bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–01–25
forty papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming.
  2. Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation.
  3. Upregulation of m6A writer WTAP by histone lactylation promotes inflammatory response via TLR2 in neutrophils.
  4. Spatiotemporal regulation of energetic charge dictates T cell function.
  5. Active LXR signaling, coupled with elevated mitochondrial and glycolytic metabolism contributes to GM-CSF-induced trained immunity.
  6. Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.
  7. Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.
  8. Targeting immunometabolism in cancer through pharmacological and lifestyle interventions.
  9. Hypoxia-induced immunosuppression in uveal melanoma is mediated by CD63+ exosomes delivering lactate to reprogram immune cells.
  10. Microbial metabolite FAD mobilizes adipocyte lipid remodeling to enhance cancer immunotherapy efficacy.
  11. Bioengineered extracellular vesicles escape lysosomal degradation and deliver Tet-PKM2 for macrophage immunometabolic reprogramming and periodontitis treatment.
  12. Orientin alleviates severe inflammation via regulating macrophage glycolysis and immune function in sepsis.
  13. NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
  14. A Melittin-Derived Lead Compound Ameliorates Severe Acute Pancreatitis by Restoring Oxidative Homeostasis and Macrophage Metabolism.
  15. TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
  16. IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes.
  17. Itaconate and its derivatives ameliorate autoimmunity by suppressing Th17 cells via regulating mitophagy.
  18. Multi-omics dissection of metabolic hijacking: Infectious bronchitis virus orchestrates lipid-centric replication through PPAR-TGF-β crosstalk.
  19. Immunometabolic reprogramming and β-cell dedifferentiation: Integrated mechanisms driving type 2 diabetes progression.
  20. Glycolytic reprogramming of resident alveolar macrophages contributes to reduced SOCS3 secretion in non-small cell lung cancer.
  21. Commensal-derived trehalose monocorynomycolate triggers γδ T cell-driven protective ocular barrier immunity.
  22. Gut microbe-derived short-chain fatty acids regulate joint inflammation and activation of infiltrating and resident myeloid cells after alphavirus infection.
  23. The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production.
  24. Integrated transcriptomic and metabolomic analyses reveal flavonoid and lipid metabolic reprogramming in Dendrobiumofficinale during Colletotrichum fructicola-induced anthracnose.
  25. GPR81 Activation by Lactate Delays Inflammation Resolution in Acute Lung Injury.
  26. Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction.
  27. Qishen Yiqi Dropping Pills ameliorate acute myocardial infarction by modulating PKM2/STAT3 pathway-mediated metabolic reprogramming in macrophages.
  28. Decoding the HIF-1-driven metabolic-inflammatory-immune axis in sepsis-associated lung injury: a comprehensive overview.
  29. Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.
  30. Adrenal and metabolic hormonal axes shape anti-Tuberculosis immune responses in HIV-TB coinfection.
  31. GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.
  32. UCP2-Driven Fatty Acid Oxidation Promotes Macrophage M2 Polarization and Renal Fibrosis.
  33. 4-week aerobic exercise training regulates systemic macrophage polarization in obese mice.
  34. Transcriptome changes in circulating immune cells of critical COVID-19 patients predict a specific metabolic and epigenetic imprint.
  35. Resilience of human tolerogenic dendritic cells to physiological oxygen supports clinical application: functional stability amidst glycolytic and differentiation shifts.
  36. Characterizing the tuberculosis and type 2 diabetes mellitus comorbidity in a South African cohort using untargeted GCxGC-TOFMS metabolomics.
  37. Metabolomics in Infectious Diseases and Vaccine Response: Insights into Neglected Tropical and Non-Neglected Pathogens.
  38. Western lifestyle linked to maladaptive trained immunity.
  39. β-Nicotinamide Mononucleotide protects against endotoxemia-induced myocardial injury through Sirt5-dependent desuccinylation of succinate dehydrogenase.
  40. A microbiota-dependent bile acid reprograms alveolar macrophages to control lung inflammation.
  1. Cancer Immunol Res. 2026 Jan 20.
    Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming.
    Phaethon Philbrook, Matthew J Dean, Maria Dulfary Sanchez-Pino, Li Qin Zheng, Jovanny Zabaleta, Julio A Vázquez-Martínez, Darwin Chang, Jessica K Mandula, Timothy I Shaw, Dorota Wyczechowska, Jone Garai, Ramesh Thylur Puttalingaiah, Amirsalar Mansouri, Weishan Huang, Satyajit Das, Shiun Chang, Jose R Conejo-Garcia, Paulo C Rodriguez, Augusto C Ochoa.
      GPR84 is a medium-chain free fatty acid receptor predominantly expressed in myeloid cells. Previous studies have identified GPR84 as an enhancer of the pro-inflammatory myeloid cell responses and a regulator of metabolic homeostasis. However, the role of GPR84 in T cell function and metabolism remains largely unexplored. This study tested the effect of GPR84 modulation on CD8+ T cell function and metabolism in vitro and examined its effect on antitumor function in adoptive cellular therapy models. Pharmacological antagonism with GLPG1205 or genetic deletion of GPR84 promoted T cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions. These functional changes were paralleled by changes in metabolic activity. Antagonism and genetic deletion increased glucose uptake, glycolysis, oxidative phosphorylation, and ATP production, which enhanced the overall cell energetic fitness, whereas agonism resulted in a quiescent energetic profile. Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T cell function and may further enhance adoptive cellular therapies.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0695
  2. PLoS Biol. 2026 Jan 21. 24(1): e3003620
    Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation.
    Yun Sok Lee.
      In obesity, nutrient excess and altered adipocyte secretory profiles reprogram cell-intrinsic metabolism, leading to the activation of immune cells within metabolically active tissues such as adipose tissue. This obesity-associated chronic low-grade metabolic inflammation (often referred to as metaflammation) is a well-established driver of insulin resistance and metabolic dysfunction. However, several lines of emerging evidence suggest that metaflammation is not merely a pathologic process, but may also serve as an adaptive response that supports metabolic homeostasis, particularly at the early stages of obesity. This Essay discusses immunometabolic mechanisms underlying the dual nature of metaflammation in obesity, highlighting how its initially beneficial effects can transition into detrimental outcomes.
    DOI:  https://doi.org/10.1371/journal.pbio.3003620
  3. Sci China Life Sci. 2026 Jan 14.
    Upregulation of m6A writer WTAP by histone lactylation promotes inflammatory response via TLR2 in neutrophils.
    Bailu Du, Wenting Song, Yiming Zhang, Yan Yin, Yuanjie Zhou, Yi Pan, Ruwen Yang, Muxiu Jiang, Nan Shen, Qihua Fu, Jianye Zang, Yue Tao, Xi Mo.
      Elevated lactate levels are a hallmark of severe infections and are associated with poor outcomes in sepsis patients, but the underlying mechanisms remain poorly understood. Recent findings have shown that lactate can covalently modify histones (e.g., histone lactylation) in macrophages, acting as a critical epigenetic regulator of inflammatory response. Here, we demonstrate that histone lactylation also occurs in neutrophils-the first immune cells mobilized during acute inflammation-and is functionally important for their activation. Using both DMSO-differentiated HL-60 (dHL-60) cells and primary neutrophils, we found that LPS stimulation significantly increased intracellular lactate levels and histone lactylation, particularly at the H4K8 site. These changes enhanced cytokine release, ROS production, and chemotaxis. Lactate further amplified these effects, while inhibition of glycolysis or p300 suppressed them. Multi-omics analyses revealed substantial enrichment of H4K8la at the promoter region of WTAP, a key m6A methyltransferase component, promoting its expression via CEBP/β recruitment. WTAP knockdown significantly reduced m6A modifications of TLR2 mRNA and impaired its stability. Both WTAP knockdown and TLR2 inhibition markedly dampened the inflammatory responses. Importantly, this glycolysis-H4K8la-WTAP-TLR2 axis was further validated in LPS-induced septic mice and pediatric sepsis patients, highlighting its clinical relevance. In summary, our findings uncover a novel lactate-driven epigenetic-post-transcriptional regulatory circuit that amplifies neutrophil inflammatory responses, expanding the regulatory framework of innate immunity and providing potential therapeutic targets for hyperinflammation.
    Keywords:  TLR2; WTAP; histone lactylation; inflammation; m6A; neutrophils; sepsis
    DOI:  https://doi.org/10.1007/s11427-024-3081-9
  4. Nat Commun. 2026 Jan 21. 17(1): 770
    Spatiotemporal regulation of energetic charge dictates T cell function.
    Aleksandra S Chikina, Béatrice Corre, Fabrice Lemaître, Philippe Bousso.
      Immune cell functions are dictated by their differentiation state and regulated by transcriptional and epigenetic changes. Immune cell differentiation also controls the preferential metabolic pathways used for energy production. However, whether the energy charge of individual immune cells itself varies across time and space and regulates cell function remains to be fully understood. Here, we show that T cells harbor distinct energetic resources and function in different anatomical locations and times of the day. To monitor ATP: ADP ratio, an indicator of cellular energetic resources, we rely on SPICE-Met, a method that dissects energy metabolism in complex cell populations in vivo. We find that cells with the highest glycolytic capacity, including effector T cells and NK cells, exhibit the highest ATP: ADP ratio. Importantly, effector T cells but not naïve T cells display higher energetic charge when present in the blood compared to lymph nodes due to differential glucose availability. Energetic resources are also regulated in a circadian manner, being highest at the early rest phase. Importantly, differences in energetic charge are directly translated at the level of T cell function, impacting IFN-γ production. Thus, modulation of energetic charge and nutrient availability dictates immune cell function across time and space.
    DOI:  https://doi.org/10.1038/s41467-026-68559-1
  5. Front Immunol. 2025 ;16 1685796
    Active LXR signaling, coupled with elevated mitochondrial and glycolytic metabolism contributes to GM-CSF-induced trained immunity.
    Yuanyuan Liu, Arslan Hamid, Hannah Hardege, Qian Zhang, Helena Körner, Merle Leffers, Noelia A Gonzalez, Gerhard Liebisch, Marcus Hoering, Hannes Findeisen, Katarzyna Placek, Mihai G Netea, Holger Reinecke, Dennis Schwarz, Yahya Sohrabi.
      Granulocyte-macrophage colony-stimulating factor (GM-CSF) contributes to the host defense and the pathogenesis of inflammatory diseases at least in part through inducing trained immunity (TI), however, the mechanism remains poorly characterized. In this paper, we systematically investigated the associated metabolic and epigenetic reprogramming, with a particular focus on the role of liver X receptors (LXRs) in this process. We employed a comprehensive experimental approach, including in vitro isolation and purification of human monocytes from healthy donors, cytokine assays, quantitative PCR, Seahorse metabolic analysis, flow cytometry, and chromatin immunoprecipitation (ChIP), shotgun lipidomics, as well as transcriptomic data analysis to investigate GM-CSF-induced trained immunity. Our results demonstrate that GM-CSF induces TI by enhancing cellular metabolism, as evidenced by increased glycolysis, mitochondrial activity, fatty acid oxidation, and pyruvate metabolism. Lipidomics and RNA sequencing analyses revealed upregulation of lipid synthesis, high triglyceride storage, and acetyl-CoA-producing pathways, leading to increased histone acetylation in GM-CSF-trained cells. Furthermore, glycolysis and mitochondrial metabolism are essential for establishing TI in these cells. Notably, pharmacological inhibition of GM-CSF activated LXR signaling, which potentially mediated via PPARγ, attenuated GM-CSF-induced TI via reducing glycolytic flux and histone acetylation while activation of LXR amplified these effects. Together, these results highlight the role of LXR in linking cellular metabolism with epigenetic reprogramming and demonstrate that elevated metabolic activity and active LXR signaling both are essential for GM-CSF-induced trained immunity. Importantly, these pathways may represent therapeutic targets for modulating GM-CSF-driven maladaptive inflammation in chronic inflammatory diseases.
    Keywords:  GM-CSF; acetyl-CoA; glycolysis; histone modification; mitochondrial metabolism; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2025.1685796
  6. Nat Metab. 2026 Jan 19.
    Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.
    Renhui Sun, Deyan Jiao, Wenjing Yuan, Hao Wang, Lingtong Ren, Zhendong Fu, Jiaxuan Zhang, Xuetian Yue, Zhuanchang Wu, Chunyang Li, Huili Hu, Jianping Wang, Lifen Gao, Chunhong Ma, Xiaohong Liang.
      Psychological stress is increasingly linked to liver disease, but the underlying mechanisms remain unclear. Here we show that chronic stress disrupts a brain-liver circuit that impairs hepatic CD8+ T cell immunity and accelerates liver cancer progression. Using both oncogene-driven and carcinogen-driven liver cancer models in male mice, we find that psychological stress disrupts catecholamine/β2-adrenergic receptor (ADRB2) signalling, which suppresses the expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme of the kynurenine pathway, in hepatocytes. QPRT loss diverts kynurenine metabolism away from nicotinamide adenine dinucleotide (NAD+) synthesis towards kynurenic acid (KA) accumulation. This shift results in mitochondrial impairment and reduced effector function of liver CD8+ T cells. We confirm that ADRB2/QPRT expression correlates with hepatic NAD+ and KA levels and with CD8+ T cell frequency and function in human liver tissues. Importantly, ADRB2/QPRT overexpression in hepatocytes, or nicotinamide administration, recovers CD8+ T cell function in stressed mice and reduces liver cancer progression. These findings identify a stress-responsive metabolic checkpoint in the liver that links the nervous system to immune surveillance and may be therapeutically targeted in liver cancers.
    DOI:  https://doi.org/10.1038/s42255-025-01430-7
  7. Nat Immunol. 2026 Jan 19.
    Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.
    Floortje J van Haften, Tetje C van der Sluis, Hanna S Hepp, Nils Mülling, Reza Nadafi, Bharath Sampadi, Suzanne van Duikeren, J Shirin Mostert, Rosemarijn van der Sterre, Peter A van Veelen, Graham A Heieis, Dominique M B Veerkamp, Thomas H Wesselink, Ward Vleeshouwers, Macha Beijnes, Iris N Pardieck, Eralin L F van Horssen, Anne F de Groot, Manon van der Ploeg, Judith R Kroep, Noel F C C de Miranda, Sabina Y van der Zanden, Jacques Neefjes, Hailiang Mei, Alfred C O Vertegaal, Bart Everts, Sjoerd H van der Burg, Ramon Arens.
      Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8+ T cells that undergo synchronized proliferation and differentiation. How CD8+ T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8+ T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8+ T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8+ T cells following arrest. Transient arrest in vivo enables superior CD8+ T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8+ T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-025-02407-0
  8. PLoS Biol. 2026 Jan 20. 24(1): e3003617
    Targeting immunometabolism in cancer through pharmacological and lifestyle interventions.
    Rachael Julia Yuenyinn Tan, Yalei Liu, Weixin Chen, Yuteng Liang, Guang Sheng Ling.
      Immunometabolism, a fundamental biogenic process that supports the function of immune cells, is often disrupted in diseases such as cancer. Tackling metabolic dysregulation at a cellular level has therefore emerged as a focus in drug development. However, as cellular metabolic rewiring takes place in response to both intrinsic factors, which can be targeted pharmacologically, and environmental changes, which cannot, fostering a homeostatic systemic metabolism through diet, exercise, and stress management is essential to support and sustain cellular fitness. This Essay conceptualizes immunometabolism as a process that can be regulated intrinsically and extrinsically and explores the potential for incorporating lifestyle changes and drug therapies that target immunometabolism into treatments for cancer.
    DOI:  https://doi.org/10.1371/journal.pbio.3003617
  9. Front Mol Biosci. 2025 ;12 1743009
    Hypoxia-induced immunosuppression in uveal melanoma is mediated by CD63+ exosomes delivering lactate to reprogram immune cells.
    Lei Dong, Suilian Zheng, Yixia Feng.
      Uveal melanoma (UM) is characterized by profound immunosuppression, resistance to immunotherapy, and significant hypoxia. This study investigates the role of hypoxia in mediating metabolic crosstalk with immune cells via CD63-enriched exosomes. Single-cell transcriptomic analysis identified a CD63-high tumor subpopulation in UM associated with lactate metabolism and vesicle transport. Under hypoxic conditions (1% O2 vs. 21% O2 normoxia), UMT2 cells exhibited upregulation of CD63 expression, increased exosome secretion, and elevated exosomal lactate levels. In co-culture assays, these hypoxic exosomes promoted macrophage M2 polarization, as indicated by increased CD206+ expression and elevated Extracellular Acidification Rate/Oxygen Consumption Rate (ECAR/OCR) ratios in macrophages and induced CD8+ T cell exhaustion, as evidenced by higher PD-1+TIM-3+ expression, and promoted the secretion of immunosuppressive cytokines such as TGF-β and IL-10. Importantly, these effects, which were driven by exosomal lactate transfer leading to macrophage metabolic reprogramming, were abolished upon CD63 knockdown using siRNA. Mechanistically, CD63 facilitates a hypoxia-induced exosomal lactate shuttle. We conclude that CD63-mediated transfer of hypoxic exosomal lactate establishes a critically immunosuppressive microenvironment in UM. Targeting the hypoxia/CD63/exosomal lactate axis may represent a promising novel therapeutic strategy to restore anti-tumor immunity in UM.
    Keywords:  exosomes; hypoxia; immunosuppression; lactate; uveal melanoma
    DOI:  https://doi.org/10.3389/fmolb.2025.1743009
  10. Cell Metab. 2026 Jan 21. pii: S1550-4131(25)00543-1. [Epub ahead of print]
    Microbial metabolite FAD mobilizes adipocyte lipid remodeling to enhance cancer immunotherapy efficacy.
    Tianying Tong, Xiaowen Huang, Lingxi Li, Muni Hu, Xiaoqiang Zhu, Beiyao Zhu, Yanru Ma, Lijun Ning, Yi Jiang, Yue Zhang, Yilu Zhou, Zhenyu Wang, Jinmei Ding, Ying Zhao, Baoqin Xuan, Youwei Zhang, Xiuying Xiao, Jing-Yuan Fang, Jie Hong, Yan Yin, Fenglin Liu, Haoyan Chen.
      Crosstalk between gut microbiota and adipose tissue critically shapes immunotherapy responses in patients with cancer. An obesity-associated microbial signature enriched in riboflavin-producing taxa was identified, along with increased microbial riboflavin biosynthesis pathway and elevated levels of flavin adenine dinucleotide (FAD), in obese responders to immune checkpoint blockade (ICB). In diet-induced obese (DIO) mice, fecal microbiota transplantation (FMT), administration of Lachnospiraceae bacterium, or FAD supplementation significantly enhanced the therapeutic efficacy of anti-PD-1 therapy. These interventions increased the cytotoxicity of tumor-infiltrating CD8+ T cells via mesenteric adipocyte-driven synthesis of polyunsaturated fatty acids (PUFAs). Inhibiting fatty acid desaturase 2 (FADS2) eliminated the benefits of FAD, underscoring a critical role for adipocyte-intrinsic lipid remodeling in mediating immune responses. Clinically, elevated systemic levels of PUFAs, particularly docosahexaenoic acid (DHA), were positively correlated with intratumoral CD8+ T cell infiltration and favorable immunotherapy outcomes. Dietary DHA supplementation improved ICB responses in lean mice. This study highlights that a microbiota-adipose axis shapes antitumor immunity, enabling potential personalized metabolic and microbial immunotherapy strategies.
    Keywords:  adipocyte; gut microbiota; immunotherapy; microbial metabolite; obesity; unsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.012
  11. Bioact Mater. 2026 May;59 607-628
    Bioengineered extracellular vesicles escape lysosomal degradation and deliver Tet-PKM2 for macrophage immunometabolic reprogramming and periodontitis treatment.
    Wen-Jie Zhang, Bei-Min Tian, Fang Li, Xuan Li, Rui-Xin Wu, Yuan Yin, Jia Wang, Dao-Kun Deng, Yu-Zhe Chen, Hong-Yu Wang, Yu-Xuan Du, Xuan Wang, Yin Xiao, Xiao-Tao He, Fa-Ming Chen.
      Modulating macrophage phenotype and function via immunometabolic reprogramming represents a new therapeutic paradigm to combat chronic inflammatory diseases such as periodontitis. Tetrameric pyruvate kinase M2 (Tet-PKM2), a highly active metabolic enzyme involved in the flux of glucose-derived carbons into the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), was found to be dramatically decreased in response to inflammation, rendering a potential immunometabolic target for developping new therapeutics. Hence, we report a large extracellular vesicle (LEV) that is bioengineered to intracellularly deliver Tet-PKM2 for the reprogramming of proinflammatory macrophages and the restoration of their aberrant immunometabolism. We engineered Tet-PKM2-enriched LEVs modified by tannic acid (LEVsTet-PKM2@TA) that can intracellularly deliver Tet-PKM2 and increase their ability to escape lysosomal degradation for the intracellular delivery of Tet-PKM2. In vitro, LEVsTet-PKM2@TA were able to rescue aberrant pyruvate metabolism in lipopolysaccharide (LPS)-activated macrophages by increasing TCA cycle activity and enhancing mitochondrial OXPHOS metabolism. In vivo, LEVsTet-PKM2@TA exerted robust immunomodulatory effects by increasing pyruvate kinase (PK) activity and coaxing macrophages toward the M2 phenotype, ultimately resulting in robust periodontal tissue regeneration in a mouse ligature-induced periodontitis model. This study provides a versatile and safe method for the targeted delivery of Tet-PKM2 via EVs to modulate macrophage phenotype and function. Our work demonstrates a new concept for immunometabolic reprogramming to treat chronic inflammatory diseases.
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.01.002
  12. Free Radic Biol Med. 2026 Jan 16. pii: S0891-5849(26)00021-3. [Epub ahead of print]246 196-208
    Orientin alleviates severe inflammation via regulating macrophage glycolysis and immune function in sepsis.
    Yanjun Zheng, Li Chen, Hongqi Li, Jingrong Lin, Jian Ma.
      Sepsis is a heterogeneous syndrome triggered by a dysregulated host response to infection, with glycolysis playing a vital role in maintaining macrophage immune function, which is critical for immune homeostasis and host survival during severe sepsis. Targeting glycolytic enzymes may offer effective strategies to mitigate macrophage-mediated inflammatory responses during sepsis. This study investigated the anti-inflammatory and metabolic modulatory effects of Orientin (Ori) in murine models of endotoxemia and sepsis, with a particular focus on its interaction with the glycolytic enzyme phosphofructokinase liver type (PFKL). Ori was administered at varying dosages in vivo, while in vitro experiments involved lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) and RAW264.7 cells. Inflammatory responses were assessed using Western blot, Enzyme-Linked Immunosorbent Assay (ELISA), and immunofluorescence, while glycolytic activity was evaluated through lactate production, glucose uptake, and extracellular acidification rate (ECAR). Cellular Thermal Shift Assay (CETSA) and molecular docking confirmed the direct binding between Ori and PFKL, and further analyses using network pharmacology and PFKL overexpression elucidated the enzyme's role in mediating Ori's effects. Ori significantly improved survival, reduced lung injury, and suppressed cytokine release in septic mice, while in vitro it attenuated LPS-induced inflammatory cytokine expression and glycolysis. Notably, macrophage-specific PFKL overexpression abrogated Ori's protective effects. These findings demonstrate that Ori alleviates sepsis-induced inflammation and metabolic dysfunction by directly targeting PFKL, highlighting its potential as a novel therapeutic candidate for sepsis.
    Keywords:  Glycolysis; Macrophages; Ori; PFKL; Sepsis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.013
  13. Front Immunol. 2025 ;16 1734203
    NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
    Oded Shamriz, Zahala Bar-On, Omri Yosef, Leonor Cohen-Daniel, Ayelet Sheer, Or Reuven, Wajeeh Salaymeh, Amijai Saragovi, Raz Somech, Atar Lev, Hagar Mor-Shaked, Yuval Tal, Aviva Fattal-Valevski, Simon Edvardson, Michael Berger.
       Introduction: Mitochondrial metabolism is essential for T-cell function, but the roles of individual electron transport chain (ETC) components are unclear. Here, we aimed to explore the role of mitochondrial complex I (CI) subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (NDUFS4) in T-cell metabolic fitness and immunity.
    Methods: We used a T cell-specific Ndufs4 knockout mouse model to find that NDUFS4 deficiency disrupts CI function, leading to metabolic and redox imbalances. Additionally, T cells from a patient with Leigh syndrome induced by NDUFS4 loss-of-function were analyzed.
    Results: Ndufs4-deficient T cells exhibit impaired OXPHOS, reduced respiratory capacity, and increased glycolysis, accompanied by reactive oxygen species (ROS) accumulation and defective TCR-driven activation, including reduced proliferation and cytokine production. In vivo, Ndufs4(-/-) mice show T-cell lymphopenia and impaired humoral and cytotoxic immunity. Importantly, T cells from a single Leigh syndrome patient with an NDUFS4 loss-of-function variant showed similar defects, including impaired activation and proliferation.
    Discussion: These findings highlight the importance of NDUFS4 for human immunity and establish a mechanistic link between complex I dysfunction and T-cell immunodeficiency. Our results identify NDUFS4 as a key regulator connecting mitochondrial integrity to adaptive immune function.
    Keywords:  NDUFS4; NDUFS4 knockout mice; T cells; leigh syndrome (LS); mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2025.1734203
  14. Inflammation. 2026 Jan 22.
    A Melittin-Derived Lead Compound Ameliorates Severe Acute Pancreatitis by Restoring Oxidative Homeostasis and Macrophage Metabolism.
    Xiaolong Chen, Ya Chen, Yunyun Mao, Xinxin Chen, Yilin Zhou, Jianfeng Tu.
      Severe acute pancreatitis (SAP) is a life-threatening inflammatory condition driven by macrophage-mediated oxidative stress and metabolic dysregulation. While bioactive peptides such as melittin show anti-inflammatory potential, their clinical application is limited by cytotoxicity and unclear mechanisms. In this study, we developed HMLT, a melittin-derived peptide with histidine substitutions designed to reduce cytotoxicity. Compared with native melittin, HMLT exhibited significantly lower cytotoxicity in RAW264.7 macrophages while maintaining potent anti-inflammatory activity, as demonstrated by reduced TNF-α release and downregulated expression of TNF-α, IL-6 and IL-1β. Flow cytometry analysis revealed that HMLT reduced ROS accumulation and protected mitochondrial membrane potential in LPS-stimulated macrophages. Additionally, HMLT decreased nitric oxide release and suppressed inducible nitric oxide synthase expression. Metabolomic analysis showed that HMLT restored metabolic balance by increasing endogenous antioxidants including O-acetylcarnitine and ornithine, while downregulating glycolytic intermediates such as phosphoenolpyruvic acid, 2-phospho-D-glyceric acid and 3-phosphoglyceric acid. In a caerulein and LPS-induced murine SAP model, HMLT administration significantly alleviated pancreatic injury, as evidenced by reduced serum amylase and lipase levels, diminished edema. Further mechanistic studies revealed that HMLT inhibited TNF-α secretion and suppressed PKM2-mediated glycolysis in M2-like macrophages. Collectively, these findings demonstrate that HMLT overcomes the toxicity limitations of native melittin and ameliorates SAP through coordinated restoration of oxidative homeostasis and metabolic reprogramming in macrophages, highlighting its promise as a lead compound for SAP treatment.
    Keywords:  Anti-inflammatory activity; Macrophage oxidative stress; Melittin; Metabolic reprogramming; Severe acute pancreatitis
    DOI:  https://doi.org/10.1007/s10753-025-02444-9
  15. FASEB J. 2026 Jan 31. 40(2): e71467
    TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
    Yuxuan Zhang, Ximeng Wang, Dachuan Li, Xiao Lu, Zhaoyang Gong, Zhidi Lin, Hanqiu Sun, Hongli Wang, Zian Lu, Xiaosheng Ma, Guangyu Xu, Jianyuan Jiang.
      The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia toward the pro-inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.
    Keywords:  TFAM; cell polarization; fatty acid oxidation; glycolysis; metabolism; microglia; mitochondria
    DOI:  https://doi.org/10.1096/fj.202503182RR
  16. Nat Metab. 2026 Jan 21.
    IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes.
    Kang Lei, Xinyu Li, Ting Zhong, Rong Tang, Qiaolin Deng, Paul E Love, Zhiguang Zhou, Bin Zhao, Xia Li.
      The innate immune system is increasingly recognized as a contributor to the development of type 1 diabetes (T1D), but the role of natural killer (NK) cells remains largely unclear. Here, we identify an expanded subset of transcriptionally active CD226+CD56dimCD16+ NK cells at the onset of T1D that contracts in remission. Using single-cell RNA sequencing integrated with cross-sectional and longitudinal analyses in patients with T1D, we show that CD226+ NK cell frequency correlates with disease progression. CD226+ NK cells exhibit enhanced cytotoxicity, inflammation and glucose metabolism. Mechanistically, CD161+CD4+ T cells promote pathogenic NK cell generation through interleukin-21 (IL-21) and mTOR signalling. Inhibition of this pathway by CD226 blockade, IL-21 receptor fusion protein, IL-21 knockout or mTOR inhibition attenuates NK cell activation, reduces pancreatic infiltration and delays diabetes onset in female mice. Our data reveal a mechanistic link, bridging adaptive and innate immunity, in the progression and remission of T1D that could potentially be exploited in T1D immunotherapy.
    DOI:  https://doi.org/10.1038/s42255-025-01439-y
  17. Cell Commun Signal. 2026 Jan 22.
    Itaconate and its derivatives ameliorate autoimmunity by suppressing Th17 cells via regulating mitophagy.
    Fuli Li, Qing Huang, Naisheng Zheng, Wenyu Zhang, Shan Luo, Ruowen Wang, Thulasiram Bathini, Pengkai Sun, Xinjian Li, Xian Huang, Tomasz Maj.
      
    Keywords:  Autoimmunity; Immunometabolism; Itaconate; Mitophagy; Th17 lymphocytes
    DOI:  https://doi.org/10.1186/s12964-025-02621-1
  18. Virulence. 2026 Jan 21. 2620271
    Multi-omics dissection of metabolic hijacking: Infectious bronchitis virus orchestrates lipid-centric replication through PPAR-TGF-β crosstalk.
    Kun Yan, Xiuling Wang, Zongyi Bo, Chengcheng Zhang, Mengjiao Guo, Xiaorong Zhang, Yantao Wu.
      Avian infectious bronchitis virus (IBV) belongs to the genus Gammacoronavirus (family Coronaviridae), causes severe multi-system disease in chickens, inflicting major global economic losses. The molecular interplay between IBV and host metabolic networks remains poorly understood. Through integrated transcriptomic, metabolomic, and lipidomic profiling of oviduct tissues from specific-pathogen-free (SPF) chickens infected with the IBV QXL strain, we demonstrate tripartite metabolic reprogramming: (1) redirected glucose flux through the pentose phosphate pathway (PPP) to fuel nucleotide synthesis, (2) rewired lipid metabolism to prioritize de novo membrane biogenesis over fatty acid β-oxidation, and (3) orchestrated glycerophospholipid remodeling. This integrated analysis revealed a coordinated upregulation of fatty-acid biosynthesis genes and accumulation of specific glycerophospholipids and eicosanoids. Mechanistically, IBV co-opts the Warburg effect and PPP activation while uniquely suppressing fatty acid β-oxidation to channel fatty acids toward lipid droplets (LDs) biogenesis. Phosphatidylserine (PS) overproduction (e.g. 2.55-fold increase in PS(22:0/22:6)) and phospholipase A2 (PLA2)-mediated lysophospholipids (Lyso-PLs) and eicosanoids generation (e.g. 7.09-fold increase in prostaglandin E2 (PGE2)) emerged as critical regulators of membrane dynamics and inflammatory signaling. This process was centrally coordinated by the significant activation of peroxisome proliferator-activated receptor (PPAR) (e.g. 1.74-fold increase in ACSL1) and transforming growth factor-beta (TGF-β) (e.g. significant increase in p-SMAD2) signaling pathways, directly linking lipid remodeling to immunomodulation. Functionally, targeting acetyl-CoA carboxylase (ACC) or glucose-6-phosphate dehydrogenase (G6PD), alongside TGF-β pathway modulation, synergistically curtailed viral replication in vitro. Our findings delineate a critical PPAR-TGF-β cross-talk that governs lipid remodeling during infection and identify host metabolic nodes that are potentially targetable for antiviral intervention.
    Keywords:  Infectious bronchitis virus; PPAR-TGF-β; lipid homeostasis; metabolic reprogramming; multi-omics; viral replication
    DOI:  https://doi.org/10.1080/21505594.2026.2620271
  19. Diabetes Res Clin Pract. 2026 Jan 19. pii: S0168-8227(26)00030-6. [Epub ahead of print] 113111
    Immunometabolic reprogramming and β-cell dedifferentiation: Integrated mechanisms driving type 2 diabetes progression.
    Ritu Dahiya, Ajay Pal Singh, Aruna Rawat.
      Type 2 diabetes is increasingly recognised as a condition driven by sustained metabolic overload and chronic low-grade inflammation rather than a simple decline in insulin secretion. Findings from single-cell transcriptomics, human islet studies, and metabolic profiling show that pancreatic β-cells undergo progressive alterations in identity when exposed to glucotoxic, lipotoxic, oxidative, and inflammatory stress. In parallel, cytokines, lipid intermediates, adipose-derived factors, hepatokines, myokines, and gut microbial metabolites generate an immunometabolic environment that accelerates β-cell dedifferentiation and promotes transitions toward progenitor-like or alternative endocrine states. Originally described through lineage-tracing studies in experimental models, β-cell dedifferentiation is now recognized as a dynamic and potentially reversible process shaped by immunometabolic stress in diabetes. This review synthesizes current evidence to illustrate how metabolic and immune pathways converge on key molecular regulators of β-cell fate. It further describes how interorgan communication reinforces these disturbances and contributes to the gradual shift of β-cells along a continuum of stress adaptation, functional decline, and identity loss. A conceptual framework, referred to as the beta-cell identity clock, is presented to capture the dynamic and potentially reversible nature of these transitions. Finally, emerging therapeutic strategies are discussed, including anti-inflammatory agents, metabolic modulators, epigenetic regulators, and regenerative approaches aimed at preserving or restoring β-cell identity in the context of modern metabolic stress.
    Keywords:  Adipose–islet axis; Dedifferentiation; Immunometabolism; Mitochondrial stress; Type 2 diabetes; β-cell identity
    DOI:  https://doi.org/10.1016/j.diabres.2026.113111
  20. Front Immunol. 2025 ;16 1708467
    Glycolytic reprogramming of resident alveolar macrophages contributes to reduced SOCS3 secretion in non-small cell lung cancer.
    Jennifer M Speth, Mikel D Haggadone, Marc Peters-Golden.
      Alveolar macrophages (AMs), the resident immune cells of the lung, play a critical role in maintaining pulmonary homeostasis, in part through the secretion of suppressor of cytokine signaling 3 (SOCS3)-a recognized tumor suppressor-within extracellular vesicles (EVs). While we have previously observed that SOCS3 secretion by AMs is diminished in tumor-bearing lungs, the mechanisms underlying this impairment remain unclear. Here, we investigated whether increased glycolytic metabolism in AMs contributes to this defect within the tumor microenvironment. The analysis of published single-cell RNA-sequencing datasets from an orthotopic Lewis lung cancer (LLC) model of adenocarcinoma and non-small cell lung cancer (NSCLC) patients revealed distinct AM clusters in tumor-bearing lungs enriched for glycolysis-associated genes. In a Kras G12D mutant mouse model of lung cancer, we found that AMs isolated from tumor-bearing lungs exhibited increased glucose uptake, which inversely correlated with SOCS3 secretion. Importantly, the pharmacologic inhibition of glycolysis with 2-deoxy-d-glucose restored SOCS3 secretion in these AMs. Together, our findings demonstrate that lung tumor-associated AMs undergo a time-dependent metabolic shift toward glycolysis, resulting in impaired SOCS3 secretion-a phenotype that can be reversed by targeting glycolytic flux. These results highlight a potential therapeutic approach for modulating immune suppression in the tumor microenvironment.
    Keywords:  SOCS3; alveolar macrophage; extracellular vesicles; glycolysis; lung cancer
    DOI:  https://doi.org/10.3389/fimmu.2025.1708467
  21. Immunity. 2026 Jan 19. pii: S1074-7613(25)00563-1. [Epub ahead of print]
    Commensal-derived trehalose monocorynomycolate triggers γδ T cell-driven protective ocular barrier immunity.
    Xiaoyan Xu, Yannis E Rigas, Mary J Mattapallil, Jing Guo, Keiko Sakamoto, Keisuke Nagao, Vijayaraj Nagarajan, Eric Bohrnsen, Crystal Richards, Akriti Gupta, Guillaume Gaud, Paul E Love, Timothy Jiang, Amy Zhang, Biying Xu, Zixuan Peng, Yingyos Jittayasothorn, Mary A Carr, M Teresa Magone, Nathan T Brandes, Jackie Shane, Benjamin Schwarz, Anthony J St Leger, Rachel R Caspi.
      Commensals shape host physiology through molecular crosstalk with host receptors. Identifying specific microbial factors that causally influence host immunity is key to understanding homeostasis at the host-microbe interface and advancing microbial-based therapeutics. Here, we identified trehalose monocorynomycolate (TMCM) from Corynebacterium mastitidis as a potent stimulator of interleukin 17 (IL-17) production by Vγ4 γδ T cells at the ocular surface. Mechanistically, TMCM-induced IL-17 responses depended on IL-1R and γδ T cell receptor (TCR) signaling, with TCR engagement further enhancing IL-1R1 expression on γδ T cells. Synthetic TMCM alone recapitulated the effect of Corynebacterium mastitidis in eliciting protective γδ T cell immunity at the ocular surface to prevent bacterial infection. Moreover, TMCM also promoted protective immunity in downstream eye-draining tissues and skin. These findings establish TMCM as a broadly applicable mediator of commensal-driven immune defense and highlight its therapeutic potential to strengthen IL-17-mediated protection at barrier sites.
    Keywords:  IL-17A; IL-1R; barrier defense; commensal; corynomycolates; mucosal immunity; ocular immunity; γδ T cells; γδ TCR
    DOI:  https://doi.org/10.1016/j.immuni.2025.12.007
  22. bioRxiv. 2025 Dec 03. pii: 2025.12.03.691668. [Epub ahead of print]
    Gut microbe-derived short-chain fatty acids regulate joint inflammation and activation of infiltrating and resident myeloid cells after alphavirus infection.
    Fang R Zhao, Maksim Kleverov, Emma S Winkler, Russell B Williams, Hana Janova, Lindsay Droit, Leran Wang, Ting-Ting Li, Leah Heath, Ana Jung, Matthias Mack, Megan T Baldridge, Thaddeus S Stappenbeck, Larissa B Thackray, Chyi-Song Hsieh, Scott A Handley, Chun-Jun Guo, Michael A Fischbach, Maxim N Artyomov, Michael S Diamond.
      Although oral antibiotics can predispose to joint inflammation, this phenomenon remains poorly understood. Here, we leverage mouse models of alphavirus-induced arthritis to investigate the roles of gut commensals, metabolites, and host immune mechanisms in promoting musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya (CHIKV) or Mayaro virus infections. This phenotype was associated with loss of short chain fatty acids (SCFA), greater intestinal permeability, and activation of gut-associated immune cells, and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4 + T cells, and pro-inflammatory cytokines. Administration of exogenous SCFA or colonization of mice with bacterial species that generate SCFA mitigated CHIKV-induced joint inflammation. Single-cell RNA sequencing revealed that gut-derived SCFA ameliorate the inflammatory phenotype of synovial CD4 + T cells, infiltrating monocytes, and resident osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.
    DOI:  https://doi.org/10.64898/2025.12.03.691668
  23. EMBO J. 2026 Jan 22.
    The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production.
    Zeming Feng, Lulu Wang, Shujun Chen, Sihan Cao, Miao Lei, Xiuzhen Yang, Kaixiong Ma, Shi Yu, Huina Hu, Kaixuan Zheng, Xin Xu, Qi Zheng, Shaobo Wang, Wenxiang Hu, Chun-Yan Lim.
      Lysosomes are emerging as important signaling hubs for antiviral defense, yet how they enable type I interferon (IFN-β) production is unclear. Here, we identify an evolutionarily repurposed lysosomal pathway, centered on the LAMTOR-Rag GTPase complex, that governs IFN-β production through dual transcriptional and post-transcriptional regulation. Genetic ablation of LAMTOR or Rag GTPases in macrophages abolishes IFN-β responses despite intact pattern recognition receptor (PRR) signaling, uncovering a lysosome-specific checkpoint essential for antiviral immunity. Mechanistically, Rag GTPase activity controls IRF expression to prime IFN transcription, while upon PRR stimulation, the tumor suppressor FLCN recruits p38 MAPK to lysosomes, where Rag-dependent p38 phosphorylation stabilizes Ifnb1 mRNA. Nutrient availability dynamically modulates Rag nucleotide states and thereby its activation, linking IFN production to metabolic capacity. Notably, this checkpoint operates independently of mTORC1, illustrating how an ancient nutrient-sensing module has been co-opted for immune regulation. Disruption of the LAMTOR-Rag-FLCN-p38 axis impairs IFN induction in vitro and antiviral responses in vivo, underscoring its physiological significance. Our findings support the role of the lysosome as a central signaling hub integrating metabolic and immune cues, suggesting future directions for potential therapeutic strategies against viral infections.
    Keywords:  Innate Immunity; LAMTOR/Ragulator; Lysosomes; Type I Interferon; p38 MAPK
    DOI:  https://doi.org/10.1038/s44318-026-00695-2
  24. PeerJ. 2026 ;14 e20563
    Integrated transcriptomic and metabolomic analyses reveal flavonoid and lipid metabolic reprogramming in Dendrobiumofficinale during Colletotrichum fructicola-induced anthracnose.
    Jun Yang, Xinqiao Zhan, Yahui Zhang, Yichun Qian, Minxia Pang, Guoxiang Yao, Bizeng Mao.
      Anthracnose disease caused by Colletotrichum fructicola severely compromises the medicinal value and yield of Dendrobium officinale. To elucidate the host metabolic response to pathogen infection, we integrated transcriptomic and metabolomic analyses of D. officinale challenged with C. fructicola. Our results revealed a profound metabolic reprogramming orchestrated by the pathogen, characterized by upregulated flavonoid biosynthesis (e.g., DFR, LDOX activation) and enhanced lipid catabolism (e.g., β-oxidation via LACS, DECR, HACL). Metabolite profiling demonstrated a significant reduction in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) alongside increased free fatty acids, indicating active lipid degradation. Notably, acyl-CoA intermediates linked lipid catabolism to flavonoid production, suggesting a metabolic axis where pathogen-induced lipid breakdown fuels defense-related secondary metabolite synthesis. This study identifies flavonoid and lipid metabolic reprogramming as critical axes in host-pathogen interactions, providing a foundation for developing targeted disease control strategies.
    Keywords:  Fatty acid catabolism; Host-pathogen interaction; Medicinal orchid; Secondary metabolite biosynthesis
    DOI:  https://doi.org/10.7717/peerj.20563
  25. FASEB J. 2026 Jan 31. 40(2): e71423
    GPR81 Activation by Lactate Delays Inflammation Resolution in Acute Lung Injury.
    Zhongjie Liang, Chengxi Shen, Junyan Zeng, Xingling Wei, Jinling Wei, Yuan Cao, Shengwei Jin, Qian Wang.
      Acute respiratory distress syndrome (ARDS) involves impaired macrophage function in clearing apoptotic cells. The link between clinical hyperlactatemia in ARDS patients and poor outcomes prompted this study on the immunometabolic role of lactate in disease progression. In an LPS-induced ARDS mouse model, mice received either exogenous lactate or a lactate dehydrogenase inhibitor. Inflammatory cell infiltration was evaluated through flow cytometry and histological analysis with hematoxylin and eosin staining. Lactate signaling was confirmed in GPR81-deficient mice. In vitro, lactate metabolism during efferocytosis was studied using primary Alveolar Macrophages (AMs). Lactate accumulation, neutrophil infiltration, and elevated inflammatory factors were observed in this ARDS model. External lactate delayed inflammation resolution and worsened lung injury. GPR81-/- mice exhibited reduced neutrophil infiltration and better outcomes. Macrophages produced substantial amounts of lactate during efferocytosis in vitro, concurrent with upregulated expression of the glucose transporter Glut1, the lactate transporter MCT1, and the lactate receptor GPR81. Pharmacological inhibition using an LDH inhibitor, an MCT1 antagonist, or extra lactate significantly impaired efferocytic capacity. Efferocytosis triggered Myc upregulation in vitro, which was suppressed by exogenous lactate. Genetic ablation of GPR81 elevated both MCT1 and Myc expression. Silencing Myc via siRNA significantly impaired efferocytosis in vitro. These findings indicate that the activation of GPR81 by lactate delays the resolution of inflammation in acute lung injury. This effect may be attributed to the suppression of alveolar macrophage efferocytosis, which subsequently impairs the clearance of apoptotic cells and exacerbates lung injury.
    Keywords:  ARDS; Efferocytosis; GPR81; Macrophages; lactate
    DOI:  https://doi.org/10.1096/fj.202501547RR
  26. Redox Biol. 2026 Jan 19. pii: S2213-2317(26)00038-8. [Epub ahead of print]90 104040
    Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction.
    Zhengyu Yu, Hua Lin, Jingran He, Linfeng Li, Zhongwang Wang, Kun Li, Ting Niu, Bingquan Qiu.
      Metabolic disorders mediated chimeric antigen receptor - T cell (CAR-T) exhaustion impaired cancer immunotherapy. Endogenous sulfur dioxide (SO2) derived from L-cysteine catalysis regulated immune cell functions. However, its role in CAR-T cell exhaustion remained unknown. In this study, we identified that SO2 accumulated in the bone marrow microenvironment of relapsed multiple myeloma patients inhibited CD8+ T cell and CAR-T cell infiltration and promoted a transcriptional profile consistent with functional exhaustion, leading to impaired antitumor immunity. Tumor cell derived SO2 altered mitochondrial morphology and disrupted mitochondrial membrane potential in CAR-T cells, accompanied by impaired cytokine secretion and loss of cytotoxic function. Mechanistically, SO2 enhanced interaction of dynamin-related protein 1 (DRP1) and voltage-dependent anion channel 1 and mitochondrial fission via DRP1 sulphenylation at cysteine 607 (Cys607), with abnormal increases in DRP1 GTPase activity, disrupting mitochondrial integrity. Site mutation of Cys607 in CAR-T cells abrogated DRP1 sulphenylation and restored mitochondrial structure and improves antitumor immunity. These findings define a novel redox-mediated mechanism of mitochondrial dysfunction in CAR-T cells exhaustion and identify the SO2-DRP1 axis as a potential therapeutic target to overcome metabolic exhaustion in CAR-T cell therapy.
    Keywords:  CAR-T cell exhaustion; CAR-T therapy; DRP1; Mitochondrial dynamics; Multiple myeloma; Sulfur dioxide
    DOI:  https://doi.org/10.1016/j.redox.2026.104040
  27. Phytomedicine. 2026 Jan 08. pii: S0944-7113(26)00021-8. [Epub ahead of print]151 157784
    Qishen Yiqi Dropping Pills ameliorate acute myocardial infarction by modulating PKM2/STAT3 pathway-mediated metabolic reprogramming in macrophages.
    Aodi Fan, Yuting Huang, Qiuyu Lyu, Ke Yang, Yakun Yang, Haixia Li, Ziyou Liu, Guanwei Fan, Lan Li.
       BACKGROUND AND PURPOSE: Acute myocardial infarction (AMI) is the leading cause of cardiovascular mortality worldwide. Timely reperfusion therapy is crucial to save the ischemic myocardium and prevent infarct expansion. Inflammation, a central pathological mechanism in AMI, exacerbates myocardial tissue damage by triggering immune activation in a cascading manner. Macrophage metabolic reprogramming plays a crucial role in regulating inflammatory phenotypes in this process. Qishen Yiqi Dropping Pills (QSYQ), a traditional Chinese medicine compound, greatly improves the cardiac inflammatory microenvironment after myocardial ischemia‒reperfusion (MI/R) injury. It also inhibits myocardial fibrosis and effectively reduces cardiac dysfunction. However, it remains unclear whether QSYQ exerts cardioprotective effects by modulating the metabolic reprogramming of cardiac macrophages and the underlying mechanisms involved.
    METHODOLOGY: To evaluate the effects on myocardial injury and the inflammatory response, QSYQ intervention was administered to a mouse model of myocardial infarction (MI) established in this study. After that, macrophages from the ischemic zone were extracted, and the expression of genes linked to metabolic reprogramming was analyzed via proteomics in conjunction with q‒PCR technology. By using this approach, the regulatory role of QSYQ in macrophage metabolism and the key target signal transducer and activator of transcription 3 (STAT3) were clarified. By utilizing the Cre-loxP system, we were able to generate mice with macrophage-specific STAT3 knockout. We then used spatial metabolomics and targeted metabolomics to confirm the regulatory pathway mechanisms in vivo. Proximity ligation assay (PLA), coimmunoprecipitation (Co-IP), and nuclear‒cytoplasmic fractionation Western blotting were used in vitro to elucidate the pyruvate kinase muscle isozyme M2 (PKM2)-STAT3 protein interaction network.
    RESULTS: QSYQ significantly alleviates cardiac inflammatory damage and ventricular remodeling induced by MI/R. Proteomic analysis revealed that QSYQ promotes the restoration of the tricarboxylic acid cycle and electron transport chain function by downregulating the expression of key glycolytic enzymes, such as PKM2 and LDHA, in macrophages in the MI/R-damaged area. It also identifies STAT3 as a core target closely associated with metabolic reprogramming. Spatial and targeted metabolomics analyses revealed that the deletion of STAT3 in macrophages suppresses glycolysis in the ischemic core region of a heart attack while also facilitating the recovery of the TCA cycle. Within macrophages, PLA and Co-IP experiments confirmed that a physical complex is formed by STAT3 with PKM2, the key rate-limiting enzyme of glycolysis. Using DSS chemical cross-linking reactions further demonstrated that blocking STAT3 expression hinders the transformation of PKM2 tetramers into dimers and prevents the nuclear translocation of the STAT3/PKM2 complex, leading to decreased STAT3 phosphorylation levels and reduced expression of proinflammatory factors such as IL-6, IL-1β, and TNF-α. Moreover, the metabolic regulatory effects of the QSYQ pellets were confirmed to depend on STAT3 via the use of STAT3-specific knockout mice in macrophages. Additionally, the QSYQ pellets demonstrated long-lasting regulatory effects on MI/R by altering macrophage metabolic reprogramming.
    CONCLUSION: QSYQ hinders glycolysis by lowering STAT3 levels in macrophages, obstructing the shift from PKM2 tetramers to dimers and opposing the creation of PKM2/STAT3 complexes. As a result, there is a reduction in STAT3 phosphorylation levels, suppression of proinflammatory factor release, and improvement in AMI-induced cardiac inflammatory damage and ventricular remodeling.
    Keywords:  Macrophages; Metabolic reprogramming; Myocardial ischemia‒reperfusion injury; PKM2/STAT3; QSYQ
    DOI:  https://doi.org/10.1016/j.phymed.2026.157784
  28. Front Immunol. 2025 ;16 1658103
    Decoding the HIF-1-driven metabolic-inflammatory-immune axis in sepsis-associated lung injury: a comprehensive overview.
    Shuang Zhang, Beilin Hu, Yuang Fang, Mudi Liu, Qingmei Liu, Ye Chen, Jun Zhou.
      Sepsis is a systemic inflammatory response syndrome triggered by infection that frequently involves multiple organs, ultimately leading to multiple organ failure. Among affected organs, the lungs represent the most vulnerable target. Sepsis-associated lung injury (S-ALI) is a common critical illness that can progress to acute respiratory distress syndrome in severe cases, resulting in high morbidity and mortality. Currently, clinical management relies predominantly on mechanical ventilation and supportive care, as no specific pharmacological treatment exists for S-ALI. The pathogenesis of S-ALI is characterized by uncontrolled inflammation, microcirculatory dysfunction, immune dysregulation, mitochondrial impairment, and oxidative stress. Notably, mitochondrial dysfunction and oxidative stress are closely associated with tissue hypoxia and metabolic reprogramming. Hypoxia-inducible factor-1 (HIF-1) is a pivotal transcription factor that regulates gene expression under hypoxic conditions. It becomes activated during hypoxia and inflammatory responses, thereby coordinating cellular metabolic adaptation and inflammatory pathways. In S-ALI, both the expression and activity of HIF-1 are markedly upregulated, playing a critical role in modulating inflammation, immunity, and metabolic reprogramming. These findings suggest that targeted modulation of HIF-1-mediated metabolic reprogramming in S-ALI may improve patient outcomes by simultaneously addressing inflammatory, immune, and metabolic dysfunction. This review examines the pathogenesis of S-ALI, HIF-1-mediated metabolic reprogramming in S-ALI, the crosstalk between HIF-1 and multiple signaling pathways, and its impact on inflammatory responses and immune function. Our goal is to identify novel therapeutic targets for S-ALI treatment.
    Keywords:  HIF-1; immunity; lung injury; metabolic reprogramming; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2025.1658103
  29. iScience. 2026 Jan 16. 29(1): 114277
    Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.
    Yushan Yi, Ce Luo, Jingyi Wang, Yujia Wang, Lixue Jin, Xiuyuan Sun, Jie Hao, Guoping Deng, Rong Jin, Qing Ge.
      Stress-response elements are required during late-phase T cell activation and differentiation. To investigate whether they are indispensable during the first 12-24 h post-stimulation when mitochondrial activation and metabolic reprogramming are critical, we activated Atf4-sufficient and Atf4-deficient T cells and tracked their earliest activation dynamics. We demonstrate that T cell activation-induced mTOR and GCN2 phosphorylation leads to the upregulation of ATF4 protein as early as 12 h after stimulation. This early induction of ATF4 has transcriptional activities that regulate stress response, signaling, and metabolism. Loss of Atf4 in T cells alters transcriptome dynamics, impairs amino acid transport and biosynthesis, and disrupts adaptive responses to ER stress and oxidative stress, resulting in defective effector cell differentiation in vitro or in vivo. Our findings suggest that a basal level of ATF4 during the early phase of T cell activation enhances the preparedness of cells to cope with integrated stresses during the activation course.
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2025.114277
  30. Neuroimmunomodulation. 2026 Jan 19. 1-21
    Adrenal and metabolic hormonal axes shape anti-Tuberculosis immune responses in HIV-TB coinfection.
    María Belén Vecchione, Denise Anabella Giannone, Milagros Victoria Acevedo, Natalia Santucci, María Florencia Quiroga.
       BACKGROUND: Tuberculosis (TB) remains a leading cause of mortality worldwide among infectious agents, and HIV increases the risk of developing into active disease. HIV-TB coinfection impairs immune responses, while chronic inflammation and infection-associated stress activate neuroendocrine pathways that deeply impact immune homeostasis. Adrenal steroids such as cortisol, dehydroepiandrosterone (DHEA) and its metabolites, along with metabolic hormones like leptin and adiponectin, have emerged as critical regulators of immune function, although their role in TB pathogenesis, particularly in coinfected individuals, remains underexplored.
    SUMMARY: This review navigates over current evidence on the neuroendocrine-immune crosstalk in HIV-TB coinfection, focusing on adrenal and metabolic hormonal axes. We first summarize how HIV-driven CD4⁺ T cell depletion, chronic immune activation, and altered granuloma dynamics predispose individuals to TB reactivation. We then examine findings indicating that TB and HIV disrupt hypothalamic-pituitary-adrenal (HPA) axis homeostasis, leading to elevated cortisol levels, reduced DHEA and its metabolites, and an unfavorable cortisol/DHEA ratio, which correlated with poor immune control and disease severity. Preclinical studies highlight immunomodulatory properties of DHEA derivatives, such as 7-oxo-DHEA (7-OD), which restore Th1 responses, limit Treg expansion, and enhance macrophage antimicrobial activity. Metabolic hormones, particularly leptin and adiponectin, further shape host immunity and energy allocation; their dysregulation in coinfection contributes to wasting, impaired granuloma formation, and increased immune reconstitution inflammatory syndrome (IRIS) risk. Despite compelling preclinical findings, clinical studies on hormonal modulation remain scarce, emphasizing the need for translational research that links endocrinology and infectious disease immunology.
    KEY MESSAGES: HIV-TB coinfection creates a neuroendocrine-immune imbalance, with dysregulation of the hypothalamic-pituitary-adrenal axis and metabolic hormones contributing to impaired immune control and accelerated disease progression. Adrenal hormones such as DHEA and its metabolite 7-oxo-DHEA show potential as immunomodulatory agents, capable of restoring Th1 responses, limiting Treg expansion, and supporting host-directed therapies. Additionally, leptin and adiponectin emerge as crucial metabolic players that integrate nutritional status and immune activity and may serve as potential biomarkers for TB management. Altogether, integrating endocrine profiling into TB research and advancing the clinical evaluation of hormonal immunomodulators may unlock novel avenues for precision medicine, improving treatment strategies for populations affected by the HIV and TB epidemics.
    DOI:  https://doi.org/10.1159/000550045
  31. Cytokine Growth Factor Rev. 2026 Jan 13. pii: S1359-6101(26)00004-3. [Epub ahead of print]88 47-57
    GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.
    Lingeng Lu, Caroline H Johnson, Sajid A Khan, Melinda L Irwin.
      Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8+ T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15's multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.
    Keywords:  Cancer immunotherapy; Colorectal cancer; GDF15; Immunometabolism; Obesity; Pancreatic cancer; Spatial metabolomics; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.01.004
  32. Kidney Dis (Basel). 2026 Jan-Dec;12(1):12(1): 29-38
    UCP2-Driven Fatty Acid Oxidation Promotes Macrophage M2 Polarization and Renal Fibrosis.
    Xingyue Wang, Yuxi Li, Liu Li, Xinyan Gu, Chunsun Dai, Lei Jiang.
       Introduction: During renal fibrosis, macrophages play a crucial role in multiple processes, such as initiating inflammation, mediating tissue repair, and promoting interstitial fibrosis. Macrophage polarization is a key determinant of their functional properties. This study aimed to investigate the roles and mechanism of macrophages with distinct phenotype in renal fibrosis.
    Methods: We established unilateral ureteral obstruction and ischemia-reperfusion injury models using macrophage-specific Ucp2-KO mice induced by tamoxifen. Bone marrow-derived macrophages treated with TGF-β1 and IL-4 were used for in vitro experiments. We also employed a chimeric model via adoptive transfer of macrophages.
    Results: We indicated that the energy metabolism pattern is a key factor during macrophage phenotypic switching. Specifically, uncoupling protein 2 (UCP2), a mitochondrial inner membrane protein, was found to regulate the metabolic profile of macrophages. Knockout of Ucp2 in macrophages led to reduced fatty acid oxidation, downregulation of M2 phenotype markers, and alleviation of renal fibrosis. Attenuation of renal interstitial fibrosis was observed in wild-type mice receiving Ucp2-deficient (Ucp2-KO) macrophages. In contrast, adoptive transfer of wild-type macrophages into Ucp2-KO mice resulted in a marked aggravation of renal fibrosis.
    Conclusion: In summary, we identified UCP2 as a key regulator of macrophage metabolic reprogramming and a critical promoter of renal fibrosis, suggesting that targeting UCP2 represents a promising therapeutic strategy.
    Keywords:  Fatty acid oxidation; Macrophage; Metabolic reprogramming; Renal interstitial fibrosis; UCP2
    DOI:  https://doi.org/10.1159/000549918
  33. PeerJ. 2026 ;14 e20604
    4-week aerobic exercise training regulates systemic macrophage polarization in obese mice.
    JingAo Qin, HaiBin Zhang, XinPeng Gao, Nan Zhang, Xin Zhang, Jeong-Sun Ju.
       Background: Obesity is accompanied by chronic low-grade inflammation, largely driven by imbalances in macrophage polarization. While pro-inflammatory M1 macrophages accumulate in adipose tissue and circulation, contributing to insulin resistance and metabolic disruption, alternatively activated M2 macrophages exert anti-inflammatory and tissue-protective effects. Exercise is widely recognized as a non-pharmacological strategy to improve metabolic health; however, the extent to which short-term aerobic training influences systemic macrophage polarization in obesity is not fully understood. This study examined whether a 4-week aerobic exercise intervention alters systemic macrophage polarization in diet-induced obese mice and explored its role in attenuating obesity-related inflammation.
    Methods: Male C57BL/6J mice (8 weeks old) were fed either a standard chow diet (Ch) or a high-fat diet (HF; 60% kcal from fat) for 12 weeks. Following obesity induction, HF-fed mice were assigned to either a sedentary (HF-Sed) or exercise-trained (HF-Exe) group. The training protocol involved treadmill running at moderate intensity, performed twice daily, 5 days per week, for 4 weeks. Plasma concentrations of M1-associated markers (TNF-α, IFN-γ , IL-1β, IL-6) and M2-associated markers (IL-10, Arg1, CD163) were measured by an enzyme-linked immunosorbent assay (ELISA). Statistical differences were analyzed using analysis of variance (ANOVA) with post hoc testing.
    Results: After 12 weeks of high-fat feeding, mice exhibited approximately 20% higher body weight than chow controls, confirming obesity induction. Four weeks of exercise training did not significantly reduce body weight but improved metabolic indices, including plasma glucose and insulin sensitivity. HF-Sed mice displayed elevated circulating M1 cytokines, whereas HF-Exe mice had significantly lower levels of IL-6, and TNF-α. Conversely, exercise enhanced M2-associated markers, including IL-10, Arg1, and CD163. Thus, aerobic training shifted systemic macrophage polarization away from a pro-inflammatory toward an anti-inflammatory profile, independent of substantial weight loss.
    Conclusion: Short-term aerobic exercise is sufficient to promote M2 macrophage polarization and dampen systemic inflammation in obese mice. These findings underline the rapid immunomodulatory potential of exercise and support its role as an effective non-pharmacological approach to counteract obesity-related inflammation and metabolic dysfunction.
    Keywords:  Aerobic exercise training; Anti-inflammatory; High-fat diet; Inflammation; Macrophage polarization; Obesity; Pro-inflammatory
    DOI:  https://doi.org/10.7717/peerj.20604
  34. J Transl Med. 2026 Jan 22.
    Transcriptome changes in circulating immune cells of critical COVID-19 patients predict a specific metabolic and epigenetic imprint.
    Federico Virga, Daniela Taverna, Giulio Ferrero, Marine Leclercq, Najla El Hachem, Gerard Godoy-Tena, Cato Jacobs, Sonia Tarallo, Barbara Pardini, Alessio Naccarati, Joost Wauters, Hanne Moon Lauwers, Els Wauters, Pierre Close, Francesca Orso, Massimiliano Mazzone.
      
    Keywords:  Epigenetics; Immune responses; Metabolic analysis; SARS coronavirus; miRNA; tRNA
    DOI:  https://doi.org/10.1186/s12967-025-07665-y
  35. Exp Hematol Oncol. 2026 Jan 22. 15(1): 8
    Resilience of human tolerogenic dendritic cells to physiological oxygen supports clinical application: functional stability amidst glycolytic and differentiation shifts.
    Antonia Peter, Tamara Traitteur, Sara Calitz, Morgane Vermeulen, Mats Van Delen, Amber Dams, Stefanie Peeters, Carole Faghel, Hans De Reu, Waleed F A Marei, Zwi N Berneman, Nathalie Cools.
      Tolerogenic dendritic cells (tolDCs) hold promise for treating autoimmune diseases, potentially restoring antigen-specific immune tolerance without systemic immunosuppression. However, their behavior in vivo remains incompletely understood, particularly in response to microenvironmental factors such as oxygen (O2) tension. While tolDCs are typically generated and functionally validated under atmospheric O2 (21%), physiological O2 levels (physioxia) in human tissues are considerably lower (3-9%). The primary aim of this study was to assess whether tolDCs manufactured under atmospheric O2 conditions retain their function under physioxia at 4% O2, mimicking tissue environments encountered upon clinical administration. To contextualize these findings, we also evaluated the effect of physioxia during in vitro generation and investigated underlying metabolic adaptations. We demonstrate that tolDCs generated under atmospheric O2 conditions remain functionally effective in physioxic environments, preserving migratory capacity and the ability to induce T cell hyporesponsiveness. Furthermore, physioxia during tolDC generation impaired monocyte-to-tolDC differentiation efficiency, whereas hallmark tolerogenic features, including low expression of CD80, CD83, and CD86, remained intact. Metabolic profiling revealed a distinct shift under physioxia, with reduced mitochondrial reserve capacity and increased glycolytic activity. This suggests metabolic plasticity without loss of function across O2 environments. Our findings indicate that physiological O2 shapes tolDC differentiation and metabolism but does not compromise immunoregulatory traits. Importantly, tolDCs generated under atmospheric O2 remained functionally competent in physioxic environments, reinforcing their suitability for therapeutic use. By modeling in vivo-relevant O2 levels, this study provides new insights into how microenvironmental O2 may shape tolDC behavior following clinical administration.
    Keywords:  Dendritic cell-based vaccine; Immunometabolism; Oxygen; Tolerance; Tolerogenic dendritic cells
    DOI:  https://doi.org/10.1186/s40164-025-00731-7
  36. Metabolomics. 2026 Jan 19. 22(1): 19
    Characterizing the tuberculosis and type 2 diabetes mellitus comorbidity in a South African cohort using untargeted GCxGC-TOFMS metabolomics.
    Karla Reinecke, Léanie Kleynhans, Katharina Ronacher, Du Toit Loots.
       INTRODUCTION: Tuberculosis (TB) and type 2 diabetes mellitus (T2DM) are highly prevalent diseases resulting in high mortality rates globally. Furthermore, T2DM increases susceptibility to TB and vice versa, worsening disease outcomes. This comorbidity is, however, not well described nor understood, despite its rising prevalence globally.
    OBJECTIVES: This investigation aimed to better characterize the urinary metabolic profiles of patients with the TB and T2DM comorbidity in a South African cohort, to better understand its metabolic basis and associated clinical implications.
    METHODS: Using untargeted GCxGC-TOFMS metabolomics, urine samples from 17 patients with TB and T2DM and 34 healthy controls were analyzed and statistically compared to identify significantly altered urinary metabolites.
    RESULTS: TB-T2DM comorbid patients were characterized by altered metabolism of: (1) tryptophan and kynurenine (reduced kynurenic acid, anthranilic acid, picolinic acid) associated with changes to NAD+ synthesis and a redox imbalance, (2) nucleotides (reduced 3-aminoisobutyric acid, orotic acid, thymine, β-alanine, adenine, hypoxanthine), (3) tyrosine (reduced 3,4-dihydroxyphenylglycol, 4-hydroxy-3-methoxyphenylglycol, hydroxyphenylpyruvate), (4) lipids (reduced dec-2-enedioate, adipic acid, methylmalonic acid), (5) reduced concentrations of various glycine conjugates associated with glycine depletion, and (6) reduced urinary concentrations of various gut microbial metabolites indicative of microbial dysbiosis.
    CONCLUSION: These results indicate several metabolic disruptions to amino acids, nucleotides, lipids, NAD⁺ homeostasis and the host microbiome, in TB-T2DM patients, mainly driven by inflammation and oxidative stress. Overall, the findings indicate synergistic amplification of metabolic stress, associated with immune suppression and TB-T2DM disease progression, and subsequently suggests how TB increases T2DM susceptibility and vice versa, as foundation for further investigations.
    Keywords:  Comorbidity; Diabetes; Metabolomics; Tuberculosis; Urine
    DOI:  https://doi.org/10.1007/s11306-025-02389-y
  37. Infect Dis Rep. 2026 Jan 12. pii: 10. [Epub ahead of print]18(1):
    Metabolomics in Infectious Diseases and Vaccine Response: Insights into Neglected Tropical and Non-Neglected Pathogens.
    Mahbuba Rahman, Hasbun Nahar Hera, Urbana Islam Barsha.
       BACKGROUND/OBJECTIVES: Metabolomics has emerged as a powerful systems-biology tool for deciphering dynamic metabolic alterations occurring during infectious diseases and following vaccination. While genomics and proteomics provide extensive molecular and regulatory information, metabolomics uniquely reflects the biochemical phenotype associated with infection, immune activation, and immunometabolic reprogramming. The objective of this review is to provide an integrated analysis of metabolomics applications across both neglected tropical diseases (NTDs) and non-NTD pathogens, highlighting its dual role in biomarker discovery and vaccine response evaluation.
    METHODS: A comprehensive literature-based synthesis was conducted to examine metabolomic studies in infectious diseases and vaccinology. Metabolic perturbations associated with specific pathogens, as well as vaccine-induced metabolic changes and correlates of immune responses, were systematically analyzed and compared across NTD and non-NTD contexts.
    RESULTS: Distinct pathogen- and vaccine-associated metabolic signatures were identified, reflecting alterations in glycolysis, amino acid metabolism, lipid remodeling, and immunoregulatory pathways. Comparative analysis revealed both shared and disease-specific metabolic biomarkers across NTDs and non-NTD infections. Importantly, vaccine-related metabolic correlates were shown to mirror immune activation states and, in some cases, predict immunogenicity and response durability.
    CONCLUSIONS: This review bridges metabolomics research in infectious disease pathogenesis and vaccine immunology across the NTD and non-NTD spectrum. By integrating these domains, it introduces the concept of "metabolic immuno-signatures" as predictive and translational tools for evaluating vaccine efficacy and immune response outcomes.
    Keywords:  infectious diseases; metabolomics; neglected tropical disease; non-neglected tropical disease; vaccine
    DOI:  https://doi.org/10.3390/idr18010010
  38. Elife. 2026 Jan 21. pii: e105835. [Epub ahead of print]15
    Western lifestyle linked to maladaptive trained immunity.
    Aurelia Josephine Merbecks, Christabel Mennicken, Dennis Marinus de Graaf, Kateryna Shkarina, Theresa Wagner, Eicke Latz.
      Trained immunity (TI) refers to a state of innate immune cells that, after encountering an initial stimulus and undergoing epigenetic reprogramming and metabolic changes, allows them to respond more effectively to a subsequent challenge. TI yields a survival advantage, particularly in a pathogen-rich context. However, maladaptive TI may damage the host by exacerbating inflammatory diseases. Here we review which aspects of Western lifestyle may contribute to maladaptive TI, including a Western diet, periodontitis, chronic psychological stress, and environmental triggers such as air pollution and microplastics. Finally, we consider lifestyle intervention as a way to prevent or reduce the impact of maladaptive TI.
    Keywords:  Western diet; autoinflammation; immunology; infectious disease; inflammation; interleukin-1; maladaptive; trained immunity
    DOI:  https://doi.org/10.7554/eLife.105835
  39. Eur J Pharmacol. 2026 Jan 16. pii: S0014-2999(26)00044-0. [Epub ahead of print] 178562
    β-Nicotinamide Mononucleotide protects against endotoxemia-induced myocardial injury through Sirt5-dependent desuccinylation of succinate dehydrogenase.
    Hongmei Tao, Qian Dong, Yang Long, Ling Liu, Shu Qin, Yu Wang.
      During endotoxemia, dysfunction of succinate dehydrogenase (SDH) in myocardial tissue serves as a significant contributor to impaired cardiac function. Previous study has suggested that Sirtuin 5 (Sirt5)-mediated SDH desuccinylation exerts a cardioprotective effect. However, in the context of endotoxemia, the level of nicotinamide adenine dinucleotide (NAD+), an essential co-substrate for Sirt5 in myocardial tissue, is diminished, leading to the inability to maintain Sirt5 activity. This study aims to investigate whether supplementation with the NAD+ precursor β-nicotinamide mononucleotide (NMN) ameliorates endotoxemia-induced myocardial injury by activating Sirt5-mediated desuccinylation of SDH. Mice were intraperitoneally administered NMN (500 mg/kg) for 1, 7, 14, 21, and 28 consecutive days. Myocardial NAD+ levels gradually increased to a saturation level (peaking at 14 days), with no obvious adverse effects. In LPS-induced myocardial injury, NMN supplementation significantly improved survival rates, reduced serum cardiac troponin I (cTnI), enhanced cardiac function, restored ATP production, downregulated pro-inflammatory cytokines, and alleviated oxidative damage. We further discovered that NMN corrected the aberrant catalytic function of SDH, reduced succinate accumulation, and increased fumarate levels. Mechanistically, NMN supplementation specifically reduced SDH succinylation (but not acetylation) and promoted the binding of Sirt5 to SDH. After cardiomyocyte-specific knockdown of Sirt5, the protective effects of NMN on SDH desuccinylation and myocardial protection were significantly attenuated. In summary, NMN supplementation elevates myocardial NAD+ levels, promotes Sirt5-mediated SDH desuccinylation, corrects succinate metabolism disorder, and thereby mitigates endotoxemia-induced myocardial injury.
    Keywords:  Myocardial Injury; Nicotinamide Mononucleotide; Sirt5; Succinate Dehydrogenase; Succinylation
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178562
  40. Signal Transduct Target Ther. 2026 Jan 17. 11(1): 35
    A microbiota-dependent bile acid reprograms alveolar macrophages to control lung inflammation.
    Magdalena Wolska, Pilar Rodríguez-Viso, Anna Świątkowska, Edyta Bulanda, Tomasz P Wypych.
      
    DOI:  https://doi.org/10.1038/s41392-025-02552-w
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