bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–02–15
forty-six papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Substrate availability and citrate alter TCA cycle metabolism and SLC13A3 in macrophage immune responses.
  2. Immunometabolism Reframes Alzheimer's Disease: From Systemic Dysmetabolism to Glial Rewiring.
  3. FASN-mediated metabolic reprogramming drives CD4+ T cell hyperactivation in Sjögren's syndrome via fatty acid oxidation-dependent oxidative phosphorylation.
  4. Editorial: Unraveling immune metabolism: single-cell & spatial transcriptomics illuminate disease dynamics.
  5. SAICAR Drives T Regulatory Cell Differentiation and FOXP3 Maintenance to Promote Immunotherapy Resistance.
  6. Cystine fuels ILC2s to survive lung inflammation.
  7. Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine.
  8. Suppression of CD4 T cells by Tregs dictates metabolic remodeling of CD8 T cells during effector to memory transition.
  9. HIF1α Activates Glycolysis to Suppress Mycobacterium tuberculosis Growth in Mouse Bone Marrow-Derived Macrophages.
  10. Global Metabolomic Analysis of Lytic KSHV Infection: Induced Host Nucleotide Metabolism is Required for Infectious Virus Production.
  11. MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.
  12. Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver.
  13. Tissues Guide Dependence of Treg on the Transferrin Receptor.
  14. Metabolic reprogramming and immunosenescence: a new sight for glioma therapy.
  15. 650 nm red-light therapy attenuates sepsis-induced acute lung injury via adiponectin-mediated immune-metabolic reprogramming.
  16. Salmonella-Host-microbiota interactions: Immunity and metabolism.
  17. Regulatory mechanisms and targeted therapeutic strategies of glycolytic metabolism in rheumatoid arthritis.
  18. Glutamine supports human cytomegalovirus induced lipidome remodeling through reductive carboxylation.
  19. Aberrant interferon-γ signaling disrupts trophoblast invasion via IDO1/AHR signaling and metabolic reprogramming associated with recurrent pregnancy loss.
  20. Host kynurenine monooxygenase (KMO) serves as a critical immune defense factor restricting Toxoplasma gondii proliferation.
  21. RT-ICI therapy induces a distal immunometabolic axis that shapes systemic macrophage polarization and enhances local T cell immunity.
  22. Targeting the fatty acid metabolism pathway represents a promising antiviral strategy against diverse viral infections.
  23. GDF15 orchestrates mitochondrial-immune crosstalk via SMAD7-HIF-1α-PKM2 cascade to attenuate septic liver injury.
  24. Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
  25. Distinct immunometabolic signatures of type 1 versus type 2 diabetes in a murine model of myocardial infarction.
  26. Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
  27. Immunometabolism as a New Bimodal Therapeutic Concept in Inflammatory Bowel Disease and Immune-Mediated Inflammatory Disorders.
  28. HIF-1α as a Central Regulator of Monocyte Responses to Hypoxia.
  29. Polymer of methyl malonic acid suppress inflammation by downregulating IL-2 through ROS overproduction.
  30. Hormonal rewiring of immunity during dietary restriction ensures host defense and systemic glucose conservation.
  31. Cancer cell-intrinsic inflammasome protein ASC links innate immunity with mitochondrial metabolism in driving pancreatic cancer.
  32. CAR Signaling Informs Mechanisms to Enhance Metabolism and Function in γδ T Cells.
  33. The dopamine D3 receptor regulates dopamine-induced activation and glycolytic metabolism of synovial fibroblasts in rheumatoid arthritis.
  34. Reactive sulfur species as emerging immunomodulators: mechanistic insights and therapeutic prospects.
  35. Bacteroides intestinalis -Driven Arabinoxylan Fermentation Mitigates Inflammatory and Metabolic Dysfunction.
  36. Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses.
  37. Lipid oxidation reprogramming in cancer-associated fibroblasts enhances CD8+ T cell cytotoxicity and therapeutic response.
  38. Anti-inflammatory and antibacterial hydrogel of chitosan-dimethyl itaconate conjugate.
  39. Immunometabolism: A Novel Therapeutic Target and Its Pharmacological Modulation for Intervertebral Disc Degeneration.
  40. PLIN3-triggered lipophagic flux releases FFAs to facilitate CSFV propagation.
  41. RSAD2/VIPERIN and CMPK2 Coordinate an Immunometabolic Response to Epstein-Barr Virus.
  42. Dysregulation of Farnesoid X Receptor on Neutrophil Homeostasis Exacerbates Intestinal Inflammation via the mTORC1-Glycolysis Signaling Pathway.
  43. Amikacin-eravacycline combination mediates the synergistic elimination of carbapenem-resistant pathogens via in vitro and in vivo metabolic reprogramming.
  44. Fumaric acid restores neomycin efficacy against carbapenem-resistant Vibrio parahaemolyticus through metabolic reprogramming.
  45. Ddx17 Mitigates Sepsis-Induced Cardiomyopathy by Regulating Mitochondrial Dynamics in Cardiomyocytes.
  46. Integrated multi-platform metabolomics reveals fatty acid-mediated inflammatory signatures in pretibial myxedema.
  1. Immunol Lett. 2026 Feb 09. pii: S0165-2478(26)00020-9. [Epub ahead of print] 107147
    Substrate availability and citrate alter TCA cycle metabolism and SLC13A3 in macrophage immune responses.
    Lea Woyciechowski, Hanna F Willenbockel, Thekla Cordes.
      Cell culture media are commonly formulated to enhance cell growth and often lack the physiological nutrient composition found in human blood plasma. The impact of substrate availability on immune cell metabolism and function remains incompletely understood. Here, we demonstrate that changes in culture medium composition affect mitochondrial metabolic pathways, immune responses, and transport in macrophages. Using mass spectrometry and stable isotope tracing, we identify citrate as a mediator linking extracellular substrate availability to intracellular metabolism. We also observe increased IL-6 secretion and elevated expression of plasma membrane transporter NaDC3 (SLC13A3) under physiological carbon source conditions that are reversed when citrate is excluded from the medium. Our findings demonstrate that extracellular substrate composition influences macrophage immunometabolism and identify citrate as an extracellular signal that modulates immune responses. This work highlights the importance of physiologically relevant nutrient availability in studying and targeting immunometabolic pathways.
    Keywords:  SLC13A3; citrate; immunometabolism; itaconate; mass spectrometry; mitochondrial metabolism; substrate availability; tracing
    DOI:  https://doi.org/10.1016/j.imlet.2026.107147
  2. Cell Mol Neurobiol. 2026 Feb 13.
    Immunometabolism Reframes Alzheimer's Disease: From Systemic Dysmetabolism to Glial Rewiring.
    Duc-Hiep Bach, Thanh Liem Nguyen.
      Alzheimer's disease (AD) is increasingly recognized as a disorder of dysregulated immunometabolism at the neurovascular-glia-neuron interface. Systemic metabolic stressors such as insulin resistance, dyslipidaemia, and obesity converge on brain innate immune cells to reprogram energy pathways and sustain maladaptive inflammation. In microglia, metabolic rewiring across glycolysis-oxidative phosphorylation balance, glutaminolysis, and lipid handling governs trained-immunity programs that dictate amyloid and tau clearance, synaptic maintenance, and neurotoxicity. These processes converge on druggable nodes including AMPK-mTOR signaling, HIF-1α, and tricarboxylic-acid intermediates. Neurovascular fuel delivery is likewise impaired: endothelial GLUT1 loss and mitochondrial stress at the blood-brain barrier accelerate amyloid accumulation and neuronal injury. Lipid metabolism bridges metabolism and inflammation, as APOE4-driven microglial lipid droplets link genetic risk to inflammatory phenotypes. NLRP3 integrates metabolic danger signals into chronic neuroinflammation. Translational momentum now builds around metabolic interventions particularly GLP-1 receptor agonists and SGLT2 inhibitors that modulate glial metabolism, systemic inflammation, and barrier integrity. Converging metabolomic, lipidomic, and extracellular-vesicle biomarkers enable tracking of these pathways in humans, defining an immunometabolic axis of AD and supporting precision-medicine strategies to reprogram metabolism for disease modification.
    Keywords:  Alzheimer’s disease; Blood–brain barrier; Immunometabolism; Metabolic dysfunction; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1007/s10571-026-01691-0
  3. Arthritis Res Ther. 2026 Feb 13.
    FASN-mediated metabolic reprogramming drives CD4+ T cell hyperactivation in Sjögren's syndrome via fatty acid oxidation-dependent oxidative phosphorylation.
    Lei Ye, Xijun Wang, Junhao Yin, Huan Shi, Jiayao Fu, Baoli Wang, Lingyan Zheng.
       BACKGROUND: Sjögren's syndrome (SS) is a chronic systemic autoimmune disease in which CD4+ T cells play a critical role. Recent advances in immunometabolism suggest that metabolic reprogramming contributes to autoimmune pathogenesis. This study investigates the role of fatty acid synthase (FASN) in CD4+ T cell dysfunction in SS.
    METHODS: Peripheral blood CD4+ T cells were isolated from SS patients and healthy controls. FASN expression was assessed via PCR, Western blot, and immunofluorescence. Functional and metabolic assays, including flow cytometry, Seahorse analysis, transcriptomic profiling, and global metabolomics (Q300) were performed using murine and human CD4+ T cells treated with the FASN inhibitor orlistat. Rescue experiments were conducted with oleic acid (OA) and palmitoleic acid (PA). In vivo efficacy was evaluated in NOD/LtJ and experimentally-induced SS (ESS) mouse models.
    RESULTS: FASN was significantly upregulated in CD4+ T cells from SS patients and activated murine T cells, correlating with disease activity markers. Orlistat-mediated FASN inhibition suppressed T cell proliferation, activation (CD25/CD69), and glycolytic metabolism, while enhancing oxidative phosphorylation (OXPHOS), leading to elevated ROS and mitochondrial dysfunction. Metabolomics identified reduced OA and PA levels upon FASN inhibition. Exogenous OA and PA partially restored metabolic balance and activation markers. In murine models, orlistat reduced salivary gland lymphocytic infiltration, pro-inflammatory cytokines (IL-17/TNF-α), and improved salivary flow.
    CONCLUSION: FASN drives CD4+ T cell hyperactivation and metabolic reprogramming in SS. Its inhibition shifts cell metabolism from glycolysis to OXPHOS, reducing inflammation and ameliorating disease in preclinical models. These results identify FASN as a potential therapeutic target for SS.
    Keywords:  Fatty acid synthase (FASN); Metabolic reprogramming; Oxidative phosphorylation (OXPHOS); Sjögren’s syndrome (SS); T cells
    DOI:  https://doi.org/10.1186/s13075-026-03765-2
  4. Front Endocrinol (Lausanne). 2026 ;17 1779505
    Editorial: Unraveling immune metabolism: single-cell & spatial transcriptomics illuminate disease dynamics.
    Yejun Tan, Yafeng Zhu, Zhengtao Liu.
      
    Keywords:  immune microenvironment; immunometabolism; metabolic reprogramming; scRNA sequencing; spatial transcriptomics
    DOI:  https://doi.org/10.3389/fendo.2026.1779505
  5. Cancer Res. 2026 Feb 11.
    SAICAR Drives T Regulatory Cell Differentiation and FOXP3 Maintenance to Promote Immunotherapy Resistance.
    Mao Li, Yaqi Chen, Anyi Liu, Qi Wu, Changsheng Huang, Da Song, Fuqing Hu, Jingqin Lan, Chen Huang, Junbo Hu, Guihua Wang.
      Regulatory T cells (Tregs) within the tumor microenvironment critically undermine the efficacy of PD-1 immune checkpoint blockade. Metabolic reprogramming has emerged as a critical determinant of antitumor immunity, highlighting the need to define the metabolic cues that program Treg differentiation in cancer. Here, we identified the purine biosynthesis intermediate succinylaminoimidazole carboxamide ribose-5'-phosphate (SAICAR) as a key metabolic driver of Treg induction and resistance to anti-PD-1 immunotherapy. Mechanistically, SAICAR directly bound to the serine/threonine phosphatase PPM1A, inhibiting SMAD3 dephosphorylation and thereby sustaining TGF-β-SMAD3 signaling. Persistent SMAD3 activation enhanced FOXP3 transcription and stabilized the Treg lineage. In both human tumors and mouse models, elevated intratumoral SAICAR levels were associated with increased Treg accumulation, suppression of effector T cell function, and failure of PD-1 blockade. Genetic or pharmacological reduction of SAICAR restored antitumor immunity and sensitized tumors to PD-1 therapy. Notably, low-dose 6-mercaptopurine disrupted SAICAR-driven immunosuppression and synergized with anti-PD-1 treatment without inducing systemic immune toxicity. Together, these findings establish SAICAR as an immunometabolic regulator that links purine metabolism to immune evasion and highlight a therapeutically actionable pathway to overcome metabolite-driven resistance to immune checkpoint blockade.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4373
  6. Immunity. 2026 Feb 10. pii: S1074-7613(26)00039-7. [Epub ahead of print]59(2): 232-234
    Cystine fuels ILC2s to survive lung inflammation.
    Yuchao Jing, Jie Zhou.
      Tissue inflammation introduces unique, and often harsh, environments for immune cells. During allergic airway inflammation, pathogenic ILC2s proliferate robustly and drive pathology, but how do they overcome the nutrient-depleted environment? In this issue of Immunity, Wientjens et al. define mechanisms that endow pathogenic ILC2s with metabolic flexibility and resilience.
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.018
  7. bioRxiv. 2026 Jan 29. pii: 2026.01.27.702014. [Epub ahead of print]
    Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine.
    Beth Kelly, Minsun Cha, Tatjana Gremelspacher, Jacob L Martin, Massimo Andreis, Gustavo E Carrizo, Mia Gidley, Michal A Stanczak, Petya Apostolova, David E Sanin, Ananya Majumdar, Erika L Pearce.
      Delineating how acquired nutrients are partitioned into different intracellular pathways, and how these various fates support distinct functions in T cells is limited. We show that CD8 + T cells acquire cysteine to serve both as a substrate for glutathione (GSH) production, which modulates effector functions, and to cede its sulfur for NFS1-dependent FeS-cluster synthesis, which supports proliferation. NFS1 deletion in activated CD8 + T cells promotes exhaustion and dampens anti-cancer immunity, while blocking cysteine flux into GSH, or enforcing FeS metabolism, enhance tumor control. This role for disrupted FeS metabolism in T cell exhaustion is echoed in data from human HCC. Elucidating how different intracellular pathways use cysteine enables targeted control of cysteine flux to retain beneficial effects of cysteine while abolishing those that restrain function. We illustrate this concept for one metabolite, cysteine, but it is likely to apply to other metabolites relevant for immune cell function.
    DOI:  https://doi.org/10.64898/2026.01.27.702014
  8. bioRxiv. 2026 Feb 03. pii: 2026.02.01.703100. [Epub ahead of print]
    Suppression of CD4 T cells by Tregs dictates metabolic remodeling of CD8 T cells during effector to memory transition.
    Adithya K Vegaraju, Vandana Kalia, Surojit Sarkar.
      Metabolic transitions between naïve, effector and memory T cell states are largely orchestrated by TCR, costimulatory and cytokine signals along with nutrient availability in the immune microenvironment. Treg cells have been shown to play a critical role in the effector-to-memory (E-M) transition of virus-specific CD8 T cells through regulation of proliferation and cytotoxic functional programs. However, the precise Treg-dependent metabolic changes that occur in the microniches and, the underlying molecular and cellular mediators of E-M transition remain undefined. Here we show that Treg cells promote the metabolic remodeling of memory-precursor effector CD8 T cells (MPEC) from aerobic glycolysis to fatty acid oxidation as they enter quiescence after antigen clearance. Our data implicate the anatomic microniche of the splenic white pulp as a site for Treg-MPEC interactions. We further show that optimal E-M metabolic transition requires regulation of effector CD4 T cells and inflammatory myeloid cells through inhibitory CTLA4 signals from Treg cells. Moreover, antagonism of inflammatory cytokine interferon-γ (IFN-γ) signals partially rescues the memory defects associated with absence of Treg cells. Together, these findings support a metabolic triad model of memory CD8 T cell differentiation where Treg-dependent regulation of inflammation from effector CD4 T cells promotes the transition of CD8 T cells from cytotoxic effector to quiescent memory metabolic programs. These studies define novel molecular targets that may be exploited to manipulate metabolism, migration and memory function during vaccination.
    DOI:  https://doi.org/10.64898/2026.02.01.703100
  9. Immunology. 2026 Feb 08.
    HIF1α Activates Glycolysis to Suppress Mycobacterium tuberculosis Growth in Mouse Bone Marrow-Derived Macrophages.
    Junghwan Lee, Jaewhan Kim, Ji-Ae Choi, Tam Doan Nguyen, Seoyeon Jo, Chang-Hwa Song.
      Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge due to the pathogen's ability to evade host immune responses and persist within macrophages. We investigated the metabolic changes in mouse bone marrow-derived macrophages (BMDMs) upon Mtb infection and identified significant alterations in gene expression related to key metabolic pathways through RNA sequencing analyses. Among them, glycolysis-related genes, including hypoxia-inducible factor 1α as a key regulator of glycolysis, are upregulated in Mtb-infected BMDMs. To investigate whether glycolysis plays a critical role in reducing intracellular Mtb growth, we cultured Mtb-infected BMDMs under high- or low-glucose conditions. We found that high-glucose conditions increased glycolytic enzyme levels, inducible nitric oxide synthase expression and proinflammatory cytokine production, reducing Mtb's intracellular survival. HIF1α agonist treatment increased glycolysis, reactive oxygen species levels and proinflammatory cytokine production, enhancing bactericidal activity against Mtb. In contrast, inhibition of HIF1α by a specific inhibitor FM19G11 leads to decreased glycolysis, reduced proinflammatory cytokine production and increased Mtb survival. Since succinate has been known to increase the stabilisation and activation of HIF1α, we added succinate to Mtb-infected BMDMs to evaluate the function of succinate related to HIF1α activation. As expected, succinate treatment enhanced glycolysis through HIF1α stabilisation and shifted BMDMs to proinflammatory M1-like phenotype. Our findings indicate that Mtb-induced glycolysis plays a central role in the reduction of intracellular Mtb in BMDMs. Succinate is a key factor for HIF1α-mediated glycolysis in Mtb-infected BMDMs.
    Keywords:   Mycobacterium tuberculosis ; HIF1α; glycolysis; macrophages; succinate
    DOI:  https://doi.org/10.1111/imm.70116
  10. bioRxiv. 2026 Feb 03. pii: 2026.02.02.703314. [Epub ahead of print]
    Global Metabolomic Analysis of Lytic KSHV Infection: Induced Host Nucleotide Metabolism is Required for Infectious Virus Production.
    Fatima Hisam, Emma Winn, Spandan Mukherjee, Savannah Price, Yennifer A Gaspar, Claire Wang, Hamid R Baniasadi, Tracie Delgado, Erica L Sanchez.
      Kaposi's Sarcoma Herpes Virus (KSHV) is the etiological agent of Kaposi's Sarcoma (KS) which is known to cause 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 the doxycycline-inducible 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 to lytic replication. During lytic KSHV infection, pathway enrichment analysis shows that the top two most significantly impacted and dysregulated pathways are purine and pyrimidine metabolism. 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 inhibits cellular DHFR and decreases nucleotide metabolism by reducing tetrahydrofolate cofactors, significantly reduced KSHV late lytic viral gene expression upon reactivation compared to control. Additionally, titering cell-free supernatants from MTX-treated lytic KSHV-infected cells showed a significant reduction in infectious virion production. Furthermore, by adding folinic acid (FA), a downstream metabolite of the MTX-DHFR inhibition step, in the presence of MTX, late lytic gene expression and infectious virion production were significantly rescued. Furthermore, we observed a significant decrease in viral titer of murine herpesvirus 68 (MHV-68), a model virus to study gammaherpesvirus, after MTX treatment. Overall, our study demonstrates that metabolic inhibition during lytic gammaherpesvirus infection decreases productive infection and hence, serves as a potential therapeutic antiviral target.
    DOI:  https://doi.org/10.64898/2026.02.02.703314
  11. Gut. 2026 Feb 09. pii: gutjnl-2025-336323. [Epub ahead of print]
    MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.
    Yang Chen, Gao-Wei Jin, Li-Hong He, Yu Dong, Yan-Na Zhang, Han-Xiang Guo, Yi-Ting Xu, Zi-Yang Wei, Bin-Fei Dang, Chun-Yang Mu, Wan-Yue Cao, Yi-Ze Zhang, Xiao-Bao Wei, Yu-Xiong Feng, Yun-Hua Liu, Qi Zhang, Ting-Bo Liang.
       BACKGROUND: Liver metastasis is a common and fatal event for patients with pancreatic ductal adenocarcinoma (PDAC). Dysregulated mitochondrial dynamics reshape biological processes, including metabolism reprogramming, which disrupts immune cell function and promotes metastatic progression.
    OBJECTIVE: To identify key drivers that reprogramme PDAC mitochondrial function and its role in remodelling the immunosuppressive tumour microenvironment (TME) during PDAC liver colonisation.
    DESIGN: Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screening, in vivo mouse model screening and in vitro anoikis-resistant cell selection were employed to identify key drivers during PDAC liver colonisation. PDAC organoids, metabolic flux analysis, single-cell RNA sequencing, spatial metabolomics and glutathione S-transferase (GST) pull-down assay were used to explore the regulation of mitochondrial fission process protein 1 (MTFP1) on PDAC liver colonisation and unravel the underlying mechanism.
    RESULTS: We revealed MTFP1, a protein that plays an important role in cell viability and mitochondrial dynamics, as a driver of PDAC liver colonisation. Mechanistically, MTFP1 is recognised as a novel ATP synthase modulator through its interaction with numerous ATP synthase subunits, thereby enhancing oxidative phosphorylation (OXPHOS). Increased mitochondrial fission and subsequent redox signalling (ROS production) upregulates solute carrier family A1 member 5 (SLC1A5) expression by activating the PI3K/AKT/c-MYC pathway, competing for glutamine uptake and impaired antitumour responses of CD8+ T cells. By performing virtual screening, we identified KPT 9274 (ATG-019) as an effective inhibitor of MTFP1. Limitation of glutamine uptake in PDAC cells or MTFP1 inhibition reverses the immunosuppressive TME and reduces liver colonisation of PDAC.
    CONCLUSION: Our data demonstrate that the enhanced MTFP1 expression leads to an upregulated glutamine-OXPHOS axis in PDAC liver colonisation. This metabolic shift is triggered by the ROS/PI3K/AKT/c-MYC/SLC1A5 pathway. Targeting MTFP1 may be a potential therapeutic strategy for PDAC patients with liver metastasis.
    Keywords:  CANCER IMMUNOBIOLOGY; LIVER METASTASES; OXIDATIVE METABOLISM; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2025-336323
  12. Exp Mol Med. 2026 Feb 13.
    Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver.
    Tae Hyun Kim, Seong Hun Lim, Hyesung Lee, Young Chan Chae, Do Sik Min.
      The tumor microenvironment (TME) is a complex ecosystem composed of not only malignant cells but also diverse stromal and immune cell populations that collectively shape tumor behavior. Metabolism is a central regulator of the TME, orchestrating intercellular communication through altered nutrients and signaling pathways to influence both the metabolic plasticity of cancer cells and functional balance of immune populations, ultimately determining tumor progression and antitumor immunity. Although tumor-intrinsic metabolic programs have been extensively characterized, emerging evidence highlights stromal metabolism as the dominant force sculpting immune responses within the TME. Among the nonmalignant stromal constituents, cancer-associated fibroblasts and cancer-associated adipocytes have emerged as metabolically active hubs that release and redistribute key metabolites, such as lactate, fatty acids and amino acids, to modulate the activity of both tumor and immune cells. Here we integrate recent advances in the understanding of stromal-immune metabolic crosstalk and elucidates how diverse metabolic mechanisms, including nutrient competition, mitochondrial remodeling, redox imbalance and immunometabolic rewiring, collectively reinforce an immunosuppressive TME and drive therapeutic resistance. Our study highlights the emerging strategies for selectively reprogramming these metabolic networks as potential therapeutic avenues. Deciphering these multilayered interactions will establish a conceptual and mechanistic foundation for reprogramming TME, restoring immune competence and enhancing the efficacy of current immunotherapies through metabolism-targeted interventions.
    DOI:  https://doi.org/10.1038/s12276-026-01650-1
  13. bioRxiv. 2026 Feb 03. pii: 2026.02.01.703140. [Epub ahead of print]
    Tissues Guide Dependence of Treg on the Transferrin Receptor.
    Michelle Montoya, Yasmine T Toudji, Ata Ur Rehman, Anton Zhelonkin, KayLee K Steiner, Teresa Tamborra-Walton, Katherine N Gibson-Corley, Samantha St Jean, Denis A Mogilenko, Jeffrey C Rathmell, Kelsey Voss.
      Activated T cells increase transferrin-bound iron uptake via the transferrin receptor, also called CD71. We previously demonstrated that targeting CD71 with an antibody to reduce iron update can modify CD4 T cell function, with different effects on T H 1, T H 17, and regulatory T (Treg) cells. CD71 blocking antibody-treated Tregs had no loss of viability or differentiation, and Foxp3 expression was increased. However, a genetic deletion of Tfrc (the gene for CD71) driven by Foxp3 -Cre was reported to cause a lethal autoimmunity. Whether altered immune homeostasis or insufficient early developmental tolerance drive the phenotype of CD71 knockout (KO) Treg mice were unclear. Here, we examined the Foxp3 - YFP -Cre KO mouse model and a tamoxifen-inducible KO model in adults to determine the role of CD71 expression in Treg cells. We hypothesized that due to a lack of iron for mitochondrial metabolism, KO Treg adapt to rely heavily on glycolysis and become unstable, promoting pro-inflammatory exTreg cells. This effect was not universal, however, and necropsy analyses revealed tissue-specific inflammation. While the colons of mice with KO Treg cells appeared healthy, skin and lung tissue were severely inflamed. Metabolically, KO Treg cells had a significant decrease in their glycolytic capacity and instead increased oxidation of amino acids and fatty acids. In inflamed skin, which that promotes increased oxidative stress, CD71 expression in Treg cells suppressed tissue inflammation in a model of atopic dermatitis-like disease. These results indicate the CD71-iron axis as a new immunometabolic regulator of Treg cell functions in immune and non-immune organs.
    Capsule Summary: A loss of the transferrin receptor in Tregs causes severe autoimmunity and here we clarify how Tregs rely on this receptor for iron in specific tissues and disease settings including atopic dermatitis.
    DOI:  https://doi.org/10.64898/2026.02.01.703140
  14. Front Cell Dev Biol. 2026 ;14 1754980
    Metabolic reprogramming and immunosenescence: a new sight for glioma therapy.
    Huali Fan, Shizhuo Yang, Qing Lu, Liming Chang.
      Gliomas, the most prevalent primary tumor of the central nervous system, are characterized by a poor prognosis and a high recurrence rate. The glioma microenvironment is highly immunosuppressive, which poses a major obstacle to effective immunotherapy. Metabolic reprogramming is a hallmark of glioma, driving tumor progression and therapy resistance. Key alterations include the Warburg effect, increased glutamine dependency, enhanced pentose phosphate pathway activity, and dysregulated lipid metabolism. Immunosenescence, the age-dependent decline in immune function that contributes to disease pathogenesis, encompasses immune dysregulation, senescence-associated secretory phenotype (SASP) accumulation, and epigenetic changes, which together drive immune cell dysfunction and foster an immunosuppressive microenvironment. Meantime, senescent immune cells may change the metabolic microenvironment, whereas metabolic reprogramming also influence immune system. Thus, this small essay is on the purpose of demonstrating the significance and function of metabolic reprogramming and immunosenescence in gliomas, providing evidence of promising therapeutic strategies.
    Keywords:  epigenetic regulation; glioma; immunosenescence; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1754980
  15. Front Immunol. 2026 ;17 1710363
    650 nm red-light therapy attenuates sepsis-induced acute lung injury via adiponectin-mediated immune-metabolic reprogramming.
    Yiqiu Zhang, Wei Ni, Jianghan Li, Yubing Bai, Yier Bai, Zhixuan Jiang, Jiadie Wang, Yu He, Yafeng Li, Jing Yuan, Min Yao.
       Background: Sepsis-induced acute lung injury (ALI) is driven by dysregulated innate immunity and mitochondrial dysfunction. Monocyte/macrophage trafficking and polarization critically shape disease trajectory, yet clinically tractable immunometabolic interventions are limited. We hypothesized that 650 nm red-light photobiomodulation (PBM) alleviates septic ALI by reprogramming myeloid responses and preserving mitochondrial function via adiponectin signaling.
    Methods: Septic ALI was induced by cecal ligation and puncture (CLP) in mice. Animals received 650 nm PBM (10 min, every 6 h, three times within 24 h). Survival, lung edema, histology, and serum cytokines were assessed. Lung chemokines/cytokines were profiled by 23-plex Luminex. Immune composition was analyzed by flow cytometry, and CCR2+/CX3CR1+ subsets were visualized in CcrRFP-Cx3cr1GFP mice using 3D cryo-fMOST. IHC quantified CX3CR1, CCR2, CD68, CD86, and CD206. Adiponectin was measured in serum/BALF and lung. Pathway relevance was tested by AdipoR1 siRNA. In LPS-stimulated RAW264.7 macrophages, PBM effects on cytokines, ATP, mitochondrial ROS (MitoSOX), membrane potential (JC-1), and MitoTracker fluorescence were evaluated, with/without AdipoR1 knockdown.
    Results: PBM prolonged survival, reduced lung edema, improved histopathology, and lowered systemic TNF-α, IL-6, IL-1β, and MCP-1. Luminex showed broad suppression of pro-inflammatory mediators (e.g., G-/GM-CSF, IL-1 family, IL-6, IL-12, IL-17A, TNF-α) and chemokines (CCL11, CXCL1, MCP-1/CCL2, CCL3/4/5), with increases in IL-4/IL-10/IL-13. Flow cytometry revealed decreased neutrophils, monocytes, and inflammatory macrophages, alongside restored eosinophils and resident macrophages. Cryo-fMOST and IHC demonstrated reduced CCR2+/CD86+ inflammatory cells and enrichment of CX3CR1+/CD206+ reparative cells. PBM elevated adiponectin in serum, BALF, and lung; AdipoR1 knockdown abrogated anti-inflammatory effects and myeloid rebalancing. In vitro, PBM dose-dependently suppressed LPS-induced TNF-α/IL-6 and IL-1β while increasing IL-10, restored ATP, reduced mitochondrial ROS, and improved membrane potential, that benefits lost with AdipoR1 silencing.
    Conclusions: Septic ALI modulated by 650 nm PBM was characterized by suppressing CCR2+ inflammatory recruitment, enriching CX3CR1+/M2-like macrophages, and preserving mitochondrial function through adiponectin-AdipoR1 signaling. These data position red-light PBM as a mechanistically grounded, non-invasive method for sepsis-associated lung injury.
    Keywords:  adiponectin; mitochondrial function; monocyte/macrophage; photobiomodulation; sepsis-induced ALI
    DOI:  https://doi.org/10.3389/fimmu.2026.1710363
  16. IMetaOmics. 2024 Sep;1(1): e16
    Salmonella-Host-microbiota interactions: Immunity and metabolism.
    Bingxin Tang, Wenwen Cui, Xiao Li, Huan Yang.
      Salmonella establish a foundation for systemic infection through induced inflammation and immune evasion. Salmonella manipulates host metabolism to favor its own proliferation within the host. Salmonella infection can disrupt the balance of gut commensal bacteria and use microbial metabolites to fuel its own energy metabolism.
    DOI:  https://doi.org/10.1002/imo2.16
  17. Autoimmun Rev. 2026 Feb 08. pii: S1568-9972(26)00018-2. [Epub ahead of print]25(3): 104004
    Regulatory mechanisms and targeted therapeutic strategies of glycolytic metabolism in rheumatoid arthritis.
    Miao Wang, Ke Wan, Han Shu, Xue Yang, Tongsheng Zhou, Qingqing Xia, Ying Chen, Lu Wang, Jun Li, Xiao-Feng Li.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease where glycolytic metabolism plays a crucial role in its pathogenesis. This paper delves into the characteristics, key roles, and potential therapeutic applications of glycolytic metabolism in RA. In the synovial tissues and immune cells of RA patients, glycolytic metabolism is frequently observed to be enhanced, with key enzymes such as HK2, PFK-1/PFKFB3, and PKM2 showing abnormal expression and activation. Lactate, the end product of glycolysis, is increasingly recognized as an active signaling molecule that may contribute to the maintenance of inflammation and tissue destruction through multiple proposed mechanisms. Abnormal glycolytic metabolism in immune cells (macrophages, T cells, B cells, DCs) and synoviocytes (fibroblast-like synoviocytes, osteoclasts) respectively promote inflammatory responses and joint damage. Intervention strategies targeting glycolytic metabolism, such as the use of inhibitors for HK, PKM2, LDH, and PFK-1, have been proposed. However, numerous unresolved issues remain, necessitating further basic research to clarify the regulatory mechanisms and intercellular interactions of glycolytic metabolism, as well as in-depth studies on the clinical application value of related biomarkers.
    Keywords:  Glycolytic enzyme inhibitors; Glycolytic metabolism; Immune cells; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.autrev.2026.104004
  18. bioRxiv. 2026 Jan 27. pii: 2026.01.26.701865. [Epub ahead of print]
    Glutamine supports human cytomegalovirus induced lipidome remodeling through reductive carboxylation.
    Rebekah L Mokry, Caleb B de Lacy, John G Purdy.
      Lipidome remodeling during human cytomegalovirus (HCMV) replication is a complex process that requires induction of lipogenic proteins and altered metabolite flow to support synthesis of fatty acids and lipids. HCMV infection increases the utilization of glucose and acetate to provide enough carbons to support increased demand for lipogenesis during virus replication, but other carbon contributors have not been studied. Here, we identify glutamine as a carbon source for lipogenesis during HCMV infection. Metabolic tracing with 13 C-labeled glutamine revealed carbons from glutamine are enriched in phospholipids and neutral lipids during infection, including phosphatidylcholine, phosphatidylethanolamine, diacylglycerol, and triacylglycerol. Additional metabolic tracing demonstrates that HCMV infection promotes glutamine flow to fatty acid synthesis primarily through reductive carboxylation, i.e., conversion of glutamine to citrate through isocitrate. Through the use of two different 13 C-labeled forms of glutamine, we found that ∼30% of the carbons from glutamine are delivered to fatty acid synthesis through additional metabolic means. Our current understanding of metabolite utilization during HCMV replication is based on cell culture models where there is an excess amount of glucose, suggesting that deriving carbons from glutamine might be needed when glucose levels are low. To determine if concentrations of glucose and glutamine change their contributions to fatty acid synthesis, we investigated lipogenesis when glucose and glutamine are at physiological levels (5 mM and 0.55 mM, respectively). We determined that physiological levels of glucose and glutamine are sufficient to support the increased demand for fatty acid synthesis caused by HCMV infection, despite a reduction in virus production. Using metabolic tracing with 13 C-labeled forms of glucose or glutamine, we determined that both carbon sources still contribute to fatty acid synthesis when present at physiological levels. Overall, our results identify viral activation of reductive carboxylation that increases glutamine flow to lipogenesis during infection. This work provides additional insight into metabolic reprogramming that supports HCMV-induced lipidome remodeling.
    Author Summary: Many viruses hijack cellular metabolic processing to obtain the components needed for replication. Human cytomegalovirus (HCMV) uses several mechanisms to reprogram lipid metabolism and remodel the lipidome of infected cells. HCMV promotes synthesis of very long chain fatty acids that are found in phospholipids and triacylglycerol. Glucose and acetate contribute carbon to fatty acid synthesis and elongation following HCMV infection. In this work, we demonstrate that glutamine is an additional carbon source for fatty acid and lipid synthesis. Phospholipids and neutral lipids are enriched with carbons from glutamine during HCMV infection. Mechanistically, HCMV induces reductive carboxylation to increase glutamine flow to fatty acid synthesis and increased metabolite availability supports additional carbon flow to fatty acids. Overall, this study provides additional insight into virus-induced metabolic remodeling that supplies the molecular building blocks for virus replication.
    DOI:  https://doi.org/10.64898/2026.01.26.701865
  19. Life Sci. 2026 Feb 07. pii: S0024-3205(26)00064-0. [Epub ahead of print]390 124256
    Aberrant interferon-γ signaling disrupts trophoblast invasion via IDO1/AHR signaling and metabolic reprogramming associated with recurrent pregnancy loss.
    Linwei Zhou, Lijun Yang, Jinya Zhang, Hongli Li, Guangmin Song, Hongbo Qi, Xiaobo Zhou, Hua Zhang, Man Zhang.
       AIMS: Recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder in which immune dysregulation has been increasingly implicated. This study aimed to elucidate how interferon-γ (IFN-γ) signaling affects trophoblast function and metabolism and to explore the underlying immunometabolic mechanisms contributing to RPL pathogenesis.
    MATERIALS AND METHODS: Human trophoblast cells were treated with IFN-γ to assess proliferation, apoptosis, migration, and invasion. Metabolic alterations were analyzed using Seahorse extracellular flux assays, glucose uptake measurements, and metabolomic profiling. Molecular mechanisms were investigated by examining IDO1 expression, kynurenine production, aryl hydrocarbon receptor (AHR) activation, and hypoxia-inducible factor-1α (HIF-1α) signaling. IDO1 expression was further evaluated in chorionic villi from RPL patients and healthy controls.
    KEY FINDINGS: IFN-γ selectively suppressed trophoblast migration and invasion without affecting proliferation or apoptosis. IFN-γ markedly upregulated IDO1, leading to increased kynurenine accumulation and activation of AHR signaling through nuclear translocation and ARNT dimerization, thereby shifting trophoblasts toward an epithelial-like phenotype. Concurrently, IFN-γ stabilized HIF-1α and enhanced glycolytic flux, glucose uptake, and lactate secretion, accompanied by reduced tricarboxylic acid cycle intermediates. Pharmacological inhibition of glycolysis with 2-DG attenuated IFN-γ-induced IDO1 expression in a dose-dependent manner. Aberrant IDO1 expression was also observed in chorionic villi from RPL patients.
    SIGNIFICANCE: These findings demonstrate that IFN-γ signaling impairs trophoblast invasion through coordinated activation of the IDO1/kynurenine/AHR axis and metabolic reprogramming, revealing an immunometabolic mechanism that may contribute to the pathogenesis of recurrent pregnancy loss.
    Keywords:  Human trophoblast cells; IDO1; IFN-γ; Metabolism; Recurrent pregnancy loss
    DOI:  https://doi.org/10.1016/j.lfs.2026.124256
  20. Acta Trop. 2026 Feb 06. pii: S0001-706X(26)00046-X. [Epub ahead of print]275 108012
    Host kynurenine monooxygenase (KMO) serves as a critical immune defense factor restricting Toxoplasma gondii proliferation.
    Sheng-Jie Tang, Zhong-Yang Chen, Ya-Fei Song, Yanlong Gu, Yanmin You, Dong-Hui Zhou.
      Toxoplasma gondii is an obligate intracellular protozoan parasite capable of infecting virtually all warm-blooded animals. The kynurenine pathway (KP), a key route of tryptophan catabolism, serves as a critical immunometabolic checkpoint in cancer, autoimmune disorders, and neurodegenerative diseases. Although the kynurenine monooxygenase (KMO)-derived metabolite quinolinic acid (QUIN) has well-documented antiviral effects, its role in antiparasitic immunity remains unexplored. Here, we identify KMO as a critical mediator of host defense against T. gondii. Upon infection, T. gondii significantly suppresses host KMO expression along with its downstream metabolites, including 3-hydroxykynurenine (3-HK) and QUIN. Functional studies in Vero cells demonstrate that KMO overexpression effectively restricts parasite proliferation, whereas RNA interference (RNAi)-mediated knockdown (KD) of KMO increases parasite burden. Collectively, these findings establish KMO as a non-canonical determinant of anti-T. gondii immunity and nominate KP potentiation as a therapeutic strategy for toxoplasmosis.
    Keywords:  Antiparasitic immunity; Host-pathogen interactions; Kynurenine 3-monooxygenase (KMO); Kynurenine pathway; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.actatropica.2026.108012
  21. Cell Commun Signal. 2026 Feb 07.
    RT-ICI therapy induces a distal immunometabolic axis that shapes systemic macrophage polarization and enhances local T cell immunity.
    Yizhi Ge, Haitao Liu, Jiayi Shen, Hongming Xu, Yong Feng, Dan Zong, Lijun Wang.
      Colorectal cancer (CRC) liver metastases remain refractory to immunotherapy due to a profoundly immunosuppressive tumor microenvironment. Here, we conducted a prospective clinical study enrolling 18 patients with microsatellite-stable CRC liver metastases treated with high-dose radiotherapy (RT) followed by anti-PD-1 immune checkpoint inhibitors (RT-ICI). Integrative analysis of single-cell RNA-sequencing, spatial transcriptomics, and peripheral immune profiling revealed that RT-ICI therapy reprograms both tumor-intrinsic and immune compartments. RT triggered the emergence of an APOA2⁺ tumor cell state characterized by enhanced lipid metabolic activity and transient elevation of circulating HDL. This metabolic reprogramming, in turn, promoted systemic activation of CETP⁺ M2-like macrophages, a population marked by high LXR/RXR transcriptional activity and enriched expression of immunosuppressive and lipid-processing genes. Despite their expansion, CETP⁺ macrophages localized preferentially to non-irradiated tumor regions, suggesting a distal immunometabolic effect driven by HDL-mediated signaling. Concurrently, combination therapy expanded GZMB⁺ effector T cells and induced a novel population of inflammatory-toxic T cells (IT_T), which exhibited high cytotoxicity and spatial co-localization with CXCL10⁺ macrophages. Ligand-receptor analysis and pseudotime modeling revealed that irradiated tumor cells acted as "in situ vaccines" by enhancing MHC-TCR interactions and promoting T cell differentiation along non-exhausted cytotoxic lineages. Together, these findings reveal a dual mechanism by which RT-ICI therapy enhances local anti-tumor immunity while modulating systemic lipid metabolism and macrophage polarization, offering insights for combinatorial immunotherapy design in immunologically "cold" tumors.
    Keywords:  Colorectal cancer; High-dose radiotherapy; Liver metastasis; Single-Cell sequence; Spatial transcriptomic; Tumor environment
    DOI:  https://doi.org/10.1186/s12964-026-02689-3
  22. Antiviral Res. 2026 Feb 11. pii: S0166-3542(26)00023-9. [Epub ahead of print] 106364
    Targeting the fatty acid metabolism pathway represents a promising antiviral strategy against diverse viral infections.
    Fanxin Liu, Yuechi Hou, Yan Huang, Shiji Xiao, Chunchun Meng, Chan Ding, Qinqin You, Yudan Zuo, Yuying Yang, Xusheng Qiu, Jun Dai.
      Fatty acids (FAs) are important regulators of immune responses and innate defense mechanisms, which can be hijacked by viruses to impair the host innate immune response and establish persistent infections. Interestingly, FAs are also known for their broad-spectrum antiviral properties. Yet the precise mechanisms by which FAs regulate viral replication remain incompletely understood. Emerging evidence now suggests that virus infection regulates the expression of fatty acid metabolic enzymes, driving lipid remodeling that supports multiple stages of the viral life cycle. Additionally, FAs can enhance viral gene expression, protein stability, and the formation of replication complexes. Conversely, host cells also require reprogramming FAs biosynthesis to resist viral infections. Intriguingly, some fatty acid ratios may serve as a prognostic indicator after virus infection. Therefore, limiting FAs synthesis will impair infectivity of viruses, which could be an effective antiviral strategy. This review summarizes the impact of FA synthesis and elongation on the virus lifecycle, focusing on the underlying mechanisms of how viruses exploit host FAs and their downstream product lipid droplets to facilitate viral replication. We have also provided valuable insights on the development and utilization of antiviral drugs by manipulating FA metabolism.
    Keywords:  Antiviral targets; Antiviral therapy; Fatty acid metabolic enzymes; Fatty acid metabolism; Lipid droplets; Virus
    DOI:  https://doi.org/10.1016/j.antiviral.2026.106364
  23. Front Immunol. 2025 ;16 1712741
    GDF15 orchestrates mitochondrial-immune crosstalk via SMAD7-HIF-1α-PKM2 cascade to attenuate septic liver injury.
    Xiandong Kuang, Zhili Niu, Wenqiang Liu, Zhaoyang Huang, Shuo Li, Ye Zhang, Li Wang, Xin Cai, Faxi Wang, Pingan Zhang.
       Background: Sepsis-induced multi-organ failure involves pathological crosstalk between mitochondrial dysfunction and hyperinflammation, yet endogenous protective mechanisms remain incompletely defined. This study investigates Growth Differentiation Factor 15 (GDF15) as a potential regulator of sepsis tolerance.
    Methods: Using LPS-challenged mouse endotoxemia and a murine macrophage (RAW264.7) cell line model, we assessed GDF15's functional role through: (1) recombinant Adeno-Associated Virus serotype 8 (rAAV8)-mediated tissue-specific overexpression, (2) siRNA knockdown, (3) pharmacological modulation (BAY 87-2243/Hypoxia-Inducible Factor 1-alpha (HIF-1α) inhibitor, Shikonin/PKM2 inhibitor, Asiaticoside/SMAD7 activator), and (4) comprehensive metabolic-inflammatory phenotyping including mitochondrial complex integrity (assessed via UQCRC1, Ubiquinol-Cytochrome c Reductase Core Protein 1), cytokine dynamics (TNF-α, IL-6) and lactate metabolism.
    Results: LPS challenge induced time-dependent mitochondrial dysfunction concurrent with cytokine storms and compensatory GDF15 upregulation in both liver and macrophages. Hepatocyte-specific GDF15 overexpression attenuated injury through restored mitochondrial integrity, diminished macrophage infiltration, and reduced systemic inflammation, as evidenced by significantly lower levels of circulating TNF-α and IL-6. Mechanistically, GDF15 preserved mitochondrial homeostasis by inducing SMAD7 expression while suppressing HIF-1α accumulation and PKM2 nuclear translocation. Pharmacological HIF-1α/PKM2 inhibition recapitulated GDF15's protective effects, restoring mitochondrial function and reducing inflammation even in GDF15-deficient models. Clinical analysis of a sepsis patient cohort (n=119) confirmed a significant elevation of circulating GDF15, with its levels strongly correlating with disease severity scores. Critically, SMAD7 activation attenuated HIF-1α accumulation and rescued mitochondrial failure independently of GDF15 status.
    Conclusion: GDF15 orchestrates sepsis tolerance through the SMAD7-HIF-1α axis, preserving mitochondrial integrity while resolving metabolic-inflammatory dysregulation, notably by suppressing the release of pro-inflammatory cytokines such as TNF-α and IL-6. This study identifies GDF15 as a central guardian of mitochondrial-immune homeostasis in sepsis, positioning it as both a robust severity biomarker and a promising therapeutic target for mitochondrial resuscitation.
    Keywords:  GDF15; SMAD7-HIF-1 α axis; metabolic-inflammatory dysregulation; mitochondrial dysfunction; mitochondrial resuscitation; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2025.1712741
  24. Nat Commun. 2026 Feb 12. 17(1): 1645
    Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
    Veronica Bergo, Pavlos Bousounis, Giang To Vu, Mélodie Douté, Aikaterini Polyzou, Maria-Eleni Lalioti, Bogdan B Grigorash, Lyudmila Tsurkan, Nicholas Morchel, Ward Deboutte, Frédéric Brau, Thomas Manke, Sagar, Hind Medyouf, Dmitry V Bulavin, Nina Cabezas-Wallscheid, Marta Derecka, Eirini Trompouki.
      "Inflammaging", the chronic increase in inflammatory signaling with age, remains poorly understood in hematopoietic aging. Here, we identify the innate immune RNA sensor melanoma differentiation-associated protein 5 (MDA5) as an important factor of hematopoietic stem cell (HSC) aging. Aged Mda5-/- mice exhibit reduced HSC accumulation and myeloid bias. Importantly, aged Mda5-/- HSCs retain greater quiescence and superior repopulation capacity in noncompetitive transplants compared to wild-type counterparts. Multiomic analyses- including chromatin accessibility, transcriptomics, and metabolomics-reveal decreased inflammatory signaling, a youthful metabolic profile, and improved proteostasis in Mda5-/- HSCs, through regulation of HSF1 and phospho-EIF2A, key proteostasis regulators. Activation of HSF1 in aged wild-type HSCs partially restores youthful features, supporting a causal role for proteostasis maintenance. Collectively, our findings demonstrate that attenuating MDA5-dependent inflammation preserves HSC function during aging by maintaining metabolic fitness and proteostasis and provide insight into potential therapeutic strategies for mitigating hematopoietic aging.
    DOI:  https://doi.org/10.1038/s41467-026-69424-x
  25. Cardiovasc Diabetol. 2026 Feb 08.
    Distinct immunometabolic signatures of type 1 versus type 2 diabetes in a murine model of myocardial infarction.
    Katherine R O'Quinn, Catharyne B Wright, Mursalin Khan, Rob W Spitz, Nadiyeh Rouhi, Jemylle G Morato, Patricio A Vidal, Ana C M Omoto, Alex A da Silva, Jussara M do Carmo, Zhen Wang, Xuan Li, John E Hall, Alan J Mouton.
       BACKGROUND: Diabetes mellitus (DM), which consists of type I and type 2 diabetes (T1D and T2D), is a known risk factor for myocardial infarction (MI) and negatively impacts post-MI outcomes. However, the mechanisms by which DM exacerbates cardiac remodeling in T1D versus T2D have not been well defined. Here, we assessed acute and chronic post-MI outcomes in T1D and T2D mice, focusing on immune and metabolic pathways.
    METHODS: T1D was induced in adult male mice by a single high dose of streptozotocin (STZ), and T2D induced by high fat/fructose feeding and multiple low STZ doses. Two weeks following STZ administration, MI was induced by permanent coronary artery ligation, and mice were studied at days (D) 0, 3, 7, and 28 post-MI. Cardiac function was assessed by echocardiography.
    RESULTS: Compared to non-diabetic mice, T1D and T2D mice had worse cardiac dysfunction after MI, including increased wall thinning and decreased ejection fraction, despite similar infarct sizes. T1D mice also displayed acute pulmonary congestion. By RNA-sequencing analysis, T1D and T2D mice displayed upregulation of genes associated with canonical chemokine/monocyte-mediated inflammatory pathways, and downregulation of genes associated with extracellular matrix remodeling. T1D and T2D delayed activation of M2-like (CD206+) macrophages in the heart, and impaired normal collagen and elastin deposition after MI. T2D also increased expression of genes associated with T cell activation, and increased CD8 + T cells in the infarct. T1D and T2D hearts showed signs of impaired glucose and ketone oxidation, and T1D hearts had increased markers of fatty acid oxidation. Extracted D3 cardiac macrophages from T1D and T2D mice exhibited higher basal oxygen consumption, and increased M1 markers and chemokine expression. Plasma from T1D and T2D mice increased chemokine expression (Ccl2, Ccl7, Cxcl1) in cultured bone marrow macrophages, and T2D plasma impaired mitochondrial function.
    CONCLUSIONS: DM promotes adverse cardiac remodeling, which is associated with activation of overlapping and unique inflammatory pathways, impaired ECM remodeling, remote metabolic remodeling, and alterations in macrophage metabolism. Our results provide novel insights into potential therapeutic pathways for DM patients suffering from MI.
    Keywords:  Cardiac remodeling; Diabetes; Heart failure; Immunometabolism; Inflammation; Metabolism; Myocardial infarction; Obesity
    DOI:  https://doi.org/10.1186/s12933-026-03099-y
  26. Nat Commun. 2026 Feb 12. 17(1): 1493
    Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
    Sathish Babu Vasamsetti, Samreen Sadaf, Mohammad A Uddin, Jixing Shen, Ebin Johny, Awishi Mondal, Jonathan Florentin, Liqun Lei, Aleef Mannan, Krithika Sudhakar Rao, John Sembrat, Mauricio Rojas, Ian Sipula, Jake Kastroll, Michael J Jurczak, Sruti Shiva, Robert M O'Doherty, Vijay Yechoor, Partha Dutta.
      How cellular metabolism facilitates tissue-resident macrophage maintenance remains elusive. Here we show that visceral adipose tissue (VAT)-resident macrophages, unlike monocyte-derived macrophages, are enriched with mitochondrial-specific antioxidant enzymes restraining inflammation and promoting VAT homeostasis and insulin sensitivity. Additionally, VAT resident macrophages express high levels of plasminogen activator inhibitor type 2, encoded by SerpinB2, which is involved in the blood coagulation cascade. SerpinB2 promotes adipose resident macrophage survival by regulating mitochondrial oxidative phosphorylation and preventing the release of pro-apoptotic cytochrome c from the mitochondria into the cytoplasm via antioxidant glutathione production. Chronic inflammation, such as obesity, diminishes SerpinB2 expression in VAT macrophages in patients and mice, leading to the decline of this macrophage subset. Mechanistically, interferon-γ elevation in diabetes induces Ikaros, a transcriptional suppressor, which binds to the SerpinB2 promoter and decreases SerpinB2 expression. Congruently, selective depletion of the IFN-γ receptor in myeloid cells or supplementation of macrophage-specific SerpinB2 deficient mice with N-acetylcysteine, a glutathione precursor, restores VAT resident macrophage survival, decreases adipocyte size, and improves glucose tolerance and insulin sensitivity. Our data thus reveal an unexpected function of SerpinB2 in the regulation of mitochondrial function and survival of tissue-resident macrophages.
    DOI:  https://doi.org/10.1038/s41467-026-69196-4
  27. Inflamm Bowel Dis. 2026 Feb 10. pii: izaf315. [Epub ahead of print]
    Immunometabolism as a New Bimodal Therapeutic Concept in Inflammatory Bowel Disease and Immune-Mediated Inflammatory Disorders.
    Virginia Solitano, Laurent Peyrin-Biroulet, Severine Vermeire, Marla C Dubinsky, Britta Siegmund, Rebecca Mosig, Fabio Cataldi, Louis Derluyn, Silvio Danese, Bram Verstockt.
      Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism, putting it at the center of many immune-mediated inflammatory disorders (IMIDs). Research has shown that immunometabolic pathways may act as a dual checkpoint for the inflammatory cycle to return the system to homeostasis by inactivating inflammatory pathways and shifting metabolism in favor of regulatory phenotypes. In addition, immunometabolic targets may act in non-immune cells such as epithelial and mesenchymal cells. Therefore, the therapeutic approach to targeting the uniquely robust mechanisms of immunometabolism may ameliorate aspects of IMIDs that remained to be addressed. Several emerging targets, including mitochondrial regulators (eg NLRX1), membrane-bound receptors (eg PLXDC2), and hormonal peptides (eg GLP-1), illustrate the diverse ways immunometabolism can be leveraged therapeutically. Preclinical models of inflammatory bowel disease (IBD) and other IMIDs have highlighted the bimodal immunoregulatory roles of these pathways. Preliminary clinical data support the potential utility of immunometabolic modulation, particularly in combination with existing therapies, to overcome the current therapeutic ceiling in clinical efficacy. Continued research is needed to validate the efficacy, safety, and mechanistic precision of immunometabolic agents across the spectrum of IMIDs.
    Keywords:  GLP-1 receptor agonists; IMID; immunometabolism; inflammatory bowel disease (IBD)
    DOI:  https://doi.org/10.1093/ibd/izaf315
  28. Biology (Basel). 2026 Jan 23. pii: 213. [Epub ahead of print]15(3):
    HIF-1α as a Central Regulator of Monocyte Responses to Hypoxia.
    Nadia Lampiasi, Roberta Russo.
      Hypoxia is a common feature of inflamed and ischemic tissues and represents an important regulatory signal for innate immune cells. The master regulator of this response is hypoxia-inducible factor-1α (HIF-1α), a transcription factor whose stabilization and activity are tightly regulated by the presence of oxygen, inflammatory signaling, and cellular metabolism. Monocytes, key players in innate immunity, rapidly sense oxygen deprivation and display specific responses during acute hypoxia, primarily aimed at adapting and maintaining cellular homeostasis. Unlike macrophages, in which HIF-1α activity is known, the mechanisms regulating HIF-1α stabilization, subcellular localization, and transcriptional activity in circulating monocytes remain incompletely elucidated. Recent studies indicate that acute hypoxia primarily triggers post-translational stabilization of HIF-1α, calcium- and PKC-dependent signaling, metabolic reprogramming, and early inflammatory responses, while transcriptional activation of HIF-1α may require additional inflammatory or stress-related signals. Furthermore, extensive crosstalk between HIF-1α and NF-κB integrates hypoxic and inflammatory signals, modulating cytokine production, cell migration, and survival. Epigenetic regulators can also modulate these responses and contribute to hypoxia-induced trained immunity. In this review, we summarize current knowledge of the mechanisms controlling the stabilization, localization, and function of HIF-1α in human monocytes and monocyte-macrophages during acute hypoxia, highlighting the key differences between these cell types and discussing their implications for inflammation, tissue homeostasis, and disease.
    Keywords:  HIF-1α; NF-κB; cytokines; inflammation; innate immunity; macrophages
    DOI:  https://doi.org/10.3390/biology15030213
  29. bioRxiv. 2026 Jan 12. pii: 2026.01.11.698915. [Epub ahead of print]
    Polymer of methyl malonic acid suppress inflammation by downregulating IL-2 through ROS overproduction.
    Sanmoy Pathak, Madhan Mohan Chandra Sekhar Jaggarapu, Taravat Khodaei, Abhirami Thumsi, Joel P Joseph, Abhinav P Acharya.
      Metabolites belonging to the propionate metabolism pathway can regulate immune cell responses in the context of autoimmunity and chronic inflammation. Methyl malonic acid (MMA), a metabolite in this pathway is known to cause dysregulation of T cell oxidative phosphorylation (OXPHOS) and downregulating pro inflammatory T cell effector functions. However, the effects of MMA on T cell signaling and T cell activation is not clearly known. Furthermore, since MMA is a small molecule, using it in the context of therapy remains a problem. It gets metabolized in a short time and millimolar concentrations are required to get effective results. This work describes a novel polymer, 1,6 MMA, synthesized using 1,6 Hexane-diol and MMA, which helps in slow, steady and continuous release of the small molecule. Doses in micromolar ranges generate long lasting and robust immunosuppression of activated T cells via an IL2 dependent mechanism in both human and mice T cells without causing non-specific toxicity. This causes a dysregulated expression of pSTAT5 which eventually enhances BLIMP1 mediated T cell apoptosis. Finally, 1,6 MMA mediated T cell suppression is caused due to increase in mitochondrial ROS production. Extrapolation of our findings in-vivo showed the polymer inhibited autoreactive T cell responses in mice with collagen induced arthritis (CIA). Overall, 1,6 MMA, a novel metabolite polymer, has major therapeutic potential in combating inflammatory disorders.
    DOI:  https://doi.org/10.64898/2026.01.11.698915
  30. Immunity. 2026 Feb 10. pii: S1074-7613(26)00002-6. [Epub ahead of print]
    Hormonal rewiring of immunity during dietary restriction ensures host defense and systemic glucose conservation.
    Luisa Menezes-Silva, Mingeum Jeong, Charles Carr, Riley M Schneider, Silvia Pires, Ana C Codo, Jazib Uddin, Alexander Grier, Randy S Longman, Niels Olsen Saraiva Camara, David Artis, Seong-Ji Han, Nicholas Collins.
      Food shortages and infectious diseases were constant threats throughout mammalian evolution and often occurred simultaneously. When food availability is reduced, it is unclear how the host adapts to support glucose-demanding immune processes while preventing hypoglycemia. In the context of dietary restriction (DR), we found that glucocorticoids (GCs) aligned naive, effector, and memory T cell populations with the nutritional status of the host. DR-induced GCs promoted naive T cell homing to the bone marrow, which supported their homeostasis at steady state. Following a primary infection, DR-induced GCs rewired immunity to simultaneously uphold pathogen control and systemic glucose homeostasis. GCs achieved this by dampening effector T cells and enhancing the response of neutrophils with reduced glucose dependence. Although the total effector T cell pool was decreased during DR, GCs enriched memory-precursor effector cells to preserve memory formation. Thus, GCs align immunity and metabolic physiology to ensure host fitness when food availability is reduced.
    Keywords:  T cell; caloric restriction; glucocorticoids; hormones; metabolism; neutrophil; nutrition
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.003
  31. Nat Commun. 2026 Feb 07.
    Cancer cell-intrinsic inflammasome protein ASC links innate immunity with mitochondrial metabolism in driving pancreatic cancer.
    Yu C J Chey, Bassam Kashgari, Louise McLeod, Georgette A Radford, Linden J Gearing, Ruby E Dawson, Malvika Kharbanda, Joanne Lundy, Daniel Croagh, Charlotte Girard-Guyonvarc'h, Cem Gabay, Brooke A Pereira, David Herrmann, Paul Timpson, John W Finnie, Mohamed I Saad, Dharmesh D Bhuva, Bernardo S Franklin, Florian I Schmidt, Brendan J Jenkins.
      Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., KRAS) coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation. However, the identity of innate immune molecular regulators as therapeutic targets in PDAC is ill-defined. Here, we show in PDAC patients that elevated tumoral expression of the inflammasome adaptor protein ASC and its downstream effector Caspase-1 is primarily colocalized to the pancreatic ductal epithelium and prognostic for poor survival. In the mutant Kras-driven KPC PDAC mouse model, global and conditional (pancreatic epithelial) ablation of ASC, or nanobody-mediated targeting of extracellular ASC, suppresses pancreatic tumorigenesis. Whole transcriptome profiling and multiplex immunofluorescence reveal that the tumor-promoting activities of epithelial-derived ASC align with molecular pathways for mitochondrial respiration, metabolism (glycolysis), and immune responses. Our discovery that ASC-containing inflammasomes promote PDAC by acting as a molecular bridge between innate immunity, mitochondrial dysfunction and metabolic reprogramming provides the rationale to therapeutically target ASC in cancers.
    DOI:  https://doi.org/10.1038/s41467-026-69398-w
  32. Res Sq. 2026 Feb 02. pii: rs.3.rs-8704178. [Epub ahead of print]
    CAR Signaling Informs Mechanisms to Enhance Metabolism and Function in γδ T Cells.
    Daniel Abate-Daga, Xiomar Bustos Perez, Leticia Tordesillas, Elena Martinez-Planes, Miguel G Fontela, Renata Marques Rossetti, Victoria Izumi, Bin Fang, John Koomen, Eric Welsh, Patrick Hwu.
      γδ T cell-based immunotherapies have gained relevance as an alternative to the conventional αβ T cell products with pre-clinical data demonstrating tumor burden reduction and mitigation of tumor-induced damage. Given that most CAR constructs were optimized for αβ T cells, we hypothesized that distinct T cell types may require tailored CAR architectures to achieve optimal function. To test this hypothesis, we conducted a systematic comparative analysis between γδ and αβ T cells transduced with a second-generation PSCA-targeting CAR (PSCA-8t28z). We found that although γδ and αβ CAR-T cells exhibit comparable cytotoxicity, they differ phenotypically. Through a system level phosphoproteomic analysis, we identified 307 phospho-sites with differential abundance between γδ and αβ CAR-T cells. Pathway enrichment analysis placed glycolysis/gluconeogenesis and TCR signaling within the top significantly overrepresented signaling networks. Functional validation studies confirmed that γδ CAR-T cells show lower glycolytic and oxidative phosphorylation capacity than αβ, and weaker Activator Protein 1 (AP-1) activation. Notably, we identified Thioredoxin-Interacting Protein as a potential actionable target to enhance γδ CAR-T cell metabolism. Finally, we designed a new synthetic co-stimulatory receptor that potentiates AP-1 activation resulting in improved in-vivo persistence. These results highlight fundamental biological differences between γδ and αβ T cells and support the development of cell type-specific receptor engineering strategies to maximize γδ CAR-T cell function and therapeutic benefit.
    DOI:  https://doi.org/10.21203/rs.3.rs-8704178/v1
  33. Clin Exp Immunol. 2026 Feb 09. pii: uxag008. [Epub ahead of print]
    The dopamine D3 receptor regulates dopamine-induced activation and glycolytic metabolism of synovial fibroblasts in rheumatoid arthritis.
    Li Xue, Shiwen Xu, Ming Li, Biao Wang, Ping Kang, Jianhong Zhu, Felix I L Clanchy, Richard O Williams, David Abraham, Yan Geng.
       INTRODUCTION: Increased glycolytic metabolism in synovial fibroblasts contributes to their activated phenotype in rheumatoid arthritis (RA). Our previous results revealed that the activation of the dopamine D3 receptor (D3R) in mast cells reduced inflammation in a mouse model of RA. In this study, we explored the role of D3R in regulating dopamine-induced activation and glycolysis in synovial fibroblasts from patients with RA (RASFs).
    METHOD: RASFs were cultured in the presence of dopamine. Pharmacological modulation of D3R by D3R agonist (7-OH-DPAT) and antagonist (NGB2904) was used to investigate the regulatory role of D3R in dopamine-induced activation and glycolysis in RASFs.
    RESULTS: Dopamine stimulation induced a dose-dependent increase in cell viability and α-SMA expression in RASFs. Dopamine also caused significant and dose-dependent upregulation of glycolysis-related enzymes in RASFs. Treatment with 7-OH-DPAT inhibited dopamine-induced increases inα-SMA expression and inflammatory response in RASFs, whereas NGB2904 treatment resulted in the enhancedeffects stimulated by dopamine. NGB2904 treatment upregulated glycolysis and the expression of glycolytic enzymes induced by dopamine, whereas 7-OH-DPAT treatment downregulated glycolysis and glycolytic enzymes in RASFs. NGB2904 attenuated the ability of 7-OH-DPAT to inhibit the dopamine-induced elevation in cAMP levels of RASFs. Involvements of the cAMP pathway was confirmed by findings that H89 (a PKA inhibitor) abrogated the upregulation of activation, glycolysis, and expression of glycolytic enzymes mediated by the D3R antagonist, NGB2904, in RASFs.
    CONCLUSION: D3R downregulates dopamine induced activation and glycolysis of RASFs by suppressing PKA activity. Therefore, inhibition of glycolysis by manipulating the D3R pathway may provide a novel therapeutic strategy to reduce the activation of RASFs.
    Keywords:  Activation and glycolytic metabolism; Dopamine D3 receptor; Rheumatoid arthritis; Synovial fibroblasts
    DOI:  https://doi.org/10.1093/cei/uxag008
  34. Front Immunol. 2026 ;17 1736794
    Reactive sulfur species as emerging immunomodulators: mechanistic insights and therapeutic prospects.
    Youbang Chen, Ruiying Ji, Yixing Wu, Xiang Li, Hui Zhang, Chun-Tao Yang.
      Inflammation is a vital component of host defense and tissue repair, but its dysregulation contributes to chronic metabolic and immune-mediated diseases. In recent years, reactive sulfur species (RSS) have emerged as crucial regulators of immune homeostasis. Unlike reactive oxygen and nitrogen species, RSS dynamically regulates cellular signaling networks through reversible protein persulfidation. Rather than exerting uniformly pro- or anti-inflammatory actions, RSS display context-dependent, bidirectional effects that fine-tune immune responses according to the cellular redox state, metabolic and inflammatory conditions. This review integrates current advances in understanding how RSS mediate immune regulation across both innate and adaptive systems. We discuss how RSS shape macrophage polarization, modulate neutrophil activation and NETosis, influence dendritic cell differentiation, and control T and B cell function. We further examine translational efforts employing diverse RSS donors, including H2S-releasing compounds, persulfide and polysulfide donors, and engineered biomaterial delivery systems, to achieve targeted immune modulation. Finally, we highlight key challenges, such as context specificity, donor controllability, and redox balance, that must be resolved to realize the therapeutic potential of RSS.
    Keywords:  adaptive immunity; immunoregulation; innate immunity; metabolic disease; neutrophil NETosis; reactive sulfur species
    DOI:  https://doi.org/10.3389/fimmu.2026.1736794
  35. bioRxiv. 2026 Jan 29. pii: 2026.01.28.702158. [Epub ahead of print]
    Bacteroides intestinalis -Driven Arabinoxylan Fermentation Mitigates Inflammatory and Metabolic Dysfunction.
    Ziyu Zhou, Ka Lam Nguyen, Sijie Chen, Yuexi Wang, Min Li, David Biachi, Weihao Ge, Shanny Kuo, Salwa Gharieb, Emily Tung, Ronak Parmar, Jie Ji, Rohit Khorana, Ahmed Hetta, Isaac Cann, Roderick Mackie, Gee Lau, Jing Yang, Wenyan Mei.
      Insufficient dietary fiber intake is strongly associated with gut microbiome dysfunction and an increased risk of noncommunicable diseases. Synergistic synbiotics, which pair defined microbial strains with their preferred carbohydrate substrates, offer a promising strategy to restore these functions. However, the rational design of such interventions remains challenging by insufficient understanding of microbial fiber-degrading capacities and the host-relevant bioactivities of fermentation-derived metabolites. Here, we identify human colonic commensal Bacteroides intestinalis ( B . intestinalis ) as a key microbial mediator of dietary fiber-driven metabolic, immune, and neuronal benefits. We demonstrate that the synergistic interaction between B . intestinalis and its preferred substrate, insoluble wheat arabinoxylan abundant in dietary fiber, enhances the production of anti-diabetic and anti-steatotic bile acid species, hyocholic acid and hyodeoxycholic acid, anti-inflammatory, antioxidant phenolic compounds, and a spectrum of neuroactive compounds. These metabolic effects are accompanied by coordinated transcriptional remodeling in the colon and spleen implicating pathways governing circadian rhythm regulation, lipid metabolism, and immune defense. Importantly, these beneficial effects are preserved in conventionally raised mice with established high fat diet-induced obesity, where BI and inWAX improve glucose tolerance. Our findings uncover a mechanistic framework linking B . intestinalis -mediated fiber fermentation to gut-liver-brain crosstalk and establish a rational foundation for precision synbiotic design.
    DOI:  https://doi.org/10.64898/2026.01.28.702158
  36. Mol Cell. 2026 Feb 06. pii: S1097-2765(26)00030-4. [Epub ahead of print]
    Asparagine sensing by TBK1 controls its phase separation to drive antiviral innate immune responses.
    Jie Du, Chaoqun Li, Li Chai, Fabao Zhao, Lin Lv, Zongcheng Yang, Zhiyuan Zhao, Rong Gong, Liu Yang, Meng Wu, Meng Nie, Jihui Jia, Dongwei Kang, Chengjiang Gao, Wei Zhao, Mutian Jia.
      Competition between the host and invading viruses for cellular nutrients determines the outcomes of infectious diseases. Nutrients are increasingly being recognized as regulators that interact with immunological signals, but how immune cells sense specific nutrients to regulate antiviral innate immune responses remains elusive. Here, we establish asparagine (Asn) as an intercellular nutritional checkpoint that is sensed by TANK-binding kinase 1 (TBK1) to drive innate immune responses in human and murine cells. Mechanistically, Asn directly binds to TBK1, which robustly induces TBK1 phase separation and forms liquid-like droplets, promoting TBK1 transautophosphorylation and activation. Moreover, viral infection reduces asparagine synthetase (ASNS) expression to establish an Asn-restricted microenvironment, thereby evading TBK1-triggered host immune defenses. Overall, our results suggest that TBK1 is a natural Asn sensor that links host nutritional homeostasis to antiviral immune responses and reveal that targeting Asn availability is a promising therapeutic strategy for diseases involving dysregulated TBK1 activation.
    Keywords:  IFN responses; TBK1; asparagine; phase separation; virus infection
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.010
  37. Cancer Cell. 2026 Feb 12. pii: S1535-6108(26)00051-6. [Epub ahead of print]
    Lipid oxidation reprogramming in cancer-associated fibroblasts enhances CD8+ T cell cytotoxicity and therapeutic response.
    Zikun Ma, Yuzhao Wang, Weikai Wang, Wanyang Sun, Rong Wang, Xue Ding, Zibin Chen, Xiangdong Li, Zhiyong Li, Yunlin Ye, Yize Mao, Jianhua Yin, Guibo Li, Rong-Rong He, Xiaoyu Liang, Zhuowei Liu.
      Cancer-associated fibroblasts (CAFs) are major stromal components of the tumor microenvironment, yet how their metabolic states shift during therapy and influence anti-tumor immunity remains unclear. By integrating clinical cancer samples, single-cell RNA analyses, and functional studies, we identify a chemotherapy-conditioned PTGER3+ CAF subset characterized by enhanced lipid oxidation. This metabolic reprogramming strengthens antitumor immunity by promoting CD8+ T cell activation and cytotoxicity through the suppression of PTEN-related signaling. Clinically, higher proportions of therapy-induced PTGER3+ CAFs correlate with improved treatment responses and better patient prognosis. Together, these findings reveal a previously unrecognized stromal metabolic adaptation that supports CD8+ T cell immunity and highlight CAF-driven lipid oxidation and its regulation of CD8+ T cell PTEN signaling as potential avenues to enhance chemotherapy and immunotherapy efficacy.
    Keywords:  CD8(+) T cell anti-tumor immunity; PI3K/AKT/mTOR; PTEN; bladder cancer; cancer-associated fibroblasts; cell metabolism; chemotherapy; immunotherapy; lipid metabolism; tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.012
  38. Int J Biol Macromol. 2026 Feb 08. pii: S0141-8130(26)00740-3. [Epub ahead of print]348 150814
    Anti-inflammatory and antibacterial hydrogel of chitosan-dimethyl itaconate conjugate.
    Yi Li, Tian Tu, Shasha Zhou, Aixia Jiang, Jinglei Wu.
      Hydrogels with anti-inflammatory and antibacterial capacity have gained increasing attention in regenerative medicine. Dimethyl itaconate (DMI), a derivative of itaconic acid, exhibits powerful anti-inflammatory activity. Herein, we report a green synthesis of a chitosan-dimethyl itaconate (CS-DMI) conjugate through a nucleophilic substitution reaction, where primary amines of chitosan attack the ester carbonyl groups of DMI to form conjugation under mild alkaline conditions. The resulting conjugate was subsequently crosslinked with genipin into a hydrogel. Our findings indicate that this reaction fundamentally changed the nature of CS, converting it from acidic aqueous solution into a nearly neutral aqueous CS-DMI solution. It improved the efficiency of genipin crosslinking while maintaining the robust antibacterial activity of CS. The CS-DMI hydrogel showed sustained drug release of DMI and greater compression strength over the CS hydrogel. The CS-DMI conjugate showed good cytocompatibility, significantly promoted macrophage polarization toward an M2-like phenotype, reducing reactive oxygen species and nitric oxide production in lipopolysaccharide-stimulated macrophages. In a murine subcutaneous implantation model, the CS-DMI hydrogel significantly reduced immune cell infiltration, primarily by suppressing neutrophil recruitment and promoting a shift in macrophage polarization toward the pro-healing M2 phenotype. These findings confirm a viable strategy for developing multifunctional hydrogels that simultaneously address anti-inflammatory and antibacterial needs for modulating inflammation in regenerative medicine.
    Keywords:  Anti-inflammatory; Chitosan; Dimethyl itaconate; Hydrogel; Macrophage
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150814
  39. Int J Mol Sci. 2026 Jan 23. pii: 1133. [Epub ahead of print]27(3):
    Immunometabolism: A Novel Therapeutic Target and Its Pharmacological Modulation for Intervertebral Disc Degeneration.
    Mengting Cheng, Yichen Liu, Moran Suo, Kaizhong Wang, Xin Chen, Zhonghai Li.
      Intervertebral disc degeneration (IDD) is a leading cause of low back pain (LBP) and imposes a substantial social and economic burden. Current treatments mainly relieve symptoms but rarely halt or reverse disc degeneration, and key gaps remain in our understanding of its pathophysiology. Accordingly, promoting intervertebral disc regeneration (IVDR) has been proposed as a potential therapeutic aim. Immunometabolism, which refers to the bidirectional interplay between immune responses and cellular metabolism, is increasingly recognized as a key factor affecting the balance of disc homeostasis and degeneration and has become an emerging research focus. In this review, we synthesize evidence supporting a dual and context-specific role of immunometabolism in IDD and IVDR. On the one hand, certain immune cells and anabolic cytokines or growth factors may promote a regenerative microenvironment by supporting disc cell survival and extracellular matrix (ECM) synthesis. On the other hand, pro-inflammatory mediators and metabolic disorders, including oxidative stress, mitochondrial dysfunction, and lipid or amino acid imbalance, drive a catabolic cascade that accelerates ECM breakdown and cellular senescence. We summarize current knowledge regarding key immune cell subsets, cytokine networks, and metabolic pathways implicated in IDD pathogenesis and IVDR, and we discuss how these immunometabolic principles are being leveraged in emerging interventions such as stem cell-based therapies, gene therapy, and advanced biomaterials. By integrating mechanistic insights with translational advances, this review aims to clarify actionable immunometabolic targets and to inform the rational development of regenerative strategies for disc-related diseases.
    Keywords:  biomaterials; immunometabolism; intervertebral disc degeneration (IDD); mesenchymal stem cells (MSCs); oxidative stress; regenerative medicine
    DOI:  https://doi.org/10.3390/ijms27031133
  40. Virulence. 2026 Feb 08. 2629674
    PLIN3-triggered lipophagic flux releases FFAs to facilitate CSFV propagation.
    Bingke Li, Linke Zou, Chenchen Sun, Jianan Jiang, Shurou Li, Jiaxin Wang, Yintao He, Yuwei Qin, Sen Zeng, Yiwan Song, Weijun Zeng, Lin Yi, Shuangqi Fan, Jinding Chen, Keke Wu.
      Viruses hijack host metabolic resources for replication. Previous studies have shown that classical swine fever virus (CSFV) infection induces host lipid metabolic reprogramming.However, research into the exact regulatory mechanisms between CSFV and lipid metabolism remains limited. Lipophagy refers to the degradation of lipid droplet contents to release free fatty acids(FFAs), CSFV induces autophagy to promote its replication, the regulatory mechanism between CSFV and lipophagy is unclear. In this study, we found that lipid droplets(LDs) initially accumulate and then decrease following CSFV infection. Autophagy activity was negatively correlated with lipid drople levels. Subsequent experiments revealed that CSFV induces lipophagy in HSCs (Hepatic stellate cells)and upregulates PLIN3(perilipin 3) expression, a LD-associated protein that facilitates viral replication. Further studies demonstrated that PLIN3 activates the AMPK signaling pathway to promote lipophagy-mediated free fatty acid (FFA) release. This FFA increase could be blocked by autophagy inhibitors. Notably, exogenous FFA addition reversed the shPLIN3-induced impairment of CSFV replication. Overall, this finding provides new insights into the mechanisms of virus-host lipid metabolism interactions.
    Keywords:  AMPK; CSFV; Lipid droplets; Lipophagy; PLIN3(perilipin 3)
    DOI:  https://doi.org/10.1080/21505594.2026.2629674
  41. bioRxiv. 2026 Feb 04. pii: 2026.02.04.703699. [Epub ahead of print]
    RSAD2/VIPERIN and CMPK2 Coordinate an Immunometabolic Response to Epstein-Barr Virus.
    Urvi S Zankharia, Adam M Glass, Qing Zhu, Janvhi Suresh Machhar, Ying Ye, Bhanu Chandra Karisetty, Jayamanna Wickramasinghe, Andrew Kossenkov, Jozef Madzo, Sun Sook Chung, Samantha S Soldan, R Jason Lamontagne, Lawrence Harris, Tyler L Grove, Steven Jacobson, Chengyu Liang, Paul Lieberman.
      Epstein-Barr Virus (EBV) infection and reactivation in B-lymphocytes is tightly regulated by host antiviral response genes. In the present study, we identify interferon stimulated genes RSAD2 (radical S-adenosyl methionine domain-containing 2) and CMPK2 (Cytidine/Uridine Monophosphate Kinase 2) as key modulators of EBV expression and cellular response during EBV infection and reactivation. EBV primary infection and reactivation lead to a coordinated up-regulation of RSAD2 and CMPK2. Depletion of RSAD2 reduced cell viability and limited EBV reactivation, while depletion of CMPK2 led to reactivation of EBV lytic gene expression during latency. Transcriptomic analysis revealed that RSAD2 and CMPK2 have overlapping functions in regulating IFN-signaling pathways, as well as oxidative phosphorylation, protein translation, and unfolded protein response during reactivation. Despite distinct subcellular localizations, RSAD2 at the Endoplasmic Reticulum (ER), and CMPK2 in mitochondria, both genes converge on shared immunometabolic pathways, including control of Gasdermin D (GSDMD) associated pyroptosis and ATF-4 associated unfolded protein response (UPR). EBV reactivation induced formation of antiviral ribonucleotide ddhCTP during lytic EBV reactivation which was strictly dependent on RSAD2. Knockdown of RSAD2 and CMPK2 had significant effects on global metabolites consistent with a remodeling of glycolysis, fatty acid biosynthesis and degradation of superoxides. These observations demonstrate that RSAD2-CMPK2 function in a coordinated ER-mitochondria stress-Interferon signaling axis that shapes EBV reactivation and host immune control, including a novel layer of immunometabolic regulation modulating viral latency and reactivation.
    Authors Summary: Understanding how Epstein-Barr virus (EBV) regulates host factors to control infection, latency and reactivation is critical for developing targeted therapies against EBV-associated diseases. This study identifies Interferon Stimulated Genes RSAD2 (Viperin) and CMPK2 as key regulators of EBV reactivation and host interferon responses in B-cells. Despite distinct organelle localizations, both genes converge on a shared immunometabolic pathways, revealing a coordinated ER-mitochondria axis that shapes viral expression and immune signaling. These findings provide new insights into the roles of host antiviral effectors and uncover potential targets for modulating EBV activity in inflammatory and oncogenic contexts.
    DOI:  https://doi.org/10.64898/2026.02.04.703699
  42. MedComm (2020). 2026 Feb;7(2): e70637
    Dysregulation of Farnesoid X Receptor on Neutrophil Homeostasis Exacerbates Intestinal Inflammation via the mTORC1-Glycolysis Signaling Pathway.
    Dengfeng Kang, Ai Li, Xiangqi Xie, Han Liu, Liang Chen, Zhongsheng Feng, Xiang Gao, Han Gao, Xiaohan Wu, Huiying Lu, Xiaoyu Li, Jinghan Hua, Long Ju, Haifeng Lian, Xue Li, Zhanju Liu.
      Neutrophils significantly accumulate within the inflamed intestinal mucosa of patients with inflammatory bowel disease (IBD), where the farnesoid X receptor (FXR) is typically downregulated. However, the mechanisms by which FXR modulates neutrophil-mediated mucosal inflammation in IBD remain elusive. Here, we demonstrated that FXR expression is markedly decreased in neutrophils from patients with active IBD. Fxr -/- mice exhibited exacerbated colitis following DSS insults or Citrobacter rodentium infection, evidenced by heightened neutrophil-driven immune responses including increased neutrophil infiltration and neutrophil extracellular trap (NET) formation. Adoptive transfer of Fxr -/- neutrophils into WT recipients exacerbated DSS-induced intestinal inflammation, indicating that FXR suppresses the pathogenic activity of neutrophils in a neutrophil-intrinsic manner. An ex vivo functional assay revealed that Fxr -/- neutrophils display elevated ROS production, NET formation, and migratory capacity upon inflammatory challenge. Mechanistically, RNA-sequencing and functional assays revealed enhanced mTORC1 signaling and glycolysis in Fxr -/- neutrophils. Consistently, pharmacological activation of FXR with INT-747 significantly restrained the mTORC1-glycolysis-mediated proinflammatory responses in neutrophils from IBD patients. Our findings identify FXR as a critical regulator of neutrophil-mediated mucosal inflammation via the mTORC1-glycolysis pathway, highlighting its therapeutic potential in IBD.
    Keywords:  farnesoid X receptor; inflammatory bowel disease; mucosal homeostasis; neutrophil
    DOI:  https://doi.org/10.1002/mco2.70637
  43. PLoS Pathog. 2026 Feb;22(2): e1013938
    Amikacin-eravacycline combination mediates the synergistic elimination of carbapenem-resistant pathogens via in vitro and in vivo metabolic reprogramming.
    Xiaoli Yang, Yili Chen, Jinmei Yang, Jiaying Lei, Tinghua Liu, Yougang Mai, Xikang Tang.
      Carbapenem-resistant (CR) organisms (CRO) have been identified as critical priority pathogens, emphasizing the urgent need for novel therapeutic strategies. Combination therapy emerges as a promising approach to address multidrug-resistant bacterial infections. Here we demonstrate that eravacycline (ERV), in combination with amikacin (AMK), effectively eliminates a panel of clinically isolated CR Escherichia coli, CR Klebsiella pneumoniae, and CR Acinetobacter baumannii. Mechanistically, the AMK-ERV combination enhances bacterial oxidative phosphorylation, leading to an accumulation of reactive oxygen species, which induce oxidative stress and accelerate bacterial cell death. Notably, this combination significantly improves survival rates in mouse models of intra-abdominal infection, demonstrating efficacy against infections induced by CR pathogens. Furthermore, serum metabolomics reveals that the AMK-ERV combination upregulates metabolic pathways of lipids and amino acids. Interestingly, the amino acid methionine significantly enhances the antibacterial activity of ERV against CR pathogens both in vitro and in vivo. Our findings underscore the potential of repurposing AMK in combination with ERV to combat CR pathogens and propose a novel strategy for controlling these infections through the combination of antibiotics with specific metabolites such as methionine.
    DOI:  https://doi.org/10.1371/journal.ppat.1013938
  44. J Hazard Mater. 2026 Feb 08. pii: S0304-3894(26)00408-5. [Epub ahead of print]504 141430
    Fumaric acid restores neomycin efficacy against carbapenem-resistant Vibrio parahaemolyticus through metabolic reprogramming.
    Ziyi Zhang, Zhuoying Cao, Jiao Fei, Beibei Yan, Ting Zhang, Lvyuan Fan, Wenting Zhang, Chao Wang, Hao Wang, Yubin Su.
      Carbapenems are last-resort antibiotics for multidrug-resistant bacterial infections. The emergence of carbapenem-resistant Vibrio parahaemolyticus (CRVP) therefore represents a growing threat to aquaculture and public health, yet its resistance mechanisms remain poorly understood. In this study, we employed liquid chromatography-mass spectrometry metabolomics to explore metabolic changes associated with meropenem resistance in V. parahaemolyticus. Meropenem-resistant V. parahaemolyticus exhibited marked disruption of the pyruvate/tricarboxylic acid (TCA) cycle, including reduced enzymatic activity, lower NADH and ATP levels, and impaired energy metabolism. Building on this metabolic profile, we tested a reprogramming strategy using exogenous fumaric acid. Fumaric acid restored antibiotic resistance by activating the downstream TCA cycle flux, enhancing nitric oxide production through arginine biosynthesis, and increasing bacterial membrane permeability. It also disturbed the proton motive force, impaired efflux activity, and promoted intracellular neomycin accumulation, resulting in bacterial death. In a Nile tilapia infection model, the combined fumaric acid and neomycin treatment significantly improved survival rates, eradicated CRVP from infected organs, and reduced tissue damage. These results identify a metabolic vulnerability underlying carbapenem resistance and demonstrate that metabolic reprogramming can resensitize CRVP to antibiotics. This approach offers a promising therapeutic strategy for controlling antibiotic-resistant infections in aquaculture and mitigating associated public health risks.
    Keywords:  Carbapenem-resistance Vibrio parahaemolyticus; Fumaric acid; Metabolic reprogramming; Nitric oxide; Pyruvate/TCA cycle
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.141430
  45. Clin Exp Pharmacol Physiol. 2026 Feb;53(2): e70105
    Ddx17 Mitigates Sepsis-Induced Cardiomyopathy by Regulating Mitochondrial Dynamics in Cardiomyocytes.
    Ya-Ting Jiang, Li-Ran Su, Fang-Jing Ni, Luo-Ye Lu, Yu-Qiang Gong, Jun Luo, Chen-Xi Shen, Yang Cao.
      Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, in which mitochondrial dysfunction contributes to poor outcomes. DEAD-box helicase 17 (Ddx17), a member of the DEAD-box RNA helicase family, is known to regulate mitochondrial function, but its role in SICM remains unclear. In this study, mice with cardiomyocyte-specific Ddx17 knockdown (Ddx17-cKD) and overexpression (Ddx17-OE) were generated, and sepsis models were established using cecal ligation and puncture. Mechanistic findings were further validated in vitro using immunoprecipitation and dual-luciferase assays. Ddx17 expression was markedly reduced in the cardiac tissues of septic mice and in lipopolysaccharide-treated cardiomyocytes. Knockdown of Ddx17 increased mitochondrial reactive oxygen species accumulation, enhanced cell death and decreased superoxide dismutase activity. In contrast, Ddx17 overexpression attenuated mitochondrial apoptosis and oxidative stress, restored adenosine triphosphate production and mitochondrial membrane potential and improved cardiac function in septic mice. Mechanistically, Ddx17 interacted with signal transducer and activator of transcription 3 (STAT3) to suppress transcription of the mitochondrial fission protein dynamin-related protein 1 while maintaining the level of the fusion protein mitofusin 1, thereby preserving mitochondrial integrity and cardiomyocyte homeostasis. These findings demonstrate that Ddx17 protects against sepsis-induced cardiomyopathy by regulating mitochondrial dynamics, reducing oxidative stress and preventing apoptosis, thereby highlighting Ddx17 as a potential therapeutic target for septic cardiac dysfunction.
    Keywords:  Ddx17; STAT3; mitochondrial dynamics; oxidative stress; sepsis‐induced cardiomyopathy
    DOI:  https://doi.org/10.1111/1440-1681.70105
  46. Front Endocrinol (Lausanne). 2026 ;17 1734953
    Integrated multi-platform metabolomics reveals fatty acid-mediated inflammatory signatures in pretibial myxedema.
    Jiayi Cai, Li Zhang, Jie Zheng, Meng Pan, Xia Li, Xiaoqing Zhao, Shuoting Wang, Zirou Shang, Han Cao, Xiaoying Chen.
       Context: Pretibial myxedema (PTM) is a refractory autoimmune dermopathy associated with Graves' disease. Although metabolic dysregulation has been recognized in thyroid-associated disorders, the metabolic profile and its functional role in PTM remain unclear.
    Objective: To characterize the metabolic landscape of PTM lesions and explore the contribution of fatty acids to fibroblast dysfunction and inflammation.
    Methods: We performed untargeted metabolomic profiling of PTM skin lesions and healthy controls using LC-MS and GC-MS, integrated with spatial metabolomics to localize metabolic changes. Functional assays were conducted by stimulating human foreskin fibroblasts (HFFs) with palmitic acid (PA) and oleic acid (OA), followed by RNA sequencing, cytokine assays, and immunohistochemistry.
    Results: PTM lesions exhibited substantial metabolic dysregulation, including accumulation of fatty acids and elevated tricarboxylic acid cycle intermediates. Spatial metabolomics confirmed pronounced lipid deposition in the dermis, the primary site of PTM pathology. RNA-seq of fibroblasts stimulated with PA and OA revealed enrichment of inflammatory pathways, including IL-17 and NF-κB signaling, and marked upregulation of IL-8 (CXCL8). Fatty acid stimulation induced robust IL-8 secretion, consistent with increased IL-8 expression in PTM lesions. Moreover, PA promoted α-SMA expression in fibroblasts, suggesting induction of myofibroblast differentiation.
    Conclusions: Our findings demonstrate that dermal fatty acid accumulation in PTM may contribute to fibroblast-mediated inflammation and fibrosis. This study provides novel insights into the metabolic-immunologic interface underlying PTM pathogenesis.
    Keywords:  fatty acid metabolism; fibroblast activation; pretibial myxedema; spatial metabolomics; untargeted metabolomics
    DOI:  https://doi.org/10.3389/fendo.2026.1734953
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