bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–06–07
48 papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Macrophage metabolic reprogramming in sepsis-associated acute lung injury: mechanisms and therapeutic strategies.
  2. Editorial: Immune cell metabolism beyond energy supply - an emerging era to showcase novel roles in immune effector functions.
  3. Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
  4. Targeting macrophage metabolism: Ghrelin regulates macrophage polarization via dual modulation of the AMPK/mTOR axis in immune-mediated diseases.
  5. VDAC1 mediates LPS-induced T cell inflammation via mtDNA release and cGAS-STING activation.
  6. CMPK2 restricts Mycobacterium tuberculosis replication and regulates macrophage gene expression.
  7. Identification of a metabolic-immune crosstalk in Still's disease: monocyte/macrophage-derived immunometabolite itaconate dictates hepatic immunopathology via the CXCL10-CD8 T cell axis.
  8. Redox-metabolic circuits as a central regulator of T cell-based immunotherapy.
  9. Targeted silencing of CLYBL with platelet-mimetic siRNA nanoparticles drives itaconate-mediated macrophage reprogramming and protects against sepsis-triggered lung cell death.
  10. Wavelength-Dependent Photobiomodulation Regulates Macrophage Polarization via Mitochondrial Dynamics and Metabolic Reprogramming.
  11. Integrating host-microbiota metabolic networks: how aromatic amino acids shape immune homeostasis and affect disease progression.
  12. Mitochondrial OXPHOS restricts SARS-CoV-2 replication.
  13. A metabolic constraint in de novo NAD+ synthesis drives mucosal inflammation in IBD.
  14. NOD2 activation reprograms infiltrating inflammatory monocytes in the Zika virus infected CNS to maintain neural correlates of learning and memory.
  15. Host metabolic responses to SARS-CoV-2 and influenza viruses: parallels and contrasts.
  16. PRMT1-Mediated LDHA Methylation Drives STAT3 Lactylation to Orchestrate Intestinal Inflammation and Tumorigenesis.
  17. Salmonella Typhimurium hijacks a host glucose transporter for intravacuolar proliferation.
  18. Hepatic immunometabolic reprogramming of Sebastes schlegelii in response to Photobacterium damselae subsp. piscicida infection: biochemical, transcriptomic and metabolomic analyses.
  19. Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.
  20. Astaxanthin-metformin conjugate nanomicelles-loaded hydrogel reprograms macrophage metabolism via mitochondrion-targeted regulation for diabetic wound healing.
  21. SIRT6 bridges glycolysis and epigenetics to neutrophilic asthma.
  22. lncRNA-mRNA Co-expression Network Unveils Neutrophil Metabolic Reprogramming in Human Sepsis.
  23. Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation.
  24. High-fat overfeeding is associated with tissue-specific liver-adipose immunometabolic remodeling in rainbow trout.
  25. IRG1/itaconate rewires macrophage and lung tumor metabolism through G6PD inhibition.
  26. ACLY integrates metabolism and chromatin accessibility to enable B Cell activation and humoral immunity.
  27. The immunometabolic mechanisms and therapeutic targets of metabolic dysfunction-associated steatohepatitis.
  28. Oleoylethanolamide Enhances Regulatory T Cell Function to Accelerate Plaque Regression in Atherosclerosis via PPARα Activation.
  29. Immunometabolic reprogramming and glycolysis-associated signatures in sepsis: insights from single-cell RNA sequencing and machine learning.
  30. Protocatechuic acid prevents obesity caused by long-chain saturated fatty acid-induced inflammation in mouse microglia via inhibition of the NF-κB pathway.
  31. Rheumatoid arthritis synovial fibroblasts promote the glycolysis of myeloid-derived suppressor cells via TREM1/mTOR axis.
  32. Neutrophil-derived itaconate facilitates tiered pulmonary inflammation via Kdm5b-associated epigenetic remodeling in alveolar macrophages.
  33. Polyamine sequestration of 2'3'-cGAMP constrains intercellular transmission and STING engagement to subvert antitumor immunity.
  34. Polyphosphates Attenuate Interleukin-12 Production in Macrophages Infected With Legionella pneumophila.
  35. Solute Carrier Transporter Family Modulates Neutrophil Metabolism During Health and Disease.
  36. Cell-specific energy crisis in the ageing brain: Mitochondrial dynamics drives neuron-glia metabolic uncoupling and neurodegeneration.
  37. BVDV utilizes PGC-1α downregulation to remodel the mitochondrial metabolic microenvironment, enhancing viral replication and impairing host immunity.
  38. Soft fibrin matrix instructs macrophage M2 polarization via FABP4-mediated enhancement of fatty acid β-oxidation to alleviate MASH.
  39. BVDV hijacks the IDO1-dependent tryptophan-kynurenine axis to promote viral replication by limiting interferon-STAT1 antiviral signaling.
  40. Salmonella lipopolysaccharide stimulates uptake of long-chain fatty acids in the small intestine.
  41. Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity.
  42. CIDEB and CGI-58 differentially regulate liver lipid-droplet cholesterol to modulate metabolic dysfunction-associated steatohepatitis severity.
  43. Dual role of homocysteine in enhancing metabolic activity and suppressing inflammatory cytokines in murine immune cells.
  44. Glucose restriction reprograms lipid metabolism and enhances immunotherapy through ZNRF3-Wnt-SCD signaling axis.
  45. Sphingosine kinase-2 inhibition promotes immunogenic differentiation of myeloid-derived suppressor cells through an Acetyl-CoA carboxylase-phosphatidylcholine axis.
  46. Environmental regulation of mucosal-associated invariant T cells: Adding food for thought.
  47. PKM2-driven glycolysis mediates rotenone neurotoxicity via MG-Hs in Parkinson's disease.
  48. Nicotinamide N-methyltransferase in inflammatory bowel disease: Multidimensional regulation, mechanistic insights, and therapeutic potential.
  1. Front Immunol. 2026 ;17 1808474
    Macrophage metabolic reprogramming in sepsis-associated acute lung injury: mechanisms and therapeutic strategies.
    Ran Pan, Yiyi Sun, Lu Chen, Jianping Pan, Junping Guo.
      Sepsis-associated acute lung injury (S-ALI) remains a life-threatening condition with high mortality and limited therapeutic options. Macrophages, as key sentinels of innate immunity, exhibit remarkable heterogeneity and functional plasticity. These properties are fundamentally driven by metabolic reprogramming, which tailors their effector functions to specific microenvironmental demands. Beyond the traditional M1/M2 binary classification, macrophage activation is now appreciated as a continuous functional spectrum. Pro-inflammatory macrophages preferentially utilize aerobic glycolysis and the pentose phosphate pathway, coupled with suppressed oxidative phosphorylation (OXPHOS), whereas reparative macrophages rely predominantly on OXPHOS and fatty acid oxidation (FAO). Key glycolytic enzymes such as PFKFB3 and PKM2, the transcriptional regulator HIF-1α, and TCA cycle intermediates including succinate and itaconate serve as critical metabolic checkpoints governing macrophage inflammatory responses. During S-ALI, the metabolic landscape undergoes dynamic temporal shifts: the early hyperinflammatory phase is characterized by enhanced glycolysis, while the late immunosuppressive phase exhibits impaired OXPHOS and FAO. This review synthesizes recent advances in understanding how metabolic reprogramming orchestrates macrophage polarization during S-ALI, encompassing glycolysis, the TCA cycle, FAO, and amino acid metabolism. Natural compounds, pharmacological inhibitors, and innovative delivery platforms have shown promise in reprogramming macrophage metabolism to restore immune homeostasis. Notable examples include aerosolized CRISPR/Cas9 nanotherapeutics, biomimetic nanoplatforms, pH-responsive nanoparticles, and engineered exosomes. However, challenges such as broad cytotoxicity, limited macrophage selectivity, incomplete pharmacokinetic characterization, and the timing of intervention in the evolving septic milieu must be addressed. Future strategies should focus on developing cell-type-restricted delivery systems, validating targets in human-relevant models, and designing phase-specific interventions tailored to the metabolic trajectory of S-ALI.
    Keywords:  Acute lung injury; macrophage; metabolic reprogramming; sepsis; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2026.1808474
  2. Front Immunol. 2026 ;17 1869468
    Editorial: Immune cell metabolism beyond energy supply - an emerging era to showcase novel roles in immune effector functions.
    Hao Wu, Henry Kurniawan, Bin Zheng, Wei He.
      
    Keywords:  T cell; cell metabolism; choline; fumarate; itaconate; macrophage; mesaconate; neutrophil
    DOI:  https://doi.org/10.3389/fimmu.2026.1869468
  3. J Cancer Immunol (Wilmington). 2026 ;8(1): 17-22
    Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
    Prakash Jeysankar, Sonal Srikanth, Beibei Wu, Yousang Gwack.
      Effector T cells rely on tightly coordinated metabolic and epigenetic programs to sustain immune function. Emerging evidence highlights a central role for mitochondria in integrating these programs through nutrient utilization and regulation of metabolite flux. The electron transport chain (ETC), localized to the inner mitochondrial membrane, directs cellular metabolism toward oxidative phosphorylation. The efficiency of ETC activity is governed by the highly folded architecture of the inner mitochondrial membrane into cristae. Although mitochondrial metabolism is well recognized as a key determinant of cellular metabolic states, the regulatory roles of cristae-organizing structural proteins, particularly in T cells, remain poorly defined. Our recent study identifies the inner mitochondrial membrane protein TMEM11 as a critical structural determinant of cristae organization and demonstrates how cristae integrity governs effector T cell function by controlling oxidative phosphorylation and metabolite flux. TMEM11 deficiency disrupts cristae architecture in T cells without affecting mitochondrial biogenesis or cell viability. Mechanistically, loss of TMEM11 impairs ETC function, leading to elevated mitochondrial reactive oxygen species (mtROS), which diverts acetyl-CoA away from histone acetylation toward fatty acid synthesis, thereby suppressing cytokine production. Collectively, these findings reveal a structural-metabolic-epigenetic axis that is essential for effector T cell immunity and suggest potential relevance for T cell-mediated cancer therapy.
    Keywords:  Cristae; Effector T cells; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.33696/cancerimmunol.8.120
  4. Int Immunopharmacol. 2026 Jun 04. pii: S1567-5769(26)00748-4. [Epub ahead of print]184 116902
    Targeting macrophage metabolism: Ghrelin regulates macrophage polarization via dual modulation of the AMPK/mTOR axis in immune-mediated diseases.
    Shiwang Wu, Chang Zheng, Xinyi Ye, Yamei Huang, Haotian Yuan, Huiyi Wang, Si Chen, Nan Zhang, Shan Wang.
      Macrophages are immune cells important in the coordination of an organism's immune response. Ghrelin binds to the GHS-R1a receptor which is present in macrophages and modulates macrophage metabolic reprogramming and functional polarization. This review investigates the metabolic actions of ghrelin and its therapeutic potential for immunomodulation; evidence so far will be discussed. There is a tight connection between the metabolic profiles of macrophages and their polarization (M1 versus M2). Research indicates that ghrelin can activate the AMPK signaling pathway, which promotes fatty acid oxidation and improved mitochondrial function, thereby enhancing the anti-inflammatory capacity of M2 macrophages. Ghrelin seems to inhibit mTOR, which limits glycolysis in M1 macrophages and reduces pro-inflammatory cytokine production, at the same time. This dual regulation of AMPK activation and mTOR inhibition by ghrelin shows therapeutic potential in inflammatory diseases, metabolic disorders, and cancer. It also provides a new approach for modulating macrophage metabolism.
    Keywords:  AMPK/mTOR signaling; Ghrelin; Immunotherapy; Macrophages; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.intimp.2026.116902
  5. Cell Signal. 2026 Jun 03. pii: S0898-6568(26)00295-0. [Epub ahead of print] 112642
    VDAC1 mediates LPS-induced T cell inflammation via mtDNA release and cGAS-STING activation.
    Ren Yuqian, Guangyao Zhu, Zhang Yucai, Cui Yun, Gu Jie, Zhou Yiping.
      Sepsis, a life-threatening condition characterized by dysregulated immune responses, leads to high mortality and morbidity. While splenic T cells are pivotal in systemic inflammation, their underlying mechanisms remain elusive. Here, we investigated the impact of bacterial endotoxin lipopolysaccharide (LPS) on mouse spleen tissue and primary T cells. LPS challenge provoked splenic inflammation, as evidenced by elevated levels of TNF-α, IFN-γ, IL-6, and IL-18 in whole spleen tissue. Transcriptomic profiling of whole spleen tissue implicated the cytosolic DNA-sensing pathway. Mechanistic studies in purified primary splenic CD3+ T cells revealed that LPS triggered mitochondrial dysfunction, characterized by increased mitochondrial ROS (mtROS), Ca2+ mobilization, and mitochondrial DNA (mtDNA) release into the cytosol, concurrent with VDAC1 oligomerization. Mechanistically, VDAC1 oligomerization was essential for LPS-induced mtDNA release and subsequent activation of the cGAS-STING-TBK1 axis. Notably, the VDAC1 oligomerization inhibitor VBIT-12 reversed cGAS-STING activation and cytokine expression. Collectively, our findings unveil a novel pathway wherein LPS induces VDAC1 oligomerization, leading to mtDNA leakage and activation of the cGAS-STING-TBK1 pathway in T cells, thereby fueling inflammation. This mechanism not only deepens our understanding of T cell-mediated immunopathology in endotoxemia but also highlights VDAC1 and associated mitochondrial function as potential therapeutic targets for sepsis and related inflammatory diseases.
    Keywords:  Inflammation; VDAC1 oligomerization; cGAS-STING; mtDNA
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112642
  6. bioRxiv. 2026 May 22. pii: 2026.05.19.726211. [Epub ahead of print]
    CMPK2 restricts Mycobacterium tuberculosis replication and regulates macrophage gene expression.
    John Neff, Victoria A Ektnitphong, Priscila C Campos, Kubra F Naqvi, Beatriz R S Dias, Kathryn C Rahlwes, Zhenyu Zhong, Michael U Shiloh.
      Host cell metabolic pathways influence innate immune responses to intracellular pathogens, but the contribution of nucleotide metabolism to antimicrobial defense remains incompletely defined. Here, we identify the mitochondrial nucleoside monophosphate kinase CMPK2 as a regulator of macrophage responses to Mycobacterium tuberculosis (Mtb). Using a targeted genetic screen of candidate host factors, we found that depletion of CMPK2 enhances intracellular Mtb replication in human macrophages. This phenotype was confirmed using both shRNA-mediated knockdown and CRISPR-Cas9-mediated knockout approaches. CMPK2 expression increased following macrophage activation and Mtb infection. Transcriptomic profiling revealed that loss of CMPK2 is associated with broad alterations in gene expression, including reduced expression of genes linked to innate immune and inflammatory responses early after infection. In contrast, myeloid-specific deletion of Cmpk2 in mice did not significantly alter bacterial burden or survival following aerosol Mtb infection, indicating that the contribution of CMPK2 to host defense is context dependent. Together, these findings identify CMPK2 as a host factor that limits Mtb replication in human macrophages and shapes innate immune gene expression programs.
    DOI:  https://doi.org/10.64898/2026.05.19.726211
  7. Exp Mol Med. 2026 Jun 05.
    Identification of a metabolic-immune crosstalk in Still's disease: monocyte/macrophage-derived immunometabolite itaconate dictates hepatic immunopathology via the CXCL10-CD8 T cell axis.
    Junna Ye, Fan Wang, Zhuochao Zhou, Jinchao Jia, Ziang Wu, Yijun You, Nadiem Atiq, Yutong Su, Huihui Chi, Jianfen Meng, Mengyan Wang, Yuning Ma, Shirin Hosseini, Martin Korte, Jialin Teng, Chengde Yang, Karsten Hiller, Qiongyi Hu, Wei He, Yue Sun.
      Still's disease (SD) is a chronic and systemic autoinflammatory disorder, with the possibility of resulting in life-threatening complications, including macrophage activation syndrome (MAS). The metabolic-immune interplay underlying the immunopathology of SD/MAS remains largely unexplored. In this study, we identified itaconate - a myeloid cell-specific metabolite derived from the tricarboxylic acid cycle via the enzyme ACOD1 - as a dual regulator of inflammation and chemokine-driven tissue injury in SD/MAS. Clinical metabolomics revealed elevated serum itaconate in patients with SD, attributable to peripheral blood monocytes and correlated with disease severity. This was consolidated by the identification of the Acod1-itaconate axis in monocytes and macrophages in both a mouse model of MAS and in vitro cell cultures. Although itaconate suppressed IL-1β, IL-6, CXCL1 and CCL2 in vitro, it paradoxically amplified CXCL10 secretion in vitro and in vivo. This was in line with the observations of elevated plasma CXCL10 levels in patients with MAS. In the CpG ODN 1826-induced MAS mouse model, ablation of Acod1 ameliorated disease manifestations and hepatic inflammation, accompanied by a reduced CXCL10 level as well as attenuated hepatic infiltration of CD8+ T cells. Collectively, our study reveals a previously unrecognized metabolic-immune crosstalk in AOSD/MAS, positioning monocyte/macrophage-derived itaconate as a dual regulator that suppresses canonical pro-inflammatory cytokines while licensing CXCL10-mediated CD8+ T cell-driven tissue injury. Therefore, discovery from this study calls for scrutiny of an itaconate-based anti-inflammatory strategy in chronic inflammatory diseases.
    DOI:  https://doi.org/10.1038/s12276-026-01751-x
  8. Front Immunol. 2026 ;17 1807087
    Redox-metabolic circuits as a central regulator of T cell-based immunotherapy.
    Sarah McPhedran, Tian Zhao, Julian J Lum.
      T cell-based immunotherapies have transformed cancer treatment, yet their efficacy in solid tumors is constrained by the nutrient-poor and oxidative tumor microenvironment (TME). Accumulating evidence indicates that reactive oxygen species (ROS), methionine metabolism, and the amino acid stress sensor general control nonderepressible 2 (GCN2) are tightly interconnected regulators of T cell activation, differentiation, and effector function. In this review, we detail how these pathways form an integrated redox-metabolic circuit that dynamically tunes T cell responses to environmental stress. Physiological ROS are essential for T cell receptor signaling, glycolytic reprogramming, and cytotoxicity, whereas excessive or prolonged oxidative stress drives exhaustion and apoptosis. GCN2 links amino acid availability, particularly methionine and cysteine, to adaptive transcriptional and metabolic programs that regulate glutathione synthesis and redox homeostasis. We highlight how therapeutic manipulation of methionine availability, GCN2 signaling and ROS produces highly context-dependent outcomes across immune checkpoint blockade and adoptive cell therapy settings in solid tumors. Finally, we discuss emerging strategies to interrogate and modulate this circuit using integrated omics, CRISPR-based screening, and pharmacological approaches, emphasizing the need for context-aware and temporally controlled metabolic interventions to enhance T cell-based immunotherapies in solid tumors.
    Keywords:  GCN2; T cells; immunometabolism; immunotherapy; methionine; redox
    DOI:  https://doi.org/10.3389/fimmu.2026.1807087
  9. Cell Death Discov. 2026 May 30.
    Targeted silencing of CLYBL with platelet-mimetic siRNA nanoparticles drives itaconate-mediated macrophage reprogramming and protects against sepsis-triggered lung cell death.
    ZuoJun Huang, Jialin Zhong, Li Zhang, Xianggui Huang, Shanshan Liang, Youfeng Zhu, Rui Zhang, Hongzhi He, Chengcheng Xu, Wang Chen, Jing Wang, Xiaolong Wu, Yumin Liang, Jian Zou, Shuyao Zhang.
      Excessive inflammation and metabolic dysregulation fuel alveolar cell death in sepsis-induced lung injury, yet effective molecular interventions are lacking. We identify citrate lyase beta-like (CLYBL) as a previously unrecognized metabolic driver of macrophage-mediated tissue damage. In a murine cecal ligation and puncture model, CLYBL was strongly upregulated in lung tissue and peritoneal macrophages. To therapeutically target this pathway, we engineered platelet-derived extracellular vesicle-coated poly(lactic-co-glycolic acid) nanoparticles (PEVs@PLGA) encapsulating CLYBL-specific small interfering RNA. This platelet-mimetic system enabled efficient, biocompatible delivery of siRNA and robust CLYBL knockdown both in vitro and in vivo. CLYBL silencing triggered accumulation of the anti-inflammatory metabolite itaconate, limited M1 macrophage polarization, and preserved alveolar epithelial integrity, thereby reducing cell death and improving pulmonary repair. Transcriptomic analysis revealed broad immunometabolic remodeling consistent with enhanced resolution of inflammation. Biosafety evaluation confirmed negligible systemic toxicity. These findings uncover CLYBL as a critical metabolic checkpoint linking macrophage activation to alveolar cell death and highlight platelet-mimetic siRNA nanoparticles as a potent therapeutic strategy. Our work provides a mechanistic and translational framework for targeting macrophage immunometabolism to prevent fatal organ damage during sepsis.PEVs@PLGA@si-CLYBL promote itaconate accumulation, induce immune cell functional remodeling, and facilitate lung epithelial repair, offering a novel therapeutic approach for sepsis-induced lung injury (Created with BioRender.com).
    DOI:  https://doi.org/10.1038/s41420-026-03119-6
  10. Adv Sci (Weinh). 2026 Jun 02. e75920
    Wavelength-Dependent Photobiomodulation Regulates Macrophage Polarization via Mitochondrial Dynamics and Metabolic Reprogramming.
    Qiusheng Shi, Hao Jia, Jianfei Dong, Linhao Li, Jingqi Cao, Xun Chen, Zhenzhen Jia, Jing Na, Zhijie Yang, Xinyuan Chen, Yubo Fan, Shuhua Yue, Lisha Zheng.
      Photobiomodulation (PBM) provides a non-invasive means to regulate immune function, yet its clinical translation is hindered by a lack of mechanistic links between light parameters and biological outcomes. Here, we demonstrate that specific wavelengths act as metabolic switches that direct macrophage polarization through the selective engagement of distinct immunometabolic pathways. In both in vitro and in vivo wound healing models, 850-nm light enhances fatty acid oxidation and lipid droplet-mitochondria interactions, driving anti-inflammatory M2 polarization and accelerating tissue repair. Conversely, 625 nm light increases glycolytic flux and lactate production, promoting a pro-inflammatory M1 state that delays healing. We identify mitochondrial dynamics as the key interface: 850 and 625 nm light promote mitochondrial fusion and fission, respectively, to dictate metabolic routing. Causality was confirmed via metabolic interventions, which reversed wavelength-specific polarization outcomes. Together, these findings define photo-immunometabolism as a wavelength-dependent framework in which light regulates macrophage fate through coordinated control of mitochondrial dynamics and metabolism. This framework provides a mechanistic basis for precision, wavelength-tailored PBM therapies for wound repair and other immune-mediated inflammatory disorders.
    Keywords:  fatty acid oxidation; glycolysis; macrophage polarization; mitochondrial dynamics; photobiomodulation; wound healing
    DOI:  https://doi.org/10.1002/advs.75920
  11. Cell Mol Immunol. 2026 Jun 01.
    Integrating host-microbiota metabolic networks: how aromatic amino acids shape immune homeostasis and affect disease progression.
    Yanan Zhang, Xinya Zhao, Haoran Wang, Zhuobiao Zhang, Hui Shi, Yuhao Wang, Shu Jeffrey Zhu.
      Gut microbial metabolism is intimately linked to host immune homeostasis. Aromatic amino acids (AAAs) serve as substrates for both host and microbial enzymes, yielding a diverse array of metabolites that shape immune responses at local and systemic sites. In this review, an integrated framework is provided for understanding how AAA metabolites orchestrate immune cell function. The journey of AAAs from dietary intake through intestinal absorption and microbial utilization is traced, emphasizing the cooperative metabolic networks that generate immunomodulatory compounds. How these metabolites act on dendritic cells, macrophages, T cells, and B cells through membrane receptors, nuclear receptors, and epigenetic modifications to achieve cell‑type‑specific effects is subsequently examined. Drawing on recent discoveries, including cooperative microbial interactions in tryptophan metabolism, AAA metabolism is best understood as an integrated network rather than separate host and microbial compartments. How the dysregulation of these pathways contributes to inflammatory bowel disease and infectious diseases is further discussed, and emerging therapeutic strategies targeting the microbiota‑metabolite‑immune axis are highlighted. By synthesizing molecular mechanisms, cellular targets, and disease contexts, this review offers a conceptual roadmap for precision interventions that leverage the intricate metabolic connections between the host and microbiota.
    Keywords:  Aromatic amino acid metabolites; Gut microbiota; Host‒microbe interactions; Immune regulation; Immunometabolism
    DOI:  https://doi.org/10.1038/s41423-026-01435-6
  12. Sci Adv. 2026 Jun 05. 12(23): eadz3081
    Mitochondrial OXPHOS restricts SARS-CoV-2 replication.
    Yentli E Soto Albrecht, Ryan M Morrow, Devin Kenney, Arnold Z Olali, Alan Wacquiez, Nader Chehadeh, Zimu Cen, Jeffrey A Haltom, Ian Chen, Sujata S Ranshing, Gabrielle A Widjaja, Alessia Angelin, Jesus A Tintos-Hernandez, Wanqing Xie, Prasanth Potluri, Marie T Lott, Shiping Zhang, Mohsan Saeed, Deborah G Murdock, Susan R Weiss, Florian Douam, Douglas C Wallace.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rewires host metabolism to optimize virus production. Although glycolysis is necessary for virus production, the importance of mitochondrial oxidative phosphorylation (OXPHOS) is unknown. The mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS polypeptides plus the 22 transfer RNAs (tRNAs) and 2 ribosomal RNAs (rRNAs) for mitochondrial protein synthesis. We found an ∼5- to 100-fold greater SARS-CoV-2 virus production in infected human ACE2-expressing A549 lung cells when OXPHOS was inhibited by mtDNA depletion (ρ0 cells), inhibition of mitochondrial translation with chloramphenicol (CAP), or chemical inhibition of OXPHOS complexes. OXPHOS inhibition led to a marked increase in the size and distribution of viral replication centers and accelerated the production and release of infectious particles, occurring ∼2 hours earlier than in parental A549-ACE2 (wild type) cells. Subsequently, we found that increased glycolytic capacity was required for enhanced viral replication whereas differences in innate immune pathway activation were not. Reintroduction of mtDNA from a well-defined maternal lineage into the ρ0 cells reinstated OXPHOS, impaired SARS-CoV-2 replication, and reversed associated viral and glycolytic correlates. Thus, metabolic balance regulates SARS-CoV-2 replication, with OXPHOS exerting an antiviral effect.
    DOI:  https://doi.org/10.1126/sciadv.adz3081
  13. J Crohns Colitis. 2026 May 08. pii: jjag043. [Epub ahead of print]20(5):
    A metabolic constraint in de novo NAD+ synthesis drives mucosal inflammation in IBD.
    Lina Wehkamp, Danielle M M Harris, Na-Mi Kim, Abrar I Alsaadi, Qicong Wu, Mhmd Oumari, Jan Taubenheim, Valery Volk, Graziella Credidio, Eric Koncina, Pranab K Mukherjee, Florian Tran, Taous Mekdoud, Meiping Yu, Laura K Sievers, Polychronis Pavlidis, Nick Powell, Shihan Wang, Ivan Fung, Georg H Waetzig, Christel Rousseaux, Pierre Desreumaux, Florian Rieder, Elisabeth Letellier, Silvio Waschina, Thomas F Meyer, Timon Adolph, Geert D'Haens, Christoph Kaleta, Friedrich Feuerhake, Bram Verstockt, Melanie R McReynolds, Philip Rosenstiel, Stefan Schreiber, Konrad Aden.
       BACKGROUND: Inflammatory bowel disease (IBD) is associated with energy deficiency and perturbed metabolism of the essential amino acid tryptophan (Trp).
    OBJECTIVE: We aimed to determine whether excessive Trp degradation fuels or compensates for inflammation through de novo nicotinamide adenine dinucleotide (NAD+) synthesis.
    DESIGN: A prospective systems medicine approach (metabolomics, transcriptomics) was employed longitudinally in patients with advanced IBD therapy. Findings were validated with targeted Trp metabolomics in experimental colitis and in vitro in fibroblasts, intestinal epithelial cells (IECs), and peripheral blood mononuclear cells (PBMCs).
    RESULTS: Active IBD is marked by enhanced Trp degradation driven by inflammatory cytokines through the JAK/STAT pathway. Trp catabolism results in accumulation of quinolinic acid (QA) and NAD + depletion due to reduced expression of QPRT, the enzyme converting QA to NAD+. QPRT knockdown enhances inflammation, while NAD + precursor supplementation (e.g. nicotinamide riboside [NR]) restores cellular energy and reduces inflammation in vitro and in dextran sodium sulfate (DSS)-induced colitis.
    CONCLUSION: A metabolic bottleneck at QPRT prevents efficient NAD+ synthesis from Trp in IBD, sustaining inflammation. Restoring NAD + is a promising therapeutic strategy.
    Keywords:  IBD; NAD; metabolism; quinolinic acid; tryptophan
    DOI:  https://doi.org/10.1093/ecco-jcc/jjag043
  14. bioRxiv. 2026 May 21. pii: 2026.05.19.726300. [Epub ahead of print]
    NOD2 activation reprograms infiltrating inflammatory monocytes in the Zika virus infected CNS to maintain neural correlates of learning and memory.
    Jeremy D Hill, Alice H W Dong, Joshua Liu, Marina Diniz Barbezani, Tallulah S Andrews, Robyn S Klein.
      Zika virus (ZIKV) encephalitis induces cytokine-mediated cognitive deficits which persist long-term. Here, we determined if NOD2-mediated conversion of monocytes from Ly6C Hi inflammatory to Ly6C Lo anti-inflammatory phenotypes during ZIKV encephalitis preserves neural correlates of learning and memory within the hippocampus. Short-term administration of the NOD2 agonist, muramyl dipeptide (MDP), during peak ZIKV infection prevents synapse elimination and loss of adult hippocampal neurogenesis, without impacting CNS virologic control. Transcriptomic analyses of forebrain immune cells in MDP-treated mice revealed functional modulation of infiltrated monocytes and T cells, reducing their expression of pro-inflammatory cytokines, with limited effects on microglia, compared to controls. Notably, NOD2 activation in peripheral immune cells alone balances innate immune signals, preserving synapses, and increasing macrophage phagocytic capacities that do not target synapses. Our findings identify infiltrating Ly6C Hi monocytes as key drivers of long-term cognitive dysfunction following ZIKV encephalitis and as potential therapeutic targets for limiting synapse loss.
    Highlights: NOD2 activation via MDP phenotypically shifts monocyte subsets from inflammatory to anti-inflammatory during the acute phase of ZIKV encephalitis.Short-term MDP administration increases phagocytic machinery and reduces inflammatory cytokine/chemokine production within macrophage populations.Synapse elimination is attenuated within the hippocampus of ZIKV-infected animals treated with MDP.MDP derived effects are mediated through peripherally derived immune cells.
    DOI:  https://doi.org/10.64898/2026.05.19.726300
  15. Metabolomics. 2026 Jun 02. pii: 92. [Epub ahead of print]22(3):
    Host metabolic responses to SARS-CoV-2 and influenza viruses: parallels and contrasts.
    Charles Terra, Olivier Terrier, Audrey Le Gouellec.
       BACKGROUND: SARS-CoV-2 and Influenza virus are two major respiratory viruses, responsible for the COVID-19 and the flu respectively. To achieve their replication, these viruses do not merely hijack host cells; they reprogram them, and the host's metabolism is no exception.
    AIM OF THE REVIEW: This review explores how two major respiratory pathogens, SARS-CoV-2 and influenza virus, manipulate host metabolism to fuel their replication and drive disease.
    KEY SCIENTIFIC CONCEPTS OF THE REVIEW: Despite differences in their genome organization and replication strategies, both viruses disrupt central metabolic pathways, including glucose processing, the Krebs cycle, amino acid and nucleotide synthesis. Common effects include enhanced anaerobic glycolysis, depletion of key amino acids, activation of the kynurenine pathway, and disruption of purine signaling. However, each virus leaves a distinct metabolic fingerprint. SARS-CoV-2 infection leads to glucose accumulation, alters late-stage Krebs cycle metabolites, and significantly disrupts nucleotide production. In contrast, influenza viral infection depletes glucose and dampens Krebs cycle activity, with a less consistent impact on nucleotide pathways. Viral proteins, such as SARS-CoV-2 ORF3a and influenza virus NS1, play a crucial role in these metabolic shifts. These changes not only reflect viral strategies but also correlate with disease severity. As metabolomics technologies advance, understanding these virus-specific and shared metabolic changes could unlock new diagnostic tools, prognostic markers, and treatment strategies.
    Keywords:  COVID-19; Host metabolism; Influenza virus; SARS-CoV-2; Virus-host interactions
    DOI:  https://doi.org/10.1007/s11306-026-02454-0
  16. Adv Sci (Weinh). 2026 Jun 01. e16577
    PRMT1-Mediated LDHA Methylation Drives STAT3 Lactylation to Orchestrate Intestinal Inflammation and Tumorigenesis.
    Hui Wang, Mengyu Zhang, Weipeng Gong, Jiaxuan Wu, Junping Zhang, Wenxiu Zhang, Yue Liu, Kui Wang, Canhua Huang, Jun Zhou, Sijin Wu, Yan Li, Tianliang Li.
      Signal transducer and activator of transcription 3 (STAT3) activation is crucial in intestinal inflammation and tumorigenesis. However, its metabolic regulation is not well understood. Herein, we identified a macrophage-dependent methionine-S-adenosylmethionine (SAM)-protein arginine methyltransferase 1 (PRMT1)-lactate dehydrogenase A (LDHA)-lactate axis that controls intestinal inflammation through STAT3 regulation. Specifically, SAM promoted STAT3 Y705 phosphorylation and upregulated anti-inflammatory interleukin-10 expression in macrophages. Additionally, genetic ablation of PRMT1 in myeloid cells not only impairs STAT3 activation but also exacerbates colitis and promotes inflammation-associated tumorigenesis. Mechanistically, PRMT1 directly methylates LDHA at R268/R269, thereby enhancing its activity and lactate production. Subsequently, the resulting lactate induces STAT3 lactylation at K709, stabilizing an open conformation that facilitates Y705 phosphorylation. Importantly, disruption of this modification through K709-specific inhibition effectively blocks STAT3 activation and, consequently, exacerbates colitis progression. Overall, this study reveals STAT3 lactylation as a novel post-translational modification that integrates methionine metabolism with glycolytic flux to regulate intestinal inflammation, highlighting the critical role of immunometabolism in colonic inflammation.
    Keywords:  PRMT1; STAT3; interleukin‐10; intestinal inflammation; lactylation
    DOI:  https://doi.org/10.1002/advs.202516577
  17. Cell Commun Signal. 2026 Jun 05.
    Salmonella Typhimurium hijacks a host glucose transporter for intravacuolar proliferation.
    Xianglan Fang, Liuliu Shi, Yan Ding, Youwei Wang, Wei Chen, Juan Xue, Long Wang, Yuanjian Hui, Xinyuan Tao, Wanmo Xiao, Jin Yang, Lijie Du, Zheng Cao, Duoshuang Xie, Kun Meng.
      Salmonella is an intracellular pathogen that can reside within a vacuole, which protects it from cytosolic host defenses at the expense of limited nutrient access. Glucose serves as a critical carbon source supporting Salmonella's intracellular replication. However, the molecular mechanisms driving glucose uptake of host cells and the pathways by which cytosolic glucose becomes accessible to intravacuolar Salmonella remain poorly understood. Here, we elucidate a three-pronged strategy through which Salmonella Typhimurium (S. Typhimurium) exploits Glut1 to co-opt host glucose metabolism for pathogenic advantage. Firstly, S. Typhimurium infection upregulates the glucose transporter Glut1 by activating the MAPK signaling cascade, enhancing host glucose uptake, and accelerating glycolytic flux. Secondly, S. Typhimurium utilizes Glut1 to the bacterial vacuolar membrane to establish a glucose-import conduit that facilitates bacterial acquisition of cytosolic glucose. Thirdly, K29-linked ubiquitination on bacterial vacuolar membranes is a previously unrecognized regulatory mechanism that potentiates Glut1 transporter activity. Inhibition of Glut1 potentiates S. Typhimurium-triggered innate immune responses and attenuates bacterial virulence in vitro and in vivo. Collectively, these findings delineate a novel paradigm of metabolic hijacking, wherein S. Typhimurium systematically rewires host glucose metabolic networks to support intracellular proliferation, providing new insights into host-directed antimicrobial interventions.
    Keywords:  Anti-bacterial immunity; Glucose metabolism; Glut1; Intravacuolar bacterial
    DOI:  https://doi.org/10.1186/s12964-026-02981-2
  18. Fish Shellfish Immunol. 2026 Jun 01. pii: S1050-4648(26)00375-X. [Epub ahead of print]176 111471
    Hepatic immunometabolic reprogramming of Sebastes schlegelii in response to Photobacterium damselae subsp. piscicida infection: biochemical, transcriptomic and metabolomic analyses.
    Hao Jing, Guang-Hua Wang, Kai Yang, Zi-Yue Chen, Zhi-Shu Zhu, Nuo Sun, Yi-Lin Du, Zi-Qi Wang, Min Zhang.
      Photobacterium damselae subsp. piscicida (PDP) is a highly virulent pathogen causing substantial economic losses in marine aquaculture, yet the molecular mechanisms of host-pathogen interactions remain poorly understood. In this study, we established a PDP infection model in black rockfish S. schlegelii and systematically investigated hepatic immunometabolic responses through integrated histopathological examination, biochemical enzyme assays, and multi-omics analyses. Time-course analysis identified 24 h post-infection as a critical window for host immune activation, characterized by peak activities of innate immune effectors, metabolic enzymes, and antioxidant enzymes. Integrated transcriptomic and metabolomic profiling at this pivotal time point revealed extensive metabolic reprogramming centered on three interconnected pathways. Energy metabolic reprogramming was evidenced by enhanced glycolytic flux and glutamine-dependent TCA cycle anaplerosis, reflecting the classical Warburg effect. Glycerophospholipid metabolism was profoundly disrupted, characterized by decreased phosphatidylcholine and phosphatidylethanolamine, accumulation of lysophospholipid derivatives, and altered expression of key regulatory genes, compromising membrane integrity while generating damage-associated molecular patterns that initiate innate immune signaling. Amino acid metabolism was extensively reprogrammed, with significant depletion of L-glutamine, L-cysteine, L-arginine, and multiple functional dipeptides, reflecting both host immune utilization and pathogen nutrient sequestration, which exacerbated oxidative damage. These immunometabolic events drive dual outcomes, namely the initiation of anti-infective immune defense and progressive liver injury. This integrated model identifies key metabolic nodes as potential therapeutic targets, providing a theoretical foundation for developing disease control strategies against bacterial septicemia in marine aquaculture.
    Keywords:  Mechanism; Metabolomic; Photobacterium damselae subsp. piscicida; Teleost; Transcriptomic
    DOI:  https://doi.org/10.1016/j.fsi.2026.111471
  19. Cell Metab. 2026 Jun 04. pii: S1550-4131(26)00191-9. [Epub ahead of print]
    Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.
    Drew Adler, Alejandro Martín-Ávila, Evan Cheng, Mauricio M Oliveira, Muxian Zhang, Harrison T Evans, Deliang Yuan, Richard Sam, Nicole D Zhang, Maria Clara Selles, Olivia Mosto, Wendy J Liu, Victor T Wu, Amy X Guo, Shane A Liddelow, Robert C Froemke, Moses V Chao, Wen-Biao Gan, Eric Klann.
      De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here, we demonstrate that microglia, the resident macrophages of the brain, are required for metabolic coupling between endothelial cells, astrocytes, and neurons, which fuels protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, which increases glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit that is required for on-demand protein synthesis in mouse motor cortex.
    Keywords:  astrocyte-neuron-lactate-shuttle; brain immunometabolism; brain metabolism; immunometabolism; mRNA translation; microglia; microglia-endothelial interaction; microglia-neuron interaction; microglial-metabolic coupling; neuroimmunology; protein synthesis
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.006
  20. Bioact Mater. 2026 Oct;64 763-780
    Astaxanthin-metformin conjugate nanomicelles-loaded hydrogel reprograms macrophage metabolism via mitochondrion-targeted regulation for diabetic wound healing.
    Xin-Nan Teng, Hui Wang, Yue Zhu, Shu-Chang Wang, Run-Long Pan, Chen Du, Run-Fang Song, Shuai-Shuai Zhang, Jun-Rong Li, Song-Bai Zhang, Feng Xu, Qian Zhang, Min Zhang.
      Diabetic wounds struggle to heal because of ROS-mediated immune dysfunction, in which the mitochondrial metabolic reprogramming of macrophages is critical for inflammation resolution and tissue repair. Here, we innovatively combine the antioxidant astaxanthin (Ast) and the metabolic activator metformin (Met) via pH-responsive dynamic Schiff base linkages to form amphiphilic Ast-PEG-Met conjugates, which self-assemble into nanomicelles (NMs). This strategy effectively improves the solubility of Ast and enables synergistic delivery of the two complementary drugs. NMs target macrophage mitochondria, where Ast scavenges mtROS and Met activates energy metabolism pathways in a synergistic manner. The two drugs synergistically activate the AMPK-PPARγ axis and promote mitophagy, thereby restoring mitochondrial function and regulating immunometabolic reprogramming. For on-demand release, the NMs were further encapsulated into a ROS-responsive self-healing hydrogel crosslinked by dynamic phenylboronate ester bonds. This system responds to high levels of ROS and an acidic wound microenvironment with favorable biocompatibility. In a diabetic full-thickness skin defect model, this integrated platform markedly accelerated wound healing, promoted collagen deposition and angiogenesis, and alleviated chronic inflammation. This work provides a promising combined strategy involving antioxidant-metabolic regulation for chronic diabetic wound therapy via a dual-responsive hydrogel drug delivery system.
    Keywords:  Astaxanthin-metformin conjugate; Diabetic wound healing; Hydrogel; Macrophage reprogramming; Mitochondria
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.031
  21. Trends Immunol. 2026 Jun 05. pii: S1471-4906(26)00127-4. [Epub ahead of print]
    SIRT6 bridges glycolysis and epigenetics to neutrophilic asthma.
    Zhan Wang, Xuewei Zhu.
      Neutrophil asthma is a severe, corticosteroid-resistant subtype characterized by airway neutrophilia and declining lung function. Su et al. identify a sirtuin 6-lactate dehydrogenase A-histone lactylation axis that links macrophage glycolysis to epigenetic chemokine regulation, offering mechanistic insight into neutrophil recruitment and highlighting potential therapeutic targets.
    Keywords:  asthma; chemokines; histone lactylation; neutrophils
    DOI:  https://doi.org/10.1016/j.it.2026.05.002
  22. Inflammation. 2026 Jun 04.
    lncRNA-mRNA Co-expression Network Unveils Neutrophil Metabolic Reprogramming in Human Sepsis.
    Peng Zhang, Fupeng Wang, Kang Zhao, Zeqing Miao, Yang Yu, Aiqing Wen, Huang Wu.
      Sepsis is a life-threatening inflammatory syndrome driven by dysregulated immunity. Metabolic reprogramming and epigenetic regulation are now recognized as critical mechanisms underlying persistent immune cell alterations in sepsis. Neutrophils play a central role in sepsis by forming NETs, releasing inflammatory cytokines, and phagocytosing pathogens. During these processes, neutrophils undergo metabolic adaptation that supports their effector functions. Long non-coding RNAs (lncRNAs) have been implicated in multiple facets of sepsis progression, including the regulation of immune cell functions and organ injury. Recent studies further indicate that lncRNAs modulate metabolic reprogramming across various cell types during sepsis, highlighting extensive crosstalk between metabolic and epigenetic pathways. Nevertheless, the relationship between lncRNAs and metabolic reprogramming in neutrophils remains poorly understood. To better characterize the regulatory interplay between metabolic alterations and lncRNAs in neutrophils during sepsis, we performed RNA sequencing of neutrophils isolated from septic patients. We identified a set of hub differentially expressed genes enriched in amino acid metabolic processes and uncovered potential lncRNA networks that may regulate these genes. Our study delineates a broader landscape of neutrophil metabolic reprogramming in sepsis and provides a foundational co-expression network, offering new directions for investigating lncRNA-mediated amino acid metabolic alterations in neutrophils during sepsis.
    Keywords:  Metabolism; Neutrophil; Sepsis; lncRNAs
    DOI:  https://doi.org/10.1007/s10753-026-02532-4
  23. Front Immunol. 2026 ;17 1806420
    Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation.
    Zekai Hu, Jinyan Wang, Sicong Ma, Jie Zhuang, Jing Shi, Yan Zhu.
      Inflammation-driven fatigue is a clinically significant feature of several chronic inflammatory conditions, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-COVID condition, autoimmune disease, and cancer-related fatigue. Across these conditions, partially overlapping disturbances in immune regulation, cellular metabolism, and neuroimmune signaling may contribute to persistent fatigue, despite important differences in initiating context and biological substrate. Current evidence implicates mitochondrial dysfunction, altered glycolysis and fatty acid utilization, lactate- and succinate-associated signaling, metabolite-sensing G protein-coupled receptor (GPCR) pathways, epigenetic acylation, and immune remodeling in the maintenance of fatigue. This narrative review synthesizes both shared and disease-context-specific mechanisms underlying inflammation-associated fatigue, with particular emphasis on immunometabolism, peripheral-central neuroimmune crosstalk, metabolite-GPCR signaling, and epigenetic regulation. We highlight GPCR signaling as a potentially important regulatory interface in inflammatory and metabolic pathways relevant to fatigue, while recognizing that direct causal evidence in human fatigue syndromes remains limited. The review also examines how metabolite-mediated epigenetic acylation may influence immune cell function and fatigue-related biology, although this association remains incompletely validated in fatigue-specific settings. By integrating metabolic dysregulation, neuroimmune signaling, and immune dysfunction, this review consolidates current knowledge on candidate biomarkers, mechanistic pathways, and emerging therapeutic targets in chronic inflammation-driven fatigue. Overall, this review provides a multidimensional framework for understanding fatigue across inflammatory disorders and for guiding future mechanistic and translational research.
    Keywords:  GPCR signaling; bioactive metabolites; chronic inflammation; epigenetic acylation; fatigue; histone modification; immunometabolism; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2026.1806420
  24. Fish Shellfish Immunol. 2026 Jun 01. pii: S1050-4648(26)00376-1. [Epub ahead of print] 111472
    High-fat overfeeding is associated with tissue-specific liver-adipose immunometabolic remodeling in rainbow trout.
    Jiyeon Park, Do-Hyung Kim.
      The excessive accumulation of visceral adipose tissue is associated with ectopic lipid deposition, impairing the function of major metabolic organs, including the liver, and contributing to systemic inflammatory responses. In aquaculture, farmed fish have limited capacity to autonomously regulate feed intake, as caloric intake is largely determined by feeding practices, predisposing them to excessive energy consumption and metabolic imbalance. This study investigated how excessive feeding affects metabolic and immune responses in the liver and adipose tissue of rainbow trout and whether these alterations increase susceptibility to infection. A total of 195 rainbow trout were assigned to three feeding regimes: normal feeding with an 8% fat diet (NF8), normal feeding with a 22% fat diet (NF22), and overfeeding with a 22% fat diet (OF22). Fish were fed for 12 weeks and sampled at 2, 4, 8, and 12 weeks to assess growth performance, serological parameters, immune responses, and pathogen susceptibility. RNA sequencing-based transcriptomic analysis was conducted on liver samples at weeks 2 and 8 and on adipose tissue samples at weeks 2, 4, and 8. Fish in the OF22 group exhibited significantly increased body weight, body mass index, and serum aspartate aminotransferase, alanine aminotransferase, and triglyceride levels compared to the other groups, accompanied by adipocyte hypertrophy. Transcriptomic analysis revealed the upregulation of fatty acid biosynthesis and oxidative phosphorylation pathways in the liver, and the downregulation of immune-related pathways, including complement and coagulation cascades. In contrast, adipose tissue showed enhanced lipid and energy metabolism, elevated expression of pro-inflammatory markers (interleukin (il)-1β, il-6, tumor necrosis factor-α, and inducible nitric oxide synthase), reduced anti-inflammatory and M2 macrophage-associated markers (il-10 and cd163), and the sustained activation of complement-related pathways. These tissue-specific immunometabolic changes were linked to a higher susceptibility to Aeromonas salmonicida infection and increased mortality after the challenge. Overall, the study results show that the OF22 condition was associated with tissue-specific immunometabolic imbalance in farmed fish, leading to metabolic disturbances and weakened immune responses.
    Keywords:  Adipose tissue inflammation; Complement system; Disease susceptibility; Immunometabolism; Overfeeding
    DOI:  https://doi.org/10.1016/j.fsi.2026.111472
  25. Cell Metab. 2026 Jun 03. pii: S1550-4131(26)00190-7. [Epub ahead of print]
    IRG1/itaconate rewires macrophage and lung tumor metabolism through G6PD inhibition.
    Siavash Mansouri, Golnaz Hesami, Anoop Ambikan, Annika Karger, Stephan Klatt, Ujjwal Neogi, Konda Babu Kurakula, Blerina Aliraj, Anne Miller, Boryana Petrova, Miloslav Sanda, Evelyn Sirait-Fischer, Stefan Guenther, Carsten Kuenne, Clemens Ruppert, Ibrahim Alkoudmani, Stefan Gattenlöhner, Sven Zukunft, Ingrid Fleming, Arvand Haschemi, Thorsten Stiewe, Friedrich Grimminger, Martin Reck, Andreas Weigert, Werner Seeger, Soni Savai Pullamsetti, Rajkumar Savai.
      Tumor-associated macrophages (TAMs) possess both tumor-promoting and tumor-inhibiting roles. Here, we explore TAMs' anti-tumor functions, focusing on the immune responsive gene 1 (IRG1) and its product, itaconate, in lung cancer development. Spatial metabolomics reveals that endogenous itaconate is markedly depleted within lung tumor regions compared with adjacent non-tumor tissue. Single-cell RNA sequencing shows that macrophages are the primary cells expressing IRG1 in human and mouse lung tumors. Both IRG1 knockout and transplantation of IRG1-depleted bone marrow leads to increased lung tumor growth in various mouse lung tumor models. Additionally, 4-octyl itaconate (Octyl Ita) reduces tumor growth in vitro, in vivo, and in ex vivo human tumor precision-cut lung slices. An integrated multi-omics analysis shows that IRG1/itaconate causes a metabolic shift in cancer cell and pro-tumor macrophages, mainly by inhibiting the pentose phosphate pathway (PPP) through targeting glucose-6-phosphate dehydrogenase (G6PD) activity, thereby suppressing cancer cell growth and transforming pro-tumor macrophages into anti-tumor macrophages. Thus, leveraging IRG1/itaconate's tumor-suppressive effects or using Octyl Ita could be a novel lung cancer therapy.
    Keywords:  glucose-6-phosphate dehydrogenase; itaconate; lung cancer; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.005
  26. bioRxiv. 2026 May 27. pii: 2026.05.24.727510. [Epub ahead of print]
    ACLY integrates metabolism and chromatin accessibility to enable B Cell activation and humoral immunity.
    Meilu Li, Zhiqiang Zhang, Xian Zhou, Yanfeng Li, Xingxing Zhu, Aditya Bhagwate, Nagaswaroop Kengunte Nagaraj, Hu Zeng.
      B cell activation and differentiation into antibody-secreting cells require extensive metabolic and epigenetic remodeling, yet the molecular mechanisms that integrate these programs remain incompletely understood. ATP-citrate lyase (ACLY) links glucose metabolism to acetyl-CoA production, supporting lipid biosynthesis and protein acetylation. However, its role in humoral immunity has not been fully defined. Here, using genetic and integrated multi-omics approaches, we show that B cell activation is accompanied by coordinated metabolic, transcriptional, and epigenetic reprograming. Although ACLY is dispensable for B cell development and homeostasis, it is required to establish chromatin accessibility programs in activated B cells, with a more pronounced impact on the epigenetic landscape than on transcriptional output. ACLY-deficient B cells exhibit profound defects in TLR and BCR elicited activation, survival and metabolic fitness ex vivo . In vivo , B cell-intrinsic loss of ACLY results in impaired antigen-specific antibody production, associated with reduced germinal center and plasmablast formation, but normal homeostatic proliferation. Deletion of ACLY after B cell activation reduces plasmablast generation in vivo , indicating a continued requirement for ACLY beyond the initial activation phase. Together, these findings identify ACLY as a central regulator that links metabolism to epigenetic programing that supports B cell activation and humoral immunity.
    DOI:  https://doi.org/10.64898/2026.05.24.727510
  27. Front Med (Lausanne). 2026 ;13 1801906
    The immunometabolic mechanisms and therapeutic targets of metabolic dysfunction-associated steatohepatitis.
    Jiang Yu, Yong Peng.
       Background: Metabolic dysfunction-Associated Steatohepatitis (MASH) is a progressive subtype of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis, which may evolve to cirrhosis and hepatocellular carcinoma. Despite its growing global burden, no widely approved pharmacotherapy is available, highlighting the need to elucidate immunometabolic mechanisms and identify effective therapeutic targets.
    Content: This review summarizes the epidemiology and clinical features of MASH and focuses on key pathogenic pathways, including insulin resistance, lipotoxicity, mitochondrial dysfunction, and gut-liver axis disturbance. Immune dysregulation mediated by Kupffer cell activation, macrophage polarization, inflammasome signaling, and cytokine networks is discussed in depth. The critical role of immunometabolic crosstalk in disease progression is emphasized. Current and emerging therapeutic targets-such as PPARs, FXR, THR-β, the GLP-1/FGF21 axis, DGAT2, and CCR2/CCR5-are systematically reviewed, together with advances in oligonucleotide therapy, cell-based interventions, and combination strategies.
    Conclusion: MASH results from the complex coupling of metabolic imbalance and immune-driven inflammation, making single-target therapy insufficient. Precision stratification based on immunometabolic networks and multi-target interventions represent promising directions for future drug development and individualized treatment.
    Keywords:  immunometabolism; macrophage; metabolic dysfunction-associated steatohepatitis; nuclear receptor; therapeutic targets
    DOI:  https://doi.org/10.3389/fmed.2026.1801906
  28. J Biol Chem. 2026 Jun 04. pii: S0021-9258(26)02108-3. [Epub ahead of print] 113236
    Oleoylethanolamide Enhances Regulatory T Cell Function to Accelerate Plaque Regression in Atherosclerosis via PPARα Activation.
    Tong Ren, Yanchao Jiao, Le Zhang, Yijun Liu, Xilin Jiang, Lu Peng, Changsheng Yan, Jianbo Jia, Xin Jin.
      Regulatory T cells (Tregs) are essential for maintaining immune balance and limiting inflammatory damage within atherosclerotic plaques. Although the endogenous lipid mediator oleoylethanolamide (OEA) has reported anti-inflammatory and metabolic benefits, its effects on Treg differentiation and function during atherosclerosis are incompletely defined. Here, we tested OEA using in vitro naïve CD4+ T-cell polarization assays and in vivo atherosclerosis models. OEA increased CD25+Foxp3+ Treg differentiation in polarization cultures and shifted the Treg compartment in atherosclerotic mice toward a more functional phenotype. PPARα dependence was supported by pharmacologic inhibition with MK886 and by genetic loss of PPARα, both of which abrogated OEA-induced Treg differentiation and functional enhancement. Mechanistically, OEA engaged a PPARα-RORγt pathway consistent with suppression of RORγt-associated programs during Treg differentiation. In therapeutic studies, adoptive transfer of OEA-conditioned Tregs promoted regression of established atherosclerotic plaques. Together, these data identify OEA as a modulator of Treg differentiation and activity and support its potential as a PPARα-dependent strategy to promote plaque regression and immune homeostasis in atherosclerosis.
    Keywords:  OEA; PPARα; RORγt; atherosclerosis
    DOI:  https://doi.org/10.1016/j.jbc.2026.113236
  29. Front Immunol. 2026 ;17 1817391
    Immunometabolic reprogramming and glycolysis-associated signatures in sepsis: insights from single-cell RNA sequencing and machine learning.
    Tao Li, Yun Liu, WanZhao Wang, QiuYue Li, Bing Chen.
       Background: Immunometabolic remodeling is central to sepsis, yet robust glycolysis-associated biomarkers and their cell-type context remain unclear.
    Methods: We integrated peripheral blood scRNA-seq (GSE175453) and a whole-blood microarray cohort (GSE100159). Glycolysis activity was scored by AUCell (HALLMARK_GLYCOLYSIS), hub genes were prioritized by LASSO/random forest/Boruta, communication was inferred by ligand-receptor analysis, and qRT-PCR was performed in CLP vs control mice.
    Results: Sepsis showed myeloid predominance and increased glycolysis scores, most evident in monocytes and plasma cells. Five candidates (GLRX, MDH1, MDH2, TGFBI, COPB2) displayed good discriminatory performance in bulk data; TGFBI was monocyte-enriched and centrally positioned in a dense communication network with B cells/plasma cells/neutrophils. qRT-PCR confirmed a significant between-group difference for TGFBI in the CLP model.
    Conclusions: These findings link enhanced glycolysis-associated programs to a monocyte-centered TGFBI communication pattern and prioritize TGFBI as a candidate biomarker for further validation in sepsis.
    Keywords:  biomarkers; glycolysis; immunometabolism; machine learning; sepsis; single-cell RNA sequencing (scRNA-seq)
    DOI:  https://doi.org/10.3389/fimmu.2026.1817391
  30. PLoS One. 2026 ;21(6): e0347055
    Protocatechuic acid prevents obesity caused by long-chain saturated fatty acid-induced inflammation in mouse microglia via inhibition of the NF-κB pathway.
    Ken-Yu Hironao, Shoma Fujino, Yusei Johta, Kevin Odongo, Hitoshi Ashida, Yoko Yamashita.
      Long-chain saturated fatty acids (LCSFAs), abundant in animal fats, can directly activate microglia and elicit inflammatory responses. Excessive intake of LCSFA-rich high-fat diets (HFDs) has been linked to microglial activation in the brain (particularly within the hypothalamus, a central regulator of energy metabolism) and to metabolic disorders, including obesity. Here, we report that protocatechuic acid (PCA) suppressed the inflammatory response in murine microglia induced by LCSFAs. PCA inhibited the ubiquitin-proteasome degradation of IκBα induced by LCSFAs, suppressing the nuclear translocation of NF-κB and the expression of pro-inflammatory cytokine genes, which was indicated to be attributed to the suppression of I kappa B kinase. In addition, PCA prevented obesity by inhibiting the accumulation of activated microglia in the ARC of HFD-fed mice. This study is the first to demonstrate that PCA suppresses the inflammatory response of microglia induced by LCSFAs and ARC inflammation in HFD-fed mice. These findings provide new evidence and insights into the mechanisms by which polyphenols, including PCA and its analogs, ameliorate diet-induced obesity.
    DOI:  https://doi.org/10.1371/journal.pone.0347055
  31. Int Immunopharmacol. 2026 Jun 04. pii: S1567-5769(26)00807-6. [Epub ahead of print]184 116961
    Rheumatoid arthritis synovial fibroblasts promote the glycolysis of myeloid-derived suppressor cells via TREM1/mTOR axis.
    Bishun Deng, Guojun Liang, Lin Zeng, Huijie Huang, Yan Ma, Yi Wang, Jingyao Yan, Xiaohui Huang, Kai Lan, Peifeng Ke, Anping Peng, Min He.
      Myeloid-derived suppressor cells (MDSCs) are pathologically expanded in rheumatoid arthritis (RA), yet the underlying metabolic drivers remain elusive. Single-cell RNA sequencing (scRNA-seq) and flow cytometry (FC) were systematically performed to characterize metabolic reprogramming in MDSCs from RA patients. Spatial transcriptomics was used to map in situ cell distributions within synovial tissue. The regulatory effects of human RA fibroblast-like synoviocytes (FLSs) MH7a cells on MDSCs glycolysis were validated by detecting the extracellular acidification rate, glucose uptake capacity and lactate production. Pharmacological inhibitors were employed to interrogate the pathway for orchestrating glycolytic reprogramming of RA-MDSCs. We found that RA-MDSCs underwent glycolytic reprogramming during differentiation, which directly potentiated their inflammatory phenotype. Mechanistically, RA-FLSs induced triggering receptor expressed on myeloid cell 1 (TREM1) overexpression in MDSCs through direct cell-cell contact, initiating a PI3K-AKT-mTOR-HIF-1α signaling cascade that fueled glycolytic flux. Pharmacological blockade of TREM1 not only attenuated inflammatory monocytic MDSCs (M-MDSCs) differentiation, but also restored the suppressive activity of MDSCs. Our results established a critical role for TREM1 signaling in mediating the FLSs-MDSC crosstalk in RA, which unveiled TREM1 as a therapeutic target to restore MDSC metabolic homeostasis in autoimmune arthritis.
    Keywords:  Glycolysis; Metabolic reprogramming; Myeloid-derived suppressor cells; Rheumatoid arthritis; TREM1
    DOI:  https://doi.org/10.1016/j.intimp.2026.116961
  32. Cell Rep. 2026 Jun 02. pii: S2211-1247(26)00490-0. [Epub ahead of print]45(6): 117412
    Neutrophil-derived itaconate facilitates tiered pulmonary inflammation via Kdm5b-associated epigenetic remodeling in alveolar macrophages.
    Gyumin Lim, Juyeon Kim, Doyoung Park, Jeong Hee Lee, Yeon Jin Roh, Moses Yang, Soowan Lee, Seungbok Yang, Sojeong Baek, Jumi Park, Hae Chan Lim, Ji-Hyeon Lee, Sehan Kim, Hwiwon Seo, Yong-Hoon Kim, Su Myung Jung, Hanseul Yang, Pureum Sun, Seong Eun Lee, Yea Eun Kang, Young-Jun Park, Young Min Son, Hyon-Seung Yi, Jun Young Hong, Luis F Moita, Da Hyun Kang, Hongsook Kim, Chuna Kim, Sung-Jin Yoon, Dong Wook Choi.
      Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present a substantial clinical burden, magnified by conditions such as COVID-19. While these conditions provide a model for exploring complex inflammatory processes, the environmental factors coordinating these responses remain poorly understood. Here, we employ comprehensive multi-omics and biochemical analyses and identify neutrophil-derived itaconate as an extracellular factor associated with sequential immune cell infiltration, including neutrophils, T cells, and monocytes. Mechanistically, extracellular itaconate metabolically facilitates Kdm5b-associated epigenetic changes at the Il6, Ccl5, and Cxcl10 gene promoters in alveolar macrophages, which are important for immune cell recruitment. Consistent with this, Mrp8-Cre Acod1fl/fl mice lacking neutrophil-derived itaconate are significantly protected from ALI-induced inflammation, with similar patterns observed in an Acinetobacter baumannii infection model. Collectively, these findings identify neutrophil-derived itaconate as an environmental factor that epigenetically shapes tiered inflammatory responses in the lung.
    Keywords:  ALI; AMs; CP: immunology; CP: metabolism; Itaconate; KDM5B; Lung Inflammation; acute lung injury; alveolar macrophages; environmental factor; lysine demethylase 5b; neutrophils
    DOI:  https://doi.org/10.1016/j.celrep.2026.117412
  33. J Clin Invest. 2026 Jun 01. pii: e201460. [Epub ahead of print]136(11):
    Polyamine sequestration of 2'3'-cGAMP constrains intercellular transmission and STING engagement to subvert antitumor immunity.
    Yunjin Ma, Chunyuan Zhao, Jiacheng Guo, Yue Fu, Wei Wang, Jiangong Zhang, Kun Zhao, Xiangbo Meng, Zhongshang Yuan, Chengjiang Gao, Mutian Jia, Ying Qin, Hui Song, Wei Zhao.
      The cyclic dinucleotide 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) serves as a central immunotransmitter that propagates stimulator of interferon gene-dependent (STING-dependent) innate immunity across tissues; however, how microenvironmental metabolites regulate its spatiotemporal dynamics remains unknown. Here, we identified polyamines (spermine and spermidine) as critical rheostats controlling 2'3'-cGAMP functionality. Mechanistically, polyamines sequestered 2'3'-cGAMP into polymer-like aggregates, blocking intercellular propagation and suppressing intracellular STING activation by reducing ligand-receptor binding affinity. Deficiency of spermidine and spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism, elevated polyamine levels to entrap extracellular 2'3'-cGAMP and inhibit STING activation. Synergistic administration of endogenous 2'3'-cGAMP with SAT1 stabilizer N1,N11-diethylnorspermine restored 2'3'-cGAMP bioavailability and STING signaling, facilitated type I interferon responses to reprogram immunologically suppressive tumors into immunologically active states and enhanced tumor clearance. Our study established polyamine-cGAMP interactions as a critical spatiotemporal regulatory mechanism for tissue-level immunity, providing a unified model for metabolite-mediated cyclic GMP-AMP synthase-STING (cGAS-STING) regulation across diseases.
    Keywords:  Cancer immunotherapy; Cellular immune response; Immunology; Innate immunity; Metabolism
    DOI:  https://doi.org/10.1172/JCI201460
  34. FASEB J. 2026 Jun 15. 40(11): e71954
    Polyphosphates Attenuate Interleukin-12 Production in Macrophages Infected With Legionella pneumophila.
    Kara Vasilew, Archana Jayaraman, Johannes Platten, Shuang Xu, Sarah Josinsky, Julian Roewe, Maximilian Mimmler, Jonathan Kilroy, Fedoua Echahidi, Ziya Kaya, Dario S Zamboni, Christoph Reinhardt, Markus Bosmann.
      Polyphosphates are evolutionarily conserved linear chains of phosphate residues present in all living cells. Bacteria accumulate polyphosphates under stress and starvation for energy and phosphate storage, protein folding, and stress adaptation. During infection, bacteria release polyphosphates that may impair host responses, although the exact mechanisms remain elusive. In this study, polyphosphates were found to be elevated in bronchoalveolar lavage fluids from patients with Legionnaires' disease, in Legionella pneumophila cultured alone, or during infection of bone marrow-derived macrophages (BMDMs) from C57BL/6J mice. We performed RNA-sequencing of infected BMDMs co-incubated with or without long-chain, bacterial-type polyphosphates. Among nearly 500 differentially expressed genes, Il12b (p40) showed the strongest suppression among highly expressed genes. IL-12p40 protein release was dose-dependently reduced by long-chain polyphosphates (~Pi700), but not by short-chain, mammalian-type polyphosphates (~Pi70), indicating a specific bacterial mechanism targeting innate immune signaling. In contrast, IL-18, processed by inflammasome activation and synergizing functionally with IL-12, was not consistently suppressed. Polyphosphates predominantly inhibited LPS/TLR4 signaling, with Legionella-induced IL-12 relying on the MyD88 pathway, but not TRIF. RAGE and P2Y1, previously implicated in polyphosphate biology, were not required for IL-12 suppression. However, PI3K/AKT signaling appeared to mediate polyphosphate effects, which were reversed by the PI3K inhibitors, LY294002, copanlisib, and eganelisib. Finally, long-chain polyphosphates suppressed IL-12 release also from human monocyte-derived macrophages exposed to L. pneumophila or LPS. In summary, our findings identify a selective inhibition of IL-12 by long-chain bacterial polyphosphates, suggesting that these molecules act as bacterial effectors capable of suppressing protective innate immune responses.
    Keywords:  atypical pneumonia; cytokines; inflammation; polymer
    DOI:  https://doi.org/10.1096/fj.202502405RRR
  35. bioRxiv. 2026 May 22. pii: 2026.05.20.726273. [Epub ahead of print]
    Solute Carrier Transporter Family Modulates Neutrophil Metabolism During Health and Disease.
    Sunayana Malla, Rajib Saha.
      Neutrophils are the most abundant leukocytes in humans and play a central role in immune regulation. Although traditionally viewed as terminally differentiated cells with limited plasticity, growing evidence indicates that neutrophils exhibit substantial functional heterogeneity in response to stress. To date, however, most studies have focused on transcriptional and signaling changes, while metabolic heterogeneity, especially beyond central carbon metabolism, remains poorly characterized. Here, we systematically investigate metabolic reprogramming in neutrophils under three stress conditions: granulocyte colony-stimulating factor (G-CSF) treatment, hematopoietic stem cell transplantation (HSCT), and pancreatic ductal adenocarcinoma (PDAC). Using condition-specific genome-scale metabolic (GSM) models, we identify distinct metabolic vulnerabilities across neutrophil states. Vitamin metabolism emerged as a key differentiating feature between G-CSF- and HSCT-treated neutrophils, whereas PDAC-associated neutrophils displayed globally enhanced metabolic activity coupled with restricted metabolite exchange fluxes. Furthermore, solute carrier (SLC) family transporters were identified as major metabolic regulators underlying stress-induced neutrophil reprogramming. Together, our findings demonstrate that neutrophil heterogeneity extends beyond transcriptional programs to encompass profound metabolic specialization, highlighting metabolism as a critical dimension of neutrophil plasticity in health and disease.
    DOI:  https://doi.org/10.64898/2026.05.20.726273
  36. Mech Ageing Dev. 2026 Jun 01. pii: S0047-6374(26)00058-8. [Epub ahead of print] 112206
    Cell-specific energy crisis in the ageing brain: Mitochondrial dynamics drives neuron-glia metabolic uncoupling and neurodegeneration.
    Kai Wang, Yongchao Liu, Haojia Zhang, Xiaomin Li, Rui Zhou, Wei Shao, Zijin Sun.
      Ageing is the primary risk factor for neurodegeneration and age-related cognitive decline, which is increasingly recognised as a systemic collapse of metabolic crosstalk between neurons and glial cells in the brain. This narrative review elucidates that mitochondrial dynamics - encompassing biogenesis, fusion, fission, and mitophagy - acts as the core regulatory mechanism governing this multicellular interaction network, and drives the cell-specific energy crisis that underpins pathological progression in the ageing brain. We delineate that senescent astrocytes disrupt the astrocyte-neuron lactate shuttle, oligodendrocytes develop ATP deficits triggering myelin breakdown, and microglia undergo maladaptive immunometabolism and metabolic reprogramming via excessive Drp1-mediated mitochondrial fission, which collectively initiates and amplifies chronic neuroinflammation and neurodegenerative damage. Crucially, we highlight intercellular mitochondrial transfer as a vital endogenous rescue mechanism, wherein glial cells donate functional mitochondria to stressed neurons to mitigate damage. Finally, we synthesise emerging therapeutic strategies targeting the glia-neuron mitochondrial social network, providing a holistic framework for restoring brain bioenergetic homeostasis and delaying age-related neurodegenerative progression.
    Keywords:  Cell-Specific Energy Crisis; Immunometabolism; Intercellular Mitochondrial Transfer; Metabolic Reprogramming; Mitochondrial Dynamics
    DOI:  https://doi.org/10.1016/j.mad.2026.112206
  37. Front Vet Sci. 2026 ;13 1799048
    BVDV utilizes PGC-1α downregulation to remodel the mitochondrial metabolic microenvironment, enhancing viral replication and impairing host immunity.
    Hongming Zhou, Yixing Zhao, Yuxin Kong, Jiying Yin, Ning He, Qi Wang, Jiayin Liu, Tongbo Zhou, Yu Han, Shouyi Dong, Yaru Zhao, Naichao Diao, Kun Shi, Rui Du.
       Introduction: Bovine viral diarrhea virus (BVDV) is a major pathogen affecting global livestock production, and virus-induced mitochondrial remodeling is closely associated with viral replication. However, the role of PGC-1α-mediated mitochondrial quality control in cytopathic BVDV strain NADL infection remains unclear.
    Methods: MDBK cells were infected with CP BVDV(NADL) to establish an in vitro infection model. Mitochondrial morphology, function, mitophagy levels, and the expression of related proteins were examined using transmission electron microscopy, fluorescence staining, confocal microscopy, Western blotting, and the pADV-CMV-FH-cox8-EGFP-mCherry vector dual-fluorescence system. PGC-1α expression was manipulated by plasmid-mediated overexpression or shRNA-mediated knockdown.Viral replication was quantified by qRT-PCR, and IFN-β secretion was assessed by ELISA.
    Results: CP BVDV(NADL) infection caused mitochondrial structural damage and dysfunction, accompanied by persistent downregulation of PGC-1α and its downstream target TFAM. Meanwhile, Drp1 expression was increased, shifting mitochondrial dynamics toward excessive fission. CP BVDV(NADL) infection also markedly enhanced PINK1-mediated mitophagy. Functionally, PGC-1α overexpression restored mitochondrial homeostasis, inhibited PINK1-dependent mitophagy, reduced IFN-β expression, and ultimately suppressed CP BVDV(NADL) replication. Conversely, PGC-1α interference further promoted mitophagy and increased mPTP opening.
    Discussion: These findings demonstrate for the first time that CP BVDV(NADL) promotes viral replication by manipulating PGC-1α-mediated mitochondrial quality control. This mechanism reveals a novel metabolic strategy used by BVDV and provides potential therapeutic targets for controlling CP BVDV(NADL) infection.
    Keywords:  BVDV; PGC-1α; mitochondrial biogenesis; mitochondrial quality control; viral replication
    DOI:  https://doi.org/10.3389/fvets.2026.1799048
  38. Cell Mol Life Sci. 2026 Jun 04.
    Soft fibrin matrix instructs macrophage M2 polarization via FABP4-mediated enhancement of fatty acid β-oxidation to alleviate MASH.
    Ranran Zhang, Jialong Liu, Wenqing Shan, Haizhou Wang, Liping Gao, Yizhang Li, Lilan Fan, Chaoran Yang, Guoqingyuan Li, Jing Liu.
       BACKGROUND: Macrophage-driven inflammation is a key pathogenic factor in metabolic dysfunction-associated steatohepatitis (MASH). While fibrin deposition is observed in MASH livers, its role in regulating macrophage polarization and disease progression remains unclear.
    METHODS: We investigated fibrin deposition in liver tissues from MASH patients and high-fat diet (HFD)-induced MASH mice. Macrophages were cultured in soft or stiff 3D fibrin matrices to assess polarization phenotypes. In vivo, macrophages pre-cultured in soft or stiff fibrin were adoptively transferred into HFD-fed mice. Mechanistic studies involved siRNA-mediated knockdown, overexpression, chromatin immunoprecipitation, co-immunoprecipitation, and metabolomic analyses. Macrophage-specific FABP4 knockdown was achieved using an AAV8 vector expressing F4/80-driven FABP4 shRNA and eGFP.
    RESULTS: Fibrin deposition was significantly elevated in MASH livers and correlated with pro-inflammatory macrophage infiltration. Macrophages cultured in soft fibrin matrices exhibited enhanced anti-inflammatory (M2) polarization, characterized by increased Arg1 and CD206 and decreased iNOS and TNFα expression. Adoptive transfer of soft fibrin-cultured macrophages alleviated hepatic steatosis, insulin resistance, and oxidative stress in MASH mice. Mechanistically, soft fibrin downregulated FABP4 expression by inhibiting ITGB2/STAT1 signaling. FABP4 competitively bound to PPARα, thereby sterically hindering the access of USP53, which functions as a deubiquitinase, to PPARα. This displacement prevented USP53-mediated deubiquitination, resulting in increased PPARα ubiquitination and proteasomal degradation, ultimately leading to suppression of fatty acid β-oxidation. Macrophage-specific FABP4 knockdown mirrored the therapeutic effects of soft fibrin, ameliorating MASH pathology.
    CONCLUSIONS: Our findings reveal that soft fibrin matrices promote anti-inflammatory macrophage polarization and mitigate MASH by enhancing fatty acid β-oxidation via downregulation of FABP4 and stabilization of PPARα. Targeting the Fibrin-FABP4-PPARα axis may offer a novel therapeutic strategy for MASH.
    Keywords:  FABP4; Fibrin matrix; Macrophage immunometabolism; Metabolic dysfunction-associated steatohepatitis; PPARα
    DOI:  https://doi.org/10.1007/s00018-026-06266-2
  39. Vet Microbiol. 2026 May 30. pii: S0378-1135(26)00228-2. [Epub ahead of print]320 111096
    BVDV hijacks the IDO1-dependent tryptophan-kynurenine axis to promote viral replication by limiting interferon-STAT1 antiviral signaling.
    Tian-Yi Liu, Shan-Shan Liu, Pei-Long Li, Yong Zhou, Yu-Xin Song, Wei-Jia Yao, Ze-Chen Zhang, Chong Zhao, Jiao Li, Lan-Bo Tian, Nan Li, Yu Liu, Ze-Cai Zhang, Yu-Long Zhou, Xue Wang, Zhan-Bo Zhu.
      Bovine viral diarrhea virus (BVDV) causes persistent infection and immunosuppression, yet whether it hijacks host immunometabolism to facilitate replication remains unclear. Using untargeted metabolomics in bovine turbinate (BT) cells, we found that BVDV infection significantly elevated xanthurenic acid within the tryptophan-kynurenine (Trp-Kyn) pathway. BVDV persistently upregulated indoleamine 2,3-dioxygenase 1 (IDO1), resulting in decreased extracellular tryptophan and increased kynurenine levels. Supplementation with L-tryptophan or IDO1 inhibition suppressed viral replication, whereas L-kynurenine promoted it. Rescue of viral replication by L-kynurenine in IDO1-silenced cells confirmed that IDO1 promotes BVDV proliferation through downstream kynurenine generation. Mechanistically, IDO1 inhibition enhanced STAT1 phosphorylation and upregulated ISG15, MX1, and OAS1 expression. A negative feedback loop was identified between IFN-γ/STAT1 signaling and the IDO1-kynurenine axis. Furthermore, L-kynurenine activated the aryl hydrocarbon receptor (AhR) target gene CYP1A1, and the AhR antagonist CH-223191 partially reversed its pro-viral effects. In conclusion, BVDV hijacks the IDO1-dependent Trp-Kyn metabolic axis to limit interferon-STAT1 antiviral signaling, while AhR-related signaling may act as a possible partial downstream branch contributing to a pro-viral intracellular environment.
    Keywords:  AhR; BVDV; IDO1; Immunometabolism; Kynurenine; STAT1; Tryptophan
    DOI:  https://doi.org/10.1016/j.vetmic.2026.111096
  40. bioRxiv. 2026 May 20. pii: 2026.05.19.726283. [Epub ahead of print]
    Salmonella lipopolysaccharide stimulates uptake of long-chain fatty acids in the small intestine.
    Eugene Koo, Gabriella Quinn, Cassie L Behrendt, Brian Hassell, Katie N Kang, Kelly A Ruhn, Gonçalo Vale, Jeffrey G McDonald, Wenhan Zhu, Sebastian E Winter, Lora V Hooper.
      Enteric bacterial pathogens profoundly alter intestinal physiology during infection, yet their effects on host lipid metabolism remain poorly understood. Using mass spectrometry lipidomics, we found that infection of the mouse intestine with the bacterial pathogen Salmonella enterica serovar Typhimurium ( S . Typhimurium) stimulates uptake of long-chain fatty acids by small intestinal epithelial cells. This response coincided with increased expression of epithelial genes involved in lipid uptake and transport and required the long-chain fatty acid transporter CD36. Fatty acid uptake was triggered by S . Typhimurium lipopolysaccharide (LPS) and was impaired by bacterial mutations that alter LPS acyl chains. Mechanistically, S . Typhimurium induced lipid absorption through myeloid cell Toll-like receptor 4, a receptor for LPS. Escherichia coli , a related commensal bacterium, also induced intestinal lipid absorption through LPS, although to a lesser extent than S . Typhimurium. Finally, disruption of long-chain fatty acid absorption impaired host defense during bacterial stimulation, suggesting that bacteria-induced lipid uptake contributes to protection against enteric infection. Together, these findings identify LPS from Gram-negative intestinal bacteria as a key regulator of dietary lipid uptake by the intestinal epithelium.
    DOI:  https://doi.org/10.64898/2026.05.19.726283
  41. J Clin Invest. 2026 Jun 01. pii: e199716. [Epub ahead of print]136(11):
    Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity.
    Yuheng Liao, Hanze Wang, Hengxin Liu, Xi Chen, Renqiang Sun, Xie Li, Zhen Yang, Chenying Liu, Wei Wu, Ziqian He, Yuzheng Zhao, Ying Mao, Dan Ye, Hui Yang.
      Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Genetically or aminooxyacetic acid-mediated (AOA-mediated) pharmacologically reducing aspartate levels markedly potentiated the cGAS-STING pathway, leading to stronger upregulation of type I interferons and interferon-stimulated genes. Mechanistically, disruption of de novo pyrimidine synthesis, a major downstream pathway of aspartate, induced mtDNA replication stress and increased mtDNA double-strand breaks, promoting mtDNA release into the cytosol. Cytosolic mtDNA synergized with cGAS-STING agonists to upregulate Z-DNA binding protein 1 (ZBP1), which recruits RIPK1/3 to sustain IRF3 phosphorylation, forming a positive feedback loop that amplifies innate immune signaling. In immunocompetent mouse models, AOA enhanced the antitumor efficacy of STING agonists, chemotherapy, or radiotherapy, whereas aspartate supplementation abrogated these effects. Consistently, aspartate levels negatively correlated with antitumor immunity in colorectal cancer patient samples. Together, our study identifies aspartate-pyrimidine metabolism as a critical metabolic checkpoint that licenses STING signaling by enabling mtDNA stress to cooperate with agonist stimulation, driving type I interferon-dependent ZBP1 induction and feed-forward amplification of STING signaling, thus offering a promising strategy to enhance antitumor immunity.
    Keywords:  Cellular immune response; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI199716
  42. Cell Rep. 2026 Jun 02. pii: S2211-1247(26)00447-X. [Epub ahead of print]45(6): 117369
    CIDEB and CGI-58 differentially regulate liver lipid-droplet cholesterol to modulate metabolic dysfunction-associated steatohepatitis severity.
    Ikki Sakuma, Rafael C Gaspar, Henrique N Morgan, Jie Zheng, Ali R Nasiri, Sylvie Dufour, Mario Kahn, Mateus T Guerra, Yuki Taki, Yusuke Kawashima, Dean Yimlamai, Mark Perelis, Daniel F Vatner, Kitt Falk Petersen, Varman T Samuel, Tomoaki Tanaka, Gerald I Shulman.
      Metabolic dysfunction-associated steatohepatitis (MASH) increases liver-related mortality, and new therapies targeting its underlying mechanisms are warranted. We examined whether two lipid-droplet proteins, CIDEB and CGI-58, exert opposing control over MASH by altering cholesterol in liver lipid droplets. Using antisense oligonucleotides, we silenced CIDEB or CGI-58 in the livers of C57BL/6J mice fed a choline-deficient, L-amino acid-defined high-fat diet. CIDEB silencing decreased both triglyceride and cholesterol levels in liver lipid droplets and lowered plasma transaminases and the number of crown-like structures. These protective effects were abrogated by cholesterol supplementation. Conversely, CGI-58 knockdown raised triglyceride and cholesterol levels and exacerbated MASH; bempedoic acid, a cholesterol-synthesis inhibitor, reversed these changes. Dual CIDEB/CGI-58 silencing confirmed that CGI-58 loss abrogated the protective effects of CIDEB knockdown. Our data establish liver lipid-droplet cholesterol as a critical determinant in MASH mediated by CIDEB and CGI-58 and demonstrate that CIDEB knockdown confers protection by enhancing CGI-58-dependent lipolysis.
    Keywords:  ATGL; CGI-58/ABHD5; CIDEB; CP: metabolism; antisense oligonucleotide; cholesterol; choline-deficient, L-amino acid-defined high-fat diet; lipid droplet protein; lipid-droplet cholesterol; metabolic dysfunction-associated steatohepatitis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117369
  43. Korean J Physiol Pharmacol. 2026 Jun 02.
    Dual role of homocysteine in enhancing metabolic activity and suppressing inflammatory cytokines in murine immune cells.
    Thi Len Ho, Eun-Ju Ko.
      Homocysteine (HCy) is a sulfur-containing metabolic intermediate with largely unexplored potential as a damage-associated molecular pattern. This study investigated the immunomodulatory profile of HCy alone and in combination with the TLR4 agonist monophosphoryl lipid A (MPL). To model acute metabolic stress, we evaluated murine bone marrow-derived dendritic cells (DCs), macrophages, and splenocytes treated with HCy (6.25-600 μg/ml) in vitro, and assessed inflammatory cell recruitment in vivo in mice injected intraperitoneally with HCy (100 or 500 μg/mouse). HCy treatment significantly increased mitochondrial metabolic activity (CCK-8) without generalized necrosis. However, high concentrations (400-600 μg/ml) paradoxically suppressed MPL-induced splenocyte proliferation. HCy displayed distinct cell-specificity, acting as a direct agonist for macrophage maturation (upregulating CD40, CD86, and MHC-II) while failing to activate purified DCs. Notably, flow cytometry revealed that while metabolic signals increased, high-dose HCy induced late apoptosis in macrophages starting at 25 μg/ml, suggesting a state of metabolic stress rather than enhanced viability. Crucially, HCy exerted a regulatory effect on TLR4 signaling: co-treatment with HCy (200-600 μg/ml) dose-dependently suppressed MPL-induced pro-inflammatory cytokine secretion (TNF-α, IL-6) while maintaining phenotypic maturation. In vivo, HCy functioned as a chemotactic agent, recruiting DCs and monocytes to the peritoneal cavity and inducing an activated, M2-like (CD206+) macrophage phenotype. These findings demonstrate that HCy functions as a dual-action immune modulator that promotes phenotypic maturation and antigen-presenting cell recruitment while dampening excessive cytokine release through a stress-mediated regulatory mechanism.
    Keywords:  Dendritic cells; Homocysteine; Macrophages
    DOI:  https://doi.org/10.4196/kjpp.26.005
  44. J Immunother Cancer. 2026 Jun 03. pii: e014927. [Epub ahead of print]14(6):
    Glucose restriction reprograms lipid metabolism and enhances immunotherapy through ZNRF3-Wnt-SCD signaling axis.
    Yarui Ma, Qi Zhang, Zhewen Wei, Zhendiao Zhou, Xue Wang, Chungui Xu, Xiu Liu, Shitong Min, Peng Wang, Fangqing Yuan, Yuchen Jiao, Guangwen Yuan.
       BACKGROUND: Glucose restriction is a hallmark of the tumor microenvironment (TME), yet how tumor cells adapt to this metabolic stress and the impact of metabolic reprogramming on the TME remains incompletely understood.
    METHODS: A genome-wide CRISPR knockout positive screen was performed to identify key mediators of cellular adaptation to glucose restriction. Using biochemistry, molecular biology, metabolomics and confocal immunofluorescent microscopy to elucidate the underlying molecular mechanisms. Additionally, single-cell RNA sequencing and orthotopic tumor models were used to characterize TME remodeling and assess therapeutic efficacy.
    RESULTS: We identified zinc and ring finger 3 (ZNRF3) as a key mediator of cellular adaptation to glucose restriction through genome-wide CRISPR/Cas9 screening. Multiple tumor cells adaptively survived in glucose-restricted conditions with downregulated ZNRF3. Mechanistically, low glucose suppresses ZNRF3 expression, leading to Wnt pathway activation and subsequent transcriptional repression of stearoyl-CoA desaturase (SCD). This metabolic rewiring enhances antitumor immunity by increasing T-cell infiltration and cytotoxicity. In multiple preclinical models, dietary glucose restriction synergizes with immune checkpoint blockade to suppress tumor growth.
    CONCLUSION: These findings establish the ZNRF3-Wnt-SCD axis as a metabolic checkpoint controlling tumor cell fate under glucose restriction and provide a rationale for combining dietary intervention with immunotherapy.
    Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; Nutrition; Tumor Burden
    DOI:  https://doi.org/10.1136/jitc-2026-014927
  45. Nat Commun. 2026 Jun 02.
    Sphingosine kinase-2 inhibition promotes immunogenic differentiation of myeloid-derived suppressor cells through an Acetyl-CoA carboxylase-phosphatidylcholine axis.
    Paramita Chakraborty, Shilpak Chatterjee, Mohamed Faisal Kassir, Wyatt Wofford, Seungho Choi, Natalia Oleinik, Ozge Saatci, Odai Darawshi, Satyajit Das, Nathaniel Oberhoeltzer, Anupam Gautam, Stephanie Mills, Reid DeMass, Zacharia Hedley, Yueying Liu, Rasesh Y Parikh, Sandip Paul, Souvik Seal, Charles D Smith, Michael B Lilly, Vamsi K Gangaraju, Yuri Peterson, Meenal Mehrotra, Elizabeth Hill, Ozgur Sahin, Norbert Leitinger, Paulo C Rodriguez, Besim Ogretmen, Shikhar Mehrotra.
      Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) limit the efficacy of adoptive T cell therapies, highlighting the need to overcome tumor-associated immunosuppression. Sphingosine-1-phosphate (S1P), is an abundant signaling lipid in the TME. Here, we show that inhibition of sphingosine kinase-2 (SphK2), the enzyme generating S1P in MDSCs, reduces the suppressive activity of monocytic MDSCs (M-MDSCs) while promoting their differentiation toward a mature, immunogenic phenotype characterized by enhanced antigen presentation. Pharmacological SphK2 inhibition enhances the response to anti-PD-1 therapy in preclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSC-mediated suppression and limiting tumor progression. Mechanistically, S1P directly binds acetyl-CoA carboxylase-1 (ACC1) to inhibit its activity, thereby rewiring fatty-acid metabolism. Lowering intracellular S1P restores ACC activity, promotes phosphatidylcholine synthesis, and reduces MDSC immunosuppression. These findings identify the SphK2-ACC-phospholipid axis as a metabolic checkpoint controlling the immunogenicity of MDSCs and a potential therapeutic target for enhancing cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-73827-1
  46. Sci Signal. 2026 Jun 02. 19(940): eaec6992
    Environmental regulation of mucosal-associated invariant T cells: Adding food for thought.
    Eimear K Ryan, Linda V Sinclair, Andrew E Hogan.
      Mucosal-associated invariant T (MAIT) cells are a population of innate-like, unconventional T cells characterized by the expression of a semi-invariant, non-MHC-restricted T cell receptor (TCR), which play an important role in mediating innate immune responses to bacterial and viral pathogens. Emerging research continues to describe the many environmental signals that influence the types of responses elicited downstream of MAIT cell activation. In this Review, we highlight five key factors that determine the metabolic and functional responses of MAIT cells, including TCR engagement, costimulation, chemokine signaling, cytokine stimulation, and nutrient availability. We further define the importance of optimal nutrient availability as "signal 5" in promoting MAIT cell fitness and in governing their capacity to respond appropriately to challenge. In understanding the ways in which MAIT cells are influenced by their microenvironment, we can continue to identify the potential factors that drive dysregulated responses in hostile circumstances, enabling restoration of their protective nature in the context of infection or in the tumor microenvironment.
    DOI:  https://doi.org/10.1126/scisignal.aec6992
  47. Sci Rep. 2026 May 30.
    PKM2-driven glycolysis mediates rotenone neurotoxicity via MG-Hs in Parkinson's disease.
    Rong Li, Jia Wen Ma, Hui Chen, Dan Mu, Lang Qu, Dan Wang, Ya Zhao.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder lacking disease-modifying therapies. Rotenone (Rot) is widely used to model PD, but its neurotoxicity is not fully understood beyond mitochondrial complex I inhibition. Here, we identify a glycolytic mechanism that contributes to Rot-induced neuronal damage downstream of complex I inhibition. Our in vitro data demonstrate that Rot enhances glycolytic flux, leading to accumulation of methylglyoxal-derived hydroimidazolones (MG-Hs), which drive irreversible cellular damage. Shikonin effectively attenuates Rot-induced apoptosis by inhibiting PKM2, thereby suppressing glycolysis and reducing MG-Hs formation. In a rat model, shikonin robustly improves motor function and preserves nigrostriatal dopaminergic neurons. Collectively, our findings reveal a previously unrecognized glycolytic-mediated pathway involving PKM2-driven glycolysis and MG-Hs accumulation that contributes to rotenone neurotoxicity alongside mitochondrial dysfunction, and highlight shikonin as a promising neuroprotective agent for Parkinson's disease intervention.
    Keywords:  Glycolytic activation; MG-Hs; PKM2; Parkinson’s disease; Shikonin
    DOI:  https://doi.org/10.1038/s41598-026-54865-7
  48. Exp Cell Res. 2026 Jun 01. pii: S0014-4827(26)00213-2. [Epub ahead of print]461(1): 115096
    Nicotinamide N-methyltransferase in inflammatory bowel disease: Multidimensional regulation, mechanistic insights, and therapeutic potential.
    An Liu, Xiao-Juan Zhu, Wei-Dong Sun, Shuang-Zhou Bi, Chen-Ying Zhang, Jiang-Hua Li.
      Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder involving immune, metabolic, microbial, and epigenetic dysregulation. Nicotinamide N-methyltransferase (NNMT) connects nicotinamide metabolism with NAD+ availability, methyl-donor homeostasis, and epigenetic regulation. Accumulating evidence shows that NNMT is upregulated in intestinal tissues from patients with IBD and may promote disease progression by reducing nicotinamide adenine dinucleotide (NAD+) availability, increasing homocysteine (Hcy) accumulation, and disturbing DNA and histone methylation. These changes may contribute to mitochondrial dysfunction, epithelial barrier impairment, gut microbiota dysbiosis, and enteric nervous system disturbance. This review summarizes current evidence on the role of NNMT in IBD and discusses emerging NNMT-targeted strategies, including small-molecule inhibitors, RNA-based silencing approaches, and exercise-based interventions. Collectively, NNMT represents a metabolic-epigenetic hub in IBD pathogenesis and a promising target for future therapeutic development.
    Keywords:  Epigenetics; Gut microbiota; Gut-brain axis; Inflammatory bowel disease; Nicotinamide N-methyltransferase (NNMT); Therapeutic targets
    DOI:  https://doi.org/10.1016/j.yexcr.2026.115096
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