bims-imicid 2026-03-08 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–03–08
33 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Leishmania mediated regulation of host metabolism: impact on host immunity.
Hyodeoxycholic acid attenuates atherosclerosis by antagonizing FXR and modulating the PD-1/mTORC1 signaling axis.
Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP.
Dietary myo-inositol exerts pleiotropic effects on T cell activation, antioxidant defense and fatty acid metabolism to enhance anti-bacterial immunity in tilapia.
PGK1 Lactylation-Driven Self-Reinforcing Loop Orchestrates Glycolytic Reprogramming in FSP1+ Macrophages in Liver Fibrosis.
Telitacicept alleviates IgA nephropathy by targeting PDHA1 lactylation to inhibit B cell metabolic reprogramming and lactate-mediated renal injury.
Marek's disease virus hijacks host nucleotide metabolism via UL23-mediated c-Myc activation.
A novel cell indirect calorimetry method unveils the metabolic fluxomic signatures of human monocyte derived M(LPS+IFN-γ) and M(IL-4) macrophages.
An acetylation-dependent switch underlies host disease tolerance during streptococcal infection.
Tryptophan metabolism reprogramming regulates Th1/Th2 immune balance and inhibits mast cell activation.
The Porcine Colitis Model Recapitulates the Visceral Adipose Metabolic Reprogramming of Human Ulcerative Colitis.
Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation.
Immunophenotypic skewing of B cells toward IgD⁻CD27⁻IgG⁺ subtype and metabolic attenuation in colorectal cancer.
Dihydroartemisinin facilitates intestinal mucosal healing in inflammatory bowel disease by targeting 11βHSD-1 to reprogram macrophage metabolism.
High fat diet promotes asthma by inhibiting the differentiation of regulatory T cells via E3 ubiquitin ligase ITCH.
Pathway thermodynamic analysis postulates change in glutamate metabolism as a key factor in modulating immune responses.
Cross-talk between lipopolysaccharide tolerance and AGEs in the regulation of macrophage inflammation and cholesterol efflux.
Stromal cell-derived itaconate promotes endometriosis via macrophage NRF2 and lysosomal pH modulation.
Dietary ferulic acid boosts the immunity and antioxidant activity of T lymphocytes in Nile tilapia (Oreochromis niloticus) challenged with Aeromonas hydrophila.
Proline/serine-rich coiled-coil 1 alleviates atherosclerosis via remodeling tryptophan metabolism mediated by Akkermansia muciniphila.
Dysregulation of Oral Microbial Eicosapentaenoic Acid Induced by Chronic Restraint Stress Exacerbates Periodontitis via M1 Macrophage Polarization.
A metabolic alarmin from keratinocytes potentiates systemic humoral immunity.
Nanoassembly-mediated immunometabolic reprogramming of CD4+ T cells suppresses β-cell autoimmunity in type 1 diabetes.
Sensory Nerve-Derived CGRP Controls Osteoclastogenesis by Limiting Macrophage Bioenergetics in Bone Repair.
Gomphus floccosus (Schw.) Sing. extract attenuates alcoholic liver disease by suppressing macrophage glycolysis and M1 polarization.
Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1.
Targeting metabolic reprogramming to enhance adoptive immunotherapy: emerging mechanisms and translational perspectives.
Effect of PKM2 on M. tuberculosis Rv1987-induced macrophage M2 polarization.
Dietary carboxymethylcellulose metabolite promotes heart allograft rejection through induction of pro-inflammatory macrophages via lysophosphatidic acid.
The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
Pharmacological stabilization of hypoxia-inducible factor 1-α dampens the interferon response and promotes glycolysis in Aicardi-Goutières syndrome.
α-Ketoglutarate protects against cartilage damage via epigenetically driven metabolic reprogramming in osteoarthritis models.
Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer.

Front Immunol. 2026 ;17 1750304

Leishmania mediated regulation of host metabolism: impact on host immunity.

Somtochukwu S Onwah, Gaurav Gupta, Romaniya Zayats, Amol Singh Banga, Kashish Chottaria, Gurtej Ahluwalia, Jude E Uzonna.

  Leishmaniasis, a vector-borne disease affecting millions worldwide, is caused by protozoan parasite Leishmania. In mammalian hosts, Leishmania survives in the hostile environment of macrophages by exploiting key metabolic pathways to evade their destruction and subvert the host immune responses. Understanding of how Leishmania alters host immune cell metabolism could reveal novel targets for vaccines and therapeutics for effective control of Leishmaniasis. This review focuses on Leishmania-induced modulation of host immune response, with particular focus on reprograming of key metabolic pathways in macrophages, dendritic cells, T cells and other immune cells.

Keywords:  Leishmania; host parasite; immune cells; immune response; metabolism

DOI:  https://doi.org/10.3389/fimmu.2026.1750304
Redox Biol. 2026 Feb 21. pii: S2213-2317(26)00094-7. [Epub ahead of print]92 104096

Hyodeoxycholic acid attenuates atherosclerosis by antagonizing FXR and modulating the PD-1/mTORC1 signaling axis.

Feng Yang, Wenqiong Huang, Zongzhen Meng, Meijun Liu, Aiping Lyu, Claudio Mauro, Kenneth C P Cheung.

  Accumulating evidence suggested that bile acids play a significant role in modulating metabolic and inflammatory diseases. In this study, we investigated the roles of the farnesoid X receptor (FXR) and its endogenous antagonist hyodeoxycholic acid (HDCA) in the development of atherosclerosis (AS). We found that serum HDCA was significantly reduced in patients with AS, and systemic HDCA therapy attenuated plaque burden in vivo. Adoptive transfer of HDCA-treated Foxp3+ Tregs into ApoE-deficient recipients reduced lesion growth, whereas FXR-deficient Tregs failed to confer benefit. HDCA enhanced Treg migration and accumulation within plaques and reprogrammed Treg metabolism by antagonizing FXR and modulating PD-1/mTORC1 signaling. This shift relieved CPT1a-driven fatty acid oxidation bias, increased glycolysis and ATP production, and improved migratory capacity and effector function. We further identify ZNF671 as a transcriptional inhibitor of Treg migration that is mitigated by HDCA-dependent metabolic switching. Collectively, HDCA reduced FXR-mediated metabolic constraints while activating glycolytic and migratory programs in Tregs, thereby improving lipid handling and immune regulation within the plaque microenvironment. These findings position the HDCA-FXR-PD-1/mTORC1 axis as a novel immunometabolic target for AS.

Keywords:  Atherosclerosis; FXR; Glycolysis; Hyodeoxycholic acid; Metabolism; PD-1; Regulatory T cells; Treg migration; mTORC1

DOI:  https://doi.org/10.1016/j.redox.2026.104096
Biomed Pharmacother. 2026 Mar 02. pii: S0753-3322(26)00159-9. [Epub ahead of print]197 119127

Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP.

Yanxing Hu, Huyan Chen, Chenyun Ding, Shengbo Zhang, Qing Chen, Hongying Sun, Qiaozhen Yang.

  Mitochondrial metabolism and innate immune signaling are increasingly recognized as intersecting pathways in chronic inflammatory disease. Here, we identify a metabolically driven mechanism linking the TCA cycle imbalance to mucosal inflammation in oral lichen planus (OLP). Multi-omics analysis revealed that fumarate hydratase (FH) is upregulated in OLP tissues and cells, leading to significant fumarate depletion. This metabolic shift induces mitochondrial dysfunction, characterized by enhanced oxidative phosphorylation, proton leak, and TFAM downregulation. These changes destabilize the mitochondrial genome, promote mtDNA leakage into the cytosol, and activate the cGAS-STING pathway, resulting in TBK1-IRF3- NF-κB -driven inflammatory responses. Genetic knockdown of FH or pharmacological supplementation with monomethyl fumarate (MMF) restored mitochondrial homeostasis, prevented mtDNA release, and attenuated immune activation. Furthermore, depletion of mtDNA using 2',3'-dideoxycytidine (ddC) validated the essential role of mtDNA in sustaining cGAS-STING dependent inflammation. Co-treatment with fumarate further suppressed cytosolic mtDNA and enhanced repression of innate signaling. These findings uncover a functional FH-fumarate-mtDNA-cGAS-STING axis in OLP and reveal fumarate as a key metabolic modulator of mitochondrial immune surveillance. Our work provides conceptual and therapeutic insight into the role of mitochondrial metabolism in non-infectious mucosal inflammation.

Keywords:  Citric acid cycle; DNA; Fumarate hydratase; Inflammation; Lichen planus; Mitochondrial; Mitochondrial diseases; Oral

DOI:  https://doi.org/10.1016/j.biopha.2026.119127
Fish Shellfish Immunol. 2026 Mar 03. pii: S1050-4648(26)00155-5. [Epub ahead of print] 111251

Dietary myo-inositol exerts pleiotropic effects on T cell activation, antioxidant defense and fatty acid metabolism to enhance anti-bacterial immunity in tilapia.

Zhichao Fang, Yuying Zheng, Minghui Zhang, Jiaying Xie, Chenxin Shen, Yating Zhu, Qiqi Jiang, Yishan Lu, Xiumei Wei, Jialong Yang.

  Bacterial diseases cause major economic losses in aquaculture, underscoring the need for feed additives that enhance fish immunity. Myo-inositol (MI), an essential nutrient for fish growth, possesses antioxidant and lipid-metabolism modulating properties. However, the role of MI in regulating T cell function remains unclear. In this study, Nile tilapia (Oreochromis niloticus) individuals were fed diets containing 850 or 1700 mg/kg MI to evaluate its effects on T cell immunity. The results demonstrated that dietary MI at 850 mg/kg significantly enhanced host anti-bacterial immunity in Nile tilapia by systematically improving T cell function. Specifically, during Edwardsiella piscicida infection, dietary MI increased the absolute number of T cells in Nile tilapia, and promoted their activation, proliferation, and cytokine production while reducing apoptosis. Mechanistically, MI elevated antioxidant enzymes expression to reduce intracellular reactive oxygen species (ROS) in T cells and drove fatty acid metabolic reprogramming. These coordinated enhancements collectively accelerated pathogen clearance and significantly improved host survival upon E. piscicida infection. Therefore, these findings reveal the pivotal role of dietary MI in promoting T cell mediated anti-bacterial immunity in Nile tilapia, and establish a foundation for using nutritional immunomodulation to improve health and disease resistance in farmed fish.

Keywords:  Adaptive immunity; Feed additive; Myo-inositol; Nile tilapia; T cells

DOI:  https://doi.org/10.1016/j.fsi.2026.111251
Research (Wash D C). 2026 ;9 1177

PGK1 Lactylation-Driven Self-Reinforcing Loop Orchestrates Glycolytic Reprogramming in FSP1+ Macrophages in Liver Fibrosis.

Min Tang, Mengxue Sun, Hui Zhang, Jinwei Chen, Yuanben Wang, Yan Jiang, Linhua Qin, Hao Wang, Fengshang Zhu, Changqing Yang.

Liver fibrosis shows limited treatment efficacy, driven by metabolic reprogramming and epigenetics, while the role of lactate-mediated lactylation in hepatic microenvironment remains unclear. Here, through integrative analysis of public databases and human cirrhotic liver tissues, we identified a pathogenic FSP1+ (fibroblast specific protein 1) macrophage subset as a key therapeutic target. We uncovered a novel FSP1-glycolysis-lactylation axis that drives fibrotic progression through metabolic-immune crosstalk. Expanded FSP1+ macrophage infiltration was observed in human cirrhotic liver tissues and myeloid-specific Fsp1 knockout markedly attenuates inflammation and fibrosis. Mechanistic investigations reveal that FSP1 physically interacts with pyruvate kinase M2 (PKM2) in macrophages, inhibiting its ubiquitin-proteasome degradation to stabilize the enzyme. This FSP1-PKM2 interaction enhances glycolytic flux and lactate production, which in turn promotes KAT2B-dependent lactylation of phosphoglycerate kinase 1 (PGK1) at lysine 353 (K353). The posttranslational modification creates a positive feedback loop by concurrently activating PGK1 and pyruvate dehydrogenase kinase 1, which blocks mitochondrial pyruvate metabolism, thereby amplifying glycolysis and PGK1 lactylation. Notably, we developed a cell-penetrating peptide targeting PGK1-K353 lactylation that effectively attenuates the progression of liver fibrosis. Our findings establish lactate-mediated lactylation of PGK1 as a critical node in fibrotic metabolism and reveal a previously unrecognized FSP1-glycolysis axis that sustains the pro-fibrotic microenvironment. Targeting PGK1-K353 lactylation represents a promising therapeutic strategy for chronic liver diseases.

DOI: https://doi.org/10.34133/research.1177
Eur J Med Res. 2026 Mar 03.

Telitacicept alleviates IgA nephropathy by targeting PDHA1 lactylation to inhibit B cell metabolic reprogramming and lactate-mediated renal injury.

Lu Xu, Jing-Jing Zhang, Wen-Ting Xu.

   BACKGROUND: Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis, is driven by galactose-deficient IgA1 (Gd-IgA1) production from autoreactive B cells. Current therapies inadequately target core pathogenic mechanisms. Telitacicept (a recombinant fusion protein inhibiting BLyS/APRIL) shows clinical promise, but its molecular mechanisms in modulating B cell metabolism and lactylation-mediated pathways remain unclear.
METHODS: IgAN patients and healthy controls were enrolled; B cells were isolated for metabolic flux analysis (OCR/ECAR), lactylation assays (IP/WB/LC-MS/MS), and PDH activity tests. Patients received Telitacicept (160 mg/week) or placebo. Murine IgAN models were established and Telitacicept (1 or 5 mg/kg) was administered. Co-cultures of IgAN patient B cells and human mesangial cells (HMCs) assessed lactate's role in renal injury. Site-directed mutagenesis (PDHA1-K336R) and siRNA knockdown (SIRT3/PDHA1) validated functional mechanisms.
RESULTS: IgAN patient B cells exhibited hyperlactylation of PDHA1 at lysine 336 (K336la), which suppressed pyruvate dehydrogenase (PDH) activity, elevated lactate production, and drove metabolic reprogramming toward glycolysis. This promoted IgA1 secretion and renal dysfunction. Telitacicept, a dual BAFF/APRIL inhibitor, significantly reduced PDHA1-K336la levels, restored PDH activity and OXPHOS, and suppressed lactate/IgA1 production. Mechanistically, Telitacicept upregulated the mitochondrial deacylase SIRT3, which directly bound PDHA1. SIRT3 knockdown abolished Telitacicept's effects. Critically, lactate from IgAN B cells triggered HMC inflammation, fibrosis, and apoptosis, effects reversed by Telitacicept but restored by exogenous lactate. In vivo, Telitacicept dose-dependently attenuated renal injury, fibrosis, and mortality in IgAN rats, while PDHA1 depletion exacerbated B cell metabolic dysfunction and renal damage.
CONCLUSION: Telitacicept confers renoprotection by inducing SIRT3-dependent PDHA1 delactylation to reverse metabolic reprogramming in IgAN. Targeting the PDHA1 lactylation-SIRT3 axis represents a novel therapeutic strategy for IgAN and related autoimmune disorders.

Keywords:  B cell; IgAN; Lactylation; PDHA1; Telitacicept

DOI:  https://doi.org/10.1186/s40001-026-04175-5
Vet Microbiol. 2026 Feb 27. pii: S0378-1135(26)00089-1. [Epub ahead of print]315 110958

Marek's disease virus hijacks host nucleotide metabolism via UL23-mediated c-Myc activation.

Qingsen Wang, Hongxia Shao, Kun Qian, Jianqiang Ye, Aijian Qin.

  Marek's disease virus (MDV), an avian α-herpesvirus, heavily relies on host metabolic reprogramming during infection. However, the precise regulatory mechanisms governing MDV-induced nucleotide metabolic remodeling remain poorly characterized. The study explores how MDV induces changes in nucleotide metabolism during infection. Our results demonstrated that MDV infection significantly upregulates nucleotide synthesis metabolism, particularly purine de novo synthesis in chicken embryonic fibroblast (CEF) cells. Metabolomic analysis identified 19 upregulated metabolites related to nucleotide metabolism post-infection. Functional assays revealed that adenine and guanine supplementation enhanced MDV replication, while the purine inhibitor 6-mercaptopurine (6MP) suppressed it. The transcription factor c-Myc was found to activate purine synthesis enzymes during MDV infection, with c-Myc knocked down reducing viral replication and overexpression increasing it. Additionally, MDV thymidine kinase UL23 was identified as crucial in reprogramming nucleotide metabolism, promoting c-Myc-mediated nucleotide anabolism and viral replication. This research highlights the potential of targeting nucleotide metabolism as an antiviral strategy.

Keywords:  C-Myc; MDV; Nucleotide metabolism; Thymidine kinase UL23; Virus-host interaction

DOI:  https://doi.org/10.1016/j.vetmic.2026.110958
Am J Physiol Cell Physiol. 2026 Mar 02.

A novel cell indirect calorimetry method unveils the metabolic fluxomic signatures of human monocyte derived M(LPS+IFN-γ) and M(IL-4) macrophages.

Gloria Cinquegrani, Valentina Spigoni, Federica Fantuzzi, Anna D'Antuono, Francesca Bagnaresi, Elisabetta Giordano, Alberto Burato, Alessandra Dei Cas, Riccardo C Bonadonna.

  Macrophages (MΦ) display distinct immunometabolic phenotypes upon polarization. While transcriptomic analyses have suggested divergent metabolic programs in human M(LPS+IFN-γ) and M(IL-4) MΦ, a comprehensive assessment of their metabolic fluxes is lacking. Aim of this study is to 1. develop and validate a novel indirect microcalorimetry method for quantifying cellular metabolic fluxes, and 2. exploit it to characterize fluxomic signatures of polarized human monocyte-derived macrophages. Methods. MΦ from healthy donors were differentiated into M0, M(LPS+IFN-γ), and M(IL-4) phenotypes and studied in four defined media: substrate-free, glucose, glycyl-glutamine, and glucose + glycyl-glutamine. A steady-state fluxomic model was constructed by integrating four independent measures - oxygen consumption and proton production (Seahorse XFp), lactate and ammonia release (microfluorimetry) - into stoichiometric equations of metabolism (SAAM II software). Results. Fluxes revealed that macrophages rely on glucose to sustain glycolysis, contributing ~30% of citrate synthase flux, and predominantly on lipids for net citrate synthesis (first step of TCA cycle). Upon polarization, M(LPS+IFN-γ) macrophages showed increased anaerobic glycolysis versus M0 and M(IL-4), with similar TCA fluxes to M0. In contrast, M(IL-4) macrophages exhibited higher TCA and malic enzyme fluxes, especially with glucose and glycyl-glutamine, and a trend toward enhanced lipid oxidation. Conclusions. This novel method enables precise quantification of bioenergetic fluxes. In human MΦ, it reveals that M(LPS+IFN-γ) and M(IL-4) subsets exhibit distinct metabolic phenotypes, consistent with their immunological roles. These results resolve transcriptomic-metabolic discrepancies and provide a robust framework for assessing immunometabolism in primary human cells.

Keywords:  cell metabolism; fluxomics; human macrophages; immunometabolism; indirect calorimetry

DOI:  https://doi.org/10.1152/ajpcell.00635.2025
Sci Rep. 2026 Mar 04.

An acetylation-dependent switch underlies host disease tolerance during streptococcal infection.

Sumit Kumar Paudel, Sowmya Gannavaram, Michael G Caparon, Wei Xu.

  Building on our finding that Streptococcus pyogenes pyruvate dehydrogenase (PDH) suppresses host disease tolerance (DT) via short-chain fatty acid (SCFA)-mediated modulation of host acetyl-CoA and IL-10 levels, we characterize the global transcriptomic and epigenetic mechanisms underlying this immunometabolic manipulation. Combining new histological and ultrastructural analyses with an in-depth re-analysis of single-cell and bulk RNA-seq datasets to more comprehensively characterize the DT response, we show that PDH deficiency is associated with broad immunologic rewiring, characterized by intracellular bacterial containment within phagocytes, expansion of pro-resolving myeloid cells, and altered cell-cell communication. Metabolic analysis of ΔPdh-infected tissues revealed a shift away from acetyl-CoA metabolism towards glycolysis and the coordinated activation of a multi-faceted DT program, encompassing hypoxia signaling, iron handling, and the NRF2-mediated antioxidant response. Crucially, a focused re-analysis of existing transcriptome datasets from Histone Deacetylase (HDAC)-inhibited macrophages suggested that Trichostatin A (TSA) abrogates the protective transcriptome in ΔPdh infection, indicating that acetylation-dependent repression functions as a key regulator of the host DT response. By integrating new experimental data with advanced computational analyses, our work reveals a bacterial strategy of metabolic-epigenetic crosstalk, suggesting acetylation as a critical control point for mitigating infection-associated tissue damage.

Keywords:   Streptococcus pyogenes ; Acetyl-CoA; Disease tolerance; Histone deacetylases; Immunometabolism; Pyruvate dehydrogenase; Short-chain fatty acids

DOI:  https://doi.org/10.1038/s41598-026-42565-1
Amino Acids. 2026 Feb 28.

Tryptophan metabolism reprogramming regulates Th1/Th2 immune balance and inhibits mast cell activation.

Dongsheng Huang, Dongxuan Huang, Lianhui Su, Chaowen He, Xiaopeng Zhang, Jianfeng Peng, Lumei Fan, Yahui Cao, Licheng Chen, Huifen Tong.

  Asthma is characterized by chronic airway inflammation and an imbalanced Th1/Th2 response. Although tryptophan metabolism has been implicated in immune regulation, its direct influence on Th1/Th2 differentiation and mast-cell activation remains insufficiently understood. CD4⁺ T cells were cultured under graded tryptophan concentrations (25, 50, 75 and 100 µM) to examine how tryptophan availability alters Th1/Th2 polarization. Flow cytometry, western blotting and RT-qPCR were used to evaluate phenotype markers and related metabolic pathways. In parallel, IgE-activated LAD2 mast cells were exposed to different tryptophan concentrations with or without the IDO1/TDO inhibitor HY-149,411, followed by immunofluorescence staining and ELISA to assess tryptase expression and histamine release. High tryptophan availability markedly enhanced Th1 differentiation, with increased Notch1/Jagged1 levels and elevated IL-2 and IFN-γ, while IL-4 expression was reduced. RT-qPCR showed upregulated T-bet and mTOR and downregulated GATA3, together with increased IDO1 and TDO mRNA levels in CD4⁺ T cells, indicating Th1-biased immunometabolic activation. In mast cells, tryptophan treatment suppressed tryptase expression and lowered histamine secretion, demonstrating reduced activation. HY-149,411 attenuated tryptophan-dependent differences in histamine release, suggesting that tryptophan catabolism contributes to mast-cell regulation. Tryptophan availability reprograms immune metabolism to promote Th1 differentiation and suppress mast-cell activation, offering a dual mechanism through which tryptophan may help correct Th1/Th2 imbalance and ameliorate allergic inflammation. These findings highlight tryptophan metabolism as a potential immunometabolic target for asthma therapy.

Keywords:  Asthma; Mast cells; Th1/Th2; Tryptophan metabolism reprogramming

DOI:  https://doi.org/10.1007/s00726-026-03508-2
FASEB J. 2026 Mar 15. 40(5): e71612

The Porcine Colitis Model Recapitulates the Visceral Adipose Metabolic Reprogramming of Human Ulcerative Colitis.

Yu Peng, Qipin Lv, Xu Han, Chenyu Zhao, Haocen Luo, Jiayu Tang, Yifan Jiang, Tianwen Wu, Shulin Yang, Yanfang Wang, Cong Tao.

  Adipose tissue dysfunction is integral to the pathophysiology of ulcerative colitis (UC), yet the conservation of adipose immunometabolic responses across species remains unclear. Here, we employed a comparative transcriptomic approach to analyze adipose remodeling in dextran sulfate sodium (DSS)-induced porcine and murine colitis models alongside human UC datasets. We report that intestinal inflammation induced widespread adipocyte atrophy and triggered a convergent inflammatory response across physiologically distinct visceral and subcutaneous depots. Mechanistically, this remodeling was defined by a systemic suppression of fatty acid synthesis pathways. Importantly, the expression levels of key lipogenic enzymes were negatively correlated with the severity of colonic inflammation, indicating that intestinal injury directly dictates the magnitude of lipogenesis inhibition. Cross-species alignment revealed a critical distinction: while murine visceral fat exhibited fatty acid metabolism activation, the porcine response mirrored the fatty acid metabolism downregulation observed in human patients. These results identify a fundamental species-specific difference and establish the porcine model as a translational tool, which faithfully replicates the atrophy and fatty acid metabolism suppression characteristic of human inflammatory bowel disease.

Keywords:  adipose tissue; colitis; fatty acid synthesis; immunometabolism; pig

DOI:  https://doi.org/10.1096/fj.202504741R
Cell. 2026 Feb 27. pii: S0092-8674(26)00110-8. [Epub ahead of print]

Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation.

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

  Glycolysis is a central metabolic pathway that converts glucose into pyruvate. Although pyruvate has been well documented to be a key and terminal metabolite of glycolysis with both energetic and biosynthetic roles, its non-metabolic functions remain unexplored. Here, we report a pyruvate-mediated protein post-translational modification (PTM), protein pyruvylation. We reveal that high glucose-upregulated glycolysis promotes signal transducer and activator of transcription 1 (STAT1) pyruvylation at Lys201 (K201), which blocks STAT1 and signal transducer and activator of transcription 2 (STAT2) interaction, thus suppressing type I interferon (IFN-I) signaling and antiviral immune activity. Consequently, STAT1-K201R knockin mice exhibit enhanced IFN-I antiviral immunity. Importantly, high glucose promotes STAT1 pyruvylation and attenuates immune response to either virus infection or IFN-I treatment in humans. This study identifies the protein pyruvylation modification, reveals a non-metabolic function of the metabolite pyruvate, and provides insights into how high glucose impairs IFN-I antiviral immunity through pyruvate, offering strategies to improve IFN-I immune activity for both preventing and treating viral infections.

Keywords:  STAT1; antiviral immunity; innate immunity; interferon; pyruvate; pyruvylation

DOI:  https://doi.org/10.1016/j.cell.2026.01.023
Sci Rep. 2026 Feb 28.

Immunophenotypic skewing of B cells toward IgD⁻CD27⁻IgG⁺ subtype and metabolic attenuation in colorectal cancer.

Eleonora Martinis, Silvia Tonon, Viviana Valeri, Alessandra Colamatteo, Carolina Ricci, Caterina Trevisan, Eleonora Capezzali, Matteo Pivetta, Serena Battista, Marta Mozzon, Alessandro Uzzau, Giuseppe Matarese, Andrea Cossarizza, Barbara Frossi, Carlo Pucillo.

Colorectal cancer (CRC) is the third most prevalent cancer and understanding its tumor microenvironment (TME) is crucial for the development of innovative therapies. Despite the presence of B cells in CRC infiltrate, their clinical significance is poorly understood. In this study, we observed an enrichment of double-negative (DN) B cells, a subset lacking surface IgD and CD27, in CRC biopsies. Typically underrepresented in physiological conditions, DN B cells expand in certain chronic infections, autoimmune diseases, and cancers. Within this subpopulation, low CD21 expression-a phenotypic hallmark of exhaustion-was observed. Consistently, DN B cells displayed low metabolic activity. Accordingly, total B cells infiltrating CRC tissues showed a diminished capacity to differentiate into antibody-secreting cells (ASCs) upon stimulation. In the murine setting, CRC organoids decreased the frequency of ASCs in co-cultured B cells and induced metabolic dysfunction, marked by altered glucose and fatty acid uptake and dysregulated expression of key metabolic proteins. Moreover, B cells displayed reduced glycolysis and mitochondrial respiration, despite increased mitochondrial dependence. This study provides evidence for DN B cell accumulation within CRC infiltrate and metabolic reprogramming of B cells, suggesting that targeting B cell metabolism may represent a promising strategy to potentiate anti-tumor immune responses.

DOI: https://doi.org/10.1038/s41598-026-41446-x
Phytomedicine. 2026 Jan 04. pii: S0944-7113(26)00011-5. [Epub ahead of print]153 157774

Dihydroartemisinin facilitates intestinal mucosal healing in inflammatory bowel disease by targeting 11βHSD-1 to reprogram macrophage metabolism.

Xinke Du, Li Liu, Yang Zhang, Bingqi Zhang, Lina Yang, Ming Chu, Liu Zhou, Yuchen Li, Jianshi Zhu, Keshan Dong, Xiaohui Su, Qing Yang, Ying Chen, Xiaoxi Kan, Jiayin Han, Xiaoxin Zhu, Jiang Xu, Qi Li.

   BACKGROUND: Mucosal healing is a major clinical challenge and a critical prognostic factor in inflammatory bowel disease (IBD). Achieving mucosal healing requires the functional reprogramming of macrophages to facilitate intestinal stem cells (ISCs)-mediated repair, a process impaired in IBD due to dysregulated macrophage activity. Dihydroartemisinin (DHA), a derivative of artemisinin, shows promise in treating IBD, but its therapeutic potential remains underexplored due to its common classification as an anti-inflammatory agent.
PURPOSE: This study aims to evaluate the efficacy of DHA in promoting mucosal healing in IBD and to elucidate the underlying mechanisms of macrophage reprogramming, thereby expanding the therapeutic potential of DHA beyond its conventional anti-inflammatory actions.
METHODS: The therapeutic efficacy of DHA and its underlying mechanisms were systematically investigated using a DSS-induced colitis mouse model, with a focus on the repair phase. Mucosal healing was assessed through comprehensive histopathological and functional evaluations. DHA's role in macrophage metabolic reprogramming was explored through transcriptomic and metabolic analyses, and its effect on epithelial regeneration was examined using macrophage-organoid co-cultures. A molecular target discovery approach, integrating Mendelian randomization, molecular docking, and direct binding assays, identified 11βHSD-1 as a molecular target of DHA, which was subsequently confirmed through genetic and pharmacological loss-of-function studies in macrophages.
RESULTS: Our findings demonstrated that DHA significantly promoted mucosal healing in a DSS-induced colitis model during the repair phase, as evidenced by reduced disease activity scores, increased colon length, and decreased histological damage. DHA also facilitated the recovery of gut functions, including barrier integrity, absorption, secretion, and motility. Macrophages were found to be essential for therapeutic effects of DHA. Specifically, DHA reprogrammed macrophage metabolism from glycolysis to oxidative phosphorylation, inducing a pro-repair phenotype characterized by enhanced secretion of Relmα and Wnt3a, which promoted the proliferation and differentiation of intestinal organoids. Mechanistically, we found that DHA directly bound to and activated 11βHSD-1, a key metabolic regulator in macrophages. This activation triggered STAT3/6 signaling, establishing a positive feedback loop that reinforced metabolic remodeling and facilitated the release of repair-promoting factors.
CONCLUSION: Our findings demonstrate that DHA promotes intestinal mucosal healing by reprogramming macrophage metabolism, thereby enhancing ISC proliferation and differentiation. These results provide new insights into the potential of DHA in reshaping immune homeostasis, offering promising therapeutic strategies for IBD.

Keywords:  11β Hydroxysteroid dehydrogenase 1; Dihydroartemisinin; Inflammatory bowel disease; Macrophages metabolism; Mucosal healing

DOI:  https://doi.org/10.1016/j.phymed.2026.157774
Mol Immunol. 2026 Mar 05. pii: S0161-5890(26)00046-5. [Epub ahead of print]192 32-44

High fat diet promotes asthma by inhibiting the differentiation of regulatory T cells via E3 ubiquitin ligase ITCH.

Lin Tong, Lin Su, Jing He, Yi Chen, Zhimin Chen, Lanfang Tang, Xiling Wu.

  Obesity, a rising global health issue, has been linked to the exacerbation of asthma, increasing both the risk of onset and disease severity. High-fat diet (HFD) has been shown to influence immune responses and worsen asthma in murine models, although the exact mechanisms remain unclear. In our study, we found that HFD significantly reduced the population of regulatory T cells (Tregs) in the lungs and led to increased eosinophilic inflammation in asthma. HFD was linked to alterations in lipid metabolism, particularly through the activation of the lipogenic enzyme acetyl-CoA carboxylase (ACC1) and inhibition of fatty acid oxidation. Additionally, treatment with Etomoxir, a CPT-1a inhibitor, diminished Treg proportions and Foxp3 expression. We also revealed that the E3 ubiquitin ligase ITCH, which regulates Treg function, was downregulated at the protein level under HFD conditions, despite unchanged mRNA levels. Overall, our research findings highlight the impact of high-fat diets on Treg function and immune regulation, providing insights for potential therapeutic strategies targeting lipid metabolism in inflammatory diseases like asthma.

Keywords:  Asthma; High fat diet; ITCH; Treg

DOI:  https://doi.org/10.1016/j.molimm.2026.02.013
Immunometabolism (Cobham). 2026 Jan;8(1): e00077

Pathway thermodynamic analysis postulates change in glutamate metabolism as a key factor in modulating immune responses.

Sunayana Malla, Rajib Saha.

   Background: Temperature, as seen during fever, plays a pivotal role in modulating immune responses and maintaining cellular homeostasis. Shifts in temperature influence the thermodynamic feasibility of metabolic reactions, with Gibbs free energy (ΔG) serving as a key indicator of the spontaneity of reactions under specific conditions. By altering ΔG in response to temperature changes across various metabolite concentrations and cell types, we can gain insights into the thermodynamic properties of metabolic pathways and identify critical factors involved in metabolism and immune function. Using Max-min Driving Force (MDF) analysis, we can assess changes in ΔG by varying temperature and metabolite concentrations, allowing for a detailed examination of thermodynamic feasibility at both the pathway and individual reaction levels.
Method: Minimum driving force analysis was conducted to estimate the thermodynamic feasibility of metabolic pathways, including glycolysis, gluconeogenesis, oxidative phosphorylation, the pentose phosphate pathway, the tricarboxylic acid cycle, arginine and proline metabolism, amino sugar and nucleotide sugar metabolism (collectively referred to as amino sugar metabolism), leukotriene metabolism, and other amino acid pathways. The analysis was performed across a temperature range of 310.15 to 314.15 K. In addition, the ΔG for each reaction was calculated using standard Gibbs free energy values obtained from the equilibrator.
Results: In this study, MDF analysis is applied to measure the changes in the driving force of pathways and the ΔG of each reaction at normal human core temperature (310.15 K) and elevated temperatures (up to 314.15 K). Additionally, we explore how shifts in the thermodynamic feasibility of reactions under immune activation, compared with normal physiological conditions, highlight key metabolic intermediates, such as fructose-1,6-bisphosphate, glucose-6-phosphate, and several steps in glutamate utilization, as important regulators of metabolic processes and immune responses.
Conclusion: In conclusion, this study demonstrates that MDF-based thermodynamic analysis effectively captures temperature-dependent shifts in metabolic pathway feasibility and highlights glutamate metabolism as a key regulator of immune function. These findings underscore the utility of thermodynamic frameworks in advancing system-level understanding of human metabolism and immune regulation.

Keywords:  driving force; glutamate fate; immune activation; temperature; thermodynamic feasibility

DOI:  https://doi.org/10.1097/IN9.0000000000000077
Front Immunol. 2026 ;17 1669028

Cross-talk between lipopolysaccharide tolerance and AGEs in the regulation of macrophage inflammation and cholesterol efflux.

Danielle Ribeiro Santos, Monique de Fatima Mello Santana, Eduarda Palanca, Milena Gomes Vancini, Sayonara Ivana Santos de Assis, Aritania Sousa Santos, Denise Frediani Barbeiro, Suely Kunimi Kubo Ariga, Maria Lucia Correa-Giannella, Francisco Garcia Soriano, Marisa Passarelli.

   Introduction: Immune cell infiltration with high expression of receptors for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) promotes vascular inflammation and accelerates atherosclerosis. Advanced glycated albumin (AGE-albumin) primes macrophages for heightened inflammatory responses to lipopolysaccharide (LPS). Here, we investigated whether LPS-induced tolerance modulates AGE-driven inflammatory priming and cholesterol efflux in macrophages.
Methods: Cholesterol-enriched bone marrow-derived macrophages (BMDMs) and RAW264.7 macrophages were subjected to LPS tolerance induction, treated with control (C)- or AGE-albumin, and rechallenged with LPS. In parallel, LPS tolerance was induced in vivo by repeated low-dose LPS injections, followed by BMDM differentiation, cholesterol loading, albumin treatments, and secondary LPS stimulation. Tumor necrosis factor (TNF) secretion was assessed by ELISA, gene expression by RT-qPCR, and HDL-mediated ¹4C-cholesterol efflux using conditioned media or direct HDL incubation.
Results: In BMDMs, LPS tolerance reduced TNF secretion following C-albumin treatment but not AGE-albumin. In RAW264.7 macrophages, TNF secretion was reduced by 53% and 77.6% after C- and AGE-albumin treatment, respectively. BMDMs from LPS-tolerant mice exhibited reduced TNF secretion following both albumin treatments. Gene expression analysis revealed that AGE-albumin selectively increased Ager and Tlr4 expression in tolerant BMDMs, whereas C-albumin was associated with broad suppression of pro-inflammatory genes. Conditioned media from tolerant BMDMs markedly enhanced HDL-mediated cholesterol efflux in naïve macrophages, while direct exposure of tolerant BMDMs to AGE-albumin reduced HDL-mediated efflux by 40%.
Discussion: These findings demonstrate that LPS tolerance promotes an atheroprotective macrophage phenotype characterized by attenuated inflammatory signaling and enhanced cholesterol efflux. However, this protective immunometabolic program is selectively disrupted by AGE exposure, highlighting a critical interface through which chronic metabolic stress may override innate immune tolerance and contribute to atherosclerotic progression.

Keywords:  advanced glycation; atherosclerosis; inflammation; lipopolysaccharide tolerance; macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1669028
Redox Biol. 2026 Feb 27. pii: S2213-2317(26)00099-6. [Epub ahead of print]92 104101

Stromal cell-derived itaconate promotes endometriosis via macrophage NRF2 and lysosomal pH modulation.

Zhaoyang Zhong, Shuang Wang, Qianhui Ren, Xue Jiao, Le Xu, Xiaoyu Dong, Na Li, Hongwei Guan, Ran Chu, Ming Yuan, Jincheng Liu, Yanbo Du, Keke Wei, Lei Yan, Guoyun Wang.

  Endometriosis (EM) is driven by immune dysregulation and macrophage dysfunction, yet the underlying mechanisms remain unclear. Here, metabolomic profiling revealed excessive itaconate accumulation in EM lesions, primarily due to elevated cis-aconitate decarboxylase 1 (ACOD1) expression in ectopic stromal cells (ESCs). ESC-derived itaconate was internalized by peritoneal macrophages, where it suppressed pro-inflammatory activity and phagocytosis, thereby facilitating ESC survival and dissemination. Mechanistically, itaconate exerted dual regulatory effects on macrophages: it activated NRF2 signaling to repress the transcription of pro-inflammatory genes, and it enhanced lysosomal acidification, thereby reducing lysosomal calcium release, which in turn inhibited p38-MAPK activation and further attenuated pro-inflammatory gene expression. In vivo, ACOD1 inhibition restored macrophage function and reduced lesion burden, while exogenous 4-octyl itaconate aggravated disease progression. These findings define a novel "ESC-ACOD1-itaconate-macrophage" axis that mediates immunosuppression in EM and identify ACOD1 as potential therapeutic targets.

Keywords:  ACOD1; Endometriosis; Itaconate; Lysosome; Macrophage

DOI:  https://doi.org/10.1016/j.redox.2026.104101
Fish Shellfish Immunol. 2026 Mar 03. pii: S1050-4648(26)00154-3. [Epub ahead of print] 111250

Dietary ferulic acid boosts the immunity and antioxidant activity of T lymphocytes in Nile tilapia (Oreochromis niloticus) challenged with Aeromonas hydrophila.

Jiansong Zhang, Yuqing Yang, Jingwen Chang, Jingfeng Ding, Shiqi Tang, Yishan Lu, Xiumei Wei, Jialong Yang.

  Functional feed additives are increasingly incorporated into aquafeeds to improve growth performance, metabolic status, and overall health of farmed fish. However, their regulatory effects on adaptive immunity, particularly T cell-mediated immune responses, remain poorly characterized. In this study, we evaluated the effects of dietary ferulic acid supplementation on T cell immunity and antioxidant capacity in Nile tilapia (Oreochromis niloticus). Fish were fed diets supplemented with 0, 200, or 400 mg/kg ferulic acid and subsequently challenged with Aeromonas hydrophila. Compared with the basal diet group, supplementation with 200 mg/kg ferulic acid significantly enhanced T cell proliferation and survival during infection, accompanied by increased proportions and absolute numbers of CD4-1+ T cells. In parallel, ferulic acid supplementation elevated expression of key T cell functional molecules, including interferon-γ (IFN-γ), perforin A, tumor necrosis factor α (TNF-α), and Fas ligand (Fas-L), together with reduced bacterial burden, alleviated hepatic inflammatory infiltration and lesions, and improved survival. In addition, ferulic acid markedly enhanced antioxidant capacity in lymphocytes, as evidenced by increased activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), elevated total antioxidant capacity (T-AOC), and reduced malondialdehyde (MDA) levels. Consistently, intracellular reactive oxygen species (ROS) accumulation in T cells and the expression of pro-inflammatory genes were significantly reduced following 200 mg/kg ferulic acid supplementation. Taken together, we demonstrate that dietary ferulic acid supplementation functionally enhances T cell-mediated immune responses and antioxidant capacity in tilapia during bacterial infection, with 200 mg/kg identified as the optimal concentration, supporting its potential application as a functional feed additive in aquaculture.

Keywords:  Adaptive immunity; Anti-oxidation; Ferulic acid; Nile tilapia; T cell immunity

DOI:  https://doi.org/10.1016/j.fsi.2026.111250
Exp Mol Med. 2026 Mar 06.

Proline/serine-rich coiled-coil 1 alleviates atherosclerosis via remodeling tryptophan metabolism mediated by Akkermansia muciniphila.

Qiao Wu, Kexin Hu, Qianqian Wang, Tiantian Luo, Lu Hu, Jichen Liu, Danfeng Zou, Jing Hu, Zhigang Guo.

Genome-wide association studies have implicated proline/serine-rich coiled-coil 1 (PSRC1) in coronary artery disease (CAD) pathogenesis. Our previous studies demonstrated that Psrc1 deficiency accelerates atherosclerosis via gut microbial dysbiosis, characterized by a substantial depletion of Akkermansia muciniphila. Recent studies implicate microbiome-dependent tryptophan metabolism as a novel checkpoint in atherosclerosis, with specific microbial taxa regulating metabolite-driven immune responses. The mechanism by which Psrc1 modulates atherosclerosis through A. muciniphila and its regulation of tryptophan metabolism remains unclear. Here Psrc1 knockout mice exhibited reduced colonic mucin content, altered tryptophan metabolic enzyme expression and diminished levels of Trp metabolites including indoleacetic acid (IAA), with concomitant suppression of Ahr signaling in macrophages. In vivo analysis revealed that Psrc1 knockout diminishes Ahr through A. muciniphila-dependent IAA depletion. In vitro experiments further uncovered that Psrc1 stabilizes Ahr protein via ubiquitin carboxyl terminal hydrolase L3 (Uchl3)-mediated deubiquitylation. In addition, we identified plasma IAA levels positively correlating with decreased PSRC1 expression in peripheral blood mononuclear cells from patients with CAD. Furthermore, therapeutic restoration of a live A. muciniphila-IAA axis through oral supplementation reversed atherosclerosis in Psrc1 knockout mice. Notably, oral IAA supplementation substantially ameliorated atherosclerosis in Psrc1 knockout mice by suppressing plaque macrophage apoptosis. Crucially, co-administration of the Ahr antagonist CH-223191 abolished these benefits, confirming Ahr dependence. Our findings position PSRC1 as a critical regulator of the A. muciniphila-IAA-Ahr axis and nominate microbiome-targeted Ahr activation as a precision therapeutic strategy for patients with CAD with PSRC1 loss-of-function variants.

DOI: https://doi.org/10.1038/s12276-026-01668-5
Adv Sci (Weinh). 2026 Mar 05. e21346

Dysregulation of Oral Microbial Eicosapentaenoic Acid Induced by Chronic Restraint Stress Exacerbates Periodontitis via M1 Macrophage Polarization.

Shihong Luo, Fangzhi Lou, Peiran Yang, Yu Zhang, Li Yan, Yunmei Dong, Bing Yang, Haiyang Wang, Yiyun Liu, Juncai Pu, Richard D Cannon, Peng Xie, Ping Ji, Xin Jin.

  The intricate interplay between chronic psychological stress and periodontitis, mediated by oral microbiota and macrophage polarization, remains largely enigmatic. Here, we demonstrate that chronic restraint stress (CRS) exacerbates periodontitis by inducing oral microbial dysbiosis and a consequential shift in host metabolism. Clinical observations reveal a significant correlation between depressive symptoms and the severity of periodontitis, which is underpinned by a distinct oral microbiome. Crucially, fecal microbiota transplantation from CRS-exposed mice into germ-free mice was sufficient to transmit the heightened periodontitis phenotype, establishing a causal role for the stress-altered microbiota. Metabolomic profiling identified a depletion of eicosapentaenoic acid (EPA) in stressed, ligature-induced periodontitis mice. Mechanistically, supplementation with EPA ameliorates periodontitis by suppressing the NF-κB signaling pathway, thereby inhibiting the pro-inflammatory M1 polarization of macrophages. Our findings unveil a novel gut-oral axis mediated by microbiota and metabolites under stress, and position the omega-3 fatty acid EPA as a promising therapeutic agent for mitigating stress-aggravated inflammatory disorders.

Keywords:  chronic restraint stress; eicosapentaenoic acid; macrophages; oral microbiota; periodontitis

DOI:  https://doi.org/10.1002/advs.202521346
Nature. 2026 Mar 04.

A metabolic alarmin from keratinocytes potentiates systemic humoral immunity.

Zhenglin Ji, Ji Gao, Shaocun Zhang, Jiajie Li, Haijing Wu, Jing Yao, Xianqiang Ma, Yue Xin, Yongjie Zhu, Meng Zhao, Zhidan Zhao, Kai Shen, Tao Wu, Xinmin Qian, Juanjuan Wang, Haoran An, Yuxin Li, Wenbo Sun, Qiancheng Zhao, Xiaoying Zhou, Ruiyu Gao, Qinghui Duan, Cuifeng Li, Xiaoke Geng, Ming Yang, Rong Xiao, Juan Liu, Wang Wang, Ji Wang, Yesheng Fu, Jing-Ren Zhang, Xiangjun Chen, Pei Tong, Gong Cheng, Hai Qi, Li Wu, Wenwen Zeng, Qiaoran Xi, Lingqiang Zhang, Yuping Lai, Wei Yang, Yonghui Zhang, Qianjin Lu, Wanli Liu.

How a local infection triggers systemic humoral immunity remains unclear. Here we identify farnesyl pyrophosphate (FPP), a mevalonate pathway metabolic intermediate1, as an endogenous alarmin that enhances IgG antibody responses through keratinocyte-derived IL-6 and CCL20. This signalling axis potentiates the differentiation of T follicular helper cells and migratory dendritic cells2,3. FPP accumulates within keratinocytes after infection or ultraviolet irradiation through the activation of the mevalonate pathway mediated by the unfolded protein response-SREBF pathway, amplifying germinal centre (GC) responses in draining lymph nodes. Mechanistically, accumulated FPP in the cytosol engages transient receptor potential vanilloid 3 (TRPV3) by binding to its intracellular domains, inducing Ca2+ influx that subsequently activates the calmodulin-calcineurin-NFAT and PYK2-RAS-ERK pathways to enhance IL-6 and CCL20 production. This FPP-TRPV3-IL-6/CCL20-GC axis potentiates pathogen-specific antibody production, conferring protection in wild-type but not TRPV3-deficient mice. Single-cell RNA-sequencing analyses of systemic lupus erythematosus (SLE) skin lesions and pathogen-infected mouse skin demonstrate hyperactivation of this signalling axis, particularly in the TRPV3high keratinocyte subset. In mouse models of SLE, the activation of this axis correlates with exacerbated disease pathology. Thus, FPP potentiates systemic humoral immunity through the TRPV3-IL-6/CCL20-GC signalling axis, providing insights for the development of vaccine adjuvants and potential therapeutics for SLE.

DOI: https://doi.org/10.1038/s41586-026-10167-6
J Control Release. 2026 Mar 02. pii: S0168-3659(26)00180-X. [Epub ahead of print] 114778

Nanoassembly-mediated immunometabolic reprogramming of CD4+ T cells suppresses β-cell autoimmunity in type 1 diabetes.

Xixi Nan, Shuotong Zhang, Xinyue Chu, Simiao Chen, Xinge Zhang, Zhongming Wu.

  The pathogenesis of type 1 diabetes mellitus (T1DM), known as autoimmune diabetes, is thought to be mediated by T cell-driven destruction of β cells, with the hyperactivation of CD4+ T cells playing a central role by triggering increased T helper (Th)1 and Th17 differentiation and impaired regulatory T (Treg) cell function. Herein, we constructed a nanoassembly (aNAJPH) capable of regulating immunometabolic reprogramming of activated CD4+ T cells, thereby suppressing β-cell autoimmunity in T1DM. The anti-CD154-F(ab')2 fragments on the surface of aNAJPH blocked the essential secondary costimulatory signal required for the pathogenic response, while the encapsulated L-type amino acid transporter 1 inhibitor suppressed the hyperactive metabolic pathways in activated CD4+ T cells. This synergistic mechanism achieved a specific reduction in the frequency of pathogenic CD4+ T cells and restoration of immune homeostasis by redirecting their differentiation away from pro-inflammatory Th1/Th17 lineages and toward protective Treg lineage. Through this effect, it ultimately reduced CD4+ T cell infiltration into pancreatic islets, preserved islet architecture, maintained blood glucose homeostasis, and lowered systemic inflammatory cytokine levels. This work presents a synergistic immunometabolic targeting strategy to restore immune homeostasis and suppress β-cell autoimmunity, offering a precision framework for treating a broader range of autoimmune diseases.

Keywords:  CD4(+) T cell; Immunometabolic reprogramming; Precise targeting; Type 1 diabetes mellitus

DOI:  https://doi.org/10.1016/j.jconrel.2026.114778
Adv Sci (Weinh). 2026 Mar 01. e18303

Sensory Nerve-Derived CGRP Controls Osteoclastogenesis by Limiting Macrophage Bioenergetics in Bone Repair.

Jiaying Liu, Ting Zhang, Yuqing Mu, Lili Li, Ju Jin, Kevin J Dudley, Wendong Gao, Donglin Cai, Fuhua Yan, Lan Xiao, Yin Xiao.

  Bone healing is a tightly orchestrated, multiphase process that requires coordinated interactions between immune cells and skeletal cells. Sensory nerves act as intrinsic effectors of the inflammatory response, whose role in osteoimmunology during healing remains poorly defined. Using a bone healing model with sensory denervation, it's shown that sensory nerves protect bone repair by suppressing excessive osteoclastogenesis. During the acute inflammatory phase, sensory nerves are upstream regulators of macrophage activation. At the molecular level, calcitonin gene-related peptide (CGRP), a sensory neuron-derived neuropeptide, is identified to modulate macrophage activation by restricting key functions such as migration, phagocytosis, and pro-inflammatory cytokine production. Importantly, CGRP rapidly constrains adenosine triphosphate (ATP) synthesis and mitochondrial respiration in activating macrophages, accompanied by downregulation of genes associated with oxidative phosphorylation and mitochondrial complex components. Following the metabolic alterations, macrophages exposed to CGRP show attenuated osteoclastogenic capacity, with decreased secretion of multiple key factors that support osteoclast differentiation and survival. Together, these findings indicate a neuro-immune-metabolic axis in bone healing, where sensory nerve-derived CGRP influences macrophage bioenergetics and thereby contributes to osteoimmunoligical regulation. It emphasizes the potential of incorporating sensory signals into therapeutic strategies, particularly those targeting immunometabolism in bone regeneration.

Keywords:  CGRP; bone repair; immunometabolism; neuro–immune interaction; osteoclastogenesis; osteoimmunology; regenerative medicine

DOI:  https://doi.org/10.1002/advs.202518303
Front Immunol. 2026 ;17 1772592

Gomphus floccosus (Schw.) Sing. extract attenuates alcoholic liver disease by suppressing macrophage glycolysis and M1 polarization.

Tianyin Ruan, Xutao Li, Mingyue Li, Siyuan Wang, Li Shen, Chenghai Liu, Yuan Peng, Yanyan Tao.

   Background: Alcoholic liver disease (ALD) remains a leading cause of global mortality, yet the development of safe and effective multi-target therapies continues to be a significant challenge. Macrophage-mediated inflammation plays a pivotal role in the pathogenesis of ALD, with macrophage glycolysis reprogramming emerging as a critical immunometabolic checkpoint that drives disease progression. Gomphus floccosus (Schw.) Sing (Gf), a mushroom traditionally employed in southwestern China for the treatment of hepatobiliary disorders, holds therapeutic potential. However, its clinical application is limited by gastrointestinal side effects, and its active components and underlying mechanisms in ALD remain largely unexplored. This study aims to determine whether a standardized extract of Gf alleviates ALD by specifically modulating the macrophage glycolysis-M1 polarization axis.
Methods: Ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was utilized to characterize the chemical profile of the Gf extract. An in vivo ALD mouse model was established using the Lieber-DeCarli ethanol diet with two distinct administration routes. In vitro studies were conducted using lipopolysaccharide (LPS)/ethanol-stimulated macrophages (RAW264.7 and THP-1 cell lines). Comprehensive analyses, including transcriptomic sequencing, pathway enrichment studies, and validation through immunohistochemistry, immunofluorescence, qRT-PCR, Western blotting, and metabolic flux analysis, were performed to elucidate the underlying mechanisms.
Results: Three major constituents were identified in the Gf extract. Treatment with Gf extract significantly mitigated ALD pathology, as evidenced by reductions in steatosis, oxidative stress, and inflammation. Transcriptomic analysis identified 231 differentially expressed genes, with significant enrichment in the glycolysis pathway. Mechanistically, the Gf extract suppressed key glycolytic enzymes, including GLUT1, GCK, HK2, PKM2, and LDHA, as well as lactate production in macrophages. This inhibition effectively reduced pro-inflammatory cytokine secretion, chemotaxis, and M1 polarization.
Conclusion: The hepatoprotective effects of Gf extract against ALD are mediated through the suppression of macrophage glycolytic reprogramming and M1 polarization, providing an immunological basis for its traditional use in hepatobiliary disorders.

Keywords:  Gomphus floccosus (Schw.) Sing.; M1 polarization; alcoholic liver disease (ALD); immunometabolism; macrophage glycolysis; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2026.1772592
Immunometabolism (Cobham). 2026 Jan;8(1): e00078

Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1.

Rafael Moura Maurmann, Kierstin Davis, Negin Mosalmanzadeh, Brenda Landvoigt Schmitt, D Pence.

   Background: Severe coronavirus disease 2019 (COVID-19) is characterized by a hyperinflammatory state associated with an exacerbated inflammatory activation of monocytes and macrophages in the respiratory tract. Metformin has been identified as a potent monocyte inflammatory suppressor, and it has been demonstrated to attenuate inflammation in COVID-19. The mechanisms underlying metformin's anti-inflammatory effects are, however, unclear. We thus sought to investigate metformin's main interactions and their respective isolated effects in modulating monocyte inflammatory response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) stimulation.
Methods: Classical human monocytes were isolated from healthy 18 to 40-year-old individuals and stimulated in vitro with recombinant spike protein subunit 1 (rS1) to assess glycolytic and oxidative metabolic responses by Seahorse extracellular flux analysis and inflammatory gene expression by quantitative polymerase chain reaction. Stimulated monocytes were either pretreated with metformin, rotenone, S1QEL, or A769662.
Results: Monocytes stimulated in vitro with rS1 showed an increased glycolytic response associated with production of pro-inflammatory cytokines. Metformin pretreatment reduced glycolytic activation while partially suppressing inflammation. Rotenone-dependent mitochondrial complex I inhibition was not able to replicate the same effect, and neither was complex I-specific reactive oxygen species scavenging. Conversely, A769662-induced AMP-activated protein kinase (AMPK) activation led to suppressed glycolytic inflammatory response and cytokine expression pattern similar to metformin, thus suggesting AMPK modulation as a possible central component for metformin's mode of action upon S1 stimulation.
Conclusions: In summary, further investigation into the interactions underlying AMPK activity on monocytes in the context of SARS-CoV-2 may provide a better elucidation of metformin's anti-inflammatory effect.

Keywords:  AMPK; immunometabolism; innate immunity; metformin; severe acute respiratory syndrome coronavirus-2

DOI:  https://doi.org/10.1097/IN9.0000000000000078
J Transl Med. 2026 Feb 28.

Targeting metabolic reprogramming to enhance adoptive immunotherapy: emerging mechanisms and translational perspectives.

Liu Yang, Chengyu Zhang, Zhongxiang Zhang, Songlin Yao, Jing Shen, Zhuo Zhang, Zhangang Xiao, Shurong Wang, Zhigui Wu.



Keywords:  Adoptive cell therapy; Immune cell metabolism; Immune responses; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-026-07887-8
Front Cell Infect Microbiol. 2026 ;16 1740892

Effect of PKM2 on M. tuberculosis Rv1987-induced macrophage M2 polarization.

Wenzhen Wang, Hanyu Yang, Guoying Deng, Yufang Ma, Shanshan Sha.

   Introduction: Mycobacteria induce host macrophage M2 polarization to construct a kindly environment for their intracellular growth. In our previous study, we found that M. tuberculosis Rv1987 protein induced macrophage polarization to M2-like phenotype. However, little is known about the changes of host metabolites and the effects of related enzymes in this process.
Methods: Here, using our previously constructed infection model by M. smegmatis overexpressing Rv1987 protein, we analyzed the alterations of energy metabolism-related metabolites and the function of M2 isoform of pyruvate kinase (PKM2), the key enzyme of glycolysis, in mycobacteria-induced M2 macrophages.
Results: The results showed that the expression, enzyme activity and nucleus translocation of PKM2 were all impaired in Rv1987-induced M2 macrophages. Activation of PKM2 by its activator TEPP-46 reversed the M2 polarization and enhanced the inflammation of macrophages, and subsequently reduced the mycobacterial load in mouse lung tissues during infection.
Conclusion: All these results suggested that host PKM2 is closely associated with M. tuberculosis Rv1987-induced M2 polarization, which can be considered as an intervention target in anti-tuberculosis therapy.

Keywords:  M2 polarization; Mycobacterium tuberculosis; PKM2; macrophage; tuberculosis

DOI:  https://doi.org/10.3389/fcimb.2026.1740892
Am J Transplant. 2026 Mar 02. pii: S1600-6135(26)00116-4. [Epub ahead of print]

Dietary carboxymethylcellulose metabolite promotes heart allograft rejection through induction of pro-inflammatory macrophages via lysophosphatidic acid.

Xinyi Ma, Yang Xu, Yeqi Nian, Rongshen Luo, Tianran Chen, Keke Su, Teng Li, Chunlin Shen, Baiyi Xie, Helong Dai, Jie Zhao, Yunhan Ma.

  Carboxymethylcellulose (CMC), a common food emulsifier, induces microbiota dysbiosis and systemic inflammation; however, its impact on transplant immunity remains unclear. Allogenic heart rejection was observed in CMC-fed recipient mice, with increased abundance of lysophosphatidic acid (LPA)-producing bacteria and increased serum LPA concentration. CMC-induced transplant rejection was caused by the gut microbiota, as confirmed by fecal microbiota transplantation and gut microbiota depletion. Furthermore, LPA-treated macrophages demonstrated a pro-inflammatory ability to accelerate allograft rejection in cytotoxic T lymphocyte-associated protein 4 immunoglobulin-induced allograft survival by upregulating glycolysis. Conversely, the administrated of a glycolysis inhibitor resulted in allograft survival and abrogated the detrimental effect of LPA. Mass spectrometry and single-cell RNA sequencing confirmed that human transplant rejection patients showed significantly elevated serum LPA levels and LPAR6 expression in graft-infiltrate macrophages. Mechanistically, LPA preferentially promoted LPAR6 expression, which interacted with Rho-associated protein kinase 2 to activate the mTOR/HIF-1α pathway, thereby enhancing glycolysis and inducing pro-inflammatory macrophage polarization. Treatment with Ki16425, an LPAR antagonist, prolonged allograft survival in CMC-fed recipients. Our findings reveal a major detrimental effect of CMC on macrophage physiology and suggest that controlling LPAR6 expression or glycolysis in macrophage may improve allograft survival in transplant recipients.

Keywords:  Carboxymethylcellulose; LPAR6; glycolysis; macrophage; transplantation

DOI:  https://doi.org/10.1016/j.ajt.2026.02.030
Nat Aging. 2026 Mar 06.

The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.

Zengqing Song, Huaibin Hu, Wanpeng Zhang, Xincheng Zheng, Liyun Liang, Bing Zhao, Guangping Song, Jianing Li, Sen Li, Yuqi Wen, Biyu Zhang, Wen Wang, Guozhen Deng, Cunjin Zhang, Hua Jiang, Supei Hu, Haiqing Tu, Min Wu, Huiyan Li.

Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.

DOI: https://doi.org/10.1038/s43587-026-01087-1
Nat Commun. 2026 Mar 03.

Pharmacological stabilization of hypoxia-inducible factor 1-α dampens the interferon response and promotes glycolysis in Aicardi-Goutières syndrome.

Maxime Batignes, Marine Luka, Surabhi Jagtap, Camille de Cevins, Ivan Nemazanyy, Jacqueline Leib, Tinhinane Fali, Alexandre Pierga, Mohammed Zarhrate, Víctor García-Paredes, Francesco Carbone, Brieuc P Pérot, Bénédicte Neven, Brigitte Bader-Meunier, Pierre Quartier, Marie Hully, Alexandre Belot, Alice Lepelley, Marie-Louise Frémond, Alain Fischer, Mickaël M Ménager.

Aicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterized by neurological involvement with onset in utero or in childhood. Here, we analyze peripheral blood samples from patients bearing AGS-causing mutations in ADAR1, RNASEH2B or SAMHD1 using single-cell transcriptomics and targeted metabolomics. Using machine-learning approaches and differential gene expression analysis, we identified a loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch favoring oxidative phosphorylation and glutathione metabolism over glycolysis in monocytes and dendritic cells. Evidences of mitochondrial stress and accumulation of cytosolic double-stranded DNA and RNA were also found. The energy metabolic switch was confirmed at the metabolic level in primary peripheral blood mononuclear cells of AGS patients. Chemical stabilization of HIF-1α using a synthetic drug in in vitro cellular models of AGS, reversed the energy metabolic switch towards glycolysis, attenuated mitochondrial stress, and markedly reduced the IFN response and IP-10 production. We therefore propose that an energy metabolic switch contributes to chronic inflammation in AGS and that targeting this pathway might represent a potential therapeutic approach.

DOI: https://doi.org/10.1038/s41467-026-69979-9
J Clin Invest. 2026 Mar 02. pii: e172380. [Epub ahead of print]136(5):

α-Ketoglutarate protects against cartilage damage via epigenetically driven metabolic reprogramming in osteoarthritis models.

Shuaijun Li, Jiefeng Huang, Ting Shang, Laiya Lu, Orion R Fan, Peisheng Jin, Xin Zou, Zixin Cai, Wuyan Lu, Shuangmeng Jia, Linxiao Li, Ke Fang, Fengting Niu, Jiaojiao Li, Cheng Zhao, Qian Wang, Ruizhu Sun, Si Shi, Feng Yin, Yun Zhang, Yi Eve Sun, Lei Cui.

  The link between glutaminolysis and osteoarthritis (OA) has only recently begun to be elucidated. Here, we report the association of obesity- and injury-induced cartilage damage with impaired glutaminolysis in chondrocytes. Defective glutaminolysis triggered the onset and progression of OA, with enhanced catabolism and decreased anabolism. Supplementation of α-ketoglutarate (αKG), a key component in glutaminolysis and an epigenetic factor, effectively protected cartilage against degradation in vivo via a TCA cycle- and HIF-1α-independent manner. Mechanistically, OA pathogenic factors increased H3K27me3 deposition on promoters of key glutaminolysis genes, including Slc1a5 and Gls1, leading to impaired glutaminolysis. Conversely, αKG facilitated Kdm6b-dependent H3K27me3 demethylation of not only glutaminolysis genes to rescue Gln metabolism but also Ube2o to reverse OA. Elevated Ube2o expression led to TRAF6 ubiquitination and subsequent inhibition of NF-κB signaling, thereby reversing the pathological reprogramming of glycolysis and oxidative phosphorylation and protecting against cartilage destruction. Collectively, these results demonstrated that OA pathogenic factors impair glutaminolysis through epigenetic regulation, which further exacerbate OA. Moreover, αKG restores metabolic homeostasis and alleviates OA through H3K27me3 demethylation.

Keywords:  Cartilage; Inflammation; Metabolism

DOI:  https://doi.org/10.1172/JCI172380
Signal Transduct Target Ther. 2026 Mar 04. pii: 78. [Epub ahead of print]11(1):

Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer.

Meggy Suarez-Carmona, Mareike Hampel, Xin-Wen Zhang, Alexandra Pöchmann, Silke A Grauling-Halama, Nektarios A Valous, Pornpimol Charoentong, Dyke Ferber, Jannis Wissfeld, Alicia Höflich, Stanislas Goriely, Aurélie Detavernier, Abdulkader Azouz, Anthony Rongvaux, Sven Zukunft, Ingrid Fleming, Jürgen G Okun, Vickie Baracos, Mathias Heikenwalder, Laurence Zitvogel, Xinyi Xu, Chenqi Xu, Michael Volkmar, Daniel Schraivogel, Lars Steinmetz, Junzo Hamanishi, Masaki Mandai, Matthias Gaida, Theresa Mokry, Johanna Nattenmüller, Oliver Sedlaczek, Nanna Monje, Roxana Schwab, Annette Hasenburg, Athanasios Mavratzas, Regina Johanna Boger, Frederik Marmé, Sarah Schott, Niels Halama.

Immunotherapy with immune checkpoint blockade (ICB) in epithelial ovarian carcinoma (EOC) shows limited clinical benefit only for a small subset of patients. Overall response rates are low, so that overcoming immunotherapy resistance and improved stratification are key. In this study, we investigated the immunometabolic landscape of EOC with a focus on omental metastases, identifying lipid-laden macrophages as central elements for actionable therapeutic vulnerabilities and giving rise to biomarkers for improved patient stratification. Using patient-derived explants, we demonstrated a functional dichotomy inside the typically lipid-rich microenvironment of omental metastases: augmented maintenance of effector T cell function, while lipid uptake and processing by tumor-associated macrophages (TAMs) induces oxidative stress-dependent signaling programs, which drive macrophage dysfunction and immune suppression. Pharmacological modulation of lipid-driven signaling pathways through CCR5 inhibition (inflammation modulation through maraviroc) or blockade of the lipid scavenger receptor CD36 reprograms TAMs, restores T cell activity, and enhances antitumor immune responses within lipid-rich tumor niches. Mechanistically, studies in humanized mouse models reveal that maraviroc-mediated CCR5 inhibition induces transcriptional programs associated with immune activation in stressed, lipid-laden human TAMs. Consistent with these mechanistic insights, we demonstrated that the specific immunometabolic niche in omental metastases is clinically associated with responsiveness to ICB. We propose a non-invasive radiomics and machine-learning-based analysis of imaging data to assess omental involvement for patient stratification.

DOI: https://doi.org/10.1038/s41392-026-02594-8