bims-imicid 2026-03-22 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–03–22
37 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Editorial: Lipids in immunometabolism.
Ferroptosis-driven metabolic reprogramming in macrophages: Reshaping glucose utilization landscapes.
Immunometabolic Dysregulation in Psoriasis: Mechanisms Driving Inflammation and Emerging Therapeutic Targets.
Beyond drug delivery: nanoparticles as active modulators of immunometabolism for treating inflammatory diseases.
Oxidizing to optimize stemness and antitumor immunity.
Targeting neuroinflammation: itaconate and mesaconate as therapeutic strategies against H7N7 influenza-associated CNS damage.
Scap stabilizes PKM2 to promote glycolysis and enhance anti-fungal immunity in macrophages.
The crosstalk between iron metabolism and immune tolerance in autoimmunity.
Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.
Proteasome-guided haem signalling axis contributes to T cell exhaustion.
The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations.
S1P-S1PR1 signaling impairs CD8+ T cell metabolism and effector function in tumors.
Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and histone modifications in Treg cells.
ALOX15-Derived Oxylipins Attenuate Macrophage Inflammatory Signaling Via a Gαq-PLC-PKC Pathway.
Trem1 regulates neutrophil metabolism and recruitment in lung ischemia-reperfusion injury.
Disturbed LTB4 Metabolism in ILC2s Aggravates Ulcerative Colitis via Intercellular ATP Accumulation.
Macrophage reprogramming and functional plasticity in sepsis.
Dimethyl fumarate alleviated DSS-induced colitis by regulating Th17/Treg balance via suppressing JAK2/STAT3 and NF-κB signaling.
Microglia cause HIV-induced transcriptional and metabolic changes in human neural organoids.
Siah2 Regulates Lipid Uptake in Adipose Tissue Macrophages.
Macrophage-intrinsic and IL-9-dependent arginine metabolism promotes lung tumor growth.
Hypoxia-inducible protein 2 mediates metabolic adaptation of Ly6ChighLy6Glow monocytes after stroke.
Microglial fructose metabolism is essential for glioblastoma growth.
INPP5D/SHIP1-mediated immunometabolic remodeling of renal monocytes in idiopathic membranous nephropathy.
An immunometabolic signature of major depressive disorder in systemic lupus erythematosus.
ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
Glycogen phosphorylase L confers metabolic flexibility in neutrophils to fight fungal infections in nutrient-deprived tissues.
A putative Mycobacterium tuberculosis glyoxalase Rv0801 promotes bacterial fitness by alleviating methylglyoxal stress and blunts NRF2-mediated antioxidant defenses.
Histone H3K9 lactylation activates the TXNIP/NLRP3 pathway to drive macrophage inflammation after spinal cord injury.
Comparative 1H NMR Lipoprotein Profiling of Rheumatoid Arthritis and Systemic Lupus Erythematosus Patients Highlights Disease-Specific Lipoprotein Dysregulation.
A review of the mechanisms linking Th2 immune storm to NETosis through neutrophil glycolytic activation.
Current understanding and advances regarding the adipose-immune-metabolic axis in disease tolerance during sepsis.
Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1.
Paraquat induces neuroinflammation through glycolysis reprogramming in microglia: evidence from network toxicology analysis and in vitro experiments.
Mechanisms and therapeutics of immunometabolic reprogramming driving macrophage-ECs interactions in sepsis-associated ARDS from the gut-lung axis perspective.
Estrogen receptor β deficiency increases susceptibility to sepsis through metabolic reprogramming-induced macrophage pyroptosis.
Crosslinked ionizable lipids reprogram dendritic cell metabolism for potent mRNA vaccination.

Front Immunol. 2026 ;17 1812630

Editorial: Lipids in immunometabolism.

Francesco Nicoli, Anshu Agrawal, Fabrizia Bonacina, Gareth S D Purvis.



Keywords:  T cell metabolism; immunometabolism; lipid metabolism; macrophage polarization; metabolic diseases; sphingolipids

DOI:  https://doi.org/10.3389/fimmu.2026.1812630
Chin Med J (Engl). 2026 Mar 17.

Ferroptosis-driven metabolic reprogramming in macrophages: Reshaping glucose utilization landscapes.

Yasheng Deng, Yafang Zheng, Qian Zhou, Taijin Lan, Qiu Chen.

   ABSTRACT: Ferroptosis, an iron-dependent form of programmed cell death, has attracted significant attention in the field of immunometabolism. Macrophages, which are key immune cells, undergo metabolic reprogramming and polarization, influencing disease progression. This review investigates the interplay between ferroptosis signaling and macrophage glycometabolic reprogramming. To this end, it highlights the roles of iron, lipid, and amino acid metabolism in ferroptosis, alongside the distinct glycometabolic pathways in M1 and M2 macrophages. It also examines how gluconeogenesis, lactate, nicotinamide adenine dinucleotide phosphate, glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway regulate ferroptosis. Furthermore, the review investigates the feedback mechanisms between macrophage polarization and ferroptosis signaling and discusses the implications of these interactions in diseases such as cancer, metabolic disorders, infections, neurodegenerative conditions, and cardiovascular diseases. Finally, it proposes therapeutic strategies targeting ferroptosis to modulate macrophage polarization, offering new insights for disease treatment. Thus, this work provides a foundation for understanding ferroptosis-macrophage metabolism interactions and identifies potential therapeutic targets.

Keywords:  Ferroptosis; Glucose; Glycometabolic pathways; Macrophages; Metabolic reprogramming; Polarization

DOI:  https://doi.org/10.1097/CM9.0000000000004046
Immunol Invest. 2026 Mar 16. 1-27

Immunometabolic Dysregulation in Psoriasis: Mechanisms Driving Inflammation and Emerging Therapeutic Targets.

Aditya Jaswal, Aman Kumar, Preeti Patel, Balak Das Kurmi.

   BACKGROUND: Psoriasis is increasingly recognized as a systemic immuno-metabolic disorder in which chronic inflammation interacts with alterations in cellular energy metabolism.
OBJECTIVE: To summarize current evidence on immunometabolic dysregulation in psoriasis and highlight emerging metabolic-targeted therapeutic strategies.
METHODS: A narrative review of recent literature examining metabolic pathways, immune responses, and therapeutic interventions involved in psoriasis pathogenesis was conducted.
RESULTS: Psoriatic keratinocytes, T cells, dendritic cells, and macrophages undergo significant metabolic reprogramming characterized by increased glycolysis, altered lipid metabolism, mitochondrial dysfunction, and excessive reactive oxygen species production. These metabolic disturbances contribute to keratinocyte hyperproliferation and sustain Th17-driven inflammation, linking skin pathology with systemic comorbidities such as obesity, insulin resistance, dyslipidaemia, and endothelial dysfunction. Key nutrient-sensing regulators, including mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), hypoxia-inducible factor-1α (HIF-1α), sirtuin-1 (SIRT1), and PGC-1α, integrate metabolic status with inflammatory signaling. Additionally, adipokine imbalance and metabolic stress promote chronic metaflammation.
CONCLUSION: Targeting immunometabolic pathways through glycolysis inhibitors, AMPK activators, mTOR modulators, mitochondrial-targeted antioxidants, and lipid-regulating agents may restore metabolic homeostasis and reduce inflammation. Advances in multi-omics approaches may further facilitate biomarker discovery and precision-based therapeutic strategies in psoriasis management.

Keywords:  Psoriasis; glycolysis; immunometabolism; metaflammation; mitochondrial dysfunction; therapeutic targeting

DOI:  https://doi.org/10.1080/08820139.2026.2645963
J Drug Target. 2026 Mar 16. 1-33

Beyond drug delivery: nanoparticles as active modulators of immunometabolism for treating inflammatory diseases.

Hailing Wang, Ahequeli Gemingnuer, Yinan Wang, Yan Liu, Xin Meng.

  Immunometabolism is central to chronic inflammatory diseases, with metabolic reprogramming including dysregulated glycolysis, mitochondrial dysfunction, and excessive ROS production driving pathology in conditions like IBD, rheumatoid arthritis, and psoriasis. Although metabolic regulators hold therapeutic promise, their efficacy is limited by poor site-specific delivery and bioavailability. Nanotechnology-based platforms (e.g., liposomes, polymeric nanoparticles, nanoemulsions, metal nanoparticles) address these barriers by enhancing bioavailability and forming a protein corona that modulates nanoparticle uptake by macrophages and T cells, directly influencing metabolic fate. Advanced organelle-targeting strategies such as mitochondria-directed liposomes and lysosome-responsive polymers enable precise metabolic rescue by restoring mitochondrial respiration or modulating nutrient-sensing pathways. By targeting key metabolic nodes including HIF-1α, mTOR, and AMPK, nanocarriers actively shift immune cells from pro-inflammatory glycolysis toward anti-inflammatory oxidative phosphorylation, minimizing toxicity and restoring immune homeostasis. Thus, nanocarriers function not as passive delivery vehicles but as sophisticated immunometabolism modulators. Despite progress, a comprehensive review bridging nanomaterial design and metabolic intervention remains lacking. This review addresses that gap by highlighting nanoscale phenomena such as stimulus-responsive release, membrane perturbation, and organelle-specific targeting.

Keywords:  Immune Modulation; Inflammatory Diseases; Metabolic Reprogramming; Nanoparticles; Targeted Drug Delivery

DOI:  https://doi.org/10.1080/1061186X.2026.2647069
Cell Chem Biol. 2026 Mar 19. pii: S2451-9456(26)00067-X. [Epub ahead of print]33(3): 280-281

Oxidizing to optimize stemness and antitumor immunity.

Julian J Lum.

In this issue of Cell Chemical Biology, Pang et al.1 address the question of how effector CD8⁺ T cells acquire stem-like durability. They uncover a redox-driven metabolic program in which NQO1-mediated cycling of lawsone enhances pentose phosphate pathway, remodels mitochondrial function, and connects effector differentiation to sustained antitumor immunity.

DOI: https://doi.org/10.1016/j.chembiol.2026.02.011
Front Immunol. 2026 ;17 1776302

Targeting neuroinflammation: itaconate and mesaconate as therapeutic strategies against H7N7 influenza-associated CNS damage.

Melanie Ohm, Wei He, Dunja Bruder, Karsten Hiller, Martin Korte, Shirin Hosseini.

   Introduction: Influenza A virus (IAV) infection is primarily associated with respiratory disease; however, accumulating evidence indicates that neurotropic strains can induce central nervous system (CNS) inflammation and contribute to persistent neurological dysfunction. Aberrant immune activation is thought to play a critical role in these outcomes, yet therapeutic approaches that effectively attenuate neuroinflammation while preserving antiviral immunity remain limited. Immunometabolic regulators, including the endogenous metabolite itaconate, have recently emerged as key modulators of innate immune responses, although their contribution to virus-induced CNS pathology remains incompletely understood.
Methods: In the present study, we investigated whether systemic administration of itaconate or its structural isomer mesaconate modulates neuroinflammatory responses and hippocampal synaptic integrity during infection with the neurotropic IAV strain rSC35M (mouse-adapted A/Seal/Mass/ 1/80, H7N7). Using a murine model, treatment was initiated at the onset of clinical symptoms, and both peripheral and central immune responses were assessed at the peak of disease.
Results and discussion: Neither itaconate nor mesaconate significantly altered overall disease severity, as assessed by body weight loss, although mesaconate attenuated infection-associated hypothermia. Pulmonary inflammatory responses were largely unaffected by treatment; in contrast, mesaconate selectively reduced IL-1β levels in the brain. At the cellular level, H7N7 infection induced pronounced microglial activation within hippocampal subregions, characterized by increased cell density and soma volume, altered process complexity, and enhanced engulfment of postsynaptic material. These infection-induced microglial alterations were partially prevented by mesaconate treatment and largely abrogated by itaconate treatment. Notably, attenuation of microglial density and reactivity during the acute phase was associated with long-term preservation of hippocampal synaptic plasticity. Collectively, these findings indicate that therapeutic administration of itaconate and mesaconate, potentially through distinct mechanisms, can modulate microglia-driven synaptic pathology during neurotropic IAV infection. Targeting immunometabolic pathways may therefore represent a promising strategy to prevent persistent neurological sequelae associated with viral disease.

Keywords:  hippocampus; influenza A virus infection; metabolites; microglia; synaptic plasticity

DOI:  https://doi.org/10.3389/fimmu.2026.1776302
Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00184-1. [Epub ahead of print]45(3): 117106

Scap stabilizes PKM2 to promote glycolysis and enhance anti-fungal immunity in macrophages.

Jiaqi Huang, Yuejue Wang, Fei Li, Nan Zhang, Guoxiong Tian, Dongyu Guo, Yanqi Guo, Zhengyuan Liu, Yinfang Wu, Xiaoping Li, Fei Xu, Zhongnan Qin, Ruixin Jia, Lingling Dong, Shenwei Gao, Jinkang Yu, Jian Lou, Songmin Ying, Daniel H Scharf, Wen Li, Zhihua Chen.

  Fungal infection induces substantial but poorly understood metabolic reprogramming in macrophages. We demonstrate that fungal stimulation reduces Scap levels in human monocytes and murine bone-marrow-derived macrophages (BMDMs), and Scap deficiency impairs cytokine production and phagocytosis, leading to more severe fungal infections. Although Scap canonically regulates lipid synthesis, pharmacological inhibition of lipid synthesis and genetic ablation of SREBP1/2 reveal that Scap-dependent anti-fungal immunity is largely independent of this pathway. Instead, Scap interacts with and stabilizes PKM2, a key glycolysis enzyme, by competitively inhibiting STUB1-mediated ubiquitination and degradation of PKM2 at Lys-311. PKM2 agonist DASA58 enhances fungus-induced production of pro-inflammatory cytokines and phagocytic activity in wild-type BMDMs and partially rescues these functions in Scap-deficient macrophages, whereas myeloid-specific deletion of PKM2 recapitulates the effects of Scap deficiency. These results identify Scap as a critical regulator of PKM2-mediated glycolysis and demonstrate its potential as a therapeutic target for modulation of anti-fungal immunity.

Keywords:  CP: immunology; CP: metabolism; PKM2; STUB1; Scap; anti-fungal immunity; glycolysis; macrophages; phagocytosis; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2026.117106
Inflamm Res. 2026 Mar 17. pii: 52. [Epub ahead of print]75(1):

The crosstalk between iron metabolism and immune tolerance in autoimmunity.

Fatemeh Tavassoli Razavi, Esmaeil Yazdanpanah, Alireza Shadab, Atena Emami, Dariush Haghmorad.

   BACKGROUND: Iron metabolism has emerged as a critical regulator of immune homeostasis, influencing both innate and adaptive immune responses. Dysregulation of iron balance is increasingly recognized as a key driver of autoimmunity, contributing to oxidative stress, ferroptosis, immune cell dysfunction, and the breakdown of immune tolerance.
FINDINGS: This review explores the complex interplay between iron metabolism and autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). We highlight how iron overload and deficiency impact immune cell differentiation, macrophage polarization, Treg/Th17 balance, and B cell activation, thereby promoting chronic inflammation and tissue damage. Moreover, we discuss disease-specific mechanisms such as iron accumulation in the CNS in MS, synovial iron overload in RA, and hepcidin-driven anemia and ferroptosis in SLE.
CONCLUSIONS: Emerging therapeutic approaches, including iron chelation, hepcidin modulation, ferroptosis inhibition, and microbiome-targeted interventions, are examined as potential strategies to restore immune tolerance and mitigate autoimmune pathology. Finally, we emphasize the need for precise iron-targeted therapies, integration with immunomodulatory treatments, and the development of reliable iron-related biomarkers to optimize clinical management of autoimmunity.

Keywords:  Autoimmunity; Ferroptosis; Immune tolerance; Iron chelation; Iron metabolism; Oxidative stress

DOI:  https://doi.org/10.1007/s00011-025-02149-7
J Biol Chem. 2026 Mar 12. pii: S0021-9258(26)00237-1. [Epub ahead of print] 111367

Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.

Karen Slattery, Gearóid Conlon, Ethan Collins, Derek P Nolan, Clair M Gardiner, Geraldine M O'Connor.

Natural Killer (NK) cells are innate lymphocytes that are key to intrinsic cancer immunosurveillance and an important target for cancer immunotherapy. Understanding fundamental human NK cell metabolism provides opportunities for optimising NK cell therapies. Little is known about how glutamine, an important cell nutrient and carbon source, is utilised by human NK cells. To address this, we performed U13C-glutamine tracing experiments by Liquid Chromatography Mass Spectrometry (LCMS) and Gas Chromatography Mass Spectrometry (GCMS) analysis of human NK cells stimulated with IL-2 for 18 hours to provide a global overview of glutamine usage by these cells. Our results show that glutamine is taken up by resting NK cells and that this increases further upon IL-2 stimulation. Metabolite labelling analysis identified that IL-2 results in greater conversion of glutamine to glutamate, allowing for anaplerotic flux into the TCA cycle. The fate of the glutamine-derived carbons diverged at oxaloacetate (OAA) allowing both bioenergetic and biosynthetic outcomes - some carbons continued around the TCA cycle while others were exported, converted to aspartate and subsequently used for pyrimidine synthesis. Nucleotide synthesis by IL-2 activated NK cells was found to be essential for expression of the activation marker CD69. The data indicate that glutamine is a key nutrient taken up by human NK cells, and that IL-2 drives glutaminolysis. Subsequent glutamate is used to support the TCA cycle, generating energy and providing intermediates for de novo pyrimidine synthesis.

DOI: https://doi.org/10.1016/j.jbc.2026.111367
Nature. 2026 Mar 18.

Proteasome-guided haem signalling axis contributes to T cell exhaustion.

Yingxi Xu, Yangtao Shangguan, Yu-Ming Chuang, Tzu-Hsuan Chang, Wenbing Liu, Jhan-Jie Peng, Josep Garnica, Leling Xie, Pei-Chun Hsueh, Mei-Chun Lin, Yi-Hao Wang, Karina Lobo Hajdu, Yibo Wu, Maryam Akrami, Chen Wang, Anna Kohl, Alfred Zippelius, Wei Qi, Min Wang, Bugi Ratno Budiarto, Shih-Yu Chen, Zhengtao Xiao, Panagiota Vardaka, Rahul Roychoudhuri, Zhiliang Bai, Rong Fan, Santiago Carmona, Yi-Ru Yu, Christoph Scheiermann, Jianxiang Wang, Ping-Chih Ho.

The accumulation of depolarized mitochondria commits T cells to exhaustion1-3, yet the precise mechanism remains unclear. Here we find that exhausted CD8+ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19+ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8+ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy.

DOI: https://doi.org/10.1038/s41586-026-10250-y
Pathol Res Pract. 2026 Mar 09. pii: S0344-0338(26)00094-4. [Epub ahead of print]282 156443

The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations.

Amirhossein Faghih Ojaroodi, Samin Shokravi, Shabnam Eskandarzadeh, Armin Ghahremanzadeh, Fatemeh Alizadeh, Farinaz Amirikar, Golnaz Mobayen, Danial Mahrooghi, Masoud Lahouty, Karim Shamsasenjan, Mehdi Talebi.

  Tumor-induced hypoxia remains a pivotal characteristic of the tumor microenvironment (TME), significantly impacting immune cell functionality by fostering immunosuppression, tumor advancement, and resistance to therapies. This review consolidates established and emerging insights into how hypoxia, chiefly orchestrated by hypoxia-inducible factors (HIFs), metabolically and functionally reprograms key immune populations such as B cells, CD4 + T-cells, CD8 + T-cells, natural killer (NK) cells, regulatory T-cells (Tregs), and macrophages. We examine hypoxia-driven metabolic adaptations, signaling alterations, and evasion strategies, including enhanced glycolysis, lactate accumulation, and immune checkpoint upregulation. Furthermore, we integrate cutting-edge findings, such as hypoxia's modulation of NK cell cytotoxicity, immune metabolic reprogramming in the TME, HIF-mediated immune modulation, effector T-cell transcriptomic shifts akin to non-responsive tumor-infiltrating lymphocytes, and autophagy-dependent MHC-I suppression for immune evasion. These advancements underscore therapeutic opportunities in targeting hypoxia to bolster antitumor immunity and mitigate immunotherapy resistance in cancer.

Keywords:  Anti-tumor response; HIF signaling; Hypoxia; Immunomodulation; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2026.156443
EMBO Rep. 2026 Mar 19.

S1P-S1PR1 signaling impairs CD8+ T cell metabolism and effector function in tumors.

Debashree Basak, Puspendu Ghosh, Anupam Gautam, Ishita Sarkar, Arpita Bhoumik, Soham Chowdhury, Shaun Mahanti, Anwesha Mandal, Rajeswari Chakraborty, Anwesha Kar, Snehanshu Chowdhury, Krishna Kumar, Shubhrajit Barman, Senthil Kumar Ganesan, Saikat Chakrabarti, Sandip Paul, Shilpak Chatterjee.

  Sphingosine-1-phosphate receptor 1 (S1PR1) signaling has been linked to the regulation of immunosuppressive cell populations within the tumor microenvironment (TME); however, its role in shaping anti-tumor CD8⁺ T cell responses remains poorly defined. Herein, we demonstrate that intratumoral CD8⁺ T cells express S1PR1, with expression predominantly enriched in the terminally exhausted subset. Transcriptomic profiling, combined with pharmacological inhibition and genetic knockdown, reveals that S1PR1-S1P signaling activates the PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase)-CHOP (C/EBP homologous protein) axis of the endoplasmic reticulum stress response. CHOP, in turn, upregulates transcription of Map3k13 and Map3k15, triggering downstream MAPK signaling and culminating in activation of p38MAPK. Activation of this pathway impairs CD8⁺ T cell metabolism and effector function while increasing apoptotic susceptibility. This ultimately limits the persistence and accumulation of functional CD8⁺ T cells within the TME, thereby compromising their responsiveness to anti-PD-1 therapy. Targeting the S1PR1-S1P axis or its downstream effectors offers a promising strategy to improve cancer immunotherapy outcomes.

Keywords:  CD8+ T Cells; ER Stress; S1P-S1PR1

DOI:  https://doi.org/10.1038/s44319-026-00734-3
Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00162-2. [Epub ahead of print]45(3): 117084

Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and histone modifications in Treg cells.

Siyi Xie, Taiqi Chen, Linfeng Li, Chunyu Tan, Peng Jiang.

  Metabolic regulation is central to the tumor suppressor function of p53. By analyzing the human patients with autoimmune diseases, we found that p53 expression was significantly reduced in Treg cells, negatively correlating with abnormally elevated BCL-6 levels. p53 loss causes dysregulated immune homeostasis and dampens Treg function in vitro and in vivo. Mechanistically, p53 transcriptionally activates ALDH6A1 expression and propionyl-CoA anabolism to upregulate functional Treg gene expression via histone propionylation. Treg-specific knockout of ALDH6A1 phenocopies the autoimmune responses of p53 deficiency, and propionyl-CoA restoration largely recovers Treg cell function in mice lacking p53 or ALDH6A1. Clinically, impaired p53-ALDH6A1-histone propionylation signaling is observed in patients with autoimmune diseases and correlates with poor efficacy of first-line therapies. Together, these findings reveal a direct connection between propionyl-CoA metabolism and histone modifications, which is governed by p53 and is crucial for Treg cell function and immune tolerance suppression.

Keywords:  CP: immunology; CP: metabolism; Treg cells; autoimmunity; histone propionylation; p53; propionyl-CoA anabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117084
FASEB J. 2026 Mar 31. 40(6): e71696

ALOX15-Derived Oxylipins Attenuate Macrophage Inflammatory Signaling Via a Gαq-PLC-PKC Pathway.

Adrian Hilman, Yoshiki Ishii, Bambang Dwi Wijatniko, Dina Mustika Rini, Takuya Suzuki.

  Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal inflammation, yet endogenous lipid-mediated mechanisms that restrain inflammatory responses remain incompletely understood. Oxylipins generated by arachidonate 15-lipoxygenase (ALOX15) have been implicated in intestinal inflammation; however, their functional roles and underlying signaling mechanisms are controversial. Here, we investigated the temporal regulation and anti-inflammatory actions of ALOX15-derived oxylipins in experimental colitis and macrophages. In a dextran sulfate sodium-induced murine colitis model, colonic expression of Alox15 and levels of its downstream oxylipins, including 12-hydroxyeicosatetraenoic acid (12-HETE) and 13-hydroxyoctadecadienoic acid (13-HODE), were increased during the early and middle phases of colitis and declined at later stages. Both intestinal epithelial cells and lamina propria immune cells contributed to Alox15 expression. Functional analyses revealed that 12-HETE and 13-HODE suppressed lipopolysaccharide (LPS)-induced production of tumor necrosis factor-α and interleukin-6 in RAW264.7 macrophages without affecting cell viability or epithelial barrier permeability. Mechanistically, both oxylipins attenuated inflammatory signaling through inhibition of NF-κB, p38, and ERK pathways. Pharmacological analyses demonstrated that these anti-inflammatory effects were mediated via Gαq-dependent G protein-coupled receptor signaling and downstream activation of phospholipase C and protein kinase C. Notably, 12-HETE required Ca2+-dependent conventional PKCs, whereas 13-HODE selectively involved PKCε. Together, our findings identify ALOX15-derived oxylipins as endogenous regulators that attenuate macrophage inflammatory signaling via a Gαq-PLC-PKC pathway, providing mechanistic insight into lipid-mediated control of intestinal inflammation.

Keywords:  G‐protein‐coupled receptors; arachidonate 15‐lipoxygenase; colitis; inflammation; macrophages; oxylipins; protein kinase C; signal transduction

DOI:  https://doi.org/10.1096/fj.202600272R
Redox Biol. 2026 Jan 14. pii: S2213-2317(26)00024-8. [Epub ahead of print]92 104026

Trem1 regulates neutrophil metabolism and recruitment in lung ischemia-reperfusion injury.

Fengjing Yang, Song Tong, Junhao Wan, Yixing Li, Jiani Gao, Yan Sun, Xiangfu Sun, Huikang Fu, Wenzhuo Luo, Jiayang Xu, Ting Zhou, Sowe Babou, Junqi Wu, Guangjian Zhang, Chang Chen, Sihua Wang.

  Primary graft dysfunction (PGD) caused by ischemia-reperfusion injury (IRI) is a major complication after lung transplantation, yet its underlying mechanisms remain unclear. Triggering receptor expressed on myeloid cells 1 (Trem1) is an important mediator of inflammation, but its role in neutrophil function and metabolic reprogramming during lung IRI is not well understood. In this study, we used a murine orthotopic lung transplantation model with cold ischemia and reperfusion, and Trem1 knockout (Trem1-/-) and myeloid-specific Trem1 conditional knockout mice (LysmCreTrem1fl) to explore the role of Trem1 in neutrophil recruitment, neutrophil extracellular trap (NET) formation, and metabolism. Our results show that Trem1 expression increases in both mouse and human lungs after reperfusion and correlates with neutrophil infiltration and lung injury. Trem1 deficiency significantly reduced neutrophil and macrophage recruitment, NET formation, and tissue damage. Multi-omics analysis revealed that Trem1 deletion suppressed oxidative phosphorylation (OXPHOS) and induced a metabolic shift in neutrophils toward glycolysis. In clinical samples, the abundance of TREM1+ neutrophils was correlated with PGD severity and OXPHOS activity. These findings identify Trem1 as a key regulator of neutrophil metabolism and recruitment in lung IRI, and suggest that targeting Trem1 may provide a novel therapeutic strategy to mitigate PGD and improve lung transplant outcomes.

Keywords:  Lung ischemia-reperfusion injury; Neutrophil; Oxidative phosphorylation; Trem1

DOI:  https://doi.org/10.1016/j.redox.2026.104026
Inflammation. 2026 Mar 16.

Disturbed LTB4 Metabolism in ILC2s Aggravates Ulcerative Colitis via Intercellular ATP Accumulation.

Weijia Li, Mengqi Zheng, Yue Wang, Yatai Chen, Hao Bai, Ruijia Li, Shiyang Li, Yanqing Li.



Keywords:  ATP; ILCs; LTB4; Metabolic rewiring; Mitochondria; Ulcerative colitis

DOI:  https://doi.org/10.1007/s10753-026-02486-7
Front Immunol. 2026 ;17 1731805

Macrophage reprogramming and functional plasticity in sepsis.

Tengyue Huang, Huiling Cheng, Qianru Zhao, Min Li.

  Sepsis remains one of the leading causes of mortality worldwide, driven not by the infection itself but by a dysregulated host response that spirals into a cytokine storm and subsequent immune paralysis. This maladaptive immune reaction frequently culminates in life-threatening complications, including multiple organ failure and acute lung injury. Among the immune cells orchestrating this process, macrophages serve as pivotal sentinels of the innate immune system, coordinating inflammatory and reparative programs in response to microbial and endogenous cues. Increasing evidence now reveals that their behavior during sepsis is profoundly shaped by epigenetic regulation. Dynamic changes in DNA methylation, histone modifications, and non-coding RNAs fine-tune macrophage activation, polarization, and memory throughout the septic course. This review will dissect how these epigenetic programs dictate the initiation, progression, and resolution of sepsis, integrating recent discoveries to clarify underlying mechanisms and highlight promising epigenetic targets for therapeutic intervention.

Keywords:  epigenetics; immunity; macrophages; sepsis; therapy

DOI:  https://doi.org/10.3389/fimmu.2026.1731805
Cell Signal. 2026 Mar 14. pii: S0898-6568(26)00139-7. [Epub ahead of print] 112488

Dimethyl fumarate alleviated DSS-induced colitis by regulating Th17/Treg balance via suppressing JAK2/STAT3 and NF-κB signaling.

Lan Jin, Fuxin Guo, Jinmeiqi Liang, Ao Dai, Yajie Wang, Peiqiong Yang, Boyu Du, Xiaodong Wang, Disi Lin, Xueyan Xi, Yang Guo.

  Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by immune dysregulation. Restoring Th17/Treg balance represents a promising therapeutic strategy for UC. Gut metabolism has been reported to critically regulates Th17 and Treg cell homeostasis. However, the role of fumarate in the pathogenesis of UC and the immunoregulatory effect of Dimethyl fumarate (DMF) in the treatment of UC remain unclear. Herein, results demonstrated decreased fumarate levels in colonic tissues of DSS-induced colitis mice, whereas DMF administration elevated colonic fumarate concentrations and relieved DSS-induced colitis by suppressing the inflammatory response and pro-inflammatory cytokines in vivo. Moreover, DMF treatment significantly decreased the frequency of Th17 cells, increased the frequency of Treg cells, thus improved Th17/Treg balance in vitro. Mechanistically, DMF significantly inhibited Th17 cell differentiation via interrupting JAK2/STAT3 and NF-κB signaling. Taken together, these results indicated that DMF alleviated DSS-induced UC by suppressing JAK2/STAT3 and NF-κB signaling to restore Th17/Treg balance. Furthermore, these findings preliminary demonstrate a role for fumarate in the pathogenesis of UC and suggest that DMF treatment leading to fumarate accumulation is a potential metabolic mechanism for colitis mitigation. Collectively, DMF-mediated immunometabolic reprogramming constitutes a novel strategy for UC immunotherapy.

Keywords:  Dimethyl fumarate (DMF); Immunoregulatory; JAK2/STAT3 signaling pathway; NF-κB signaling pathway; Th17/Treg balance; Ulcerative colitis (UC)

DOI:  https://doi.org/10.1016/j.cellsig.2026.112488
Commun Biol. 2026 Mar 19.

Microglia cause HIV-induced transcriptional and metabolic changes in human neural organoids.

Pamela E Capendale, Leanne C Helgers, Anoop T Ambikan, Renata Vieira de Sá, Katja C Wolthers, Teunis B H Geijtenbeek, Adithya Sridhar, Ujjwal Neogi, Dasja Pajkrt.

Human immunodeficiency virus (HIV) can invade the central nervous system during the initial stages of infection and contribute to HIV-associated neurocognitive disorder, affecting up to 50% of people living with HIV (PLWH). To investigate HIV-1-induced immunometabolic changes in the brain, we used a three-dimensional microglia-embedded human neural organoid model. Transcriptomic analysis and genome-scale metabolic modeling revealed that HIV-1 infection led to more pronounced transcriptional changes in the presence of microglia, including upregulation of pro-inflammatory pathways. We identified CCR6, important for HIV-1 permissiveness, to be significantly upregulated upon infection. Metabolic analysis showed increased expression in metabolite transport-related genes, including solute carrier (SLC) genes and altered amino acid metabolism, particularly involving arginine, proline, and tyrosine. These microglia-driven immunometabolic changes may contribute to neuronal dysregulation and, subsequently, neurological complications, which are often observed in PLWH. Early detection of these alterations could support timely therapeutic intervention to improve HIV-related neurologic insult.

DOI: https://doi.org/10.1038/s42003-026-09864-9
J Biol Chem. 2026 Mar 17. pii: S0021-9258(26)00250-4. [Epub ahead of print] 111380

Siah2 Regulates Lipid Uptake in Adipose Tissue Macrophages.

Bhaswati Ghosh, Pradip R Panta, Matthew C Scott, Jessica Taylor, Robbie Beyl, Krisztian Stadler, Z Elizabeth Floyd.

  In obesity, adipose tissue macrophages (ATMs) reprogram their metabolism to influence adipose tissue remodeling and function. Ubiquitin ligases are critical in modulating degradation of key proteins implicated in macrophage lipid metabolism. Yet, the role of ubiquitin ligases in ATM lipid metabolism is largely unexplored. Previously, we reported that the ubiquitin ligase Siah2 is crucial in mediating adipogenic pathways and adipose tissue inflammation. Here, we co-cultured bone marrow-derived macrophages with adipose tissue as an ex vivo model of bone marrow-derived ATMs to investigate Siah2's role in ATM lipid metabolism. We found that adipose tissue- induced lipid accumulation in ATMs was exacerbated by Siah2 deficiency via increased CD36-mediated lipid uptake and reduced lipid delivery to lysosomes. Together, these changes contributed to excessive lipid accumulation, lipid peroxidation and an inflammatory phenotype. Our data reveals a central role for Siah2 as a lipid uptake sensor in maintaining the balance between lipid influx and degradation in ATMs.

Keywords:  Adipose tissue macrophages; CD36; Inflammation; Lipid metabolism; Lipolysis; Lysosome; PPARγ; Siah2; Ubiquitin ligase

DOI:  https://doi.org/10.1016/j.jbc.2026.111380
J Immunol. 2026 Mar 17. pii: vkag026. [Epub ahead of print]215(3):

Macrophage-intrinsic and IL-9-dependent arginine metabolism promotes lung tumor growth.

Anthony Cannon, Jilu Zhang, James Ropa, Abigail Pajulas, Cherry C L Cheung, Michelle Liu Niese, Ahmed M Abdelaal, Sabrina Khan, Emily Bromley, Gyoyeon Hwang, Maya Krishnan, Basar Bilgicer, Teresa L Mastracci, Daniella Muallem Schwartz, Mark H Kaplan.

  Tumor-associated macrophages are an abundant, tumor-infiltrating cell population that supports the evasion of tumor cells from antitumoral immune cell detection by generating an immunosuppressive tumor-immune microenvironment (TIME). The immunosuppressive function of macrophages is dictated by the cytokine environment. IL-9 is a pleiotropic cytokine that can be a positive or negative regulator of tumor growth. Our lab previously identified a protumoral role of IL-9 by expanding lung interstitial macrophage (IM) populations and inducing the expression of arginase 1 (ARG1) to enhance tumor growth. However, the underlying mechanism by which IL-9 receptor/ARG1+ IMs promote tumor progression remains incomplete. Here, we demonstrate that macrophage-targeting nanoparticles containing Arg1 siRNA can therapeutically reduce tumor burden and reduce protumor arginine-derived metabolite production. Furthermore, using bulk RNA sequencing of lung macrophages isolated from Il9r-/-:wild-type mixed-bone marrow chimeric mice, we demonstrate that IL-9 intrinsically alters the transcriptomic landscape of lung IMs. Mechanistically, IL-9 promotes intrinsic Arg1 expression through an IRF4-dependent regulatory pathway and modulates arginine and polyamine concentration within IMs and lung tissue, resulting in increased lung tumor growth and altered macrophage phenotypes. Thus, our work defines a protumor function of IL-9-responsive macrophages mediated by altered intrinsic arginine metabolism in lung IMs that enhances lung tumor growth.

Keywords:  ARG1; IL-9; arginine metabolism; interstitial macrophages; polyamines

DOI:  https://doi.org/10.1093/jimmun/vkag026
J Exp Med. 2026 Apr 06. pii: e20242025. [Epub ahead of print]223(4):

Hypoxia-inducible protein 2 mediates metabolic adaptation of Ly6ChighLy6Glow monocytes after stroke.

Weijie Chen, Xin Wang, Tingting Huang, Yan Li, Chen Chen, Yueman Zhang, Wanqing Xie, Dan Tang, Qiuyue Fan, Rui Pang, Jiemin Yin, Tim Sparwasser, Zhenghong Wang, Arthur Liesz, Yu Gan, Weifeng Yu, Florent Ginhoux, Peiying Li.

Ly6Chigh monocytes, previously recognized as a pro-inflammatory subset, play critical roles in secondary neuroinflammation in the stroke brain. Growing evidence reveals increased infiltration of myeloid cells with substantial heterogeneity, raising the question of how Ly6Chigh monocyte-derived macrophages in the stroke brain adapt to the ischemic environment. Here, by combining analysis of stroke patient samples with in vivo and in vitro murine studies and single-cell transcriptomic profiling, we identify hypoxia-inducible lipid droplet-associated protein (Hilpda)/hypoxia-inducible protein 2 (HIG2) as a critical mediator of anti-inflammatory property of Ly6ChighLy6Glow monocyte-derived macrophages in the stroke brain. Mechanistically, HIG2 promotes phosphatidylcholine synthesis via Hif1α-dependent transcriptional regulation of choline kinase α, initiating lipid metabolism reprogramming that underpins the anti-inflammatory phenotype of Ly6ChighLy6Glow monocyte-derived macrophages in the ischemic brain after stroke. Intranasal delivery of recombinant HIG2 protein improves neurological outcomes after stroke. These findings suggest that targeting HIG2 might represent a novel immunometabolic strategy to mitigate poststroke neuroinflammation.

DOI: https://doi.org/10.1084/jem.20242025
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2521256123

Microglial fructose metabolism is essential for glioblastoma growth.

Leah K Billingham, Susan L DeLay, Yasmina Eshac, Tzu-Yi Chia, Shashwat Tripathi, Ian E Olson, Kaylee Zilinger, Jay Subbiah, Zhaoquan Wang, Nishanth S Sadagopan, Hinda Najem, Guillaume Cognet, Joshua L Katz, Ruochen Du, Khizar R Nandoliya, Lauren K Boland, Gustavo Ignacio Vázquez-Cervantes, Si Wang, Hanxiao Wan, Allie B Lipshutz, Alina R Murphy, Joseph Duffy, Irina V Balyasnikova, Peng Zhang, Dieter Henrik Heiland, Atique U Ahmed, Catalina Lee-Chang, Amy B Heimberger, Justin S A Perry, Alexander Muir, Navdeep S Chandel, Jason Miska.

  Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors in adults. Its immune microenvironment is dominated by tumor-associated macrophages, including both infiltrating monocytes and brain-resident microglia. While metabolic rewiring of infiltrating myeloid cells has been shown to support tumor progression, the role of microglial metabolism in GBM remains incompletely understood. Here, we demonstrate that microglia uniquely express the fructose transporter GLUT5 and are the only immune cells in the GBM microenvironment capable of metabolizing fructose. Using murine orthotopic glioma and Replication-Competent Avian sarcoma leuko virus Splice acceptor (RCAS)-derived tumor models, we show that global deletion of GLUT5 confers profound resistance to tumor growth. This effect is driven by loss of fructose metabolism in microglia and occurs independently of contributions from peripheral immune compartments. In GLUT5-deficient mice, tumors exhibit increased infiltration and activation of both innate and adaptive immunity, including enhanced antigen presentation, clonal expansion of CD8+ T cells, and increased cytokine production. Depletion of B-cells or CD8+ T cells abrogated survival phenotypes in knockout mice, demonstrating that GLUT5 suppresses adaptive immunity. These findings identify microglial fructose metabolism as a critical regulator of immune suppression in GBM and suggest that targeting this pathway may improve immunotherapeutic responses.

Keywords:  fructose metabolism; glioblastoma; microglia; redox homeostasis

DOI:  https://doi.org/10.1073/pnas.2521256123
Front Immunol. 2026 ;17 1755723

INPP5D/SHIP1-mediated immunometabolic remodeling of renal monocytes in idiopathic membranous nephropathy.

Haoran Dai, Baoli Liu, Hongliang Rui, Liuxiao Yang, Hanxue Jiang, Qihan Zhao, Wu Liu.

   Background: Idiopathic membranous nephropathy (IMN) is an antibody-mediated glomerulopathy in which podocyte-directed autoimmunity is well characterized, whereas the immunometabolic programs of innate immune cells within the renal microenvironment remain poorly defined. Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1, encoded by INPP5D) is a key negative regulator of PI3K signaling in myeloid cells and an emerging immunopharmacologic target, but its role in IMN is unknown.
Methods: Bulk and single-cell RNA-seq analyses were performed using public human IMN datasets, and the passive Heymann nephritis (PHN) rat model was used specifically for in vivo validation of key histopathological and signaling readouts to dissect INPP5D/SHIP1-centered immunometabolic pathways in IMN. Public glomerular transcriptomes from IMN and control kidneys were deconvoluted using CIBERSORT and ESTIMATE to quantify immune/stromal components and infer infiltrating leukocyte subsets. Differentially expressed genes were intersected with curated immune- and metabolism-related gene sets to identify immunometabolic hubs. Single-cell RNA-sequencing datasets were used to localize INPP5D and related pathways to specific renal cell populations, reconstruct monocyte differentiation trajectories and metabolic states, and infer ligand-receptor communication with podocytes. Key findings were validated in PHN rats by assessing proteinuria, renal histopathology, immune cell markers, podocyte proteins and SHIP1-related signaling molecules.
Results: IMN kidneys exhibited elevated immune and stromal scores, with increased infiltration of monocytes and naïve B cells and a relative depletion of regulatory T cells. Cross-differential analyses identified five overlapping immune-metabolic genes (INPP5D, PLCG1, KL, ACO1, ARG2), among which INPP5D was significantly upregulated and predominantly expressed in monocytes. Single-cell analyses revealed that renal monocytes in IMN displayed enhanced steroid biosynthesis, a skewed trajectory toward an M1-like state and strengthened SPP1-mediated communication with podocytes. In PHN rats, we recapitulated key clinical and histological features of IMN, accompanied by increased monocyte/macrophage infiltration, altered podocyte markers, and upregulation of SHIP1 and downstream PI3K/Akt signaling.
Conclusions: These data delineate an INPP5D/SHIP1-centered immunometabolic program in renal monocytes as a potential regulatory factor of pathological monocyte-podocyte crosstalk in IMN. Targeting SHIP1-related PI3K/Akt pathways and monocyte immunometabolism may offer novel immunomodulatory strategies for risk stratification and disease modification in membranous nephropathy.

Keywords:  INPP5D/SHIP1; idiopathic membranous nephropathy; immunometabolism; metabolism; passive Heymann nephritis

DOI:  https://doi.org/10.3389/fimmu.2026.1755723
Ann Rheum Dis. 2026 Mar 19. pii: S0003-4967(26)00134-2. [Epub ahead of print]

An immunometabolic signature of major depressive disorder in systemic lupus erythematosus.

Pierre Ellul, Nicolas Tchitchek, Grete Kvedaraviciute, Roberta Lorenzon, Isabelle Melki, Richard Delorme, Michelle Rosenzwajg, David Klatzmann.

OBJECTIVES: Systemic lupus erythematosus (SLE) frequently affects the central nervous system, leading to neuropsychiatric SLE (NPSLE). Major depressive disorder in SLE (SLEMDD) is the most frequent manifestation of NPSLE and is believed to arise from an immune-mediated process. However, biomarkers for SLEMDD remain lacking. The aim of this study was to identify candidate immunometabolic biomarkers associated with SLEMDD.
METHODS: We analysed deep flow cytometry immune phenotyping, gut microbiota profiling, and targeted mass spectrometry-based metabolomics from 99 patients from the LUPIL-2 study (NCT02955615). Biological signatures were identified using unsupervised principal component analysis and supervised decision tree classification. They were then validated in an independent cohort from the TRANSIMMUNOM study (NCT02466217).
RESULTS: SLEMDD patients exhibited a distinct immune profile with decreased naïve CD4⁺ T cells and naïve regulatory T cells (Tregs), alongside increased ICOS⁺ effector memory Tregs (94% classification accuracy). Gut microbiota diversity was reduced with depletion of Akkermansia muciniphila and enrichment of Faecalibacterium prausnitzii. Metabolomic analyses revealed disruptions in kynurenine and short-chain fatty acid pathways, including decreased butyrate levels. Integrative analyses demonstrated coordinated alterations linking Treg activation, microbial metabolites, and immune pathways, distinguishing SLEMDD from SLEnon-MDD with up to 85% accuracy.
CONCLUSIONS: SLEMDD is associated with an immunometabolic signature involving alterations in Treg phenotype, gut microbiota composition, and metabolic pathways. These findings provide a rationale for future immunoregulatory or microbiota-targeted therapeutic strategies in SLEMDD.

DOI: https://doi.org/10.1016/j.ard.2026.02.019
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2534066123

ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.

Ziqi Zou, Jiajie Zhou, Yanhua Lu, Yuting Huang, Linru Zhou, Xiaoyu Wang, Jiahui Chen, Hengrui Tian, Xinnuo Ge, Chenyao Guo, Weiran Yao, Xiaosheng Zheng, Jia He, Yue Du, Yiting Zhou, Yinjing Song, Wei Luo, Qingqing Wang, Jun-Ping Liu, Meng Xia.

  Neuro-immune crosstalk is increasingly recognized in Parkinson's disease (PD), and ATP13A2 is well known for its neuroprotective role. However, it remains unclear whether ATP13A2 mutations carried by PD patients contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that many ATP13A2 mutations result in a loss-of-expression phenotype. ATP13A2 is highly expressed in macrophages. Myeloid ATP13A2 deficiency causes uncontrolled NLRP3 inflammasome activation driven by lysosomal alkalization and subsequent disrupted mitochondrial homeostasis, rendering mice susceptible to a PD-like phenotype. PD-linked ATP13A2 loss-of-expression mutants fail to restore the ATP13A2 levels required to suppress NLRP3 hyperactivation in ATP13A2-depleted human THP-1 monocytes. Macrophages from a PD patient carrying the ATP13A2 loss-of-expression L927P mutation exhibit excessive NLRP3 activation due to lysosomal-mitochondrial dysfunction. Our findings provide insight into PD pathogenesis, emphasizing genetic factor-driven dysregulated macrophage NLRP3 activation, particularly in ATP13A2 loss-of-expression mutation cases.

Keywords:  ATP13A2 mutation; NLRP3 inflammasome; Parkinson’s disease; macrophage; neuroinflammation

DOI:  https://doi.org/10.1073/pnas.2534066123
Cell Host Microbe. 2026 Mar 18. pii: S1931-3128(26)00083-1. [Epub ahead of print]

Glycogen phosphorylase L confers metabolic flexibility in neutrophils to fight fungal infections in nutrient-deprived tissues.

Wonseok Choi, De-Dong Li, Colin T McLaughlin, Doureradjou Peroumal, Kiyoshi P Shiomitsu, Gillian A Moschetta, Hossein Rahimi, Shuxia Wang, Kiaan Biswas, Danielle Xie, Charles K Vorkas, Partha S Biswas.

  Neutrophils are crucial for defense against systemic Candida albicans infections and rely on glucose for their antifungal functions, including the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs). In infected tissues, glucose availability is limited due to fungal consumption, posing metabolic challenges for neutrophils. We demonstrate that neutrophils overcome glucose deprivation by activating the glycogen phosphorylase liver form (PYGL) enzyme, which mobilizes intracellular glycogen stores that fuel antifungal activity. Upon C. albicans infection, fungal sensing by dectin-1 and downstream signaling through Syk and protein kinase A (PKA) kinases drive glycogenolysis in neutrophils. Neutrophil-specific deletion of PYGL in mice increases susceptibility to candidiasis, associated with defective ROS and NET generation. Treatment with a β₂-adrenergic receptor agonist, a clinically approved PYGL activator, enhances host defense in candidiasis. These findings reveal a metabolic reprogramming mechanism that supports neutrophil function in nutrient-deprived environments and identify PYGL as a potential strategy to bolster antifungal defenses.

Keywords:  Candida albicans; glucose deprivation; glycogen; immune response; immunometabolism; invasive candidiasis; kidney; neutrophils; tissue microenvironment

DOI:  https://doi.org/10.1016/j.chom.2026.02.015
Front Immunol. 2026 ;17 1745502

A putative Mycobacterium tuberculosis glyoxalase Rv0801 promotes bacterial fitness by alleviating methylglyoxal stress and blunts NRF2-mediated antioxidant defenses.

Haiqi Chen, Qi'ao Zhang, Wei Wu, Xinyi He, Abulimiti Abudukadier, Yun Qi, Qun Sun, Peibo Li, Jianping Xie.

   Introduction: Methylglyoxal (MG), a toxic metabolic byproduct, functions as a potent antibacterial weapon deployed by macrophages. The glyoxalase system represents the primary microbial defense against MG, yet its role in Mycobacterium tuberculosis pathogenesis remains incompletely defined.
Methods: To define the function of the putative M. tuberculosis glyoxalase Rv0801 and its homolog MSMEG_5827, we used genetic engineering in Mycobacterium smegmatis MC2-155, coupled with growth and macrophage infection assays. Host mechanisms were dissected via transcriptomic and biochemical analysis of the KEAP1-NRF2 antioxidant pathway and pro-inflammatory responses.
Results: We demonstrate that Rv0801, conferring robust MG tolerance in a mycothiol (MSH)-dependent manner, is essential for bacterial fitness under MG stress. Mechanistically, Rv0801 orchestrates a dual-pathway interference within infected macrophages: by detoxifying MG, it suppresses the host KEAP1-NRF2 antioxidant pathway and concurrently dampens immunoprotective responses. This coordinated suppression compromises macrophage-mediated bacterial clearance.
Discussion: These findings establish Rv0801-mediated MG stress management as a critical virulence mechanism and highlight the bacterial glyoxalase as a promising target for tuberculosis therapy.

Keywords:  KEAP1-NRF2 pathway; Mycobacterium tuberculosis; glyoxalase system; macrophage immunity; methylglyoxal (MG); mycothiol (MSH)

DOI:  https://doi.org/10.3389/fimmu.2026.1745502
Redox Biol. 2026 Feb 26. pii: S2213-2317(26)00076-5. [Epub ahead of print]92 104078

Histone H3K9 lactylation activates the TXNIP/NLRP3 pathway to drive macrophage inflammation after spinal cord injury.

Chaoran Shi, Feifei Yuan, Xingyi Chen, Sheng Xu, Yinghe Ding, Haicheng Wen, Chunyue Duan, Tianding Wu, Hongbin Lu, Jianzhong Hu, Jiaqi Xu, Liyuan Jiang.

  Spinal cord injury (SCI) induces metabolic and immune disruptions that impede tissue repair. However, the underlying mechanisms are poorly understood. In this study, we identified lactate accumulation as a critical driver of macrophage-mediated inflammation through histone H3K9 lactylation (H3K9la). Targeted metabolomics revealed elevated serum lactate levels in SCI patients, which were linked to increased glycolysis and lactate dehydrogenase activity. In mice, lactate accumulation after SCI was found to drive histone H3K9la in lesion-infiltrating macrophages and circulating monocytes. Integrated CUT&Tag and RNA-seq analysis revealed that thioredoxin-interacting protein (TXNIP) is a direct H3K9la target that activates the TXNIP-NLRP3 pathway, exacerbating inflammation and impairing mitochondrial function. In vitro, glycolytic inhibition reversed lactate-induced inflammation and mitochondrial dysfunction. In vivo, a hypoxia-responsive peptide inhibitor (H3K9la-pe) selectively reduced macrophage lactylation and inflammation, restored mitochondrial integrity, promoted axon regeneration, and significantly improved functional recovery in SCI mouse model. These findings elucidate a subacute metabolic-epigenetic-inflammatory axis in SCI and highlight that blocking macrophage H3K9la is a promising therapeutic strategy.

Keywords:  H3K9la; Lactylation; Macrophage; Neuroinflammation; Spinal cord injury; TXNIP

DOI:  https://doi.org/10.1016/j.redox.2026.104078
J Proteome Res. 2026 Mar 17.

Comparative 1H NMR Lipoprotein Profiling of Rheumatoid Arthritis and Systemic Lupus Erythematosus Patients Highlights Disease-Specific Lipoprotein Dysregulation.

Nancy Paola Duarte-Delgado, Luz Stella Rodríguez C, Stefano Cacciatore.

  Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are systemic autoimmune diseases associated with increased cardiovascular risk and metabolic alterations. We applied 1H NMR spectroscopy to profile lipoproteins and metabolites in women with RA, SLE, and healthy controls. Both RA and SLE showed shared alterations in HDL metabolism, including reduced HDL particle size and lower concentrations of small HDL particles compared with controls. RA exhibited additional changes, notably a significant reduction in small LDL particle concentration. Metabolite profiling further differentiated RA, revealing significantly lower circulating levels of glutamine, alanine, and GlycB. Correlation analyses demonstrated that in RA, LDL particle concentrations were positively associated with disease activity (DAS28-ESR), and large LDL particles correlated positively with IFN-γ and VEGF. In SLE, HDL particle measures were associated with complement components, with small HDL particles positively correlated with C3 and HDL particle size inversely correlated with C3, while large LDL particles correlated positively with IL-6 and negatively with MDC. Together, these results indicate that RA and SLE share common lipoprotein alterations, while RA displays additional metabolic changes. NMR-derived lipoprotein and metabolite profiles may provide complementary information for assessing inflammation and cardiovascular risk in autoimmune diseases.

Keywords:  1H NMR; lipoproteins; metabolites; rheumatoid arthritis; systemic lupus erythematosus

DOI:  https://doi.org/10.1021/acs.jproteome.5c00957
Int J Biol Macromol. 2026 Mar 18. pii: S0141-8130(26)01418-2. [Epub ahead of print] 151492

A review of the mechanisms linking Th2 immune storm to NETosis through neutrophil glycolytic activation.

Jingyi Piao, Jianing Yang, Yunong Li, Yi Yang, Zhien Li, Guanxi Jin, Jingmei Chai, Chongyang Wang.

  The core metabolic mode of neutrophils is ATP generation, dominated by glycolysis, which is tailored to meet their demands for rapid response and short-term survival. The Th2 immune storm drives neutrophil metabolic reprogramming through inflammatory cytokines and hypoxia signals, leading to a burst in glycolysis (a "Warburg-like" state). This results in the upregulation of key rate-limiting enzymes, including Hexokinase 2 (HK2), Lactate Dehydrogenase A (LDHA), and Pyruvate Kinase M2 (PKM2), as well as lactate accumulation. Glycolysis induces the release of Neutrophil Extracellular Traps (NETs) through the PKM2-HIF-1α transcriptional complex and ATP-dependent chromatin remodeling. Although NETs can capture pathogens and activate immune responses, their excessive release triggers the emission of damage associated molecular patterns (DAMPs), ultimately driving disease chronicity. This forms a vicious cycle, driving persistent inflammation, tissue damage, and disease. This series of pathology processes driven by metabolic reprogramming constitutes the core mechanism of glucocorticoid resistance and chronic inflammation in allergic diseases. This review systematically summarizes the related metabolic foundations, providing new strategies for treatments targeting glycolysis or NETosis.

Keywords:  Glycolysis; NETs; Th2 immune response

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151492
Front Immunol. 2026 ;17 1755423

Current understanding and advances regarding the adipose-immune-metabolic axis in disease tolerance during sepsis.

Quanyue Du, Fanghao He, Shanchi Zhang, Xiongyan Lan, Yanqiu Pan, Jiajun Wang.

  Sepsis remains a critical global health challenge characterized by high mortality and morbidity, primarily due to the limitations of current pathogen-centric therapies and a poor understanding of host-defense mechanisms. This review synthesizes the pivotal role of the adipose-immune-metabolic axis as a central regulator of disease tolerance-a host defense strategy that limits tissue damage without directly reducing pathogen load. We delineate how adipose tissue is reprogrammed from a passive energy reservoir into an active immunometabolic hub during sepsis. This functional shift is governed by three core hypotheses: "Metabolic Defense Priority," which describes the preferential mobilization of fat to spare skeletal muscle protein; "Bidirectional Immunometabolic Crosstalk," wherein immune cells such as macrophages and B cells precisely regulate lipolysis via specific cytokine signals (e.g., IL-1β and TGF-β); and "Stage-Specific Adaptation," which outlines the dynamic evolution of axis function from the acute to chronic phases of sepsis. We further dissect key molecular pathways, including the Insulin-INSR-Thermogenesis, TGFβ-PDE3b-cAMP, and STING-ER Stress-mtROS axes, that orchestrate this complex interplay. Finally, we discuss contemporary challenges in mechanistic understanding, model translatability, and clinical translation, while proposing future directions to leverage this axis for developing novel, tolerance-based therapeutic strategies to improve sepsis outcomes.

Keywords:  adipo-immune-metabolic axis; disease tolerance; lipid metabolism; lipolysis; sepsis

DOI:  https://doi.org/10.3389/fimmu.2026.1755423
bioRxiv. 2025 Sep 12. pii: 2025.09.12.675877. [Epub ahead of print]

Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1.

Rafael Moura Maurmann, Kierstin Davis, Negin Mosalmanzadeh, Brenda Landvoigt Schmitt, Brandt D Pence.

Background: Severe COVID-19 is characterized by a hyperinflammatory state associated with an exacerbated inflammatory activation of monocytes and macrophages in the respiratory tract. Metformin has been identified as a potent monocyte inflammatory suppressor, and it has been demonstrated to attenuate inflammation in COVID-19. The mechanisms underlying metformin anti-inflammatory effects are, however, unclear. We thus sought to investigate metformin's main interactions and their respective isolated effects in modulating monocyte inflammatory response to SARS-CoV-2 stimulation.
Methods: Classical human monocytes were isolated from healthy 18-40-year-old individuals and stimulated in vitro with recombinant spike protein subunit 1 (rS1) to assess glycolytic and oxidative metabolic responses by Seahorse extracellular flux analysis, and inflammatory gene expression by qPCR. Stimulated monocytes were either pre-treated with metformin, rotenone, S1QEL, or A769662.
Results: Monocytes stimulated in vitro with rS1 showed an increased glycolytic response associated with production of pro-inflammatory cytokines. Metformin pre-treatment reduced glycolytic activation while partially suppressing inflammation. Rotenone-dependent mitochondrial complex I inhibition was not able to replicate the same effect, and neither complex I specific ROS scavenging. Conversely, A769662 induced AMPK activation led to suppressed glycolytic inflammatory response and cytokine expression pattern similar to metformin, thus suggesting AMPK modulation as a possible central component for metformin's mode of action upon S1 stimulation.
Conclusions: In summary, further investigation into the interactions underlying AMPK activity on monocytes in the context of SARS-CoV-2 may provide a better elucidation of metformin's anti-inflammatory effect.

DOI: https://doi.org/10.1101/2025.09.12.675877
Chem Biol Interact. 2026 Mar 14. pii: S0009-2797(26)00145-6. [Epub ahead of print] 112037

Paraquat induces neuroinflammation through glycolysis reprogramming in microglia: evidence from network toxicology analysis and in vitro experiments.

Yi Yang, Yin Xu, Qingtai Meng, Xinyang Wang, Ya Tian, Liang Lyu, Xiaofeng Zhang.

  Paraquat (PQ) has been strongly linked to Parkinson disease, although the underlying mechanisms remain incompletely defined. Network toxicology analysis was used to predict the possible targets and pathways of PQ neurotoxicity, and BV2 cells were used to validate the predicted results and possible mechanisms through molecular biology techniques. The analysis of network toxicology showed that PQ-targeted microglia may be accompanied by glucose metabolism disorder. PQ markedly enhanced glycolysis in BV2 cells, showing the increase of lactate content, expression level of HK2 and GLUT-1, and glycolysis flux. PQ activated mTOR while inhibiting AMPK, which enhanced glycolysis in microglia and promoted their pro-inflammatory polarization. Notably, inhibiting glycolysis with glucose analogue or silencing hk2 effectively attenuated PQ-induced inflammatory response and apoptosis of dopaminergic neurons. These findings uncover an unrecognized mechanism by which glycolysis reprogramming in microglia contributes to PQ neurotoxicity through promoting neuroinflammation, highlighting microglial glycolysis as a potential intervention target for environmental toxicants-associated neurodegenerative disorders.

Keywords:  Glycolysis reprogramming; Microglia; Network toxicology; Neuroinflammation; Paraquat

DOI:  https://doi.org/10.1016/j.cbi.2026.112037
Front Immunol. 2026 ;17 1730799

Mechanisms and therapeutics of immunometabolic reprogramming driving macrophage-ECs interactions in sepsis-associated ARDS from the gut-lung axis perspective.

Jia Tang, Mi Yan, Yanfei Liu, Wanwei Li, Zhangxue Hu.

  Acute respiratory distress (ARDS) caused by sepsis is a critical inflammatory condition with high mortality rates in clinical settings. The gut-lung axis plays a crucial role in regulating the immune response in both the intestinal and pulmonary environments, significantly impacting the development of ARDS. Immunometabolic reprogramming, a fundamental regulator of immune cell function, has recently been shown to profoundly affect the activity of macrophages and endothelial cells (ECs), as well as their crosstalk, thereby shaping the pathogenesis of ARDS. While a great deal has been learned about the potential inflammatory pathways involved, few clinically actionable therapies are available in part due to an incomplete understanding of gut-lung crosstalk in their shared ecosystem of cells and molecules. The current review systematically advances novel insights into the immunometabolic reprogramming that influences macrophage-ECs interactions via sepsis-induced ARDS, with a specific regard to the gut-lung axis. Here, we summarize the key biochemical pathways that control immune cell phenotypes and endothelial function, review the latest experimental evidence for their intercellular crosstalk, and describe the molecular targets that might be targeted to inform therapeutic strategies. Integrating the current evidence, this review seeks to provide a comprehensive theoretical framework and novel methods for the precise treatment of sepsis-associated ARDS, which could be beneficial to clinical practices and patients' prognoses.

Keywords:  ARDS; ECS; cell interaction; gut-lung axis; immunometabolic reprogramming; inflammatory response; macrophages; sepsis

DOI:  https://doi.org/10.3389/fimmu.2026.1730799
J Clin Invest. 2026 Mar 17. pii: e196636. [Epub ahead of print]

Estrogen receptor β deficiency increases susceptibility to sepsis through metabolic reprogramming-induced macrophage pyroptosis.

Yanrong Zhu, Gang Li, Yilei Guo, Yue He, Wanyi Zhang, Lei Gao, Jing Zhang, Pengxiang Guo, Haochang Lin, Wenjie Zhang, Zhifeng Wei, Yufeng Xia, Yue Dai.

  Understanding susceptibility factors of sepsis is crucial for early diagnosis and development of personalized treatment strategies. However, the genetic determinants for initiation and progression of sepsis remain unclear. Here, we showed that the expression levels of estrogen receptor (ER) β are significantly reduced in the peripheral blood of sepsis patients, which were negatively correlated with disease severity. The results from human samples and experimental animals demonstrated that ERβ deficiency enhances the body's susceptibility to sepsis by inducing macrophage pyroptosis, thereby impairing bacterial clearance. Mechanistically, ERβ deficiency enhanced fatty acid oxidation, increased acetyl-CoA levels, and promoted acetylation of stomatin-like protein 2 (Stoml2) at K221, leading to mitochondrial dysfunction and macrophage pyroptosis. Mutating the Stoml2 K221 site mitigated these effects and improved survival of septic mice. These findings suggest ERβ deficiency as a potential genetic factor in sepsis susceptibility.

Keywords:  Immunology; Inflammation; Macrophages

DOI:  https://doi.org/10.1172/JCI196636
Nat Mater. 2026 Mar 17.

Crosslinked ionizable lipids reprogram dendritic cell metabolism for potent mRNA vaccination.

Dongyoon Kim, Ningqiang Gong, Mohamad-Gabriel Alameh, Emily L Han, Hanxun Wang, Jinjin Wang, Ellie Feng, Il-Chul Yoon, Amanda M Murray, Qiangqiang Shi, So-Jeong Moon, Kaitlin Mrksich, Drew Weissman, Michael J Mitchell.

Modulating metabolism in immune cells is an effective approach to induce desired immune responses. Here we develop a lipid nanoparticle (LNP) capable of metabolic reprogramming of dendritic cells for mRNA vaccine applications. Using imidoester-based conjugation chemistry, we design a crosslinked ionizable lipid, C12-2aN, which possesses intrinsic metabolic modulatory properties. This multifunctional ionizable lipid not only promotes effective mRNA expression by facilitating endosomal escape but also stimulates glycolysis through mTORC2 pathway activation. As both an mRNA carrier and a metabolic modulator, C12-2aN LNPs lead to potent vaccine efficacy in both SARS-CoV-2 and OVA cancer vaccine models, resulting in stronger neutralization of pseudovirus infection and improved survival rates, respectively, compared with control LNPs without the crosslinker. Moreover, C12-2aN LNPs outperformed FDA-approved LNPs in terms of reduced off-target delivery and lower immunogenicity. Overall, the integration of mRNA delivery and metabolic reprogramming induced by the ionizable lipid component presents significant potential for next-generation mRNA LNP vaccines.

DOI: https://doi.org/10.1038/s41563-026-02512-x