bims-imicid 2026-01-18 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–01–18
34 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?
Probiotic extracellular vesicles reprogram macrophage immunometabolism: From gut crosstalk to host health.
Metabolic adaptation in CD4+ T cells promotes immunosuppression in sepsis.
Metabolites as signalling molecules in the tumour immune microenvironment.
Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis.
Crosstalk between arachidonic acid metabolism and glycolysis drives integrated metabolic-inflammatory reprogramming in macrophages.
A Closed Computational-Experimental Loop Identifies Metabolic Collapse at the Root of Macrophage Dysfunction due to Zinc Dyshomeostasis.
Baicalin inhibits macrophage glycolysis and succinate-driven HIF-1α signaling by targeting PKM2 to alleviate RSV-induced inflammation.
Baicalin attenuates HIF-1α-driven histone lactylation and neutrophil extracellular trap (NET) formation in autoimmune uveitis.
CCL20-CCR6 signaling alters the metabolic reprogramming to promote the pathogenic Th17 cell differentiation.
Targeting the CMKLR1-Mediated Signaling Rebalances Immunometabolism State in Middle-Age Testicular Macrophages.
Targeted PPARδ activation reprograms microglial immunometabolism and improves insulin sensitivity in HFD-fed rats.
Excessive Kynurenine Metabolism Impairs Lysosomal acidification and Triggers mtDNA Release via the AHR/CISH/ATP6V1A Axis in Decidual Macrophages Associated with Unexplained Recurrent Pregnancy Loss.
6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
Loss of Acid Ceramidase in Myeloid Cells Protects from Chronic Colitis in IL10-Deficent Mice.
The Increased Secretion of Lactate Observed in Obesity and Aging Leads to the Generation of Pathogenic B Cells.
Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy.
Metabolic Stress and Immune Activation in Heart Failure With a Preserved Ejection Fraction.
Lasting bone marrow defects imprinted by hyperglycemia shape the immunological characteristics of differentiated M1 and M2 macrophages.
Dynamics of natural killer cell function upon recurrent stimulation.
Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells.
Cancer might evade immune defences by stealing mitochondria.
Dental Pulp Stem Cells Orchestrate Macrophage Polarisation in Pulpitis via Mitochondrial Transfer.
Reprogramming immunity at the metabolic-epidermal interface in obesity-associated psoriasis.
From inflammation to innovation: Exploring the emerging roles of itaconate in ARDS.
Tryptophan and polyamine metabolism dysregulation serves as an early marker of high-fat diet-induced glucose intolerance.
Bergenin attenuates traumatic brain injury via inhibition of microglial PFKFB3-driven glycolytic-inflammatory crosstalk.
Excitatory amino acid transporters support mast cell degranulation via α-KG-mediated methylation of Spp1.
PARP inhibition generates enhanced CD8+ central memory T cells by transcriptional and metabolic reprogramming.
Urolithin A Attenuates Sleep Deprivation-Induced Neutrophilic Inflammation by Suppression of the ROS-H3K18la Feedback Loop.
Increased triacylglyceride and ceramide levels are key for MERS-CoV replication.
Metabolic Basis of Post-Infectious Sequelae After Ebola Virus Disease.
Narciclasine Alleviates Endothelial Inflammation and Atherosclerosis Initiation by Inhibiting Histone Lactylation-Mediated NF-κB Activation.

Biochem Pharmacol. 2026 Jan 08. pii: S0006-2952(26)00025-0. [Epub ahead of print]245 117694

Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?

Brian J Day.

  Immunometabolism is an emerging field that explores how metabolic pathways shape immune cell function, fate, and response. Immune cells undergo dynamic metabolic reprogramming to meet the energetic and biosynthetic demands of activation, differentiation, and effector activity. While glycolysis and oxidative phosphorylation (OxPhos) are well-established regulators of immune responses, recent discoveries suggest that endogenously produced cyanide may serve as a novel modulator of mitochondrial metabolism. Traditionally viewed as a toxic compound, cyanide is now being recognized for its potential role in regulating OxPhos through inhibition of complex IV in the electron transport chain, thereby influencing the balance between glycolysis and mitochondrial respiration. This review synthesizes current knowledge on the metabolic regulation of immune cells-including T cells, macrophages, dendritic cells, B cells, and natural killer (NK) cells-and highlights the role of core pathways such as glycolysis, fatty acid oxidation (FAO), and amino acid metabolism. It also explores how cyanide formation and metabolism intersect with innate immunity, particularly through the generation of thiocyanate and its role in antimicrobial defense. Furthermore, the review discusses how nutritional status integrate with metabolic cues to fine-tune immune responses. Finally, the clinical implications of immunometabolic regulation are examined in the context of autoimmune diseases, cancer, infections, and metabolic disorders. The potential of cyanide as a therapeutic modulator of immune metabolism is considered, offering new perspectives on immune regulation and disease intervention.

Keywords:  Cancer; Immunity; Infection; Inflammation; Metabolic disorders; Metabolic switch; Therapeutics

DOI:  https://doi.org/10.1016/j.bcp.2026.117694
Gut Microbes. 2026 Dec 31. 18(1): 2614115

Probiotic extracellular vesicles reprogram macrophage immunometabolism: From gut crosstalk to host health.

Yan Li, Yihong Liu, Xubiao Wei, Changfa Wang, Muhammad Zahoor Khan, Qingshan Ma.

  Probiotic-derived extracellular vesicles (PEVs) are functional nanovesicles secreted by various microbiota. As a novel class of microbial signals, they encapsulate proteins, nucleic acids, lipids, and microbial-associated molecular patterns, emerging as potent modulators of communication between gut microbiota and host immune cells, such as macrophages. Macrophages, as a crucial component of the innate immune system, rely heavily on specific metabolic reprogramming to execute their immune functions effectively. Recent evidence demonstrates the pivotal role of macrophage immunometabolism in orchestrating inflammatory responses and regulating systemic metabolic health. This review provides the first comprehensive synthesis of current evidence linking PEVs to the function and metabolic reprogramming of macrophages. We first conducted a detailed exploration of the release rationale, biosynthesis, composition, uptake by macrophages, and biological activity of PEVs. Subsequently, we elucidated how these vesicles and their cargo influence macrophage polarization through several metabolic pathways, including glycolysis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and amino acid metabolism. We further explore the implications of macrophage immunometabolism in chronic inflammation and metabolic disorders, including inflammatory bowel disease (IBD), neurodegenerative diseases, and atherosclerosis. Additionally, emerging evidence indicates that PEVs may be influenced by various factors, which in turn can affect host immunity and metabolism. Finally, we briefly discuss the limitations and future challenges in this field. This review highlights new research targets concerning the impact of gut microbiota on host immunity and metabolism.

Keywords:  Probiotics; bacterial extracellular vesicles; immunometabolism; macrophage; metabolic pathways

DOI:  https://doi.org/10.1080/19490976.2026.2614115
Nat Immunol. 2026 Jan 15.

Metabolic adaptation in CD4+ T cells promotes immunosuppression in sepsis.

Nicole M Chapman, Hongbo Chi.

DOI: https://doi.org/10.1038/s41590-025-02403-4
Nat Rev Immunol. 2026 Jan 12.

Metabolites as signalling molecules in the tumour immune microenvironment.

Youxiang Mao, Wenjun Xia, Peng Jiang.

Alterations in key metabolic pathways are required for tumour development and the adaptation of tumour cells to intrinsic or extrinsic stresses, as well as for the regulation of immune cell fate and immune responses in the tumour microenvironment. In particular, the dysregulation or alteration of certain metabolites produced by tumour cells has been shown to be important in creating the immunosuppressive tumour microenvironment. Recent studies have broadened our understanding of the interactions between metabolites and antitumour immunity. Here we highlight how, beyond their metabolic role, metabolites can function as signalling molecules to modulate the behaviours of immune cells and tumour cells. We also discuss potential therapeutic strategies targeting specific metabolites and future research directions in metabolite sensing.

DOI: https://doi.org/10.1038/s41577-025-01258-y
Nat Immunol. 2026 Jan 15.

Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis.

Matthew T Stier, Allison E Sewell, Erin L Mwizerwa, Chooi Ying Sim, Samantha M Tanner, Casey M Nichols, Heather H Durai, Erin Q Jennings, Paul Lindau, Erin M Wilfong, Sarah N Obeidalla, V Eric Kerchberger, Dawn C Newcomb, Julie A Bastarache, Lorraine B Ware, Jeffrey C Rathmell.

Metabolic and immunologic dysfunction, including pathological CD4+ T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we characterized the metabolic properties of human CD4+ T cells from critically ill patients with and without sepsis and healthy adults. CD4+ T cells in critical illness showed subset-specific metabolic plasticity, with regulatory T (Treg) cells preferentially acquiring glycolytic capacity that associated with sustained cellular fitness and worsened clinical illness. Adapted Treg cells were more metabolically flexible and stabilized suppressive markers FOXP3 and TIGIT under mitochondrial stress. Single-cell transcriptomics suggested reactive oxygen species (ROS) and kynurenine metabolism as drivers of Treg cell remodeling. Subsequent inhibition of ROS and kynurenine metabolism attenuated glycolytic adaptation and suppressive rewiring, respectively, in Treg cells. These findings indicate that metabolic dysfunction was a contributor to CD4+ T cell remodeling in critical illness and suggest avenues to restore effective immunity.

DOI: https://doi.org/10.1038/s41590-025-02390-6
Int J Biol Sci. 2026 ;22(2): 771-785

Crosstalk between arachidonic acid metabolism and glycolysis drives integrated metabolic-inflammatory reprogramming in macrophages.

Yuanyuan Cheng, Ni Fan, Xiuying Zhang, Wei Zhao, Baoping Xie, Jia Zhao, Marlene Rong, Xuechen Li, Hung-Fat Tse, Jianhui Rong.

  Arachidonic acid (AA)-derived lipid mediators play pivotal roles in inflammation and its resolution. While glycolysis is a key metabolic pathway determining macrophage polarization, the crosstalk between specific AA metabolites and glycolytic reprogramming remains poorly understood. In this study, we explore whether certain AA metabolites modulate macrophage function through covalent protein modification, with therapeutic implications for myocardial ischemia-reperfusion injury. Unlike conventional specialized pro-resolving mediators (SPMs) that primarily act via receptors, here we identify an endogenous electrophilic AA metabolite, 15-keto-prostaglandin F2α (15KPF), that covalently modifies pyruvate kinase M2 (PKM2) at Cys49. Such interaction enhanced PKM2 tetramerization, suppressed the PKM2/HIF-1α/STAT3 axis, redirected energy metabolism from glycolysis to mitochondrial respiration, and promoted pro-resolving M2 macrophage polarization. Mutated PKM2(C49S) failed to inhibit STAT3 signaling and blocked the effect of 15KPF on M1 to M2 phenotype switch. Moreover, 15KPF reduced infarct size and preserved myocardial integrity in in vivo model. Taken together, covalent 15-keto-PGF2α-PKM2 conjugation represents a self-regulatory mechanism linking AA metabolism to glycolysis to drive macrophage metabolic-inflammatory reprogramming. This pathway positions 15KPF as a promising therapeutic candidate for inflammatory and metabolic diseases, including ischemia-reperfusion injury, and distinguishes it from synthetic allosteric PKM2 activators such as TEPP-46.

Keywords:  15-keto-PGF2α; arachidonic acid metabolism; cardioprotection; glycolysis; macrophages; pyruvate kinase M2

DOI:  https://doi.org/10.7150/ijbs.116671
bioRxiv. 2026 Jan 11. pii: 2026.01.09.698698. [Epub ahead of print]

A Closed Computational-Experimental Loop Identifies Metabolic Collapse at the Root of Macrophage Dysfunction due to Zinc Dyshomeostasis.

Sunayana Malla, Deandra R Smith, Ashley M Peer, Derrick R Samuelson, Daren L Knoell, Rajib Saha.

Zinc plays a crucial role in immune regulation, the oxidative stress response, and epithelial barrier integrity, yet zinc's precise role in regulating metabolic and immunological functions in myeloid cells remains poorly understood. Here, we employ a systems biology approach using constraint-based modeling to elucidate the consequences of myeloid-specific loss of ZIP8 on macrophage metabolic function and antibacterial capabilities. We demonstrate that macrophage populations in the lung of ZIP8 knockout ( Zip8 KO) mice exhibit widespread metabolic disruption, spanning glycolysis, butanoate metabolism, amino acid metabolism, and mitochondrial function. Specifically, Zip8 KO macrophages exhibit impaired nutrient uptake and dysregulated energy metabolism, which is exacerbated following Streptococcus pneumoniae infection. Genome-scale metabolic modeling and flux analysis revealed a paradoxical pattern of metabolic suppression prior to infection, followed by overcompensation post-infection, potentially driving immune dysfunction. Consistent with these predictions Zip8 KO bone marrow-derived macrophages displayed increased ATP demand and disrupted mitochondrial energetics, compromising their ability to control infection. Importantly, we identified succinate, and kynurenic acid as metabolites capable of restoring immune responses and validated their ability to enhance bacterial clearance in Zip8 KO BMDMs. Together, these findings establish ZIP8 as a central regulator of immune-metabolic homeostasis and suggest potential therapeutic avenues to restore immune function in settings of zinc deficiency.

DOI: https://doi.org/10.64898/2026.01.09.698698
Microb Pathog. 2026 Jan 14. pii: S0882-4010(26)00017-3. [Epub ahead of print] 108291

Baicalin inhibits macrophage glycolysis and succinate-driven HIF-1α signaling by targeting PKM2 to alleviate RSV-induced inflammation.

He Yang, Yaqian Gu, Yingying Dong, Huan Sun, Shuangshuang Liufu, Haiyan Xu, Ke Du, Linxiu Peng, Weichen Xu, Lili Lin, Tong Xie, Jinjun Shan, Xia Zhao.

  Respiratory syncytial virus (RSV) infection triggers excessive inflammation, contributing to disease severity. Baicalin exerts therapeutic effects against RSV infection by inhibiting viral replication and alleviating inflammation. However, the mechanisms underlying its immunoregulatory during RSV infection remain unclear. Here we found that baicalin alleviated RSV induced inflammation by regulating the macrophage immunometabolism. To investigate metabolic modulation, metabolomic analysis was performed, revealing an obvious reversal in the metabolic profile by baicalin administration. Further metabolic flux analysis using isotope tracers demonstrated that baicalin suppressed the accumulation of lactate and succinate induced by RSV infection. Mechanistically, baicalin inhibited glycolytic metabolism and succinate driven hypoxia-inducible factor 1α (HIF-1α) signaling during RSV infection, thereby suppressing NLR family, pyrin domain containing protein 3 (NLRP3) activation and reducing IL-1β release. The effects were validated in vitro using a glycolysis activator to confirm the suppression of glycolytic metabolism, and through co-treatment with dimethylsuccinate and RSV to verify the involvement of HIF-1α-mediated hypoxia pathway. Final targeting for baicalin at pyruvate kinase M2 (PKM2) was confirmed via molecular docking and limited proteolysis-coupled mass spectrometry. Taken together, these data elucidate a mechanism of baicalin through regulatory immunometabolism of macrophage to alleviate RSV-induced inflammation, which have critical roles in the treatment of RSV infection.

Keywords:  Baicalin; Glycolysis; Hypoxia; Metabolic reprogramming; Respiratory syncytial virus

DOI:  https://doi.org/10.1016/j.micpath.2026.108291
Int J Biol Macromol. 2026 Jan 14. pii: S0141-8130(26)00190-X. [Epub ahead of print] 150264

Baicalin attenuates HIF-1α-driven histone lactylation and neutrophil extracellular trap (NET) formation in autoimmune uveitis.

Bin Liu, Yuan Peng, Congling Wang, Huixia Wei, Yixue Yin, Hongsheng Bi, Xuewei Yin, Dadong Guo.

  Uveitis is a group of vision-threatening intraocular inflammatory disorders that can affect the uveal tract, retina, optic nerve, and vitreous, leading to irreversible structural damage and vision loss. Neutrophil extracellular trap (NET) formation is a key driver of acute uveitis (AU) pathology, but the immunometabolic mechanisms governing NETosis remain unclear. Here, we identified hypoxia-inducible factor-1α (HIF-1α) as a central regulator that links neutrophil metabolism to NET formation. DIA-based lactyl-proteomic profiling revealed widespread nuclear protein lactylation, with histone H3 lysine 18 lactylation (H3K18la) strongly associated with chromatin decondensation during NETosis. In neutrophils from patients with AU, elevated glycolytic activity, including the upregulation of hexokinase 2 and lactate dehydrogenase A, increased intracellular lactate levels, which in turn promoted H3K18la modification. Mechanistically, HIF-1α interacted with the NET-related proteins myeloperoxidase and neutrophil elastase, and its knockdown suppressed glycolytic flux, H3K18la, and NET release. Pharmacological inhibition of glycolysis (2-deoxy-d-glucose) or oxidative stress (Tempol) similarly attenuated NET formation. Notably, baicalin counteracted HIF-1α-mediated metabolic reprogramming, leading to reduced lactate production, decreased levels of H3K18la and citrullinated histone H3, restoration of mitochondrial membrane potential, and suppression of NET formation. Collectively, our findings establish a mechanistic axis in which HIF-1α-driven glycolysis promotes lactate-dependent histone lactylation, which facilitates NET formation in AU. These findings reveal a novel immunometabolic pathway and highlight baicalin as a potential therapeutic agent targeting HIF-1α-mediated NETosis.

Keywords:  Autoimmune uveitis; HIF-1α; NET formation

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150264
iScience. 2026 Jan 16. 29(1): 114385

CCL20-CCR6 signaling alters the metabolic reprogramming to promote the pathogenic Th17 cell differentiation.

Heikrujam Thoihen Meitei, Neeraja Kulkarni, Amey Shirolkar, Srikanth Rapole, Praveen Kumar Sharma, Vikkarasan Rehman Mujeeb, Sharad Srivastava, Girdhari Lal.

  CCR6 is a G-protein-coupled receptor that binds to its ligand CCL20. Th17 and Foxp3+CD4+ T cells express CCR6, enabling their migration to inflamed tissues with unique metabolic environments. The factors that regulate their metabolic adaptation and functional roles in these tissues remain unclear. Using inflammatory bowel disease patient samples and experimental colitis models in mice, we demonstrated that the intrinsic signaling of CCL20-CCR6 in CD4+ T cells promotes the differentiation of inflammatory Th1-like Th17 cells (T-bet+RORγt+) during colitis. This signaling induces the rapamycin-sensitive phosphorylation of PI3K, Akt, mTORC1, and STAT3 in a CCR6-dependent manner. RNA-seq and proteomics analysis revealed that the addition of CCL20 during Th17 differentiation affects several metabolic pathways, including energy metabolism. CCL20 significantly increased glycolysis and inhibited oxidative phosphorylation, thereby driving the differentiation of pathogenic Th17 cells. Our findings suggest that alterations in CCR6-induced changes in Th17 metabolism offer an interesting therapeutic target for gut inflammation and autoimmunity.

Keywords:  Biological sciences; Components of the immune system; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.114385
Adv Sci (Weinh). 2026 Jan 15. e15166

Targeting the CMKLR1-Mediated Signaling Rebalances Immunometabolism State in Middle-Age Testicular Macrophages.

Zhendong Zhu, Feifei Du, Yang Liu, Jinchunzi Yang, Lei Ge, Tianxia Xiao, Mengxia Li, Jie Chen, Jia Tang, Yali Yang, Jian V Zhang.

  Age-related male hypogonadism is often associated with obesity-related metabolic disorders and impaired regulation of the testicular anti-inflammatory microenvironment. However, how adipose-mediated signals intersect with local testicular immunity remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) of human and mouse testes identified a conserved CD206LoMHCIIHi macrophage subset, which undergoes CMKLR1-mediated metabolic reprogramming toward glycolysis and pro-inflammatory state during middle age. This immunometabolic shift is further found to impair spermatogenesis. CMKLR1 is identified as a viable target in vivo for restoring immunometabolic balance in aging testes. Systemic administration of a newly developed CMKLR1 antagonist peptide (P12C5) or non-pharmacological intervention such as high-intensity interval training (HIIT) rescued spermatogenesis in middle-aged humans and mice, and reversed the pro-inflammatory immunometabolic phenotype in testicular macrophages. Together, these findings validate CMKLR1 as a key modulator of testicular immunometabolism and a therapeutic target for mitigating age-related immunometabolic dysfunction.

Keywords:  CMKLR1; HIIT; metabolic reprogramming; spermatogenesis; testicular macrophages

DOI:  https://doi.org/10.1002/advs.202515166
J Lipid Res. 2026 Jan 08. pii: S0022-2275(26)00004-0. [Epub ahead of print] 100978

Targeted PPARδ activation reprograms microglial immunometabolism and improves insulin sensitivity in HFD-fed rats.

Han Jiao, Fernando Cázarez-Márquez, Valentina Sophia Rumanova, Yalin Wang, Andries Kalsbeek, Gertjan Kramer, Shanshan Guo, Chun-Xia Yi.

  Microglia lipid metabolism plays a crucial role in maintaining immune function and supporting neuronal health. Previous studies have shown that a high-fat diet promotes lipid accumulation in microglia, while disruption of lipid uptake and utilization impairs neuroimmune competency and accelerates obesity in response to a high-fat diet, highlighting the importance of lipid processing under obesogenic condition. However, whether enhancing microglial lipid metabolism can restore their immune function and mitigate obesity-associated hypothalamic dysfunction remains unclear. In this study, we investigated whether activation of peroxisome proliferator-activated receptor delta (PPARδ), a key regulator of lipid metabolism, could counteract obesity-related metabolic disturbances. Using thermal proteome profiling, we identified GW0742 as the most potent PPARδ agonists among those tested. Treatment of microglial cells in vitro with GW0742 enhanced phagocytosis, reduced inflammation, and improved microglial metabolic flexibility. To assess therapeutic potential in vivo, we selectively delivered GW0742 to mediobasal hypothalamic microglia in high-fat diet-fed rats using polymeric nanoparticles (NPs-GW0742). This targeted intervention reprogrammed microglial activity and improved insulin sensitivity without affecting body weight or food intake, suggesting a direct central metabolic benefit. Our findings highlight the therapeutic potential of targeting microglial lipid metabolism to improve metabolic health in obesity.

Keywords:  Immunometabolism; Insulin sensitivity; Microglia; Nanoparticles; Obesity; PPARδ

DOI:  https://doi.org/10.1016/j.jlr.2026.100978
Int J Biol Sci. 2026 ;22(2): 895-919

Excessive Kynurenine Metabolism Impairs Lysosomal acidification and Triggers mtDNA Release via the AHR/CISH/ATP6V1A Axis in Decidual Macrophages Associated with Unexplained Recurrent Pregnancy Loss.

Guangmin Song, Hongli Li, Man Zhang, Yun Li, Xinyi Tao, Andi Wang, Jianqi Wang, Boris Novakovic, Richard D Cannon, Richard Saffery, Hongbo Qi, Hua Zhang, Xiaobo Zhou.

  Metabolic disturbances of decidual macrophages (dMφs) may contribute to the pathology of miscarriage, yet the underlying mechanisms remain poorly defined. Here, we document upregulated tryptophan metabolic pathway in dMφs from women with unexplained recurrent pregnancy loss (URPL), with increased kynurenine (KYN) levels in the decidua and elevated aryl hydrocarbon receptor (AHR) expression in dMφs. Excessive activation of the KYN-AHR axis compromises both mitochondrial and lysosomal integrity. This impairment facilitates the leakage of mtDNA into the cytoplasm and subsequent release into the extracellular space, thereby activating the cGAS-STING signaling cascade. Mechanistically, AHR directly binds to the xenobiotic response element within the CISH promoter region, promoting its transcription. The upregulation of CISH promotes the ubiquitination and degradation of ATP6V1A, disrupting lysosomal acidification and exacerbating mtDNA release. In vivo, excessive administration of KYN in pregnant mice increases the rate of embryo resorption, whereas pharmacological inhibition of AHR partially attenuates cGAS-STING pathway activation in dMφs and ameliorates fetal loss in an abortion-prone mouse model. Collectively, our findings describe a pivotal role for the AHR/CISH/ATP6V1A axis in orchestrating immune dysfunction within the decidua that may contribute to URPL, which sheds new light on the potential pathogenesis of URPL and paves the way for improving pregnancy outcomes.

Keywords:  aryl hydrocarbon receptor; decidual macrophages; extravillous trophoblasts; mitochondrial DNA; recurrent pregnancy loss

DOI:  https://doi.org/10.7150/ijbs.121947
Nat Commun. 2026 Jan 14. 17(1): 229

6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.

Saeed Daneshmandi, Qi Yan, Eduardo Cortes Gomez, Jee Eun Choi, Eriko Katsuta, Ehsan Gharib, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Elizabeth A Repasky, Philip L McCarthy, Hemn Mohammadpour.

The mechanisms underlying the metabolic adaptation of myeloid cells within the tumor microenvironment remain incompletely understood. Here, we identify 6-phosphogluconate dehydrogenase (6PGD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), as an important regulator of monocytic-myeloid derived suppressor cell (M-MDSC) function. Our findings reveal that tumor M-MDSCs upregulate 6PGD expression via IL-6/STAT3 signaling. Blocking 6PGD, using either genetic or pharmacological approaches, impairs the immunosuppressive function of M-MDSCs and suppresses tumor growth. Mechanistically, 6PGD inhibition leads to the accumulation of its substrate, 6-phosphogluconate (6PG), within M-MDSCs, activates the JNK1-IRS1 and PI3K-AKT-pDRP1 signaling pathways, leading to mitochondrial fragmentation and elevated mitochondrial reactive oxygen species (ROS). This metabolic shift drives M-MDSCs toward an M1-like proinflammatory phenotype. Furthermore, 6PGD blockade synergizes with anti-PD-1 immunotherapy in a preclinical tumor model, substantially improving therapeutic outcomes. Our data reveals 6PGD as a possible therapeutic target to disrupt M-MDSC function and improve cancer immunotherapy outcomes.

DOI: https://doi.org/10.1038/s41467-025-68102-8
bioRxiv. 2026 Jan 06. pii: 2026.01.05.697503. [Epub ahead of print]

Loss of Acid Ceramidase in Myeloid Cells Protects from Chronic Colitis in IL10-Deficent Mice.

Keila S Espinoza, Brandon K Dahl, Jessica N Wysong, Ella M Ryan, Mary R Gordon, Chelsea L Doll, Marilyn T Marron, Cameron A Beard, Pujarini D Dey, Richard J Simpson, Justin M Snider, Justin E Wilson, Pawel R Kiela, Ashley J Snider.

Background & Aims: Patients with inflammatory bowel disease (IBD) exhibit elevated expression of acid ceramidase (AC), a sphingolipid metabolism enzyme. Recent studies have shown that myeloid cells contribute to the elevated expression of AC, such that the conditional loss of AC is protective in IBD.
Methods: Bone marrow derived macrophages (BMDMs) and neutrophils (BMDNs) were utilized to assess the role of AC in immune cell mediated inflammation. We then crossed conditional ASAH1 LyzM CRE knockout mice with IL10 knockout mice to determine the role of AC in a model of spontaneous colitis. Colon tissues were analyzed for lipids, mRNA, and protein. We performed flow cytometry to determine the role of myeloid AC in recruiting effector T cells in disease.
Results: In this study, we found that loss of AC impaired secretory and migratory functions in BMDMs, but not BMDNs. Further, the conditional loss of AC protected from spontaneous, chronic colitis. Loss of AC reduced inflammatory markers, increased colon ceramides, and reduced the inflammatory metabolite sphingosine-1-phosphate (S1P). Recruitment of immune cells into intestinal tissue was significantly impaired, namely neutrophils and effector Th1/Th17 T cells.
Conclusions: Loss of AC reduced inflammation and impaired immune cell recruitment in chronic colitis. Targeting AC may serve as a promising therapeutic potential for patients with IBD by modulating immune cell sphingolipid metabolism.
WHAT YOU NEED TO KNOW: BACKGROUND AND CONTEXT: Acid ceramidase expression is increased in immune cells in patients with inflammatory bowel disease, specifically in macrophages.NEW FINDINGS: We determined that loss of acid ceramidase (AC) in macrophages, but not neutrophils, impairs inflammatory functions in vitro, and that loss of AC in myeloid cells partially protects from spontaneous colitis in vivo by reducing immune cell recruitment into intestinal tissue. LIMITATIONS: The IL10 knockout model of colitis exhibits highly variable onset and severity of disease, which may be challenging to distinguish the extent of protection.CLINICAL RESEARCH RELEVENCE: This study identifies AC as a promising therapeutic target for treating inflammatory bowel disease.BASIC RESEARCH RELEVENCE: This study contributes to our understanding of the role that AC plays in inflammation within immune cells, specifically myeloid cells. Additionally, this study underscores the role of immune cell sphingolipid metabolism in inflammatory bowel disease.LAY SUMMARY: Loss of acid ceramidase in myeloid cells protects from chronic colitis by decreasing inflammation, altering immune cell function, and impairing the recruitment of effector immune cells to the colon.

DOI: https://doi.org/10.64898/2026.01.05.697503
Eur J Immunol. 2026 Jan;56(1): e70120

The Increased Secretion of Lactate Observed in Obesity and Aging Leads to the Generation of Pathogenic B Cells.

Maria Romero, Amanda Virtue, Kate Miller, Andrew Gelsomini, Dhananjay Suresh, Sophie LaPointe, Suresh Pallikkuth, Daniela Frasca.

  Lactate is a metabolite with immunoregulatory functions. We evaluated lactate secretion and its effects on B cells from individuals with different body composition: YLEAN, YOBESE, and ELEAN individuals. Results show higher serum metabolic profiles in YOBESE and ELEAN versus YLEAN individuals, evaluated by levels of lactate dehydrogenase, the enzyme that converts pyruvate into lactate, which is associated with increased secretion of lactate in blood-derived B cells. Double negative (DN) B cells, which expand in the blood of YOBESE and ELEAN individuals, are the major contributors to this metabolic profile. When lactate was added in vitro to B cells from YLEAN, YOBESE, and ELEAN individuals, we found increased secretion of pathogenic autoimmune antibodies in B cells from YLEAN, compared to those from YOBESE and ELEAN individuals, likely because B cells from YOBESE or ELEAN individuals have already been exposed to, and chronically stimulated by lactate in vivo, becoming refractory to further stimulation. Mechanistically, the effects of lactate are mediated by phosphorylated signal transducer and activator of Transcription 3 (p-STAT3). These effects are inhibited in the presence of a neutralizing antibody that blocks the lactate transporter SLC5A12, responsible for lactate uptake and activation of inflammatory and pathogenic responses, and p-STAT3.

Keywords:  B cells; aging; lactate; obesity

DOI:  https://doi.org/10.1002/eji.70120
Adv Sci (Weinh). 2026 Jan 15. e20815

Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy.

Wang Yi, Di Wu, Jing Liu, Shi Chen, Liu Song, Bin Xie, Aini Xie, Peixiang Lan, Zhishui Chen.

  Chronic allograft vasculopathy (CAV) is driven in part by stem-like CD4+ T cells, but how these cells sustain their progenitor programs during chronic rejection remains unclear. Here, a metabolic-epigenetic axis is identified in which Mapk13 phosphorylates Tcf1 at T289, enabling Tcf1 to activate the amino acid transporter Slc7a5 and enhance methionine uptake. This rewires one-carbon metabolism and increases H3K4me3 enrichment at the Tcf7 locus, thereby maintaining stem-like CD4+ T cells within rejecting grafts. Disruption of this circuit-via genetic deletion of Mapk13 or Slc7a5, or through dietary methionine restriction-reduces Tcf1+ CD4+ T cell stemness and prevents CAV in mouse models. These findings reveal the Mapk13-Tcf1-Slc7a5 axis as a critical metabolic dependency of pathogenic T cells and highlight one-carbon metabolism as a promising target to promote long-term graft survival.

Keywords:  TCF1; chronic allograft vasculopathy; methionine restriction; one‐carbon metabolism; stem cell‐like T cells

DOI:  https://doi.org/10.1002/advs.202520815
Immunol Rev. 2026 Jan;337(1): e70103

Metabolic Stress and Immune Activation in Heart Failure With a Preserved Ejection Fraction.

Ana Pereira, Santiago Alvarez-Argote, Isaac Meite, Hiroyasu Inui, Jacob K Sterling, Evette J Thorp, Matthew J Feinstein, Mallory Filipp, Edward B Thorp.

  Inflammation is triggered by imbalances to systemic and cellular metabolism. This occurs in the setting of cardiometabolic heart failure, for which low-grade inflammation is a commonly reported feature. In experimental models, immune cells are causal determinants in the pathophysiology of metabolic syndromes. Herein we discuss evidence for the contribution of metabolic stress to immune cell activation during cardiometabolic heart failure with preserved ejection fraction. We also discuss related therapeutic approaches along the way.

Keywords:  HFpEF; immunometabolism; inflammation

DOI:  https://doi.org/10.1111/imr.70103
Genes Genomics. 2026 Jan 13.

Lasting bone marrow defects imprinted by hyperglycemia shape the immunological characteristics of differentiated M1 and M2 macrophages.

In-Gu Lee, Jeonghyeon Lee, Ji Young Bang, Young-Jin Seo, So-Hee Hong.

   BACKGROUND: Hyperglycemia in type 1 diabetes (T1D) disrupts immune function, yet it remains unclear whether hyperglycemia-induced immunological defects in the bone marrow (BM) persist in BM-derived M1 and M2 macrophages.
OBJECTIVE: We investigated the immunological and metabolic features of BM-derived M1 and M2 macrophages from prediabetic and diabetic non-obese diabetic (NOD) mice to determine the impact of hyperglycemic memory on polarized macrophages.
METHODS: Macrophages were differentiated from BM cells of prediabetic and diabetic NOD mice and subsequently polarized with lipopolysaccharide (LPS; M1 macrophages) or interleukin-4 (IL-4; M2 macrophages). Transcriptomic profiles were assessed using RNA sequencing and gene set enrichment analysis of differentially expressed genes (DEGs). In parallel, glycolysis, oxygen consumption, and cytokine production were evaluated.
RESULTS: Hyperglycemia induced pronounced transcriptomic alterations in both M1 and M2 macrophages, modifying immune and metabolic gene expression. Immune pathways, including inflammatory responses and cytokine production, were consistently suppressed in both subsets from diabetic mice compared with those from prediabetic mice. Metabolically, M1 macrophages preserved mitochondrial and glycolytic activity under diabetic conditions, whereas M2 macrophages exhibited impaired oxidative phosphorylation and glycolysis, resulting in diminished energy production. Functionally, both subsets from diabetic mice secreted lower levels of inflammatory cytokines upon stimulation relative to prediabetic counterparts.
CONCLUSION: These findings demonstrate that hyperglycemia imprints persistent transcriptomic and functional defects in BM-derived M1 and M2 macrophages. This work provides new insights into how chronic hyperglycemia contributes to impaired host defense and dysregulated inflammation in diabetes.

Keywords:  Hyperglycemia; M1/M2 macrophage; NOD mice; Type 1 diabetes

DOI:  https://doi.org/10.1007/s13258-025-01736-6
Biotechnol Prog. 2026 Jan 13. e70100

Dynamics of natural killer cell function upon recurrent stimulation.

Jennifer One, Janani Narayan, Frank Cichocki, Wei-Shou Hu, Samira M Azarin.

  Natural killer (NK) cells have shown potential for allogeneic cell-based cancer immunotherapies. For development of economical off-the-shelf allogeneic therapies, maximal expansion of the NK cells from each donor must be achieved while maintaining efficacy and uniformity of the cell product. The standard method for robust expansion utilizes weekly stimulation with engineered feeder cells derived from the K562 cell line. However, the effects of repeated stimulation on NK cell growth, metabolism, and function are not well understood. In this study, we demonstrated a distinct shift in growth kinetics and metabolism around week 3-4 of repeated K562 feeder cell stimulation, followed by a change in cytokine secretion and killing ability. Seahorse metabolic flux assays and transcriptomics suggested a transition from glycolytic metabolism to oxidative metabolism after the first week of stimulation, but the shift in growth kinetics generally correlated to reduced metabolic activity. Collectively, these results indicate that serial stimulation sustains large-fold NK cell expansion that can be exploited for NK cell therapy; however, this expansion has important impacts on NK cell growth, metabolism, and function. Careful characterization is critical when developing large-scale biomanufacturing processes to ensure efficacy of the final cellular product.

Keywords:  biomanufacturing; cytotoxicity; growth; metabolism; natural killer cells

DOI:  https://doi.org/10.1002/btpr.70100
Science. 2026 Jan 15. 391(6782): eadq9006

Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.

Danhui Liu, Chuanli Zhou, Xiaochen Wang, Zhou Luo, Ruiyao Xu, Shanshan Huo, Lina Guo, Xuemei Luo, Shuhan Yang, Arielle Click, Janiece Vancil, Paola Barajas, Victor Mijares, Hamid Baniasadi, Nan Yan, Jan Rehwinkel, Dustin C Hancks, Elizabeth H Chen, Shuang Liang, Zhenyu Zhong.

Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome hyperactivation and excessive interleukin (IL)-1β production in macrophages by disrupting SAM and HD domain-containing protein 1 (SAMHD1), a deoxynucleoside triphosphate (dNTP) hydrolase crucial for nucleotide balance. This caused aberrant accumulation of dNTPs, which can be transported into mitochondria, and initiated mitochondrial DNA (mtDNA) neosynthesis, which increased the presence of oxidized mtDNA and triggered NLRP3 hyperactivation. Deletion of SAMHD1 promoted NLRP3 hyperactivation in cells isolated from zebrafish, mice, and humans. SAMHD1-deficient mice showed elevated circulating IL-1β, insulin resistance, and metabolic dysfunction-associated steatohepatitis. Blocking dNTP mitochondrial transport prevented NLRP3 hyperactivation in macrophages from obese patients and SAMHD1-deficient mice. Our study revealed that obesity by inhibiting SAMHD1 rewired macrophage nucleotide metabolism, thereby triggering NLRP3 inflammasome hyperactivation to drive disease progression.

DOI: https://doi.org/10.1126/science.adq9006
Sci Immunol. 2026 Jan 23. 11(115): eadz7275

PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells.

Keling Huang, Xiaoxue Li, Wenhua Liang, Shuyao Wu, Youqiong Ye, Yan Lu, Junke Zheng, Weifang Wang, Qifan Zheng, Guo Fu, Song Gao, Feng Wang.

Immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often limited by the progressive exhaustion of tumor-reactive CD8 T cells. By analyzing transcriptomes of CD8 T cells from patients treated with ICB across cancer types, we found that prothymosin alpha (PTMA) is highly expressed in progenitor exhausted T (TPEX) cells and is associated with treatment response. PTMA expression was directly controlled by T cell factor 1 (TCF1), a central regulator of TPEX cell maintenance in the tumor microenvironment. In mice, genetic deletion of Ptma from T cells compromised CD8 T cell persistence in tumors and abolished the therapeutic effect of programmed cell death protein 1 (PD-1) blockade. PTMA preserved mitochondrial DNA integrity through interaction with mitochondrial transcription factor A (TFAM), sustaining T cell oxidative phosphorylation under metabolic stress. Our findings identify the TCF1-PTMA axis as a molecular link between mitochondrial fitness and durable T cell-mediated antitumor immunity, offering insights and potential directions for future therapeutic strategies to boost immunotherapy efficacy.

DOI: https://doi.org/10.1126/sciimmunol.adz7275
Nature. 2026 Jan 14.

Cancer might evade immune defences by stealing mitochondria.

Laura Dattaro.



Keywords:  Cancer; Immunology; Metabolism

DOI:  https://doi.org/10.1038/d41586-026-00123-9
Int Endod J. 2026 Jan 11.

Dental Pulp Stem Cells Orchestrate Macrophage Polarisation in Pulpitis via Mitochondrial Transfer.

Xiaoqian Gong, Lisha Zhu, Can Wang, Yu Wang, Yao Sun.

   AIM: Pulpitis represents a prevalent clinical condition in dentistry. Macrophages play pivotal roles in pulpitis immunopathology, while dental pulp stem cells (DPSCs) serve as key effectors in pulp tissue repair and immune regulation. Although mesenchymal stem cells are known to regulate immunity through mitochondrial transfer, this mechanism remains unexplored in pulpitis. This study investigated how mitochondrial transfer influences pulpitis progression and resolution.
METHODOLOGY: To investigate DPSC-macrophage mitochondrial transfer and its role in polarisation of macrophages, Lipopolysaccharide-stimulated cocultures were established. Transfer dynamics were analysed by fluorescence microscopy and flow cytometry. Macrophage polarisation (assessed via quantitative real-time polymerase chain reaction (qRT-PCR)/flow cytometry) in the cocultures was detected after mitochondrial transfer agonist/inhibitor treatment. Macrophage polarisation (assessed via qRT-PCR/flow cytometry) and mitochondrial function (reactive oxygen species production, membrane potential) were compared between mitochondria-receiving (Mito+) and non-receiving (Mito-) macrophages. Immunometabolic profiles (itaconate/succinate) were evaluated by qRT-PCR/immunofluorescence. Human dental pulp explants and experimental rat pulpitis models demonstrated the anti-inflammatory and reparative effects of mitochondrial transfer agonists. Data were analysed by one-way ANOVA and unpaired t-tests (α = 0.05).
RESULTS: Mitochondrial transfer from DPSCs to macrophages reduced during inflammation. Pharmacological inhibition of mitochondrial transfer exacerbated M1 macrophage polarisation, whereas its enhancement promoted M2 polarisation. Mito+ macrophages exhibited stronger M2 polarisation, improved mitochondrial function, and reduced itaconate/succinate metabolism compared to Mito- cells. Notably, using the inflamed dental pulp explant and the experimental rat pulpitis model, we demonstrated that augmenting mitochondrial transfer can effectively alleviate pulpitis and promote repair.
CONCLUSIONS: Mitochondrial transfer from dental pulp stem cells to macrophages via tunnelling nanotubes improved macrophage metabolic profiles. Enhanced mitochondrial transfer promoted M2 macrophage polarisation, thereby alleviating pulpal inflammation and promoting repair.

Keywords:  dental pulp stem cells; macrophage polarisation; metabolic reprogramming; mitochondrial transfer; pulpitis

DOI:  https://doi.org/10.1111/iej.70097
Cytokine Growth Factor Rev. 2026 Jan 09. pii: S1359-6101(26)00003-1. [Epub ahead of print]88 32-46

Reprogramming immunity at the metabolic-epidermal interface in obesity-associated psoriasis.

Jinsun Jang, Minji Park, Hee Joo Kim, YunJae Jung.

  Obesity and psoriasis are chronic inflammatory disorders, now recognized to be interconnected, in which metabolic overload drives immune dysregulation and therapeutic resistance. Excess adiposity converts adipose tissue into an inflammatory organ that releases adipokines and cytokine-like mediators, reprogramming keratinocytes and immune cells to sustain cytokine-driven inflammatory circuits in the skin. Excess nutrients and lipotoxic stress impair mitochondrial function, enhance glycolysis, and induce epigenetic remodeling in myeloid and epithelial lineages, generating metabolic memory that perpetuates inflammation. Increased body mass index and insulin resistance are clinically associated with reduced responses to biologics targeting tumor necrosis factor, interleukin (IL)-17, and IL-23, whereas metabolic interventions including caloric restriction and glucagon-like peptide-1 receptor agonists improve responsiveness. Recent multi-omics, single-cell, and spatial studies demonstrate that obesity reshapes dermal and adipose immune niches and rewires epidermal innate immunity, attenuating cytokine blockade. Obesity-associated psoriasis thus represents a metabolically imprinted inflammatory state driven by chronic metabolic stress. This review integrates mechanistic and clinical insights and discusses strategies to restore metabolic-immune plasticity to sustain disease remission.

Keywords:  Innate immunity; Myeloid cells; Obesity; Psoriasis; Treatment resistance

DOI:  https://doi.org/10.1016/j.cytogfr.2026.01.003
Life Sci. 2026 Jan 12. pii: S0024-3205(26)00017-2. [Epub ahead of print]388 124209

From inflammation to innovation: Exploring the emerging roles of itaconate in ARDS.

Guixiang Yang, Ling Hu, Min Zhong, Xia Huang, Jianhua Li.

  Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure characterized by diffuse alveolar damage, pulmonary edema, and decreased lung compliance. It represents the most severe manifestation of acute lung injury (ALI). Conditions such as sepsis, acute pancreatitis, and trauma are well-recognized triggers of ALI/ARDS. Given the high mortality rate and limited therapeutic options, current management strategies primarily rely on lung-protective ventilation, careful fluid management, and pharmacological interventions. Consequently, there is an urgent need to develop novel and more effective therapeutic approaches. Itaconate, a metabolite generated during immune cell activation, exhibits potent anti-inflammatory and antioxidant properties. Emerging evidence suggests that itaconate confers protective effects in various inflammatory diseases. This review explores the mechanisms and functions of itaconate in the context of ARDS, providing new insights into its potential as a therapeutic agent.

Keywords:  ARDS; Cell death; Immunometabolism; Itaconate; Oxidative stress

DOI:  https://doi.org/10.1016/j.lfs.2026.124209
J Lipid Res. 2026 Jan 13. pii: S0022-2275(26)00006-4. [Epub ahead of print] 100980

Tryptophan and polyamine metabolism dysregulation serves as an early marker of high-fat diet-induced glucose intolerance.

Jianfang Gao, Li Zhang, Shumin Zhan, Zhou Peng, Juan Du, Zhongxiao Zhang, Liling Xu, Shan Huang, Xingyun Wang, Xirong Guo.

   BACKGROUND: A high-fat diet (HFD) induces metabolic dysfunction early, before the onset of the classic obese phenotype. However, understanding this early process remains limited, and potential diagnostic systems are still poorly investigated, particularly in childhood obesity.
METHODS: Continuous blood glucose monitoring was performed in mice to evaluate the early metabolic effects of HFD exposure. Metabolomic and transcriptomic analyses were conducted to characterize metabolic and transcriptional changes at various HFD feeding stages and investigate underlying mechanisms. Venn analysis was applied to identify metabolites specific to early HFD exposure. These metabolites were further compared with those detected in obese children to identify potential early-warning biomarkers of obesity.
RESULTS: Week 3 of HFD feeding was identified as a critical turning point in metabolic dysfunction in mice. Metabolomic profiling revealed that significant metabolic remodeling had occurred before glucose intolerance, particularly involving alterations in tryptophan metabolism, polyamine metabolism, and glycerophospholipid metabolism. Moreover, 54 HFD-specific metabolites were identified during this early stage. Further analysis identified serotonin, formiminoglutamate, inosine and spermine as potential early-warning biomarkers for HFD-induced obesity. Finally, transcriptomic profiling revealed early activation of IL-17A and type I interferon pathways, implicating immune involvement in metabolic perturbations.
CONCLUSIONS: Early HFD exposure induces metabolic reprogramming before the onset of glucose intolerance. These findings provide new insights into the mechanisms of diet-induced metabolic dysfunction and support the identification of potential biomarkers for early detection, particularly in childhood obesity.

Keywords:  Dysglycemia; High-fat diet; Metabolic perturbations; Polyamine metabolism; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.jlr.2026.100980
Int Immunopharmacol. 2026 Jan 10. pii: S1567-5769(26)00024-X. [Epub ahead of print]172 116181

Bergenin attenuates traumatic brain injury via inhibition of microglial PFKFB3-driven glycolytic-inflammatory crosstalk.

Boyu Sun, Aobo Zhang, Shiyao Feng, Abdul Wahab Jamali, Ziyang Jia, Yaran Xu, Zijian Wang, Jingnan Zhao, Guozhu Sun, Liqiang Liu.

  Traumatic brain injury (TBI) initiates a complex cascade of neuroinflammatory and metabolic disturbances that exacerbate neuronal loss and neurological dysfunction. Microglial glycolytic reprogramming, particularly driven by the rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), has emerged as a key driver of secondary injury. Bergenin, a naturally occurring C-glycoside with antioxidant and anti-inflammatory activities, has demonstrated multi-organ protective potential, but its underlying mechanisms of immunometabolic regulation in TBI remain unclear. Here, we integrated transcriptomic profiling, weighted gene co-expression network analysis (WGCNA), and multi-database target prediction to identify PFKFB3 as a critical target of Bergenin in TBI. Machine-learning-based screening and molecular docking, dynamics, and surface plasmon resonance (SPR) assays confirmed a direct and stable Bergenin-PFKFB3 interaction (KD = 6.33 μM). In vivo, Bergenin improved neurological recovery in TBI mice, evidenced by reduced neuronal damage, apoptosis, and pro-inflammatory cytokine production (TNF-α, IL-6, and IL-1β). It also downregulated PFKFB3 and its downstream glycolytic enzymes (HK2, PKM2, and LDHA), indicating attenuation of glycolytic activation after injury. Single-cell transcriptomic analysis revealed microglia-enriched PFKFB3 expression associated with inflammatory signaling and altered intercellular communication patterns. In vitro, Bergenin treatment and silencing of PFKFB3 inhibited LPS + IFN-γ-induced microglial activation, reduced glycolytic activity and promoted a phenotypic shift from pro-inflammatory to anti-inflammatory states, with no further enhancement upon their combination. These findings identify PFKFB3 as an immunometabolic regulation hub in TBI and uncover Bergenin as a promising natural compound that directly targets microglial PFKFB3, reprograms immunometabolic pathways, and alleviates post-traumatic neuroinflammation.

Keywords:  Bergenin; Glycolysis; Immunometabolism; Microglia; Neuroinflammation; PFKFB3; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.intimp.2026.116181
Cell Mol Immunol. 2026 Jan 13.

Excitatory amino acid transporters support mast cell degranulation via α-KG-mediated methylation of Spp1.

Zhending Gan, Yaoyao Xia, Peng Bin, Muyang Zhao, Youyou Zhou, Bingnan Liu, Wenkai Ren.

  Excitatory amino acid transporters (EAATs) mediate the progression of inflammatory diseases. However, the involvement of EAATs in the activation of mast cells (MCs) and MC-associated diseases remains unclear. Here, we demonstrate that EAAT2 expression (encoded by Slc1a2) directed by immunoglobulin E (IgE)-mediated high-affinity IgE receptor (FcεRI)-p38 signaling is indispensable for MC degranulation through osteopontin (OPN, encoded by Spp1). Mechanistically, EAAT2 regulates intracellular glutamate/alpha-ketoglutarate/reactive oxygen species (ROS) metabolism to reduce the DNA and histone H3K9 methylation of Spp1. Most importantly, MC-specific depletion of Slc1a2 alleviates the allergic response in mice, and EAAT2 expression is positively correlated with MC-associated diseases in humans. Taken together, our findings establish a mechanistic link between amino acid transporters and epigenetic modifications with MC activation and provide potential therapeutic targets for allergic diseases.

Keywords:  Excitatory amino acid transporter 2; Mast cell; Methylation; OPN; α-KG

DOI:  https://doi.org/10.1038/s41423-025-01375-7
Nat Immunol. 2026 Jan 12.

PARP inhibition generates enhanced CD8+ central memory T cells by transcriptional and metabolic reprogramming.

Wael Traboulsi, Pankaj Gaur, Subhadip Kundu, Zainab Ramlaoui, Christopher Priestley-Milianta, Aishwariya Iyengar, Nour Shobaki, Dareen Sarhan, Min-Jung Lee, Jung-Min Lee, George N Pavlakis, Mikayel Mkrtichyan, Viia E Valge-Archer, Simon T Barry, Vivek Verma, Seema Gupta, Samir N Khleif.

CD8+ central memory T (TCM) cells provide stronger antitumor immunity than more-differentiated effector memory counterparts. Here we show that poly(ADP-ribose) polymerase (PARP) inhibition induces CD8+ TCM cells with superior memory by activating the SIRT-1-FOXO1 pathway and inducing metabolic and transcriptional switches through inhibition of enzymatic activity and enhanced PARP trapping. Together, this results in suppression of the cell cycle and upregulation of memory and fatty acid oxidation gene expression, and reprogramming CD8+ T cells into TCM cells with enhanced metabolic fitness and substantially higher recall capabilities. PARP inhibitor treatment of tumor-bearing mice resulted in an increase in the number of 'superior TCM' cells within the tumor microenvironment and enhanced immune-mediated antitumor responses. PARP inhibitor-treated CD8+ T cells were more effective in adoptive cell therapy. Furthermore, the frequency of CD8+ memory T cells and the expression of their memory markers was increased in patients with cancer treated with PARP inhibitor. Together, these data show that PARP inhibition directly reprograms CD8+ T cells, enhancing metabolic fitness and generating highly effective therapeutically superior memory cells.

DOI: https://doi.org/10.1038/s41590-025-02383-5
J Agric Food Chem. 2026 Jan 12.

Urolithin A Attenuates Sleep Deprivation-Induced Neutrophilic Inflammation by Suppression of the ROS-H3K18la Feedback Loop.

Ren Zhou, Keyun Li, Haoyi Zhang, Yili Wang, Chunjiao Wei, Shuhao Fan, Zongjun Yin, Xiaodong Zhang, Dalong Ren.

  Sleep loss drives metabolic and immune dysfunction, yet the epigenetic links to inflammation remain poorly defined. Using larval zebrafish with a continuous-swim paradigm, we demonstrate that acute sleep deprivation (SD) induces sleep fragmentation, systemic oxidative stress, and sustained neutrophilic inflammation─phenotypes associated with elevated histone H3K18 lactylation (H3K18la), an epigenetic modification from glycolytic lactate. Critically, gut microbiota metabolite Urolithin A (UA) exerts potent protection: it downregulates ROS-generating and glycolysis-related genes and reduces intracellular lactate and histone lactylation, collectively disrupting the pathogenic ROS-H3K18la feedback loop. Mechanistically, UA reduces aberrant H3K18la deposition at the il6 and cybb promoters to suppress transcription. Functional assays confirm that UA rescues SD-impaired inflammation resolution, reduces excessive neutrophil recruitment/retention at injury sites, and restores antioxidant homeostasis. These findings identify UA as a multitarget modulator that mitigates SD-associated inflammation via the ROS-H3K18la-inflammation axis, highlighting its translational potential for sleep loss-related immune/metabolic disorders.

Keywords:  H3K18la; ROS; UA; inflammation; neutrophil; sleep deprivation

DOI:  https://doi.org/10.1021/acs.jafc.5c10266
mSphere. 2026 Jan 15. e0052325

Increased triacylglyceride and ceramide levels are key for MERS-CoV replication.

Hugh D Mitchell, Jennifer Kyle, Kristin Engbrecht, Madelyn Berger, Kristie L Oxford, Amy C Sims.

  Emerging viruses remain a threat to human health; however, many aspects of their infection cycle are still poorly understood. Host lipid structures and abundances are observed to be significantly altered during infection, and the mechanisms regulating lipid synthesis and modification remain largely unknown. In this work, we analyzed a large multi-omic data set from three Middle East respiratory syndrome coronavirus (MERS-CoV)-infected primary human lung cell types, all derived from three distinct donors to investigate the changes in lipid species during infection. Analysis of lipidomics data identified perturbations of various lipid classes, and we hypothesized and confirmed that MERS-CoV infection orchestrates an increase in ceramide via sphingomyelinase pathways required for infection. We also identified a minor subset of proteins with lipid-related functions with increased differential expression among a striking majority of lipid-related proteins with decreased differential expression. The most prominent of these is ACSL3, a long-chain acyl-CoA synthetase that is key for the synthesis of triacylglycerides and is associated with lipid droplet formation, an established feature of coronavirus-infected cells. Accordingly, the inhibition of acyl-CoA synthetase activity reduced MERS-CoV replication. These results suggest a model wherein coronaviruses perturb overall cellular metabolism to shift resources to the production of ceramides and triacylglycerides, particularly through acyl-CoA synthetase activity. Our findings suggest a strategy for targeting CoV replication through the inhibition of specific subsets of lipid metabolism.
IMPORTANCE: Combating emerging viral threats requires an in-depth understanding of how the virus commandeers host resources to facilitate replication. Viral particles are comprised of protein and lipids; hence, the synthesis of both is critical for virus spread. Our studies have demonstrated that the synthesis of two lipid species, ceramides and triacylglycerides, is essential for Middle East respiratory syndrome coronavirus replication and that virus replication is impaired if these synthetic pathways are blocked. These results suggest a model wherein coronaviruses perturb overall cellular metabolism to shift resources to the production of ceramides and triacylglycerides. Our findings suggest a strategy for targeting coronavirus replication through the inhibition of specific subsets of lipid metabolism.

Keywords:  ACSL3; MERS-CoV; infection phenotypes; lipid metabolism; lipidomics; proteomics

DOI:  https://doi.org/10.1128/msphere.00523-25
medRxiv. 2026 Jan 06. pii: 2026.01.02.25343095. [Epub ahead of print]

Metabolic Basis of Post-Infectious Sequelae After Ebola Virus Disease.

Anna Sanford, Nell Bond, Samuel Ficenec, Charlotte Osterman, Payton Farkas, Emily Engel, Bronwyn Gunn, Donald S Grant, Robert Samuels, Kevin Zwezdaryk, John Schieffelin.

Ebola virus disease (EVD) survivors often present with clinical sequelae after acute disease resolution, called post-Ebola syndrome (PES). Why some survivors develop these sequelae and others do not is poorly defined. Altered metabolism has been noted in acute EVD but not studied in PES. We identified differential expression of metabolites involved in multiple metabolic pathways in EVD survivors with PES. This included the tricarboxylic acid cycle, amino acid, nucleotide, and short chain fatty acid metabolism. Several of these pathways are associated with immune dysfunction. The identified metabolites have potential use as biomarkers of post-Ebola syndrome.

DOI: https://doi.org/10.64898/2026.01.02.25343095
Inflammation. 2026 Jan 16.

Narciclasine Alleviates Endothelial Inflammation and Atherosclerosis Initiation by Inhibiting Histone Lactylation-Mediated NF-κB Activation.

Ziqian Wang, Zhengbin Zhang, Ran Xin, Mingrui Ma, Zeyu Sun, Zhongxuan Li, Chen Zhang, Liangliang Liu, Zhengfeng Wu, Yingqian Zhang, Yundai Chen.

  Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation, characterized by upregulated glycolysis, initiates atherosclerosis, yet the contribution of histone lactylation remains undefined. Although narciclasine exhibits anti-inflammatory and antioxidant properties, its impact on endothelial inflammation in atherosclerosis is unknown. Connectivity Map (CMap) analysis predicted narciclasine as an inhibitor of oscillatory shear stress and TNF-α-induced endothelial inflammation. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with 20 nM narciclasine significantly suppressed ox-LDL-induced expression of VCAM1, ICAM1, SELE, and CCL2, reduced reactive oxygen species (ROS) production, and inhibited monocyte adhesion and migration. In vivo, administration of narciclasine (0.02 mg/kg) attenuated carotid artery endothelial inflammation and macrophage infiltration, consequently reducing early atherogenesis in partial carotid ligation model in ApoE-/- mice. Mechanistically, ox-LDL upregulated GLUT1 and PFKFB3 expression, enhancing endothelial glycolysis and lactate production. Increased lactate accumulation promoted histone H3 lysine 18 lactylation (H3K18la). Both pharmacological (2-DG, DCA) suppression of lactate production or genetic (LDHA, P300 silencing) suppression reduced H3K18la levels and inhibited ox-LDL-induced endothelial inflammation. Reanalysis of public CUT&Tag data (GEO: GSE267661) and chromatin immunoprecipitation (ChIP) validation revealed ox-LDL-induced enrichment of H3K18la at key promoters of NF-κB pathway genes (TRAF2, TRAF6, RIP1, cIAP1, RELA). Narciclasine treatment suppressed GLUT1 and PFKFB3 expression, thereby reducing H3K18la enrichment and inhibiting NF-κB pathway activation. Our findings provide novel insights into the functional role of lactylation-mediated epigenetic regulation in glycolysis-driven endothelial inflammation. Collectively, this study identifies narciclasine as a potential therapeutic candidate, which mitigates endothelial inflammation and early atherosclerosis by targeting a glycolysis-H3K18la network linked to NF-κB activation.

Keywords:  Atherosclerosis; Endothelial inflammation; H3K18la; Lactylation; Narciclasine

DOI:  https://doi.org/10.1007/s10753-025-02446-7