bims-imicid 2026-08-30 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–08–30
thirty-two papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Metabolic switch: lymphocytes and the onset of T-cell-mediated autoimmunity.
Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.
Metabolic reprogramming of the immune response in periodontitis.
The Glucose Transporter GLUT3 Controls Regulatory T Cell Function.
Farnesoid X receptor activates STAT3 to promote fatty acid oxidation and suppress inflammatory macrophage responses in cholestasis.
Branched-chain amino acid metabolism and macrophage polarization: potential regulatory nodes and therapeutic targets in diabetes-associated metabolic inflammation.
The crosstalk between PFKFB3 and RSPO2 drives sepsis-induced lung injury by coupling metabolic rewiring to macrophage inflammation.
Microglial Immunometabolic Remodeling After Ischemic Stroke: The Interplay Between Mitochondrial Stress and the Ischemic Microenvironment.
Germanane Quantum Dots Promote Metabolic Reprogramming of Immune Cells Toward Regulatory T Cells and Suppress Inflammation In Vitro and In Vivo.
Immunometabolism in HIV Reservoirs: Implications for Latency and Comorbidities.
d-Sorbose Promotes Regulatory T-Cell Differentiation and Ameliorates Autoimmune and Allergic Diseases via Hexosamine Biosynthetic Pathway Inhibition.
Microbiota-derived 4-HPAA alleviates Crohn's disease by stabilizing SIRT1 and reprogramming macrophage immunometabolism.
Metabolomic Analysis of Lytic KSHV Infection: Induced Host Nucleotide Metabolism Is Required for Infectious Virus Production.
TSPO Regulates TLR4-Mediated Inflammation Through Calcium Homeostasis and Immunometabolic Adaptation.
AMPK-Orchestrated Metabolic Reprogramming in Some Flavivirus Infections: Mechanisms and Therapeutic Opportunities.
ACC1 inhibition enhances BCG-induced trained immunity by reprogramming Acetyl-CoA metabolism.
Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.
Linoleic acid metabolic reprogramming is linked to immunometabolic remodeling and post-transplant recurrence risk in hepatocellular carcinoma.
Modulatory effects of S1QEL on OxLDL-induced metabolic alterations and inflammatory responses in human monocytes.
Daily HIV pre-exposure prophylaxis enhances monocyte activation and reprogrammes immune cell metabolism.
CD8+ T cell heterogeneity and function in lupus nephritis: a focused review.
Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells.
IL-37 and IL-38 in sepsis: immune-metabolic rheostats in a dynamic inflammatory continuum.
Mitochondria-derived peptide hydrogel augments mitochondrial transplantation for promoting cardiac repair via macrophage metabolic reprogramming.
Integrated multi-omics and functional analyses reveal a GDCA-TGR5-mediated immunometabolic signature in anorexia nervosa.
Psoriasis-like skin inflammation drives an elongated mitochondrial network marked by functional failure in keratinocytes.
SIRT2 deacylase modulators control B cell metabolic reprogramming in EBV infection and mitogenic activation.
Palmitic Acid Amplifies Microglial Inflammatory Activation Involving C5aR1-Sensitive Inflammatory Signaling and JMJD3/H3K27me3-Related Epigenetic Changes.
Lactate as a Master Regulator of Immune Suppression: From Metabolic Waste to Epigenetic Checkpoint in Colorectal Cancer.
Itaconic Acid Directly Binds to the Cysteine Residue of PurF: A Novel Mechanism for Inhibiting Purine Metabolism in Porcine Pathogenic Escherichia coli.
Metabolic, viral, and immune phenotypes in long COVID.
TRIM32-mediated ubiquitination of STING promotes glycolysis and tumor progression.

Cell Mol Immunol. 2026 Aug 24.

Metabolic switch: lymphocytes and the onset of T-cell-mediated autoimmunity.

Andisheh Mosaffa Jahromi, Fatemeh Mirzaei, Sara Mirzazadeh, Seppo Meri, Dieter Kabelitz, Kurosh Kalantar.

  T cell-mediated autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D), are being increasingly recognized as disorders driven not only by immune dysregulation but also by profound metabolic reprogramming in lymphocytes. Emerging evidence from the field of immunometabolism reveals that altering the balance between oxidative phosphorylation (OXPHOS) and aerobic glycolysis, along with enhancing fatty acid synthesis and dysregulated glutamine metabolism, critically shapes lymphocyte activation, differentiation, and pathogenicity. Here, we review the metabolic pathways that regulate T cells and B cells. We discuss how changes in glucose, lipid, and mitochondrial metabolism influence immune responses that lead to chronic inflammation and autoimmunity in MS, RA, and T1D. Interestingly, similar immunometabolic changes, such as increased glycolysis, mitochondrial dysfunction, and mTOR signaling, have been identified in another autoimmune disorder, systemic lupus erythematosus (SLE). Connecting metabolic dysregulation to immune tolerance failure, this review highlights immunometabolism as a key mechanism in autoimmunity. Immunometabolic pathways represent a new avenue for precision immunotherapy, although challenges persist in targeting cells specifically without systemic toxicity. Understanding these metabolic adaptations and epigenetic-metabolic crosstalk will be essential for translating these insights into next-generation therapies.

Keywords:  Autoimmunity; B cells; Immunometabolism; T cells

DOI:  https://doi.org/10.1038/s41423-026-01460-5
Immunol Res. 2026 Aug 25. pii: 94. [Epub ahead of print]74(1):

Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.

Priya Sharma.

  Development of Immunometabolism as a central paradigm in the modern immunology has revolutionized the understanding of metabolism from being a passive supplier of energy to an important determinant of immune cell fate and function. Immune cells are activated, differentiated, survive and undergo programmed cell death through the activity of distinct metabolic programs, including those involving glycolysis, oxidative phosphorylation (OXPHOS), nutrient sensing through Mechanistic Target of Rapamycin (mTOR), AMP-Activated Protein Kinase (AMPK), and HIF‑1α. Rapid proliferation and production of cytokines by effector T cells and pro-inflammatory macrophages is mediated by glycolysis, while persistence and tolerance by memory T cells and reparative macrophages is mediated by oxidative metabolism. Metabolic input and output are also coupled with immune specialization and cell death mechanisms, such as apoptosis, Pyroptosis and ferroptosis, via mitochondrial bioenergetics and production of Reactive Oxygen Species (ROS). Altered immunometabolism is linked to a variety of pathologies: competition for nutrients in tumor physiology leads to T cell exhaustion; an unchecked glycolytic pathway maintains a state of autoimmune inflammation; pathogens exploit host metabolism to escape immunological control; and metabolic diseases, such as obesity and diabetes, foster chronic low‑grade inflammation. Therapies such as rapamycin, metformin, glycolysis and glutamine inhibitors, and metabolic adjuvants in vaccines underscore the translational potential of targeting metabolic checkpoints. But there are still debates on the specificity of the metabolic intervention, the balance between the effector and regulation responses, and the restrictions of the existing experimental models. New strategies, such as single-cell metabolomics and precision medicine, are expected to bring in more sophisticated ways for fine-tuning immune metabolism. Immunometabolism is thus a paradigm shift, with metabolism now being at the heart of immune regulation, and providing new opportunities for critical evaluation and translational innovation in cancer, autoimmunity, infections and metabolic disease.

Keywords:  Cancer immunotherapy; Glycolysis; Immune cell death; Immunometabolism; Metabolic reprogramming; Nutrient sensing

DOI:  https://doi.org/10.1007/s12026-026-09831-w
Periodontol 2000. 2026 Aug 25.

Metabolic reprogramming of the immune response in periodontitis.

Rafael Scaf de Molon, Melissa Grant, Iain Chapple, Joao Paulo Steffens.

   OBJECTIVE: Periodontitis, a highly prevalent chronic inflammatory disease, is characterized by the progressive destruction of the tooth-supporting tissues, ultimately causing tooth loss. In recent years, the emerging field of immunometabolism has revealed that immune cell function is tightly regulated by intracellular metabolic pathways that govern cellular activation, differentiation, and effector responses. Therefore, the aim of this review was to synthesize current evidence on the role of immunometabolism in the pathogenesis of periodontitis, with a particular focus on how metabolic reprogramming regulates innate and adaptive immune responses, contributes to inflammatory bone loss, and represents a potential target for host-modulatory therapies.
MATERIALS AND METHODS: A comprehensive narrative review of the contemporary literature was conducted to integrate experimental, translational, and clinical evidence on immunometabolic mechanisms involved in periodontitis. The review examines metabolic regulation of innate and adaptive immune cells, the influence of microbial and systemic metabolic signals on periodontal inflammation, and emerging therapeutic strategies targeting immunometabolic pathways.
RESULTS: Current evidence demonstrates that persistent microbial challenge and inflammatory signaling induce profound metabolic reprogramming of immune cells within the periodontal microenvironment. Activated neutrophils, macrophages, dendritic cells, and lymphocytes undergo coordinated shifts in glycolysis, mitochondrial oxidative phosphorylation, fatty acid oxidation, and amino acid metabolism, which regulate immune cell activation, differentiation, and effector functions. These metabolic adaptations promote the production of reactive oxygen species, pro-inflammatory cytokines, and osteoclastogenic mediators, thereby amplifying inflammation and disrupting osteoimmune mechanisms that maintain bone homeostasis. In addition, microbial-derived metabolites further influence host immune metabolism, reinforcing chronic inflammation and periodontal tissue destruction. Emerging preclinical evidence suggests that pharmacological modulation of key immunometabolic pathways may attenuate inflammation and preserve periodontal tissues.
CONCLUSION: Immunometabolic reprogramming is a fundamental mechanism linking microbial dysbiosis to dysregulated host immunity and inflammatory bone loss in periodontitis. A better understanding of the metabolic pathways governing immune cell function may provide important mechanistic insights into disease pathogenesis. By integrating insights from (osteo-)immunology and metabolism, this review proposes immunometabolism as a critical determinant of inflammatory bone loss and a fruitful avenue for the development of novel host-modulatory periodontal therapies aimed at restoring immune homeostasis and preventing periodontal tissue destruction.

Keywords:  alveolar bone; bone; cytokines; immunometabolism; inflammation; pathogenesis; periodontitis

DOI:  https://doi.org/10.1111/prd.70073
Eur J Immunol. 2026 Aug;56(8): e70272

The Glucose Transporter GLUT3 Controls Regulatory T Cell Function.

Katrin Sinning, Miriam Eckstein, Xiufeng Zhao, Alexandra Freitag, Mathias Rosenfeldt, Sophia M Hochrein, Martin Vaeth.

  Regulatory T (Treg) cells are central mediators of immune tolerance and are generally considered to rely predominantly on mitochondrial metabolism rather than glucose-driven glycolysis. To define the role of glucose metabolism in Treg cells, we investigated the contribution of the hexose transporters GLUT1 and GLUT3. Genetic ablation of GLUT1 in T cells or selectively in Treg cells had minimal impact on Treg cell numbers, phenotype, or immune homeostasis, indicating that GLUT1 is largely dispensable in this lineage. By contrast, deletion of GLUT3 in T cells resulted in a marked reduction in Treg cell numbers. However, it remained unclear whether this reduction reflected diminished IL-2 production by GLUT3-deficient conventional T cells or a cell-intrinsic requirement for GLUT3 in Treg cells. To investigate this, we generated mice with Treg cell-specific deletion of GLUT3. These animals developed severe systemic inflammation accompanied by lethal cellular and humoral autoimmunity. Mechanistically, GLUT3-deficient Treg cells exhibited reduced glycolytic activity and mitochondrial respiration, leading to impaired suppressive function and defective effector and follicular Treg cell differentiation. Collectively, our findings demonstrate a nonredundant requirement for GLUT3 in Treg cell metabolic fitness and immune regulation, refining the prevailing view that Treg cells operate largely independently of glucose metabolism. Our data further suggest that therapeutic strategies targeting glucose uptake and glycolysis in autoimmune and inflammatory diseases should account for potential adverse effects on Treg cell-mediated immune tolerance.

Keywords:  biology; cell biology; cellular differentiation; glucose transporter; glucose uptake; glycolysis; immune tolerance; immunology; regulatory T cell

DOI:  https://doi.org/10.1002/eji.70272
J Biol Chem. 2026 Aug 27. pii: S0021-9258(26)02380-X. [Epub ahead of print] 113508

Farnesoid X receptor activates STAT3 to promote fatty acid oxidation and suppress inflammatory macrophage responses in cholestasis.

Swati Ghosh, Michael W Devereaux, Colin C Anderson, Amy Argabright, David J Orlicky, Ronald J Sokol.

  Inflammatory cholangiopathies such as primary sclerosing cholangitis involve bile duct injury, macrophage-driven inflammation, and progressive fibrosis. While farnesoid X receptor (FXR) regulates bile acid metabolism and immune responses, its role in macrophage immunometabolic reprogramming during cholestasis remains unclear. Here, we investigated whether FXR regulates liver immunometabolism through STAT3-dependent mechanisms in cholestatic liver disease. Using transcriptomic, oxylipin lipidomic, histological, and metabolomic analyses in a chronic murine model of DDC-induced cholangiopathy, we explored the role of FXR-induced STAT3 signaling in regulating inflammatory and metabolic responses. FXR agonists significantly reduced biochemical and histologic cholestatic liver injury, as well as suppression of macrophage infiltration. Liver RNA-seq revealed that cholestatic injury activated inflammatory, TGF-β, and arachidonic acid (AA) metabolic pathways and reduced fatty acid oxidation (FAO) programs, while FXR restored pathways linked to FAO. Mechanistically, FXR activation in the liver increased STAT3 phosphorylation and acetylation and mitochondrial translocation, boosted STAT3 binding to promoters of genes involving FAO pathways, and triggered the mRNA expression of FAO genes. Pharmacologic STAT3 activation with colivelin reproduced protective effects of GW4064-mediated FXR activation. Conversely, co-administration of the STAT3 inhibitor C-188-9 partially reversed GW4064-mediated suppression of inflammatory and fibrogenic gene programs and reduced induction of FAO genes. Arachidonic acid injection of mice induced macrophage activation and hepatocyte apoptosis, both of which were attenuated by GW4064. STAT3 siRNA knockdown in hepatocyte and macrophage cell systems also blunted FXR agonist-induced transcriptional responses. These findings identify a novel FXR agonist-driven STAT3 immunometabolic axis that integrates bile acid signaling, FAO, and macrophage reprogramming to regulate inflammation during cholestatic liver injury.

Keywords:  LRH-1; biliary atresia; cholestasis; macrophage; primary sclerosing cholangitis

DOI:  https://doi.org/10.1016/j.jbc.2026.113508
Front Cell Infect Microbiol. 2026 ;16 1902640

Branched-chain amino acid metabolism and macrophage polarization: potential regulatory nodes and therapeutic targets in diabetes-associated metabolic inflammation.

Ruisi Yang, Ruodi Yang, Han Zhang, Yufeng Yang, Yan Shi, Juntong Liu.

  T2DM is characterized by chronic low-grade metabolic inflammation, and imbalanced macrophage polarization is a key immunological mechanism contributing to insulin resistance (IR), pancreatic β-cell damage, and diabetes progression. Recent studies in immunometabolism suggest that BCAA metabolism regulates macrophage polarization in a context-dependent manner. Physiological BCAA catabolism supports M2-like oxidative metabolism and repair functions, whereas chronic overload of BCAA and its catabolic metabolites in diabetes may promote pro-inflammatory responses through multiple pathways. Disruptions in BCAA metabolism mediate the remodeling of macrophage immunometabolism and polarization imbalance, thereby inducing the onset and progression of metabolic inflammation in diabetes. Accordingly, this study will conduct a systematic literature search in PubMed, Web of Science, and Google Scholar to review the mechanisms by which BCAA metabolic disorders in diabetes mediate the immunometabolic reprogramming of macrophages and regulate the imbalance in M1/M2 polarization. Current evidence suggests that BCAA metabolic dysregulation can drive macrophage metabolic reprogramming through multiple pathways, leading to an imbalance in M1/M2 polarization and promoting diabetes-associated metabolic inflammation. Importantly, interventions including low-BCAA diets, caloric restriction, exercise, activators of BCAA catabolism, PPARγ agonists, berberine, ginsenoside Rb1, mulberry leaf and twig extracts, probiotics, and other gut microbiota-targeted strategies have shown potential to modulate BCAA metabolism, improve insulin sensitivity, and alleviate metabolic inflammation. Therefore, BCAA metabolism may serve as a critical link connecting metabolic dysregulation in diabetes with macrophage immunometabolic reprogramming and chronic inflammatory responses. Targeting BCAA metabolism is expected to provide new multi-target intervention strategies for metabolic inflammation in diabetes.

Keywords:  branched-chain amino acid metabolism; diabetes mellitus; immunometabolic reprogramming; macrophage polarization; metabolic inflammation

DOI:  https://doi.org/10.3389/fcimb.2026.1902640
Transl Res. 2026 Aug 28. pii: S1931-5244(26)00184-2. [Epub ahead of print]

The crosstalk between PFKFB3 and RSPO2 drives sepsis-induced lung injury by coupling metabolic rewiring to macrophage inflammation.

Yao Wang, Juan Zeng, Xiang Dai, Rui Peng, Dan Wang.

  Aberrantly activated macrophages drive acute lung injury (ALI), but how metabolic reprogramming fuels their dysfunction remains elusive. Here, we investigated PFKFB3, a glycolytic enzyme converting fructose-6-phosphate to fructose-2,6-bisphosphate, in ALI. PFKFB3 was upregulated both in LPS-stimulated macrophages and septic mice, cascading RSPO2 activation. Pharmacological inhibition of PFKFB3 by PFK15 not only mitigated LPS-induced macrophage injury via NF-κB suppression but also protected against ALI in CLP mice. PFK15 effectively blunted PFKFB3-dependent glycolysis and curtailed pro-inflammatory responses by inhibiting RSPO2/β-catenin signaling both in vitro and in vivo. Genetic silencing of PFKFB3 similarly reduced inflammation and suppressed RSPO2/β-catenin signaling. Notably, RSPO2 knockdown ameliorated LPS-induced macrophage dysfunction characterized by hyperglycolysis and excessive inflammation. This protective effect was phenocopied by KYA1797K, an RSPO2/β-catenin inhibitor, which reduced macrophage inflammation and glycolytic activity, thereby alleviating ALI. Collectively, our data support a model wherein a positive feedback loop interconnecting PFKFB3-driven glycolysis and RSPO2 signaling synergizes with the NF-κB pathway to potentiate macrophage inflammation, ultimately exacerbating septic ALI. These findings establish the PFKFB3-RSPO2 circuit as a promising therapeutic target for ALI.

Keywords:  ALI; Glycolysis; Macrophage inflammation; PFKFB3; RSPO2; Sepsis

DOI:  https://doi.org/10.1016/j.trsl.2026.08.009
Transl Stroke Res. 2026 Aug 22. pii: 100. [Epub ahead of print]17(5):

Microglial Immunometabolic Remodeling After Ischemic Stroke: The Interplay Between Mitochondrial Stress and the Ischemic Microenvironment.

Cui Liu, Qiang Liu, Weiyao Jing, Limei Liu, Long Wei, Xing Li, Xiaozheng Du.

  Following ischemic stroke, marked alterations in the local metabolic and inflammatory milieu of the brain drive immunometabolic remodeling and mitochondrial dysfunction in microglia, thereby shaping inflammation, damage clearance, and tissue repair. Existing studies have largely focused on individual metabolic pathways, leaving the relationships among the ischemic microenvironment, mitochondrial responses, and microglial functional changes incompletely understood. Available evidence indicates that the effects of these metabolic alterations vary with stroke phase, local injury severity, and mitochondrial status. This review summarizes current evidence on glycolysis and lactate transport, the tricarboxylic acid cycle and succinate signaling, lipid handling, and danger-signal sensing, with particular emphasis on their relationships with mitochondrial redox homeostasis and quality control. We also critically evaluate divergent findings across studies. By examining the interaction between the ischemic microenvironment and mitochondrial responses, this review aims to clarify the metabolic basis of microglial functional changes and to inform the assessment of potential therapeutic targets in microglial immunometabolism.

Keywords:  Ischemic stroke; Metabolic regulation; Microglia; Mitochondria

DOI:  https://doi.org/10.1007/s12975-026-01492-z
Adv Funct Mater. 2026 Apr 27. 36(34): e21057

Germanane Quantum Dots Promote Metabolic Reprogramming of Immune Cells Toward Regulatory T Cells and Suppress Inflammation In Vitro and In Vivo.

Abhay Srivastava, Alireza Rafieerad, Weiang Yan, Keshav Narayan Alagarsamy, Qingdong Guan, Leena Regi Saleth, Michel Aliani, Sanjiv Dhingra.

  Recently, nanomaterials have emerged as a tool in developing novel therapies against inflammatory diseases. Metabolic changes in immune cells direct the phenotype and function of the host immune system. Therefore, next-generation immunomodulatory biomaterials should be designed to target metabolic pathways and trigger specific changes in immune cells to direct their fate toward an anti-inflammatory phenotype. The current study reports the fabrication and first application of germanane quantum dots (GeHQDs) to modulate inflammation in cell culture and in vivo mouse model. Using rational design and synthesis strategies, our GeHQDs leverage the intrinsic anti-inflammatory properties of germanane to provide a novel nanoplatform to trigger metabolic reprogramming of immune cells toward an anti-inflammatory phenotype. These GeHQDs are spontaneously uptaken into the immune cells and trigger a switch in their phenotype toward regulatory T (Treg) cells. Metabolomic analysis suggested a downregulation in glycolytic flux and upregulation in fatty acid oxidation with an increase in mitochondrial respiration in the GeHQDs-treated group, which is a typical signature of Treg cells. In an in vivo mouse model of systemic inflammation, GeHQDs treatment upregulated the circulating Treg cell number, improved the metabolomic profile and downregulated inflammation. The current study presents a new paradigm in targeting inflammatory diseases by modulating immune cell metabolism using next-generation nanomaterials.

Keywords:  immunomodulation; metabolic reprogramming; nanomaterials; quantum dots; regulatory T cells; sea‐horse analysis

DOI:  https://doi.org/10.1002/adfm.202521057
Viruses. 2026 Jul 24. pii: 813. [Epub ahead of print]18(8):

Immunometabolism in HIV Reservoirs: Implications for Latency and Comorbidities.

Mary-Elizabeth Zipparo, Rebecca T Veenhuis.

  Compelling research has consistently demonstrated a strong relationship between immunometabolism and infectious disease, including the ways in which viral infections alter the metabolic state of immune cells to promote survival. Human immunodeficiency virus (HIV) has been particularly noted for its ability to reprogram the metabolism of cells that contribute to viral persistence. The purpose of this review is to summarize current knowledge of the metabolic state of CD4 T cells and myeloid cells (monocytes/macrophages), two of the primary cell types targeted by HIV. The studies discussed reveal distinct metabolic profiles in both cell types during initial infection, active replication, and latency. In addition, we examine how these metabolic alterations may contribute to the increased frequency and severity of comorbidities observed in people with HIV (PWH). Understanding the impact of HIV infection and latency on immunometabolism may provide deeper insight into long-term viral persistence and support the identification of novel therapeutic targets to reduce chronic inflammation and inform future cure strategies for PWH.

Keywords:  CD4 T cells; HIV; comorbidities; immunometabolism; latency; macrophages; monocytes; reservoir

DOI:  https://doi.org/10.3390/v18080813
FASEB J. 2026 Sep 15. 40(17): e72252

d-Sorbose Promotes Regulatory T-Cell Differentiation and Ameliorates Autoimmune and Allergic Diseases via Hexosamine Biosynthetic Pathway Inhibition.

Fumiaki Sato, Masato Hoshi, Hiroyuki Yokoi, Sayaka Yoshida, Ryosuke Takenaka, Nao Shimoga, Nanaka Morita, Chieko Tashita, Kyoka Yamazaki, Yuka Kishimoto, Hiroyuki Tezuka, Hiroyasu Ito, Kuniaki Saito.

  Monosaccharides are fundamental biomolecules involved in various biological processes. Rare sugars, naturally scarce monosaccharide derivatives, exhibit unique physiological effects independent of standard energy metabolism. Among them, d-sorbose, the C-3 epimer of d-fructose, has poorly understood biological functions. This study investigated the immunometabolic effects of d-sorbose, focusing on regulatory T-cell (Treg) differentiation and immune modulation. Ex vivo assays using splenic naïve CD4+ T cells revealed that d-sorbose significantly increased Foxp3+ Treg frequencies to levels comparable to d-mannose, without inducing the CD8+ T cell reduction observed with d-mannose. In vivo, continuous d-sorbose administration ameliorated ovalbumin-induced airway inflammation and prevented autoimmune diabetes in non-obese diabetic mice by selectively increasing interleukin-10-producing Tregs in regional lymph nodes and inflamed tissues. Histological analyses revealed reduced inflammatory cell infiltration and preserved tissue architecture in d-sorbose-treated groups. Metabolomic profiling indicated that d-sorbose suppressed glycolysis, the pentose phosphate pathway, and the hexosamine biosynthetic pathway (HBP), as evidenced by decreased UDP-GlcNAc levels, while elevating the tricarboxylic acid cycle intermediate malate. Pharmacological inhibition of glutamine-fructose-6-phosphate aminotransferase, combined with glutamine restriction and GlcNAc rescue assays, demonstrated that d-sorbose promotes Treg differentiation through coordinated metabolic reprogramming of glucose partitioning and glutamine catabolism rather than passive HBP inhibition. Notably, d-sorbose treatment did not alter T-cell survival and demonstrated a favorable safety profile during long-term administration. These findings identify d-sorbose as a novel immunoregulatory sugar that promotes functional Treg differentiation by orchestrating intracellular glucose and glutamine metabolism, highlighting its potential as a dietary or therapeutic agent for controlling inflammatory and autoimmune diseases.

Keywords:  OVA‐induced asthma model; d‐sorbose; hexosamine biosynthetic pathway; non‐obese diabetes (NOD) model; rare sugar; regulatory T cell

DOI:  https://doi.org/10.1096/fj.202601110R
Apoptosis. 2026 Aug 23. pii: 215. [Epub ahead of print]31(9):

Microbiota-derived 4-HPAA alleviates Crohn's disease by stabilizing SIRT1 and reprogramming macrophage immunometabolism.

Chao Cheng, Shaoqi Cheng, Wenliang Jiang, Shuqiang Fu, Yangjie Shang, Xiufang Tang, Jie Zhao, Honggang Wang.

  Crohn's disease (CD) is characterized by mucosal immune dysregulation, gut microbiota disturbance, and epithelial barrier dysfunction. This study investigated whether an Aronia berry polyphenol-rich diet attenuates CD-related intestinal inflammation through microbiota-derived metabolic signals. IL-10-/- and TNBS-induced colitis mouse models were used to evaluate the effects of dietary intervention, bacterial strain supplementation, and candidate metabolite administration. Integrated metagenomic, metabolomic, and transcriptomic analyses were combined with in vivo and in vitro mechanistic experiments to identify diet-responsive microbial taxa, metabolites, and host regulatory pathways. This diet alleviated colitis, reduced mucosal injury, and improved epithelial barrier integrity. Multi-omics analyses identified Flavonifractor plautii enrichment and increased microbiota-derived 4-hydroxyphenylacetic acid (4-HPAA) levels as major diet-associated changes. F. plautii supplementation was associated with increased 4-HPAA production, while 4-HPAA administration partially reproduced the intestinal protective phenotype in vivo. In macrophages, 4-HPAA suppressed pro-inflammatory activation and promoted oxidative metabolic remodeling. Mechanistically, 4-HPAA stabilized SIRT1 by limiting ubiquitination-mediated proteasomal degradation, thereby activating SIRT1-PGC-1α signaling. Myeloid SIRT1 deficiency attenuated the effects of 4-HPAA on macrophage polarization, inflammatory cytokine expression, and epithelial barrier-associated proteins. These findings identify a diet-associated microbial metabolite pathway involving F. plautii, 4-HPAA, and SIRT1 signaling, linking polyphenol-rich dietary intervention to macrophage immunometabolic regulation and intestinal barrier protection. This microbial metabolite-centered mechanism may provide insight into nutritional intervention strategies for CD-related intestinal inflammation.

Keywords:   Flavonifractor plautii ; 4-Hydroxyphenylacetic acid; Crohn’s disease; Macrophage immunometabolism; Ubiquitination

DOI:  https://doi.org/10.1007/s10495-026-02417-9
Viruses. 2026 Aug 11. pii: 877. [Epub ahead of print]18(8):

Metabolomic Analysis of Lytic KSHV Infection: Induced Host Nucleotide Metabolism Is Required for Infectious Virus Production.

Fatima Hisam, Emma A Winn, Spandan Mukherjee, Savannah E Price, Yennifer A Gaspar, Claire Wang, Hamid R Baniasadi, Tracie Delgado, Erica L Sanchez.

  Kaposi's Sarcoma Herpesvirus (KSHV) is the etiological agent of Kaposi's Sarcoma (KS), which induces metabolic stress in infected host cells. KSHV reprograms host metabolic pathways for efficient viral replication and infectious virion production. Here, we report a time-course global metabolomics study conducted in iSLK.BAC16 cells to compare latent and lytic KSHV infection. Our data show that amino acid, central carbon, and nucleotide metabolic pathways are highly dysregulated upon reactivation. During lytic KSHV infection, pathway enrichment analysis identifies purine and pyrimidine metabolism as the top two most significantly impacted and dysregulated pathways. Further experiments have shown that nucleotide metabolism is required during lytic KSHV infection to produce maximal infectious virus. Treatment with the FDA-approved drug, methotrexate (MTX), a folate antagonist that decreases nucleotide metabolism by reducing tetrahydrofolate cofactors, significantly reduced KSHV copy number and late lytic viral gene expression upon reactivation compared to controls. Additionally, titers of cell-free supernatants from MTX-treated lytic samples showed a significant reduction in infectious virion production. Furthermore, MTX significantly decreased the viral titer of murine herpesvirus 68 (MHV-68), a model virus to study gammaherpesvirus. Overall, our study demonstrates that metabolic inhibition during lytic gammaherpesvirus infection decreases productive infection and hence serves as a potential therapeutic antiviral target.

Keywords:  Kaposi’s Sarcoma (KS); Kaposi’s Sarcoma Herpesvirus (KSHV); lytic replication; metabolomics; methotrexate (MTX); nucleotide metabolism

DOI:  https://doi.org/10.3390/v18080877
Int J Mol Sci. 2026 Aug 17. pii: 7336. [Epub ahead of print]27(16):

TSPO Regulates TLR4-Mediated Inflammation Through Calcium Homeostasis and Immunometabolic Adaptation.

Xiaoqin Wu, Yaru Zhu, Bo Liu, Xiaoni Liu, Xiangjun Chen.

  Bacterial infection triggered excessive inflammatory responses, yet the mechanisms linking inflammatory activation to immunometabolic adaptation remained incompletely understood. The mitochondrial translocator protein (TSPO) has been implicated in inflammatory activation and cellular metabolism. This study aimed to investigate the role of TSPO in inflammation mediated by Toll-like receptor 4 (TLR4). Herein, we integrated transcriptomic data from the human peripheral blood dataset GSE72829, and single-cell transcriptomic profiles from the CELLxGENE platform with cellular mechanistic experiments in BV2 microglia and RAW264.7 macrophages. Transcriptomic analyses revealed that TSPO expression was markedly upregulated in patients with bacterial infection (n = 52) and exhibited diagnostic potential to distinguish bacterial infection from healthy controls (HCs, n = 16) and viral infection (n = 92). TSPO-correlated genes were enriched in Toll-like receptor (TLR) signaling, inflammatory response, and immunometabolic pathways. Mechanistically, TSPO interacted with TLR4 and selectively modulated TLR4-driven inflammatory activation. TSPO deficiency augmented lipopolysaccharide (LPS) induced tumor necrosis factor‑α (TNF-α) and interleukin‑6 (IL-6) secretion, accompanied by disrupted Ca2+ homeostasis, impaired cholesterol balance, and compensatory metabolic remodeling characterized by elevated L-lactate and sustained Adenosine triphosphate (ATP) levels. Collectively, these findings identified TSPO as an immunometabolic regulator bridging TLR4 signaling and metabolic adaptation during inflammatory activation. Besides, TSPO represented a promising biomarker and therapeutic target to limit exaggerated inflammatory responses.

Keywords:  LPS; TLR4; TSPO; inflammation; metabolic reprogramming

DOI:  https://doi.org/10.3390/ijms27167336
Viruses. 2026 Aug 19. pii: 910. [Epub ahead of print]18(8):

AMPK-Orchestrated Metabolic Reprogramming in Some Flavivirus Infections: Mechanisms and Therapeutic Opportunities.

Kaci Craft, Imaan Muhammad, Shaokai Pei, Qiyi Tang.

  5'-Adenosine monophosphate-activated protein kinase (AMPK) is the principal cellular energy sensor that coordinates metabolic adaptation by balancing anabolic and catabolic pathways in response to energic stress. Beyond its canonical role in maintaining energy homeostasis, AMPK has emerged as a central regulator of host-pathogen interactions by integrating lipid metabolism, autophagy, mitochondrial dynamics, oxidative stress, and innate immune signaling. Flaviviruses, including dengue virus, Zika virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus, extensively remodel host metabolism to establish productive infection. As a master regulator of cellular metabolism, AMPK can either restrict or facilitate flavivirus replication in a context-dependent manner by regulating lipid droplet biogenesis, fatty acid synthesis and beta-oxidation, autophagy, mitochondrial homeostasis, and interferon-mediated antiviral responses. Conversely, flaviviruses actively manipulate AMPK signaling and its downstream metabolic networks to promote endoplasmic reticulum remodeling, replication organelle biogenesis, energy production, and immune evasion. In this review, we summarize recent advances in understanding the multifaceted roles of AMPK during flavivirus infection, with an emphasis on its regulation of metabolic reprogramming, organelle remodeling, and antiviral immunity. We further discuss the therapeutic potential of pharmacologically targeting AMPK and its downstream pathways as a host-directed strategy for broad-spectrum antiviral intervention against flaviviruses.

Keywords:  AMPK; Zika virus; autophagy; dengue virus; flavivirus; host-targeted antiviral therapy; innate immunity; lipid droplets; lipid metabolism; metabolic reprogramming; mitochondrial dynamics

DOI:  https://doi.org/10.3390/v18080910
Mol Ther. 2026 Aug 25. pii: S1525-0016(26)00714-8. [Epub ahead of print]

ACC1 inhibition enhances BCG-induced trained immunity by reprogramming Acetyl-CoA metabolism.

Ilayda Baydemir, Fabian Nikolka, Özlem Bulut, Anaísa V Ferreira, Gizem Kilic, Büsra Geckin, Robbin Kramer, Jorge Cuenca-Escalona, Evelien Floor, Marisol Báez-Magaña, Vasiliki Matzaraki, Jeroen Deckers, Tom Anbergen, Yuri van Elsas, Thijs Beldman, Simone Jcfm Moorlag, L Charlotte J de Bree, Victoria Spanou, Theano Andriopoulou, Yang Li, Evangelia Karagianni, Boris Novakovic, Yahya Sohrabi, Leo A B Joosten, Karsten Hiller, Jorge Domínguez-Andrés.

Trained immunity enhances long-term innate immune responsiveness through metabolic and epigenetic rewiring. Using BCG as a model, we demonstrate that inhibition of acetyl-CoA carboxylase 1 (ACC1) enhances BCG-induced trained immunity by increasing intracellular acetyl-CoA (ACoA) availability. This shift redirects ACoA from lipid biosynthesis towards enhanced tricarboxylic acid (TCA) cycle flux and histone acetylation, reinforcing metabolic and epigenetic programs that sustain trained immunity. ACC1 inhibitors amplify cytokine production, mitochondrial respiration, and glutamine metabolism in monocytes, with heightened histone H3K27 acetylation and reduced H3K9 methylation at pro-inflammatory loci. In vivo, ACC1 inhibition amplified BCG-driven myelopoiesis, increasing granulocyte-macrophage progenitors and systemic cytokine responses. Notably, genetic variation in ACoA metabolism genes influenced trained immunity responses in BCG-vaccinated individuals. These findings highlight ACC1 as a metabolic checkpoint linking cellular metabolism to innate immune memory. Targeting ACoA metabolism may represent a promising strategy to optimize vaccine efficacy and enhance broad-spectrum protection against infections.

DOI: https://doi.org/10.1016/j.ymthe.2026.08.033
Cell Metab. 2026 Aug 28. pii: S1550-4131(26)00328-1. [Epub ahead of print]

Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.

Yong Tang, Ziqing Chen, Hirak Sarkar, Yong Wei, Sereno L Lopez-Darwin, Asael Roichman, Ji Woo Park, Qinglan Li, Cao Fang, Zihong Chen, James Gow, Minhong Shen, Jennifer Shi, Lifei Jiang, Richard Klar, Xiang Hang, Janette R Lugo, Christina J DeCoste, Jennifer M Miller, Wei Wang, Peter Romanienko, Alana L Welm, Ileana M Cristea, Liling Wan, Joshua D Rabinowitz, Yibin Kang.

  Cancer progression is systemically influenced by distant organ dysfunction induced by primary tumors, yet how long-distance tumor-organ crosstalk regulates antitumor immunity remains unclear. Here, we identify host metadherin (MTDH) as a critical regulator of tumor-induced immunosuppression and metabolic reprogramming via tumor-liver interactions. Using Mtdh knockout mouse models, we show that concurrent MTDH loss in hepatocytes and CD8+ T cells enhances effector T cell function and suppresses tumor growth and metastasis. Mechanistically, tumor-derived extracellular vesicles and particles (EVPs) activate Kupffer cells to secrete tumor necrosis factor α (TNF-α) and TGF-β, which suppress hepatic PPARα-mediated lipid oxidation via nuclear factor κB (NF-κB) signaling. MTDH loss restores hepatic lipid catabolism, reduces systemic lipid levels, and promotes mitochondrial metabolic reprogramming in CD8+ T cells under lipid-reduced conditions, thereby boosting antitumor immunity. Genetic or pharmacological targeting of MTDH synergizes with anti-PD-1 therapy. These findings establish host MTDH as a key mediator of tumor-liver crosstalk through metabolic and immune interactions, driving systemic cancer progression.

Keywords:  CD8(+) T cells; EVP; MTDH; PPARα; extracellular vesicles and particles; immunotherapy; lipid metabolism; tumor-liver interaction

DOI:  https://doi.org/10.1016/j.cmet.2026.08.003
Front Immunol. 2026 ;17 1862165

Linoleic acid metabolic reprogramming is linked to immunometabolic remodeling and post-transplant recurrence risk in hepatocellular carcinoma.

Ruixin Zhang, Anhong Zhang, Tian Gao, Chengjie Zhang, Yiqian Liu, Lixin Liu.

   Background: Lipids serve as both metabolic substrates and signaling mediators that critically regulate immune cell fate, function, tolerance, and intercellular communication. In hepatocellular carcinoma (HCC), it remains unclear how intratumoral linoleic acid (LA) allocation between desaturation and oxidative catabolism influences immunometabolic remodeling and post-transplant recurrence.
Methods: Multi-omics profiling was conducted in a liver transplant-associated HCC cohort using paired tumor/non-tumor tissues and serum samples. The intratumoral lipid milieu (C4-C24 fatty acids) was quantified by targeted gas chromatography, whereas lipid-immune programs were resolved by single-nucleus RNA sequencing (snRNA-seq) integrated with targeted transcriptomic profiling. Key immune phenotypes and candidate genes were validated by serum inflammatory mediator profiling, flow cytometric lymphocyte immunophenotyping, spatially resolved tissue assays, and qRT-PCR. LA perturbation experiments provided functional support in vitro.
Result: Fatty acid profiling revealed that non-recurrent tumors were characterized by a higher intratumoral LA/AA ratio and a lower estimated Δ6-desaturation index than recurrent tumors, whereas recurrent tumors exhibited a higher estimated Δ6-desaturation index than their matched distant non-tumor liver tissues. snRNA-seq identified fatty acid catabolism as the most prominently downregulated metabolic pathway in recurrent tumors; malignant-cell analysis further highlighted EHHADH and ACSL3 as key genes involved in recurrence-associated lipid metabolic remodeling. In vitro, exogenous LA-BSA increased ROS accumulation and reduced SPP1 and NECTIN2 expression in HCC cells. Cell-cell communication analysis showed enhanced tumor-Treg signaling in recurrence, with VISTA- and CD80-related networks shifting from Kupffer cells toward SPP1+ macrophages and Tregs. Peripheral and tissue immunophenotyping showed reduced CD8+ T cells and higher IL-10 in recurrent tumors.
Conclusion: Multi-omics analyses indicate that, in primary pre-transplant HCC, post-transplant recurrence is associated with an imbalance between a higher estimated Δ6-desaturation index and attenuated oxidative catabolism-related features of linoleic acid, accompanied by Treg-associated immunosuppressive remodeling. These findings provide a biologically informed framework for post-transplant recurrence risk stratification and further translational investigation.

Keywords:  fatty acid desaturation; fatty acid oxidation; hepatocellular carcinoma; immunometabolism; linoleic acid; liver transplantation; neoplasm recurrence; regulatory T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1862165
Immunometabolism (Cobham). 2026 Oct;8(4): e00090

Modulatory effects of S1QEL on OxLDL-induced metabolic alterations and inflammatory responses in human monocytes.

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

   Background: Oxidized low-density lipoprotein (OxLDL) plays a key role in initiating monocyte activation, glycolytic reprogramming, and pro-inflammatory cytokine production-processes that contribute to aging and progression of age-related diseases such as atherosclerosis and steatohepatitis. Mitochondrial reactive oxygen species (ROS), particularly from complex I, are known modulators of these responses. This study aimed to evaluate the impact of OxLDL on the metabolic and inflammatory responses of primary human monocytes and determine whether co-treatment with site-1 Qo electron leak (S1QEL), a mitochondrial complex I-specific ROS suppressor, could mitigate these effects.
Methods: Monocytes were isolated from healthy human donors and treated with OxLDL alone or in combination with S1QEL. Metabolic parameters including extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured using the Seahorse XF Analyzer. Pro-inflammatory gene expression (IL1B, CXCL8, IL6, TNF) was assessed using quantitative real-time polymerase chain reaction.
Results: OxLDL treatment significantly increased ECAR, indicating enhanced glycolytic activity, without altering mitochondrial respiration (OCR). This metabolic shift was attenuated by S1QEL co-treatment. OxLDL also upregulated IL1B, CXCL8, and IL6 expression, which was significantly reduced by S1QEL. TNF expression remained unchanged across all conditions.
Conclusions: S1QEL effectively suppresses both glycolytic reprogramming and pro-inflammatory cytokine expression induced by OxLDL in human monocytes. These findings underscore the role of mitochondrial complex I-derived ROS in monocyte activation and highlight S1QEL as a potential therapeutic agent for targeting inflammation in aging and several age-related diseases.

Keywords:  glycolysis; immunometabolism; inflammation; monocyte; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1097/IN9.0000000000000090
Front Immunol. 2026 ;17 1910812

Daily HIV pre-exposure prophylaxis enhances monocyte activation and reprogrammes immune cell metabolism.

Grainne Jameson, Dearbhla M Murphy, Isabella Batten, Sarah A Connolly, Adam H Dyer, Annmarie White, Sarah Cochrane, Dearbhla Murphy, Laura Quinn, Emma Devitt, Giovanni Villa, Sharee A Basdeo, Liam Townsend.

   Introduction: Pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine (TDF/FTC) is highly effective for HIV prevention. While antiretroviral therapy (ART) is linked to chronic inflammation in people living with HIV, its direct effects on immune phenotype, function, and metabolism in HIV-negative individuals remain unclear. This study aimed to investigate how daily TDF/FTC pre-exposure prophylaxis modulates immune activation, functional responses, and metabolic programming in innate and adaptive immune cells in HIV-negative individuals.
Methods: Gay, bisexual, and other men who have sex with men (gbMSM) on daily TDF/FTC PrEP underwent immunophenotyping and single-cell metabolic profiling using SCENITH™. Cytokine and chemokine responses were measured ex vivo and after lipopolysaccharide or Mycobacterium tuberculosis stimulation. Responses were compared with those of a demographically similar PrEP-naïve cohort, and five participants were followed longitudinally for 6-9 months after PrEP initiation.
Results: Monocytes from people taking PrEP (n=15; median 533 days) exhibited higher activation marker expression (HLA-DR, CD14) ex vivo and enhanced IL-1β and TNF after bacterial challenge compared with PrEP-naïve individuals (n=11). Longitudinal follow-up of a pilot cohort (n=5) suggested that PrEP initiation increased monocyte activation marker expression (HLA-DR, CD14, CD40, TNFRI/II) and cytokine production (IL-1β, TNF, GM-CSF, IFN-γ, Granzyme B, MIP-1α). Reduced glucose dependency was observed in monocytes, CD56dim NK cells and CD4+ T cells 6-9 months after PrEP initiation.
Discussion: Daily TDF/FTC promotes monocyte activation, enhances pro-inflammatory responses, and appears to reprogramme immune cell metabolism, highlighting ART's potential to modulate immune-mediated inflammatory pathways in HIV-negative individuals.

Keywords:  HIV - human immunodeficiency virus; antiretroviral therapy; immunometabolism; monocytes; pre-exposure prophylaxis (PrEP); tenofovir disaproxil fumarate and emtricitabine

DOI:  https://doi.org/10.3389/fimmu.2026.1910812
Front Immunol. 2026 ;17 1844836

CD8+ T cell heterogeneity and function in lupus nephritis: a focused review.

Zhaomin Mao, Luoyi Wang, Jing Chen, Ming Guan.

  Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus marked by immune complex deposition and tissue-specific inflammation. Advances in single-cell transcriptomics and high-dimensional immune profiling have revealed that CD8+ T cells form a highly heterogeneous and compartment-dependent landscape across peripheral blood, kidney, and urine. This review aims to delineate how compartment-specific phenotypes and signaling programs of CD8+ T cells collectively shape the immunopathogenesis of lupus nephritis (LN). We synthesize current evidence into a unified blood-kidney-urine circuit model, in which systemic priming of circulating CD8+ T pools is followed by renal recruitment, tissue retention and functional reprogramming of kidney-infiltrating populations, cytotoxic and inflammatory tissue injury, and subsequent release of intrarenal immune signatures into urine. Circulating CD8+ T cells include IFN-I-primed naïve-like, effector-memory, and cytotoxic subsets that contribute to systemic immune activation. Within the kidney, infiltrating CD8+ T cells display pronounced clonal expansion, tissue-resident and exhaustion-associated phenotypes, and metabolic reprogramming, all of which correlate with local inflammation and histopathologic severity. Urine-derived CD8+ T cells, increasingly recognized as a non-invasive proxy for intrarenal immunity, recapitulate key transcriptional programs of kidney-infiltrating populations and provide a dynamic readout of ongoing renal injury. Across these anatomical niches, CD8+ T-cell effector and regulatory functions are shaped by pivotal pathways, including type I IFN conditioning, JAK-STAT signaling, NLRP3 inflammasome activation, mitochondrial stress responses, and modulation by immune checkpoints. Collectively, these insights highlight CD8+ T cells as an important effector and regulatory component within the broader multicellular immune network of LN and suggest that resolving their compartmental heterogeneity and signaling circuits may accelerate the development of mechanistically grounded biomarkers and targeted immunomodulatory strategies.

Keywords:  CD8+ T; biomarker; lupus nephritis; pathogenesis; subset

DOI:  https://doi.org/10.3389/fimmu.2026.1844836
Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2601318123

Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells.

Jing Wang, Zegui Ni, Xinxin Zhang, Linling He, Xinyue Zhang, Xu Cheng, Haimo Wang, Guoying Sun, Zhenwei Lu, Chengxu Liu, Hongjie Qian, Youli Lu, Gangyi Liu, Jingying Jia, Jian Ye, Linzhang Huang, Haobin Ye, Rong Li, Wufan Tao, Peng Li, Tong-Jin Zhao, Xingrong Du.

  Amino acid sufficiency is critical for T cell metabolic reprogramming, yet how T cells maintain amino acid homeostasis remains poorly defined. Here, we identify the CORVET and HOPS (CORVET/HOPS) tethering complexes as essential upstream regulators. In activated T cells, they sustain intracellular amino acid levels by promoting macropinocytosis to acquire extracellular nutrients. This function enables dual signaling outcomes: suppression of the integrated stress response (ISR) and activation of mTORC1, which together license metabolic plasticity and effector function. Genetic ablation of core subunits (VPS18 or VPS11) of CORVET/HOPS induces severe amino acid scarcity, triggers pathological ISR activation, and impairs mTORC1 signaling, leading to reduced peripheral T cell numbers and abrogating both inflammatory and protective immunity in vivo. These defects are mechanistically linked: BIM deletion or enforced mTORC1 activity rescues the survival and proliferative failures, respectively, of CORVET/HOPS-deficient T cells. Our work establishes CORVET/HOPS as fundamental couplers linking nutrient acquisition to immune signaling, revealing a targetable node for immuno-metabolic therapy.

Keywords:  CORVET/HOPS; T cells; amino acid; integrated stress response; metabolism

DOI:  https://doi.org/10.1073/pnas.2601318123
Front Immunol. 2026 ;17 1869119

IL-37 and IL-38 in sepsis: immune-metabolic rheostats in a dynamic inflammatory continuum.

Hailong Yan, Lintong Ma, Xiujuan Huang, Xingbo Dang, Longyang Ma, Wei Dai, Wensheng Gao, Weizhou He, Shisan Bao, Gongliang Du.

  Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection, characterised by dynamic and overlapping phases of hyperinflammation and immune suppression. Despite advances in critical care, effective immunomodulatory therapies remain lacking, reflecting an incomplete understanding of its complex immunopathology. Central to sepsis progression is the cytokine storm, a transient but dominant inflammatory surge that contributes to endothelial injury, microvascular dysfunction, and multi-organ failure, followed in some patients by compensatory immunosuppression. Within this evolving immunological landscape, IL-37 and IL-38 have emerged as key members of the IL-1 cytokine family with context-dependent immunoregulatory functions. IL-37 broadly suppresses NF-κB- and MAPK-mediated inflammatory signalling and reprogrammes immunometabolism via mTOR inhibition, thereby attenuating pro-inflammatory cytokine production and modulating innate immune cell activity. IL-38, in contrast, exerts protective effects through regulation of inflammasome activation, promotion of regulatory T (Treg) cell responses, and suppression of effector T cell differentiation, collectively contributing to improved bacterial clearance and reduced systemic inflammation. Although both cytokines are elevated in sepsis and generally associated with disease severity, experimental evidence suggests that they function as endogenous brakes that limit excessive immune activation. However, clinical data remain heterogeneous, particularly regarding IL-10 regulation and stage-specific effects, highlighting context-dependent and compartment-specific actions. This mini-review synthesises current evidence on IL-37 and IL-38 in sepsis, emphasising their roles as integrated immunometabolic regulators rather than phase-specific mediators. We further discuss translational limitations and propose future directions centred on longitudinal immune profiling and precision immunomodulation.

Keywords:  IL-37; IL-38; cytokine storm; intergrade; sepsis

DOI:  https://doi.org/10.3389/fimmu.2026.1869119
Bioact Mater. 2027 Jan;67 458-476

Mitochondria-derived peptide hydrogel augments mitochondrial transplantation for promoting cardiac repair via macrophage metabolic reprogramming.

Hang Li, Yushan Zhang, Yifan Jian, Fang Fang, Wenbin Ouyang, Donglin Zhuang, Wenhao Ju, Rui Gao, Yu Gao, Shaoyang Kang, Pengxu Kong, Yuwei Li, Xiangbin Pan, Weiwei Wang, Zujian Feng.

  Myocardial infarction (MI) is characterized by severe oxidative stress, excessive inflammation, and profound mitochondrial dysfunction. Although mitochondrial transplantation offers therapeutic promise for MI, its clinical translation is severely hampered by the extreme fragility of donor mitochondria with rapid loss of functional viability after isolation. Here, inspired by the intrinsic cellular defense mechanisms against mitochondrial dysfunction, MOTS-c, a mitochondria-derived peptide (MDP), is selected and further conjugated with self-assembling peptide (Q11) to fabricate a hydrogel-based mitochondrial delivery system (MQgel@Mito) for cardiac repair after MI. It has been observed that MQgel significantly extends the survival of isolated mitochondria and maintains metabolic enzyme activity for at least 8 h. More importantly, MQgel not only shields donor mitochondria from oxidative stress and calcium overload, but also enhances mitochondrial internalization by macrophages through an adenosine 5'-monophosphate-activated protein kinase (AMPK)-dependent mechanism. Furthermore, MQgel@Mito facilitates metabolic reprogramming of macrophages by suppressing pro-inflammatory glycolysis and enhancing oxidative phosphorylation (OXPHOS), thereby attenuating M1 polarization. Additionally, MQgel@Mito maintains mitochondrial homeostasis, reduces reactive oxygen species (ROS), and rescues apoptosis of macrophages. In a rat MI model, MQgel@Mito reduces M1 macrophage infiltration and cardiomyocyte damage by delivering viable mitochondria, thereby improving cardiac function and limiting pathological remodeling. These findings establish a paradigm for mitochondrial protection and demonstrate macrophage immunometabolism as a viable therapeutic strategy for MI.

Keywords:  Cardiac repair; Hydrogel; Mitochondrial transplantation; Myocardial infarction; Peptide

DOI:  https://doi.org/10.1016/j.bioactmat.2026.06.010
Eur Arch Psychiatry Clin Neurosci. 2026 Aug 27.

Integrated multi-omics and functional analyses reveal a GDCA-TGR5-mediated immunometabolic signature in anorexia nervosa.

Yanbo Sun, Conghui Xu, Jing Luo, Yunyun Cen, Shengguo Zao, Lijin Zhou, Yuyue Cao, Yanli Li, Weiming Li.

   BACKGROUND: Anorexia nervosa (AN) is frequently accompanied by metabolic disturbances and immune dysregulation, yet its peripheral molecular mechanisms and therapeutic targets remain poorly understood. This study integrates multi-omics analyses with experimental validation to investigate causal relationships between circulating metabolites and immune features in AN.
METHODS: Two-sample Mendelian randomization (MR) analyses based on two independent cohorts were conducted to screen metabolism- and immune-related factors associated with AN. Differential expression analysis combined with machine learning was used to identify core pathogenic genes and immune infiltration patterns, which were cross-validated with MR results. The immunoregulatory role of the core gene G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) was further validated in vitro using mouse bone marrow-derived macrophages (BMDMs) treated with the bile acid metabolite glycodeoxycholic acid (GDCA).
RESULTS: MR analysis revealed significant causal associations between eight circulating metabolites, multiple immune cell traits, and AN. Integrated transcriptomic and machine learning analyses identified TGR5 as a key gene associated with AN. Functional enrichment and immune infiltration analyses indicated that AN is characterized by an immunosuppressive microenvironment, closely correlated with TGR5 expression and activation of the primary bile acid biosynthesis pathway. Molecular docking predicted a stable interaction between GDCA and TGR5. In vitro experiments showed that GDCA increased the proportion of CD206+macrophages and upregulated Arg1 and CD206 expression in a TGR5-dependent manner. Mechanistically, GDCA activated the TGR5/cAMP/PKA pathway, promoted STAT3 and STAT6 phosphorylation, and induced M2 macrophage polarization, shifting cytokine secretion toward an anti-inflammatory phenotype.
CONCLUSIONS: These findings suggest that metabolic alterations in AN directly influence immune regulation. Activation of the GDCA/TGR5/cAMP/PKA/STAT3/6 axis promotes M2 macrophage polarization and anti-inflammatory responses, revealing a novel metabolic-immune pathway with therapeutic potential in AN.

Keywords:  Anorexia Nervosa; Bile acid metabolism; Glycodeoxycholic acid; Metabolic–immune axis; TGR5

DOI:  https://doi.org/10.1007/s00406-026-02367-y
J Dermatol Sci. 2026 Aug 11. pii: S0923-1811(26)00128-3. [Epub ahead of print]

Psoriasis-like skin inflammation drives an elongated mitochondrial network marked by functional failure in keratinocytes.

Luís Eduardo Duarte Gonçalves, Anthony Gabry da Silveira, Luisa Menezes Silva, Bruno Ghirotto Nunes, Marcella Cipelli, Daniel Marconi Mendes, Patrick Cesar Ferreira, Ranieri Coelho Salgado, Lillian Nunes Gomes, Andressa Godoy Amaral, Paulo José Basso, Meire Ioshie Hiyane, Alessandra Sussulini, Antônio Condino Neto, Maria Fernanda Forni, Niels Olsen Saraiva Câmara.

   BACKGROUND: Psoriasis is characterized by a pathogenic, hyperproliferative state of keratinocytes. While inflammation is known to drive this proliferation and induce metabolic reprogramming to regulate immune effector functions, the specific mitochondrial and metabolic alterations in keratinocytes during psoriatic inflammation remain poorly understood.
OBJECTIVE: To determine how cutaneous inflammation dynamically modulates mitochondrial networks and bioenergetics within the epidermal compartment, and to evaluate the metabolic consequences of disrupting this morphology.
METHODS: Using a standardized mouse model of psoriasis-like inflammation, keratinocyte culture and in silico human psoriatic samples, we assessed mitochondrial health. We analyzed mitochondrial membrane potential and quantified metabolites associated with the Tricarboxylic Acid (TCA) cycle. Additionally, we evaluated the expression and activity of mitochondrial fusion and structural synthesis machinery in mouse tissues.
RESULTS: Imiquimod-driven inflammation induces mitochondrial dysfunction, marked by reduced membrane potential and suppression of key TCA cycle intermediates. Rather than undergoing fragmentation, psoriatic keratinocytes exhibit a shift toward fused network state marked by Pgc-1α presence. Pharmacological disruption of this architecture via Mdivi-1 fails to restore function and ameliorate disease progression in vivo; instead, it increases reactive oxygen species production and acts synergistically with IL-17A to robustly amplify pro-inflammatory cytokine secretion.
CONCLUSION: This study shows that an elongated, fused mitochondrial network architecture is a feature of the epidermal compartment under chronic psoriatic inflammation. Furthermore, our findings demonstrate that promoting this structural state via mitochondrial division inhibitors does not improve psoriasis-like inflammation in vivo but rather exacerbates cellular oxidative stress and sustains skin inflammation.

Keywords:  Inflammatory response; Mitochondrial bioenergetics; Oxidative phosphorylation; Skin immunity

DOI:  https://doi.org/10.1016/j.jdermsci.2026.08.002
Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2532225123

SIRT2 deacylase modulators control B cell metabolic reprogramming in EBV infection and mitogenic activation.

Kaeden K Hill, Ashley P Barry, Nicolas M Reinoso-Vizcaino, Lauren E Haynes, Emmanuela N Bonglack, Davis F Ferreira, Sara E Miller, Matthew D Hirschey, Lillian W Chiang, Stacy Remiszewski, Micah A Luftig.

  Sirtuin-2 (SIRT2) is a cellular deacylase, regulating cell cycle progression and metabolic homeostasis. Recently, SIRT2 has emerged as a target with both anticancer and antiviral potential. However, the role and targetability of SIRT2 in viral-driven cancers remains unexplored. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with oncogenic potential that establishes latency in B lymphocytes and is typically controlled by a robust T cell immune response. In settings that compromise this response, such as immune suppression following transplant, EBV can cause B cell lymphomas. With broad immunosuppression and varying response rates limiting the effectiveness of existing lymphoma therapeutics, new strategies are necessary. Here, we report that SIRT2-selective compounds block EBV-mediated B cell transformation and EBV or mitogen-driven B cell division in vitro. SIRT2 modulation significantly alters gene expression and metabolism of EBV-infected B cells, reducing mitochondrial respiration, driving mitochondrial swelling, and inducing nutrient stress and autophagy. Treatment with SIRT2 modulators drives hyperacetylation of targets involved in lipid metabolism, central carbon metabolism, and oxidative phosphorylation. EBV-positive and EBV-negative B cell lymphomas rely on glycolysis to avoid cell death after SIRT2 modulation, revealing a metabolic vulnerability that can be harnessed to kill lymphoma cells. Overall, we have identified how SIRT2 could be implicated as a target of therapeutic potential for B cell lymphomas, while also defining fundamental roles for extranuclear lysine acetylation in regulating B cell proliferation and metabolism.

Keywords:  B cell; Epstein–Barr virus; lymphoma; mitochondria; sirtuin

DOI:  https://doi.org/10.1073/pnas.2532225123
J Neuroimmune Pharmacol. 2026 Aug 26. pii: 44. [Epub ahead of print]21(1):

Palmitic Acid Amplifies Microglial Inflammatory Activation Involving C5aR1-Sensitive Inflammatory Signaling and JMJD3/H3K27me3-Related Epigenetic Changes.

Liqing Chen, Sanqing Xu, Yan Liu, Xiaoping Luo.

  Microglial pro-inflammatory activation contributes to neuroinflammatory processes in many neurological disorders. Saturated fatty acids such as palmitic acid (PA) are increasingly recognized as inflammatory cues, yet the molecular mechanisms linking PA to microglial inflammatory responses remain incompletely defined. In this study, using BV-2 microglia as an exploratory in vitro model, we investigated whether C5aR1-sensitive signaling and JMJD3/H3K27me3-related epigenetic changes are involved in PA-associated inflammatory responses. PA exposure increased Iba1 expression, altered CD86/CD206 expression, and enhanced the secretion of IL-1β, IL-6 and TNF-α. Exogenous C5a produced broadly similar inflammatory changes. Under heat-inactivated serum conditions, PA increased cell-associated C5a immunoreactivity and extracellular C5a levels, and these C5a-related readouts were reduced by PMX53. PMX53 also attenuated PA-associated increases in inflammatory markers and in the expression of TLR4, total NF-κB p65, c-Fos, and c-Jun. In parallel, PA and C5a increased JMJD3 expression and JMJD3 enrichment at selected IL-1β and IL-6 promoter regions, accompanied by reduced H3K27me3 enrichment at these loci. Pharmacological KDM6 inhibition with GSK-J4 attenuated PA-associated increases in IL-1β and IL-6 expression. Together, these findings support the involvement of C5aR1-sensitive inflammatory signaling and JMJD3/H3K27me3-related epigenetic regulation in PA-associated microglial inflammatory responses.

Keywords:  BV-2 microglia; C5a; Histone demethylase; Inflammation; Palmitic acid

DOI:  https://doi.org/10.1007/s11481-026-10308-8
Int J Mol Sci. 2026 Aug 21. pii: 7495. [Epub ahead of print]27(16):

Lactate as a Master Regulator of Immune Suppression: From Metabolic Waste to Epigenetic Checkpoint in Colorectal Cancer.

Beiyan Chen, Shuang Gao, Xin Chen, Qingping Shi, Mingli Shen, Jieru Han.

  Colorectal cancer, especially the microsatellite-stable subtype, which accounts for 85% to 95% of cases, resists immune checkpoint inhibitors largely due to metabolic reprogramming in the tumor microenvironment. Lactate has evolved from a waste product into a central immunosuppressive regulator. Oncogenic KRAS and BRAF mutations drive aerobic glycolysis, causing glucose deprivation and massive lactate accumulation in the tumor microenvironment. Lactate suppresses immunity through three parallel mechanisms. It signals via GPR81 to recruit polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and inhibit T-cell function. It contributes to histone H3K18 lactylation, which silences effector genes including IFN-γ and GZMB while upregulating PD-L1 expression. It also acidifies the microenvironment to pH 6.0-6.5, directly impairing NK and T-cell activity. Concurrent lipid abundance stabilizes the MCT4 lactate exporter, forming a bidirectional feed-forward loop that amplifies lactate effects. Spatial metabolic heterogeneity creates distinct immune battlefields, with a supportive 'metabolic oasis'-a concept proposed in this review-at the invasive front and a deeply immunosuppressive core. Thus, lactate acts as an epigenetic and signaling hub that bridges oncogenic mutations, metabolic competition and immune evasion. Targeting lactate metabolism through LDHA or MCT4 inhibition, modulation of histone lactylation, or disruption of lactate-lipid crosstalk, when combined with classical immune checkpoint blockade and guided by spatial biomarkers, offers a promising strategy to overcome immunotherapy resistance in this challenging subtype.

Keywords:  colorectal cancer; histone lactylation; immunotherapy resistance; lactate; metabolic checkpoint; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms27167495
Microorganisms. 2026 Aug 20. pii: 1852. [Epub ahead of print]14(8):

Itaconic Acid Directly Binds to the Cysteine Residue of PurF: A Novel Mechanism for Inhibiting Purine Metabolism in Porcine Pathogenic Escherichia coli.

Haozhen Liu, Xin Li, Xinyu Zhang, Yao Ge, Yinfeng Chen, Xinjian Li, Zhenlong Wu.

  Itaconic acid has been reported to possess anti-inflammatory and antibacterial properties. However, its specific mechanisms of action against pathogenic bacteria, especially in the context of purine metabolism, remain poorly understood. Here, we investigate the impact of itaconic acid on the purine metabolism of PCN033, a highly pathogenic porcine extraintestinal pathogenic Escherichia coli (ExPEC) strain. Our in vitro and in vivo experiments demonstrated that itaconic acid significantly inhibited the proliferation of PCN033. Multi-omics analyses, including transcriptome and metabolome sequencing, revealed that itaconic acid severely disrupted the purine metabolism pathway of PCN033. Further mechanistic studies identified PRPP amidotransferase (PurF), a key enzyme in de novo purine synthesis, as a direct target of itaconic acid. Molecular docking and click chemistry experiments provided compelling evidence that itaconic acid specifically binds to the second cysteine residue (2C) of PurF, leading to the inhibition of its enzymatic activity. These data reveal a novel and critical mechanism by which itaconic acid exerts its antibacterial effects in response to bacterial infection. Importantly, our in vivo data show that supplementation with itaconic acid alleviated weight loss, organ damage, and inflammatory responses induced by PCN033 infection in mice and nursery pigs. These novel findings enhance our understanding of the antibacterial mechanisms of itaconic acid. Supplementation with itaconic acid could serve as a therapeutic strategy for treating pathogenic bacterial infections in humans and other animals.

Keywords:  PRPP amidotransferase (PurF); itaconic acid; porcine extraintestinal pathogenic Escherichia coli (PCN033); purine metabolism

DOI:  https://doi.org/10.3390/microorganisms14081852
Front Endocrinol (Lausanne). 2026 ;17 1899115

Metabolic, viral, and immune phenotypes in long COVID.

Ivette F Emery, Seynt Jiro Sahagun, Elizabeth R M Zunica, Christopher Axelrod, Robbie A Beyl, Eunhan Cho, Guillaume Spielmann, Samantha Costa, Joanne T DeKay, Carolyn Chlebek, Shinya Amano, Katherine Stevens, Philipp E Scherer, Dawei Bu, Aida Javidan, Brian S Finlin, Xiaohua D Zhang, Barbara Nikolajczyk, Catherine Blish C, Carolyn Bramante, Tracey McLaughlin, Soneida DeLine-Caballero, Kalani Ratnasiri, Uma Mangalanathan, Jonathan Z Li, Brooke M Leeman, Gregory Edelstein, Elizabeth W Karlson, John P Kirwan, Philip A Kern, Sergei Ryzhov, Clifford J Rosen.

   Context: Long COVID is characterized by persistent symptoms ≥ 3 months after acute SARS-CoV-2 infection. To date, the underlying pathophysiology is unclear.
Objective: To characterize the immune and metabolic features of Long COVID and the potential role of viral persistence in adipose tissue.
Design: Case-control, cross-sectional study under the RECOVER initiative.
Setting: Maine, Louisiana, and Kentucky.
Participants: Adults from the RECOVER study with high or low symptom burden assessed by the PROMIS scoring system or the Long COVID RECOVER Index (LCRI), matched by age, sex, BMI comparing post infected individuals with Long COVID vs those without sequelae.
Main outcome measures: The primary outcome was a difference in T cell mitochondrial respiration by symptom severity. Secondary outcomes included glucose tolerance, body composition, T cell surface markers, subcutaneous adipose biopsy.
Results: There were 54 participants, 80% female, mean age was 51.7 years, mean BMI 31. Time from initial infection was 894 days. The participant cohort by symptom burden was elucidated using a PROMIS symptom score subdivided by the following: High Symptom Burden (HSB) >15:n=25, Intermediate Symptom Burden (ISB) 10-15: n=14 and Low Symptom Burden (LSB) <10;n=15. Using the LCRI, n=15 were Long COVID+ (LC+) and n=39 were Indeterminate. The primary outcome, T-cell oxidative phosphorylation, did not differ between LC+ and Indeterminate nor by PROMIS scores. BMI and fat mass did not differ but T cell glycolytic activity was greater in those with LC+ vs Indeterminate. Lean mass and femoral BMD trended lower in the HSB vs LSB by both classifications. Prevalence of Type 2 diabetes did not differ by symptom scores, but HOMA-IR was higher and HOMA-B was lower in LC+ vs Indeterminate. SARS-CoV-2 viral RNA was not detectable in subcutaneous adipose tissue biopsies. CD26+ T cell number, and DPP-4 (CD26) activity were higher in the HSB and correlated significantly with symptom scores (r=0.52, p<0.01); plasma cytokines and stimulated T-cell cytokines did not differ by symptom group in either classification.
Conclusions: Individuals with Long COVID symptoms show subtle impairments in glucose tolerance, serum leptin, lean mass and enhanced T-cell DPP-4 activity. Participants with Long COVID have subtle changes in glucose metabolism that are not driven by SARS-CoV-2 virus in subcutaneous adipose tissue.

Keywords:  T cells; glucose metabolism; glucose metabolism glycolysis; glycolysis; leptin; leptin T cells

DOI:  https://doi.org/10.3389/fendo.2026.1899115
Cell Death Differ. 2026 Aug 27.

TRIM32-mediated ubiquitination of STING promotes glycolysis and tumor progression.

Huaxin Zhou, Zhengyao Guan, Zhaoqing Yin, Biaofeng Shan, Jun Wu, Kangping Lu, Jiazheng Li, Hao Zhang, Jianyun Wang, Chongzhong Liu, Zhangshuo Yang, Xiangyu Zhai.

The Warburg effect, a hallmark of metabolic reprogramming, drives tumor progression, but its upstream regulation remains unclear. Using hepatocellular carcinoma (HCC) as a model, we identify TRIM32, an E3 ubiquitin ligase, as a potent activator of glycolysis that promotes malignancy. TRIM32 is upregulated in HCC tissues and cell lines, correlating with aggressive features and poor prognosis. Gain- and loss-of-function studies show that TRIM32 enhances proliferation, invasion, and migration in vitro and accelerates tumor growth and lung metastasis in xenografts. Mechanistically, TRIM32 mediates K48- and K63-linked polyubiquitination of STING, accelerating its degradation and relieving glycolytic suppression. Reduced STING elevates HK2 and promotes its mitochondrial localization, sustaining glycolysis and bioenergetics. TRIM32 knockdown decreases tumor burden, metastasis, and glycolytic activity, while hepatocyte-targeted STING knockdown rescues tumorigenesis in liver-specific TRIM32 knockout mice. These findings define a TRIM32-STING-HK2 axis that links ubiquitin-mediated suppression of innate immune signaling to glycolytic activation. Although validated in HCC, this mechanism likely applies broadly across solid tumors and nominates TRIM32 as a therapeutic target to reprogram tumor metabolism and limit malignancy.

DOI: https://doi.org/10.1038/s41418-026-01855-x