bims-imicid 2026-02-08 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–02–08
39 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Itaconate-based nanoparticles induce immunometabolic reprogramming in macrophages and alleviate diet-induced obesity.
Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.
Shifts in immunometabolism in autoimmune diseases.
Metabolic reprogramming tailors T cell immunity in sepsis.
Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells.
Disengaging the Engine: Histone Deacetylases 1 and 2-Mediated Acetylation of Hexokinase-2 Regulates Energy Metabolism in Microglia Following Intracerebral Hemorrhage.
From Damage Signals to Immune Modulators: Oxidized Lipids in Immunometabolic Inflammation.
Macrophage immunometabolic reprogramming impairs tissue regeneration in type 2 diabetes zebrafish model.
Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.
STING controls glycolysis and histone lactylation to drive macrophage metabolic reprogramming in postoperative ileus.
Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in Chronic HIV-1 Infection.
Immunometabolism, an emerging field in perioperative and critical care medicine: a narrative review.
Gut microbiota-derived butyrate primes systemic immunity in honey bees by mediating lipid metabolic reprogramming.
Sepsis and the immunometabolic inflammatory response.
Single-cell immune atlas of mouse testes unveils metabolic reprogramming of FOLR2 + macrophages in orchestrating testicular immunity during aging.
Microplastics drives ILC2s function and fatty acid metabolism in allergic airway inflammation via PPARγ signaling.
ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.
Fungal infection drives metabolic reprogramming in epithelial cells via aerobic glycolysis and an alternative TCA cycle shunt.
IL-9 orchestrates immune regulation through CD39/CD73 dependent metabolic reprogramming.
Targeting macrophage glycogen metabolism attenuates ulcerative colitis by suppressing IL-1β production through UDPG-P2Y14 signaling.
The Gut Microbiome and Short-Chain Fatty Acid Metabolites in Sepsis.
Mitochondria at the membrane provide a route to inflammatory cell death.
Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1alpha axis plays a key role in host resistance to Plasmodium infection.
Dynamic metabolic modelling of ATP allocation during viral infection.
Lactate transmission from hypoxic tumor cells promotes macrophage senescence and M2 polarization via the DNMT1-NHE7 axis to accelerate endometrial cancer progression.
Developmental origins of immunometabolic health.
Histone H4 lysine 5 Lactylation: A Key Regulator of Immune Metabolism in Microglia During Ischemic Stroke.
Glucose availability tunes latent CD8+ T cell expansion potential through a mitogen-independent, mTOR-dependent regulatory switch.
Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells.
JNK1 mediates serine phosphorylation of STAT3 in response to fatty acids released by lipolysis.
β-Hydroxybutyrate impairs the functional response of bovine neutrophils to mammary pathogenic Staphylococcus aureus and a TLR2/1 agonist by limiting glucose metabolism.
Pyruvate kinase muscle 2 (PKM2) promotes CD4 T cell survival by regulating pyruvate oxidation during homeostasis and expansion.
Lactate-driven ATP6V1B2 lactylation triggers asthmatic inflammation by linking lysosomal dysfunction to mitochondrial ROS-dependent pyroptosis.
Plasmacytoid dendritic cell-mediated L-glutamate catabolism links gut microbiota to male infertility.
Intermittent fasting and immune aging: implications for immunosenescence, inflammaging, neuroinflammation, and frailty.
Dynamic magneto-mechanical force in lysosomes induces durable macrophage repolarization for antitumor immunity.
Acetate ameliorates glucolipid metabolic dysregulation and neuroinflammation in diabetic cognitive impairment via enhanced mitophagy.
Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.
Multi-omics analysis reveals that ginsenoside Rb1 improves prognostic outcomes in sepsis by modulating mitochondrial metabolism MTHFD2 targets.

Res Sq. 2026 Jan 28. pii: rs.3.rs-8604693. [Epub ahead of print]

Itaconate-based nanoparticles induce immunometabolic reprogramming in macrophages and alleviate diet-induced obesity.

Ryan Pearson, Andrea Cottingham, Neda Mohaghegh, Sara Kolhatkar, Fanny Xu, Shruti Dharmaraj, Jacob Shaw, Sanmoy Pathak, Victor Andrade, Yan Shu, Abhinav Acharya, Alireza Najafabadi.

Obesity is driven by chronic adipose tissue inflammation and macrophage dysfunction. Here, we report a cargo-free nanoparticle (NP) platform derived from itaconate-based polyesters (pITA-NPs) that reprograms macrophage immunometabolism and alleviates diet-induced obesity. pITA-NPs rapidly induce CD206 presentation through a translationally independent mechanism and drive a non-canonical M2-like transcriptional and metabolic state distinct from IL-4/STAT6 polarization, while restraining inflammatory activation and macrophage-adipocyte crosstalk to reduce lipid accumulation. Bioenergetic profiling revealed context-dependent metabolic tuning, with pITA-NPs promoting a non-canonical M2-like metabolic transition in resting macrophages characterized by increased mitochondrial mass and oxidative phosphorylation, while inducing a metabolically restrained, quiescent-like state in M1-like macrophages. In obese mice, subcutaneous pITA-NP treatment suppresses weight gain, reduces adiposity, promotes adipose tissue beiging and brown fat activation, and mitigates systemic inflammatory responses. Together, these findings establish pITA-NPs as an effective immunometabolic nanotherapy that leverages materials-driven macrophage reprogramming and coordinates immune and metabolic regulation to treat obesity.

DOI: https://doi.org/10.21203/rs.3.rs-8604693/v1
Cell Chem Biol. 2026 Feb 04. pii: S2451-9456(26)00023-1. [Epub ahead of print]

Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.

Wei Liu, Tianyi Zhang, Bohong Wang, Hang Yin.

  Bacteria-infected macrophages undergo pyroptosis to release inflammatory cytokines, which contributes to host defense. It has been known that activated macrophages involve metabolic reprogramming. However, the metabolic changes and the role of metabolites in pyroptotic macrophages are not fully understood. Here, we revealed that aerobic glycolysis product, lactate, could promote NLRP3 inflammasome activation induced pyroptosis. We found that endogenous lactate facilitates ASC recruitment to NLRP3 cores on the organelle membrane, thus inducing NLRP3 inflammasome complex formation. Mechanistically, we identified NLRP3 as a target protein modified by lactate, which is lactylated by AARS2. We confirmed lactylated sites on NLRP3 by LC-MS/MS analysis and verified that lactylation at K24 and K565 of NLRP3 facilitates inflammasome activation in macrophage. In vivo, inhibition of lactate production alleviates inflammatory responses in polymicrobial sepsis. Overall, our results indicate the role of lactate in regulating macrophage pyroptosis and the crosstalk between metabolism and innate immunity.

Keywords:  NLRP3 inflammasome; lactylation; pyroptosis

DOI:  https://doi.org/10.1016/j.chembiol.2026.01.003
Immunol Res. 2026 Feb 07. 74(1): 11

Shifts in immunometabolism in autoimmune diseases.

Sadichha Sanjay Mantri, Gaurav Mahesh Doshi.



Keywords:  Autoimmune diseases; Cytokine regulation; Glycolysis; Immunometabolism; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s12026-026-09747-5
Front Immunol. 2025 ;16 1679493

Metabolic reprogramming tailors T cell immunity in sepsis.

Di Xian, Feng Chen, Bing Liu, Lei Wang.

  Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by persistently high morbidity and mortality. Current treatment strategies have limitations, particularly the persistence of an immunosuppressed state. Recent studies have revealed that sepsis not only causes immune system dysregulation but also leads to metabolic disturbances, specifically metabolic reprogramming in T cells-a field still in its early stages. This review systematically explores the mechanisms of T-cell metabolic reprogramming in sepsis, including enhanced glycolysis, mitochondrial dysfunction, and dysregulated amino acid metabolism. It further analyzes how these alterations, mediated by signaling pathways such as HIF-1α, mTOR, and AMPK, as well as key metabolic enzymes, exacerbate T-cell exhaustion and immunosuppression. The article elaborates on the role of metabolic reprogramming in T-cell dysfunction and susceptibility to secondary infections, and summarizes potential therapeutic strategies targeting metabolic pathways-such as IL-7 therapy and IDO1 inhibitors-for restoring T-cell function, offering new directions for sepsis immunotherapy.

Keywords:  T-cell immunity; immunosuppression; metabolic reprogramming; sepsis; therapeutic strategies

DOI:  https://doi.org/10.3389/fimmu.2025.1679493
Nat Commun. 2026 Feb 04.

Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells.

Victoria Stavrou, Myah Ali, Nancy Gudgeon, Emma L Bishop, Taylor Fulton-Ward, Bethany Turley, Silke Heising, Sally H Mohamed, Sofia Hain, Lorna George, Minghao Deng, Jack McCowan, Lozan Sheriff, Scott P Davies, Bryan Marzullo, Daniel A Tennant, Craig L Doig, David A Bending, Ed W Roberts, Gareth G Lavery, Rebecca A Drummond, Sarah Dimeloe.

T cell metabolism increases upon activation, underpinning immune effector functions. Nicotinamide adenine dinucleotide (NAD/H) is an essential redox cofactor for glycolysis and mitochondrial substrate oxidation. It's phosphorylation to NADP/H regulates reactive oxygen species (ROS) abundance. NAD/H levels increase upon T cell activation, but synthesis pathways and implications are not fully characterised. Here, we interrogate the role of the NAD/H-synthesis enzyme nicotinamide riboside kinase 1 (NRK1), the expression of which increases upon stimulation of both human and murine CD4+ T cells. Functionally, NRK1 activity restrains activation and cytokine production of CD4+ T cells while promoting survival. These activities are linked to increased NRK1 expression in the cytoplasm, where it locally raises NAD/H levels. This supports glycolysis, but more profoundly impacts cytoplasmic NADP/H generation, thereby controlling ROS abundance and nuclear NFAT translocation. During fungal and viral infection, T-cell-intrinsic NRK1 maintains effector CD4+ T cell abundance within affected tissues and draining lymph nodes, supporting infection control. Taken together, these data confirm that subcellular regulation of immune cell metabolism determines immune responses at the level of whole organism.

DOI: https://doi.org/10.1038/s41467-026-68863-w
Adv Sci (Weinh). 2026 Feb 03. e00194

Disengaging the Engine: Histone Deacetylases 1 and 2-Mediated Acetylation of Hexokinase-2 Regulates Energy Metabolism in Microglia Following Intracerebral Hemorrhage.

Zhiwen Jiang, Heng Yang, Xinjie Gao, Zengyu Zhang, Ruiyuan Weng, Yuchao Fei, Jiabin Su, Hanqiang Jiang, Wei Ni, Yuxiang Gu.

  Microglia-mediated neuroinflammation is closely associated with the pathogenesis of secondary brain injury following spontaneous intracerebral hemorrhage (ICH). However, the relationship between immune response regulation and metabolic patterns in microglia remains unclear. Histone Deacetylases 1 and 2, a class of lysine deacetylases, regulates gene transcription by modulating histone acetylation modifications and is widely involved in various cellular activities of microglia. In this study, we observed that knockout of HDAC1/2 in microglia alleviated neurological deficits caused by ICH, preserved white matter integrity, and accelerated hematoma clearance post-ICH. Mechanistically, we found that after ICH, microglia exhibited increased expression of hexokinase 2 (HK2) and enhanced glycolysis. HDAC1/2 knockout/pharmacological inhibition affected the acetylation level of HK2, inhibited its glycolytic activity, and promoted a metabolic shift in activated microglia from glycolysis to fatty acid oxidation. This shift was associated with reduced pro-inflammatory responses and enhanced phagocytic activity in microglia. Enhanced fatty acid oxidation may have a detrimental effect on mitochondrial function, and HDAC1/2 inhibition simultaneously promoted mitophagy in microglia. Additionally, HDAC1/2 inhibition triggered microglial apoptosis and suppressed proliferation, ultimately leading to a reduction in microglial cell numbers. Overall, this study reveals the potential mechanisms by which targeting HDAC1/2, through acetylation modifications and transcriptional regulation, modulates microglial function and metabolism after ICH, thereby exerting protective effects.

Keywords:  HK2; acetylation; autophagy; fatty acid oxidation; glycolysis; histone deacetylase 1/2; intracerebral hemorrhage; microglia; mitochondrial

DOI:  https://doi.org/10.1002/advs.202500194
J Lipid Res. 2026 Jan 29. pii: S0022-2275(26)00016-7. [Epub ahead of print] 100990

From Damage Signals to Immune Modulators: Oxidized Lipids in Immunometabolic Inflammation.

Neetu Srivastava, Xiaoxiao Wan.

Oxidized lipids, once viewed as byproducts of oxidative stress, are now recognized as critical mediators linking metabolism, redox imbalance, and immunity. Generated through enzymatic and non-enzymatic oxidation of polyunsaturated fatty acids, oxidized phospholipids, lipid aldehydes, and oxidized lipoproteins act as context-dependent signals regulating immune activation, resolution, and metabolic adaptation. In metabolic inflammation, these lipids engage scavenger and Toll-like receptors to influence macrophage polarization, dendritic-cell function, and T-cell differentiation. Their context and concentration determine whether oxidized lipids amplify inflammation or promote immune tolerance. Accumulation of these species connects oxidative stress to immune dysfunction, contributing to diseases such as atherosclerosis, obesity, diabetes, cancer, and autoimmunity. This review synthesizes mechanistic and disease-specific insights into how oxidized lipids shape innate and adaptive immune responses in metabolic and autoimmune inflammation. As advances in lipidomics and immunology converge, a deeper understanding of oxidized-lipid regulation and function will enable the development of targeted strategies to restore immune and metabolic balance in chronic inflammatory disease.

DOI: https://doi.org/10.1016/j.jlr.2026.100990
Front Immunol. 2025 ;16 1698674

Macrophage immunometabolic reprogramming impairs tissue regeneration in type 2 diabetes zebrafish model.

Leonel Witcoski Junior, Jordana Dinorá de Lima, André Guilherme Portela de Paula, Thais Sibioni Berti Bastos, Rebeca Bosso Dos Santos Luz, Israel Henrique Bini, Matheus Brandemarte Severino, Luis Eduardo Alves Damasceno, Lais Cavalieri Paredes, Amanda Girardi Somensi, Elaine Cristina de Almeida Abreu, Lucas Brito de Souza Santos, Gabriel Costa Lourenço, Mariana Rodrigues Davanso, Rilton Alves de Freitas, Juliana Bello Baron Maurer, Niels Olsen Saraiva Câmara, José Carlos Alves Filho, Karin Braun Prado, Tárcio Teodoro Braga.

   Introduction: Type 2 diabetes mellitus (T2D) is a metabolic disorder characterized by chronic hyperglycemia, insulin resistance, and meta-inflammation, which significantly compromise tissue regeneration. Although macrophage dysfunction is implicated in impaired wound healing in T2D, the immunometabolic mechanisms linking hyperglycemia to defective tissue repair remain incompletely understood.
Methods: Zebrafish larvae were exposed to hyperglycemic conditions (4% dextrose) to establish a T2D-like model. Survival, glycemic and biochemical parameters were assessed, followed by caudal fin amputation to evaluate regenerative capacity. Total (Mpeg1+) and pro-inflammatory (Mpeg1+/TNF+) macrophages were quantified in vivo using confocal microscopy. Additionally, renal-derived macrophages were differentiated ex vivo under normoglycemic or hyperglycemic conditions and analyzed for mitochondrial function, reactive oxygen species (ROS) production, glucose uptake, and glycolytic metabolism using fluorescence probes and Seahorse assays.
Results: Hyperglycemia induced severe metabolic dysregulation, including a 3.5-fold increase in lactate levels and elevated glycemia, and resulted in a 50% reduction in caudal fin regeneration at 72 hours post-injury. Hyperglycemic larvae exhibited a 2.3-fold increase in pro-inflammatory macrophages at the injury site. Ex vivo, macrophages exposed to hyperglycemic conditions showed a 64% reduction in mitochondrial mass, increased mitochondrial ROS production, enhanced glucose uptake, and elevated glycolytic activity, indicating a metabolic shift toward aerobic glycolysis.
Discussion: These findings demonstrate that hyperglycemia drives immunometabolic reprogramming of macrophages, sustaining a pro-inflammatory phenotype that impairs tissue regeneration. The zebrafish T2D model provides a robust platform to investigate macrophage-driven immunometabolic mechanisms underlying defective wound healing and to explore therapeutic strategies targeting macrophage metabolism in T2D.

Keywords:  immunometabolic reprogramming; macrophages; tissue regeneration; type 2 diabetes; zebrafish

DOI:  https://doi.org/10.3389/fimmu.2025.1698674
JCI Insight. 2026 Jan 29. pii: e195170. [Epub ahead of print]

Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.

Natalia W Fluder, Morgane Humbel, Emeline Recazens, Alexis A Jourdain, Camillo Ribi, George C Tsokos, Denis Comte.

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol-features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.

Keywords:  Autoimmune diseases; Autoimmunity; Immunology; Lupus; NK cells

DOI:  https://doi.org/10.1172/jci.insight.195170
Commun Biol. 2026 Feb 04.

STING controls glycolysis and histone lactylation to drive macrophage metabolic reprogramming in postoperative ileus.

Kai Chen, Guofang Li, Ye Cheng, Xudong Zhu, Xingzhou Wang, Qiongyuan Hu, Wenxian Guan, Song Liu.

Postoperative ileus (POI) is characterized by dysregulated inflammation within the intestinal muscular layer, which significantly disrupts gastrointestinal motility and presents a major challenge to postoperative recovery. Although macrophages are known to contribute to inflammation through glycolytic bursts that support rapid energy production, the role of the stimulator of interferon genes (STING) in orchestrating macrophage glycolysis and modulating phenotypic polarization remains poorly defined. To address this gap, we examined the regulatory relationship between STING and macrophage metabolism. Here, we demonstrate that lipopolysaccharide (LPS)-stimulated RAW 264.7 cells display a pronounced enhancement of glycolysis, an effect that was markedly attenuated in STING knockout (STING KO) cells. Further analysis revealed that STING deletion reduces histone lactylation, consequently restricting chromatin accessibility at the hexokinase 2 (HK2) gene loci. Through CUT&Tag sequencing, we identified IRF3 as a transcription factor that directly binds to the promoter regions of HK2 and enhances its expression. Our results delineate a STING-regulated glycolytic feedback loop in macrophages: STING stabilizes hypoxia-inducible factor 1-alpha (HIF1α), thereby amplifying glycolysis and promoting histone lactylation at HK2 loci. This epigenetic modification facilitates IRF3 binding to the HK2 promoter, further boosting HK2 expression and sustaining glycolytic flux. Together, these findings elucidate a molecular mechanism through which STING modulates macrophage polarization via metabolic reprogramming, highlighting the therapeutic potential of targeting STING to regulate macrophage metabolism, alleviate inflammation, and improve outcomes in POI.

DOI: https://doi.org/10.1038/s42003-026-09602-1
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699280. [Epub ahead of print]

Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in Chronic HIV-1 Infection.

Amanda Cabral Da Silva, Luke Flantzer, Jaclyn Weinberg, Shuya Kyu, Lisa Daley-Bauer, Ana Carolina Santana, Aarthi Talla, Amber Lynn Rittgers, Sarah Welbourn, David Ezra Gordon, Jeffery Alan Tomalka, Vincent C Marconi, Dean P Jones, Souheil-Antoine Younes.

The role of aromatic gut-derived bacterial metabolites (GDBMs) in shaping immune cell metabolism and function remains poorly explored. Using ex vivo metabolomic profiling of paired plasma and CD4⁺ T-cells from people living with HIV-1 (PLWH), we identified a network of aromatic GDBMs whose cell-associated abundance, rather than systemic levels, was linked to broad alterations in CD4⁺ T-cell metabolic and functional states. Among these metabolites, p-cresol sulfate (PCS) emerged as a mechanistic prototype investigated in depth. Ex vivo flow cytometry and single-cell RNA sequencing of CD4⁺ T-cells stratified by cell-associated PCS levels revealed dose-dependent enrichment of transcriptional programs associated with impaired differentiation capacity, regulatory-like identity, and cellular senescence. Consistently, in vitro transcriptomic and proteomic analyses of PCS-exposed CD4⁺ T cells demonstrated induction of cell-cycle arrest, mitochondrial dysfunction, and senescence-associated programs, including upregulation of p16 and p21. Integration of these immunometabolic features with measurements of HIV-1 reservoir size in PLWH revealed that CD4⁺ T-cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. Together, these findings define a microbiome-derived axis that reshapes CD4⁺ T-cell metabolism and fate and promotes immune aging-associated states in PLWH. Our data suggest that cell-associated GDBMs may foster immunometabolic CD4⁺ T-cell states previously linked to long-term HIV-1 reservoir persistence in vivo.

DOI: https://doi.org/10.64898/2026.01.13.699280
Br J Anaesth. 2026 Feb 03. pii: S0007-0912(26)00005-X. [Epub ahead of print]

Immunometabolism, an emerging field in perioperative and critical care medicine: a narrative review.

Isabell Nessel, Victoria S K Tsang, Johannes Schroth, Henrike Janssen.

  Metabolism and immune function are tightly intertwined, and have been the focus of research in the expanding field of immunometabolism. Immunometabolism focuses on the metabolic adaptation of immune cells to their environment, allowing an efficient and targeted immune response even in hypoxic or nutrient-depleted tissue. The inflammatory response can be pathologically altered in chronic metabolic disease or acute injury as a result of poor immunometabolic adaptation, contributing to short- and long-term complications. Novel techniques, including 'omics' investigations, advanced imaging, and phenotyping with flow cytometry, now allow for in-depth and near real-time profiling of the intricate interactions between cell function and metabolism. Although this has significantly increased our knowledge of immunometabolic consequences in the fields of diabetes mellitus and cancer, it has been largely underappreciated in the perioperative period, even though the perioperative period serves as a strong translational model to investigate complex and highly dynamic metabolic shifts in acute inflammation. Interventions to modulate immunometabolism are being explored, particularly through immunonutrition in critical care, with heterogeneous results underscoring the need for greater understanding of the complex underlying mechanisms. In this review, we describe immunometabolic adaptation in health and metabolic disease, and under the acute inflammatory stress caused by surgery. We also discuss potential interventions, including immunonutrition and mode of anaesthesia to modulate immunometabolism in the perioperative period and critical illness.

Keywords:  critical care; immunometabolism; immunonutrition; leucocyte; perioperative stress

DOI:  https://doi.org/10.1016/j.bja.2026.01.003
Nat Commun. 2026 Feb 02.

Gut microbiota-derived butyrate primes systemic immunity in honey bees by mediating lipid metabolic reprogramming.

Jiaming Liu, Yashuai Wu, Zhenfang Li, Junbo Tang, Xin Zhou, Shiqi Luo.

The gut microbiota plays a crucial role in insect immune priming, inducing enhanced immune response that functionally resembles acquired immunity confined to vertebrates. While gut microbiota mediates systemic immune activation in insect hemolymph, the mechanisms underlying remote immunoregulation remain largely unknown. Here we use the honey bee gut microbiota as a model, we identify butyrate as a key microbial metabolite coordinating immune-metabolic crosstalk. Butyrate supplementation restores immune competence in germ-free bees, mirroring the protective effects of microbiota-colonized individuals. Butyrate orchestrates lipid metabolic reprogramming in the fat body by activating glycerolipid and arachidonic acid metabolism through activating the G-protein coupled receptor 41 while inhibiting histone deacetylases. These changes in-turn upregulate prostaglandin E2 biosynthesis, which is essential for humoral and cellular immune activation. These findings unravel how the intricate integration of immune and metabolic systems in honey bees is driven by gut-host interactions.

DOI: https://doi.org/10.1038/s41467-026-69073-0
NPJ Metab Health Dis. 2026 Feb 02. 4(1): 4

Sepsis and the immunometabolic inflammatory response.

Samuel N Paul, Isabell Nessel, Zudin Puthucheary, Siân M Henson.

Sepsis is a life-threatening syndrome characterised by dysregulated immunity, inflammation and metabolic disruption. Despite improved care, it remains a major cause of morbidity and mortality, highlighting the need for improved mechanistic insight. Immunometabolism has emerged as a framework for understanding sepsis pathophysiology. Conventional prognostic tools reflect downstream organ injury but not the metabolic states of immune cells. Emerging technologies now enable high-resolution profiling of immunometabolic changes and integrating these approaches may yield metabolic biomarkers capable of tracking immune function and refining diagnostics. This review summarises current knowledge of leukocyte metabolic dysfunction in sepsis and highlights how immunometabolic profiling can inform patient monitoring and advance biomarker-driven precision medicine.

DOI: https://doi.org/10.1038/s44324-025-00095-w
Geroscience. 2026 Jan 30.

Single-cell immune atlas of mouse testes unveils metabolic reprogramming of FOLR2 + macrophages in orchestrating testicular immunity during aging.

Xinyu Li, Min Zhang, Ani Chi, Jiahui Mo, Xiaofeng Tan, Hongde Chen, Chunhua Deng, Xiangzhou Sun, Xin Feng, Zhihong Chen.

  Immune cells play a crucial role in maintaining tissue homeostasis during aging. However, the dynamics and functions of immune cells in testicular aging have not been well elucidated. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to analyze CD45-enriched immune cells isolated from young and old mice testis. This approach yielded a comprehensive dataset comprising 6622 immune cells, encompassing macrophages, monocytes, and T cells. Our analysis revealed a significant decline in FOLR2 + resident macrophages, accompanied by a corresponding increase in pro-inflammatory CD74 + macrophages, CCR2 + monocytes, and CD8 + T cells in old mice testis. These findings were further validated by multiplex immunofluorescence staining. Notably, during testicular aging, FOLR2 + macrophages underwent a phenotypic transition towards a pro-inflammatory state. This transition subsequently facilitated the recruitment of monocytes and CD8 + T cells via the CCL8-CCR2/CCR5 axis. Furthermore, we discovered that mitochondrial metabolic dysfunction was a key driver of FOLR2 + macrophage activation. Specifically, inhibition of IDH2, a key catalytic enzyme in the TCA cycle, significantly induced this activation. Collectively, our findings provide a detailed immune atlas of testicular aging and suggest a potential role for FOLR2 + macrophages in maintaining testicular immune homeostasis.

Keywords:  CCL8-CCR2/CCR5 axis; Macrophages; Mitochondrial metabolism; Single-cell RNA sequencing; Testicular aging

DOI:  https://doi.org/10.1007/s11357-026-02109-x
Ecotoxicol Environ Saf. 2026 Feb 05. pii: S0147-6513(26)00153-3. [Epub ahead of print]310 119824

Microplastics drives ILC2s function and fatty acid metabolism in allergic airway inflammation via PPARγ signaling.

Ying Chen, Jian Wu, Xuegang Li, Zehu Chen, Zefeng Liu, Qi Zhou, Meizhu Chen, Changli Tu, Jing Liu.

  Microplastics (MPs), emerging airborne pollutants detected in human lungs, are increasingly recognized as potential drivers of respiratory disease, yet their roles and pathogenic mechanisms in allergic airway inflammation remain poorly understood. Here we show that MPs exacerbate allergic airway inflammation in house dust mite (HDM)-sensitized mice by promoting epithelial barrier disruption and type 2 immune activation. MPs exposure elevated IL-33 release and expanded IL-5⁺IL-13⁺ ILC2s. Mechanistically, the Peroxisome proliferator-activated receptor gamma (PPARγ) was markedly expressed in MPs+HDM mice and is highly expressed in ILC2s. In epithelial-ILC2s coculture system, MPs selectively enhanced PPARγ expression in ILC2s, triggering metabolic reprogramming characterized by increased fatty acid uptake and lipid droplet accumulation. This metabolic shift fueled ILC2s activation, cytokine production and downstream ST2 activation, while pharmacological inhibition of PPARγ effectively attenuated these effects. Our findings identify a previously unrecognized epithelial-PPARγ-ILC2s axis through which MPs aggravate allergic airway inflammation, revealing a potential immunometabolic mechanism of MPs-induced lung impairment.

Keywords:  Allergic airway inflammation; Fatty acid; ILC2s; Microplastic; PPARγ

DOI:  https://doi.org/10.1016/j.ecoenv.2026.119824
Nature. 2026 Feb 04.

ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.

Siva Kumar Natarajan, Joanna Lum, James Haggerty Skeans, Minal Nenwani, Sanjana Eyunni, Mateus Mota, Jill M Bayliss, Akash Deogharkar, Erin Taya Hamanishi, Matthew Pun, Stefan R Sweha, Simon Hoffman, Eleanor Young, Qiuyang Zhang, Rijul Mehta, Olamide Animasahun, Pranav Narayanan, Sushanth Sunil, Abhijit Parolia, Peter Sajjakulnukit, Pooja Panwalkar, Robert Doherty, Madison Clausen, Derek Dang, Debra Hawes, Fusheng Yang, Mariarita Santi, Alexander R Judkins, Yelena Wilson, Thomas Vigil, Andrea Franson, Richard M Mortensen, Tatsuya Ozawa, Andrea Griesinger, Eric C Holland, Nicholas K Foreman, Kulandaimanuvel Antony Michealraj, Sameer Agnihotri, Michael Taylor, Richard J Gilbertson, Carl Koschmann, Arul M Chinnaiyan, Costas A Lyssiotis, Deepak Nagrath, Sriram Venneti.

ZFTA-RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA-RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA+ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA+ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

DOI: https://doi.org/10.1038/s41586-025-10005-1
Sci Adv. 2026 Feb 06. 12(6): eaea0405

Fungal infection drives metabolic reprogramming in epithelial cells via aerobic glycolysis and an alternative TCA cycle shunt.

Aize Pellon, Shervin Dokht Sadeghi Nasab, Gholamreza Bidkhori, James S Griffiths, Stefania Vaga, Neelu Begum, Mariana Blagojevic, Nitesh Kumar Sigh, Natalia K Kotowicz, Ifeanyi Uzochukwu, Adrien Le Guennec, Rhonda Henley-Smith, Harry Gregson-Williams, Frederick Clasen, Miranda Pryce, Nadia Karimpour, Richard Cook, Juan Anguita, Jonathan P Richardson, Selvam Thavaraj, Julian R Naglik, Saeed Shoaie, David L Moyes.

Candida albicans-induced immunometabolic changes drive complex responses in immune cells. However, whether and how C. albicans causes remodeling of oral epithelial cell (OEC) metabolism is unclear. Here, we use in vitro experiments and patient biopsies to demonstrate that OECs undergo metabolic reprogramming when infected by C. albicans independently of candidalysin secretion, increasing glycolysis and decreasing tricarboxylic acid (TCA) cycle activity. Glycolysis and glucose transport inhibition show that these pathways support OEC cytokine release, highlighting the partial control of antifungal epithelial immunity by cellular metabolism. However, glucose supplementation disrupts OEC responses both in vitro and in vivo, suggesting that the fungus benefits from these metabolic shifts and that increased aerobic glycolysis in OECs is detrimental. Genome-scale metabolic modeling predicted a shutdown of the TCA cycle and a previously unidentified role for glutamic-oxaloacetic transaminase 1 (GOT1) in response to C. albicans, which was subsequently shown to be important for OEC survival during infection. This study reveals a fundamental role for hexose metabolism and identifies a GOT1-mediated TCA cycle shunt in regulating OEC survival and immune responses during mucosal fungal infections.

DOI: https://doi.org/10.1126/sciadv.aea0405
Int Immunopharmacol. 2026 Jan 31. pii: S1567-5769(26)00146-3. [Epub ahead of print]173 116303

IL-9 orchestrates immune regulation through CD39/CD73 dependent metabolic reprogramming.

Muhammed Ali Kizmaz, Abdurrahman Simsek, Tugce Bozkurt, Ali Eren Iskin, Ferah Budak.

  Adenosine triphosphate (ATP), a principal component of cellular energy metabolism, also functions as a significant extracellular signaling molecule under pathological conditions, including tissue damage and inflammation. The hydrolysis of extracellular ATP (eATP) to adenosine, catalyzed by ectonucleotidases including CD39 and CD73, is a key pathway involved in the control of immune responses. The objective of this study was to systematically examine the capacity of interleukin-9 (IL-9) to regulate ATP-adenosine metabolism and to assess the resultant impact of this regulation on T-cell responses. Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were analyzed by flow cytometry (FC) and ELISA to characterize the phenotypic, functional, and metabolic changes induced by IL-9 and to investigate the underlying molecular mechanisms. Our findings revealed that while IL-9 did not significantly change the frequency of major T-cell populations, it potentiated the conversion of ATP to adenosine by upregulating the expression of CD39 and CD73. This activity fostered an immunosuppressive microenvironment, especially within regulatory T (Treg) cells. Furthermore, IL-9 treatment suppressed the production of pro-inflammatory cytokines, increased anti-inflammatory cytokine levels, and inhibited T-cell proliferation. The pharmacological inhibition of CD39 and CD73 largely abrogated these IL-9-mediated effects. Together, these findings suggest that IL-9 may act as a regulator of the CD39/CD73 axis and that its influence on ATP-adenosine metabolism may have relevance in inflammatory and immune-mediated conditions characterized by dysregulated purinergic signaling.

Keywords:  ATP–adenosine metabolism; CD39; CD73; IL-9; Immunometabolism; Purinergic signaling

DOI:  https://doi.org/10.1016/j.intimp.2026.116303
Mol Med. 2026 Feb 04. 32(1): 15

Targeting macrophage glycogen metabolism attenuates ulcerative colitis by suppressing IL-1β production through UDPG-P2Y14 signaling.

Shuai Tong, Tao Zhu, Shuqi Liang, Yuxiao Cui, Yuan Ma, Xin Zhang, Yuhan Bian, Keke Wei, Sha Wu, Jingwei Ma.

  Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by recurrent episodes of mucosal inflammation. During disease progression, macrophages are recruited into the intestinal lamina propria and polarized toward a pro-inflammatory phenotype, where they exacerbate tissue injury by secreting cytokines such as IL-1β, IL-6, and TNF-α. Among these, IL-1β plays a central role, exhibiting both immunomodulatory and pro-inflammatory functions that correlate with disease severity. This study revealed that glycogen metabolism critically regulates IL-1β production and secretion in inflammatory macrophages. Mechanistically, uridine diphosphate-glucose (UDPG), a metabolic intermediate of glycogen metabolism, activates the P2Y14 receptor, leading to the downstream upregulation of STAT1 expression and enhanced IL-1β production. In parallel, activation of the UDPG-P2Y14 axis suppresses intracellular cAMP levels, thereby facilitating inflammasome activation and caspase-1 cleavage, ultimately driving IL-1β secretion. Importantly, the glycogen phosphorylase inhibitor ameliorates dextran sulfate sodium induced UC in mice by inhibiting glycogen metabolism. These findings highlight the UDPG-P2Y14 pathway as a potential therapeutic target for IL-1β-driven inflammatory diseases.

Keywords:  Glycogen metabolism; IL-1β; Inflammatory macrophage; UDPG; Ulcerative colitis

DOI:  https://doi.org/10.1186/s10020-026-01430-7
Clin Chest Med. 2026 Mar;pii: S0272-5231(25)00100-5. [Epub ahead of print]47(1): 119-128

The Gut Microbiome and Short-Chain Fatty Acid Metabolites in Sepsis.

Mark D Adame, Kathleen A Stringer, Robert P Dickson.

  Sepsis profoundly perturbs the intestinal microbiome and its metabolite output, yet the mechanisms by which these changes influence organ injury remain incompletely defined. In this review, we focus on short-chain fatty acids (SCFAs) as key mediators linking gut microbes to sepsis pathophysiology. We first summarize how sepsis and its treatments reshape gut communities, depleting SCFA-producing anaerobes and altering the gut metabolome. We then examine determinants of SCFA concentrations in the intestinal lumen and describe how gut-blood trafficking of these charged metabolites depends on epithelial transporters and tight-junction-regulated paracellular pathways. We highlight emerging data on how leak and pore pathways, including claudin-2-dependent pores, are upregulated in sepsis and may misdirect microbial products into the portal and systemic circulation. Finally, we synthesize experimental and human evidence for organ-specific effects of individual SCFAs: butyrate as a colonocyte fuel and barrier stabilizer, propionate as a modulator of lung immune tone, and acetate as a systemic immunometabolite that shapes inflammatory responses and sepsis outcomes. Across these sections, we outline therapeutic strategies that aim to preserve or restore SCFA-producing microbes, modify diet, target transport and permeability pathways, or deliver microbial metabolites directly. Together, these data position SCFAs and their trafficking as central to the gut-sepsis axis and as promising targets for future precision therapies.

Keywords:  Metabolism; Metabolites; Microbiome; Sepsis; Short chain fatty acids

DOI:  https://doi.org/10.1016/j.ccm.2025.11.006
Cell Metab. 2026 Feb 03. pii: S1550-4131(25)00550-9. [Epub ahead of print]38(2): 260-262

Mitochondria at the membrane provide a route to inflammatory cell death.

Zezhao Chen, Daichao Xu.

In a recent issue of Cell, Wang et al. identify "mitoxyperilysis," a previously unknown lytic cell death pathway where combined innate immune and metabolic stress triggers prolonged mitochondria-plasma membrane contact, causing local oxidative damage and membrane rupture. This mTORC2-regulated process identifies a therapeutic axis for inflammatory diseases and cancer.

DOI: https://doi.org/10.1016/j.cmet.2025.12.019
bioRxiv. 2026 Jan 14. pii: 2024.03.26.586751. [Epub ahead of print]

Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1alpha axis plays a key role in host resistance to Plasmodium infection.

Kely Catarine Matteucci, Nathalia Pereira da Silva Leite, Patricia Aparecida Assis, Isabella Cristina Hirako, Franciele Pioto, Ogooluwa Ojelabi, Juliana E Toller-Kawahisa, Leonardo Gomes Vaz, Diego Luis Costa, Joao Santana Silva, Jose C Alves-Filho, Ricardo Gazzinelli.

TNF has a dual effect in Plasmodium infection, bolstering the host's immune defense while also triggering disease. Here, we show that TNF signaling hampers physical activity, food intake, and energy expenditure while enhancing glucose uptake by the liver and spleen as well as controlling parasitemia in P. chabaudi (Pc)-infected mice. We also demonstrate that TNF is required for expression of inducible nitric oxide synthase (iNOS), stabilization of HIF-1α, expression of glucose transporter GLUT 1 and enhanced glycolysis in monocytic cells from Pc-infected mice. Importantly, Pc-infected iNOS -/- , TNFRΔLyz 2 and HIF-1αΔLyz 2 mice show impaired release of TNF and glycolysis in monocytes, together with increased parasitemia and disease tolerance. Together, our findings reveal that TNF-iNOS-HIF-1α-induced glycolysis in monocytes plays a critical role in host defense and sickness behavior in Pc-infected mice.

DOI: https://doi.org/10.1101/2024.03.26.586751
J R Soc Interface. 2026 Feb 04. pii: 20250254. [Epub ahead of print]23(235):

Dynamic metabolic modelling of ATP allocation during viral infection.

Alvin Lu, Liam Kelley, Ilija Dukovski, Daniel Segrè.

  Viral pathogens, like SARS-CoV-2, hijack the host's macromolecular production machinery, imposing an energetic burden that is distributed across cellular metabolism. To explore the dynamic metabolic tension between the host's survival and viral replication, we developed a computational framework that uses genome-scale models to perform dynamic flux balance analysis of human cell metabolism during virus infections. Relative to previous models, our framework addresses the physiology of viral infections of non-proliferating host cells through two new features. First, by incorporating the lipid content of SARS-CoV-2 biomass, we discovered activation of previously overlooked pathways giving rise to new predictions of possible drug targets. Furthermore, we introduce a dynamic model that simulates the partitioning of resources between the virus and the host cell, capturing the extent to which the competition depletes the human cells from essential ATP. By incorporating viral dynamics into our COMETS framework for spatio-temporal modelling of metabolism, we provide a mechanistic, dynamic and generalizable starting point for bridging systems biology modelling with viral pathogenesis. This framework could be extended to broadly incorporate phage dynamics in microbial systems and ecosystems.

Keywords:  ATP tradeoff; SARS-CoV-2; dynamic flux balance analysis; metabolic modelling; viral infection

DOI:  https://doi.org/10.1098/rsif.2025.0254
Cell Death Dis. 2026 Jan 30. 17(1): 185

Lactate transmission from hypoxic tumor cells promotes macrophage senescence and M2 polarization via the DNMT1-NHE7 axis to accelerate endometrial cancer progression.

Shizhou Yang, Yuejiang Ma, Tingting Wu, Xiufeng Huang.

Although hypoxia is a well-known key driver of metabolic reprogramming in endometrial cancer (EC), its role in lactate-mediated macrophage activation remains unclear. This study investigates whether hypoxia-mediated lactate metabolism reprogramming facilitated EC progression via macrophages. Our data demonstrated that hypoxia-inducible factor 1 subunit alpha (HIF1A) drives a lactate-regulated metabolic cascade, elevating glycolytic genes and monocarboxylate transporter 3 (MCT3) in EC cells to produce and export more lactate. This lactate is transported to macrophages by MCT1 to drive M2 macrophage polarization. Mechanistically, lactate induces lactylation of Histone 3 in the promoter of DNA methyltransferase 1 (DNMT1) gene and activates transcription in macrophages, leading to the silencing of NHE7 gene expression, a key regulator of intracellular pH. Critically, NHE7 downregulation drives M2 polarization and senescence through the mitogen-activated protein kinase (MAPK) pathway activation in macrophages, ultimately facilitating EC progression. In vivo, we successfully established a xenograft tumor model using Ishikawa cells, and the data further confirmed that NHE7-overexpressing macrophages effectively abrogate exogenous lactate-accelerated xenograft tumor growth, as well as its M2 polarization and senescence. These findings uncover that hypoxia-mediated lactate production and transmission promote tumor-macrophage crosstalk via the DNMT1-NHE7 axis and EC progression, which offers novel therapeutic targets for EC.

DOI: https://doi.org/10.1038/s41419-026-08411-y
Immunometabolism (Cobham). 2026 Jan;8(1): e00075

Developmental origins of immunometabolic health.

Yem J Alharithi, Gladys Smith, Alina Maloyan.

  Obesity during pregnancy not only affects maternal health but also puts offspring at high risk of obesity and of metabolic and cardiovascular diseases later in life, often regardless of their own lifestyle choices. This process, known as developmental programming, is increasingly being recognized as a critical factor shaping long-term health outcomes. In addition, a growing body of research highlights the importance of immunometabolism, the metabolism of immune cells, in the pathogenesis of obesity, metabolic disorders, cardiovascular disease, and cancer. Although the effects of maternal obesity on offspring health have been well documented in both epidemiological studies and preclinical models, its influence on the developing immune system and immunometabolic pathways is only beginning to be revealed. In this review, we explore the metabolic and inflammatory dimensions of developmental programming and discuss how an adverse maternal environment may shape the offspring's immunometabolic landscape.

Keywords:  DOHAD; developmental programming; dipeptidyl peptidase 4; immunometabolism; inflammation; maternal obesity; pregnancy

DOI:  https://doi.org/10.1097/IN9.0000000000000075
Pharmacol Res. 2026 Feb 02. pii: S1043-6618(26)00042-3. [Epub ahead of print] 108127

Histone H4 lysine 5 Lactylation: A Key Regulator of Immune Metabolism in Microglia During Ischemic Stroke.

Yishan Li, Yang Zhou, Yan Mo, Yixin Li, Peng Wang, Yong Zhao, Li Peng.

  Histone lactylation is associated with neurological disorders and the state of reactive microglia. However, the impact of elevated lactate levels, generated through glycolysis under hypoxic conditions, on the status and functionality of reactive microglia in the context of ischemic stroke (IS) remains inadequately understood. Immunofluorescence, Western blot and co-immunoprecipitation were performed to identify the histone lactylation modification sites in microglia after IS. CUT&Tag and RNA sequencing data were used to clarify the target genes of H4K5la in microglia after cerebral ischemia. The influence of H4K5la on microglial functions was assessed through Nile Red staining, ELISA, free fatty acid assays, and energy metabolism kits. TTC, behavioral observation, HE and Nissl staining were used to study the impact of exogenous lactate on IS outcomes. Immunofluorescence, Western blot, co-immunoprecipitation, ELISA and qPCR were conducted to explore the upstream regulator of H4K5la and pro-inflammatory gene expression in microglia following IS.H4K5 lactylation level was elevated in microglia and boosted transcription of immunometabolic genes such as HK1, Fads2, and Pla2g4a. This was linked to higher ECAR, lower OCR, impaired FAO, and a reduced ATP/ADP ratio, resulting in more lipid accumulation and increased pro-inflammatory cytokine expression after IS. Exogenous lactate also increased H4K5la levels, indicating that glycolysis-driven lactate enhances histone lactylation. GCN5 was an upstream regulatory factor in modulating microglia histone lactylation and subsequent immune metabolism gene expression after IS. This study reveals the role and mechanism of H4K5la in microglia immunometabolic dysfunction, identifying a new therapeutic target for IS treatment.

Keywords:  H4K5la; Histone lactylation; Immune metabolism; Ischemic stroke; Microglia

DOI:  https://doi.org/10.1016/j.phrs.2026.108127
bioRxiv. 2026 Jan 17. pii: 2026.01.16.699963. [Epub ahead of print]

Glucose availability tunes latent CD8+ T cell expansion potential through a mitogen-independent, mTOR-dependent regulatory switch.

Tran Ngoc Van Le, Krittin Trihemasava, Lucien Turner, Kelly Rome, Aaron Wu, Will Bailis.

Mitogenic signals are understood to license cell cycle progression and the metabolic reprogramming required for cell division, with acquired nutrients serving as permissive substrates. Here, we show that nutrient availability instead functions as a mitogen-independent regulatory input that dynamically controls CD8+ T cell proliferative potential. Activating stimuli have been shown to set T cell expansion capacity through their control of c-Myc expression, with the rate of c-Myc decay functioning as a division timer. We demonstrate that nutrient availability is sufficient to control c-Myc expression dynamics and dictates how division potential is stored and later actualized. Glucose-restricted T cells sustain proliferative potential and exhibit high AKT and ERK phosphorylation, despite limited growth. Upon glucose restoration, these cells rapidly increase c-Myc expression, accelerate through the cell cycle, and return to the expansion potential of glucose-replete controls, even after days of enforced restriction. Glucose restriction thus maintains a latent metabolic and mitogenic signaling state that is rapidly realized upon recovery. Mechanistically, mTOR signaling is required for this glucose recovery-driven proliferation, despite c-Myc and pERK remaining elevated following mTOR inhibition, indicating that glucose and mitogen signals operate through parallel rather than hierarchical control points. Altogether, these findings reveal that nutrient availability is not merely rate-limiting for proliferation but dictates the kinetics at which mitogenic signals are dissipated and realized. While mitogenic and nutrient cues converge on a shared anabolic network, they operate through distinct regulatory arms to coordinate the tempo and magnitude of clonal expansion, with implications for protective immunity and immunotherapy.
Significance Statement: CD8+ T cells rapidly proliferate to fight infections and cancer, often in variable nutrient environments. Activation signals are understood to control T cell expansion potential by setting c-Myc expression and its subsequent decay, with nutrients providing fuel. Here we find that glucose availability functions as an independent regulatory switch. Glucose-restricted T cells remain proliferatively poised for days, keeping pro-growth signaling and metabolic capacity primed. Upon glucose restoration, cells undergo a proliferative burst and catch up to glucose-replete counterparts. Although c-Myc expression rises upon glucose restoration, accelerated division kinetics instead require mTOR activity. These findings reveal that nutrient availability operates in parallel with mitogenic signaling, tuning the rate at which T cells store and realize their expansion potential.

DOI: https://doi.org/10.64898/2026.01.16.699963
Sci Immunol. 2026 Feb 06. 11(116): eaef9196

Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells.

Cait A McAlindon, Rachael A Clark.

Aldehydes accumulating in response to reduced fatty acid oxidation in tumor-infiltrating lymphocytes damage mitochondria and drive T cell exhaustion.

DOI: https://doi.org/10.1126/sciimmunol.aef9196
J Lipid Res. 2026 Jan 30. pii: S0022-2275(26)00017-9. [Epub ahead of print] 100991

JNK1 mediates serine phosphorylation of STAT3 in response to fatty acids released by lipolysis.

A Melisa Aksu, Amena Akter, Preetveer Dhillon, Zane J Zerbel, Pania E Bridge-Comer, Oluwafemi Gbayisomore, Shannon M Reilly.

  Adipocytes play a central role in energy balance and metabolic health by storing excess nutrients as triglycerides in white adipose tissue (WAT). During physiological stress, sympathetic activation triggers lipolysis, releasing fatty acids and glycerol to meet systemic energy demands. Lipolytic activation in white adipocytes also increases their rate of oxygen consumption. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Ser727 is a key regulatory event in lipolysis-driven respiration. Here, we identify c-Jun N-terminal kinase 1 (JNK1) as the kinase responsible for this essential phosphorylation event and a key regulator of oxidative metabolism in lipolytic adipocytes. We show that fatty acids produced by lipolysis activate JNK, which phosphorylates lipid droplet-associated STAT3, leading to inhibition of glycerol-3-phosphate acyltransferase 3 (GPAT3) and suppression of fatty acid re-esterification. This shift in lipid handling promotes mitochondrial uncoupling and increases energy expenditure. Pharmacological inhibition of JNK1 markedly reduced lipolysis-driven respiration without altering the rate of lipolysis. The critical role of JNK1 in promoting respiration in lipolytic adipocytes was verified using genetic knockdown studies. Notably, canonical upstream MAP kinase kinases were not required for JNK1 activation, suggesting a noncanonical pathway that senses acute increases in intracellular fatty acid levels. Together, these findings identify JNK1 as a metabolic sensor linking intracellular fatty acid levels to STAT3-mediated oxidative metabolism in adipocytes, with potential implications for energy balance and metabolic disease.

Keywords:  Adipocyte; Adipose tissue; Cell signaling; Lipid droplets; Lipolysis and fatty acid metabolism; Obesity

DOI:  https://doi.org/10.1016/j.jlr.2026.100991
J Dairy Sci. 2026 Feb 04. pii: S0022-0302(26)00060-3. [Epub ahead of print]

β-Hydroxybutyrate impairs the functional response of bovine neutrophils to mammary pathogenic Staphylococcus aureus and a TLR2/1 agonist by limiting glucose metabolism.

J Quiroga, R A Burgos, C Henríquez, M D Carretta, P Alarcón, A Mella, B Guíñez, G Morán.

  Ketosis is a common metabolic disease affecting dairy cows during early lactation. β-Hydroxybutyrate, the predominant ketone body in the bloodstream of ketotic cows, has been linked to neutrophil dysfunction and a higher incidence of mastitis. Neutrophils, the first line of cellular defense against bacteria, rely heavily on carbohydrate metabolism. In this study, we investigated the effect of high BHB concentrations on glycolysis and on the functional response of bovine neutrophils to Staphylococcus aureus-a leading cause of mastitis worldwide-and to Pam3CSK4, a synthetic agonist of toll-like receptor 2/1 (TLR2/1), which is critical for S. aureus recognition by immune cells. At both 2.5- and 5.0-mM concentrations, BHB reduced basal glycolysis and restricted the glycolytic capacity of neutrophils following Pam3CSK4 stimulation. By pharmacological inhibition, we confirmed that bovine neutrophils depend on both glycolysis and glycogenolysis to mount effective responses to S. aureus and Pam3CSK4. Interestingly, both 2.5- and 5.0-mM BHB similarly impaired neutrophil responses against S. aureus and Pam3CSK4, including respiratory burst, neutrophil extracellular traps formation, matrix metallopeptidase 9 release, phagocytosis, and chemotaxis. Our findings suggest that BHB-mediated glycolytic restriction may constitute a central mechanism contributing to neutrophil dysfunction during ketosis, thereby increasing the susceptibility of dairy cows to mastitis in early lactation.

Keywords:  Staphylococcus aureus; bovine neutrophils; glycogenolysis; glycolysis; ketosis; toll-like receptor 2/1 (TLR2/1); β-hydroxybutyrate

DOI:  https://doi.org/10.3168/jds.2025-27452
Sci Adv. 2026 Jan 30. 12(5): eaec5092

Pyruvate kinase muscle 2 (PKM2) promotes CD4 T cell survival by regulating pyruvate oxidation during homeostasis and expansion.

Jeff J Subleski, Erika M Palmieri, Jessica F Walls, Steven Hsu, Ian A Bettencourt, Timothy R Gower, Scott K Durum, Daniel W McVicar.

Glycolysis is an essential metabolic pathway for rapidly expanding T cells, but the role of pyruvate kinase muscle 1 (PKM1) and PKM2 in regulating this process is underappreciated. Here, using a pharmacological activator and targeted deletion of PKM2 in T cells, we delineated distinct functions of PKM1 and PKM2 in regulating CD4 T cell survival during homeostasis and expansion. Expanding PKM2-deficient CD4 T cells increased PKM1 expression with associated mitochondrial reactive oxygen species-mediated cell death. Examination of T cell compartments revealed that PKM2-deficient CD4 T cells were unaltered in the thymus but were significantly reduced in peripheral tissues as mice aged. The inability of PKM1 to protect CD4 T cells in the absence of PKM2 led to less severe T cell-mediated colitis as PKM2-deficient pathogenic cells were significantly reduced compared with control cells. This study shows that PKM2 is critical for CD4 T cell survival during expansion and homeostasis.

DOI: https://doi.org/10.1126/sciadv.aec5092
Redox Biol. 2026 Jan 30. pii: S2213-2317(26)00057-1. [Epub ahead of print]90 104059

Lactate-driven ATP6V1B2 lactylation triggers asthmatic inflammation by linking lysosomal dysfunction to mitochondrial ROS-dependent pyroptosis.

Qiaoyun Bai, Ningpo Ding, Rixin Feng, Fengxiang Shang, Zongqi Wang, Liangchang Li, Zhiguang Wang, Yihua Piao, Guangyu Jin, Yilan Song, Guanghai Yan.

  Immunometabolic reprogramming is increasingly recognized as a driver of asthma pathogenesis, yet the molecular mechanisms linking lactate accumulation to airway inflammation via protein lactylation (Kla) remain elusive. In this study, we integrated a house dust mite (HDM)-induced asthma model with quantitative lactylomics to identify ATP6V1B2, a key V-ATPase subunit, as a core lactylation target. Combined molecular dynamics simulations and biochemical analyses revealed that intracellular l-lactate triggers lactylation at K108/K109. This modification restricts ATP6V1B2 conformational flexibility, leading to the disassembly of the V1-V0 complex and subsequent loss of proton pump activity. Crucially, the lactylation event was validated in primary human bronchial epithelial cells (HBEs), confirming that HDM and l-lactate stimulation induce ATP6V1B2 lactylation, thereby ensuring the clinical relevance of our findings. We demonstrate that this loss-of-function precipitates lysosomal alkalinization and membrane permeabilization (LMP). Crucially, LMP acts as a central node that bifurcates into two pathogenic cascades: it triggers a catastrophic mitochondrial ROS burst via Cathepsin B leakage. This oxidative burst functions as a pivotal redox signal that initiates a non-canonical Caspase-8/3/GSDME-dependent pyroptosis pathway, distinct from intrinsic apoptosis. In vivo, blocking ATP6V1B2 lactylation using an AAV-delivered lactylation-deficient (2 KR) mutant successfully severed this metabolic-inflammatory loop, significantly attenuating airway inflammation, Th2 cytokine release, and tissue pyroptosis. These findings characterize a novel "l-lactate-ATP6V1B2-GSDME" axis, establishing ATP6V1B2 lactylation as a critical metabolic switch connecting lysosomal damage to inflammatory cell death, thereby identifying a potential therapeutic target for metabolic dysregulation in chronic asthma with severe pathology.

Keywords:  ATP6V1B2; Asthma; Lactylation; Lysosomal dysfunction; Pyroptosis

DOI:  https://doi.org/10.1016/j.redox.2026.104059
Medicine (Baltimore). 2026 Feb 06. 105(6): e47440

Plasmacytoid dendritic cell-mediated L-glutamate catabolism links gut microbiota to male infertility.

Liwen Huang, Xue Li, Yao Hao, Bo Huang, Chengbin Pei, Xiuying Pei, Qian Zhang, Guodong Chen, Shuya Zhang.

  Emerging evidence suggests that gut microbiota composition influences male reproductive health; however, the immunometabolic mechanisms underlying this association remain insufficiently characterized. We investigated whether specific immune cell-mediated metabolic pathways, particularly plasmacytoid dendritic cell (pDC)-driven L-glutamate catabolism via the hydroxyglutarate pathway, contribute to the causal link between gut microbiota and male infertility. We conducted a 2-sample, 2-step Mendelian randomization (MR) analysis using inverse-variance weighting as the primary estimator and Bayesian weighted MR for robustness. Exposure data comprised 412 gut microbial taxa/metabolic pathways and 731 immune cell phenotypes from large European-ancestry genome-wide association studies. Male infertility genome-wide association studies data (1429 cases; 128,710 controls) were obtained from FinnGen R10. Only exposure-mediator-outcome pairs meeting stringent pleiotropy, heterogeneity, and reverse-causality criteria were retained for mediation analysis. Nine microbial taxa/metabolic pathways and 18 immune traits exhibited putative causal associations with male infertility. The L-glutamate degradation V pathway via hydroxyglutarate was linked to reduced infertility risk (inverse-variance weighting odds ratio [OR] = 0.68; 95% confidence interval, 0.52-0.89; P = .005). Two-step MR suggested that forward scatter area on pDCs may mediate this association, although the mediation effect was imprecise (effect = 0.0277; 95% confidence interval, -0.0348 to 0.0903). This study provides suggestive genetic evidence that pDC-mediated glutamate catabolism may connect gut microbial metabolic activity to male infertility. These findings highlight immunometabolic pathways as testable targets for mechanistic validation and microbiota-directed interventions.

Keywords:  BWMR; Mendelian randomization; gut microbiota; immunometabolism; male infertility; plasmacytoid dendritic cells

DOI:  https://doi.org/10.1097/MD.0000000000047440
Front Nutr. 2026 ;13 1736969

Intermittent fasting and immune aging: implications for immunosenescence, inflammaging, neuroinflammation, and frailty.

Dania Alkawamleh, Mohamed I Madkour, Faiza Kalam, Dana N Abdelrahim, Hanan Wael Abdallah, MoezAlIslam E Faris.

  Aging is accompanied by a progressive decline in immune function, known as immunosenescence, and by a chronic low-grade inflammatory state, termed inflammaging. Both conditions contribute to increased susceptibility to infections, reduced vaccine responses, and the development of age-related diseases. Emerging evidence suggests that intermittent fasting (IF), a dietary pattern that alternates between periods of fasting and feeding, may influence pathways associated with immune aging across mid-life and older adulthood. This review explores how IF may exert immunoregulatory effects through metabolic remodeling, cellular stress responses, and inflammatory signaling. Preclinical and human studies indicate that IF attenuates pro-inflammatory cytokine production, enhances autophagy, and improves immune cell function, potentially delaying immunosenescence and reducing inflammaging in middle-aged and older populations. Additionally, IF may protect against neuroinflammation and cognitive decline by reducing oxidative stress, activating AMPK-SIRT1 and ketone signaling via β-hydroxybutyrate (BHB), enhancing neuroplasticity, upregulating brain-derived neurotrophic factor, and suppressing pro-inflammatory cytokines, inflammation, and frailty in the aging brain. However, most evidence comes from short- to medium-term studies in selected, relatively healthy populations, with benefits often similar to those of continuous calorie restriction, and there is limited data on long-term safety, adverse effects, and outcomes in frail older adults. By reducing oxidative stress and inflammaging, IF may mitigate frailty in older adults or delay its progression when initiated earlier. By integrating insights from immunometabolism and gerontology, this review highlights the potential role of IF as a non-pharmacological strategy to promote healthy immune aging and support functional outcomes in older adults. However, evidence in frail older adults remains limited, and randomized trials in this population are warranted. Future research should directly compare IF with isocaloric non-fasting regimens, include long-term follow-up, and carefully characterize safety and adherence in high-risk groups before IF can be routinely recommended for immune aging.

Keywords:  AMPK activation; healthy aging; immune resilience; inflammasome; mTOR signaling; time-restricted eating

DOI:  https://doi.org/10.3389/fnut.2026.1736969
Cell Res. 2026 Feb 03.

Dynamic magneto-mechanical force in lysosomes induces durable macrophage repolarization for antitumor immunity.

Yingze Li, Mengge Zheng, Zhenyan Zhu, Yajuan Zhang, Peng Ning, Haotian Chen, Rui Gao, Chang Xu, Xueyan Wei, Yali Liu, Yingying Wang, Ruimei Zhou, Yuan Li, Zhenguang Li, Cheng Lv, Chen Liu, Junfang Xu, Zihan Guo, Zhixiang Hu, Lan Fang, Ke Wei, Mengying Feng, Changshi Zhou, Yunlang She, Weiyan Sun, Erzhen Chen, Gustavo R Plaza, Bin He, Jason Miska, Weiwei Yang, Yichao Tang, Haipeng Liu, Chang Chen, Yu Cheng.

Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and how organelle-level forces trigger mechanotransduction for antitumor immunity. Here, we developed a magneto-mechanical force-triggered lysosomal membrane permeabilization (MagLMP) strategy to induce durable macrophage repolarization for in vivo applications. Self-assembled magnetic nanomotors are driven by rotational magnetic fields, facilitating dynamic damage to the lysosomal membrane by a finely tuned torque-induced vortex. Intriguingly, galectin 9 (Gal9) was found to be critical for sensing cyclic MagLMP, which dynamically activated AMP-activated protein kinase (AMPK), enhanced activation of nuclear factor kappa B (NF-κB), and induced metabolic alterations for sustained M1-like macrophage repolarization, followed by mounting of antitumor immunity. Through single-cell RNA sequencing of tumor tissues, as well as macrophage depletion-reconstitution models involving intratumoral transfer of Gal9-KO bone marrow-derived macrophages (BMDMs) and AMPK shRNA-transduced Gal9-KO BMDMs, we confirmed the Gal9-AMPK-NF-κB axis as the essential pathway by which MagLMP functions in antitumor therapy. In a mouse model of lung adenocarcinoma in situ, overall survival was extended after intravenous administration of nanomotors followed by cyclic MagLMP, and one third of mice survived for more than 300 days. Together, these results demonstrate an intracellular mechanical strategy that can dynamically manipulate innate immune responses in vivo, providing a tool for durable immunotherapy through organelle mechanotransduction.

DOI: https://doi.org/10.1038/s41422-025-01217-1
Free Radic Biol Med. 2026 Jan 30. pii: S0891-5849(26)00061-4. [Epub ahead of print]246 580-597

Acetate ameliorates glucolipid metabolic dysregulation and neuroinflammation in diabetic cognitive impairment via enhanced mitophagy.

Jie Zheng, Yu An, Xin Zhang, Zhaoming Cao, Guangyi Xu, Jing Li, Jingya Wang, Li Chen, Yanhui Lu.

   BACKGROUND: Diabetic cognitive impairment (DCI) is an increasingly recognized complication of type 2 diabetes mellitus (T2DM) with limited effective therapies. Short-chain fatty acids (SCFAs) have been implicated in metabolic regulation and neuronal health, yet comparisons of acetate, propionate, butyrate, and their mixture are limited, and the mechanisms underlying neuroprotection in DCI remain insufficiently clarified.
METHODS: Ninety participants (healthy controls, T2DM, and DCI groups) were assessed for serum SCFA levels and cognitive performance using the Montreal Cognitive Assessment (MoCA). In parallel, a DCI mouse model established by a 24-week high-fat diet received 8-week supplementation with acetate, propionate, butyrate, or a mixture of the three. Glucolipid metabolism, spatial learning and memory, hippocampal neuronal damage, neuroinflammation, and mitophagy were evaluated. Based on consistency across the clinical and animal datasets, acetate was selected for mitophagy-focused mechanistic experiments, and pathway dependence was examined by co-administration of the autophagy inhibitor 3-methyladenine (3-MA).
RESULTS: Clinically, serum acetate, propionate, and butyrate were lower in T2DM and DCI than in healthy controls; only acetate showed a further significant reduction in DCI compared with T2DM. All three SCFAs were positively associated with MoCA score and inversely associated with fasting blood glucose, whereas acetate additionally showed inverse associations with lipid parameters. In mice, SCFA supplementation alleviated metabolic dysfunction, spatial learning and memory, neuronal loss, and neuroinflammation, with acetate generally producing more consistent and numerically greater improvements across these endpoints. Mechanistically, acetate enhanced hippocampal mitophagy by restoring LC3-TOMM20 colocalization and activating the PINK1/Parkin pathway. Importantly, 3-MA partially attenuated these benefits, indicating a mitophagy-dependent mechanism.
CONCLUSIONS: These integrated clinical and experimental data support a "SCFAs-mitophagy-neuroinflammation" axis linking systemic metabolism to neuronal vulnerability in DCI, and identify acetate as a promising SCFA that may enhance neuronal resilience through mitophagy activation.

Keywords:  Acetate; Diabetic cognitive impairment; Mitophagy; Neuroinflammation; PINK1/Parkin pathway; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.041
Cell Metab. 2026 Feb 04. pii: S1550-4131(26)00005-7. [Epub ahead of print]

Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.

Mingyuan Wei, Xinzhu Yi, Zhuandi Lin, Jingjing Cai, Shanze Chen, Fang Zhou, Hanqin Cai, Xinfeng Lu, Juan Tang, Yunfeng Shi, Liping Cui, Lei Yang, Xinru Jing, Yunong Zeng, Rong Wu, Tingting Shu, Yuanyuan Li, Fangyuan Yang, Yi He, Zhibin Zhao, Yuqiong Yang, Wenjiao Zhu, Qiong Jiang, Weiwei Zhang, Xiang Tan, Zhuo Ma, Xiaoying Fan, Wei Ma, Sheng Li, Wensheng Shu, Hong Wei, Zhiming Xiang, Jack A Gilbert, Shenhai Gong, Zhang Wang.

  Sepsis is characterized by impaired immunity to infection, leading to multi-organ dysfunction, with the lung being the most vulnerable organ. Here, we show that ketogenic diet (KD) alleviates sepsis-induced lung injury through a microbial-gut-lung axis. KD alters the gut microbiota in mice and humans, enriching Limosilactobacillus reuteri and Lactiplantibacillus plantarum. Specific strains of these species produce a flavin-dependent monooxygenase (FMO) that converts oleic acid in KD into azelaic acid (AZA). During sepsis, AZA translocates to the lung, where it promotes neutrophil apoptosis and expands MerTK+ alveolar macrophages (AMs) via PPAR-γ activation, enhancing efferocytosis and resolution of lung injury. In patients with sepsis, elevated AZA correlates with improved clinical outcomes, including survival rates, ventilation-free days (VFDs), and pulmonary function, along with increased MerTK+ AMs and apoptotic neutrophils in patient lungs. These findings uncover a pathway of gut-lung crosstalk mediated by diet-microbiome interactions, highlighting the therapeutic potential of KD and microbiome modulation in sepsis.

Keywords:  Lactobacillus; efferocytosis; gut-lung axis; ketogenic diet; macrophages; sepsis

DOI:  https://doi.org/10.1016/j.cmet.2026.01.005
Sci Rep. 2026 Feb 01.

Multi-omics analysis reveals that ginsenoside Rb1 improves prognostic outcomes in sepsis by modulating mitochondrial metabolism MTHFD2 targets.

Qi Shu, Huan Luo, Like Zhong, Jiaping Mo, Xiaoyan Wei, Zhenjie Zhu, Xiaojuan Chen, Han She, Fugen He, Junfeng Zhu.

  Sepsis has emerged as a major threat to human mortality. Increasing evidence explores the impact of mitochondrial metabolism on the prognosis of sepsis patients and its therapeutic potential. To enhance risk stratification and identify potential targets, we conducted a retrieval and analysis of differential expression of mitochondrial metabolism related genes (MMRG) between sepsis and normal samples from public databases. Immune infiltration analysis was preformed to gain comprehensive knowledge of features of the established risk model. Additionally, single-cell sequencing results suggested MTHFD2 may be a critical target in sepsis for regulating immune infiltration characteristics, potentially altering platelet metabolism pathways significantly, thereby influencing sepsis occurrence and progression. Utilizing molecular docking, we further screened Ginsenoside Rb1 (Grb1) as a key pharmacological target interacting with MTHFD2. Further animal experiments preliminarily indicated that Grb1 administration was associated with reduced MTHFD2 expression and improved organ function and survival in CLP-induced septic rats. These findings provide new insights and potential therapeutic targets for clinical treatment of sepsis in the future.

Keywords:  Ginsenoside Rb1; Immune infiltration; MTHFD2; Mitochondrial metabolism; Risk stratification; Sepsis

DOI:  https://doi.org/10.1038/s41598-026-37362-9