bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–11–09
48 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. NLRP3 is crucial for macrophage metabolic reprogramming during Vibrio vulnificus infection.
  2. Glucose Metabolic Reprogramming of Macrophages Against Mycobacterium tuberculosis Infection.
  3. 2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation.
  4. Metabolic reprogramming of immune cells in the battle against intracellular bacterial chronic infections: novel mechanisms and breakthroughs.
  5. Glutamine metabolism drives B cell proliferation under elevated atmospheric pressure.
  6. Intrinsic MicroRNA-10a Restricts Regulatory T Cell Suppressive Function and Intestinal Repair by Coordinating Transcriptional, Metabolic, and Epithelial Repair Pathways.
  7. Nitroalkene inhibition of pro-inflammatory macrophage effector function via modulation of signaling metabolite levels.
  8. Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.
  9. Beyond Energy Fuel: Ketone Bodies as Multifaceted Modulators of T Cell and Anti-Tumour Immunity.
  10. Porcine reproductive and respiratory syndrome virus activates the pentose phosphate pathway via the ROS/HIF-1α/G6PD axis to promote viral replication.
  11. Tunneling nanotube-mediated stem cell immunomodulation dysfunction promotes adipose inflammation and insulin resistance in GDM.
  12. Intracellular Salmonella hijacks the mitochondrial citrate carrier to evade host oxidative defenses.
  13. Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma.
  14. Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis.
  15. Mitochondrial damage drives T-cell immunometabolic paralysis after major surgery.
  16. Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses.
  17. Microbial metabolite-driven immune reprogramming in tumor immunotherapy: mechanisms and therapeutic perspectives.
  18. β-Aminoisobutyric acid targets AMPK to suppress macrophage pro-inflammatory phenotype and alleviate lipopolysaccharide-induced sepsis in mice.
  19. Impaired natural killer cell migration in HIV-infected individuals is caused by TIGIT-mediated inhibition of HIF-1α-dependent glycolysis.
  20. Ex vivo expanded human regulatory T cells promote cholesterol efflux and PON1 expression in oxLDL-exposed macrophages via gap junction-mediated cAMP transfer.
  21. Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune dysfunction.
  22. Metabolic reprogramming of glial cells: Fatty acid pathways as regulators of remyelination in multiple sclerosis.
  23. Transketolase in metabolic diseases, autoimmune diseases and cancer.
  24. Exploring the mechanisms of mutual influence between lactylation and macrophage polarization in the context of disease.
  25. Spatially divergent metabolic impact of experimental toxoplasmosis: immunological and microbial correlates.
  26. Spermidine Remodels the Mitochondrial Metabolism of Tumor-Infiltrating Lymphocytes.
  27. Protocol for halofuginone-mediated metabolic reprogramming of murine T cells via activation of the GCN2 pathway.
  28. Membrane integrity changes upon viral infection activate sphingomyelinase SMPDL3B to restrict cGAS-STING signaling via cGAMP degradation.
  29. Glycolytic flux sustains human Th1 identity and effector function via STAT1 glycosylation.
  30. Systems Biological Analysis of Immune-Metabolic Host Responses to Distinct Malaria Parasites.
  31. A Single-Cell Methodology for Energy Metabolism Analysis in Parasitic Protozoa.
  32. Dysfunctional T cells due to the abnormal glucose metabolism in patients with primary immune thrombocytopenia.
  33. Metabolic modulation of CD8⁺ T cells by metformin: A promising adjuvant strategy for CD8⁺ T Cell-Based Immunotherapies.
  34. Cysteine Metabolism Reprogramming-Motivated Catalytic Immunotherapy for Orthopedic Biofilm Infections.
  35. Parechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids.
  36. Arginine-mediated inhibition of macrophage apoptosis by Escherichia coli nissle 1917 in Salmonella typhimurium-induced intestinal inflammation.
  37. PGC1α alleviates M1 macrophage polarization through dual regulation of succinate metabolism and TRAF5 expression to mitigate TLR4/NF-κB-driven inflammatory cascades and myocardial ischemia/reperfusion injury.
  38. Time-Dependent Metabolic Response in Sepsis Severity: The Influence of Glucose in the Disease Outcome.
  39. Serine Promotes Inflammatory Macrophage Polarisation in Periodontitis via NAD+ Signalling.
  40. Defining Microbiota-Derived Metabolite Butyrate as a Senomorphic: Therapeutic Potential in the Age-Related T Cell Senescence.
  41. Microbial short chain fatty acids: Effective histone deacetylase inhibitors in immune regulation (Review).
  42. Succinate's Dual Roles in Inflammatory Bowel Disease: A Narrative Review of Microbiota-Metabolism-Immune Crosstalk and Therapeutic Implications.
  43. Lactylation and antitumor immunity.
  44. Ascorbic acid attenuates immunosenescence and cognitive decline via MYH9-Mediated CD8⁺ T cell differentiation.
  45. The m6A demethylase FTO links TLR7 to mitochondrial oxidation driving age-associated B cell formation in systemic lupus erythematosus.
  46. USP32 promotes temporomandibular joint osteoarthritis by modulating PKM2 stability and glycolytic metabolism in chondrocytes.
  47. Cholesterol and Stearamide Mediate Lymphocyte Apoptosis and Cytokine Secretion in Systemic Lupus Erythematosus.
  48. Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
  1. Microbiol Spectr. 2025 Nov 05. e0023025
    NLRP3 is crucial for macrophage metabolic reprogramming during Vibrio vulnificus infection.
    Ye-Lin Jiang, Xian-Hui Huang, Wen-Hui Zhu, Si-Qi Wei, Jing-Jing Li, Hao-Nan Lin, Huang-Kai Bian, Chen-Lin Wu, Xin-Jun Miao, Yong-Liang Lou, Lu Tang, Dan-Li Xie.
      Vibrio vulnificus is notorious for inducing rapidly progressive infections with high lethality and significant morbidity. Macrophages, being essential components of the innate immune system, play a vital role in combating infections, and their activation and effector functions are closely intertwined with metabolic reprogramming processes. However, the mechanisms governing macrophage glycolytic metabolism in response to V. vulnificus infection remain poorly elucidated. Based on our current data, we propose that NOD-like receptor 3 (NLRP3) could potentially contribute to the regulation of glycolytic metabolism in macrophages infected with V. vulnificus, though further validation is needed to confirm this relationship in both in vivo and in vitro. Upon V. vulnificus infection, NLRP3 was shown to augment glucose uptake, upregulate the aerobic glycolytic pathway, facilitate lactate release, and enhance reactive oxygen species (ROS) production. Notably, these metabolic alterations were abolished in NLRP3 knockout (KO) macrophages, as observed in both NLRP3-deficient macrophage cell lines and primary cells. We also found that the abundances of fructose 1,6-bisphosphate and 3-phosphoglyceric acid in glycolytic metabolism were decreased in V. vulnificus-infected NLRP3 KO macrophages by non-targeted metabolic flux analysis, which might be due to the reduction of PFKL that converts fructose 6-phosphate to fructose 1,6-bisphosphate in V. vulnificus-infected NLRP3 KO macrophage. These findings suggest that NLRP3 may promote inflammation in macrophages during V. vulnificus infection by driving glycolysis and increasing ROS production. The absence of these metabolic changes in NLRP3 KO macrophages underlines the crucial role of NLRP3 in modulating the immunometabolic response to V. vulnificus infection.IMPORTANCEThe results of this study demonstrate that NOD-like receptor 3 (NLRP3) is critical for metabolic reprogramming in macrophages during Vibrio vulnificus infection. NLRP3 enhances glucose uptake, upregulates glycolysis, reprograms metabolic flux, and promotes reactive oxygen species production. These findings are significant, as they reveal a previously unrecognized role of NLRP3 in regulating immune function in V. vulnificus-infected macrophages. This study identifies NLRP3 as a central mediator linking immune cell metabolism to defense against infections, providing novel insights into how innate immunity controls pathogenic bacteria and suggesting potential strategies for improving treatment or prevention of severe infections. However, further research is required to fully elucidate its impact on macrophage glycolysis in V. vulnificus-induced sepsis.
    Keywords:  NLRP3; Vibrio vulnificus; glycolysis; macrophage; metabolism; single-cell sequencing
    DOI:  https://doi.org/10.1128/spectrum.00230-25
  2. Immunotargets Ther. 2025 ;14 1209-1221
    Glucose Metabolic Reprogramming of Macrophages Against Mycobacterium tuberculosis Infection.
    Tianhui Liu, Zeliang Yang, Jing Tong, Mengqiu Gao, Yu Pang.
      Tuberculosis (TB) is a global infectious disease caused by Mycobacterium tuberculosis (Mtb). Serving as the primary effector cells, macrophages play a crucial role in host immune responses against Mtb. During Mtb infection, macrophages undergo extensive metabolic reprogramming, notably glycolysis, the pentose phosphate pathway (PPP) and the tricarboxylic acid (TCA) cycle, to adapt to the challenges posed by the pathogen, with glucose metabolic rewiring being particularly critical. This review focuses on the dynamic reprogramming of glucose metabolism in macrophages during Mtb infection, highlighting how metabolic adjustments influence the activation state, polarization, and functional capacity of macrophages. Furthermore, we explore the role of glucose metabolic reprogramming in shaping the immune responses against Mtb, particularly its contribution to granuloma formation and maintenance. By understanding the intricate interplay between metabolic rewiring and immune function, we discuss the therapeutic potential of targeting glucose metabolic pathways in macrophages as a novel strategy for TB treatment. Overall, this review emphasizes the need for a deeper understanding of the relationship between glucose metabolism reprogramming and the biological function of Mtb-infected macrophages and the development of novel immunometabolic therapies-such as metformin (AMPK activator) or PKM2 modulators already used in oncology- to improve the outcomes of TB patients.
    Keywords:  Mycobacterium tuberculosis; glucose metabolic reprogramming; macrophages
    DOI:  https://doi.org/10.2147/ITT.S552746
  3. Sci Rep. 2025 Nov 06. 15(1): 38885
    2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation.
    Payam Gharibani, Yu Guo, Shruthi Shanmukha, Judy J Lee, Katherine Kopp, Paul M Kim, Michael D Kornberg.
      Neuroinflammation plays a central role in a wide spectrum of neurological diseases, driven generally by reactive microglia and astrocytes. Inflammatory stimulation of microglia and astrocytes leads to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, which is required to support pro-inflammatory effector functions. This metabolic reprogramming is associated with impaired mitochondrial dynamics, including reduced biogenesis, increased fragmentation, and loss of membrane potential. Targeting microglia and astrocyte metabolism may offer a novel therapeutic approach for modulating neuroinflammation and restoring homeostatic immune functions. Here, we examined the potential of 2-Deoxy-D-Glucose (2DG), a glycolysis inhibitor, to attenuate neuroinflammation by restoring mitochondrial dynamics. In BV2 and primary glial cultures, low-dose 2DG reversed LPS-induced metabolic reprogramming, restoring OXPHOS, reducing mitochondrial fragmentation, and enhancing biogenesis. In vivo, it preserved spare respiratory capacity and increased complex-V activity in brain mitochondria from LPS-treated mice without affecting oxidative stress. At a mechanistic level, 2DG restored activation of AMP-activated protein kinase, a master regulator of mitochondrial dynamics. In conjunction with these metabolic effects, 2DG suppressed LPS-induced pro-inflammatory gene expression while enhancing markers associated with the resolution of inflammation and tissue repair. Critically, systemic low-dose 2DG reduced neuroinflammation and restored immune homeostasis in two LPS-induced mouse models, highlighting its therapeutic potential in neurological disorders.
    Keywords:  2-Deoxy-D-Glucose; Immunometabolism; Mitochondrial dynamics; Mitochondrial function; Neuroinflammation
    DOI:  https://doi.org/10.1038/s41598-025-22677-w
  4. Mol Biol Rep. 2025 Nov 01. 53(1): 37
    Metabolic reprogramming of immune cells in the battle against intracellular bacterial chronic infections: novel mechanisms and breakthroughs.
    Rongrong Jiang, Xiao Liu, Fangtao Xing, Yurong Fu, Zhengjun Yi.
      Chronic intracellular bacterial infections persist within host cells by evading immune clearance, imposing prolonged metabolic stress on the host. In response, the immune system undergoes metabolic reprogramming to sustain prolonged defense. A key feature of this reprogramming is the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, which enhances pro-inflammatory and antimicrobial responses. Concurrently, fatty acid and amino acid catabolism provide additional metabolic support. Beyond shaping immune function, these metabolic shifts also influence the trajectory of infection by altering the host-pathogen metabolic interplay. In this review, we focus primarily on Mycobacterium tuberculosis (Mtb) infection and integrate quantitative flux analyses of carbon and nitrogen distribution, emphasizing how these metabolic changes connect to epigenetic regulation. We also explore metabolic reprogramming in five representative immune cell types-comprising both innate and adaptive immune cells-to elucidate how their distinct metabolic profiles influence host defense mechanisms and disease progression. Building on these foundations, we propose an innovative metabolic competition model between host and pathogen, offering new insights into the intricate interplay of metabolic networks in chronic intracellular infections.
    Keywords:  Immune cells; Infection; Intracellular bacterial; Metabolic reprogramming
    DOI:  https://doi.org/10.1007/s11033-025-11218-3
  5. Biochem Biophys Res Commun. 2025 Oct 30. pii: S0006-291X(25)01608-0. [Epub ahead of print]790 152892
    Glutamine metabolism drives B cell proliferation under elevated atmospheric pressure.
    Ayato Maeda, Akihiro Nita, Toshiro Moroishi.
      Mechanical forces are increasingly recognized as critical regulators of immune cell function; however, the effects of static pressure on B cell biology remain poorly understood. In this study, we investigated how elevated atmospheric pressure influences B cell proliferation and metabolism. Using murine and human B cell lines cultured under normal or elevated static pressure, we found that increased pressure significantly enhances and sustains long-term B cell proliferation. Transcriptomic analysis revealed a downregulation of glycolytic pathways, corroborated by decreased glucose consumption. In contrast, glutamine consumption was elevated, indicating a metabolic shift toward glutaminolysis. Functional assays confirmed that both glutamine availability and glutaminase activity are essential for the pressure-induced proliferative response. These findings identify glutamine metabolism as a key mediator of B cell adaptation to mechanical pressure and suggest that static pressure is a previously underappreciated regulator of B cell function and immune metabolism.
    Keywords:  B cells; Glutaminase; Glutamine metabolism; Immunometabolism; Mechanical pressure; Mechanotransduction; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152892
  6. Adv Sci (Weinh). 2025 Nov 03. e09953
    Intrinsic MicroRNA-10a Restricts Regulatory T Cell Suppressive Function and Intestinal Repair by Coordinating Transcriptional, Metabolic, and Epithelial Repair Pathways.
    Wenjing Yang, Tianming Yu, Hui Yang, Suxia Yao, Ruihua Ma, Elizabeth M Steinert, Karen M Ridge, Weiguo Cui, Navdeep S Chandel, Yingzi Cong.
      Regulatory T cells (Tregs) are indispensable for maintaining immune homeostasis and suppressing excessive inflammatory responses in the intestine. While much attention has focused on positive regulators of Treg differentiation and function, the mechanisms that constrain Treg transcriptional and metabolic programs remain poorly understood. Here, miR-10a is identified as a key negative regulator of Treg suppressive capacity and their crosstalk with intestinal epithelial cells. Single-cell and bulk transcriptomic analyses reveal that Treg-specific deletion of miR-10a promotes an effector Treg (eTreg) phenotype characterized by elevated Blimp1 expression, a direct target of miR-10a. MiR-10a-deficient Tregs demonstrate enhanced suppressive capacity in alleviating colitis without compromising Treg stability. Mechanistically, miR-10a deficiency drives metabolic reprogramming, highlighted by altered mitochondrial oxidative phosphorylation through Uqcrq, a component of mitochondrial complex III. Loss of Uqcrq impairs Treg suppressive function in colitis but does not affect stability. Furthermore, miR-10a targets amphiregulin (Areg), an epidermal growth factor-like molecule crucial for mucosal epithelial repair. Areg-deficient Tregs exhibit decreased intestinal barrier function, whereas miR-10a-deficient Tregs exhibit enhanced barrier function in experimental colitis. These findings define a multifaceted role for intrinsic miR-10a in negatively regulating Treg function by integrating transcriptional, metabolic, and epithelial repair pathways, thereby unveiling potential therapeutic interventions in inflammatory bowel diseases.
    Keywords:  intestinal inflammation; intestinal repair; microRNA; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/advs.202509953
  7. Front Physiol. 2025 ;16 1426102
    Nitroalkene inhibition of pro-inflammatory macrophage effector function via modulation of signaling metabolite levels.
    Emily R Stevenson, James P O'Brien, Allison M Manuel, Crystal E Uvalle, Gregory J Buchan, Steven J Mullett, Karina Lockwood, Tomeka Suber, Bruce A Freeman, Stacy L Gelhaus.
       Introduction: Classically activated innate immune cells undergo a metabolic switch to aerobic glycolysis to support effector function. We report that the small-molecule nitroalkene 10-n-octadec-9-enoic acid (NO2-OA) attenuates the Warburg- like phenotype of aerobic glycolysis in lipopolysaccharide (LPS)-activated macrophages, thus inhibiting pro-inflammatory signaling.
    Methods: RAW264.7 and bone marrow derived macrophage were treated with LPS with and without NO2-OA or 1400W. Pro-inflammatory cytokines were measured by ELISA and protein expression was determined by immunoblot. Central carbon metabolites with and without 13C stable isotope tracing were measured using liquid chromatography-high resolution mass spectrometry.
    Results: Overall, the present observations indicate that nitroalkene-induced changes in central carbon metabolism contribute to the anti-inflammatory actions of this class of multi-target lipid signaling mediators. Comparison of macrophage responses to NO2-OA with the inducible nitric oxide synthase (NOS2 and iNOS) inhibitor 1400W affirms that NO2-OA inhibition of NOS2 expression and activity alone was not sufficient to account for the decreases in pro-inflammatory cytokine expression. NO2-OA treatment reduced intracellular succinate levels, which may be attributed to a concomitant reduction in intracellular itaconate and reliance on glutamine, thereby contributing to hypoxia-inducible factor 1α (HIF1α) destabilization observed in LPS-activated macrophages.
    Conclusion: The current data provide additional perspective on the actions of this small-molecule electrophile, which is currently in a Phase 2 clinical trial for the treatment of obesity-related chronic pulmonary inflammation and associated airway dysfunction.
    Keywords:  glutamine metabolism; inflammation; macrophage; metabolism; nitroalkene fatty acid
    DOI:  https://doi.org/10.3389/fphys.2025.1426102
  8. Nat Commun. 2025 Nov 03. 16(1): 9484
    Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.
    Benjamin J Jenkins, Yasmin R Jenkins, Fernando M Ponce-Garcia, Chloe Moscrop, Iain A Perry, Matthew D Hitchings, Alejandro H Uribe, Federico Bernuzzi, Simon Eastham, James G Cronin, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Marta Williams, Morgan Marsden, Douglas J Veale, Luke C Davies, Micah Niphakis, David K Finlay, Linda V Sinclair, Benjamin F Cravatt, Andrew E Hogan, James A Nathan, Ian R Humphreys, Ursula Fearon, David Sumpton, Johan Vande Voorde, Goncalo Dias do Vale, Jeffrey G McDonald, Gareth W Jones, James A Pearson, Emma E Vincent, Nicholas Jones.
      α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T-cell metabolism and function is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T-cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using murine models of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T-cells and delays the onset of diabetes in vivo in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation.
    DOI:  https://doi.org/10.1038/s41467-025-65417-4
  9. Scand J Immunol. 2025 Nov;102(5): e70067
    Beyond Energy Fuel: Ketone Bodies as Multifaceted Modulators of T Cell and Anti-Tumour Immunity.
    Zhi Gu, Minghui Zhang, Sheng Xia.
      The metabolic programme of T cells is pivotal in determining their differentiation, development and immune function. T cells undergo distinct metabolic reprogramming at various stages. Effector T cells primarily utilise glycolysis to generate energy quickly, whereas memory T cells depend on fatty acid oxidation (FAO) to sustain long-term survival and enable rapid reactivation. This metabolic differentiation is regulated through metabolic reprogramming by adjusting nutrient utilisation to meet specific demands. Ketone bodies, FAO-derived metabolites, interact with glucose and amino acid metabolism to influence the function and differentiation of T cells and other immune cell subsets. The body's metabolic equilibrium is significantly influenced by dietary patterns. A medically designed dietary intervention that elevates ketone body levels can reshape T-cell metabolism, influencing their differentiation, development and immune functions. This metabolic modulation suggests a potential interplay between nutritional strategies and T-cell immunotherapy applications, especially in the context of tumour immunology. This review explores ketone body metabolism and its impact on T-cell function, offering insights into the clinical use of diet-induced ketosis for T-cell immunotherapy. It also emphasises the potential of metabolic reprogramming to boost T cell performance and improve the efficacy of immunotherapy.
    Keywords:  T cell; immunotherapy; ketone body; ketone diet; metabolism
    DOI:  https://doi.org/10.1111/sji.70067
  10. Virulence. 2025 Dec;16(1): 2585639
    Porcine reproductive and respiratory syndrome virus activates the pentose phosphate pathway via the ROS/HIF-1α/G6PD axis to promote viral replication.
    Ying-Xian Ma, Jia-Ming Yang, Hang-Tian Mei, Lei Zeng, Guo-Yu Yang, Jiang Wang, Sheng-Li Ming, Bei-Bei Chu.
      Porcine reproductive and respiratory syndrome virus (PRRSV), a highly contagious pathogen in swine, poses significant economic challenges to global pork production. This study elucidated the regulatory interplay between PRRSV infection and the pentose phosphate pathway (PPP), a critical metabolic axis for anabolism. Comparative metabolomic profiling of porcine alveolar macrophages (PAMs) pre- and post-PRRSV infection demonstrated marked upregulation of PPP activity, concomitant with elevated levels of nucleotide biosynthesis. This metabolic shift was driven by PRRSV-induced upregulation of glucose-6-phosphate dehydrogenase (G6PD), the PPP's rate-limiting enzyme. Mechanistic investigations revealed that PRRSV infection stimulated hypoxia-inducible factor 1α (HIF-1α) expression, which transcriptionally activates G6PD. Genetic silencing of HIF-1α abolished PRRSV-mediated G6PD induction. Furthermore, reactive oxygen species (ROS) accumulation was identified as the upstream regulator of HIF-1α activation during PRRSV infection. Pharmacological ROS scavenging disrupted the ROS/HIF-1α/G6PD signaling cascade, diminished NADPH and reduced glutathione production, and consequently attenuated viral proliferation. These results established that PRRSV exploited the ROS/HIF-1α axis to reprogram host glucose metabolism through PPP potentiation, creating a biosynthetic environment conducive to viral propagation.
    Keywords:  G6PD; HIF-1α; PPP; PRRSV; ROS
    DOI:  https://doi.org/10.1080/21505594.2025.2585639
  11. Cell Rep. 2025 Nov 03. pii: S2211-1247(25)01276-8. [Epub ahead of print]44(11): 116505
    Tunneling nanotube-mediated stem cell immunomodulation dysfunction promotes adipose inflammation and insulin resistance in GDM.
    Bingnan Chen, Xuyang Chen, Jianxin Li, Ruohan Hu, Lijun Yang, Hongli Li, Xinmi Liu, Richard D Cannon, Richard Saffery, Boris Novakovic, Hongbo Qi, Hua Zhang, Xiaobo Zhou.
      Adipose-derived stem cells (ADSCs) represent a promising therapeutic resource, yet their immunometabolic regulation remains poorly defined. Here, we reveal a tunneling nanotube (TNT)-mediated communication mechanism between ADSCs and adipose tissue macrophages (ATMs) that maintains metabolic homeostasis during pregnancy. Using gestational diabetes mellitus (GDM) mouse models combined with live-cell imaging, scanning electron microscope, and multi-omics approaches, we demonstrate that mitochondrial transfer from ADSCs to ATMs via TNTs sustains ATM metabolic fitness. This process is governed by the WNT5A-RhoA-ROCK1 axis and becomes impaired under metabolic stress, driving ATMs inflammatory polarization and insulin resistance. Importantly, in situ ADSC administration restores mitochondrial transfer and improves metabolic parameters in GDM mice. Collectively, our work establishes TNT-mediated organelle sharing as a fundamental mechanism of stem cell-immune interaction and demonstrates that ADSC-based therapy represents a promising strategy for GDM by reprogramming the metabolism of immune cells.
    Keywords:  CP: Metabolism; CP: Stem cell research; adipose tissue macrophages; adipose-derived stem cells; gestational diabetes mellitus; mitochondria; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.celrep.2025.116505
  12. Nat Commun. 2025 Nov 06. 16(1): 9806
    Intracellular Salmonella hijacks the mitochondrial citrate carrier to evade host oxidative defenses.
    Chieh-Hua Fu, Yu-Ting Hsu, Shao-Chun Hsu, Nai-Shu Chen, Hsueh-Wen Hu, Ting-Yin Wu, Yi-Jou Huang, Ying-Chu Chen, An-Chi Luo, Yu-Tsung Huang, Shu-Jung Chang.
      Intracellular vacuolar pathogens replicate within membrane-bound compartments known as pathogen-containing vacuoles (PCVs). Maintaining the integrity of these vacuoles is essential for creating a permissive niche that supports pathogen survival and proliferation. In this study, we show that Salmonella enterica serovar Typhimurium co-opts the host mitochondrial citrate carrier (CIC) to promote its intracellular replication by detoxifying the Salmonella-containing vacuole (SCV). Loss of CIC significantly impairs Salmonella growth within host cells, as CIC recruitment to SCVs regulates local citrate levels and mitigates the production of reactive oxygen species (ROS), thereby reducing oxidative stress. Mechanistically, we identify the SPI-2 effector SseF as a critical factor that interacts with CIC and the GTPase RAB7, enabling CIC recruitment to the SCV membrane. These findings reveal a previously unrecognized strategy by which an intracellular pathogen hijacks a mitochondrial metabolite transporter to modulate the vacuolar environment and evade host antimicrobial defenses. Notably, pharmacological inhibition of CIC sensitizes Salmonella to host immune pressures, highlighting CIC as a potential target for host-directed antimicrobial therapy.
    DOI:  https://doi.org/10.1038/s41467-025-64779-z
  13. Immunity. 2025 Nov 03. pii: S1074-7613(25)00434-0. [Epub ahead of print]
    Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma.
    Annabell Bachem, Michele Clarke, Geraldine Kong, Ilaryia Tarasova, Lachlan Dryburgh, Lindsay Kosack, Ariane R Lee, Lewis D Newland, Teagan Wagner, Emma Bawden, Kah Min Yap, Michael D Wilson, Sven Engel, Kayla R Wilson, Brendan E Russ, Kshitij Tandon, Peter Kar Han Lau, Grant McArthur, Vanessa R Marcelino, Paul A Beavis, Stephen J Turner, Jason Waithman, Timothy P Stinear, Shahneen Sandhu, Jan Schröder, Thomas Gebhardt, Sammy Bedoui.
      A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8+ T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127+CD8+ T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127+CD8+ T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8+ T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8+ T cells.
    Keywords:  CD8 T cells; SCFAs; butyrate; melanoma; metabolism; microbiome; microbiota; stemness
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.004
  14. Cell Rep. 2025 Nov 03. pii: S2211-1247(25)01297-5. [Epub ahead of print]44(11): 116526
    Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis.
    Sumiya Dalangood, Cegui Hu, Chenwei Yuan, Xiang Li, Wen Qiao, Hanjun Li, Rongyu Zhang, Luying Li, Peng Li, Xiang Yu, Wenjin Yin, Jinsong Lu, Jun Gui.
      Cancer-associated adipocytes (CAAs) reprogram the metabolic status of the tumor microenvironment (TME). The metabolic crosstalk between CAAs and CD8+T cells in the TME remains unclear. Here, we report that CAAs undergo lipolysis, releasing free fatty acids that promote lipid peroxidation and disturb mitochondrial homeostasis in CD8+T cells, leading to their functional exhaustion. Importantly, we uncover that fibroblast growth factor 21 (FGF21) drives CAA lipolysis in an autocrine manner by upregulating adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling. FGF21 deletion in adipose tissue or ATGL inhibition impedes CAA lipolysis, mitigates lipid peroxidation, normalizes mitochondrial dynamics of CD8+T cells, and restores their effector function, consequently blunting tumor growth. Moreover, FGF21 deficiency or ATGL inhibition enhances the anti-tumor activity of CD8+T cells in response to anti-PD-1 treatment, yielding greater therapeutic efficacy. Our findings highlight the pivotal role of CAA lipolysis in CD8+T cell dysfunction within the TME, suggesting that targeting CAA lipolysis represents a valuable avenue for improving cancer immunotherapy.
    Keywords:  ATGL; CD8(+)T; CP: cancer; CP: immunology; FGF21; T cell exhaustion; cancer-associated adipocytes; lipolysis; tumor immunity
    DOI:  https://doi.org/10.1016/j.celrep.2025.116526
  15. EMBO Mol Med. 2025 Nov 03.
    Mitochondrial damage drives T-cell immunometabolic paralysis after major surgery.
    Simon Hirschberger, Martin B Müller, Hannah Mascolo, Melissa Seitz, Stefan Nibler, David Effinger, Kun Lu, Joscha Büch, Martin Bender, Tobias Kammerer, Sven Peterß, Karin Kleigrewe, Miriam Abele, Teresa Barth, Olga Kushnir, Axel Imhof, Steffen Dietzel, Bernd Wegener, Ralf Sowa, Frank Vogel, Peter Lamm, Roland Tomasi, Kristian Unger, Markus Sperandio, Erich Kilger, Simone Kreth, Max Hübner.
      Cytotoxic T cell (CTL) dysfunction is a hallmark of immune paralysis after major surgery, increasing susceptibility to severe nosocomial infections and contributing to mortality in critically ill patients. The mechanisms remain poorly understood. We demonstrate that reactive oxygen species (ROS) released by myeloid-derived suppressor cells (MDSC) transiently emerging after surgery, drive perioperative CTL immunoparalysis. These ROS damage CTL mitochondria, triggering secondary mitochondrial ROS amplification and overwhelming antioxidant defenses. The resulting oxidative cascade impairs oxidative phosphorylation and suppresses CTL effector function. Concurrently, stress-induced mitochondrial hyperfusion disrupts fission-dependent translocation to the immunological synapse, exacerbating bioenergetic failure. MitoTEMPO, a mitochondria-targeted antioxidant, partially mitigates these effects, highlighting mitochondrial stabilization as a potential strategy to prevent perioperative immune dysfunction.
    Keywords:  Cytotoxic T cells; Immunometabolism; Immunosuppression; Major Surgery; Mitochondria
    DOI:  https://doi.org/10.1038/s44321-025-00324-1
  16. Nat Immunol. 2025 Nov 07.
    Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses.
    Jie Ting Low, Youngjun Kim, Mai Matsushita, Ping-Chih Ho.
      Oxygen availability and fluctuation are common changes in tissues and organs undergoing infection and damage. While acute hypoxia can rapidly alter immune cell metabolism and activity, chronic hypoxia can induce long-lasting changes in immune responses via oxygen-guided adaptation in signaling cascades and epitranscriptomic programs. These adaptations are orchestrated mainly by oxygen-sensing hydroxylases and oxygen-sensing epigenetic modifiers that regulate downstream hypoxia-inducible factor pathways and epigenetic reprogramming. In this Review, we summarize how acute and chronic hypoxia influence innate immune cell function and metabolism, thereby tailoring immune cell behavior within the tissue microenvironment. We further highlight the dual roles of hypoxia in regulating innate immune cell function in different (patho)physiological contexts and evaluate therapeutic strategies that target oxygen-sensing pathways to restore immune competence and tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41590-025-02317-1
  17. Front Immunol. 2025 ;16 1603658
    Microbial metabolite-driven immune reprogramming in tumor immunotherapy: mechanisms and therapeutic perspectives.
    Yao Lu, Huiping Yuan, Shaojie Liang, Debing Li, Pengfei Jiang, Xian Wang, Ke Zhang, Dechun Liu.
      The gut microbiome critically regulates antitumor immunity through its metabolic byproducts, which serve as pivotal mediators of host-microbe crosstalk in tumor immunotherapy. This review synthesizes cutting-edge evidence on how microbial metabolites-including short-chain fatty acids (SCFAs), tryptophan derivatives, and bile acids-reprogram immune cell dynamics and remodel the tumor microenvironment (TME). Mechanistically, metabolites such as butyrate and indole-3-propionic acid (IPA) enhance immune checkpoint inhibitor (ICI) efficacy by epigenetic modulation or metabolic reprogramming. Conversely, kynurenine (a tryptophan metabolite) and secondary bile acids drive resistance by polarizing macrophages toward an immunosuppressive phenotype or exhausting cytotoxic T cells. Metabolite-targeted interventions (such as probiotics, dietary modulation, and engineered microbes) show synergistic potential with ICIs, but require resolution of causal inference limitations, interindividual variability, tumor-context specificity, and dose optimization. Precision microbiome engineering, guided by multi-omics profiling and artificial intelligence, may unlock personalized strategies to overcome immunotherapy resistance.
    Keywords:  immune checkpoint inhibitors; immune regulation; immunotherapy resistance; microbial metabolites; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1603658
  18. Int Immunopharmacol. 2025 Nov 03. pii: S1567-5769(25)01769-2. [Epub ahead of print]168(Pt 1): 115781
    β-Aminoisobutyric acid targets AMPK to suppress macrophage pro-inflammatory phenotype and alleviate lipopolysaccharide-induced sepsis in mice.
    Xilong Hu, Chuanzhi Wang, Peibin Zou, Tao Wu, Haiwang Shi, Binghong Gao, Ling Zhu, Rui Duan.
      Sepsis is a life-threatening syndrome caused by acute infection, marked by severe systemic inflammation and multi-organ dysfunction. Its pathogenesis involves excessive pro-inflammatory activation of macrophages. β-aminoisobutyric acid (BAIBA), a myokine produced during valine metabolism, has demonstrated beneficial effects on glucose and lipid metabolism, as well as anti-inflammatory and antioxidant properties. However, its potential to ameliorate lipopolysaccharide (LPS)-induced sepsis remains unknown. In this study, BAIBA pretreatment (150 and 500 mg/kg, orally) dose-dependently reduced mortality, systemic inflammation, and damage to the liver, lung, and kidney in LPS-induced septic mice. Notably, co-administration of BAIBA with low-dose dexamethasone (2 mg/kg, intravenous) provided enhanced therapeutic benefits. In septic mouse livers, BAIBA downregulated numerous inflammatory genes, reduced macrophage infiltration, and decreased the proportion of pro-inflammatory phenotypes. In vitro, BAIBA (10 and 20 μM) suppressed pro-inflammatory mediators and related genes in LPS/interferon-γ-stimulated RAW264.7 macrophages, accompanied by activation of the 5' AMP-activated protein kinase (AMPK) pathway. Similar anti-inflammatory effects were observed in bone marrow-derived macrophages and were abolished upon AMPK inhibition. Collectively, these findings underscore the protective role of BAIBA in sepsis- related dysfunction and macrophage activation.
    Keywords:  Inflammation; Macrophage; Metabolite; Sepsis; β-Aminoisobutyric acid
    DOI:  https://doi.org/10.1016/j.intimp.2025.115781
  19. Cell Death Dis. 2025 Nov 07. 16(1): 805
    Impaired natural killer cell migration in HIV-infected individuals is caused by TIGIT-mediated inhibition of HIF-1α-dependent glycolysis.
    Xiaowen Yu, Jie Zhou, Jie Lei, Hongchi Ge, Zining Zhang, Yajing Fu, Xiaoxu Han, Qinghai Hu, Haibo Ding, Wenqing Geng, Hong Shang, Yongjun Jiang.
      Natural killer (NK) cells serve as the first line of defense in the immune system and play a crucial role in fighting against HIV infection. The effective function of NK cells is closely related to their migratory capacity. However, the status of NK cell migration in HIV-infected individuals and the underlying regulatory mechanisms remain unknown. Here, we found that NK cell migration was significantly impaired in HIV-infected individuals, with even lower levels in immune non-responders (INRs) compared with immune responders (IRs), and was positively correlated with CD4+ T cell counts. Further investigation suggested that the reduced NK cell migration in HIV infection was caused by impaired glycolysis. Mechanistically, NK cell migration was regulated by the HIF-1α pathway. The inhibitory receptor TIGIT suppressed HIF-1α expression by inhibiting PI3K/AKT/mTORC1 and ERK signaling pathways, consequently weakening glycolysis in NK cells of HIV-infected individuals and ultimately leading to downregulation of migration. Collectively, we uncovered a mechanism of reduced NK cell migration during HIV infection and provided new insights for potential immunotherapeutic strategies. Schematic of the mechanism of regulating NK cell migration in HC and HIV-infected individuals: Under normal physiological conditions, NK cells express sufficient levels of the glucose transporter GLUT-1 to support glycolysis, enabling normal glucose uptake. Meanwhile, activation of PI3K/AKT/mTORC1 or ERK signaling pathways induces HIF-1α expression, which subsequently promotes intracellular glycolysis and maintains regular NK cell migration. During HIV infection, the expression of GLUT-1 on NK cells is down-regulated, resulting in impaired glucose uptake. Additionally, High TIGIT expression suppresses HIF-1α expression by inhibiting the PI3K/AKT/ mTORC1 or ERK signaling pathway, thereby impairing glycolysis and ultimately reducing NK cell migration.
    DOI:  https://doi.org/10.1038/s41419-025-08039-4
  20. Front Immunol. 2025 ;16 1662925
    Ex vivo expanded human regulatory T cells promote cholesterol efflux and PON1 expression in oxLDL-exposed macrophages via gap junction-mediated cAMP transfer.
    Caraugh Jane Albany, Daniela Mastronicola, Momchil Popov, Wladislaw Stroukov, Anthony S Wierzbicki, Rocio Teresa Martinez-Nunez, Giovanna Lombardi, Cristiano Scottà.
      Lipid-driven inflammation contributes to the development of atherosclerosis, and regulatory T cells (Tregs) have been proposed to influence macrophage responses to lipid stress. While adoptive Treg transfer has been shown to be safe in clinical studies, the mechanisms by which Tregs modulate macrophage lipid handling remain incompletely understood. In this study, we investigated the effects of ex vivo-expanded human Tregs on primary monocyte-derived M2-like macrophages exposed to oxidized low-density lipoprotein (oxLDL) in an in vitro coculture system. We assessed macrophage phenotype, gene expression, and cholesterol accumulation using flow cytometry, RNA sequencing, and western blotting. Our data show that coculture with Tregs attenuated oxLDL-induced pro-inflammatory responses and reduced intracellular lipid accumulation in macrophages. Mechanistically, we found evidence that Tregs transfer cyclic AMP (cAMP) into macrophages, which enhanced the ABCA1-mediated cholesterol efflux pathway and increased expression of paraoxonase-1 (PON1). These findings provide mechanistic insight into how Tregs modulate macrophage responses to oxLDL under controlled in vitro conditions. They highlight potential pathways through which Tregs may regulate macrophage lipid metabolism and inflammatory activity. Further in vivo studies will be essential to determine the physiological significance and therapeutic potential of these mechanisms.
    Keywords:  atherosclerosis; cholesterol; macrophages; paraxonase-1; regulatory T (Treg) cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1662925
  21. Front Cell Infect Microbiol. 2025 ;15 1686785
    Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune dysfunction.
    Tracy Okine, Eleanor Hill, Kate Sheran, Talia H Swartz.
      Antiretroviral therapy (ART) has transformed HIV into a chronic, manageable condition, yet people living with HIV (PLWH) continue to experience persistent immune activation and systemic inflammation that drive long-term comorbidities, including neurocognitive impairment and cardiovascular disease. This residual inflammation requires new mechanistic explanations and targeted therapeutic approaches. Increasing evidence highlights mitochondria as central hubs in the regulation of cellular metabolism and immune responses. In PLWH, both HIV and ART disrupt mitochondrial function, leading to the release of proinflammatory mediators such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These signals activate the NLRP3 inflammasome, resulting in secretion of IL-1β and other cytokines. In parallel, excess mitochondrial ATP engages purinergic receptors such as P2X1 and P2X7, propagating inflammatory signaling to surrounding immune cells. This review examines the mito-immune axis in HIV, focusing on OxPhos dysregulation, inflammasome activation, and purinergic receptor signaling, and explores potential interventions-including purinergic antagonists-that aim not only to suppress viral replication but also to restore immunometabolic balance. By recognizing mitochondria as dynamic regulators of immune function, we outline a paradigm shift in HIV treatment that addresses the underlying drivers of chronic inflammation.
    Keywords:  ATP; HIV; OxPhos; inflammasome; inflammation; mitochondria
    DOI:  https://doi.org/10.3389/fcimb.2025.1686785
  22. Neurobiol Dis. 2025 Nov 05. pii: S0969-9961(25)00396-1. [Epub ahead of print] 107179
    Metabolic reprogramming of glial cells: Fatty acid pathways as regulators of remyelination in multiple sclerosis.
    Hao Wu, Yan Mi, Chao Zheng, Yuxin Zhang, Shuting Xu, Jie Zhu, Tao Jin.
      Multiple sclerosis (MS) is an autoimmune disorder characterized by neuroinflammation and progressive demyelination, resulting in irreversible neuronal damage and disability. Although current immunomodulatory treatments slow disease progression, they can't effectively promote myelin regeneration. Recent research has emphasized the critical role of glial cells-microglia, astrocytes, and oligodendrocytes-in myelin repair, with fatty acid (FA) metabolism emerging as a central regulator of this process. Fatty acids are essential not only for maintaining myelin structure but also for the metabolic reprogramming of glial cells during remyelination. Microglial activation, influenced by FA signaling, can result in either pro-inflammatory or reparative phenotypes, which in turn affect remyelination efficiency. Similarly, astrocytes contribute to remyelination through cholesterol synthesis and FA oxidation; however, their reactive states can either promote or inhibit myelin repair, depending on the metabolic context. Oligodendrocyte precursor cells, crucial for myelin regeneration, are also regulated by fatty acids, impacting their differentiation and survival. Disruptions in FA metabolism or imbalanced glial activation can impair remyelination, underscoring the need for therapies targeting these metabolic pathways. This review examines the complex relationship between fatty acid metabolism and glial cell function, emphasizing the potential of targeting lipid signaling pathways to enhance remyelination in MS. Targeting fatty acid metabolism represents a promising yet still experimental therapeutic approach for MS and related demyelinating diseases. By modulating glial metabolism and immune responses, this strategy has the potential to decelerate disease progression and restore neural function, though further validation is required to translate these mechanisms into clinical applications.
    Keywords:  Astrocyte; Fatty acids; Metabolism; Microglia; Multiple sclerosis; Oligodendrocyte; Remyelination
    DOI:  https://doi.org/10.1016/j.nbd.2025.107179
  23. Methods Enzymol. 2025 ;pii: S0076-6879(25)00295-2. [Epub ahead of print]722 31-50
    Transketolase in metabolic diseases, autoimmune diseases and cancer.
    Zhangbing Chen, Yi Wang, Xuemei Tong.
      The metabolic enzyme transketolase catalyzes two reversible reactions in the non-oxidative phase of pentose phosphate pathway (non-oxidative PPP), bridging PPP and glycolytic metabolites from bacteria to humans. The physiological and pathological significance of transketolase in humans remains to be elucidated. We found that hyperinsulinemia promoted transketolase expression and transketolase was critical for the pentose moiety of nucleosides to enter glycolysis. By studying the function of transketolase in hepatocytes, adipocytes, regulatory T cells, and cancer cells, we revealed intriguing roles of transketolase-mediated pentose metabolism in regulating nucleoside levels, genome instability, mitochondrial function, and DNA methylation, providing new therapeutic opportunities for prevention and treatment of metabolic diseases, autoimmune diseases, and cancer. In this chapter, assays for analyzing transketolase activity and quantification of metabolites in the non-oxidative PPP in mammalian tissues are described.
    Keywords:  Autoimmune disease; Cancer; Metabolic disease; Pentose phosphate pathway; Transketolase
    DOI:  https://doi.org/10.1016/bs.mie.2025.08.001
  24. Clin Transl Med. 2025 Nov;15(11): e70499
    Exploring the mechanisms of mutual influence between lactylation and macrophage polarization in the context of disease.
    Houhua Guo, Nannan Luan, Jian Gao, Xiaoao Pang, Jianlei Bi, Liancheng Zhu.
       BACKGROUND: Lactylation, a post-translational alteration facilitated by lactic acidderived lactyl-CoA, has emerged as an epigenetic regulator that alters gene expression in macrophages. Emerging data situates lactylation at the nexus of metabolic flux and immune cell destiny, especially in tumor and inflammatory microenvironments.
    MAIN TEXT: Lactylation is significantly linked to tumor progression and the polarization of macrophages towards the M2 phenotype, a condition that exacerbates cancer and associated inflammation. Modulating lactylation levels can alter the M1/M2 balance, hence affecting the progression of cancer and inflammatory illnesses. These findings identify lactylation as aregulator that can either suppress or enhance tumor development and the related inflammatory response, contingent upon the context and degree of the change.
    CONCLUSION: This review systematically elucidates the role of lactylation in directing macrophage polarization in the context of cancer and associated inflammation. The aggregated data suggest that targeting lactylation constitutes an innovative therapeutic strategy for regulating immune cell activity and managing the advancement of cancer and related inflammatory conditions.
    KEY POINTS: The conversion of lactate to lactyl-CoA facilitates enzymatic histone lactylation, transforming glycolytic byproducts into an epigenetic regulatory mechanism for gene expression. Lactylation modification influences macrophage polarization towards M1 or M2 phenotypes, affecting outcomes in infection, cancer, and fibrosis. Targeting lactylation modifiers through pharmacological means introduces a novel metabolic-epigenetic approach for treating disorders.
    Keywords:  immunity; lactylation; macrophages; post‐translational modifications; tumours
    DOI:  https://doi.org/10.1002/ctm2.70499
  25. mSystems. 2025 Nov 06. e0112625
    Spatially divergent metabolic impact of experimental toxoplasmosis: immunological and microbial correlates.
    Mahbobeh Lesani, Caitlyn E Middleton, Tzu-Yu Feng, Jan Carlos Urbán Arroyo, Eli Casarez, Sarah E Ewald, Laura-Isobel McCall.
      Maladaptive host metabolic responses to infection are emerging as major determinants of infectious disease pathogenesis. However, the factors regulating these metabolic changes within tissues remain poorly understood. In this study, we used toxoplasmosis, as a prototypical example of a disease regulated by strong type I immune responses, to assess the relative roles of current local parasite burden, local tissue inflammation, and the microbiome in shaping local tissue metabolism during acute and chronic infections. Toxoplasmosis is a zoonotic disease caused by the parasite Toxoplasma gondii. This protozoan infects the small intestine and then disseminates broadly in the acute stage of infection, before establishing chronic infection in the skeletal muscle, cardiac muscle, and brain. We compared metabolism in 11 sampling sites in C57BL/6 mice during the acute and chronic stages of T. gondii infection. Strikingly, major spatial mismatches were observed between metabolic perturbation and local parasite burden at the time of sample collection for both disease stages. By contrast, a stronger association with indicators of active type I immune responses was observed, indicating a tighter relationship between metabolic perturbation and local immunity than with local parasite burden. Loss of signaling through the IL1 receptor in IL1R knockout mice was associated with reduced metabolic impact of infection. In addition, we observed significant changes in microbiota composition with infection and candidate microbial origins for multiple metabolites impacted by infection. These findings highlight the metabolic consequences of toxoplasmosis across different organs and potential regulators.IMPORTANCEInflammation is a major driver of tissue perturbation. However, the signals driving these changes on a tissue-intrinsic and molecular level are poorly understood. This study evaluated tissue-specific metabolic perturbations across 11 sampling sites following systemic murine infection with the parasite Toxoplasma gondii. Results revealed relationships between differential metabolite enrichment and variables, including inflammatory signals, pathogen burden, and commensal microbial communities. These data will inform hypotheses about the signals driving specific metabolic adaptation in acute and chronic protozoan infection, with broader implications for infection and inflammation in general.
    Keywords:  Toxoplasma gondii; inflammation; mass spectrometry; metabolism; microbiome
    DOI:  https://doi.org/10.1128/msystems.01126-25
  26. J Immunol Res. 2025 ;2025 7550012
    Spermidine Remodels the Mitochondrial Metabolism of Tumor-Infiltrating Lymphocytes.
    Yizhe Sun, Hao Fu, Xinyu Li, Meng Wan, Hongchao Xiong, Chaoting Zhang.
      Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TILs) has significant potential in treating various cancers; however, its effectiveness is often compromised by the tendency of TILs to become exhausted and dysfunctional. Revitalizing these essential immune cells is crucial for amplifying their antitumor efficacy. Our study investigates the influence of spermidine on the metabolic pathways of TILs, focusing on its critical contribution to T cell vitality. We assessed the impact of spermidine on glucose absorption, mitochondrial functionality, and energy production in TILs. The application of spermidine resulted in a pronounced improvement in mitochondrial functionality and energy production, indicated by a surge in mitochondrial numbers and enhanced activity of the tricarboxylic acid (TCA) cycle. Importantly, the suppression of mitochondrial metabolism negated the beneficial effects of spermidine on mitigating exhaustion and enhancing cellular activity, highlighting the essential role of mitochondrial metabolism in the action of spermidine. Our research suggests that modulation of metabolism by spermidine could be a potential strategy to strengthen the antitumor capabilities of TIL-based treatments, offering a promising method to better manage solid tumors.
    Keywords:  TCA cycle; metabolism; mitochondria; spermidine
    DOI:  https://doi.org/10.1155/jimr/7550012
  27. STAR Protoc. 2025 Oct 30. pii: S2666-1667(25)00579-9. [Epub ahead of print]6(4): 104173
    Protocol for halofuginone-mediated metabolic reprogramming of murine T cells via activation of the GCN2 pathway.
    Meghan Kates, Michael St Paul, Pamela S Ohashi, Samuel D Saibil.
      Modifying T cell metabolism and activating conserved stress pathways can enhance T cell efficacy in adoptive cell therapy for cancer treatment. Here, we present a protocol to activate the General Control Non-depressible 2 (GCN2)-mediated branch of the integrated stress response (ISR) in murine T cells using the drug halofuginone. We outline the process of isolating CD8+ T cells from T cell receptor transgenic mice, activating them with bone-marrow-derived dendritic cells, and subsequently activating GCN2 and the ISR with halofuginone. For complete details on the use and execution of this protocol, please refer to St. Paul et al.1.
    Keywords:  Cell Biology; Cell isolation; Immunology; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2025.104173
  28. Immunity. 2025 Oct 31. pii: S1074-7613(25)00461-3. [Epub ahead of print]
    Membrane integrity changes upon viral infection activate sphingomyelinase SMPDL3B to restrict cGAS-STING signaling via cGAMP degradation.
    Zhimeng Wang, Yanfei Hou, Peiyuan Liu, Ruinan Wu, Jiaming Yang, Shilong Fan, Zexu Peng, Xiaoxu Han, Bin Su, Conggang Zhang.
      The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway mediates antiviral innate immunity upon sensing cytosolic DNA. Here, we examined the impact of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a paralog of the LXR lipid metabolism-induced cGAMP-degrading enzyme SMPDL3A, on viral infection. We found that SMPDL3B was induced and stabilized by both viral infection and membrane-disturbing agents, suggesting a role in sensing membrane stress as an early signal of cellular danger. Deletion of SMPDL3B impaired DNA virus infection. Upon induction, SMPDL3B suppressed cGAS-STING signaling and downstream transcriptional pathways, including the interferon response. Mechanistically, SMPDL3B functioned as a cGAMP hydrolase; cGAMP-induced SMPDL3B dimerization enabled its hydrolase activity and a negative feedback loop that dampened STING signaling. SMPDL3B-deficient cells had elevated cGAMP concentrations, and Smpdl3b-/- mice exhibited enhanced cGAMP accumulation, heightened immune activation, and reduced viral loads upon herpes simplex virus type 1 (HSV-1) infection. Thus, SMPDL3B links membrane stress to modulation of cGAS-STING signaling through cGAMP degradation, with potential implications in the contexts of inflammation or autoimmunity.
    Keywords:  SMPDL3B; cGAMP; cGAS-STING signaling pathway; host-microbe interactions; innate immunity; viral infection
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.007
  29. Life Sci Alliance. 2026 Jan;pii: e202503315. [Epub ahead of print]9(1):
    Glycolytic flux sustains human Th1 identity and effector function via STAT1 glycosylation.
    Ariful Haque Abir, Julia Benz, Benjamin Frey, Heiko Bruns, Gerhard Krönke, Udo S Gaipl, Kilian Schober, Dimitrios Mougiakakos, Dirk Mielenz.
      T helper (Th) cell lineages are linked to metabolism, but precise mechanisms in human Th1 cells remain unclear. We addressed this question by in vitro stimulation and CRISPR/Cas9-mediated gene editing. Metabolic profiling revealed enhanced glycolytic activity in Th1 versus non-polarized cells, evidenced by increased extracellular acidification rate, ATP production via glycolysis, lactate secretion, NADH abundance, and elevated glycolysis-dependent anabolic activity. Inhibition of glycolysis reduced IFNγ production and STAT1 phosphorylation independent of JAK1/2 or SHP2 activity and STAT1 abundance, implicating glycolysis directly in sustaining STAT1-mediated Th1 functionality. O-glycosylation of STAT1 via O-glycosyltransferase was pivotal in modulating STAT1 activity. Pharmaceutical O-glycosyltransfer-ase inhibition prevented Th1 differentiation as well as STAT1 O-glycosylation. CRISPR/Cas9 mediated mutation of the O-glycosylation Ser499 and Thr510 sites diminished STAT1 Ser727 phosphorylation and IFNγ synthesis. Together, this study highlights glycolysis as key regulator of human Th1 cell identity and effector function, with STAT1 O-glycosylation selectively maintaining Th1 effector capacity. This mechanism could be explored to safeguard Th1 cells.
    DOI:  https://doi.org/10.26508/lsa.202503315
  30. ACS Omega. 2025 Oct 21. 10(41): 49061-49073
    Systems Biological Analysis of Immune-Metabolic Host Responses to Distinct Malaria Parasites.
    Davi Vinícius Lima, Tiago Paiva Guimarães, Anne Cristine Gomes Almeida, Arthur Jesuz Teixeira, Wuelton Marcelo Monteiro, Gisely Cardoso Melo, Luiz Gustavo Gardinassi.
      Recent studies suggest differential activation of immune cells and biochemical pathways during infection with distinct etiological agents of human malaria, Plasmodium falciparum or Plasmodium vivax. Rhesus monkeys infected with Plasmodium coatneyi develop pathology comparable to P. falciparum infection in humans, whereas P. vivax is modeled by infection with Plasmodium cynomolgi. To investigate host immune and metabolic responses, we analyzed and integrated public blood flow cytometry, transcriptomics, and untargeted metabolomics data from simian infection models and human malaria. We found conserved dynamics of blood dendritic cells, effector memory CD8+ T cells, and PD-1+ effector memory CD8+ T cells in simian infections; increased expression of HMOX1 and coagulation-related genes was conserved in simian infections, while the complement activation gene module was upregulated in rhesus and humans. Myeloid cell transcriptional responses were enriched in all infections, but gene modules reflecting chemokine responses and T cell differentiation were mostly associated with P. cynomolgi and P. vivax. Untargeted metabolomics analysis suggests conserved regulation of metabolites such as kynurenine and androgen- and estrogen-derived metabolites, and metabolic modules indicate tyrosine metabolism activity. Multimodal data integration from rhesus monkeys revealed distinct interacting network models. In conclusion, we identified conserved cellular, transcriptional, and metabolic responses between simian models and human malaria. Moreover, many significant variables were associated with one determined Plasmodium species, suggesting a significant impact of parasite biology on immune and metabolic host responses. However, systematic experimental comparisons are needed to distinguish species-specific host responses to Plasmodium from those that are caused by factors beyond the infection.
    DOI:  https://doi.org/10.1021/acsomega.5c07785
  31. Methods Mol Biol. 2026 ;2982 339-351
    A Single-Cell Methodology for Energy Metabolism Analysis in Parasitic Protozoa.
    Salomé C Vilchez-Larrea, Rafael J Argüello, Guillermo D Alonso.
      The metabolic adaptability of Trypanosoma cruzi, the causative agent of Chagas disease, and other trypanosomatids across their life cycle stages is a defining feature of their biology and pathogenicity. Studying parasite and host cell metabolic profiles during infections is crucial to understanding disease progression and developing targeted therapeutic interventions. Traditionally, researchers have faced limitations in effectively capturing the dynamic nature of metabolic shifts in real time, hindering our ability to unravel the complex interplay between the host and the pathogen. Approaching these questions requires a high-throughput technique capable of assessing the metabolic changes and preferences of both the parasite and the host cell under physiological conditions in infected cells and tissues. A novel analytical technique that promises to push forward our understanding of metabolic profiles during Trypanosoma cruzi infections has now been developed. Here, we describe the potential to exploit the Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH™) to examine the energetic metabolism of T. cruzi during its distinct developmental stages-epimastigote, trypomastigote, and amastigote-allowing to unveil the metabolic shifts that underpin their survival and proliferation in diverse host environments. Additionally, SCENITH allows to study how infected host cells' metabolism changes in the presence of parasites. The variability in metabolic pathways offers a unique perspective for identifying and developing stage-specific drug targets, presenting opportunities for more effective therapeutic interventions.
    Keywords:  Flow Cytometry; Host–Parasite interaction; Metabolic profile; SCENITH; Trypanosoma cruzi
    DOI:  https://doi.org/10.1007/978-1-0716-4848-3_22
  32. Br J Haematol. 2025 Nov 07.
    Dysfunctional T cells due to the abnormal glucose metabolism in patients with primary immune thrombocytopenia.
    Meiwen Tang, Bixiang Li, Juan Zhuang, Yanxia Zhan, Feng Xie, Honghui Ye, Zhitao Li, Wenzheng Pang, Yunfeng Cheng, Lili Ji.
      To investigate T-cell glucose metabolism dysfunction in primary immune thrombocytopenia (ITP) and the role of mammalian target of rapamycin complex 1 (mTORC1) in regulatory T-cell (Treg) suppression function. Gene set enrichment analysis (GSEA) assessed glycolysis and mTORC1 pathways in dysfunctional Tregs from patients with systemic lupus erythematosus (SLE). CD4+ effector T cells (Teffs) were isolated from peripheral blood mononuclear cells (PBMCs) pre- and post-dexamethasone treatment and from healthy controls. The extracellular acidification rate (ECAR) of Tregs and Teffs was measured using the Agilent Seahorse XF96 platform. Flow cytometry evaluated glucose transporter 1 (GLUT1) and phosphorylated S6 (p-S6) expression. The immune suppression function of Tregs was assessed by mTORC1 inhibiting test. GSEA revealed a possible relation of glycolysis and mTORC1 signalling in dysfunctional Tregs. Both Tregs and Teffs from ITP patients showed elevated ECAR, with Teff ECAR normalizing post-glucocorticoid treatment. Treg ECAR decreased after treatment, but remained higher than normal level. GLUT1 and p-S6 expression was significantly higher in ITP Tregs and Teffs, normalizing GLUT1 levels after glucocorticoid therapy. Inhibiting mTORC1 could recover the suppression of ITP Tregs. Dysregulated CD4+ T-cell glucose metabolism contributes to ITP pathogenesis. Targeting mTORC1 signal may offer a novel therapeutic approach for ITP.
    Keywords:  Teffs; Tregs; glucose metabolism; immune thrombocytopenia
    DOI:  https://doi.org/10.1111/bjh.70229
  33. Pharmacol Res. 2025 Oct 30. pii: S1043-6618(25)00440-2. [Epub ahead of print]222 108015
    Metabolic modulation of CD8⁺ T cells by metformin: A promising adjuvant strategy for CD8⁺ T Cell-Based Immunotherapies.
    Quynh Chau Ton Nu, Pil-Hoon Park.
      CD8⁺ T cells play a pivotal role in immune defense through their cytotoxic activity. However, persistent antigen exposure and immunosuppressive microenvironments drive CD8⁺ T cells into a dysfunctional or exhausted state, thereby limiting the effectiveness of CD8⁺ T cell-based immunotherapies. Increasing evidence indicates that CD8+ T cell activation and effector functions are tightly coupled to dynamic metabolic reprogramming that sustains the energetic and biosynthetic requirements for effective immune responses. Metformin, beyond its established role as an antidiabetic medication, demonstrates considerable promise as an immune-metabolic adjuvant capable of enhancing the efficacy of CD8⁺ T cell-based immunotherapies and reshaping immune responses across various pathological conditions. In this review, we provide a comprehensive overview of the current insights into the metabolic and functional regulation of CD8⁺ T cells by metformin in a context-dependent manner, with an emphasis on its therapeutic potential as an immunotherapeutic adjuvant. We also highlight the translational opportunities and challenges associated with the clinical integration of metformin and propose strategies to overcome context-specific barriers to its clinical application.
    Keywords:  CD8(+) T cell; Immunotherapy; Metabolic programming; Metformin
    DOI:  https://doi.org/10.1016/j.phrs.2025.108015
  34. ACS Nano. 2025 Nov 04.
    Cysteine Metabolism Reprogramming-Motivated Catalytic Immunotherapy for Orthopedic Biofilm Infections.
    Wanbo Zhu, Min Ge, Quan Liu, Chuang Yang, Qiaojie Wang, Han Lin, Xianlong Zhang.
      Immunotherapeutic strategies have proven to be very promising in the treatment of drug-resistant infections. However, breakthroughs against medical implant infections have been hampered by the presence of sophisticated bacterial biofilm defense barriers and suppressive immune cells at the biofilm-immune interface. Herein, we developed a nanointerfering catalyst (niCatalyst) for targeted modulation of cysteine metabolic processes in the biofilm-immune microenvironment (BIME). By releasing aurin tricarboxylic acid, the niCatalyst effectively blocked key enzymes involved in cysteine metabolism, thus limiting the production of hydrogen sulfide and glutathione in the biofilm defense barrier. Light-triggered burst catalysis of singlet oxygen further exacerbated the oxidative stress damage within the biofilm. Additionally, interference with cysteine metabolism inhibited cellular glutathione synthesis, leading to the enhancement of antimicrobial immune responses and antigen-presenting cell functions in macrophages. This, in turn, costimulated the immune functions of antibiofilm adaptive helper T cells and cytotoxic NK cells. In summary, our emerging niCatalysts enable reprogramming of cysteine metabolism in the BIME, as well as costimulation of innate and adaptive immunotherapy. This approach effectively eliminates drug-resistant biofilm infections with low metabolic activity, providing an alternative for metabolic immunotherapy in the postantibiotic era.
    Keywords:  biofilm eradication; catalytic immunotherapy; drug delivery; metabolism reprogramming; orthopedic surgery
    DOI:  https://doi.org/10.1021/acsnano.5c04069
  35. Cell Mol Life Sci. 2025 Nov 05. 82(1): 382
    Parechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids.
    Pamela E Capendale, Anoop T Ambikan, Inés García-Rodríguez, Renata Vieira de Sá, Dasja Pajkrt, Katja C Wolthers, Ujjwal Neogi, Adithya Sridhar.
      Parechovirus ahumpari 3 (HPeV-3) is among the main agents causing severe neonatal neurological infections such as encephalitis and meningitis. However, the underlying molecular mechanisms and changes to the host cellular landscape leading to neurological disease has been understudied. Through quantitative proteomic analysis of HPeV-3 infected neural organoids, we identified unique metabolic changes following HPeV-3 infection that indicate immunometabolic dysregulation. Protein and pathway analyses showed significant alterations in neurotransmission and potentially, neuronal excitotoxicity. Elevated levels of extracellular glutamate, lactate dehydrogenase (LDH), and neurofilament light (NfL) confirmed glutamate excitotoxicity to be a key mechanism contributing to neuronal toxicity in HPeV-3 infection and can lead to apoptosis induced by caspase signaling. These insights are pivotal in delineating the metabolic landscape following severe HPeV-3 CNS infection and may identify potential host targets for therapeutic interventions.
    Keywords:  Astrocytes; Brain organoids; CNS; Central nervous system; Immunometabolism; Neurons; Quantitative proteomics; Stem cells
    DOI:  https://doi.org/10.1007/s00018-025-05926-z
  36. Front Immunol. 2025 ;16 1684234
    Arginine-mediated inhibition of macrophage apoptosis by Escherichia coli nissle 1917 in Salmonella typhimurium-induced intestinal inflammation.
    Lu Zhang, Jiahui Yang, Qixue Shi, Yanyan Chu, Jiarui Cao, Chenglong Shang, Changlin Zhou, Lingman Ma.
       Introduction: Intestinal inflammation is a chronic, relapsing disorder of the gastrointestinal tract characterized by dysregulated immune responses, microbial dysbiosis, and environmental influence. Pathogen clearance is related to the severity of intestinal diseases and macrophage apoptosis. Escherichia coli Nissle 1917 (EcN) alleviates the intestinal inflammation caused by Salmonella enterica serotype Salmonella Typhimurium (Salmonella Typhimurium, S. Tm) infection.
    Methods: Through gene editing, we found that the regulatory gene arcA largely affects arginine production in EcN via the arginine deiminase pathway. In vitro studies demonstrated that EcN alleviates S. Tm-induced apoptosis in RAW264.7 cells by enhancing intracellular arginine levels. Specifically, arginine generated by EcN can reduce S. Tm infection-induced generation of reactive oxygen species (ROS), chromatin condensation, DNA fragmentation, disruption of plasma membrane integrity, and decrease in mitochondrial membrane potential. Additionally, arginine administration in S. Tm-challenged mice decreased bacterial burden in the gut, suppressed Caspase-3 (CASPASE3) activation, mitigated both inflammation and apoptosis, and maintained epithelial barrier.
    Result and discussion: Mechanistically, arginine suppresses S. Tm-driven B-cell lymphoma-2 (BCL2) downregulation, inhibiting apoptosis. Further analysis revealed that arginine may disrupt the interaction between ribosomal protein S3 (RPS3) and serine/serine and arginine rich splicing factor 3 (SRSF3), thereby further suppressing the expression of apoptosis-related proteins induced by S. Tm. Our research offers new targets and approaches for treating bacterial infection-induced intestinal inflammation.
    Keywords:  Escherichia coli nissle 1917; Salmonella typhimurium infection; arginine; inhibition of macrophage apoptosis; intestinal inflammation
    DOI:  https://doi.org/10.3389/fimmu.2025.1684234
  37. Inflamm Res. 2025 Nov 06. 74(1): 156
    PGC1α alleviates M1 macrophage polarization through dual regulation of succinate metabolism and TRAF5 expression to mitigate TLR4/NF-κB-driven inflammatory cascades and myocardial ischemia/reperfusion injury.
    Jiajie Leng, Zhenrui Cao, Letai Li, Dingheng Hu, Yuxiang Luo, Bin Tu, Xiaoying Cao, Rui Tao, Yingjiu Jiang, Hongtao Tie.
       OBJECTIVE: This study investigates the dual regulatory role of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in macrophage polarization and its therapeutic potential for mitigating myocardial ischemia/reperfusion injury (MI/RI).
    METHODS: By integrating in vivo murine myocardial MI/RI models with macrophage-specific genetic manipulation and multi-omics analyses, including transcriptomics, proteomics, and energy metabolomics, we comprehensively investigated the cardio-protective effects, immune regulation, and potential mechanism of PGC1α. Mechanistic validations were performed using macrophage hypoxia/reoxygenation models combined with gain- and loss-of-function experiments to elucidate the molecular interactions within the PGC1α-mediated signaling network.
    RESULTS: PGC1α emerged as a potential regulator of macrophage polarization through coordinated metabolic and protein regulation in MI/RI. It suppresses TLR4/NF-κB-driven inflammation via two prominent parallel pathways: (1) Metabolic control through SUCLG1/succinyl-CoA synthetase-mediated succinate generation; (2) negatively regulates protein by TRAF5 mRNA expression inhibition. This dual-axis regulation effectively dampens M1 macrophage polarization and pro-inflammatory cytokine storms. Furthermore, macrophage-specific PGC1α activation demonstrated cardio-protective effects by preserving cardiac function and reducing cardiomyocyte apoptosis.
    CONCLUSION: Our findings established PGC1α as a potential regulator of macrophage polarization in MI/RI, bridging mitochondrial energy metabolism and protein expression with immune responses. The PGC1α-SUCLG1/succinate axis and PGC1α-TRAF5 axis unveil therapeutic targets and potential mechanisms for modulating inflammation in MI/RI. Future studies should focus on translating these mechanisms into clinical interventions through pharmacological PGC1α activation.
    Keywords:  Immunometabolic crosstalk; M1 macrophage polarization; Myocardial ischemia–reperfusion injury; PGC1α; TLR4/NF-κB signaling
    DOI:  https://doi.org/10.1007/s00011-025-02109-1
  38. J Biol Rhythms. 2025 Nov 03. 7487304251378607
    Time-Dependent Metabolic Response in Sepsis Severity: The Influence of Glucose in the Disease Outcome.
    Camila Agustina Senna, Malena Lis Mul Fedele, Ignacio Aiello, Guido Hokama, Diego Golombek, Natalia Paladino.
      Sepsis is a syndrome caused by a dysregulated host response to pathogens, representing the leading cause of death from infection. Various murine models of sepsis have shown a time-dependent response based on the time of induction. Mice stimulated with high doses of bacterial lipopolysaccharide (LPS) at the end of the day exhibit a higher mortality rate (~80%) compared with those inoculated in the middle of the night (~30%). In this work, we assessed the differences in serum proteins of septic mice during the day and night. Through this proteomic study, we found significant variations in metabolic pathways, including glucose metabolism, which were associated with a better prognosis. Therefore, we studied the glucose response to LPS during the day and night. In this context, we found an early peak of LPS-induced glucose exclusively at the time of worse prognosis. We also observed a hypoglycemic response to LPS, which was independent of the time of sepsis induction. Finally, we performed a set of metabolic manipulations to study how hyperglycemia influences sepsis severity in mice. We observed that suppressing the glucose peak during the day, through metformin administration, reduced sepsis severity. In contrast, nocturnal glucose administration with LPS was rapidly metabolized and also decreased sepsis severity. In conclusion, sepsis severity may be influenced by the metabolic state at the time of the stimulus. Metabolic rhythms could lead to differences in early glucose management, affecting the outcome of this pathology.
    Keywords:  Sepsis; circadian rhythms; glucose; immune system; metabolism
    DOI:  https://doi.org/10.1177/07487304251378607
  39. J Clin Periodontol. 2025 Nov 02.
    Serine Promotes Inflammatory Macrophage Polarisation in Periodontitis via NAD+ Signalling.
    Lingli Fang, Jun Wang, Jing Xiang, Lei Xu, Sijing Zhao, Yunying He, Xiang Liu, Huayu Ye, Hongmei Zhang, Hua Zhang, Ping Ji, Chang Chen, Qiming Zhai, Richard Cannon.
       AIM: To investigate the role of serine in modulating macrophage polarisation and periodontal inflammation.
    MATERIALS AND METHODS: Saliva samples were obtained from periodontitis patients, healthy individuals and periodontitis remission patients for salivary metabolomics analysis. C57BL/6J mice were used to establish a ligature-induced periodontitis model. THP-1 cells were used in vitro to explore the mechanism underlying serine-mediated periodontitis. Micro-computed tomography, immunohistochemistry, quantitative real-time polymerase chain reaction, flow cytometry, western blotting, RNA sequencing and NAD+/NADH detection were performed to explore the role of serine in periodontitis and the underlying mechanism.
    RESULTS: Salivary serine concentrations were significantly elevated in patients with periodontitis and correlated with disease severity. In vivo experiments showed that locally elevated serine concentrations exacerbated alveolar bone resorption in a mouse model of periodontitis. Transcriptomic analysis revealed that serine stimulation activated inflammation-related pathways, particularly the nicotinamide salvage pathway, which modulates NAD+ levels. Inhibition of intracellular serine transport using L-phenylglycine (L-phg) and mitochondrial complex I (MCI) activity using rotenone reduced inflammatory macrophage polarisation, decreased inflammatory markers and alleviated periodontal tissue damage.
    CONCLUSION: Serine-induced inflammatory macrophage polarisation, mediated through NAD+ signalling, plays a key role in periodontitis pathogenesis. Targeting serine transport and NAD+ metabolism may offer new therapeutic strategies for managing periodontitis.
    Keywords:  L‐phenylglycine; NAD+ signalling; macrophage polarisation; periodontitis; rotenone; saliva; serine
    DOI:  https://doi.org/10.1111/jcpe.70058
  40. Aging Cell. 2025 Nov 07. e70257
    Defining Microbiota-Derived Metabolite Butyrate as a Senomorphic: Therapeutic Potential in the Age-Related T Cell Senescence.
    Nia Paddison Rees, Jessica Conway, Ben Dugan, Sayeda S Amir, Aimee Parker, Simon R Carding, Niharika A Duggal.
      Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs). Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial ROS accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB. Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.
    Keywords:  T cell; ageing; cellular senescence; inflammation
    DOI:  https://doi.org/10.1111/acel.70257
  41. Int J Mol Med. 2026 Jan;pii: 16. [Epub ahead of print]57(1):
    Microbial short chain fatty acids: Effective histone deacetylase inhibitors in immune regulation (Review).
    Jing Wang, Qin Zhao, Shuwan Zhang, Jia Liu, Xingyue Fan, Bin Han, Yaqin Hou, Xiaopeng Ai.
      Histone acetylation modification represents a common epigenetic regulatory mechanism, carrying out an indispensable role in cellular gene transcription and function. Histone deacetylases (HDACs) are responsible for regulating gene expression by controlling the deacetylation of histones and non‑histone proteins, and can serve as effective targets for participating in immune regulation. Short‑chain fatty acids (SCFAs) are important metabolites produced by the gut microbiota that modulate host immunity. SCFAs possess extensive inhibitory activities on class I and II HDACs, as well as acetylation‑modifying effects. Based on these, the present review initially introduces the microbial synthesis and intestinal absorption of SCFAs, as well as the classification and function of HDACs. Subsequently, the present review comprehensively summarizes the direct regulatory effects of SCFAs on immune cells through HDAC inhibition, encompassing innate immune cells (macrophages, dendritic cells, neutrophils, mast cells and natural killer cells) as well as T/B lymphocytes. Moreover, the present review further discusses the local intestinal and extra‑intestinal (primarily involving the liver, kidney, nerves and blood vessels) protective effects of SCFAs, which are mediated by their HDAC‑inhibiting activities. Finally, the present review summarizes the therapeutic potential of SCFAs as effective HDAC inhibitors in ameliorating intestinal and extra‑intestinal diseases and discusses the research prospects. The present review aims to elucidate the regulatory effects of SCFAs on host immunity through HDAC inhibition, highlighting their therapeutic potential for human diseases.
    Keywords:  acetylation modification; butyrate; histone deacetylase inhibition; immune regulation; short‑chain fatty acids
    DOI:  https://doi.org/10.3892/ijmm.2025.5687
  42. J Inflamm Res. 2025 ;18 15017-15032
    Succinate's Dual Roles in Inflammatory Bowel Disease: A Narrative Review of Microbiota-Metabolism-Immune Crosstalk and Therapeutic Implications.
    Meihua Zhao, Chuan Zhou, Dandan Wang, Qiong Wu, Baisui Feng.
      Inflammatory bowel disease (IBD) is a chronic intestinal condition characterized by microbial dysbiosis, metabolic alterations, and immune dysregulation. Succinate, a key tricarboxylic acid (TCA) cycle intermediate and microbiota-derived metabolite, has emerged as a central regulator within the host microbiota-metabolism-immune axis in IBD. This narrative review delineates succinate metabolism and its dual signaling roles, operating both intracellularly and through extracellular receptors. We synthesize evidence on its context-dependent immunomodulatory functions, which can paradoxically drive both pro- and anti-inflammatory responses, and elucidate the specific factors that dictate these outcomes. Finally, we critically evaluate the translational potential of targeting the succinate pathway, outlining promising avenues for future research in IBD diagnosis and treatment.
    Keywords:  immune regulation; inflammatory bowel disease; microbiota-metabolism-immune axis; precision medicine; succinate
    DOI:  https://doi.org/10.2147/JIR.S561871
  43. Front Immunol. 2025 ;16 1690068
    Lactylation and antitumor immunity.
    Biao Yang, Lingyu Li, Dongmei Shi, Tao Zhong, Huabao Xiong.
      Lactylation, a recently discovered post-translational modification (PTM), plays a critical role in cancer biology. Warburg effect induces lactate accumulation, which serves as a metabolic end-product and intercellular signaling mediator within the tumor microenvironment (TME). Beyond fueling tumor growth, elevated lactate levels drive histone and non-histone lactylation, which modulates gene expression and protein function. This epigenetic reprogramming induces immunosuppressive phenotypes in immune cells that are resident in the tumor microenvironment, including impaired effector function, enhanced immunosuppressive cytokine secretion, and altered tumor antigen presentation, collectively facilitating immune escape. This review provides a synthesis of the current understanding of lactate and lactylation in tumor immunosuppression, detailing molecular mechanisms underlying immune cell inhibition (tumor-associated macrophages, T cells, T-reg cells, NK cells and NKT cells, as well as neutrophils) and evaluating emerging therapeutic strategies (e.g., inhibitors of MCTs/LDHA, site-specific antibodies, genetic code expansion technology). We aimed to accelerate the clinical translation of lactylation-targeted anticancer therapies by highlighting recent advances.
    Keywords:  antitumor immunity; histone and non-histone lactylation; immunosuppressive phenotypes; lactate accumulation; lactylation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1690068
  44. Immun Ageing. 2025 Nov 05. 22(1): 51
    Ascorbic acid attenuates immunosenescence and cognitive decline via MYH9-Mediated CD8⁺ T cell differentiation.
    Taotao Mi, Shanshan Yang, Nan Wang, Fengjiao Huo, Meili Zhao, Shuyao Lv, Tingting Su, Shengyu Feng, Hao Wang, Liuling Guo, Jian-Kang Zhu, Hailiang Liu.
       BACKGROUND: ​​ Immune function decline (immunosenescence) accelerates systemic aging and adversely impacts cognitive function. Antioxidants may mitigate these effects; however, the role of ascorbic acid (AA), a key antioxidant, in counteracting immunosenescence and enhancing cognition remains inadequately explored.
    RESULTS: In this study, AA administration (0.1 mg/g, tail vein, every 2 days for 30 days) significantly improved cognitive function in aged (16-month) C57BL/6 mice, without altering anxiety-like behavior (as assessed in the open field test). This was associated with elevated peripheral blood lymphocytes (T cells, B cells) and CD8⁺ T cells, alongside reduced myeloid cells (CD11b⁺). Single-cell RNA sequencing of PBMCs revealed AA reversed immunosenescent signatures-increasing T/B cell populations and decreasing neutrophils/macrophages-mimicking youthful immune profiles. In vitro, AA skewed hematopoietic stem cell (HSC) differentiation toward CD8⁺ T cells (increasing DN2 stage, suppressing myeloid CD11b⁺ cells) and enhanced splenic CD8⁺ T cell generation. Mechanistically, AA bound MYH9, activating cytoskeletal pathways. MYH9 inhibition (blebbistatin) reduced CD8⁺ T cells and increased CD11b⁺ cells-effects rescued by AA. Crucially, CD8⁺ T cell depletion abolished AA's cognitive benefits, confirming their essential role.
    CONCLUSIONS: In summary, AA mitigates immunosenescence and improves cognitive function by targeting MYH9 to regulate CD8⁺ T cell differentiation and function. These findings establish a mechanistic basis for AA as a potential therapeutic agent against age-related immune and cognitive decline.
    Keywords:  Ascorbic acid; CD8+ t cells; Cognitive functions; Immunosenescence
    DOI:  https://doi.org/10.1186/s12979-025-00538-4
  45. Sci Transl Med. 2025 Nov 05. 17(823): eadu6015
    The m6A demethylase FTO links TLR7 to mitochondrial oxidation driving age-associated B cell formation in systemic lupus erythematosus.
    Qin Zeng, Lin Li, Xue Li, Linmang Qin, Tianxiao Feng, Yunfeng Zhu, Jieying Wang, Yaoyao Zou, Jianling Su, Guangfu Dong, Wuzheng Xia, Ting Xu, Guangfeng Zhang, Yang Cui, Haobo Lin, Xin Li, Yang Li.
      Extrafollicular age-associated B cells (ABCs) excessively expand and produce autoantibodies in systemic lupus erythematosus (SLE), and the regulatory mechanism remains elusive. We found that the m6A demethylase fat mass and obesity-associated protein (FTO) was highly expressed in ABCs from patients with SLE, which was positively associated with renal immune damage. FTO overexpression in murine and human B cells facilitated ABC expansion and exacerbated SLE in lupus-prone mice, whereas FTO ablation ameliorated ABC-driven autoimmunity. FTO expression was up-regulated upon activation of the toll-like receptor 7-myeloid differentiation primary response protein 88 (TLR7-MyD88) signaling pathway. FTO, in turn, promoted TLR7-driven ABC differentiation by targeting ATPase H+ transporting V1 subunit G1 (ATP6V1G1), a subunit of the vacuolar H+-ATPase (V-ATPase), in an m6A-dependent manner. Mechanistically, FTO deficiency impaired lysosomal autophagy by reducing ATP6V1G1-mediated V-ATPase activity. The accumulation of damaged mitochondria led to mitochondrial dysfunction in human and murine B cells, characterized by reduced oxidative phosphorylation and elevated reactive oxygen species. This dysfunction limited cell proliferation and blocked ABC differentiation by dampening cellular responsiveness to interleukin-12. Thus, TLR7-FTO-ATP6V1G1 signaling metabolically shapes extrafollicular ABCs in SLE, providing a potential therapeutic target.
    DOI:  https://doi.org/10.1126/scitranslmed.adu6015
  46. Cell Death Dis. 2025 Nov 03. 16(1): 781
    USP32 promotes temporomandibular joint osteoarthritis by modulating PKM2 stability and glycolytic metabolism in chondrocytes.
    Jiamin Zhao, Runjing Li, Tianjing Du, Mengying Wang, Menghong Li, Zhihui Feng, Zhongbo Liu, Kun Qi.
      Metabolic alterations in chondrocytes play a crucial role in the progression of temporomandibular joint osteoarthritis (TMJOA). However, the precise molecular mechanisms underlying these changes remain poorly understood. In this study, we identify ubiquitin-specific protease 32 (USP32) as a key regulator of TMJOA progression through its interaction with pyruvate kinase M2 (PKM2), a vital enzyme in glycolysis. Our results demonstrate that USP32 is significantly upregulated in TMJOA cartilage and inflammatory chondrocytes. USP32 stabilizes PKM2 by removing K48- and K11-linked ubiquitin chains, thereby preventing its proteasomal degradation. This stabilization promotes the accumulation of PKM2, leading to enhanced glycolysis, increased lactate production, and mitochondrial dysfunction, all of which exacerbate chondrocyte apoptosis and the degradation of extracellular matrix. Knocking down USP32 or PKM2 mitigates these detrimental effects, restoring mitochondrial function and reducing inflammation. Furthermore, cartilage-specific knockdown of USP32 alleviates TMJOA pathology in a rat model, highlighting the therapeutic potential of targeting the USP32-PKM2 axis. Our findings reveal a novel mechanism through which USP32 regulates chondrocyte metabolism and inflammation via PKM2 deubiquitination, providing new insights into the pathogenesis of TMJOA and potential therapeutic strategies for its treatment.
    DOI:  https://doi.org/10.1038/s41419-025-08053-6
  47. J Vis Exp. 2025 Oct 17.
    Cholesterol and Stearamide Mediate Lymphocyte Apoptosis and Cytokine Secretion in Systemic Lupus Erythematosus.
    Xuejia Zheng, Qingwen Wang, Liu Xiang, Ruiyuan Chen, Mingquan Guo, Huihui Tao, Tiantian Xu, Mengyao Wu, Chunmei Wen, Jingquan He, Yong Dai.
      Alterations in serum metabolite composition have been increasingly associated with systemic lupus erythematosus (SLE), yet the direct effects of these metabolites on immune cell function remain poorly defined. This study aimed to identify peripheral blood metabolites associated with SLE and evaluate their impact on apoptosis and cytokine secretion in lymphocytes derived from SLE patients. We performed a two-sample Mendelian randomization (MR) analysis to investigate the relationship between 565 serum metabolites and SLE, using the inverse-variance weighted model as the primary analytical approach. Significant findings were cross-validated using previously published untargeted metabolomics data based on liquid chromatography-mass spectrometry (LC-MS). In functional experiments, lymphocytes isolated from SLE patients were stimulated with target metabolites, followed by assessment of apoptosis and cytokine secretion. MR analysis identified 28 metabolites significantly associated with SLE. Of these, cholesterol (OR = 1.462, 95% CI: 1.100-1.940, P = 0.008) and stearamide (OR = 0.125, 95% CI: 0.020-0.660, P = 0.014) were validated through LC-MS and found to be elevated in SLE patients. Receiver operating characteristic analysis demonstrated strong diagnostic performance (AUC = 0.999 for cholesterol; AUC = 1.000 for stearamide). Functionally, both metabolites induced increased apoptosis and elevated secretion of TNF-α, IFN-γ, and TGF-β1 in SLE lymphocytes. In summary, our integrated approach combining genetic association, metabolite profiling, and functional assays reveals that cholesterol may contribute to immune dysregulation in SLE. Although stearamide showed a negative association with SLE risk in MR analysis, its in vitro effects mirrored those of cholesterol, suggesting a complex and context-dependent role. These findings underscore the importance of lipid metabolism in SLE and support further mechanistic and clinical investigation of its immunological impact.
    DOI:  https://doi.org/10.3791/69038
  48. Nat Metab. 2025 Nov 04.
    Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
    Daniel Barnett, Till S Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M Meadows, Haopeng Xiao, Man Ying Wong, Wenjie Luo, Li Gan, Edward T Chouchani, Anna G Orr, Adam L Orr.
      Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s42255-025-01390-y
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