bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–02–22
forty-one papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Roles of immune cell metabolism in rheumatoid arthritis.
  2. Phosphoglycerate dehydrogenase-mediated serine reprogramming aggravates macrophage hyperinflammation in murine Pseudomonas aeruginosa pneumonia.
  3. Metabolic Checkpoints in CD8+ T Cells within the Tumor Microenvironment: A Comprehensive Review and Emerging Insights.
  4. Convergence of immunometabolism and lung cancer therapy: redefining the tumor-immune interface.
  5. Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy.
  6. Glycolysis inhibition in tuberculosis-driven metabolic rewiring reduces HIV-1 spread in macrophages.
  7. Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels.
  8. Nonoxidative pentose phosphate pathway regulates CD8+ T cell immunity by maintaining NADPH homeostasis.
  9. Regulating the regulators via targeting CD38 in the tumor microenvironment.
  10. Mitochondrial TRPV1 exacerbates cognitive deficits in sepsis-associated encephalopathy by driving microglial metabolic reprogramming.
  11. TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.
  12. 16-h fasting optimizes cancer immunotherapy in mice and humans.
  13. Mitochondrial Metabolism in Neutrophils: Emerging Roles in Inflammatory Skin Diseases.
  14. Muscle-immune metabolic crosstalk: shared pathways in cachexia and exercise.
  15. The metabolite α-ketoglutarate induces AIM2-dependent PANoptosis through demethylase TET2.
  16. Thymidine induces macrophage M1 polarization in radiation-induced-lung-injury by ATF3/p38 pathway.
  17. Nanotherapeutic Macrophage-Neuro Reprogramming Through Immunometabolic Crosstalk Mitigates Sepsis-Induced Lung Injury and Neurologic Damage.
  18. Impaired peripheral mononuclear cell metabolism in patients at risk of developing sepsis: A cohort study.
  19. Differential effects of the microbial metabolite acetate on murine microglia in in vitro sepsis and trauma models.
  20. HHEX-PRKAR2B axis-mediated PKA activation drives glucose metabolism-dependent progression of pancreatic ductal adenocarcinoma.
  21. Effects of a metabolizable protein supply on metabolic function of CD4+ T lymphocytes in mid-lactation dairy cows.
  22. Hepatocyte PLAGL2 deficiency alleviates MASH through MYD88-licensed inactivation of inflammasome.
  23. SLC1A5-mediated kynurenine metabolism drives AHR-FANCD2 axis to remodel chromatin and induce T cell exhaustion in lung adenocarcinoma.
  24. Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair.
  25. Palmitic acid aggravates airway inflammation in asthma through induction of chemokines expression and metabolomic changes in epithelial cells.
  26. Effects and mechanism of Bifidobacterium on intestinal inflammation resulting from deoxycholic acid-induced M1 polarization of macrophages.
  27. Aging-Driven Inter-Organ Crosstalk in Postmenopausal Osteoporosis: From Immunometabolic Drift to Multisystem Frailty.
  28. GATA2 controls alveolar macrophage inflammatory gene expression and metabolic function.
  29. Lipid droplet-induced T cell death sustains autoimmune tissue inflammation.
  30. The acetylation status and metabolic characterization of the HBV-induced macrophages.
  31. Regulatory T cells safeguard liver health during metabolic-associated steatohepatitis.
  32. Glycolysis and NLRP3 inflammasome activation in diseases.
  33. Cis-aconitate therapy protects against influenza mortality by dual targeting of viral polymerase and ERK/AKT/NF-κB signaling.
  34. A shared metabolic-immune axis links local and systemic inflammation in chronic rhinosinusitis with comorbid asthma.
  35. Topical ionic liquid-mediated GLUT1 gene editing ameliorates psoriasis and prevents recurrence.
  36. Targeting Acod1/itaconate in cancer therapy: Mechanisms and opportunities.
  37. Toll Like Receptor 4: A Potential Link Between Obesity and Metabolic Diseases.
  38. Interferon-Driven Tryptophan Metabolism Links Inflammation and Mental Health in Juvenile Dermatomyositis.
  39. cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis.
  40. Siah2 is a lipid-meditated metabolic sensor in adipose tissue macrophage.
  41. The glycolytic enzyme PFKM promotes renal fibrosis by activating the NF-κB pathway via lactate-mediated H3K18 lactylation.
  1. Front Immunol. 2026 ;17 1763130
    Roles of immune cell metabolism in rheumatoid arthritis.
    Rui Xie, Zeping Chen, Shufang Deng, Xiaofeng Jiang, Yue Feng, Wei Zhao.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Recent advances reveal that immune cell metabolism plays a pivotal role in shaping RA pathogenesis. Aberrant glycolysis, lipid reprogramming, and amino acid catabolism drive functional alterations in T cells, B cells, macrophages, neutrophils, and fibroblast-like synoviocytes (FLSs), promoting inflammatory cytokine production, angiogenesis, and autoantibody generation. Key metabolites-such as lactate, succinate, and glutamine-not only serve as energy substrates but also act as immunomodulatory signals via the HIF-1α, PI3K/AKT/mTOR, and NF-κB pathways, exacerbating immune dysfunction and tissue damage. The plasticity of metabolic states contributes to Treg/Th17 imbalance, proinflammatory macrophage polarization, and FLS hyperactivation. Targeting these metabolic checkpoints has shown promise in restoring immune tolerance and alleviating disease severity. This review summarizes the complex interplay between immune cell metabolism and RA pathophysiology, highlights mechanistic insights into immunometabolic reprogramming, and discusses emerging metabolic interventions that may complement conventional RA therapies.
    Keywords:  immune cell; inflammation; metabolism; reprogramming; rheumatoid arthritis; synovial inflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1763130
  2. Nat Commun. 2026 Feb 20.
    Phosphoglycerate dehydrogenase-mediated serine reprogramming aggravates macrophage hyperinflammation in murine Pseudomonas aeruginosa pneumonia.
    Rong Chen, Ran Zeng, Mengmeng Shi, Guoliang Zhang, Feiyang Wang, Qingyuan Yang, Yanshan Jiang, Yuxuan Zhang, Yanan Li, Jieming Qu.
      Metabolic reprogramming in immune cells can determine the outcome of pathogen infection. For Pseudomonas aeruginosa, a clinically challenging pathogen, it remains unclear whether the host can exploit this strategy to combat bacterial invasion. Here, we identify phosphoglycerate dehydrogenase as a key mediator of macrophage inflammation during Pseudomonas aeruginosa infection. Pharmacological and genetic inhibition of phosphoglycerate dehydrogenase suppress macrophage hyperactivation and the production of pro-inflammatory cytokines. In a murine model of Pseudomonas aeruginosa pneumonia, myeloid-specific deletion of phosphoglycerate dehydrogenase improves survival, alleviates lung injury, and reduces bacterial load. Similarly, dietary restriction of L-serine improves prognosis in infected mice. Mechanistically, phosphoglycerate dehydrogenase fuels L-serine synthesis to augment one-carbon metabolism, which strengthens the direct interaction between histone H3 lysine 27 trimethylation and dual-specificity phosphatase 4. This cascade ultimately promotes extracellular signal-regulated kinase 1/2 phosphorylation. Our study uncovers a metabolism-epigenetics crosstalk that amplifies macrophage inflammation, proposing metabolic modulation as a therapeutic strategy for bacterial pneumonia.
    DOI:  https://doi.org/10.1038/s41467-026-69539-1
  3. Int J Biol Sci. 2026 ;22(4): 1950-1973
    Metabolic Checkpoints in CD8+ T Cells within the Tumor Microenvironment: A Comprehensive Review and Emerging Insights.
    Jiaqi Ai, Yiheng Du, Qianqian Xue, Wenbei Peng, Qiong Zhou.
      In recent years, a growing number of evidence suggests that cancer is a metabolic disease. Metabolic reprogramming is a hallmark of the TME, where various nutrients, including glucose, lipids, and amino acids, play key roles in regulating tumor development by acting on both tumor cells and immune cells. T cells are the core mediators of anti-tumor immunity. Especially CD8+ T cells are considered the primary immune cells involved in the anti-tumor immune response. Upon stimulation by tumor antigens and other immune cells, CD8+ T cells undergo metabolic reprogramming through signaling pathways. Metabolites or metabolic checkpoints induce epigenetic changes in key genes, altering the differentiation and effector function of CD8+ T cells. This review first elaborates on the anti-tumor functional characteristics and metabolic profiles of CD8+ T cells at different stages of differentiation in the TME. Then we focus on the roles of key metabolites and metabolic checkpoints in shaping CD8+ T cell differentiation, functionality, and immune responses, specifically through glucose, lipid, and amino acid metabolism. Finally, we discuss the reasons for heterogeneity in the effects of metabolic checkpoints on CD8+ T cells and explore potential clinical applications of metabolic checkpoints in treatment. Understanding the correlation between CD8+ T cell metabolism and anti-tumor immunotherapy may facilitate the development of new strategies to enhance the efficacy of CD8+ T cell-based cancer treatments.
    Keywords:  CD8+ T cell; cancer; checkpoint; immunotherapy; metabolism
    DOI:  https://doi.org/10.7150/ijbs.125206
  4. Eur J Med Res. 2026 Feb 15.
    Convergence of immunometabolism and lung cancer therapy: redefining the tumor-immune interface.
    Hailin Zhu, Rong Li, Xiurong Wen, Weiting Luo, Qinghua Liu.
      Surgery, chemotherapy, radiotherapy, and immune checkpoint blockade remain the mainstays of lung cancer treatment. Despite these approaches, lung cancer continues to be the second leading cause of cancer-related deaths worldwide. Recent insights into the metabolic reprogramming of lung tumors and their interplay with immune cells termed immunometabolism have revealed crucial mechanisms shaping tumor progression and therapeutic response. In lung cancer, T lymphocytes, natural killer cells, and macrophages undergo metabolic alterations that tumors exploit to create an immunosuppressive microenvironment, while tumor cells adopt metabolic switches that support growth, survival under stress, and evasion of immune surveillance. The dynamic regulation of glucose, oxygen, and amino acid availability in the lung tumor microenvironment influences T cell activation, macrophage polarization, and recruitment of immunosuppressive cells. Key oncogenic pathways, including c-Myc, HIF-1α, and PI3K-AKT-mTOR, coordinate these metabolic and immune adaptations. These insights have inspired novel therapeutic strategies that combine tumor metabolism-targeting with immune metabolism modulation to enhance antitumor immunity, often in conjunction with immune checkpoint blockade or adoptive cell therapy. Advances in single-cell and spatial metabolomics now enable precise characterization of metabolic heterogeneity in lung tumors, paving the way for personalized interventions exploiting immunometabolic vulnerabilities. This review emphasizes lung cancer-specific immunometabolism as a promising avenue for improving treatment outcomes, integrating molecular mechanisms, clinical trials, and emerging technologies.
    Keywords:  Immunometabolism; Lung cancer; Metabolic reprogramming; Metabolic-targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40001-026-04011-w
  5. Nat Commun. 2026 Feb 20.
    Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy.
    Lior Goldberg, Eric R Haas, Jiaqi Wu, Bryan Garcia, Ryan Urak, Vibhuti Vyas, Ruby Espinosa, Tamara Munoz, Shirley Bierkatz, Khyatiben V Pathak, Nathaniel P Hansen, Patrick Pirrotte, Jyotsana Singhal, James L Figarola, Ricardo Zerda Noriega, Zhuo Li, Dasol Wi, Erin Tanaka, Ramon Klein Geltink, Min-Hsuan Chen, Xiwei Wu, Jamie R Wagner, Jinny Paul, Mary C Clark, Dat Ngo, Ibrahim Aldoss, Stephen J Forman, Xiuli Wang.
      Although most patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) receiving CD19-targeted chimeric antigen receptor (CAR) T cell therapy achieve remission, loss of CAR T cell functionality and subsequent relapse remains an unmet therapeutic need. Herein, we apply an integrative approach to study the immunometabolism of pre- and post-infusion CD19-CAR T cells of patients with relapsed/refractory B-ALL. Pre-infusion CAR T cells of long-term responders (LTR) have increased oxidative phosphorylation, fatty acid oxidation, and pentose phosphate pathway activities, higher mitochondrial mass, tighter cristae, and lower mTOR expression compared to products of short-term responders. Post-infusion CAR T cells in bone marrow (BM) of LTR have high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induces metabolic reprogramming and enhances anti-tumor activity of CAR T cells. Our findings provide insight into immunometabolic determinants of long-term response and suggest a therapeutic strategy to improve long-term remission.
    DOI:  https://doi.org/10.1038/s41467-026-69857-4
  6. Life Sci Alliance. 2026 May;pii: e202503333. [Epub ahead of print]9(5):
    Glycolysis inhibition in tuberculosis-driven metabolic rewiring reduces HIV-1 spread in macrophages.
    Zoï Vahlas, Clara Deyts, Steven Fried, Myriam Ben Neji, Maxime Pingret, Natacha Faivre, Sarah C Monard, Quentin Hertel, Mariano Maio, Joaquina Barros, Alexandre Lucas, Thien Phong Vu Manh, Marcelo Corti, Renaud Poincloux, Fabien Blanchet, Brigitte Raynaud-Messina, Fabien Letisse, Olivier Neyrolles, Geanncarlo Lugo-Villarino, Luciana Balboa, Christel Vérollet.
      Tuberculosis (TB) is a significant aggravating factor in individuals living with HIV-1, the causative agent for AIDS. Both Mycobacterium tuberculosis (Mtb), the bacterium responsible for TB, and HIV-1 target macrophages. Understanding how Mtb subverts these cells may facilitate the identification of new druggable targets. Here, we explored how TB can induce macrophages to form tunneling nanotubes (TNT), promoting HIV-1 spread. We found that TB triggers metabolic rewiring of macrophages, increasing their glycolytic ATP production. Using several pharmacological inhibitors, glucose deprivation, and glucose or galactose supplementation, we discovered that disrupting aerobic glycolysis significantly reduces HIV-1 infection in these macrophages. Glycolysis is essential for tunneling nanotubes formation, which facilitates viral transfer and cell-to-cell fusion. Importantly, HIF-1α activation contributes to these processes. Overall, these data might facilitate the development of targeted therapies aimed at inhibiting HIF-1α-dependent glycolytic activity in TB-induced immunomodulatory macrophages to ultimately halt HIV-1 dissemination in coinfected patients.
    DOI:  https://doi.org/10.26508/lsa.202503333
  7. Sci Signal. 2026 Feb 17. 19(925): eady8398
    Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels.
    Kaitlyn E DeMeulenaere, Rogan A Grant, Megan E Martin, Hiam A Valencia, Jelena Radulovic, Michael W Salter, Murali Prakriya.
      Microglia are the brain's resident immune cells that respond to injury and disease by transitioning between homeostatic and reactive states. These cell state transitions determine whether microglia promote or resolve inflammation in the central nervous system (CNS). In this study, we explored the role of Ca2+ signaling in regulating broader microglial cell state transitions and identified Orai1 Ca2+ channels as critical regulators of microglial plasticity and neuroinflammatory signaling. Conditional deletion of Orai1 in microglia impaired their ability to adopt reactive, proinflammatory states. Transcriptomic and metabolomic profiling revealed that Orai1 deletion suppressed the expression of proinflammatory genes linked to immunity, inflammation, and cell metabolism. Conversely, Orai1-deficient microglia generated greater amounts of neuroprotective and anti-inflammatory mediators, including BDNF, ARG1, and the mitochondrial metabolite itaconate. In a model of CNS inflammation induced by peripheral lipopolysaccharide (LPS) challenge, microglial Orai1 deletion attenuated microglial and astrocyte reactivity and reduced hippocampal amounts of the proinflammatory cytokines IL-1β and IL-6. Consistent with these cellular changes, microglial Orai1 knockout mice were protected against LPS-induced decreases in motivational behaviors, including impaired reward-seeking and escape behaviors. These findings establish Orai1 channels as key regulators of microglial cell state transitions, linking Ca2+ signaling to neuroinflammation and inflammation-driven behavioral dysfunction.
    DOI:  https://doi.org/10.1126/scisignal.ady8398
  8. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2526325123
    Nonoxidative pentose phosphate pathway regulates CD8+ T cell immunity by maintaining NADPH homeostasis.
    Jingyu Feng, Qian Zhang, Li Luo, Zhichao Gu, Wen Liu, Jingsong Xu, Mengxin Qi, Zhongji Meng, Lin Li, Liangliang Lin, Zhuoshun Yang, Huafeng Zhang.
      NADPH is essential for cellular biosynthesis and redox balance in CD8+ T cells. Here, we demonstrate that the nonoxidative pentose phosphate pathway (non-oxPPP), mediated by transketolase (TKT) and transaldolase (TALDO1), is critical for CD8+ T cell activation, proliferation, and memory formation by maintaining NADPH homeostasis. Metabolomic profiling and isotopic tracing revealed upregulated non-oxPPP flux in effector (Teff) and memory (Tm) CD8+ T cells, enabling a pentose cycle that amplifies NADPH yield and sustains metabolic fitness for T cell immunity. Genetic knockdown or pharmacological inhibition of Tkt or Taldo1 impaired NADPH production, leading to ribose-5-phosphate (R5P) accumulation, oxidative stress, reduced lipid synthesis, mitochondrial dysfunction, and compromised Teff cell proliferation, cytokine production, and antitumor efficacy. Conversely, enhancing non-oxPPP activity promoted Tm differentiation, persistence, and recall responses. Targeting the non-oxPPP represents a promising strategy to enhance cancer immunotherapy and vaccine efficacy by bolstering T cell effector and memory responses.
    Keywords:  CD8+ T cell; NADPH; memory T cell; nonoxidative pentose phosphate pathway
    DOI:  https://doi.org/10.1073/pnas.2526325123
  9. Front Immunol. 2026 ;17 1745988
    Regulating the regulators via targeting CD38 in the tumor microenvironment.
    Navnita Dutta, Nabanita Halder, Eduardo Nunes Chini, Sungjune Kim, Alak Manna.
      The immunosuppressive tumor microenvironment (TME) remains a major barrier to effective cancer immunotherapy. Among the central regulators of immune suppression, CD38, a multifunctional ectoenzyme and surface glycoprotein, has emerged as a pivotal orchestrator. CD38 is abundantly expressed on regulatory T cells (Tregs), regulatory B cells (Bregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs), where it enhances survival, metabolic fitness, and suppressive activity. Invariant natural killer T (iNKT) cells, which can either promote or suppress antitumor immunity, also express CD38 upon activation, suggesting a role for CD38 in directing their context-dependent fate within the TME. Mechanistically, CD38 regulates immune suppression through NAD+ hydrolysis, calcium signaling, and promotion of fatty acid oxidation (FAO) while impairing effector T-cell glycolysis and mitochondrial fitness under chronic hypoxia-conditions that favor exhaustion rather than enhanced cytotoxicity. By depleting extracellular NAD+, CD38 diminishes glycolysis and mitochondrial oxidative phosphorylation in effector T cells, while sustaining regulatory cell persistence through FAO. Its enzymatic products, cyclic ADP-ribose (cADPR) and NAADP, further mobilize calcium fluxes that reinforce suppressive function. CD38 also integrates with hypoxia-driven pathways; in CD38+ Bregs, stabilization of HIF-1α and induction of FAO-related genes such as CPT1A and PPARα/γ promote angiogenesis, immune-evasion, and therapeutic resistance. Therapeutically, targeting CD38 with monoclonal-antibodies, small-molecule inhibitors, or combinations with checkpoint blockade and macrophage-reprogramming agents has shown promise. Such interventions reverse immune suppression, restore effector T cell activity, and enhance tumor responsiveness to immunotherapy. In summary, CD38 functions as both a metabolic regulator and an immunologic checkpoint, coordinating suppressive networks and shaping iNKT cell fate. These multifaceted roles position CD38 as a transformative target for next-generation immunotherapies.
    Keywords:  Breg; CD38; NAD; metabolism; tumor micro environment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2026.1745988
  10. Free Radic Biol Med. 2026 Feb 13. pii: S0891-5849(26)00130-9. [Epub ahead of print]247 448-468
    Mitochondrial TRPV1 exacerbates cognitive deficits in sepsis-associated encephalopathy by driving microglial metabolic reprogramming.
    Zhongmin Fan, Lixia Du, Lu Yin, Hao Liu, Mengyun Li, Jing Li, Fuhong Liu, Lin Yang, Jin Li, Qi Wang, You Wu, Hongwei Ma, Xijing Zhang.
      Transient receptor potential vanilloid 1 (TRPV1), a canonical non-selective cation channel predominantly expressed on the cellular membrane of peripheral sensory neurons, is responsible for perceiving physical and chemical stimuli. Accumulating evidence indicates TRPV1 expression in the central nervous system, the role of which remains elusive. Here, we demonstrate that, distinct from neurons or astrocytes, TRPV1 is distributed on the mitochondrial membrane of microglia in the hippocampus, mediating neurotoxic microglial responses during both acute and convalescent stages of sepsis by disrupting mitochondrial dynamics. During the pathogenesis of sepsis-associated encephalopathy (SAE), hippocampal microglia exhibit elevated TRPV1 expression concurrent with a pro-inflammatory state. Genetic ablation of TRPV1 or application of TRPV1 antagonist attenuates microglial inflammatory polarization and phagocytic dysfunction both in vivo and in vitro. This mitigates immoderate neuroinflammation and aberrant synaptic pruning, thereby reshaping synaptic plasticity and ameliorating cognitive deficits in SAE. Mechanistically, TRPV1 reprograms microglial phenotype with dysregulated capability for glycometabolism by affecting their mitochondrial function. Following LPS challenge, TRPV1 activation exacerbates mitochondrial damage and impairs ATP production in microglia, resulting in bioenergetic failure and excessive generation of mitochondrial reactive oxygen species (mtROS) and mtDNA. Conversely, TRPV1 depletion enhances oxidative phosphorylation capacity of microglia to counteract LPS toxicity. TRPV1 silencing further promotes the formation of cristae-deficient mitochondria, sustaining reductive proline biosynthesis and shifting microglia toward a protective pattern. Collectively, our findings suggest that TRPV1 compromises the metabolic reprogramming of microglia by perturbing mitochondrial dynamics, revealing a novel therapeutic target for SAE intervention.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.033
  11. Nat Commun. 2026 Feb 17.
    TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.
    Liming Meng, Jing Lv, Ying Yi, Xianchun Lan, Chenchao Yan, Lihang Zhu, Jie Yang, Wei Jiang.
      Cell fate determination is closely linked to metabolic state, yet how metabolic remodeling influences human pluripotent stem cells differentiation into three germ layers remains incompletely understood. Here, we reveal that definitive endoderm differentiation from human pluripotent stem cells requires a TGFβ-driven metabolic switch characterized by reduced lactate production and enhanced TCA cycle activity and oxidative phosphorylation, mediated by PDHB. Disruption of glucose utilization or pyruvate entry into the TCA cycle markedly impairs endoderm differentiation, whereas inhibition of lactate production enhances differentiation efficiency. Mechanistically, blockade of glucose metabolism or the TCA cycle reduces intracellular ATP levels, compromising the activity of BAF complex, an ATP-dependent chromatin remodeling complex centered on BRG1. This complex promotes chromatin accessibility and activates endodermal gene programs during differentiation. Together, these findings highlight metabolic reprogramming as a key regulator of human endoderm fate through ATP-dependent control of chromatin remodeling.
    DOI:  https://doi.org/10.1038/s41467-026-69510-0
  12. Cell Metab. 2026 Feb 19. pii: S1550-4131(26)00014-8. [Epub ahead of print]
    16-h fasting optimizes cancer immunotherapy in mice and humans.
    Sheng Chen, Tianyi Hu, Kaixiang Zhu, Yue Liu, Yidong Yang, Xiangyuan Li, Jinjie He, Wenyu Cui, Zhexu Chi, Weiwei Yu, Duojiao Chen, Zhen Wang, Jian Zhang, Ruya Sun, Dehang Yang, Siqi Dai, Qianzhou Yu, Quanquan Wang, Qian Xiao, Junbin Qian, Kefeng Ding, Di Wang.
      Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8+ T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8+ clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.
    Keywords:  diet intervention; immune checkpoint therapy; immunometabolism; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.015
  13. Br J Dermatol. 2026 Feb 18. pii: ljag060. [Epub ahead of print]
    Mitochondrial Metabolism in Neutrophils: Emerging Roles in Inflammatory Skin Diseases.
    Fangru Zhao, Yaoxing Guo, Yingdi Jiao, Wanting Zou, Yushuo Liu, Wanyu Li, Lingjie Gao, Wenyu Wan, Rui-Qun Qi.
      Neutrophils, the most abundant of the circulating leucocytes, play crucial roles in antimicrobial defence, tissue remodelling, and immune regulation. Traditionally regarded as predominantly glycolytic, relying on aerobic glycolysis (the Warburg effect) for rapid ATP generation, neutrophils are now recognised to possess broader metabolic flexibility. Emerging evidence has revealed their capacity for oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glutaminolysis. As a result, mitochondrial metabolism is dynamically reprogrammed during differentiation and activation. These metabolic shifts in mitochondria profoundly influence essential neutrophil functions, including extracellular trap (NET) formation, reactive oxygen species (ROS) generation, chemotaxis, and apoptosis. In inflammatory skin diseases, mitochondrial dysfunction amplifies pathological responses by enhancing ROS production and driving NETosis. Specifically, in conditions such as psoriasis, cutaneous lupus erythematosus, and Behçet's disease, neutrophil mitochondrial activity is markedly increased, and this increase correlates with disease activity and progression. Notably, mitochondrial ROS have emerged as critical mediators of inflammation, triggering pathways such as PAD4 (peptidylarginine deiminase type 4)-dependent NETosis, inflammasome activation, and proinflammatory cytokine release. Accordingly, therapeutic strategies targeting neutrophil mitochondrial pathways, including ROS scavengers, mitophagy inducers, and metabolic modulators, are gaining increasing attention as promising approaches to mitigate neutrophil-driven skin inflammation. In this review recent advances in understanding mitochondrial metabolism in neutrophils, with particular emphasis on the pathological roles and therapeutic potential of this metabolism as related to inflammatory skin disorders are described.
    DOI:  https://doi.org/10.1093/bjd/ljag060
  14. Curr Opin Biotechnol. 2026 Feb 19. pii: S0958-1669(26)00020-0. [Epub ahead of print]98 103455
    Muscle-immune metabolic crosstalk: shared pathways in cachexia and exercise.
    Stefanie Westermann, Bastian C Bennühr, Amy R Fumo, Maria Rohm, Karsten Hiller.
      Skeletal muscle and the immune system continuously exchange metabolites and signals that are essential for homeostasis. Disruption of this communication, such as during infection, inflammation, or cancer, triggers cachexia, a severe wasting syndrome characterized by altered amino acid flux, mitochondrial dysfunction, and systemic energy imbalance. By contrast, regular exercise activates overlapping pathways but directs them toward regeneration and hypertrophy, supported by controlled cytokine release and metabolite exchange. This review outlines the metabolic reprogramming that underlies muscle-immune crosstalk in cachexia and exercise, emphasizing how identical mediators, including interleukin-6, can promote either catabolism or adaptation depending on context. Understanding these shared yet divergent pathways opens avenues for therapeutic strategies that target metabolism and immune-metabolic communication.
    DOI:  https://doi.org/10.1016/j.copbio.2026.103455
  15. Cell Commun Signal. 2026 Feb 16.
    The metabolite α-ketoglutarate induces AIM2-dependent PANoptosis through demethylase TET2.
    Yi Li, Qing Tu, Chenchen Liu, Jiamin Ma, Yuwei Chen, Lin Wang, Ying Chen, Jinbao Li, Jiali Zhu, Yun Zou, Liangfang Yao.
      While α-ketoglutarate (α-KG) has traditionally been viewed as an anti-inflammatory metabolite, we uncover its paradoxical role in driving pathological inflammation during sepsis. This study reveals that α-KG, a tricarboxylic acid cycle (TCA) intermediate elevated in septic patients, drives inflammatory macrophage death through absent in melanoma 2 (AIM2) -PANoptosome activation. Using both clinical samples and experimental models, we demonstrate that the cell-permeable derivative dimethyl-α-ketoglutarate (DM-α-KG) exacerbates lipopolysaccharide (LPS)-induced tissue injury and cell death, whereas isocitrate dehydrogenase (IDH1) inhibition (IDH-305) or genetic ablation reduces α-KG levels and confers protection. Mechanistically, α-KG enhances the dioxygenase activity of Ten-eleven translocation 2 (TET2), promoting its binding to the AIM2 promoter, reducing methylation, and increasing AIM2 expression, thereby triggering PANoptosome assembly. The pathophysiological relevance of this axis was confirmed by attenuated inflammation following either TET inhibition (dimethyloxallyl glycine, DMOG) or AIM2 deletion. These findings establish α-KG as a critical immunometabolic checkpoint in sepsis that licenses inflammatory cell death via TET2-mediated epigenetic control of AIM2. Our work not only elucidates a novel α-KG/TET2/AIM2 signaling axis in sepsis pathogenesis but also highlights the therapeutic potential of targeting this pathway to modulate immune responses.
    Keywords:  AIM2; PANoptosis; Sepsis; TET2; α-ketoglutarate
    DOI:  https://doi.org/10.1186/s12964-026-02740-3
  16. Cell Immunol. 2026 Feb 06. pii: S0008-8749(26)00003-1. [Epub ahead of print]422 105063
    Thymidine induces macrophage M1 polarization in radiation-induced-lung-injury by ATF3/p38 pathway.
    Hao Fan, Xiangwei Ge, Xin Zhou, Pengfei Zhang, Yao Li, Zhijuan Du, Dingyuan Cheng, Yiheng Lu, Qiaowei Liu, Yi Hu.
      Radiation-induced lung injury (RILI) arises as a critical complication of thoracic radiotherapy, characterized by unresolved inflammation and macrophage-driven alveolar damage. While metabolic dysregulation post-radiation is implicated in macrophage polarization, the precise immunometabolic triggers remain undefined. Here, we uncover thymidine-a radiation-elevated metabolite released by injured lung epithelia-as an important regulator of M1 macrophage polarization through multi-omics dissection. Critically, thymidine dietary restriction or AAV9 (Adeno-associated Virus, AAV)-delivered ATF3 in murine models reversed this pathogenic loop, reducing M1 polarization and attenuating pneumonitis. Transcriptomic profiling of irradiated macrophages exposed to thymidine revealed ATF3 suppression and MAPK hyperactivation, establishing a feedforward ATF3/p38 axis that induces epithelial injury. ATF3 overexpression or pharmacological p38 inhibition (SB203580) reversed thymidine's pro-inflammatory reprogramming in vitro. These findings position the thymidine-ATF3/p38 circuit as a lynchpin of radiation-associated immunopathology and advocate metabolic or transcriptional intervention as a viable adjunct to conventional radioprotection strategies.
    Keywords:  ATF3; Macrophage; Radiation-induced lung injury; Thymidine; Transcriptomics
    DOI:  https://doi.org/10.1016/j.cellimm.2026.105063
  17. Adv Sci (Weinh). 2026 Feb 16. e20665
    Nanotherapeutic Macrophage-Neuro Reprogramming Through Immunometabolic Crosstalk Mitigates Sepsis-Induced Lung Injury and Neurologic Damage.
    Wenhui Wang, Yongrui Hai, Xintong Lu, Ye Chen, Bingjie Zhang, Renming Fan, Jiarui Dou, Jiaxin Yan, Shuo Fu, Wen Zhang, Junke Song, Gaofei Wei.
      Sepsis remains a leading cause of mortality in intensive care units, with its associated organ dysfunction primarily driven by uncontrolled inflammation and neuroimmune dysregulation. Among affected organs, the lung is particularly vulnerable, with injury involving both immune-mediated tissue damage and inflammation-induced neuronal impairment. Yet, whether coordinated targeting of immune and neural compartments can achieve synergistic and durable therapeutic benefits remains unknown. Here, we report a rationally engineered, dual-functional, enzyme-responsive nanoplatform (SJNPs) that co-delivers the glutamate production inhibitor JHU083 and the neuroprotective spermine (Spm) to reprogram macrophage-neuron immunometabolic interactions. SJNPs suppressed pro-inflammatory, M1-associated macrophage activation while promoting M2 polarization, which in turn drove robust secretion of the neurotrophic factor nerve growth factor (NGF) and preserved pulmonary neuronal integrity. Mechanistically, inhibition of glutamate metabolism reprogrammed macrophage polarization and activated NGF-mediated neurotrophic signaling, establishing NGF as a key mediator linking immune modulation to neural protection. In murine sepsis models, SJNPs attenuated systemic cytokine storms, mitigated alveolar damage, alleviated neurological injury, and improved survival. This study identifies macrophage-neuron immunometabolic crosstalk as a previously underexplored therapeutic target for septic lung injury characterized by neuronal damage, and establishes metabolic reprogramming of macrophages as a promising strategy for integrated immunomodulatory and neuroprotective therapy in sepsis.
    Keywords:  lung injury; macrophage‐neuro reprogramming; nanotherapy; neuronal repair; sepsis
    DOI:  https://doi.org/10.1002/advs.202520665
  18. J Crit Care Med (Targu Mures). 2026 Jan;12(1): 64-77
    Impaired peripheral mononuclear cell metabolism in patients at risk of developing sepsis: A cohort study.
    Velma Herwanto, Ya Wang, Maryam Shojaei, Alamgir Khan, Kevin Lai, Amith Shetty, Stephen Huang, Tracy Chew, Sally Teoh, Marek Nalos, Mandira Chakraborty, Anthony S McLean, Benjamin M P Tang.
       Introduction: Dysregulated immune responses are central to progression of sepsis and closely associated with impaired cellular metabolism. However, most existing studies have focused on late-stage sepsis, leaving metabolic alterations during earlier stages of infection poorly characterised. This study aimed to determine whether immune cell metabolic impairment is already present during uncomplicated infection, prior to the development of sepsis, and to evaluate its potential as an early indicator of immune dysfunction and risk of progression.
    Materials and methods: Forty patients with sepsis (fulfilling Sepsis-3 criteria) and 27 patients with uncomplicated infection were recruited from the emergency department along with 20 healthy volunteers. Whole blood samples were collected to assess gene expression, cytokine levels, and cellular metabolic functions, including mitochondrial respiration, oxidative stress, and apoptosis in immune cells.
    Results: Mitochondrial respiration was significantly impaired in immune cells from both uncomplicated infection and sepsis patients compared with healthy controls (p < 0.05), with more pronounced impairment in established sepsis. Downregulation of BCL2 and BBC3 gene expression was observed in sepsis patients (p < 0.05), but not in uncomplicated infection, potentially contributing to differences in the severity of metabolic impairment. Impaired mitochondrial respiration was significantly associated with increased mitochondrial oxidative stress (p < 0.05), which was elevated in uncomplicated infection and further increased in sepsis. Oxidative stress levels also correlated with tumour necrosis factor-α (r = 0.330) and the expression of CYCS, TP53, SLC25A24, and TSPO (rs = -0.4926, -0.4422, 0.4382, and 0.4835, respectively). Despite these metabolic alterations, no significant differences in immune cell apoptosis were observed between uncomplicated infection and sepsis patients.
    Conclusions: Immune cell metabolic dysfunction is present in patients with uncomplicated infection before the clinical onset of sepsis. Early mitochondrial dysfunction and oxidative stress may represent promising targets for further investigation as early biomarkers of immune dysfunction and sepsis risk.
    Keywords:  cellular metabolism; oxidative stress; peripheral blood mononuclear cells; sepsis; uncomplicated infection
    DOI:  https://doi.org/10.2478/jccm-2026-0010
  19. Brain Res. 2026 Feb 15. pii: S0006-8993(26)00075-2. [Epub ahead of print] 150217
    Differential effects of the microbial metabolite acetate on murine microglia in in vitro sepsis and trauma models.
    Qin Yang, Amanda Dave, Robert S B Clark, Hülya Bayır, Dennis Simon.
       BACKGROUND: Short chain fatty acids (SCFAs) including acetate, produced by gut microbiota, are key signaling molecules and impact microglial maturation and metabolism. Microglia play a dual role in maintaining homeostasis and neuroinflammation when activated. Despite evidence suggesting acetate's anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated microglia, no studies have examined its impact on mechanically stretched microglia, a model for traumatic brain injury (TBI).
    METHODS: We investigated the effects of acetate at physiological doses and a frequently used higher experimental concentration in in vitro sepsis and TBI models in EOC20 mouse microglial cells. The impact of acetate was assessed using assays of cell death, cytokine production and inducible nitric oxide synthase (iNOS) expression.
    RESULTS: In LPS-stimulated microglia, acetate did not reduce pro-inflammatory cytokine secretion or intracellular iNOS expression. Surprisingly, in moderate mechanically stretched microglia, physiological doses of acetate (100 µM and 300 µM) significantly reduced tumor necrosis factor-alpha (TNFα) production without affecting cell viability. Additionally, stretch injury increased nuclear localization of NF-κB that was attenuated with physiological doses of sodium acetate.
    CONCLUSION: Acetate exerted anti-inflammatory effects in microglial stretch but not LPS stimulation. Further studies are warranted to elucidate acetate's regulatory role in sterile etiologies of neuroinflammation and its therapeutic potential for TBI.
    Keywords:  Acetate; Microglia; Neuroinflammation; Sepsis; Traumatic Brain Injury
    DOI:  https://doi.org/10.1016/j.brainres.2026.150217
  20. iScience. 2026 Feb 20. 29(2): 114691
    HHEX-PRKAR2B axis-mediated PKA activation drives glucose metabolism-dependent progression of pancreatic ductal adenocarcinoma.
    Junxiang Wen, Qiuchen Li, Shuxiang Xu, Wenjun Lu, Fei Wu, Jiatao Lou, Lin Wang.
      By virtue of its function as a key metabolic regulator, malignant transformation in the pancreas not only confers high aggressiveness but also disrupts systemic metabolism. However, the causal relationship between metabolic reprogramming and the progression of pancreatic ductal adenocarcinoma (PDAC) remains incompletely understood. This study identifies aberrant protein kinase A (PKA) activation in PDAC, correlating with poor prognosis. Mechanistically, downregulation of the transcription factor hematopoietically expressed homeobox (HHEX) represses protein kinase cAMP-dependent type II regulatory subunit beta (PRKAR2B), relieving inhibition on PKA catalytic activity. A high-glucose microenvironment promotes cAMP production, further activating PKA, which then enhances glycolysis via specific upregulation of hexokinase 2 (HK2). In vivo, high glucose synergized with PKA activation to promote metastasis, whereas glycolysis inhibition blocked new metastases. Thus, HHEX-PRKAR2B-mediated PKA activation is a critical hub for PDAC progression, modulated by glucose and reinforcing glycolysis via HK2, revealing novel therapeutic targets for metabolic intervention.
    Keywords:  Cancer; Human metabolism; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2026.114691
  21. J Dairy Sci. 2026 Feb 14. pii: S0022-0302(26)00109-8. [Epub ahead of print]
    Effects of a metabolizable protein supply on metabolic function of CD4+ T lymphocytes in mid-lactation dairy cows.
    U Arshad, T Fernandez-Wallace, R Fukumori, S J Johnson, S J Kendall, L R Cangiano, F Sun, V M R Malacco, I Brown-Crowder, H M White.
      The objective of the present experiment was to determine the effects of MP supply on metabolic function of nonactivated (NA) and activated (AC) CD4+ T lymphocytes in mid-lactation dairy cows. Thirty-two multiparous Holstein cows with a mean ± SD lactation of 3.28 ± 0.99, milk yield 51.6 ± 6.1 kg/d, and milk protein 3.38% ± 0.47% were enrolled at 86 ± 18 DIM in a barn equipped with 16 bin feeders. Cows and bins (16 cows/8 bins per treatment) were randomly assigned to treatments. All cows were fed the same herd diet (MP = 3,006 g/d) during a 2-wk adaptation period before enrollment and a 1-wk covariate period following enrollment to allow acclimation to the bins and collect baseline measurements. Following the covariate period, cows received 1 of 2 treatments for 12 wk: diets formulated to be either adequate in MP supply (MPA; MP = 3,111 g/d) or MP inadequate (MPI; MP = 2,983 g/d). The difference in MP supply was achieved by including porcine blood meal in the MPA, whereas it was omitted in the MPI treatment. Blood was collected during wk 11 at 173 ± 18 DIM to isolate peripheral blood mononuclear cells followed by magnetic isolation of CD4+ T lymphocytes using bovine-specific monoclonal antibodies. Isolated CD4+ T lymphocytes from each cow were split into 2 tubes and randomly assigned to incubate in an assay medium (250 µL) or with a combination of phorbol 12-myristate 13-acetate (100 µL, 20 ng/mL) and ionomycin (10 µL, 1 µg/mL) for 2 h at 37 °C to evaluate metabolic function under metabolically NA and AC states, respectively, using an extracellular flux analyzer. Mitochondrial and glycolytic functional kinetics were recorded for NA and AC CD4+ T lymphocytes based on real-time measurement of oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and proton efflux rate (PER) under basal conditions and in response to complex V inhibitor (oligomycin A), a protonophore uncoupler (BAM 15), and complex I and complex III inhibitors (rotenone and antimycin A). Cows fed the MPI diet exhibited lower OCR leading to a reduced maximal respiration compared with MPA-fed cows. Feeding MPI diet decreased maximal respiration in both metabolically NA and AC CD4+ T lymphocytes. Feeding MPI diet decreased sparing respiratory capacity in both metabolically NA and AC CD4+ T lymphocytes. During the T-cell persistence assay, an interaction between diet and time within the assay was observed for ECAR and PER, indicating that CD4+ T cells from cows fed MPI showed a progressive decrease in aerobic glycolysis over the 1.50 to 73.0 min measurement period, whereas CD4+ T cells from cows fed MPA maintained higher glycolytic activity. Mitochondrial, glycolytic, and total ATP production rates were unaffected by MP supply; however, glycolytic ATP production rates were greater in AC than NA CD4+ T lymphocytes. These results indicate that suboptimal supply of MP reduced the metabolic fitness and persistence of CD4+ T lymphocytes, which might compromise immune responses during nutrient imbalance, such as early lactation or health challenges.
    Keywords:  T lymphocytes; amino acids; dairy cow; metabolism
    DOI:  https://doi.org/10.3168/jds.2025-27476
  22. Cell Rep. 2026 Feb 12. pii: S2211-1247(26)00020-3. [Epub ahead of print]45(2): 116942
    Hepatocyte PLAGL2 deficiency alleviates MASH through MYD88-licensed inactivation of inflammasome.
    Ran Duan, Xinyi Wang, Qi Wang, Xue Zhou, Sijia Gao, Yanan Sun, Qi Feng, Zhilin Li, Zhisen Yang, Jingwen Ding, Zhen Chen, Jingjing Duan, Yong Yang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a pressing global health concern. The transition to metabolic dysfunction-associated steatohepatitis (MASH) is characterized by pyroptosis-driven inflammation. However, the spatiotemporal regulation of this process remains elusive. Here, we identify PLAG1-like zinc finger 2 (PLAGL2) as a potent amplifier of pyroptotic signaling and a key driver accelerating MASH progression. Mechanistically, PLAGL2 sensitizes hepatocytes to pyroptosis by transcriptionally activating Myeloid Differentiation Primary Response 88 (MYD88), thereby facilitating inflammasome assembly. Hepatocyte-specific Plagl2 knockout ameliorates MASH in multiple dietary MASLD models. This effect occurs through the attenuation of hepatocyte pyroptosis, which restores hepatocyte identity and stabilizes metabolic homeostasis. The pyroptotic release induces macrophage chemotaxis and activation. These macrophages exhibit a phenotype characteristic of NASH-associated macrophages (NAMs) via JAK-STAT pathway-dependent activation. Interleukin-1β (IL-1β) released by pyroptotic hepatocytes functions as the key mediator activating JAK-STAT signaling. PLAGL2 might be a potential therapeutic target for MASH management.
    Keywords:  CP: metabolism; IL-1β; JAK-STAT signaling pathway; MASH; MASLD; MYD88; NAMs; PLAGL2; inflammasome; metabolism; pyroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2026.116942
  23. Cell Commun Signal. 2026 Feb 16.
    SLC1A5-mediated kynurenine metabolism drives AHR-FANCD2 axis to remodel chromatin and induce T cell exhaustion in lung adenocarcinoma.
    Yifei Zhu, Haoji Wang, Yanxi Yao, Hongdou Ding, Li Xu, Xinnan Xu.
       BACKGROUND: Kynurenine, a byproduct of tryptophan breakdown, is linked to immune suppression during cancer development. This study explores the involvement of the amino acid transporter solute carrier family 1 member 5 (SLC1A5) in kynurenine-mediated T cell exhaustion in LUAD and delves into its functional mechanism.
    METHODS: RNA-sequencing analysis was employed to identify transcriptome differences between T progenitor and terminal exhausted T cells (TPEX vs. TEX). The SLC1A5 expression was detected in T cells following L-kynurenine (L-ky) treatment. Mouse LUAD cells LLC were implanted into wild-type (WT), SLC1A5 knockout (SLC1A5-/-), SLC1A5flox/flox (SLC1A5fl/fl), or CD8⁺ T cell-specific SLC1A5 conditional knockout (SLC1A5cko) mice, followed by L-ky treatment, to examine the effect of SLC1A5cko on L-ky-mediated tumorigenesis and T cell exhaustion. Interacting proteins of AHR, a core transcription factor in the kynurenine pathway, were explored by liquid chromatography/mass spectrometry and bioinformatics.
    RESULTS: SLC1A5 is upregulated in TEX, and its expression in CD8+ T cells was increased by L-ky treatment dose-dependently. The tumorigenic activity of LLC cells, under L-ky treatment stimulation, was suppressed in both SLC1A5-/- and SLC1A5cko mice, accompanied by increased T cell activity within tumors. CD8+ T cells extracted from SLC1A5cko mice also showed reduced L-ky uptake and increased cytotoxicity in vitro. Mechanistically, AHR recruits the chromatin modifying enzyme FANCD2 to enhance SLC1A5 expression, promoting chromatin accessibility in T cells and cell exhaustion.
    CONCLUSION: This study suggests that SLC1A5 is upregulated in TEX, which modulates kynurenine metabolism and induces T cell exhaustion through the AHR-FANCD2 axis-mediated chromatin remodeling.
    Keywords:  AHR-FANCD2 interaction; CD8+ T cell exhaustion; Kynurenine; LUAD; SLC1A5
    DOI:  https://doi.org/10.1186/s12964-026-02732-3
  24. Cell Rep. 2026 Feb 18. pii: S2211-1247(26)00079-3. [Epub ahead of print]45(3): 117001
    Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair.
    Yiting Xu, Maria Fernanda Forni, Abigail Benvie, Nicole Castano, Diane King, Qiushi Sun, Stephan Siebel, Van Anh Tran, Richard G Kibbey, Kathryn Miller-Jensen, Valerie Horsley.
      Tissue repair requires inflammation resolution, but the molecular mechanisms involved in vivo are not fully understood. Here, we show that glutamine metabolism suppresses neutrophil recruitment to abrogate inflammation and drive skin wound repair. Integrated metabolomic and transcriptional profiling identified glutamine metabolism as enriched in macrophages during resolution. Dietary depletion studies and conditional deletion of glutaminase, the enzyme essential for glutamine metabolism, in mouse myeloid cells revealed that macrophages suppress neutrophil recruitment genes during tissue resolution to promote repair. We also found that these genes are upregulated in macrophages in patients with diabetes. Mechanistically, our data reveal that glutamine metabolism in macrophages induces suppressive chromatin remodeling of neutrophil recruitment genes, including Ccl ligands, during resolution of inflammation. These findings highlight the ability of specific metabolites to control cellular communication during tissue repair, with glutamine specifically to suppress neutrophil recruitment to advance inflammation resolution.
    Keywords:  CP: immunology; CP: metabolism; glutamine; immunology; inflammation; macrophages; metabolism; neutrophils; resolution; skin; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.celrep.2026.117001
  25. Allergol Int. 2026 Feb 17. pii: S1323-8930(26)00013-4. [Epub ahead of print]
    Palmitic acid aggravates airway inflammation in asthma through induction of chemokines expression and metabolomic changes in epithelial cells.
    Yue Wu, Jialu Ma, Cuiting Shan, Wenguan Li, Qingge Chen, Xiayi Miao, Xiongbiao Wang, Zhenhua Ni.
       BACKGROUND: Elevated palmitic acid (PA) levels have been associated with increased asthma risk, but its pathogenic role remains unclear. This study aims to investigate the relationship between serum PA levels and asthma severity and explores the pro-inflammatory effects of PA on airway epithelial cells and the underlying mechanism.
    METHODS: Serum samples were collected from asthmatic patients, and the concentrations of PA were quantified by ELISA. An HDM-induced mouse model of asthma was established and treated with PA. RNA sequencing and metabolomic profiling were used to identify PA-responsive genes and metabolites in airway epithelial cells, and key targets were validated by qPCR, Western blot, and ELISA.
    RESULTS: We found that elevated serum PA levels correlated with worse lung function, higher blood neutrophil percentages, and increased steroid needs in asthma patients. In a murine asthma model, PA exacerbated airway inflammation, hyperresponsiveness, and neutrophil infiltration. In vitro, PA stimulated airway epithelial cells to express high levels of neutrophil chemokines (CXCL2/CXCL8) via Src-ERK pathway activation. In addition, metabolomic analyses revealed that PA triggered pro-inflammatory metabolic reprogramming in airway epithelial cells, characterized by dysregulation of acylcarnitine/fatty acid β-oxidation, sphingolipid signaling, and arachidonic acid metabolism. Using of CD36 inhibitors significantly suppressed pro-inflammatory chemokines expression, Src/ERK signaling activation, and metabolic reprogramming in airway epithelial cells, as well as in the asthma mouse model.
    CONCLUSIONS: our study demonstrated elevated PA exacerbates airway inflammation in asthma by inducing neutrophil chemokine expression and metabolic reprogramming in airway epithelial cells, providing novel insights into the pathophysiology of metabolically dysregulated asthma.
    Keywords:  Asthma; Chemokines; Metabolomic; Neutrophil; Palmitic acid
    DOI:  https://doi.org/10.1016/j.alit.2026.01.004
  26. World J Gastroenterol. 2026 Feb 14. 32(6): 113010
    Effects and mechanism of Bifidobacterium on intestinal inflammation resulting from deoxycholic acid-induced M1 polarization of macrophages.
    Peng-Chun Yang, Chun-Yan Xiao, Jing Wang, Cai-Hua Yan, Qi-Yi Li, Shi-Yu Li, Jian Li, Li-Jing Zhang, Chi-Bing Dai.
       BACKGROUND: A high-fat diet (HFD) can cause systemic low-grade inflammation, metabolic and inflammatory diseases, and alter the composition of intestinal microbiota. Although probiotics mitigate intestinal inflammation, it is still unclear whether they can directly inhibit the production of deoxycholic acid (DCA) to prevent or alleviate intestinal inflammation.
    AIM: To investigate changes in intestinal flora, fecal DCA levels, and cytokine profiles.
    METHODS: Vancomycin was administered to significantly reduce the population of intestinal gram-positive bacteria, which helped in reducing the fecal DCA levels. Recruitment of pro-inflammatory macrophages, polarization of macrophages, and the inflammation associated with the intestinal flora of the HFD animal model were assessed. Their expression levels were analyzed through real-time polymerase chain reaction, immunofluorescence staining, liquid chromatography-mass spectrometry, and 16S rRNA high-throughput sequencing.
    RESULTS: HFD or DCA promotes the infiltration of colon macrophages, causing their polarization toward the M1 phenotype. This polarization can be inhibited by both vancomycin and Bifidoba cterium. Bifidobacterium enhances the species richness and uniformity of the intestinal microbiota in HFD mice; however, it does not improve these parameters in the presence of vancomycin. Bifidobacterium also does not increase the abundance of microbiota in HFD-fed or HFD-and-vancomycin-treated mice. HFD alters the relative abundance of intestinal microbiota at the phylum and genus levels. Bifidobacterium or vancomycin can partially mitigate these changes.
    CONCLUSION: Bifidobacterium can inhibit HFD-induced intestinal inflammation or that resulting from DCA-induced M1 polarization of macrophages. It may also regulate bile acid levels and target cholesterol metabolism pathways, which may serve as potential therapeutic strategies for HFD-associated colitis.
    Keywords:  Bifidobacterium; Deoxycholic acid; High-fat diet; Intestinal inflammation; Macrophage polarization; Microbiota
    DOI:  https://doi.org/10.3748/wjg.v32.i6.113010
  27. FASEB J. 2026 Feb 28. 40(4): e71541
    Aging-Driven Inter-Organ Crosstalk in Postmenopausal Osteoporosis: From Immunometabolic Drift to Multisystem Frailty.
    Xianlin Rao, Xiaoyu Cai.
      Postmenopausal osteoporosis (PMOP) is increasingly recognized as an aging-associated, multisystem vulnerability state in which estrogen withdrawal amplifies immune and metabolic drift across bone marrow, muscle, adipose tissue, the gut, vasculature, and neural circuits. We synthesize evidence that key control nodes including RANKL-RANK-OPG imbalance, Th17/Treg disequilibrium, loss of regulatory B cell IL-10 restraint, inflammatory myeloid polarization, and expansion of bone marrow adipose tissue encode persistent osteoclastogenic tone and impaired formation. We map how microbiota-derived metabolites and barrier dysfunction tune osteoimmunity, and how exercise-responsive myokines and metabolites can counteract drift. Extracellular vesicles emerge as bidirectional couriers that propagate senescence and inflammation or support repair, but clinical translation requires ISEV-aligned methodological rigor and robust manufacturing, biodistribution, and safety frameworks. Building on these inter-organ axes, we propose a phenotype-aware "network reset" roadmap that integrates antifracture therapy with functional restoration, falls prevention, cardiometabolic risk control, and inflammatory monitoring, prioritizing composite endpoints and real-world implementation infrastructure. This systems framing shifts PMOP management from bone-only correction toward coordinated restoration of whole-body resilience.
    Keywords:  extracellular vesicles; frailty; immunometabolism; interorgan crosstalk; osteoimmunology; postmenopausal osteoporosis
    DOI:  https://doi.org/10.1096/fj.202505069R
  28. JCI Insight. 2026 Feb 19. pii: e196246. [Epub ahead of print]
    GATA2 controls alveolar macrophage inflammatory gene expression and metabolic function.
    Morgan Jackson-Strong, Satarupa Ganguly, Aaron Francis, Flavia Rago, Jitendra Kanshana, Brandon A Michalides, Lihong Teng, Omkar S Betsur, Sonia Kruszelnicki, Karsen E Shoger, Aaron Kim, Kay Bajpai, Amina Suleyman, Abigail Sekyere, Mika Hara, Varsha Sriram, Alok Kumar, Greg M Delgoffe, Niranjana Natarajan, John F Alcorn, Alison B Kohan, Rachel A Gottschalk.
      Alveolar macrophages (AMs) catabolize lipid-rich pulmonary surfactant to support gas exchange and have anti-inflammatory programming to limit tissue damage in response to minor challenges. GATA transcription factors (TFs) shape immune cell fates and GATA2 is expressed in a lung-specific manner in macrophages. GATA2 mutations and lung macrophage downregulation of GATA2 have been associated with chronic pulmonary pathologies in humans, but the role of GATA2 in coordinating AM function is not well defined. Using mice with myeloid-specific deletion of the GATA2 DNA binding C-terminal zinc finger domain, we show that GATA2 deficiency promotes enhanced inflammatory gene expression and metabolic dysfunction in AMs in response to type 2 stimuli. While homeostatic functions of AMs remain largely intact, GATA2 deficiency increases expression of type 2 response genes during IL-33-induced inflammation. Coincident with GATA2-dependent expression of genes in metabolic pathways, seahorse metabolic flux analysis indicates that AM metabolism is compromised in the absence of GATA2. AM GATA2-dependent gene networks are enriched for targets of TFs previously demonstrated to interact with GATA2 in other cellular contexts, including PU.1, PPARγ, and other regulators of AM function. Our data suggest that GATA2 modulates AM metabolic and transcriptomic programming to restrain responses and maintain AM identity during inflammation.
    Keywords:  Immunology; Macrophages; Pulmonology; Transcription
    DOI:  https://doi.org/10.1172/jci.insight.196246
  29. Cell Metab. 2026 Feb 18. pii: S1550-4131(26)00015-X. [Epub ahead of print]
    Lipid droplet-induced T cell death sustains autoimmune tissue inflammation.
    Jitendra Kumar, Yoshinori Takashima, Jose Morales, Brandon Wong, Lina Werner, Isabel N Goronzy, Selene Rubino, Robert T Trousdale, Gerald J Berry, Jörg J Goronzy, Cornelia M Weyand.
      Autoimmunity leading to rheumatoid arthritis (RA) involves CD4+ T cell recruitment into synovial tissue. However, metabolic conditions supporting the survival and pro-inflammatory effector functions of these tissue-invading T cells remain poorly understood. Lipidomic analysis identified the inflamed synovium as a lipid-rich environment. In functional studies, administration of the free fatty acid oleic acid exacerbated synovitis. Tissue-invading CD4+ T cells responded to fatty acid with rapid cell lysis, releasing cytoplasmic and nuclear content into the extracellular space. This T cell lytic death required sequestration of the pore-forming molecule gasdermin D and the acyltransferase zDHHC5 to lipid droplets, which translocated to the plasma membrane to trigger membrane rupture and pyroptotic cell death. Targeting lipid droplet formation in CD4+ T cells through perilipin-2 knockdown or inhibiting gasdermin activation by blocking protein acylation proved highly effective in suppressing synovitis. Thus, autoimmune CD4+ T cells lack metabolic resilience, are primed to undergo pyroptosis in lipid-rich environments, and deliver pro-inflammatory cargo to surrounding tissue.
    Keywords:  T cell; autoimmune disease; gasdermin D; inflammation; lipid droplet; protein S-acylation; pyroptosis
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.014
  30. J Proteomics. 2026 Feb 13. pii: S1874-3919(26)00029-1. [Epub ahead of print]327 105626
    The acetylation status and metabolic characterization of the HBV-induced macrophages.
    Zihao Sun, Shaoke Wu, Yongyou Luo, Ting Su, Yuerong Xiong, Jiaxin Bei.
      Hepatitis B virus (HBV) infection drives macrophages toward an M2-polarized phenotype, contributing to immune evasion and viral persistence. However, the underlying mechanisms involving post-translational modifications and metabolic reprogramming remain poorly understood. This study integrates multi-omics and functional analyses to characterize lysine acetylation and lipid metabolic alterations in HBV-induced macrophages. In vitro and in vivo models confirmed HBV-promoted M2 polarization, marked by elevated CD206/CD163 expression and anti-inflammatory cytokine secretion. Acetylomic profiling identified 450 modified proteins and 432 quantifiable sites, with significant upregulation of peptides associated with chromatin remodeling and metabolic regulation. Lipidomic analysis revealed extensive reprogramming, including downregulation of phosphatidylcholines, phosphatidylinositols, and oxidized lipids, and upregulation of specific sphingolipids and triacylglycerols. Functional enrichment linked acetylated proteins to lipid metabolic processes and oxidative stress response. These findings suggest that HBV remodels macrophage acetylation and lipid metabolism, which may contribute to the development of an immunosuppressive microenvironment, providing new insights into potential therapeutic strategies targeting acetylation or lipid pathways in chronic HBV infection. SIGNIFICANCE: This study systematically characterizes lysine acetylation profiles and lipid metabolic reprogramming in HBV-induced macrophages using multi-omics and functional assays. It identifies HBV-driven acetylation changes in 450 proteins, which target chromatin remodeling and metabolic regulation, as well as distinct lipid alterations including reduced lipid storage and modified glycerophospholipids and sphingolipids. The study reveals that crosstalk between acetylation and lipid metabolism fosters an immunosuppressive microenvironment that supports HBV persistence. These findings fill critical gaps in understanding the mechanisms of HBV-induced macrophage polarization and provide novel therapeutic targets for chronic HBV infection.
    Keywords:  HBV; Lipid metabolic reprogramming; Lysine acetylation; Macrophages; Multi-omics
    DOI:  https://doi.org/10.1016/j.jprot.2026.105626
  31. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2536314123
    Regulatory T cells safeguard liver health during metabolic-associated steatohepatitis.
    Bola S Hanna, P Kent Langston, Miguel Marin-Rodero, Ricardo N Ramirez, Min Wan, Christophe Benoist, Diane Mathis.
      Metabolic-dysfunction-associated steatohepatitis (MASH) is a chronic liver disease driven by the confluence of metabolic stress and destructive inflammation. The immunoregulatory mechanisms that temper this process remain poorly understood. Multipronged data on a complementary pair of murine MASH models and published single-cell RNA-sequencing datasets from MASH patients revealed a critical protective role for Foxp3+CD4+ regulatory T cells (Tregs) in MASH. Tregs progressively accumulated in diseased livers, adopting an activated, nonlymphoid-tissue phenotype marked by expression of the transcription factor Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) as well as a reparative transcriptional program. Punctual ablation of Tregs during established MASH unleashed a catastrophic inflammatory cascade, including exaggerated T-helper (Th)1, Th2, and Th17 responses, expansion of a pathogenic CD8+ T cell population, and hepatocellular injury. Concomitantly, Treg deficiency disrupted key metabolic pathways in the liver, accelerating disease progression. These findings establish Tregs as nonredundant custodians of both immunologic and metabolic homeostasis in the liver, highlighting their promise as targets for temporally tuned immunoregulatory therapies in metabolic liver disease.
    Keywords:  MASH; Tregs; liver; regulatory T cells; steatohepatitis
    DOI:  https://doi.org/10.1073/pnas.2536314123
  32. Eur J Med Res. 2026 Feb 18.
    Glycolysis and NLRP3 inflammasome activation in diseases.
    Weijia Xu, Xiaowen Zhu, Qinghong Zhang, Qi Pang, Aihua Zhang.
      To adapt to environmental changes or external stimuli, cells often undergo a shift in the way they metabolize energy, a process known as metabolic reprogramming. Glycolytic reprogramming has emerged as a central regulatory node among the overall adaptive rewiring of energy metabolism and represents a fundamental biological strategy for maintaining functional plasticity and determining cell fate. The NLRP3 inflammasome is a multiprotein complex that drives pyroptosis-a programmed cell death mode characterized by cell swelling, plasma membrane perforation, and proinflammatory cytokine release (Zhong et al. in Int J Biol Sci. 19:242-257, 2023; Lin et al. in Front Immunol 11:580593, 2020; Hoque et al. in Gastroenterology 146:1763-1774, 2014; Lee et al. in Cell Death Differ 31:1679-1694, 2024; You et al. in Ecotoxicol Environ Saf 283:116952, 2024). However, evidence reveals that glycolytic reprogramming and NLRP3 inflammasome activation engage in reciprocal regulation across diverse cell types and disease states. This review synthesizes recent advances elucidating how glycolytic enzymes (e.g., HKs and PKM2) and metabolic intermediates (e.g., lactate) orchestrate NLRP3 activation. By bridging metabolic control with inflammatory signaling, these findings establish the glycolysis-NLRP3 axis as a promising therapeutic target for modulating cellular fate decisions in inflammatory pathologies.
    Keywords:  Glycolysis; Glycolytic enzymes; NLRP3 inflammasome
    DOI:  https://doi.org/10.1186/s40001-026-03968-y
  33. EMBO Mol Med. 2026 Feb 16.
    Cis-aconitate therapy protects against influenza mortality by dual targeting of viral polymerase and ERK/AKT/NF-κB signaling.
    Adeline Cezard, Déborah Brea-Diakite, Virginie Vasseur, Alan Wacquiez, Loic Gonzalez, Ronan Le Goffic, Bruno Da Costa, Ambre Tinard, Delphine Fouquenet, Séverine Heumel, Arnaud Machelart, Eik Hoffmann, Priscille Brodin, François Trottein, Cyrille Mathieu, Lola Canus, Florentine Jacolin, Pierre-Olivier Vidalain, Laure Perrin-Cocon, Vincent Lotteau, Julien Burlaud-Gaillard, Dominique Tertigas, Michael G Surette, Antoine Legras, Damien Sizaret, Thomas Baranek, Christophe Paget, Antoine Guillon, Mustapha Si-Tahar.
      The influenza virus poses a significant global health challenge, causing approximately 500,000 deaths annually. Its ability to evade antiviral treatments and vaccine-induced immunity underscores the need for novel therapeutic approaches. Our study identifies cis-aconitate (cis-aco), a mitochondria-derived metabolite, as a potent dual-action agent against influenza, independently of its metabolic derivative, itaconate. Cis-aco impairs viral polymerase activity, resulting in decreased viral mRNA expression and protein synthesis, as observed for the influenza A/Scotland/20/74 (H3N2) strain. This antiviral effect was further confirmed across multiple influenza A and B strains, as well as in ex vivo human airway and lung organotypic models. Beyond its antiviral properties, cis-aco exhibits potent anti-inflammatory effects, disrupting key inflammatory cascades and reducing the secretion of inflammatory mediators. In a mouse model of influenza pneumonia, cis-aco mitigates viral replication, inflammation, and immune cell activation, significantly improving survival. Notably, its efficacy persists even when administered at later stages of infection, when oseltamivir/Tamiflu® is no longer effective. These findings position cis-aco as a promising influenza treatment, combining antiviral and anti-inflammatory benefits within a clinically relevant timeframe.
    Keywords:  Anti-inflammatory; Antiviral; Influenza Virus; Pneumonia; Therapy
    DOI:  https://doi.org/10.1038/s44321-026-00379-8
  34. Front Allergy. 2025 ;6 1700350
    A shared metabolic-immune axis links local and systemic inflammation in chronic rhinosinusitis with comorbid asthma.
    Xin Peng, Zhili Li, Yibo Liang, Guimin Zhang.
       Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) comorbid with asthma (CRSwA) represents a severe "unified airway" phenotype, yet the metabolic mechanisms linking upper and lower airway inflammation remain unclear. This study aimed to identify shared metabolic signatures connecting local pathology with systemic circulation by comparing the metabolic profiles of nasal polyp tissue and serum.
    Methods: We performed an integrated analysis using non-targeted metabolomics and transcriptomics on paired nasal polyp tissue and serum samples from 22 CRSwA patients and 40 non-asthmatic CRSwNP patients to identify differential metabolites and explore their association with the immune microenvironment.
    Results: CRSwA patients exhibited distinct metabolic signatures dominated by lipids and their derivatives in both tissue and serum. An analysis of the metabolome shared between compartments revealed a weak but significant positive correlation in metabolic fold changes, suggesting a subtle systemic link to the local inflammation. This shared metabolic profile was strongly associated with a local Th2-polarized immune microenvironment. This shared profile was strongly associated with a local Th2-polarized immune microenvironment, where key metabolites (e.g., Resolvin D2, Lipoxin A4) correlated significantly with the abundance of M2 macrophages and eosinophils. Furthermore, a logistic regression model based on serum metabolites effectively distinguished CRSwA from non-asthmatic CRSwNP (AUC = 0.8322).
    Conclusion: Our study reveals a highly conserved "metabolic-immune axis" that connects local tissue inflammation with systemic circulation, positioning metabolic dysregulation as a central hub in the unified airway disease model for CRSwA. These findings offer new perspectives for developing serum-based diagnostic markers and metabolically-targeted therapies for this challenging clinical condition.
    Keywords:  asthma; chronic rhinosinusitis with nasal polyps; lipid metabolism; metabolic-immune axis; metabolomics
    DOI:  https://doi.org/10.3389/falgy.2025.1700350
  35. Biomaterials. 2026 Feb 10. pii: S0142-9612(26)00082-7. [Epub ahead of print]330 124058
    Topical ionic liquid-mediated GLUT1 gene editing ameliorates psoriasis and prevents recurrence.
    Bei Yin, Xiying Wu, Hanxue Zhou, Yu Meng, Jun Liu, Le Ding, Congcong Zhu, Zongguang Tai, Quangang Zhu, Zhongjian Chen.
      Psoriasis is a chronic inflammatory skin disorder characterized by immune dysregulation and a high relapse rate. Current therapies seldom achieve lasting remission. Aberrant overexpression of glucose transporter 1 (GLUT1) in keratinocytes enhances glycolysis, fueling inflammation and immune imbalance, thus positioning GLUT1 as a promising therapeutic target. In this work, a composite ionic liquid-mediated transdermal platform was established for the delivery of CRISPR-Cas9 ribonucleoprotein (CIL-RNP), aiming to achieve efficient GLUT1 gene editing in keratinocytes. The CIL-RNP achieved 76.6% editing efficiency, downregulated pyruvate kinase M (PKM) expression, and reduced inflammatory cytokine secretion. In a psoriasis mouse model, topical administration of CIL-RNP decreased lesion severity by 50% PASI (Psoriasis Area and Severity Index) score, alleviating epidermal hyperplasia and immune infiltration. Furthermore, the treatment inhibited M1 macrophage polarization, reduced reactive oxygen species generation, rebalanced Th17/regulatory T cells (Tregs) responses, and diminished the accumulation of tissue-resident memory T cells (TRMs), thereby lowering the risk of relapse. This study establishes ionic liquid-based CRISPR-RNP transdermal editing of GLUT1 as a novel and effective strategy for restoring immune homeostasis in psoriasis, with potential for long-term remission and broader applications in cutaneous immunopathological conditions.
    Keywords:  CRISPR-Cas9 RNP; Composite ionic liquid; Glucose transporter 1; Psoriasis; Transdermal delivery
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124058
  36. Pharmacol Res. 2026 Feb 13. pii: S1043-6618(26)00054-X. [Epub ahead of print]225 108139
    Targeting Acod1/itaconate in cancer therapy: Mechanisms and opportunities.
    Tianlin Deng, Xiuyan Li, Shuodong Wu, Jing Kong, Xiaodong Wu.
      Globally, cancer claims nearly 10 million lives annually, where tumor heterogeneity, the immunosuppressive microenvironment, and therapeutic resistance constitute fundamental clinical challenges. In recent years, immunometabolic reprogramming has emerged as a cutting-edge research frontier, revealing novel mechanisms by which metabolites orchestrate immune responses. Itaconate-an immunometabolite primarily synthesized by macrophages-serves as a pivotal molecular hub bridging metabolic stress and anti-tumor immunity. This review systematically traces the evolution of itaconate from an industrial chemical to a key immunometabolite; comprehensively elucidates its dual roles (pro-tumorigenic vs. anti-tumorigenic) within the tumor microenvironment; synthesizes preclinical evidence of itaconate and its derivatives across diverse tumor systems; and consolidates emerging adjuvant therapeutic strategies targeting the Acod1/itaconate pathway. Collectively, this work aims to provide innovative immunometabolic perspectives for overcoming current barriers in cancer therapy.
    Keywords:  Acod1; Cancer therapy; Itaconate; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.phrs.2026.108139
  37. Obes Rev. 2026 Feb 16. e70107
    Toll Like Receptor 4: A Potential Link Between Obesity and Metabolic Diseases.
    Ghadeer Alhamar, Joanna Razafiarison, Fawaz Alzaid, Fahd Al-Mulla, Rasheed Ahmad.
      Epidemiological evidence shows that obesity increases the risk of developing metabolic diseases. Nevertheless, the mechanisms behind this connection remain underappreciated. The substantial impact of these disorders on global health has led to extensive research efforts aimed at identifying the pathophysiological links between them. Chronic low-grade inflammation, induced by altered secretion of adipokines and other bioactive molecules, from adipose tissue, is believed to causally link obesity to various metabolic disorders. Multiple studies have indicated that TLR4 regulates inflammation, adipogenesis, thermogenesis, and glucose metabolism through its interaction with endotoxins, particularly in the context of obesity. The increased expression of TLR4 observed in obesity is believed to contribute to the development of type 2 diabetes (T2D), as it disrupts key physiological processes that regulate metabolic inflammation. This review aims to summarize recent research on the pathobiological roles of TLR4-mediated inflammation in obesity and its contribution to the development of metabolic disorders. Overall, current evidence supports a central role for TLR4 as a mediator of obesity-associated metabolic inflammation, highlighting TLR4 and its downstream pathways as promising targets for preventing or treating obesity related metabolic diseases.
    Keywords:  TLR; inflammation; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1111/obr.70107
  38. Inflammation. 2026 Feb 19.
    Interferon-Driven Tryptophan Metabolism Links Inflammation and Mental Health in Juvenile Dermatomyositis.
    Yang Wu, Aviya L Levy, Payton Hermanson, Abhinav Janappareddi, Ting Wang, Jorge A Gonzalez-Chapa, Jia Shi, Susan Shenoi, Mengtao Li, Xiaofeng Zeng, Christian Lood.
       BACKGROUND: Children with juvenile dermatomyositis (JDM) experience significant mental health burdens, including anxiety and depression. Inflammatory activation can alter tryptophan metabolism, particularly through IDO-driven kynurenine pathway induction, which has been implicated in diseases such as mood disorders and SLE. We therefore investigated skewed tryptophan metabolism and its association with disease activity and mental health symptoms in JDM.
    METHODS: Serum samples from JDM, juvenile idiopathic arthritis (JIA), and healthy controls (HC) were analysed for tryptophan metabolites by ELISA. Interferon-regulated genes were measured using qPCR. Ability of serum to induce indoleamine 2,3-dioxygenase (IDO) was assessed by flow cytometry in presence or absence of interferon antagonists. Cluster analysis was used to identify subgroups.
    RESULTS: In JDM patients, serum tryptophan and serotonin levels were lower, while kynurenine/tryptophan ratios, kynurenic acid, and quinolinic acid levels were higher compared to healthy controls. Metabolites from the kynurenine pathway were correlated with muscle inflammation (CRP, ESR, aldolase and CK), mental health outcomes (PSC-17 and PHQ-9 scores) and disease progression (PGA scores). Further, IDO1 mRNA levels correlated inversely with serotonin levels and positively with type I interferon signature marker MX2 in PBMCs. Serum from JDM patients induced IDO protein expression in monocytes through an IFN-dependent mechanism, which was significantly inhibited by both baricitinib and anifrolumab. Four clinical subgroups were identified.
    CONCLUSIONS: Our study reveals a novel role of IFN in JDM pathogenesis, specifically in the upregulation of IDO and subsequent skewing of tryptophan metabolism towards kynurenine pathway, which may correspond to poor mental well-being and disease progression. Targeting this pathway may offer therapeutic potential for both disease activity and psychological outcomes for JDM children.
    Keywords:  Interferon; Juvenile dermatomyositis; Mental health; Metabolism
    DOI:  https://doi.org/10.1007/s10753-026-02469-8
  39. Nat Commun. 2026 Feb 18. 17(1): 1658
    cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis.
    Hideo Negishi, Yusuke Wada, Yoshitaka Shirasaki, Tomoya Hayashi, Yuji Kubota, Tomio Iwasaki, Mina Kurosawa, Tatsuma Ban, Daisuke Muto, Yusuke Suenaga, Taichi Kojima, Yuzuki Matsuda, Sean Lord Irish, Kosuke Dodo, Toru Suzuki, Mai Yamagishi, Burcu Temizoz, Atsushi Yoshimori, Chisato Kanai, Yoji Nagasaki, Masaki Ohmuraya, Tomohiko Tamura, Atsushi Iwama, Toshifumi Inada, Etsushi Kuroda, Kouji Kobiyama, Noriko Toyama-Sorimachi, Mutsuhiro Takekawa, Cevayir Coban, Ken J Ishii.
      Self-DNA triggers cGAS-STING-mediated type I interferon (IFN-I) to induce both protective and pathogenic immune responses; however, how self-DNA activates the cytosolic cGAS-STING pathway remains unclear. Here we show that the cGAS/STING/IFN-I axis is activated by self-DNA via a process termed 'nucleocytosis', in which nuclear DNA is extracted from dying cells by macrophages. Mechanistically, lysosomal malfunction, via both proton loss and palmitoyl-protein thioesterase 1 (PPT1) inhibition, triggers cell death and calreticulin accumulation in the nuclei. Live-cell imaging of secretion activity reveals that macrophages access the calreticulin-enriched nuclei of dying cells and extract DNA for cGAS-STING activation. Consistent with these findings, PPT1-targeting cationic amphiphilic drugs induce a cGAS-STING-dependent IFN-I response in vitro and in vivo. Our findings thus identify nucleocytosis as a macrophage function for nuclear DNA extraction and induction of the cGAS/IFN-I axis, and suggest that nucleocytosis-inducing cell death could be a druggable target for treating self-DNA-related inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-026-68839-w
  40. J Lipid Res. 2026 Feb 12. pii: S0022-2275(26)00025-8. [Epub ahead of print] 100999
    Siah2 is a lipid-meditated metabolic sensor in adipose tissue macrophage.
    Thanh N Dang, Bhaswati Ghosh, Pradip R Panta, Jessica M Taylor, Gail Kilroy, Robbie Beyl, Krisztian Stadler, Z Elizabeth Floyd.
      Adipose tissue macrophage lipid accumulation is associated with developing obesity-related insulin resistance, yet the underlying mechanisms influencing excess lipid accumulation in adipose tissue macrophage are not well-understood. Global deletion of the ubiquitin ligase SIAH2 improves glucose tolerance and insulin sensitivity while reducing adipose tissue inflammation with obesity. While Siah2 mRNA is expressed in preadipocytes and adipocytes, recent snRNA-sequencing data show Siah2 is broadly expressed in adipose tissue immune cells, including macrophage. Here, we generated a macrophage-specific SIAH2 deletion mouse model to assess the role of macrophage SIAH2 in the relationship between adipose tissue expansion and insulin resistance with a high-fat dietary challenge. Loss of SIAH2 in macrophage robustly increased glucose intolerance and insulin resistance without relative increases in body weight, serum lipids or lipid accumulation in skeletal muscle or liver in male mice compared to wild-type male mice fed a high-fat, but not a low-fat diet. The physiological changes in the male mice were associated with increased adipose tissue inflammation and increased lipid accumulation in the adipose tissue macrophage. Macrophage Siah2 depletion also increased the expression of Cd36, Trem2, Tyrobp, Hilpda1 in adipose tissue. Using the M1-like, M2-like paradigm of proinflammatory and anti-inflammatory macrophage, we found that Siah2 mRNA is stimulated by a proinflammatory lipid and suppresses expression of selected PPARγ target genes involved in lipid metabolism and inflammation. These findings place SIAH2 as a lipid-stimulated stress response protein that functions to regulate lipid accumulation in adipose tissue macrophage and the associated obesity-induced systemic insulin resistance.
    Keywords:  PPARgamma; SIAH2; adipose tissue; cell signaling; inflammation; insulin resistance; macrophages; obesity; ubiquitin
    DOI:  https://doi.org/10.1016/j.jlr.2026.100999
  41. Cell Mol Life Sci. 2026 Feb 19.
    The glycolytic enzyme PFKM promotes renal fibrosis by activating the NF-κB pathway via lactate-mediated H3K18 lactylation.
    Yizhen Chen, Weili Wang, Meng Cheng, Liuting Wei, Yonghao Sang, Yilin Gao, Wei Zhang, Lei Zhang, Rong Dai, Yiping Wang.
      Glycolytic reprogramming is closely associated with chronic kidney disease (CKD) progression. However, the role and mechanism of phosphofructokinase muscle type (PFKM), a core rate-limiting enzyme in glycolysis, in renal fibrosis remain unclear. This study analyzed Gene Expression Omnibus (GEO) datasets of renal tissues from patients with CKD to construct a folic acid (FA)-induced mouse model of renal fibrosis. PFKM overexpression or knockdown was achieved specifically in renal tubular epithelial cells using an adeno-associated virus serotype 9 (AAV9) vector. Additionally, combined with a transforming growth factor-β1 (TGF-β1)-stimulated human kidney-2 (HK-2) cell model, the underlying mechanism was explored via histological staining, metabolic analysis, ribonucleic acid (RNA) sequencing (RNA-seq), cleavage under targets and tagmentation (CUT&Tag), and chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). The results showed that PFKM was significantly upregulated in the renal tissues of patients with CKD and in fibrotic mice, exhibiting a positive correlation with fibrosis markers. Functional experiments demonstrated that PFKM knockdown alleviated FA-induced renal fibrosis in mice, whereas PFKM overexpression exacerbated fibrosis. Mechanistically, PFKM drives glycolytic reprogramming, leading to lactate accumulation. Lactate promotes histone H3 lysine 18 lactylation (H3K18la) at the Rela promoter through modifications, thereby activating the nuclear factor-κB (NF-κB) pathway and ultimately exacerbating renal inflammation and fibrosis. Collectively, PFKM promotes renal fibrosis through the "glycolysis-lactate-H3K18la-NF-κB" axis, identifying it as a novel therapeutic target for CKD.
    Keywords:  Epigenetic regulation; Epithelial-mesenchymal transition; Immunometabolism; Warburg effect
    DOI:  https://doi.org/10.1007/s00018-026-06118-z
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