated MASH-induced liver fibrosis in mice. Mechanistically, LONP1 was shown to degrade DHODH selectively in an ATP-dependent manner, thus lowering orotic acid levels and suppressing the activating transcription factor 3 (ATF3)-mediated activation of hepatic stellate cells. These findings were validated in MASH patients, as plasma orotic acid levels correlated negatively with hepatic LONP1 levels and positively with both the expression of fibrotic genes and fibrosis scores.
CONCLUSION: Our findings demonstrate that the LONP1-DHODH interaction regulates orotic acid metabolism and alleviates MASH-induced liver fibrosis.
IMPACT AND IMPLICATIONS: Liver fibrosis is one of the main histological determinants of MASH, a disease that parallels the worldwide surge in metabolic syndromes. This study reveals that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and regulates orotic acid metabolism, contributing to the progression of MASH-induced liver fibrosis. These findings suggest that targeting orotic acid or hepatocyte LONP1 may represent a promising therapeutic strategy. Further investigation into mitochondrial orotic acid metabolism may yield novel insights into the pathogenesis of liver fibrosis.

Keywords:  Dihydroorotate dehydrogenase; Lon peptidase 1; Metabolic dysfunction-associated steatohepatitis; Mitochondrial proteostasis; Orotic acid

DOI:  https://doi.org/10.1016/j.jhep.2025.07.013
STAR Protoc. 2025 Aug 09. pii: S2666-1667(25)00430-7. [Epub ahead of print]6(3): 104024

Protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages.

Yongxiang Liu, Huan Jin, Bitao Huo, Xiaojun Xia, Jinyun Liu.

  Multiple metabolic pathways and metabolites are involved in innate immune memory induction of macrophages; however, protocols for in vitro-trained immunity assays induced by metabolites in mouse macrophages are limited. Here, we present a protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages. We describe steps for sample preparation, measurement of 24(S),25-epoxycholesterol, and establishment of an in vitro-trained immunity model. We then detail procedures for assays measuring cytokine concentration and for assay for transposase-accessible chromatin using sequencing (ATAC-seq). For complete details on the use and execution of this protocol, please refer to Liu et al.1.

Keywords:  Cell Biology; Immunology; Metabolism; Molecular Biology; model Organisms

DOI:  https://doi.org/10.1016/j.xpro.2025.104024
Metabolomics. 2025 Aug 12. 21(5): 118

Mycobacterium tuberculosis curli pili facilitates pathogenicity by modulating central carbon metabolism.

Tarien J Naidoo, Shinese Ashokcoomar, Barry Truebody, Jared S Mackenzie, Adrie J C Steyn, Manormoney Pillay.

   INTRODUCTION: Strategies specifically targeting the initial host-pathogen interactions, hold great promise in the identification of accurate biomarkers for tuberculosis (TB) prevention interventions. Mycobacterium tuberculosis (Mtb) curli pili (MTP) (encoded by mtp/Rv3312A), a surface adhesin utilised by the pathogen to interact with host receptor cells, has been reported as a suitable target for TB diagnostic and therapeutic strategies. Previous "omics" studies highlighted the role MTP potentially plays in Mtb central carbon metabolism (CCM). However, its precise contribution to metabolism remains unknown.
OBJECTIVES: This study aimed to examine the role of MTP in the bioenergetic metabolism of Mtb, using bedaquiline (BDQ) to inhibit ATP production through oxidative phosphorylation (OXPHOS), extracellular flux analysis, Mtb wildtype (WT), ∆mtp deletion mutant, and mtp-complemented strains. The role of MTP in regulation of CCM was assessed using 13C6-metabolic flux analysis.
RESULTS: MTP was associated with increased bacterial respiration and decreased carbon catabolism via glycolysis in response to the inhibition of ATP synthase by BDQ. The dependence of Mtb Δmtp on OXPHOS for energy production was demonstrated to be greater than the WT and mtp-complemented strains. In addition, metabolic flux profiles revealed that in the Δmtp mutant, CCM was dysregulated by decreasing flux through glycolysis, tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism, and the pentose phosphate pathway in comparison to the WT.
CONCLUSION: These novel findings show that MTP is associated with the regulation of bioenergetics and metabolism pathways and substantiate MTP as a potential biomarker for TB diagnostics/therapeutics, and a novel target for vaccine/drug development.

Keywords:  Bioenergetics; Central carbon metabolism; LS-MS/MS; MTP; Mycobaterium tuberculossis

DOI:  https://doi.org/10.1007/s11306-025-02320-5
Neurochem Int. 2025 Aug 08. pii: S0197-0186(25)00104-4. [Epub ahead of print]189 106031

TRPM8 modulation alters uptake of Transferrin-mediated Fe3+, mitochondrial Fe2+ and intracellular Ca2+-levels in microglia.

Raima Sing, Deep Shikha, Chandan Goswami.

  Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe2+/3+, triggering inflammatory and neurotoxic effects that contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's. Hence, the study of dysregulated microglial activation and overload of Fe2+/3+ is crucial in the context of neurodegenerative conditions. Emerging research has identified cold-sensitive ion channels, i.e., TRPM8 in microglia, which can regulate key subcellular functions. This study explores the regulatory function of the TRPM8 in Fe2+/3+ metabolism and its implications for potential ferroptosis in BV2 microglial cells. We used highly specific fluorescence probes, pharmacological modulators of TRPM8 and performed life cell imaging to understand the uptake of Transferrin-488, mitochondrial Fe2+-level, cellular Ca2+-levels in live BV2 cells under different experimental conditions. Our findings reveal that TRPM8 activation leads to enhanced Transferrin-488-mediated cytosolic Fe3+-uptake, disrupts mitochondrial superoxide levels, and promotes cell death. Interestingly, under inflammatory conditions induced by LPS treatment, TRPM8 exhibits a distinct functional role. These results position TRPM8 as an important regulator of microglial Fe2+/3+ metabolism. This study indicates the involvement of TRPM8 in overload of Fe2+/3+ leading to ferroptosis and potential for M1-M2 polarization in microglia. These findings impose TRPM8 as a potential therapeutic target for neurodegenerative diseases, and aging.

Keywords:  Alzheimer's disease; Ca(2+)-signaling; Iron homeostasis; Microglia; Mitochondrial functions; Neurodegeneration

DOI:  https://doi.org/10.1016/j.neuint.2025.106031
Immunity. 2025 Aug 12. pii: S1074-7613(25)00312-7. [Epub ahead of print]58(8): 1885-1887

Dumping polyamines helps regulatory T cells "repair" a cancerous relationship.

Krittin Trihemasava, Will Bailis.

Regulatory T (Treg) cells maintain immune and tissue homeostasis. In this issue of Immunity, Bündgen et al.1 find that intratumoral polyamines promote immunosuppressive Treg cells via CK2. Targeting the polyamine-CK2 axis shifts Treg cells to become tissue reparative, enhancing antitumor responses.

DOI: https://doi.org/10.1016/j.immuni.2025.07.003
Science. 2025 Aug 14. 389(6761): eadr6326

Mitochondria protect against an intracellular pathogen by restricting access to folate.

Tânia Catarina Medeiros, Jana Ovciarikova, Xianhe Li, Patrick Krueger, Tim Bartsch, Silvia Reato, John C Crow, Michelle Tellez Sutterlin, Bruna Martins Garcia, Irina Rais, Kira Allmeroth, Matías D Hartman, Martin S Denzel, Martin Purrio, Andrea Mesaros, Kit-Yi Leung, Nicholas D E Greene, Lilach Sheiner, Patrick Giavalisco, Lena Pernas.

As major consumers of cellular metabolites, mitochondria are poised to compete with invading microbes for the nutrients that they need to grow. Whether cells exploit mitochondrial metabolism to protect from infection is unclear. In this work, we found that the activating transcription factor 4 (ATF4) activates a mitochondrial defense based on the essential B vitamin folate. During infection of cultured mammalian cells with the intracellular pathogen Toxoplasma gondii, ATF4 increased mitochondrial DNA levels by driving the one-carbon metabolism processes that use folate in mitochondria. Triggered by host detection of mitochondrial stress induced by parasite effectors, ATF4 limited Toxoplasma access to folates required for deoxythymidine monophosphate synthesis, thereby restricting parasite growth. Thus, ATF4 rewires mitochondrial metabolism to mount a folate-based metabolic defense against Toxoplasma.

DOI: https://doi.org/10.1126/science.adr6326
Science. 2025 Aug 14. 389(6761): 685-686

Mitochondria hoard folate to starve a parasite.

Anu Suomalainen, Joni Nikkanen.

Metabolic immunity contributes to cells' defenses against Toxoplasma gondii.

DOI: https://doi.org/10.1126/science.aea0875