bims-imicid 2026-04-05 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–04–05
thirty-one papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Egg white-derived metabolic regulatory peptide AD-IR10 promotes diabetic wound healing via Keap1/Nrf2/Irg1-mediated macrophage metabolic reprogramming.
CD8+ T cell exhaustion driven by metabolic reprogramming.
4-octyl itaconate inhibits cytokine-mediated inflammation via alkylation of TYK2 and JAK1.
Visualizing the metabolic battleground: the role of PET imaging in understanding immunometabolism and the tumor microenvironment.
Sulfur partitioning from cysteine controls T cell proliferation and effector function.
ACOD1 regulates microglial arginine metabolism and inflammatory responses.
Macrophage metabolism reprogramming in sepsis: Pathogenesis and therapeutic implications (Review).
Itaconate as a Potent Regulator of Neutrophil Responses in Host Defence and Inflammation.
Copper supports regulatory T cell energetic state to sustain peripheral immune tolerance.
Metabolic reprogramming is critical to microglial activation in Huntington's disease.
Persistent IFN-I signaling inhibits mitochondrial oxidative metabolism in CD8+ T cells during HIV-1 infection under cART.
Indoleamine 2,3-dioxygenase-regulated macrophages metabolic reprogramming rescues tacrolimus-induced nephrotoxicity.
Lactic acid drives NLRP3 inflammasome activation and caspase-1-like cytokine cleavage via intracellular acidification.
Global translational and metabolic remodeling during iron deprivation in Toxoplasma gondii.
Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility.
The role of glucose metabolic reprogramming in myocarditis and advances in therapeutic strategies.
Holding cancer in line: the role of the electron transport chain in tumor-associated macrophages.
Obesity Disrupts H3K4me3-Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages.
IL-38 reprograms macrophage metabolism to restrain NLRP3 inflammasome assembly and attenuate monosodium urate crystals induced inflammation.
Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity.
Metformin drives HIF-1α-mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer.
Metabolic reprogramming of CAR-T cells: a multi-pronged strategy to conquer the immunosuppressive tumor microenvironment.
Mitochondrial kinase CMPK2 in immune homeostasis and disease: from metabolic regulation to inflammatory signaling.
LDHA-driven lactate metabolism promotes MDSC activation and immunosuppressive microenvironment in prostate cancer.
The mitochondrial metabolic shift in inflammatory monocytes during Plasmodium vivax malaria.
P2X7 receptor-mediated cGAS-STING pathway activation underlies chronic stress-induced depressive-like behaviors.
Allergic lung inflammation can be modulated by niacin and drives the development of glycolytic eosinophils.
β-hydroxybutyrate modulates enteric pathogen susceptibility through regulation of commensal bacteria and intestinal Th17 responses.
SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption.
Krüppel-like factors 2 and 3 regulate T cell exhaustion by directing T cell residency and migration.
NEK8 kinase-mediated lactate increase impairs antitumor immunity decreasing radiotherapy sensitivity in colorectal cancer.

Free Radic Biol Med. 2026 Apr 01. pii: S0891-5849(26)00183-8. [Epub ahead of print]

Egg white-derived metabolic regulatory peptide AD-IR10 promotes diabetic wound healing via Keap1/Nrf2/Irg1-mediated macrophage metabolic reprogramming.

Dan Sun, Ting Su, Xingtang Niu, Yu He, Xinhui Wang, Felix Sumampouw, Chenlu Wu, Feng Lu, Qiang Chang, Ziqing Dong.

  Chronic diabetic wounds are characterized by oxidative stress and persistent inflammation, largely due to dysregulated macrophage polarization. Here, a decapeptide, ADHPFLFFIR (AD-IR10), derived from egg white hydrolysate, was identified as a modulator of the Keap1-Nrf2 pathway. AD-IR10 reduces oxidative stress and reprograms macrophage metabolism via the IRG1-itaconate axis, shifting macrophages from pro-inflammatory M1 to reparative M2 phenotypes. Integrated transcriptomic and metabolomic analyses revealed that Nrf2 activation by AD-IR10 enhances itaconate accumulation, suppresses glycolysis, and promotes oxidative phosphorylation in the TCA cycle. Functional assays demonstrated that AD-IR10-treated macrophages display improved mitochondrial function and anti-inflammatory activity. In a diabetic mouse wound model, topical administration of AD-IR10 accelerated wound closure, increased angiogenesis and collagen deposition, and enhanced M2 macrophage infiltration. These results identify AD-IR10 as a food-derived peptide capable of modulating macrophage immunometabolism, offering a promising therapeutic strategy for chronic diabetic wound repair.

Keywords:  Antioxidative Peptide; Diabetic Wound Healing; Egg White; Immunometabolism; Itaconate; Macrophage

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.005
Cancer Cell Int. 2026 Apr 03.

CD8+ T cell exhaustion driven by metabolic reprogramming.

Wenzhi Deng, Chunhong Li, Qiang Wang, Xiulin Jiang, Yongzhi Xie.



Keywords:  CD8⁺ T cells; Fatty acid oxidation; Glycolysis; Immunotherapy; Metabolic reprogramming; Mitochondrial metabolism; T cell exhaustion; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-026-04287-2
Cell Rep. 2026 Mar 30. pii: S2211-1247(26)00257-3. [Epub ahead of print]45(4): 117179

4-octyl itaconate inhibits cytokine-mediated inflammation via alkylation of TYK2 and JAK1.

Weizhen Li, Qiong Zhang, Songqi Jing, Liting Deng, Haiyang Jiang, Jinpeng Zhang, Zhiwu Hong, Zherui Zhang, Shuai Hao, Lei Wu, Tao Zheng, Yilong Yu, Xiao Ma, Xuefeng Wang, Qingchuan Li, Zhentao Yu, Mingda Liu, Jiaxin Yang, Bin Liu, Haiqing Liu, Chujun Ni, Cunxia Wu, Zitian Hu, Pengfei Zheng, Peige Wang, Yun Zhao, Jianan Ren, Xiuwen Wu.

  Itaconate is a Krebs cycle-derived metabolite whose production is catalyzed by immune response gene 1 (IRG1). As an anti-inflammatory metabolite, itaconate primarily exerts its effects through alkylation of target proteins. Previous studies have identified the JAK-STAT pathway as a key therapeutic target in sepsis. Interestingly, we report that itaconate, a metabolite significantly upregulated during metabolic reprogramming, suppresses type I interferon (IFN-I) signaling. Exogenous supplementation with the itaconate derivative 4-octyl itaconate (4OI) inhibits the JAK-STAT pathway. Mechanistically, 4OI inhibits the binding of tyrosine kinase 2 (TYK2) to IFNAR1 and JAK1 to IFNAR2 by alkylating cysteine 192 in TYK2 and cysteine 189 in JAK1. Our research has identified the crucial role of itaconate produced by the tricarboxylic acid (TCA) cycle in restricting JAK-STAT signal transduction, thereby linking metabolism and innate immunity, and provides a theoretical basis for the therapeutic application of 4OI in sepsis.

Keywords:  4-octyl itaconate; CP: immunology; CP: metabolism; IFN-I; IRG1; JAK1; TYK2; inflammation; itaconate; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2026.117179
Nucl Med Commun. 2026 Mar 31.

Visualizing the metabolic battleground: the role of PET imaging in understanding immunometabolism and the tumor microenvironment.

Raydel Briankwee Amalo, Hendra Budiawan, Budi Darmawan.

  PET has evolved beyond tumor glucose metabolism imaging to assess the immunometabolic landscape of the tumor microenvironment (TME) and systemic immune responses. Immunometabolism, encompassing glycolysis, oxidative phosphorylation, and fatty acid oxidation, governs immune cell activation, differentiation, and effector function, shaping antitumor immunity and immunotherapy outcomes. PET radiotracers, including fluorine 18-fluorodeoxyglucose, amino acid/nucleoside tracers (11C-methionine, 18F-F-AraG), cytokine/receptor-targeted tracers (64Cu-IFNγ, 68Ga-NOTA-Nb109), and macrophage-directed tracers (11C-PK11195, gallium-68-labeled NOTA-mannosylated serum albumin), enable noninvasive visualization of immune metabolism, proliferation, and polarization. Novel agents such as gallium-68-labeled fibroblast activation protein inhibitor and 68Ga-Pentixafor further capture stromal remodeling and immune cell recruitment. Clinically, immunometabolic PET guides oncology, immunotherapy, autoimmune, inflammatory, and infectious disease management by distinguishing immune activation from tumor progression, evaluating therapeutic response, and identifying active inflammation. This emerging imaging paradigm provides mechanistic insights into immune-tumor interactions and offers a precision tool for personalized treatment strategies.

Keywords:  PET imaging; immune cell activation; immunometabolism; radiotracers; tumor microenvironment

DOI:  https://doi.org/10.1097/MNM.0000000000002150
Cell. 2026 Mar 31. pii: S0092-8674(26)00279-5. [Epub ahead of print]

Sulfur partitioning from cysteine controls T cell proliferation and effector function.

Beth Kelly, Minsun Cha, Tatjana Gremelspacher, Jacob L Martin, Massimo Andreis, Isha Maloo, Gustavo E Carrizo, Mia Gidley, Michal A Stanczak, Petya Apostolova, Joseph Longo, Lisa M DeCamp, Eric H Ma, Ryan D Sheldon, Russell G Jones, David E Sanin, Ananya Majumdar, Erika L Pearce.

  Delineating how acquired nutrients are partitioned into different intracellular pathways and how these various fates support distinct functions in T cells is limited. We show that CD8+ T cells acquire cysteine to serve both as a substrate for glutathione (GSH) production, which modulates effector functions, and to cede its sulfur for NFS1-dependent FeS cluster synthesis, which supports proliferation. NFS1 deletion in activated CD8+ T cells promotes exhaustion and dampens anti-cancer immunity, whereas blocking cysteine flux into GSH or enforcing FeS metabolism enhances tumor control. This role for disrupted FeS metabolism in T cell exhaustion is echoed in data from human hepatocellular carcinoma. Elucidating how different intracellular pathways use cysteine enables targeted control of cysteine flux to retain the beneficial effects of cysteine while abolishing those that restrain function. We illustrate this concept for one metabolite, cysteine, but it is likely to apply to other metabolites relevant for immune cell function.

Keywords:  CD8+ T cells; Fe-S clusters; T cell exhaustion; anti-tumor immunity; cysteine; glutathione; immunometabolism; iron uptake; lipid peroxidation; mitochondria

DOI:  https://doi.org/10.1016/j.cell.2026.03.012
Front Immunol. 2026 ;17 1731962

ACOD1 regulates microglial arginine metabolism and inflammatory responses.

Eleftheria Karadima, Canelif Yilmaz, Anupam Sinha, Georgia Fodelianaki, Sofia Dimothyra, Nikolaos Nirakis, Sofia Traikov, Nicola Zamboni, Ben Wielockx, Panayotis Verginis, Mirko Peitzsch, Triantafyllos Chavakis, Vasileia Ismini Alexaki.

  Itaconate is produced by inflammatory macrophages and promotes negative feedback on inflammation. It is synthesized by aconitate decarboxylase 1 (ACOD1) from cis-aconitate, a metabolite of the tricarboxylic acid cycle. Here, we focused on the role of ACOD1 in the immunometabolic reprograming of inflammatory microglia. Similar to macrophages, ACOD1 deficient microglia displayed a stronger inflammatory response to lipopolysaccharide (LPS) compared to their wild type counterparts. The proinflammatory effects of ACOD1 deficiency were associated with enhanced ATP citrate lyase (ACLY) activity and elevated acetyl-CoA amounts, and reprogramed arginine metabolism entailing enhanced argininosuccinate synthesis at the expense of polyamine biosynthesis. These effects of ACOD1 deficiency on arginine metabolism were reversed by ACLY inhibition. These findings provide new insights in the immunometabolic role of ACOD1.

Keywords:  ACLY; ACOD1; argininosuccinate; microglia; polyamines

DOI:  https://doi.org/10.3389/fimmu.2026.1731962
Int J Mol Med. 2026 Jun;pii: 152. [Epub ahead of print]57(6):

Macrophage metabolism reprogramming in sepsis: Pathogenesis and therapeutic implications (Review).

Tong Zhao, Wenzhe Zhang, Zixuan Ren, Xiujing Feng.

  Sepsis is a life‑threatening syndrome of organ dysfunction caused by infection, characterized by complex pathogenesis and high clinical mortality. As innate immune cells, macrophages serve a pivotal role in the initiation, progression and resolution of sepsis. The present review focuses on the key molecular nodes and signaling pathways of macrophage metabolic reprogramming in the process of sepsis. Key mechanisms include: i) The mammalian target of rapamycin‑hypoxia inducible factor‑1α (HIF‑1α)‑pyruvate kinase M2 axis as the primary regulator of glycolytic flux and pro‑inflammatory cytokine production; ii) tricarboxylic acid cycle interruption leading to succinate accumulation, which amplifies HIF‑1a signaling and promotes interleukin‑1β release via G protein‑coupled receptor 91, thereby exacerbating inflammation; iii) triggering receptor expressed on myeloid cells 2‑SH2‑containing protein tyrosine phosphatase‑1 axis‑mediated impairment of fatty acid oxidation, promoting lipid accumulation and pro‑inflammatory activation; and iv) amino acid depletion contributing to immune paralysis. In view of the 31.5% global mortality (21.4 million mortalities in 2021) caused by sepsis, a shift from supportive treatment to precise immune metabolism intervention is needed. The present article uniquely integrates the coordinated regulation of glucose, lipid and amino acid metabolic networks of macrophages in sepsis, and expounds the research status of immune metabolism in sepsis, in order to provide reference for the clinical treatment of sepsis. Targeted modulation of macrophage metabolism offers a new direction for individualized immunometabolic therapy in sepsis.

Keywords:  immune imbalance; macrophages; metabolic reprogramming; sepsis

DOI:  https://doi.org/10.3892/ijmm.2026.5823
Scand J Immunol. 2026 Apr;103(4): e70112

Itaconate as a Potent Regulator of Neutrophil Responses in Host Defence and Inflammation.

Chunying Cheng, Zufeng Cheng, Xinran Ye, Siwei Wang, Changqing Yan, Yiran Chen, Jie Li, Rundong Wu, Aihua Lei.

  Itaconate, derived from cis-aconitate decarboxylation by immune-responsive gene 1 (IRG1; also called cis-aconitate decarboxylase 1, ACOD1), is an intermediate metabolite of the tricarboxylic acid (TCA) cycle in the mitochondria. The production of itaconate in myeloid cells is rapidly increased to high levels in pathological conditions, such as infection and cancer. It is well known that itaconate plays an essential role in regulating macrophage-mediated inflammation and immune response through multiple mechanisms, such as regulating signal transduction and protein modification. As the first responders upon infections and injuries, neutrophils contribute to pathogen clearance and inflammation by several mechanisms, such as phagocytosis, producing reactive oxygen species (ROS), and forming neutrophil extracellular traps (NETs). Increasing evidence shows that neutrophils can also produce itaconate, which in turn modulates neutrophil activation, thereby affecting the elimination of pathogens, the resolution of inflammation, and tumour progression. In this review, we summarize the recent advancements in understanding the effects of endogenous itaconate and its derivatives on neutrophil responses, with a focus on the underlying mechanisms and potential therapeutic applications in infectious and inflammatory diseases.

Keywords:  IRG1; infection; inflammation; itaconate; neutrophils

DOI:  https://doi.org/10.1111/sji.70112
Sci Immunol. 2026 Apr 03. 11(118): eaec2573

Copper supports regulatory T cell energetic state to sustain peripheral immune tolerance.

Yage Zhang, Fan Shi, Haoyu Tang, Tianyi Wang, Hui Zhao, Jie Chang, Chengyao Zhu, Wei Xu, Zhenli Zhu, Jing-Wen Lin, Yanfang Wang, Xiangguang Shi, Jiucun Wang, Junxia Min, Fudi Wang, Qian Wu, Songmin Ying.

Fine-tuning of energy metabolism is essential for the survival and suppressive function of regulatory T cells (Treg cells). Here, we show that Treg cells with a high energetic state display enhanced functional capacity. Using a screen of mitochondrial inhibitors, we identified copper chelators and ionophores as modulators of Treg cell energetic state. T cell receptor (TCR) stimulation in vitro and human autoimmune conditions increased the labile copper pool in Treg cells. In murine Treg cells, we characterized Slc31a1 as a major copper transporter that supports oxidative phosphorylation, sustains nicotinamide adenine dinucleotide/reduced NAD+ (NAD+/NADH) homeostasis, and promotes histone acetylation at loci encoding core Treg cell functional molecules. These mechanisms collectively ensured energy production and Treg cell functionality, which were indispensable for peripheral immune tolerance but could be rescued by the copper ionophore elesclomol. Together, our findings identify copper metabolism as a critical regulator of Treg cell functionality and suggest potential therapeutic avenues for autoimmune diseases.

DOI: https://doi.org/10.1126/sciimmunol.aec2573
JCI Insight. 2026 Apr 02. pii: e201466. [Epub ahead of print]

Metabolic reprogramming is critical to microglial activation in Huntington's disease.

Abhishek Jauhari, Adam C Monek, Olena S Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S Clise, Diane L Carlisle, Robert M Friedlander.

  Huntington's disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine (CAG) repeat in the N-terminal of the Huntingtin protein (HTT). Microglial activation and elevated pro-inflammatory cytokines are observed in HD brains, but the mechanisms regulating neuroinflammation and microglial activation are poorly understood. Metformin-mediated neuroprotection has been demonstrated in experimental models of neurodegeneration, including HD. We found that metformin inhibits mitochondrial DNA (mtDNA) release and subsequent neuroinflammation in the cortex and striatum of a mouse model of HD. Moreover, elevated pro-inflammatory cytokines and microglial activation are inhibited by metformin in HD transgenic mice brain. Metformin reduced pathological microglial clusters and shifted towards a quiescent, homeostatic phenotype. Metformin improved aberrant immunometabolism in HD mouse brain and primary microglia. Mechanistically found that metformin regulates mitochondrial fission, reprograms deregulated metabolism in HD microglia, and controls microglial activation and inflammation in HD transgenic mice.

Keywords:  Glucose metabolism; Metabolism; Neurodegeneration; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.201466
Cell Mol Immunol. 2026 Apr 02.

Persistent IFN-I signaling inhibits mitochondrial oxidative metabolism in CD8+ T cells during HIV-1 infection under cART.

Liang Cheng, Guangming Li, Fei Luo, Wenwen Bi, Mengmeng Lu, Na Liu, Qiuchen Zhao, Runpeng Han, Hongyu Wang, Hao Yang, Jianping Ma, Wenjia Hu, Haisheng Yu, Wei Hou, Yong Xiong, Nilu Goonetilleke, R Brad Jones, Lishan Su.

  Persistent type I interferon (IFN-I) signaling contributes to immune exhaustion and promotes HIV-1 persistence. While we and others have demonstrated that blocking IFN-I signaling in vivo restores anti-HIV-1 T-cell function and reduces viral reservoirs, the underlying mechanism remains unclear. Here, we showed that in humanized mice (hu-mice) and cells from people living with HIV-1 (PLWH), IFN-I signaling impaired mitochondrial activity in CD8+ T cells during chronic HIV-1 infection with effective antiretroviral therapy. Reprogramming immunometabolism by transient inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) rescued mitochondrial activity, reversed aberrant immune activation, and enhanced CD8+ T-cell activity in HIV-infected hosts, both ex vivo and in vivo. When combined with an HIV-1 reservoir-activating agent, 2-DG reduced the viral reservoir size in hu-mice and suppressed HIV-1 amplification in cells from PLWH. These findings indicate that 2-DG-mediated immunometabolic reprogramming represents a novel strategy to restore host immunity and control HIV-1 reservoirs.

Keywords:  2-DG; CD8+ T cell; HIV-1; Immunometabolic reprogramming; Oxidative phosphorylation; Type I interferon

DOI:  https://doi.org/10.1038/s41423-026-01398-8
Front Pharmacol. 2026 ;17 1784153

Indoleamine 2,3-dioxygenase-regulated macrophages metabolic reprogramming rescues tacrolimus-induced nephrotoxicity.

Menghan Ye, Rui Zhang, Pengpeng Guo, Jinping Zhou, Dianwen Yu, Tianze Shang, Peixia Li, Jiaxin Li, Kaiyu Liu, Yani Liu, Shaojun Shi.

  Macrophage metabolic reprogramming toward the M1 phenotype is a key pathological feature of kidney injury. Recent studies have increasingly highlighted the importance of de novo NAD+ synthesis in the development of renal damage. In this study, we found that tacrolimus (TAC) suppressed the activity of indoleamine-2,3-dioxygenase 1 (IDO1), thereby blocking the conversion of tryptophan (Trp) to kynurenine (KYN), impairing de novo NAD+ synthesis. NAD+ deficiency enhances glycolysis, causes accumulation of medium-to long-chain fatty acids and acylcarnitines, indicating impaired fatty acid β-oxidation, thereby promoting M1 polarization and exacerbating renal injury. Further investigations revealed that restoring NAD+ levels via exogenous KYN supplementation or directly activating peroxisome proliferator-activated receptor alpha (PPARα) to enhance fatty acid oxidation effectively reversed this metabolic imbalance and alleviated TAC-induced kidney injury.

Keywords:  IDO1; fatty acid oxidation; macrophage polarization; metabolic reprogramming; tacrolimus

DOI:  https://doi.org/10.3389/fphar.2026.1784153
Cell Death Dis. 2026 Apr 03.

Lactic acid drives NLRP3 inflammasome activation and caspase-1-like cytokine cleavage via intracellular acidification.

Hsin-An Lin, Hsin-Chung Lin, Ming-Hang Tsai, Yu-Jen Chen, Bo-Ying Bao, Kuen-Jou Tsai, Chieh-Tien Shih, Jau-Song Yu, Kun-Yi Chien, Kuo-Yang Huang, David M Ojcius, Lih-Chyang Chen.

Glycolysis is critical for NLRP3 inflammasome activation, yet the link between lactic acid metabolism and inflammasome signaling remains unclear. Here, we show that stimulation of macrophages with the NLRP3 activators nigericin or ATP induces lactic acid production and efflux via a lactate dehydrogenase-dependent pathway. Accumulation of intracellular lactic acid leads to cytoplasmic acidification, which promotes NLRP3 inflammasome activation. Concurrently, elevated extracellular lactic acid impairs lactate efflux, exacerbating intracellular acidification and amplifying ASC speck formation, caspase-1 activation, and IL-1β secretion. Alkalinization of the extracellular milieu prevents intracellular acidification and abolishes inflammasome activation. Mechanistically, intracellular lactic acidification promoted mitochondrial dysfunction and reactive oxygen species production, and concurrently induced phosphorylation of the stress kinase PKR, which facilitated PKR-NLRP3 interaction and inflammasome assembly through parallel pathways. Independently of inflammasome signaling, lactic acid also directly cleaves pro-IL-1β and pro-IL-18 into mature forms through a mechanism requiring its carboxyl group and mimicking caspase-1 substrate specificity. Mass spectrometry analysis revealed lactic acid-mediated cleavage of pro-IL-1β at Asp116, the canonical caspase-1 site. In a murine model of polymicrobial sepsis induced by cecal ligation and puncture, systemic lactate administration exacerbated inflammation, increased IL-1β levels and neutrophil infiltration, induced hypothermia, and worsened survival. Together, these findings identify intracellular lactic acidification as a metabolic signal that promotes inflammation predominantly through NLRP3 inflammasome activation, while also revealing a potential inflammasome-independent cytokine processing mechanism under conditions of severe metabolic stress.

DOI: https://doi.org/10.1038/s41419-026-08708-y
mBio. 2026 Apr 02. e0378825

Global translational and metabolic remodeling during iron deprivation in Toxoplasma gondii.

Jack C Hanna, Shikha Shikha, Megan A Sloan, Clare R Harding.

  Iron is required to support essential cellular processes. Due to diverse and dynamic host environments, the obligate intracellular parasite Toxoplasma gondii must adapt to iron-limited conditions. To investigate the adaptations critical to parasite survival under these conditions, we conducted proteomic and metabolomic profiling of Toxoplasma cultured in iron-depleted conditions. We find that iron depletion results in remodeling of the parasite proteome and triggers swift translational repression, prior to decreases in the key translational factor ABCE1. In the context of repressed translation, we also observe a significant rewiring of energy metabolism. Iron-depleted Toxoplasma have altered mitochondrial morphology and a profound reduction in mitochondrial respiration. Untargeted metabolomics revealed changes in central carbon metabolism, with the accumulation of intermediates of glycolysis and the tricarboxylic acid (TCA) cycle. Stable isotope labeling revealed that iron deprivation leads to a fundamental disconnect between these pathways, with reduced incorporation of glucose-derived carbon into cellular macromolecules and disruption of the TCA cycle. Instead, iron-deprived parasites continued to take up glucose and maintain glycolysis for energy generation. Limiting glucose availability, either in culture media or by genetic ablation of glucose uptake, caused a significant increase in sensitivity to iron restriction. Conversely, the limitation of mitochondrially metabolized glutamine improved parasite fitness in iron-depleted conditions. Together, our results establish iron as a key regulator of parasite translation and metabolic flexibility and demonstrate an increased reliance on glycolysis for energy generation and survival under acute iron deprivation.IMPORTANCEThis study determines the effects of iron deprivation on the parasite Toxoplasma gondii. Using proteomics and metabolomics, we reveal iron as a novel regulator of both protein translation and energy metabolism in Toxoplasma, underpinning the importance of this nutrient for essential cellular processes. We find that iron depletion introduces a metabolic bottleneck, whereby parasites become dependent on glucose as their major carbon source. By modulating the parasite's metabolism by altering carbon source availability, we identify nutrient conditions that improve parasite survival under iron restriction. These data reveal a key role for adaptive plasticity of Toxoplasma central carbon metabolism to drive survival under iron-limited conditions. Understanding the interactions between parasite nutrient availability and metabolism allows us both to map the metabolic flexibility of these parasites and identify potential vulnerabilities.

Keywords:  Toxoplasma gondii; carbon metabolism; iron metabolism; iron regulation; mitochondrial metabolism; proteomics; translation

DOI:  https://doi.org/10.1128/mbio.03788-25
bioRxiv. 2026 Mar 28. pii: 2026.03.27.714789. [Epub ahead of print]

Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility.

Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.

Immune elimination of chronic infection or cancer requires cytotoxic CD8 + T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process and T cells subjected to chronic antigen exposure have compromised effector function despite high rates of glycolysis. Here we report the ability of the short-chain α-hydroxy acid, D-α-hydroxybutyrate, to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation, even in glucose-replete media. This conversion suppresses both AMPK phosphorylation and the integrated stress response (ISR) in activated T cells while significantly elevating the level of the phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induction of CD8-effector gene transcription was coupled to bioenergetics by enhanced ATP-dependent remodeling of chromatin accessibility at effector gene loci. DAHB enhanced CD8 + T cell antitumor activity both in vitro and in vivo, and DAHB treatment of transferred T cells led to persistent in vivo antitumor effects. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

DOI: https://doi.org/10.64898/2026.03.27.714789
Front Cardiovasc Med. 2026 ;13 1781627

The role of glucose metabolic reprogramming in myocarditis and advances in therapeutic strategies.

Xingchen Liu, Bo Han.

  Myocarditis is a heterogeneous inflammatory heart disease most commonly triggered by viral infections, such as Coxsackievirus B3, and may progress to dilated cardiomyopathy and heart failure. Growing evidence highlights the pivotal role of glucose metabolic reprogramming in cardiomyocytes and infiltrating immune cells during the initiation and progression of myocarditis. Under physiological conditions, the adult heart primarily relies on fatty acid β-oxidation for energy production, with glucose oxidation serving a supplementary role. In contrast, myocarditis is characterized by a metabolic shift from oxidative phosphorylation toward enhanced aerobic glycolysis, known as the Warburg effect. This shift results in reduced ATP efficiency, lactate accumulation, excessive reactive oxygen species production, and amplification of inflammatory responses, thereby establishing a self-sustaining immunometabolic vicious cycle. This review summarizes glucose metabolism in the normal heart and highlights the features and regulatory mechanisms of glucose metabolic reprogramming in myocarditis, including the hypoxia-inducible factor-1α/mammalian target of rapamycin axis, nuclear factor erythroid 2-related factor 2-mediated pentose phosphate pathway, immune-responsive gene 1/itaconate axis, and phosphoglycerate kinase 1. Emerging therapeutic strategies targeting glucose metabolism are discussed, as well as current challenges in clinical translation. Advances in multiomics technologies may facilitate the development of precise metabolic interventions for myocarditis.

Keywords:  glucose; glycolysis; immunometabolism; metabolic; myocarditis; regulatory mechanisms; reprogramming; therapeutic targets

DOI:  https://doi.org/10.3389/fcvm.2026.1781627
Front Immunol. 2026 ;17 1802495

Holding cancer in line: the role of the electron transport chain in tumor-associated macrophages.

Alessia Zotta.

  Tumor-associated macrophages (TAMs) are a highly heterogeneous population of innate immune cells that is widely enriched in the tumor microenvironment (TME). By suppressing anti-cancer immunity, TAMs sustain tumor growth, metastasis development and contribute to therapy resistance. Due to their remarkable plasticity, TAMs can be reprogrammed towards immune-stimulatory phenotypes, representing a compelling therapeutic option. The mitochondrial electron transport chain (ETC) is central in fueling macrophage metabolism by coupling electron flow with proton transfer to produce Adenosine Triphosphate (ATP). During inflammation, remodeling of the ETC has been shown to regulate macrophage polarization and cytokine production. However, how ETC perturbations influence macrophage phenotypes in other diseases, as during cancer progression and within a nutrient-restricted environment remains largely unexplored. In this mini-review, we examine the role of the ETC and its individual respiratory complexes in governing tumor-associated macrophage behavior, their involvement in tumor immunity, and we discuss the potential to exploit this axis for innovative immunotherapeutic strategies, while also considering current challenges and limitations.

Keywords:  cancer immunology; electron transport chain (ETC); immunometabolism; mitochondria; tumor associated macrophage (TAM)

DOI:  https://doi.org/10.3389/fimmu.2026.1802495
FASEB J. 2026 Apr 15. 40(7): e71591

Obesity Disrupts H3K4me3-Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages.

Kentaro Takahashi, Julia Drolet, Jinghua Liu, Jasmine R Jackson, Madison Babcock, Muthusamy Thiruppathi, Milie Fang, Tyler Paul, Gayathri Ganesh, Yuri Fukasawa, Yoshikiyo Akasaka, Giamila Fantuzzi, Elizaveta V Benevolenskaya, Timothy J Koh, Norifumi Urao.

  Dysregulated macrophage function drives the development of obesity-associated pathologies. While macrophages adapt to their surrounding environment to maintain tissue homeostasis, the impact of obesity on macrophage adaptation to low oxygen levels remains elusive. Here, we show that hypoxia rapidly increases histone 3 lysine-4 trimethylation (H3K4me3) in bone marrow-derived macrophages (BMDMs) and that this response is impaired in BMDMs from high-fat diet (HFD)-induced obese mice, which significantly affected the expression of genes involved in metabolic pathways, resulting in decreased lactate accumulation, histone lactylation, and expression of genes involved in the maintenance of metabolic homeostasis. Moreover, altered adaptation to hypoxia in BMDMs from HFD mice led to a decreased efferocytosis capacity under hypoxia, which was reversed by supplementation with glucose or lactate. Serial bone marrow transplantation indicated that the maladapted hypoxia response for efferocytosis was imprinted in macrophage precursors in the bone marrow of HFD mice. In BMDMs, genetic disruption of the H3K4me3 demethylase KDM5A further enhances hypoxia-induced H3K4me3 and gene expression, along with lactate accumulation. In a dorsal skin biopsy model, while extracellular lactate levels decreased immediately after wounding but sharply increased in the early phase in normal mice, whereas lactate levels remained low in HFD mice, resulting in delayed wound healing. Our findings suggest that metabolic adaptation to hypoxia involves H3K4me3 and lactate accumulation in macrophages to perform efferocytosis under hypoxic conditions. Diet-induced obesity disrupts this pathway, resulting in impaired efferocytosis and delayed healing, with implications for altered macrophage functions in pathologies associated with obesity.

Keywords:  bone marrow‐derived macrophages; epigenetics; high‐fat diet; histone modification; hypoxia; metabolism; obesity

DOI:  https://doi.org/10.1096/fj.202502626R
Cytokine. 2026 Apr 02. pii: S1043-4666(26)00037-2. [Epub ahead of print]202 157142

IL-38 reprograms macrophage metabolism to restrain NLRP3 inflammasome assembly and attenuate monosodium urate crystals induced inflammation.

Lingjiang Zhu, Liuqing Wang, Yuqi Wang, Jundi Wang, Dawei Cui, Yiwen Wang, Lei Liu, Jing Xue.

   OBJECTIVE: Although interleukin (IL)-38 is recognized as an anti-inflammatory cytokine, its precise mechanism in monosodium urate (MSU) crystals induced inflammation remains undefined, and its impact on macrophages metabolism during MSU crystals induced inflammation has not been explored.
METHOD: RAW264.7 cells, THP-1 cells and mouse peritoneal macrophages were stimulated with MSU crystals with or without recombinant IL-38. Glucose uptake, Glucose Transporter Type 1 (GLUT1) expression, Reactive Oxygen Species (ROS) levels and NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation and assembly were assessed by quantitative real-time PCR, immunofluorescence and western blot. In vivo, C57BL/6 mice received daily intraperitoneal injection of recombinant mouse IL-38(rmIL-38) or vehicle for 5 days, followed by MSU crystals intraperitoneal injection. Lavage cytokines and inflammasome proteins were quantified.
RESULTS: IL-38 attenuated MSU crystals induced up-regulation of NLRP3 inflammasome. MSU crystals rapidly up-regulated GLUT1, increased glucose uptake and ROS production, and promoted NLRP3-apoptosis-associated speck-like protein containing a CARD(ASC)-caspase-1 speck formation. In vivo, IL-38 pretreatment reduced lavage IL-1β and CC motif chemokine ligand 2 and suppressed NLRP3/caspase-1/ASC expression in peritoneal macrophages. Treatment with rmIL-38 alleviated arthritis by MSU crystals.
CONCLUSION: IL-38 acts as a metabolic regulatory cytokine that restraints GLUT1-mediated glycolysis and ROS production, thereby preventing NLRP3 inflammasome assembly and activation. These findings position IL-38 as a promising upstream therapeutic for acute gout.

Keywords:  GLUT1; Glycolysis; Gout; IL-38; NLRP3

DOI:  https://doi.org/10.1016/j.cyto.2026.157142
Science. 2026 Apr 02. 392(6793): eadv6582

Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity.

Zhiyuan You, Jiyeon Kim, Chuansheng Guo, Haoran Hu, Nicole M Chapman, Xiaoxi Meng, Hao Shi, Yan Wang, Cliff Guy, Anil Kc, Jia Li, Jordy Saravia, Gustavo Palacios, Sherri Rankin, Camenzind G Robinson, Hongbo Chi.

Antitumor immunity requires conventional type 1 dendritic cells (cDC1s). How cDC1s maintain functional fitness in the tumor microenvironment remains unclear. In this study, we established that intratumoral cDC1s exhibited discrete mitochondrial states and that OPA1-mediated mitochondrial energy and redox metabolism dictated cDC1 antitumor responses. Mechanistically, OPA1 orchestrated antigen presentation and the CD8+ T cell priming function of cDC1s by promoting nuclear respiratory factor 1 (NRF1) expression and electron transport chain integrity, thereby supporting bioenergetics and NAD+/NADH balance. During tumor progression, mitochondrial membrane potential and volume, as well as OPA1-NRF1 signaling, declined in intratumoral cDC1s. Furthermore, intratumoral administration of cDC1s with polarized mitochondria showed immunotherapeutic benefits in mice, particularly in combination with immune checkpoint blockade. Collectively, our findings reveal mitochondrial metabolism and signaling as putative targets to reinvigorate cDC1 function for cancer immunotherapy.

DOI: https://doi.org/10.1126/science.adv6582
Cancer Immunol Immunother. 2026 Apr 02. pii: 133. [Epub ahead of print]75(4):

Metformin drives HIF-1α-mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer.

Xuping Qin, Haowen Zhong, Meize Liu, Tiantian Yu, Rong Ma, Ying Zhou, Jingyu Chen, Fen Liu, Xiwei Wang, Jianting Long.

  Triple-negative breast cancer (TNBC) lacks effective targeted treatments, rendering γδ T cell immunotherapy a promising therapeutic strategy. However, the function of these immune cells is often limited by exhaustion and immunosuppression. This study investigated whether metformin can enhance γδ T cell-mediated immunity against TNBC. Results demonstrated that metformin increased the cytotoxicity, proliferation, and cytokine production of γδ T cells while reducing their exhaustion markers. It differentially modulated cellular metabolism by enhancing oxidative phosphorylation (OXPHOS) and glycolysis in γδ T cells while suppressing these pathways in cancer cells through AMPK-HIF1-α signaling. Metformin also upregulated stress ligands on tumor cells, thereby improving immune recognition. In chemoresistant models, metformin restored γδ T cell function. Clinical data further showed that high AMPK activity and increased γδ T cell infiltration were associated with improved patient survival. These findings indicate that metformin remodels immunometabolism and enhances tumor immunogenicity, supporting its potential as a combinatory agent in γδ T cell-based immunotherapy for TNBC.

Keywords:   γδ T cells; Metabolic reprogramming; Metformin; TNBC

DOI:  https://doi.org/10.1007/s00262-026-04351-w
Cell Commun Signal. 2026 Mar 31.

Metabolic reprogramming of CAR-T cells: a multi-pronged strategy to conquer the immunosuppressive tumor microenvironment.

Zhi Zheng, Zhichao Chen, Zhiwei Zhang, Zhi Zheng.



Keywords:  Amino Acid metabolism; CAR-T; Glycolytic metabolism; Lipid metabolism; TME

DOI:  https://doi.org/10.1186/s12964-026-02864-6
Int Immunopharmacol. 2026 Mar 30. pii: S1567-5769(26)00427-3. [Epub ahead of print]178 116582

Mitochondrial kinase CMPK2 in immune homeostasis and disease: from metabolic regulation to inflammatory signaling.

Junhui Yao, Mengjie Shi, Siyan Chen, Huan Zhang, Yiming Lin, Chunyan Hua, Sheng Gao.

  Cytidine monophosphate kinase 2 (CMPK2) is a pivotal mitochondrial enzyme that plays a multifaceted role in cellular nucleotide metabolism, immune regulation, and disease pathogenesis. This review comprehensively examines the structural characteristics, enzymatic functions, and regulatory mechanisms of CMPK2, emphasizing its significance in maintaining mitochondrial DNA (mtDNA) integrity and energy metabolism. We explore how CMPK2 links mitochondrial stress to inflammation through its involvement in key immune signaling pathways, including the NLRP3 inflammasome and cGAS-STING pathway, thereby modulating innate immune responses. Notably, CMPK2 is upregulated during viral infections, such as SARS-CoV-2 and Zika virus, where it restricts virus replication and enhance antiviral defenses. Furthermore, we discuss the implications of CMPK2 dysregulation in various non-communicable diseases, including systemic lupus erythematosus and neuroblastoma, highlighting its potential as a diagnostic biomarker and candidate therapeutic target. By integrating recent advances in our understanding of CMPK2's roles across infectious and non-infectious diseases, this review establishes CMPK2 as a pivotal node connecting mitochondrial metabolism, immune responses, and disease mechanisms. Our findings underscore the need for further research to elucidate CMPK2's complex functions and to explore its therapeutic potential in clinical applications, ultimately contributing to improved disease management strategies.

Keywords:  Antiviral defense; CMPK2; Immunity; Inflammation; Mitochondrial metabolism; Therapeutic target

DOI:  https://doi.org/10.1016/j.intimp.2026.116582
Oncogene. 2026 Apr 01.

LDHA-driven lactate metabolism promotes MDSC activation and immunosuppressive microenvironment in prostate cancer.

Xiyi Wei, Xiao Li, Yitong Pan, Yuwei Zhang, Da Zhong, Weiyu Kong, Yue Wang, Zijie Yu, Wenchuan Shao, Yuxiang Dong, Silin Jiang, Zige Qiu, Yuwei Zhang, Xiang Li, Yize Li, Shouyong Gu, Chenxi Tian, Chao Qin, Qingyi Zhu, Ninghan Feng, Ninghong Song, Bing Yao, Zhou Yang.

Immunotherapy has achieved limited efficacy in prostate cancer (PCa), largely due to its profoundly immunosuppressive tumor microenvironment (TME). However, the metabolic mechanisms underpinning this immune resistance remain poorly defined. Here, we identify lactate dehydrogenase A (LDHA)-driven lactate metabolism as a critical regulator of myeloid-derived suppressor cell (MDSC) activation in PCa. Integrated metabolomic, single-cell, and spatial transcriptomic analyses revealed that LDHA is highly expressed in PCa malignant epithelial cells and correlates with increased lactate production and immune exclusion. LDHA-high tumors exhibited enriched infiltration of polymorphonuclear MDSCs (PMN-MDSCs), which were spatially co-localized with LDHA-positive tumor regions. Mechanistically, lactate uptake through monocarboxylate transporter 1 (MCT1) enhanced PMN-MDSC differentiation and upregulated Arg1 and NOS2, reinforcing T cell suppression. Genetic ablation of LDHA in murine models markedly reduced PMN-MDSC infiltration, restored CD8+T cell activity, and inhibited tumor growth. Pharmacological inhibition of LDHA with FX-11 synergized with anti-PD-L1 therapy, producing durable tumor regression. Collectively, these findings define LDHA-driven lactate metabolism as a key metabolic checkpoint in PCa immune evasion and provide a rationale for combining LDHA inhibition with immune checkpoint blockade to overcome immunotherapy resistance.

DOI: https://doi.org/10.1038/s41388-026-03737-5
Curr Opin Immunol. 2026 Apr 02. pii: S0952-7915(26)00046-4. [Epub ahead of print]100 102769

The mitochondrial metabolic shift in inflammatory monocytes during Plasmodium vivax malaria.

Lis Rv Antonelli, Ricardo T Gazzinelli.

Although immunometabolism has emerged as a central area of research in infectious diseases, only a few studies have focused on Plasmodium vivax infection. Here, we discuss the results obtained in our laboratory and elsewhere that show a metabolic-mitochondria shift in highly activated monocytes during P. vivax infection. While these cells show an enhanced phagocytic and microbicidal activity, they produce high levels of proinflammatory cytokines and reactive oxygen species that may contribute to signs of disease during acute episodes of P. vivax malaria. This review focuses on human malaria caused by P. vivax, the most widely distributed species outside Africa. A dedicated section on experimental malaria is included to provide complementary mechanistic insights and to further elucidate immunometabolic pathways.

DOI: https://doi.org/10.1016/j.coi.2026.102769
Purinergic Signal. 2026 Mar 30. pii: 35. [Epub ahead of print]22(2):

P2X7 receptor-mediated cGAS-STING pathway activation underlies chronic stress-induced depressive-like behaviors.

Xi-Meng He, Yi Zhang, Cui-Yuan Chen, Yu-Li Han Tang, Xuan Li.

  Although chronic stress is known to trigger neuroinflammation and depressive-like behaviors, the mechanisms linking stress sensors to inflammatory cascades remain elusive. The purinergic receptor P2X7 (P2X7R), an extracellular ATP-gated cation channel primarily expressed in microglia, is a critical link between stress and neuroinflammation. While the cGAS-STING signaling pathway has been implicated in microglial reactivity, it remains unknown whether P2X7R signals via this pathway. Here, we demonstrate that chronic restraint stress in mice activates microglial P2X7R in the hippocampus, inducing mitochondrial damage. This was accompanied by activation of the cGAS-STING pathway, elevating phosphorylated STING and IRF3 levels along with pro-inflammatory cytokines. Pharmacological inhibition of P2X7R (JNJ-47965567) or STING (H-151) attenuated neuroinflammation and alleviated depressive-like behaviors. In vitro, LPS-stimulated BV2 microglia exhibited mtDNA release and cGAS-STING activation. P2X7R knockdown or pharmacological inhibition attenuated mitochondrial dysfunction, mtDNA release, and subsequent phosphorylation of STING and IRF3. In conclusion, our findings unveil a previously unrecognized mechanism in the neuroimmunological pathology of depressive-like behaviors, demonstrating that chronic stress triggers neuroinflammation through a microglial pathway involving P2X7R-mediated mitochondrial damage, mtDNA release, and cGAS-STING activation.

Keywords:  CGAS-STING Pathway; Depression; Microglia; Mitochondrial DNA; Neuroinflammation; P2X7 Receptor

DOI:  https://doi.org/10.1007/s11302-026-10150-w
Mucosal Immunol. 2026 Mar 28. pii: S1933-0219(26)00037-1. [Epub ahead of print]

Allergic lung inflammation can be modulated by niacin and drives the development of glycolytic eosinophils.

Rossana Azzoni, Kara J Filbey, Maria Z Krauss, Matthew R Hepworth, Joanne E Konkel, Edith M Hessel, Yashaswini Kannan, Nicola L Harris, John R Grainger.

  Eosinophils are key contributors to allergic pathology, however, increasingly eosinophils are described to have important roles in organ health and immunoregulation. The factors that define and regulate these diverse eosinophil functions remain poorly understood. Here we show the emergence of a lung-specific Siglec-Fhi inflammatory eosinophil subset that exhibits high glycolytic activity, mTOR activation and increased amino acid and glucose uptake. The emergence of glycolytic Siglec-Fhi inflammatory eosinophils was apparent in the lung in multiple models of type 2 inflammation and in response to influenza infection. Siglec-Fhi eosinophils present in the lung during allergic inflammation also expressed the niacin and butyrate receptor GPR109A and were niacin responsive. These findings reveal a unique metabolic phenotype of activated lung eosinophils and reveal niacin-GPR109A signaling as a regulator of allergic type 2 immune responses.

Keywords:  Allergy; Eosinophils; GPR109A; Lung; Niacin

DOI:  https://doi.org/10.1016/j.mucimm.2026.03.013
bioRxiv. 2026 Mar 25. pii: 2026.03.20.713262. [Epub ahead of print]

β-hydroxybutyrate modulates enteric pathogen susceptibility through regulation of commensal bacteria and intestinal Th17 responses.

Wenxuan Dong, Chi Yan, Bethany Korwin-Mihavics, Kate Stack, Gillian Hughes, Aidan Schmidt, Kevin Schwartz, Gustavo Caballero-Flores, Margaret Alexander.

T helper 17 (Th17) cells are a critical T lymphocyte subset involved in mucosal immunity and host defense against enteric pathogens. Although ketogenic diets (KD) and the major ketone body β-hydroxybutyrate (BHB) reshape gut microbiota and suppress Th17 responses under defined diet conditions, it remains unclear whether elevation of BHB alone, independent of dietary macronutrient composition and systematic metabolic shift, is sufficient to remodel Th17-inducing commensals and alter host susceptibility to enteric infection. Here, we used 1,3-butanediol (BD), a precursor metabolized to BHB independently of KD, to elevate systemic BHB levels in mice. BD treatment significantly reduced the frequency of ileal Th17 cells, as assessed by flow cytometry for Th17 markers IL-17A and RORγt. 16S rRNA gene sequencing revealed that BD altered gut microbial community structure, as indicated by beta-diversity analysis based on Bray-Curtis dissimilarity, and reduced Shannon diversity and evenness. Linear discriminant analysis effect size identified segmented filamentous bacteria (SFB) as significantly decreased in the ileum following BD treatment, and SFB abundance positively correlated with Th17 markers. Microbiota transplantation demonstrated that BD-shaped microbiota was sufficient to suppress Th17 responses in recipient mice, accompanied by reduced SFB abundance. In a Citrobacter rodentium infection model, BD treatment was associated with increased pathogen burden, and fecal C. rodentium levels were negatively correlated with SFB abundance. Together, these results indicate that BD-induced elevation of BHB reshapes commensal microbiota, including decreasing SFB levels, resulting in dampened Th17 responses and increased susceptibility to enteric infection.
IMPORTANCE: Diet is a key determinant of gut microbial composition and mucosal immune function, yet the microbial mechanisms linking how diet-mediated changes to metabolism regulate immune responses remain incompletely understood. Th17 cells play central roles in both protective mucosal immunity and inflammatory pathology, making them a critical target of immunometabolic regulation. In this study, we show that β-hydroxybutyrate (BHB), generated independently of diet, suppresses intestinal Th17 responses by reshaping the gut microbiota, reducing SFB levels, a potent Th17-inducing murine commensal. We further demonstrate that BHB-associated microbiota changes are linked to increased susceptibility to enteric infection. This work provides a mechanistic framework illustrating how metabolic state can influence host immunity through selective effects on commensal microbes. These findings inform future studies of microbiota-mediated immune regulation.

DOI: https://doi.org/10.64898/2026.03.20.713262
J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00289-9. [Epub ahead of print] 111419

SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption.

Emily A David, Elijah J Bass, Hannah M Woods, Daniel Stephenson, Kellyann Román-Cruz, Charles E Chalfant, Robert V Stahelin.

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped virus that encodes four structural proteins, including the small transmembrane envelope (E) protein. While E is known to function in viral assembly and egress, it contributes to host cell dysfunction and disease severity. We demonstrate that SARS-CoV-2 E localizes to host cell mitochondria and alters mitochondrial structure, metabolism, and redox homeostasis. Using fluorescence microscopy, we observed that E forms tubular cytoplasmic structures that colocalize with mitochondria and ceramide-rich domains. Lipidomic analysis revealed that E expression leads to reductions in cardiolipin, phosphatidylcholine, and lysophospholipids. Mitochondrial membrane potential was decreased in E-expressing cells, consistent with disrupted electron transport chain (ETC) activity, which was further supported by mitochondria stress testing via Seahorse. Despite increased mitochondrial reactive oxygen species (ROS), E did not trigger apoptosis, suggesting containment of oxidative stress within the organelle. Metabolomic profiling revealed decreased levels of key glycolytic and tricarboxylic acid (TCA) cycle intermediates, along with altered glutathione and sulfur metabolism. Notably, glutamine levels increased, potentially to compensate for reduced 2-oxoglutarate. Together, these findings suggest that E protein localizes to the mitochondria, perturbs lipid and metabolic homeostasis, and promotes ROS retention without inducing cell death. This mitochondrial dysfunction may support a shift toward aerobic glycolysis, facilitating viral replication. Our study highlights an underappreciated role for E in modulating host metabolism.

Keywords:  SARS-CoV-2; cellular localization; envelope protein; membrane potential; metabolism; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1016/j.jbc.2026.111419
Immunity. 2026 Mar 27. pii: S1074-7613(26)00091-9. [Epub ahead of print]

Krüppel-like factors 2 and 3 regulate T cell exhaustion by directing T cell residency and migration.

Jian Shen, Ryan J Brown, Yuqi Zhang, Kexin Gai, Ashley K Brown, Ashley M Bauer, Ashley Zhu, Siying Lin, Hongshen Niu, Arjun Kharel, Ziyang Xu, Gregory S Cohen, Taylor A Depauw, Eric Fagerberg, Geoffrey S Kansas, Nikhil S Joshi, Stephen C Jameson, Weiguo Cui.

  During chronic viral infection, CD8+ progenitor exhausted T (Tpro) cells give rise to either cytotoxic effector-like exhausted T (Teff) cells that are migratory or terminally exhausted T cells (Texh) that reside in the tissue parenchyma. Here, we explored how cellular localization influences exhausted T cell fate. We found that Krüppel-like factor 2 (KLF2) promoted the expression and chromatin accessibility of migratory genes, whereas its counterpart, KLF3, limited these programs and promoted tissue residency. Forcing CD8+ T cells out of the tissue environment biased differentiation from the Texh toward the Teff cell trajectory, suggesting that cellular localization can actively influence cell-fate decisions. Mechanistically, KLF2 induced KLF3, which, in turn, constrained Klf2 transcription and competed for shared chromatin-binding sites. In summary, KLF2 and KLF3 form a reciprocal regulatory circuit that governs CD8+ T cell migration and exhaustion during chronic viral infection.

Keywords:  KLF2; KLF3; T cell differentiation; T cell exhaustion; T cell migration; chromatin accessibility; chronic viral infection; sphingosine-1-phosphate signaling; tissue residency; transcriptional regulation

DOI:  https://doi.org/10.1016/j.immuni.2026.02.021
Nat Commun. 2026 Mar 28.

NEK8 kinase-mediated lactate increase impairs antitumor immunity decreasing radiotherapy sensitivity in colorectal cancer.

Mingzhou Li, Yunfei Ni, Jieqiong Wu, Xin Zou, Yining Chen, Junfeng Qiu, Yifang Li, Huayu Cai, Li Wang, Feifei Wang, Hongxia Zhang, Fangyi Han, Jinghao Huang, Zilong Chen, Bingyu Xu, Li Liang.

Radiotherapy effectively treats colorectal cancer (CRC), but local recurrence remains common and abscopal effects-regression of tumors distant from irradiated sites-are rarely observed even with immune checkpoint inhibitors. Here we show that the protein kinase NEK8, highly expressed in CRC, promotes radioresistance by suppressing anti-tumor immunity. In radiation-resistant tumors, NEK8 phosphorylates lactate dehydrogenase A (LDHA), driving lactate overproduction. This metabolite promotes histone modifications that silence antigen presentation machinery, while extracellular lactate directly impairs CD8+ T cell function, collectively excluding CD8+ T cell from the tumor microenvironment. Pharmacological inhibition of NEK8 using CX6258 restores CD8+ T cell infiltration and enhances both local and systemic tumor control following radiotherapy. These findings establish NEK8 as a promising therapeutic target for overcoming radioresistance and inducing abscopal responses in CRC.

DOI: https://doi.org/10.1038/s41467-026-70657-z