bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2026–10–25
forty-six papers selected by
Dylan Gerard Ryan, Trinity College Dublin
  1. Macrophages and immunometabolism in diminished ovarian reserve: pathological features and therapeutic implications.
  2. Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.
  3. Mitochondria-Macrophage Interactions in Sepsis at Different Immune Stages: Integrating Immunometabolic Reprogramming, Organ Damage, and Therapeutic Strategies.
  4. Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.
  5. Defective Vδ2+ T cell metabolic and functional responses in obesity are reversed with bariatric surgery.
  6. Mitochondrial Metabolic Reprogramming in Macrophages: A Key Driver of Rheumatoid Arthritis.
  7. Enterococcus faecalis biofilm rewires neutrophil metabolism to suppress antimicrobial activity.
  8. Plant-derived extracellular vesicles deliver spermidine to reprogram macrophage metabolism and ameliorate rheumatoid arthritis.
  9. Biofilm-host immunometabolic crosstalk in Staphylococcus aureus orthopedic implant infection: mechanisms and translational constraints.
  10. OxLDL drives pro-inflammatory and foam cell-prone macrophage reprogramming via NF-κB/HIF-1β-dependent metabolic rewiring.
  11. Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
  12. Yin-Yang: The Dual Role of Lactate as a Context-Dependent Immunometabolic Regulator in the Inflammatory Microenvironment.
  13. Crosstalk between gut microbiota-associated metabolites and adaptive immunity in cholecystitis: a conceptual mechanistic framework and potential therapeutic implications.
  14. Metabolic reprogramming of NK cells in chronic brucellar arthritis: role of the HIF-1α/mTOR axis.
  15. Altered OXPHOS potential in ascites immune cells is linked to CD4 T-cell exhaustion and a higher risk of spontaneous bacterial peritonitis in cirrhosis.
  16. Cholesterol dysregulation and microglial NLRP3 inflammasome activation after ischemic stroke: implications for neuroinflammation and functional recovery.
  17. HECTD1 Directs HIF-1α to Facilitate Intestinal Inflammation and Carcinogenesis via Promoting Th17 Differentiation and Glycolysis.
  18. Novel Mechanometabolic Signaling Cascade Linking Efferocytosis to Inflammation Resolution.
  19. Cross-Species Profiling of Itaconate-Mediated Modifications by a Universal Probe.
  20. Lactylation modification: a new bridge connecting macrophage metabolism and pulmonary hypertension.
  21. Caloric restriction attenuates NLRP3 inflammasome activation and oxidative stress in leukocytes of patients with obesity.
  22. Metabolic Barriers to Cancer Immunotherapy: Multiscale Mechanisms from Organelle Dysfunction to Organ-Specific Constraints.
  23. Itaconate as the endogenous brake of proinflammatory macrophage activation alleviates inflammation in liver fibrogenesis.
  24. Host-like temperature unlocks glucose uptake and metabolism in pathogenic Leptospira.
  25. TSPO in systemic-ocular immunometabolic crosstalk: mechanisms and therapeutic implications.
  26. Glucosamine-Producing Engineered Probiotics Enhance the Immune Function of Microglia.
  27. FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Myeloid Cells.
  28. Hexokinase-2 moonlights as a suppressor of STING-mediated innate immunity.
  29. Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease.
  30. Immune cell fibrotic plasticity: mesenchymal-like reprogramming of macrophages, neutrophils and T cells.
  31. Adaptive metabolic reprogramming of the brain tissue during late-stage Trypanosoma brucei infection maintains host learning and memory.
  32. RNF34 restrains endometriosis progression by promoting PKM2 ubiquitination and suppressing glycolysis.
  33. Spermidine, a chondrocyte apoptotic metabolite, delays osteoarthritis by regulating macrophage M2c polarization.
  34. Macrophage peroxisomes at the crossroads of inflammation.
  35. METTL14-mediated m6A methylation orchestrates early NK cell development by maintaining metabolic fitness.
  36. Heterogeneous nanoplastic exposure induces integrated immunometabolic transcriptional responses in human monocytes under continuous flow.
  37. Mitochondrial RNA polymerase is a critical mediator of LPS-induced inflammatory responses and septic shock.
  38. NAD+ metabolic restoration resolves the inflammation-immunocompetence trade-off in lung graft-versus-host disease.
  39. An in situ forming immunomodulatory hydrogel reinvigorates exhausted CD8+ T cells via preserving their mitochondrial fitness.
  40. Macrophage interferon regulatory factor 7 aggravates the progression of metabolic dysfunction-associated steatohepatitis.
  41. Wolbachia outcompetes mosquito-borne viruses by reprogramming host ATPSβ1-driven ATP metabolism toward symbiotic proliferation.
  42. Prophylactic and therapeutic itaconate treatment alleviates COVID-19-associated lung injury.
  43. Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
  44. The PIEZO1/CISD1/IP3R Mechanotransduction Axis Drives Macrophage Mitochondrial Dysfunction and Inflammatory Activation in Pulmonary Fibrosis.
  45. Neutrophils: Key players in the metabolic syndrome puzzle.
  46. The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion.
  1. Front Endocrinol (Lausanne). 2026 ;17 1883984
    Macrophages and immunometabolism in diminished ovarian reserve: pathological features and therapeutic implications.
    Bingxia Li, Jia Zhang, Quansheng Wu, Xiaohua Zhang.
      Diminished ovarian reserve (DOR) is a prevalent reproductive endocrine disorder that significantly impairs female fertility. While traditional research has emphasized intrinsic oocyte defects, growing evidence highlights the ovarian immune microenvironment-specifically macrophages-as a critical regulator of follicular fate and reserve maintenance. Nevertheless, the mechanisms by which macrophage dysfunction drives DOR remain incompletely understood, and the interplay between chronic inflammation and macrophage metabolic reprogramming has yet to be systematically elucidated. This narrative review synthesizes literature from immunology, metabolism, and reproductive medicine, framing current evidence as established findings, putative mechanisms, and emerging hypotheses. The key findings are threefold: 1) macrophage polarization imbalance, which is marked by sustained M1 activation and impaired M2 function, constitutes a core pathological feature of DOR; 2) this imbalance is driven by metabolic reprogramming-specifically, metabolic inflexibility in M1 (persistent glycolytic commitment) and suppressed oxidative phosphorylation in M2-which links inflammaging to ovarian fibrosis and follicular depletion; and 3) pharmacological modulation of macrophage immunometabolism (e.g., AMPK/PPARγ activators, LXR agonists, and itaconate) and engineered delivery platforms (e.g., exosomes and targeted nanocarriers) hold preclinical promise. This review establishes an "immunometabolic axis" framework that integrates macrophage polarization, metabolic dysregulation, and ovarian reserve loss, advancing the understanding of DOR pathogenesis and informing precision interventions.
    Keywords:  diminished ovarian reserve; fibrosis; inflammaging; macrophages; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fendo.2026.1883984
  2. Int J Biol Sci. 2026 ;22(15): 8302-8317
    Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.
    Liujiazi Shao, Chao Quan, Tao Dong, Yuchen Chen, Xin Yu, Wenlu Ouyang, Dan Qi, Jeffrey Chu, Erxi Wu, Zequan Yang, Jianjie Ma, Yongqing Li.
      Sepsis is a life-threatening inflammatory disorder characterized by immune dysregulation and organ failure, and while peptidylarginine deiminase-2 (PAD2) regulates immune responses via citrullination, its role in immunometabolism remains unclear. Here we identify a PAD2-dependent mechanism that impairs mitochondrial glutamine metabolism and macrophage polarization during sepsis. Through single-cell RNA sequencing of bronchoalveolar lavage fluid from septic mice, we found that Pad2 -/- promotes M2 macrophage polarization, reduces lung injury, and improves survival. Using mass spectrometry-based citrullinomics, we identified voltage-dependent anion channel-3 (VDAC3) as a PAD2 substrate, and further demonstrated that PAD2-mediated citrullination at residue R252 suppresses glutamine transport and α-ketoglutarate (α-KG) production, thereby impairing oxidative phosphorylation (OXPHOS) and M2 reprogramming. Notably, substitution of R252 with alanine recapitulated Pad2 -/-phenotypes, and consistent with this, Pad2 -/- mice exhibited enhanced OXPHOS, attenuated inflammation, and improved outcomes in a Pseudomonas aeruginosa-induced model of sepsis and lung injury. Collectively, these findings establish the PAD2-VDAC3-glutamine axis as a key immunometabolic checkpoint that links post-translational modification to mitochondrial metabolism and macrophage function, suggesting that targeting this pathway may offer a promising strategy to restore immune balance in sepsis.
    Keywords:  M2 macrophage polarization; Pad2 knockout; VDAC3; glutamine; α-ketoglutarate
    DOI:  https://doi.org/10.7150/ijbs.126368
  3. J Inflamm Res. 2026 ;19 641837
    Mitochondria-Macrophage Interactions in Sepsis at Different Immune Stages: Integrating Immunometabolic Reprogramming, Organ Damage, and Therapeutic Strategies.
    Jiaqi Li, Yuting Sun, Meilin He, Xueyi Liao, Qingfang Zou, Shuming Pan.
      Sepsis is a life-threatening disorder caused by dysregulated host responses to infection, characterized by immune dysfunction, metabolic reprogramming, and multi-organ injury. Mitochondria, beyond their role in energy metabolism, act as central signaling hubs that integrate cellular metabolism, innate immunity, and inflammatory responses. Emerging evidence suggests that disrupted mitochondria-macrophage crosstalk forms a self-amplifying loop that drives excessive inflammation and organ dysfunction during sepsis. This review highlights recent advances in understanding how mitochondrial quality control and immunometabolic remodeling regulate macrophage activation and function. We discuss the impact of key metabolic pathways, including glycolysis, oxidative phosphorylation, tricarboxylic acid cycle remodeling, and fatty acid metabolism, on macrophage polarization, as well as the dynamic roles of mitophagy, mitochondrial biogenesis, and mitochondrial dynamics throughout sepsis progression. We further summarize current challenges and potential therapeutic strategies targeting the mitochondria-macrophage axis. Elucidating this regulatory network may provide new insights into precision medicine and the development of targeted therapies for sepsis.
    Keywords:  macrophages; metabolic reprogramming; mitochondria; mitochondrial quality control; multiple organ dysfunction; sepsis
    DOI:  https://doi.org/10.2147/JIR.S641837
  4. Signal Transduct Target Ther. 2026 Oct 21. pii: 467. [Epub ahead of print]11(1):
    Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.
    Xintong Lu, Wenhui Wang, Bingjie Zhang, Qian Li, Ye Chen, Yongrui Hai, Renming Fan, Shuo Fu, Jiaxin Yan, Guiquan Ding, Zhuang Hou, Junke Song, Maosheng Cheng, Gaofei Wei.
      Sepsis is a life-threatening syndrome characterized by dysregulated immune responses and metabolic dysfunction, and remains a major cause of global mortality. While nanomedicine offers new opportunities for sepsis therapy, current strategies rarely achieve comprehensive modulation of macrophage immunometabolism and microenvironmental signaling. Here, we develop a glutathione-responsive nanotherapeutic platform (EONPs) by conjugating the stimulator of interferon genes (STING) inhibitor 4-octyl itaconate to polyethylene glycol, followed by encapsulation of the dihydroorotate dehydrogenase (DHODH) inhibitor EA6. Integrated transcriptomic, metabolomic, and metagenomic analyses combined with pharmacological assessments reveal that EONPs suppress systemic hyperinflammation, reprogram macrophages toward an anti-inflammatory phenotype, restore gut microbial homeostasis, and protect against multi-organ injury in septic models. Notably, EONPs enhance the production of the microbiota-derived metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is functionally linked to the anti-inflammatory response and may further support macrophage reprogramming. Our findings establish a previously unrecognized strategy for precise metabolic and microbiota-driven modulation of macrophages, offering a conceptual framework for further investigation of macrophage-targeted nanotherapeutics in sepsis.
    DOI:  https://doi.org/10.1038/s41392-026-02947-3
  5. JCI Insight. 2026 Oct 20. pii: e207365. [Epub ahead of print]
    Defective Vδ2+ T cell metabolic and functional responses in obesity are reversed with bariatric surgery.
    Ciara L Flynn, Eimear K Ryan, Cian Davis, Czara A Kennedy, Katherine G Egan, Aimee Brennan, Philip Mc Entee, Kirstan Murphy, Niamh Lynam-Lennon, Linda V Sinclair, Nicholas Jones, Donal O'Shea, Helen M Heneghan, Andrew E Hogan.
      Obesity is a chronic progressive disease strongly linked to numerous comorbidities. This is underpinned by a chronic inflammatory environment and significant immune dysregulation. γδ T cells are unconventional T cells that display innate and adaptive characteristics, the predominant one being their independence of MHC restriction. In humans, γδ T cells represent up to 5% of the peripheral blood T cell compartment and are capable of rapidly producing a range of effector cytokines and driving cytotoxic responses. This is critical for protection from both bacterial and viral infections. We investigated circulating γδ T cell metabolic and functional responses in cohorts of people living with obesity (PWO) and people without obesity. We showed that PWO have reduced Vδ2+ T cell frequencies, and their effector responses are diminished following stimulation. We identified that the CD98-LAMTOR5-mTORC1 metabolic axis was critical for functional responses, and demonstrated significant defects in each component of this axis in PWO. Furthermore, STAT5 the initiator of amino acid metabolism was also decreased in PWO. Finally, we showed restoration of this metabolic axis after bariatric surgery, combined with robust improvements in functional responses. Collectively, our data highlighted that obesity drives a reversible dysregulation of Vδ2+ T cells by disrupting cellular metabolism.
    Keywords:  Immunology; Metabolism; Obesity; T cells
    DOI:  https://doi.org/10.1172/jci.insight.207365
  6. J Inflamm Res. 2026 ;19 645321
    Mitochondrial Metabolic Reprogramming in Macrophages: A Key Driver of Rheumatoid Arthritis.
    Jingjing Zhao, Fuwei Pan, Guangshuai Nie, Fuzeng Zheng, Lin Wang, Chongtao Han.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis and progressive cartilage and bone destruction. Synovial macrophages are central coordinators of inflammatory signaling, stromal activation, and osteoclastogenesis, yet their pathogenic functions cannot be explained by extracellular cytokine networks alone. Increasing evidence indicates that macrophage activation is coupled to cell-intrinsic mitochondrial metabolic reprogramming. Within the hypoxic, nutrient-variable, and inflammatory RA synovium, macrophages undergo coordinated changes in glycolysis and oxidative phosphorylation, tricarboxylic acid cycle flux, mitochondrial reactive oxygen species production, fission-fusion dynamics, mitophagy, and mitochondrial DNA homeostasis. These alterations reshape bioenergetics while generating metabolites and organelle-derived danger signals that engage hypoxia-inducible factor 1α, nuclear factor-κB, the NOD-like receptor family pyrin domain-containing 3 inflammasome, and cyclic GMP-AMP synthase-stimulator of interferon genes signaling. The resulting metabolic-inflammatory circuits can stabilize pathogenic macrophage states and propagate inflammation to fibroblast-like synoviocytes, endothelial cells, and osteoclast-lineage cells. This review integrates current evidence on macrophage heterogeneity, mitochondrial remodeling, and intercellular signaling in RA. We further evaluate mitochondria-targeted antioxidants, metabolic modulation, restoration of mitochondrial quality control, inhibition of mitochondrial danger-signal sensing, and multistage nanodelivery. Particular emphasis is placed on evidence strength, macrophage-subset specificity, and the distinction between disease-driving abnormalities and compensatory adaptations. Finally, we outline the biomarkers, human-tissue validation, spatial multi-omics, and delivery strategies required to translate macrophage mitochondrial immunometabolism into precision therapy for RA.
    Keywords:  immunometabolism; mitochondrial metabolism; mitochondrial quality control; rheumatoid arthritis; synovial macrophages; targeted therapy
    DOI:  https://doi.org/10.2147/JIR.S645321
  7. Sci Adv. 2026 Oct 23. 12(43): eaej4153
    Enterococcus faecalis biofilm rewires neutrophil metabolism to suppress antimicrobial activity.
    Haris Antypas, Ronni Anderson Gonçalves da Silva, Geneve Kang Xin Wong, Cui Liang, Logeshwari Muthualagu Natarajan, Rachel Jing Wen Tan, Cheryl Jia Yi Neo, Siu Ling Wong, Kimberly A Kline.
      Enterococcus faecalis is an opportunistic pathogen that persists in biofilm-associated infections despite robust neutrophil recruitment. How E. faecalis evades neutrophils remains poorly understood. Here, we investigated how E. faecalis biofilms alter effector functions in human neutrophils and a murine wound infection model. We found that E. faecalis biofilm suppresses neutrophil extracellular trap (NET) formation, bacterial engulfment, and neutrophil-mediated control of biofilm growth. This suppression is partly driven by production of lactic acid through the lactate dehydrogenases (LDHs) of E. faecalis, which acidifies the extracellular environment, lowers neutrophil intracellular pH, and disrupts glycolysis, the tricarboxylic acid cycle, and the oxidative pentose phosphate pathway. In a murine wound infection model, loss of LDH increased neutrophil recruitment and NETosis. We also found that high bacterial density, a defining feature of biofilms, suppresses NETosis through a lactic acid-independent mechanism. Collectively, these findings identify biofilm immune evasion strategies mediated by bacterial metabolism and the high-density structural organization of biofilm-associated bacteria.
    DOI:  https://doi.org/10.1126/sciadv.aej4153
  8. J Nanobiotechnology. 2026 Jul 26. pii: 974. [Epub ahead of print]24(1):
    Plant-derived extracellular vesicles deliver spermidine to reprogram macrophage metabolism and ameliorate rheumatoid arthritis.
    Xiaocheng Wang, Jiaxin He, Yixiang Hong, Xingyue Zeng, Min Li, Shixiong Cao, Renge Liang, Gengmin Zhou, Qingwen Wang.
      Rheumatoid arthritis (RA) is driven by macrophage-mediated synovial inflammation closely linked to metabolic dysfunction, highlighting immunometabolism as a therapeutic target. Here, we engineered spermidine-loaded red cabbage-derived extracellular vesicles (RCEVs@SPD) as a plant-based nanoplatform to reprogram macrophage bioenergetics. In LPS-stimulated macrophages, RCEVs@SPD suppressed pro-inflammatory polarization and enhanced mitochondrial function, as evidenced by increased ATP production and mitochondrial membrane potential. Assay-based measurements further showed reduced extracellular acidification rate (ECAR) and elevated oxygen consumption rate (OCR), indicating a shift from glycolysis toward oxidative phosphorylation (OXPHOS). Untargeted LC-MS metabolomics revealed coordinated alterations in pathways supporting mitochondrial cofactor biosynthesis, redox balance, and central carbon metabolism. Transcriptomic analysis confirmed enrichment of OXPHOS and mitochondrial respiration gene signatures with concomitant repression of glycolytic programs and PI3K-AKT signaling. In vivo, RCEVs@SPD significantly alleviated collagen-induced arthritis, improved joint histopathology, and promoted anti‑inflammatory macrophage polarization. Notably, systemic macrophage depletion abolished the additional therapeutic benefit of RCEVs@SPD, demonstrating macrophage dependence. Collectively, these findings establish plant-derived extracellular vesicles as a biocompatible delivery system that potentiates spermidine to restore macrophage metabolic balance and mitigate RA pathology.
    Keywords:  Macrophage metabolic reprogramming; PI3K-AKT signaling; Red cabbage-derived vesicles; Rheumatoid arthritis; Spermidine
    DOI:  https://doi.org/10.1186/s12951-026-04836-x
  9. Front Immunol. 2026 ;17 1957346
    Biofilm-host immunometabolic crosstalk in Staphylococcus aureus orthopedic implant infection: mechanisms and translational constraints.
    Jixin Chen, Qinxin Zhou, Dongdong Cao, Weijie Yu, Yongming Zhang, Jianliang Chen, Xiaodong Zheng, Feng Ye.
      Orthopedic implant biofilms are not only antibiotic-tolerant bacterial communities but metabolically active niches that reshape host immunity. Compared with planktonic infection, mature biofilms impose spatial and metabolic constraints that can uncouple leukocyte recruitment from sterilizing activity. Neutrophils can penetrate and phagocytose portions of Staphylococcus aureus biofilms, but clearance becomes incomplete as biofilms mature and may coexist with degranulation and neutrophil extracellular trap-associated tissue injury. Macrophages show impaired access and bactericidal programming, and biofilm-derived lactate can promote interleukin-10 (IL-10) through histone deacetylase 11 (HDAC11)/HDAC6-dependent epigenetic reprogramming in experimental systems. Human periprosthetic joint infection (PJI) tissues are enriched in granulocytic myeloid-derived suppressor cells (G-MDSCs), whereas the glycolysis/hypoxia-inducible factor 1-alpha (HIF-1alpha) phenotype and its contribution to persistence are supported primarily by murine PJI, with limited human transcriptomic corroboration. In chronic S. aureus infection models, MDSC-derived lactate can suppress CD4-positive (CD4+) T-cell glycolysis; conversely, immune pressure drives heterogeneous bacterial metabolic, stress-response, and virulence programs. We synthesize these interactions as bidirectional biofilm-host immunometabolic crosstalk linking persistent infection to bone-interface damage. Source control and antibiotics remain essential. Local, time-limited, dysfunction-directed host interventions are presented here as a hypothesis-generating translational framework rather than evidence-based clinical recommendations, because host-directed immunometabolic therapies for PJI remain preclinical.
    Keywords:  Staphylococcus aureus; biofilm; immunometabolism; macrophages; myeloid-derived suppressor cells; neutrophils (PMNs); orthopedic implant infection
    DOI:  https://doi.org/10.3389/fimmu.2026.1957346
  10. Front Cardiovasc Med. 2026 ;13 1957621
    OxLDL drives pro-inflammatory and foam cell-prone macrophage reprogramming via NF-κB/HIF-1β-dependent metabolic rewiring.
    Maozhuo Lan, Yangyang Zhou, Yue Sun, Xingcheng Yi, Mengtuan Long, Dirk M Hermann, Fengyan Jin, Yun Dai.
       Introduction: Dysregulated lipid metabolism and inflammation are two core pathological drivers of atherosclerosis; however, their causal interplay remains incompletely elucidated. Macrophages play a central role in sustaining unresolved inflammation, which is a hallmark of atherosclerosis. Recent single-cell RNA-sequencing studies have revealed phenotypic heterogeneity among macrophages in atherosclerotic lesions, encompassing two key pro-atherogenic subsets: pro-inflammatory and foam cell-forming macrophages. Given that oxidized low-density lipoprotein (oxLDL) is a pivotal pathological factor in atherosclerosis, we investigated whether and how oxLDL drives the reprogramming of macrophages toward a pro-atherogenic phenotype.
    Methods: Transcriptomic analyses were performed on macrophages exposed to oxLDL, followed by a series of in vitro and ex vivo experiments to characterize the phenotypic, metabolic, and functional changes.
    Results: We identified a macrophage phenotype, named oxLDL-activated macrophages (OAMs), which displayed significant molecular and functional similarities to both pro-inflammatory and foam cell-forming macrophages. OxLDL-induced macrophage reprogramming was associated with a metabolic paradigm shift from oxidative phosphorylation to glycolysis, which was abrogated by inhibition of NF-κB activation, accompanied by polarization toward an anti-inflammatory phenotype. Knockdown of ARNT (encoding HIF-1β) recapitulated the effects of NF-κB inhibition, positioning HIF-1β downstream of the NF-κB pathway. Furthermore, inhibition of NF-κB also attenuated oxLDL-induced inflammasome activation and priming for a heightened secondary response, impaired the foam cell-forming capacity of OAMs, and moderately affected efferocytosis.
    Conclusions: Our findings demonstrate that oxLDL drives macrophage polarization toward a pro-atherogenic (pro-inflammatory and foam cell-prone) phenotype via metabolic rewiring and transcriptional remodeling mediated by HIF-1β-dependent crosstalk between the NF-κB and HIF pathways. This signaling axis may serve as a potential therapeutic target for atherosclerosis.
    Keywords:  atherosclerosis; macrophage; metabolic rewiring; oxidized LDL; transcriptional reprogramming
    DOI:  https://doi.org/10.3389/fcvm.2026.1957621
  11. Cell. 2026 Oct 23. pii: S0092-8674(26)01207-9. [Epub ahead of print]
    Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
    Chenyang Guan, Seungjin Ryu, Mingze Dong, Yitao Zhu, Rae Maeda, Yun-Hee Youm, Subhasis Mohanty, Hee-Hoon Kim, Lucie Orliaguet, Tamara Dlugos, Steven R Smith, Eric Ravussin, Janset Onyuru, Hal M Hoffman, Stephan Siebel, Andrew Wang, Yaqiu Wang, Yuval Kluger, Albert C Shaw, Thirumala-Devi Kanneganti, Nathan LeBrasseur, Yuki Sugiura, Vishwa Deep Dixit.
      Whether a decline in taurine drives aging is debated, and despite high millimolar intracellular concentrations, its function as a potential guardian of cytosolic homeostasis is unclear. Here, we show that aging increases circulating taurine concentrations in humans and mice. Further elevating taurine in aged mice enhances health span, engaging anti-inflammatory pathways previously linked to youthfulness, and reduces mortality from sepsis and inflammasome-mediated inflammation, suggesting an enantiostatic response. Mechanistically, diverse NLRP3-specific "danger signals" induce taurine efflux from macrophages as a proximal step to activate the inflammasome and the resultant pyroptosis. Taurine restoration in macrophages prevents NLRP3-induced trans-Golgi network disassembly, thereby suppressing NLRP3 inflammasome activation. Conversely, lowering taurine biosynthesis combined with reduced bioavailability in macrophages exacerbated inflammasome activation. In humans, sustained caloric restriction elevates adipose tissue taurine and is accompanied by lower inflammation. Together, we identify taurine as an immunometabolic rheostat that links danger sensing to NLRP3 inflammasome activation, suggesting taurine-based strategies to alleviate inflammaging and inflammasomopathies.
    Keywords:  NLRP3; aging; antiinflammation; caloric restriction; immunometabolism; inflammaging; inflammasome; lifespan; taurine; taurine efflux
    DOI:  https://doi.org/10.1016/j.cell.2026.09.061
  12. Immunology. 2026 Oct 20.
    Yin-Yang: The Dual Role of Lactate as a Context-Dependent Immunometabolic Regulator in the Inflammatory Microenvironment.
    Shihan Wang, Peirong Gan, Ya Chen, Beibei Yang, Tao Ding, Hong Wu.
      Lactate, once regarded merely as the terminal product of glycolysis, is now recognised as a pivotal immunometabolic regulator that actively shapes inflammatory responses. However, accumulating evidence reveals an apparent paradox that lactate can either amplify immune activation or promote inflammation resolution depending on the biological context. The mechanisms underlying this functional duality remain incompletely understood, limiting the development of effective lactate-targeted therapies. In this review, we propose that lactate functions as a context-dependent immunometabolic rheostat whose Yin-Yang properties are determined by the integration of four key factors: lactate concentration, cellular identity, disease stage and inflammatory microenvironment. We summarise how lactate regulates immune responses through coordinated control of metabolic reprogramming, intercellular lactate shuttling, receptor-mediated signalling, intracellular sensing, and protein lactylation, thereby orchestrating the activation and resolution of inflammation. We further discuss the cell-specific actions of lactate across endothelial cells, macrophages, fibroblast-like synoviocytes, neutrophils, and lymphocytes, highlighting how these mechanisms collectively remodel the inflammatory microenvironment. Beyond mechanistic insights, we examine evidence from representative inflammatory disease models, including rheumatoid arthritis, sepsis, and atherosclerosis, and evaluate emerging therapeutic strategies targeting lactate production, transport, sensing and metabolism. Rather than advocating indiscriminate lactate inhibition, current evidence supports context-specific modulation of lactate signalling according to disease stage and immune landscape.
    Keywords:  Yin‐Yang; bidirectional immune modulation; inflammatory microenvironment; lactate; regulatory molecule
    DOI:  https://doi.org/10.1111/imm.70215
  13. Front Microbiol. 2026 ;17 1972466
    Crosstalk between gut microbiota-associated metabolites and adaptive immunity in cholecystitis: a conceptual mechanistic framework and potential therapeutic implications.
    Xinqi Wang, Tao Zhang, Zhetan Ren, Baozhao Ju.
      The pathogenesis of cholecystitis involves the complex interplay of bile stasis, microbial dysbiosis, metabolic disturbances, and immune responses. Gut microbiota-associated metabolites can modulate adaptive immune components, including T helper 17 (Th17) cells, regulatory T (Treg) cells, CD8+ T cells, and B cells, through receptor-mediated signaling, immunometabolic reprogramming, and epigenetic regulation. Conversely, T cell-mediated immune selection and B cell-IgA responses can reshape microbial community structure and metabolic activity, thereby establishing a bidirectional microbiota-immune regulatory network. The immunological effects of metabolic signals, including secondary bile acids, short-chain fatty acids, tryptophan-related metabolites, polyamines, and lactate, are highly context dependent and may vary according to metabolite concentration, target cell type, receptor engagement, and the local tissue microenvironment. Importantly, direct mechanistic evidence specific to cholecystitis remains limited. Most of the mechanistic pathways discussed in this review are derived from studies of cholelithiasis, cholestasis, and other hepatobiliary or inflammatory disorders; therefore, several proposed links between microbial metabolism and adaptive immunity should currently be regarded as conceptual extrapolations rather than established mechanisms in cholecystitis. Focusing on this bidirectional crosstalk, we discuss its potential roles across distinct pathological settings, including gallstone-associated disease, acute inflammation, and chronic inflammation with tissue remodeling. We further summarize candidate therapeutic strategies targeting microbial ecology, bile acid metabolism, specific metabolic pathways, and adaptive immune responses. This conceptual framework may provide a basis for future mechanistic studies and facilitate the development of more precise therapeutic approaches for cholecystitis.
    Keywords:  adaptive immunity; bile acids; cholecystitis; gut microbiota; immunometabolism; microbiota-associated metabolites
    DOI:  https://doi.org/10.3389/fmicb.2026.1972466
  14. Front Immunol. 2026 ;17 1961240
    Metabolic reprogramming of NK cells in chronic brucellar arthritis: role of the HIF-1α/mTOR axis.
    Ganggang Sheng, Wenxuan Li, Da Liu, Xuanchen Ren, Mingyang Wei, Zijing Yang, Weiyu Tian, Fengbo Zhang, Yuejie Zhu, Fanxuan Zeng, Zhiqiang Zhao, Ping Xu, Hongyu Tian, Nannan Pang, Chaopeng Li, Zhendong Zhang.
       Background: Brucellar arthritis is the most common complication of brucellosis, and its chronic progression is closely associated with immune cell dysfunction. Natural killer (NK) cells play a central role in anti-infective immunity; however, their functional status and regulatory mechanisms in brucellar arthritis remain poorly understood.
    Methods: Peripheral blood and synovial tissue samples were collected from healthy controls, as well as from patients with acute-phase and chronic-phase brucellar arthritis. Single-cell RNA sequencing (scRNA-seq), flow cytometry, quantitative real-time PCR (qPCR), JC-1 mitochondrial membrane potential assay, Seahorse metabolic analysis, and Western blotting were employed to systematically evaluate NK cell phenotypes, functions, metabolic profiles, and HIF-1α/mTOR pathway activity. In vitro, heat-killed Brucella melitensis 16M (HKBA) was used to stimulate NK-92 cells and HIF-1α-knockout (KO) cell lines, with mTOR inhibitor intervention, to dissect the regulatory mechanism of the HIF-1α/mTOR axis in NK cell metabolic reprogramming.
    Results: scRNA-seq revealed enrichment of NK cells in the synovium of brucellar arthritis patients, with aberrant expression of oxidative phosphorylation (OXPHOS)-related genes. Clinical sample analyses showed that, compared with healthy controls, the proportion of peripheral blood NK cells increased in both acute- and chronic-phase patients; however, NK cells from chronic-phase patients exhibited significantly reduced IFN-γ, Granzyme B, and CD107a degranulation levels. HIF-1α protein was consistently overexpressed in patient NK cells, whereas phosphorylated mTOR-pathway proteins (p-PI3K, p-AKT, p-mTOR) were markedly suppressed. In vitro, HKBA treatment inhibited mTOR pathway activity in NK-92 cells in a dose- and time-dependent manner and reduced mitochondrial membrane potential as shown by JC-1 staining. HIF-1α knockout significantly restored NK cell cytotoxic function, upregulated OXPHOS- and glycolysis-related gene expression, and improved mitochondrial membrane potential. Transcriptomic sequencing confirmed enrichment of mTOR signaling and energy metabolism gene sets after knockout. Importantly, mTOR pathway inhibition completely blocked the HIF-1α-knockout-mediated restoration of NK cell function and mitochondrial fitness, indicating that HIF-1α primarily drives NK cell metabolic and functional abnormalities through mTOR suppression.
    Conclusions: Brucella infection induces HIF-1α overexpression, which suppresses mTOR signaling and drives metabolic reprogramming of NK cells characterized by impaired OXPHOS and functional exhaustion, thereby promoting chronicity of brucellar arthritis. Targeting the HIF-1α/mTOR axis may offer a novel therapeutic strategy for brucellar arthritis.
    Keywords:  HIF−1α; brucellar arthritis; functional exhaustion; mTOR; metabolic reprogramming; natural killer cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1961240
  15. Front Immunol. 2026 ;17 1853973
    Altered OXPHOS potential in ascites immune cells is linked to CD4 T-cell exhaustion and a higher risk of spontaneous bacterial peritonitis in cirrhosis.
    Hasan Tarik Cosgun, Pavitra Kumar, Ingrid Wei Zhang, Linda Hammerich, Virein Sudheer, Charalampos Pavlidis, Juan Wang, Hannah Schwarz, Frank Tacke, Ali Canbay, Cornelius Engelmann.
       Background and aims: Ascites marks advanced cirrhosis and increases the risk of complications including SBP. Systemic inflammation in liver disease is well characterized, but the immunometabolic properties of the peritoneal compartment remain undefined. This study evaluated the metabolic characteristics of ascites-derived immune cells.
    Method: Matched blood and ascites samples from patients with cirrhosis without SBP (n = 21) were analyzed. OXPHOS and glycolysis were assessed using the Seahorse XFe96, lactate concentrations were measured, and immune cell subsets were characterized by spectral flow cytometry.
    Results: T cells were the dominant subset in ascites and blood (58.2% vs. 49%, p=0.0822) and CD4+ T cells represented the predominant subset (57.3% vs. 64.6%, p=0.026). Ascites-derived MNCs exhibited higher basal and maximal respiration than blood-counterparts (4.4 vs 3.6, p = 0.033 and 20 vs 13.3 pmol O2/min/µg protein, p=0.004). Proton leak was increased in ascites (0.7 vs 0.4 pmol O2/min/µg protein, p<0.0001). OXPHOS potential was increased in ascites (365.9% vs. 290.9%, p<0.001) while glycolytic potential was reduced (208.0% vs. 286.8%, p < 0.001), corroborated by lower ascitic lactate concentrations (1.9 vs. 3.8 mM/L, p<0.001). Patients with low ascites OXPHOS potential had higher risk of developing SBP (p = 0.016). CD4+ T cells in ascites showed elevated PD-1 expression (36.9% vs. 14.7%, p < 0.0001), associated with reduced OXPHOS potential (407.1% vs. 324.6% in PD-1-low vs. PD-1-high cells, p = 0.036).
    Conclusion: Peritoneal immune cells exhibit a dissociated phenotype-elevated oxidative activity alongside features of immune exhaustion-reflecting their distinct role in immune regulation within the peritoneal environment.
    Keywords:  cirrhosis; immune cells; immunometabolism; mitochondria; spontaneous bacterial peritonitis
    DOI:  https://doi.org/10.3389/fimmu.2026.1853973
  16. Front Immunol. 2026 ;17 1953192
    Cholesterol dysregulation and microglial NLRP3 inflammasome activation after ischemic stroke: implications for neuroinflammation and functional recovery.
    Jing Wang, Pingxu An, Chunyan Fu, Xingqi Su, Yan Sun, Di Ma, Xu Shi, Xinyu Hong.
      Secondary neuroinflammation is an important determinant of tissue injury, repair, and neurological recovery after ischemic stroke, yet the lipid-metabolic environment in which this response develops remains incompletely integrated into current mechanistic models. This narrative review synthesizes PubMed-indexed, peer-reviewed literature published between 2010 and 2026 on post-stroke cholesterol metabolism, microglial lipid handling, NLRP3 inflammasome signaling, immunometabolic remodeling, therapeutic intervention, and recovery-related outcomes. Ischemic injury substantially remodels the local lipid environment through neuronal membrane disruption, myelin breakdown, oxidative lipid modification, altered cholesterol turnover, and blood-brain barrier dysfunction, generating a heterogeneous pool of free cholesterol, cholesteryl esters, lipid droplets, cholesterol crystals, oxysterols, and oxidized lipids. Stroke-specific studies increasingly support the emergence of cholesterol- and lipid-loaded microglial states and show that microglial lipid-processing capacity, including TREM2- and SREBP2-related mechanisms, can influence inflammatory and reparative responses. However, the causal connection between cholesterol dysregulation and NLRP3 activation remains only partly resolved. Direct stroke evidence supports the coexistence of microglial cholesterol overload and NLRP3-associated inflammatory changes, whereas detailed mechanisms involving cholesterol crystal-induced lysosomal injury, metabolic remodeling, and intracellular lipid stress remain partly dependent on cross-model evidence. Oxysterol effects are context dependent, and recent cholesterol-mobilization experiments identify mitochondrial DNA leakage-STING signaling as an alternative, more directly validated downstream pathway. Post-stroke microglia are also functionally heterogeneous, with distinct populations contributing to debris clearance, white matter repair, and neurological recovery. Therapeutically, systemic lipid management should be distinguished from experimental strategies that modify brain cholesterol handling or suppress inflammasome-associated inflammation, and no integrated cholesterol-microglia-NLRP3 treatment strategy has yet been clinically validated. Collectively, current evidence supports a proposed, evidence-stratified framework in which cholesterol-related lipid stress, microglial state, inflammasome susceptibility, and tissue repair partially converge rather than forming a single validated linear causal axis.
    Keywords:  NLRP3 inflammasome; cholesterol metabolism; immunometabolism; ischemic stroke; lipid droplets; microglia; neuroinflammation; oxysterols
    DOI:  https://doi.org/10.3389/fimmu.2026.1953192
  17. Adv Sci (Weinh). 2026 Oct 18. e78339
    HECTD1 Directs HIF-1α to Facilitate Intestinal Inflammation and Carcinogenesis via Promoting Th17 Differentiation and Glycolysis.
    Shuiyu Xu, Qiaoqiao Han, Feixiang Wang, Yuerong Zhang, Haoran Feng, Kun Liu, Fang Xiu Luo, Fei Yuan, Xuesong Zhao, Xiaoyan Yu, Haiyan Huang, Qiang Zou, Ren Zhao.
      Targeting glucose metabolism in Th17 cells may be beneficial for treating inflammatory bowel disease (IBD) and colitis-associated cancer (CAC), however, the molecular mechanisms orchestrating Th17 cell metabolism remain unclear. Here, we revealed that HECTD1 regulates IGF2BP3-dependent HIF-1α translation to promote Th17 cell glycolysis and differentiation and that HECTD1 expression correlates with IBD and CAC pathogenesis. T-cell-specific deletion of HECTD1 mitigated the severity of colitis and CAC in murine models. RNA-seq revealed enrichment of Th17 differentiation, glycolysis/gluconeogenesis, and HIF-1 signaling pathways among differentially expressed genes between HECTD1-sufficient and HECTD1-deficient CD4+ T cells. Consistently, loss of HECTD1 suppressed Th17 cell differentiation both in vitro and in vivo, and suppressed glycolytic metabolism and HIF-1α activity, revealing the mechanism underlying its protective effects against IBD and CAC. Mechanistically, HECTD1 potentiates m6A-based HIF-1α translation by mediating IGF2BP3 K63-linked ubiquitination to promote the binding of IGF2BP3 with the translation initiation machinery of Hif1a mRNA. Reciprocally, HIF-1α acts as a key transcription factor that promotes Hectd1 gene expression, establishing a distinct positive feedback loop. Our findings highlight a self-reinforcing feedback mechanism in which HECTD1 and HIF-1α engage in mutual regulation to dictate Th17 cell fate and metabolic reprogramming, providing novel potential IBD and CAC treatments targeting HECTD1.
    Keywords:  HECTD1; Th17 cells; colitis‐associated cancer; glycolysis; inflammatory bowel disease
    DOI:  https://doi.org/10.1002/advs.78339
  18. Arterioscler Thromb Vasc Biol. 2026 Oct 22.
    Novel Mechanometabolic Signaling Cascade Linking Efferocytosis to Inflammation Resolution.
    Dhananjay Kumar, Rajan Pandit, Louise Frausto, Theresea-Anne Governale, Shuai Yuan, Javier Nion Fieira, Abraham Quaye, Kyle McGee, Sandeep Das, Sumit Kumar Anand, Nilesh Pandey, Harpreet Kaur, Tanvir Ahmed, Yash Katakia, Katie Gomez, Braedyn Gates, Luke White, Charlotte Orr, Nora Sperfslage, Matthew W Breitzman, Lucas J Showman, Amanda C Doran, Adam C Straub, Babak Razani, Matthew D Woolard, Kasi Lively, Frederick W Knight, James G Traylor, Miles A Sugar, Nirav Dhanesha, Christopher B Pattillo, A Wayne Orr, Oren Rom, Arif Yurdagul.
       BACKGROUND: Apoptotic cell clearance by macrophages, termed efferocytosis, resolves inflammation and promotes tissue repair, whereas defective efferocytosis contributes to chronic inflammatory diseases such as atherosclerosis. Putrescine biosynthesis, driven by the rate-limiting enzyme ODC1 (ornithine decarboxylase 1), has emerged as a key efferocytosis-induced metabolic pathway that promotes inflammation resolution. However, the mechanisms regulating ODC1 during atherosclerosis remain undefined. Here, we investigated the mechanisms controlling ODC1 and putrescine biosynthesis and identified a novel integrin αv-FAK (focal adhesion kinase)-Rac1 (Rac family small GTPase 1)-STAT3 (signal transducer and activator of transcription 3)-MYC (MYC proto-oncogene) signaling axis that becomes progressively impaired during atherosclerosis.
    METHODS: We performed metabolomic and cytokine profiling of human atherosclerotic plaques and assessed ODC1 expression in lesional macrophages from humans and mice. Mechanistic studies used apoptotic cell- or polystyrene bead-exposed macrophages, Ldlr-/- mice with hematopoietic integrin αv deficiency fed a Western-type diet, single-nuclei RNA sequencing, and bulk RNA sequencing.
    RESULTS: Putrescine levels negatively correlated with inflammatory mediators, and ODC1 expression in lesional macrophages declined with disease progression in humans and mice. Engulfment of apoptotic cells or polystyrene beads increased ODC1 expression through an integrin αv- and actin polymerization-dependent mechanism. Hematopoietic integrin αv deficiency exacerbated lesion size and necrosis, reduced efferocytosis, and decreased fibrous cap thickness. Single-nuclei RNA sequencing showed no changes in lesional cell composition but revealed activation of inflammatory pathways specifically in integrin αv-deficient macrophages. Mechanistically, phagocytosis-induced ODC1 expression relied on integrin αv-mediated STAT3 activation and MYC-dependent Odc1 transcription. Bulk RNA sequencing showed that apoptotic cell-exposed human macrophages lacking integrin αv upregulated atherogenic mediators and inflammatory pathways, an effect reversed by restoring putrescine levels.
    CONCLUSIONS: Together, these findings uncover a previously unrecognized mechanistic link between phagocytosis and macrophage metabolism, which we identify as a case of mechanometabolism, and demonstrate how its dysregulation compromises inflammation resolution and promotes atherosclerosis.
    Keywords:  atherosclerosis; efferocytosis; inflammation; macrophages; metabolomics; phagocytosis
    DOI:  https://doi.org/10.1161/ATVBAHA.126.325444
  19. J Am Chem Soc. 2026 Oct 14. 148(40): 43200-43208
    Cross-Species Profiling of Itaconate-Mediated Modifications by a Universal Probe.
    Bin Ma, Dongyang Liu, Weidi Xiao, Chu Wang.
      The immunometabolite itaconate can covalently modify proteins through cysteine itaconation and lysine itaconylation. Current bioorthogonal itaconate probes show biased specificity for profiling cysteine itaconation in macrophages versus bacteria and are not compatible with profiling lysine itaconylation at all. Here, we report isoC3A, a universal probe designed for the comprehensive chemoproteomic profiling of these two types of itaconate-mediated modifications in both eukaryotic and prokaryotic cells. In situ profiling of Salmonella-infected macrophages by isoC3A captures the dynamic changes of itaconate-mediated modifications in the proteomes of host cells and bacteria simultaneously. It also revealed that itaconate targets critical cysteine residues on the aconitate hydratase, enhances its dehydration activity to boost the cis-aconitate level, and drives a positive feedback loop to sustain itaconate biosynthesis. Together, these findings establish isoC3A as a universal probe for exploring the covalent targets of itaconate and suggest a metabolic amplification mechanism in innate immunity.
    DOI:  https://doi.org/10.1021/jacs.6c10764
  20. Appl Microbiol Biotechnol. 2026 Jul 27. pii: 316. [Epub ahead of print]110(1):
    Lactylation modification: a new bridge connecting macrophage metabolism and pulmonary hypertension.
    Wende Ma, Yumei Ma, Cen Guo, Xiaoling Su.
      Pulmonary hypertension (PH) is a multifactorial, progressive disease characterized by pulmonary vascular remodeling and right heart failure, representing a substantial global health burden. Dysregulated interactions among multiple cell types within the pulmonary vascular microenvironment, particularly macrophage polarization imbalance with a predominant transition toward the M2 phenotype, play a critical role in driving pro-fibrotic and pro-remodeling processes in PH. Lactylation, a novel post-translational modification that covalently links lactate to lysine residues, translates glycolytic metabolic signals into persistent epigenetic changes. Recent advances have identified lactylation on histones (e.g., H3K18la), non-histone proteins, and mitochondrial proteins, revealing new layers of regulatory complexity. Elucidating the role of lactylation, particularly its impact on macrophage polarization and vascular cell function, may offer novel insights into the pathogenesis of PH and identify potential therapeutic targets. KEY POINTS: • Macrophage polarization imbalance (predominant M2 phenotype) is a critical driver of pulmonary vascular remodeling in pulmonary hypertension (PH), and lactylation serves as a novel metabolic-epigenetic bridge linking macrophage metabolic reprogramming and phenotypic switching. • Lactylation modifications occur extensively on histones, non-histone proteins, and mitochondrial proteins in PH, regulating fibrosis-related pathways, arginine metabolism signaling, and the dysfunction of pulmonary vascular cells. • Targeting lactylation and lactate metabolism represents a promising therapeutic strategy for PH, supported by our previous studies on M2 macrophage polarization and ongoing lactylomic research.
    Keywords:  Lactylation; M2 phenotype; Macrophages; Metabolic reprogramming; Pulmonary hypertension
    DOI:  https://doi.org/10.1007/s00253-026-13980-1
  21. iScience. 2026 Nov 20. 29(11): 117743
    Caloric restriction attenuates NLRP3 inflammasome activation and oxidative stress in leukocytes of patients with obesity.
    Sandra López-Domènech, Laura Perea-Galera, María Pelechá-Salvador, Zaida Abad-Jiménez, Jonathan Hermenejildo, Meylin Fernández-Reyes, Clara Luna-Marco, Julia Cacace, Silvia Veses, Carlos Morillas, Víctor M Víctor, Milagros Rocha.
      Obesity promotes chronic low-grade inflammation through metabolic stress and activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. The effects of caloric restriction on this pathway in humans are poorly understood; therefore, we evaluated the impact of a 6-month hypocaloric dietary intervention in 45 adults with obesity by assessing the metabolic, inflammatory, oxidative stress, and inflammasome-related markers in peripheral blood mononuclear cells. Weight loss improved metabolic parameters, reduced oxidative stress, and decreased the expression of nuclear factor κB (NF-κB), NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1, while there tended to be a reduction of active caspase-1. These changes were accompanied by lower circulating interleukin (IL)-1β (IL-1β) and IL-18 levels, suggesting systemic attenuation of inflammasome activity. Baseline adiposity and insulin resistance influenced the magnitude of the response to dietary intervention. These findings support caloric restriction as a strategy to mitigate obesity-associated immunometabolic dysfunction and identify the redox-inflammasome axis as a potential therapeutic target.
    Keywords:  NLRP3 inflammasome; PBMCs; caloric restriction; immunometabolism; obesity; oxidative stress; weight loss
    DOI:  https://doi.org/10.1016/j.isci.2026.117743
  22. Int J Biol Sci. 2026 ;22(15): 8408-8447
    Metabolic Barriers to Cancer Immunotherapy: Multiscale Mechanisms from Organelle Dysfunction to Organ-Specific Constraints.
    Zichen Gui, Xiaoyin Yuan, Xiaoping Chen, Qibo Huang, Bixiang Zhang, Junnan Liang.
      Immune checkpoint blockade (ICB) has reshaped cancer therapy, yet primary resistance and acquired relapse remain common despite therapeutic targeting of inhibitory receptor pathways. This limitation suggests that checkpoint release may remain insufficient when antitumor lymphocytes lack the metabolic, organelle-level, spatial, or systemic conditions required for tissue entry, functional recovery, and durable effector activity. In this review, we organize metabolic barriers to ICB into a multiscale framework comprising four interconnected axes. The Local Resource Axis captures how nutrient competition, enzymatic depletion, lipid dysregulation, suppressive metabolites, and ionic stress reshape the tumor microenvironment. The Organelle Axis examines mitochondrial dysfunction, endoplasmic reticulum stress, and intercellular mitochondrial transfer as determinants of T-cell functional recovery. The Spatial Axis addresses stromal, vascular, and organ-specific immune-metabolic niches that regulate immune access and site-specific resistance. The Systemic Axis integrates host metabolic and temporal states, including obesity, cachexia, microbial ecology, and circadian organization. Across these axes, metabolic constraints impair T-cell receptor (TCR) signaling, biosynthesis, redox homeostasis, organelle fitness, tissue infiltration, and host immune reserve, while also reducing malignant-cell susceptibility to immune-mediated killing. We further discuss therapeutic implications through a clinical-readiness and chrono-metabolic scheduling framework that distinguishes practice-ready vascular-targeted combinations from trial-prioritized or investigational dietary, microbiome-directed, metabolite-targeted, and engineered T-cell strategies. This evidence-calibrated perspective reframes tumor immunometabolism not as a static catalogue of targets, but as a set of biologically timed and compartment-specific constraints that determine the conditions under which ICB can achieve durable immune control.
    Keywords:  T cell exhaustion; immune checkpoint blockade; immunometabolism; metabolic homeostasis; tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.137618
  23. Hepatol Commun. 2026 Nov 01. pii: e1034. [Epub ahead of print]10(11):
    Itaconate as the endogenous brake of proinflammatory macrophage activation alleviates inflammation in liver fibrogenesis.
    Kai Zhang, Tong Li, Wenhui Liu, Weiyang Li, Lin Yang, Na Chang, Liying Li.
       BACKGROUND: Liver inflammation and fibrosis are reparative responses to chronic liver injury. Bone marrow-derived monocyte/macrophages (BMDMs) are key participants. Our previous study demonstrated that BMDM can be activated as a proinflammatory phenotype by sphingosine-1-phosphate (S1P). Aconitate decarboxylase 1 (ACOD1)/itaconate is an anti-inflammatory molecule. However, it remains unclear whether ACOD1/itaconate is involved in S1P-induced BMDM activation.
    METHODS: A methionine-choline-deficient and high-fat diet was used to induce liver injury and fibrosis in mice. To clarify the role of endogenous ACOD1/itaconate in BMDMs in liver fibrosis, we established 2 types of chimeric mice: (1) bone marrow (BM) Acod1 deficiency (WT or Acod1 knockout BM was transplanted into wild-type mice) and (2) exclusive BM Acod1 expression (WT or Acod1 knockout BM was transplanted into Acod1 knockout mice).
    RESULTS: Single-cell RNA sequencing data revealed that Acod1 was highly expressed in injured BMDMs. Acod1+ BMDMs exhibited a proinflammatory phenotype with elevated expression of proinflammatory genes. In vitro, ACOD1 expression and itaconate production were upregulated in S1P-treated BMDMs. Endogenous ACOD1/itaconate in BMDMs suppressed BMDM proinflammatory activation by forming negative feedback with NF-κB signaling. S1P-regulated ACOD1 expression and BMDM activation via the same signaling pathway (S1PR2/MAPK/NF-κB signaling), indicating the endogenous brake function of ACOD1/itaconate. In chimeric mice with BM Acod1 deficiency, the abolition of the endogenous brake function of ACOD1/itaconate aggravated liver inflammation/fibrosis. Exclusive BM Acod1 expression showed the opposite effects.
    CONCLUSIONS: ACOD1/itaconate exerts an endogenous brake function in the proinflammatory activation of BMDMs during chronic liver injury. Our data demonstrate the role of ACOD1/itaconate in S1P-induced BMDM activation, further indicating that ACOD1/itaconate is a potential therapeutic strategy for liver inflammation/fibrosis.
    Keywords:  ACOD1; bone marrow–derived monocyte/macrophages; chimeric mouse; single-cell RNA sequencing; sphingosine-1-phosphate
    DOI:  https://doi.org/10.1097/HC9.0000000000001034
  24. mBio. 2026 Oct 20. e0181426
    Host-like temperature unlocks glucose uptake and metabolism in pathogenic Leptospira.
    Ryo Ozuru, Michinobu Yoshimura, Deborah A Powers, Takumi Sonoda, Jason A Papin, Fumiko Obata, Glynis L Kolling, Kenji Hiromatsu.
      Pathogenic Leptospira transitions between environmental reservoirs and mammalian hosts, exposing the bacterium to distinct temperature conditions. Although Leptospira is generally considered to rely primarily on long-chain fatty acids for growth and to have limited capacity to use glucose, whether host-like temperature alters glucose-associated metabolic capacity remains unclear. Here, we used transcriptome-integrated genome-scale metabolic modeling to examine temperature-dependent metabolic states in pathogenic Leptospira. Models contextualized with transcriptomic data from cultures at 37°C predicted increased flux through glucose transport, glucose phosphorylation, and downstream glucose-associated reactions than it did at 29-30°C. Similar temperature-dependent predictions were obtained for another pathogenic Leptospira species under in vitro conditions. Consistent with these findings, analysis of leptospires cultivated intraperitoneally in dialysis membrane chambers also predicted enhanced glucose uptake and metabolism under host-temperature conditions. In vitro validation experiments showed increased bacterial uptake or accumulation of a fluorescent glucose analog, elevated expression of candidate glucose transporter genes, and glucose-dependent enhancement of bacterial growth at 37°C. Treatment with a glucose degradation pathway inhibitor, 2-deoxy-d-glucose, further supported a contribution of glucose-associated processes to proliferation at 37°C. Together, these findings indicate that pathogenic Leptospira displays condition-dependent glucose uptake and glucose-associated metabolic activity that become apparent at host-like temperature, as opposed to being glucose-incompetent at environmental-like temperature. This prediction-driven framework refines the conventional view of Leptospira carbon metabolism and provides a basis for future studies of glucose-associated metabolic capacity during mammalian infection.
    IMPORTANCE: Environmental reservoirs play a central role in the transmission of many bacterial pathogens, yet the metabolic mechanisms that enable adaptation to both environmental and host-associated niches remain largely unknown. Using a prediction-driven framework that combines contextualized genome-scale metabolic modeling with multi-omics analyses and experimental validation, we discovered that pathogenic Leptospira activates glucose uptake and metabolism only under host-like conditions. This finding resolves a long-standing misconception arising from studies performed under conventional laboratory conditions and fundamentally revises our understanding of Leptospira physiology. More importantly, our study establishes an integrative systems biology strategy for uncovering condition-dependent metabolic traits that would be difficult to identify experimentally alone, with broad applicability to diverse environmentally transmitted pathogens.
    Keywords:  Leptospira; glucose metabolism; host-pathogen interactions; metabolic modeling
    DOI:  https://doi.org/10.1128/mbio.01814-26
  25. Front Immunol. 2026 ;17 1929816
    TSPO in systemic-ocular immunometabolic crosstalk: mechanisms and therapeutic implications.
    Zuyi Yang, Xinyi Zhang, Dianzhe Tian, Xinshi Li, Xinyu Zhao, Erqian Wang, Youxin Chen.
      The eye is increasingly recognized as a tissue shaped by systemic immune and metabolic states rather than an isolated immune-privileged organ. Translocator protein (TSPO), an 18-kDa outer mitochondrial membrane protein enriched in myeloid and glial cells, links mitochondrial homeostasis, redox signaling, lipid metabolism, and immune polarization. This review synthesizes evidence for TSPO involvement in systemic-ocular immunometabolic crosstalk and organizes it into a three-stage working model: peripheral immunometabolic priming, blood-retinal barrier vulnerability, and intraocular glial amplification. We review evidence from systemic autoimmune diseases with ocular manifestations, metabolic diseases with ocular complications, and primary ocular diseases with systemic contributions. We then assess the potential of TSPO as an imaging or fluid biomarker and as a therapeutic target. Current evidence suggests that TSPO is a promising immunometabolic node and underscores the need for cross-organ disease models, cell-specific TSPO manipulation, spatial multi-omics, and local ocular delivery strategies.
    Keywords:  TSPO; blood-retinal barrier; immunometabolic regulation; mitochondrial stress; systemic-ocular crosstalk
    DOI:  https://doi.org/10.3389/fimmu.2026.1929816
  26. ACS Synth Biol. 2026 Oct 16. 15(10): 4186-4198
    Glucosamine-Producing Engineered Probiotics Enhance the Immune Function of Microglia.
    Yeyin Li, Qiushuang Zhang, Yicong Dai, Liyan Fan, Xucong Teng, Jinghong Li.
      Dysregulated microglial activation underlies both neuroinflammation and neurodegenerative pathology. GlcN has well-documented anti-inflammatory activity across multiple cell types, yet whether it acts on microglia in any meaningful way has not been directly tested. Here we show that GlcN shifts microglia toward an M2 anti-inflammatory state by altering their metabolic program, an effect accompanied by a clear improvement in immune function. A practical barrier complicates direct translation of this finding, oral GlcN is rapidly cleared and reaches target tissues at concentrations too low to be therapeutically useful. We therefore repurposed Escherichia coli Nissle 1917 (EcN) as a living production platform, introducing targeted genetic modifications to generate EcN-GlcN, a strain that continuously synthesizes GlcN within the gut lumen. In co-culture, EcN-GlcN drove the same M2 shift in microglia as exogenous GlcN. After oral gavage in mice, the strain established stable intestinal colonization and kept systemic GlcN concentrations detectable for at least 72 h. The work positions GlcN as an underappreciated neuroimmune regulator and offers a practical route to its long-term delivery through a living bacterial system.
    Keywords:  engineered probiotics; glucosamine; metabolic engineering; microglia; microglial polarization; neuroinflammation
    DOI:  https://doi.org/10.1021/acssynbio.6c00385
  27. Cancer Immunol Res. 2026 Oct 21.
    FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Myeloid Cells.
    Jianyu Yu, Jonathan Shilyansky, Jiaqing Hao, Anthony Avellino, Yanwen Sun, Xingshan Jiang, Xiaochun Han, Melissa Curry, Sonia L Sugg, Bing Li.
      Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Herein, we identify a FABP4-PD-L1 axis that links lipid metabolism to immune checkpoint regulation in myeloid cells. Single-cell transcriptomics revealed a distinct FABP4high immunosuppressive splenic macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) was shown to induce FABP4 and promote PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 was essential for this process, which enabled PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14intCD16⁺ monocyte population exhibited elevated FABP4-PD-L1 signaling and correlated with obesity and invasive breast cancer. These findings establish PD-L1 as a metabolically regulated protein and reveal a mechanism by which lipid excess drives immune evasion, suggesting FABP4 as a potential therapeutic target in cancer immunotherapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-26-0497
  28. Cell Rep. 2026 Oct 22. pii: S2211-1247(26)01266-0. [Epub ahead of print]45(11): 118187
    Hexokinase-2 moonlights as a suppressor of STING-mediated innate immunity.
    Chuchu Zhang, Fang-Xu Li, Ming Gao, Jiali Ma, Siyuan Wang, Bikun Xiao, Bo Zhong, Junjie Zhang.
      Metabolic enzymes are increasingly recognized for "moonlighting" functions beyond their primary metabolic roles. While such non-canonical activities are well characterized in cancer biology, their roles in innate immunity remain poorly defined. Here, we show that Hexokinase II (HK2), a rate-limiting enzyme of glycolysis, suppresses STING-mediated innate immune responses independently of its enzymatic activity. Upon STING activation, reactive oxygen species (ROS) trigger the dissociation of HK2 from the mitochondria to the cytosol. Cytosolic HK2 then interacts with STING, impeding its oligomerization and translocation to the Golgi apparatus, thereby dampening downstream immune signaling. Notably, HK-TAT, a peptide that induces HK2 release from the mitochondria, effectively inhibits STING-dependent immune activation and ameliorates disease phenotypes in STING-driven autoimmune mouse models. Our findings highlight the moonlighting role of HK2 as a negative regulator of STING signaling and provide a potential therapeutic approach for treating autoimmune diseases driven by STING dysregulation.
    Keywords:  CP: immunology; CP: metabolism; HK2; STING; autoimmune disease; moonlighting
    DOI:  https://doi.org/10.1016/j.celrep.2026.118187
  29. Nat Commun. 2026 09 22. pii: 11013. [Epub ahead of print]17(1):
    Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease.
    Gaurav Kumar Lohia, Ying-Tsun Chen, Samantha Chen, Ayesha Beg, Erin Theiller, Aomeng Cui, Ahmed M Moustafa, Sebastián A Riquelme.
      Cystic fibrosis (CF), caused by CFTR mutations, is characterized by progressive pulmonary remodeling, particularly during bacterial infection. This pathological environment, exacerbated by altered epithelial growth, leads to thickened airway walls, inducing permanent narrowing and long-term breathing difficulties. However, what drives this adverse milieu remains unclear. Here, we identify activation of the de novo pathway of pyrimidine synthesis (DNPPS) as a central contributor of CF lung remodeling. In response to impaired mitochondrial bioenergetics, CFTR-mutant epithelial cells engage compensatory DNPPS activity, functionally coupling mitochondrial oxidative metabolism to pyrimidine production and, inadvertently, promoting proliferation. This phenotype is reversible with CFTR modulators and pharmacologic DNPPS inhibitors using clinically established agents. Strikingly, Pseudomonas aeruginosa, the predominant CF pathogen, undergoes convergent pyrimidine adaptation, activating its own DNPPS machinery to amplify biomass and sustain a remodeled niche. Together, these findings define pyrimidine metabolism as a shared host-pathogen axis driving epithelial restructuring and bacterial persistence in the CF lung.
    DOI:  https://doi.org/10.1038/s41467-026-77940-z
  30. Front Immunol. 2026 ;17 1904807
    Immune cell fibrotic plasticity: mesenchymal-like reprogramming of macrophages, neutrophils and T cells.
    Xiaodan Long, Shaoxiang Yuan, Ziyi Luo, Yuezhong Chen, Shune Xiao, Chengliang Deng, Junzhe Chen.
      Fibrosis has traditionally been viewed as a fibroblast- and myofibroblast-centred process, in which immune cells regulate matrix deposition primarily through inflammatory mediators and paracrine signalling. However, advances in single-cell profiling, spatial analyses and lineage-resolved approaches are beginning to challenge this rigid division of cellular labour. Emerging evidence indicates that, in persistently injured and maladaptively repairing tissues, selected immune cell populations can acquire matrix producing, cytoskeletal remodelling and mesenchymal-like functions, thereby contributing more directly to structural tissue remodelling. In this Review, we introduce the concept of immune cell fibrotic plasticity and critically assess the evidence, regulatory mechanisms and pathological significance of fibrotic effector states in macrophages, neutrophils and T cells. Macrophage reprogramming towards myofibroblast-like states appears to be shaped by convergent TGF-β/SMAD signalling, metabolic adaptation and epigenetic regulation. Neutrophils can synthesize, transport and organize extracellular matrix, conferring temporally distinct functions in tissue stabilization and pathological scarring. Evidence for mesenchymal-like reprogramming of T cells remains limited, but raises the possibility that adaptive immune cells can also acquire structural effector functions. Importantly, co-expression of immune and mesenchymal markers does not, by itself, establish stable lineage conversion. These phenomena are more appropriately understood as microenvironmentally induced, context-dependent functional states rather than universal or complete transdifferentiation. Defining the origins, reversibility and quantitative contribution of these states will determine whether immune-cell fibrotic plasticity can be exploited for disease stratification and the development of more selective antifibrotic therapies.
    Keywords:  T cell; fibrosis; macrophages; mesenchymal transition; neutrophil
    DOI:  https://doi.org/10.3389/fimmu.2026.1904807
  31. PLoS Pathog. 2026 Oct 22. 22(10): e1014734
    Adaptive metabolic reprogramming of the brain tissue during late-stage Trypanosoma brucei infection maintains host learning and memory.
    Nadin Fathallah, Chloe Barnes, Rebecca Chatwin, Jayde Whittingham-Dowd, John J Worthington, Lucy Jackson-Jones, Neil Dawson, Michael D Urbaniak.
      Human African Trypanosomiasis (HAT) is a two-stage infection caused by Trypanosoma brucei ssp. In stage I the trypanosomes are in blood, lymph and tissue interstitial space and the infection progresses to stage II when the parasites enter the central nervous system (CNS), resulting in behavioural aberrations that proceed to coma and death. Here, we use a bioluminescent murine model of HAT to examine parasite localisation and the changes in host brain gene expression, metabolism and function, and behaviour that occur over the course of the infection. The murine HAT model reproduces the decrease in brain tryptophan well established in clinical samples, and we report for the first time an unprecedented 1.8-fold decrease in global brain glucose metabolism in stage II infection. These metabolic changes are accompanied by an 18-fold decrease in brain insulin transcripts without changes in pathways regulating the cellular responses to insulin. By contrast, genes involved in fatty acid and lipid metabolism are upregulated in the brain during stage II infection. Moreover, we show that transcriptional programmes regulating mitochondrial metabolism dynamically adapts across the time course of HAT infection, ultimately leading to a transcriptional programme that diverts host brain metabolism away from glycolysis during stage II infection. Overall, our data demonstrate a reprogramming of brain energy metabolism during stage II HAT infection that favours the utilization of fatty acids and lipids to meet the energy demands of the brain, with a reduced reliance on glucose metabolism. Despite the profound neurometabolic changes observed, host anxiety-like behaviour is unchanged and episodic learning and memory is not impaired, suggesting that brain metabolic reprogramming enables the utilisation of adipose reserves to maintain core brain functions. These finding may explain the progressive onset of neurological symptoms in HAT patients and inform the development therapeutic interventions to alleviate them.
    DOI:  https://doi.org/10.1371/journal.ppat.1014734
  32. Cell Signal. 2026 Oct 17. pii: S0898-6568(26)00555-3. [Epub ahead of print]149 112896
    RNF34 restrains endometriosis progression by promoting PKM2 ubiquitination and suppressing glycolysis.
    Jiayu Liu, Jie Zhang, Qiaozhu Wu, Chao Lu, Zhenhai Yu.
      Metabolic reprogramming, particularly enhanced glycolysis, is an important feature of endometriosis, yet the upstream posttranslational mechanisms governing this metabolic phenotype remain poorly understood. Transcriptomic analysis and clinical tissue validation revealed reduced RNF34 expression in endometriotic tissues and an inverse association between RNF34 and pyruvate kinase M2 (PKM2). Mass spectrometry analysis revealed that PKM2 is an RNF34-interacting protein, and biochemical assays further demonstrated this direct association. Mechanistically, RNF34 promoted PKM2 ubiquitination and reduced its protein stability in an E3 ligase-dependent manner. RNF34 suppressed glycolytic activity, proliferation, migration, and invasion in endometriotic and endometrial stromal cells, whereas reciprocal PKM2 rescue experiments supported the role of PKM2 as an important functional mediator of these effects. In a donor-recipient mouse model, RNF34-deficient uterine tissue generated larger endometriotic lesions, whereas PKM2 inhibition attenuated the increased lesion burden, supporting the role of PKM2 as a functional downstream mediator of RNF34 in vivo. As a pharmacological extension, curcumin increased RNF34 protein abundance and suppressed endometriosis-associated cellular phenotypes, whereas RNF34 depletion attenuated these effects. Curcumin also reduced endometriotic lesion burden in vivo. Collectively, these findings define an RNF34-PKM2 regulatory axis that links ubiquitin-dependent control of PKM2 stability to glycolytic reprogramming and endometriosis progression and support the pharmacological relevance of RNF34 in endometriosis.
    Keywords:  Curcumin; Endometriosis; Glycolysis; PKM2; RNF34; Ubiquitination
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112896
  33. J Nanobiotechnology. 2026 Jul 27. pii: 977. [Epub ahead of print]24(1):
    Spermidine, a chondrocyte apoptotic metabolite, delays osteoarthritis by regulating macrophage M2c polarization.
    Jiajia Lu, Hongbiao Sun, Fan Zhang, Guangnan Wang, Xianan Song, Qinling Jiang, Zhibin Zhou, Jun Ma, Qiang Fu, Lei Zhu.
       BACKGROUND: Chondrocyte apoptosis and synovial macrophage polarization represent two key pathological hallmarks of osteoarthritis (OA), but the interplay between them remains largely unknown. This study aimed to investigate the roles and mechanisms of the chondrocyte apoptotic secretome in mediating macrophage polarization during the pathological process of OA.
    METHODS: In vitro cultures of chondrocytes and macrophages, along with an in vivo surgically induced OA mouse model, were used to evaluate the effect of the chondrocyte apoptotic secretome. Untargeted metabolomics, mitochondrial function assessment, and macrophage-specific AMPKα knockout mice were used to identify key metabolites and their regulatory mechanisms. A sustained-release delivery system for spermidine (SPD) was constructed using lipid nanoparticles (LNPs) and sodium hyaluronate.
    RESULTS: Apoptotic chondrocytes increased the secretion of SPD in the metabolite secretome. SPD acts as a signaling metabolite to increase AMPKα activation in macrophages, which in turn drives increased oxidative phosphorylation (OXPHOS) and improves mitochondrial function, ultimately promoting M2c macrophage polarization during OA. Exogenous supplementation with SPD via a ROS-responsive SH@LNP@SPD hydrogel alleviated OA progression by promoting M2c macrophage polarization in vivo. Furthermore, elevated SPD levels in synovial fluid correlated with milder clinical symptoms and less severe pathological features.
    CONCLUSIONS: Our findings underscore a significant protective role of chondrocyte apoptosis in early OA mediated through the secretion of SPD, which acts on macrophages. Mechanistically, SPD-induced enhancement of AMPKα activation and OXPHOS occurs specifically in macrophages, driving their beneficial M2c polarization. Synovial fluid SPD may hold diagnostic value for early-stage OA and strategies aimed at sustaining SPD levels may represent effective therapeutic approaches for OA.
    Keywords:  Apoptosis; Apoptotic metabolites; M2c polarization; Osteoarthritis
    DOI:  https://doi.org/10.1186/s12951-026-04832-1
  34. Immunometabolism (Cobham). 2026 Oct;8(4): e00092
    Macrophage peroxisomes at the crossroads of inflammation.
    Abhishek V Thakkar, Irfan J Lodhi, Edward B Thorp.
      Macrophage plasticity of function enables the control of inflammation and its resolution. This plasticity is calibrated by the coordination of cellular signaling with intracellular metabolism. Peroxisomes are regulators of lipid metabolism, and emerging discoveries implicate these organelles in both the control of inflammation and macrophage polarization. Herein, we summarize the immunomodulatory functions of macrophage peroxisomes, with a particular focus on the integration of lipid metabolism. Highlighted are the diverse fates of inflammation due to peroxisomal activity and peroxisomal targeting as an emerging concept for regulation of inflammation and inflammatory disorders.
    Keywords:  inflammation; macrophage; peroxisome
    DOI:  https://doi.org/10.1097/IN9.0000000000000092
  35. Cell Death Dis. 2026 Jul 28. pii: 905. [Epub ahead of print]17(1):
    METTL14-mediated m6A methylation orchestrates early NK cell development by maintaining metabolic fitness.
    Huan Ma, Zhenzhen Tu, Surong Deng, Yirong Sun, Shuxin Wang, Hongxia Wang, Chen Cheng, Xiang Li, Zhongjun Dong, Shasha Chen.
      N6-methyladenosine (m6A) represents the most abundant mRNA modification, yet its role in natural killer (NK) cell development remains incompletely understood. Here we demonstrate that the m6A methyltransferase METTL14 plays an indispensable, stage-specific role in early NK cell development. Mettl14 deficiency at the progenitor stage caused severe NK cell lymphopenia by disrupting the NK progenitor to immature NK cell transition. Paradoxically, residual Mettl14-null NK cells exhibited a hypermetabolic state characterized by mTORC1 hyperactivation and enhanced mitochondrial function, which drove both hyperproliferation and activation-induced cell death via p53 and apoptotic pathway activation. Despite developmental defects, these cells demonstrated superior capacity to control melanoma metastasis in vivo. Mechanistically, METTL14 fine-tuned IL-15 responsiveness likely by sustaining SOCS3 expression to restrain JAK-STAT5 signaling. Terminal deletion of Mettl14 produced no phenotype, underscoring its specific requirement during early development. Our findings establish METTL14 as a crucial checkpoint coordinating transcriptional and metabolic programs to ensure NK cell homeostasis.
    DOI:  https://doi.org/10.1038/s41419-026-09069-2
  36. Environ Pollut. 2026 Oct 21. pii: S0269-7491(26)01763-X. [Epub ahead of print] 129393
    Heterogeneous nanoplastic exposure induces integrated immunometabolic transcriptional responses in human monocytes under continuous flow.
    Vladimir Kovacevic, Nevena Milivojević Dimitrijević, Marko Zivanovic, Milos Ivanovic, Andreja Zivic, Marina Gazdic Jankovic, Aleksandra Kovacevic, Uršula Prosenc Zmrzljak, Feđa Puac, Nenad Filipović, Marija Mihailovich, Biljana Ljujic.
      Nanoplastics interact continuously with circulating immune cells, yet how particle size and exposure complexity shape immune transcriptional responses under dynamic exposure conditions remains poorly understood. Here, controlled microfluidic exposure was combined with single-cell RNA sequencing to investigate the effects of size-defined polystyrene nanoplastics (PSNPs; 40 nm, 200 nm, and 40 + 200 nm) on primary human peripheral blood mononuclear cells (PBMCs) under continuous flow conditions. Across immune populations, PSNP exposure induced a conserved ribosome-associated and RNA-regulatory transcriptional program, indicating a shared intracellular transcriptional response. Monocytes displayed particularly prominent transcriptional remodeling, characterized by coordinated modulation of ribosome-associated, metabolic, and inflammatory signaling pathways across exposure conditions. Exposure to 40 nm PSNPs showed negative enrichment of mitochondrial metabolic pathways, whereas 200 nm PSNPs showed enrichment of inflammatory signaling programs. Heterogeneous particle-size exposure induced concurrent metabolic and inflammatory pathway engagement without evidence of major inter-lineage connectivity disruption or discrete inflammatory state transitions. Orthogonal flow cytometry measurements in PBMCs from three donors showed trends towards increased frequencies of IL-6- and TNF-α-positive monocytes following PSNP exposure. In contrast, adaptive immune cells exhibited comparatively modest and lineage-preserving transcriptional modulation. Together, these findings indicate that size-defined PSNP exposure conditions and exposure composition are associated with coordinated immunometabolic transcriptional responses in human immune cells under continuous flow conditions and establish a framework for studying dynamic material-immune interactions at single-cell resolution.
    Keywords:  PBMCs; immunometabolism; microfluidics; monocytes; polystyrene nanoplastics; scRNA-seq
    DOI:  https://doi.org/10.1016/j.envpol.2026.129393
  37. Biol Direct. 2026 Jul 27. pii: 213. [Epub ahead of print]21(1):
    Mitochondrial RNA polymerase is a critical mediator of LPS-induced inflammatory responses and septic shock.
    Jie Qiong Ping, Tao Guo, Shi Wei Zhang, Cheng Kong, Xiang Yu Gao, Hong Peng Li.
      Sepsis, particularly septic shock, is a life-threatening condition driven by a dysregulated inflammatory response. Mitochondria are vital for orchestrating the LPS (lipopolysaccharide)-induced innate immune response. At the core of mitochondrial functionality lies mitochondrial RNA Polymerase (POLRMT). This study delineates POLRMT's functional role and underlying mechanisms in LPS-induced pro-inflammatory responses across various macrophage models and in vivo. Through multiple genetic strategies, including stable shRNA-mediated knockdown and CRISPR/Cas9-mediated ablation, we demonstrated that POLRMT deficiency in THP-1 human macrophages, peripheral blood mononuclear cells (PBMCs), and murine bone marrow-derived macrophages (BMDMs) consistently attenuated LPS-induced transcriptional upregulation and secretion of key pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). Conversely, POLRMT overexpression in THP-1 cells augmented these inflammatory responses. LPS-induced enhancements in mitochondrial Complex I activity and ATP content, alongside NFκB activation, were dependent on POLRMT expression. Genetic perturbation of POLRMT directly correlated with altered mitochondrial function and NFκB activity. Pharmacological inhibition of POLRMT with a specific inhibitor IMT1 also suppressed LPS-induced cytokine production, mitochondrial activation, and NFκB activity in vitro. The in vivo studies revealed that knockdown of POLRMT in CD68-expressing cells protected mice from LPS-induced septic shock, reducing mortality and systemic cytokine levels. Oral administration of IMT1 similarly conferred protection against septic shock, correlating with diminished circulating pro-inflammatory cytokines and reduced NFκB activity in murine PBMCs. Collectively, these findings establish POLRMT as a mediator of LPS-induced inflammatory responses in macrophages/monocytes.
    DOI:  https://doi.org/10.1186/s13062-026-00917-x
  38. Sci Adv. 2026 Oct 23. 12(43): eaef3338
    NAD+ metabolic restoration resolves the inflammation-immunocompetence trade-off in lung graft-versus-host disease.
    Jing Li, Zheng Zhou, Jiaqian Qi, Fan Zhang, Ziyan Zhang, Xueqian Li, Shuhui Jiang, Xiang Li, Luyao Wang, Xiahong Xie, Jinfeng Chen, Kanghua Zeng, Yue Han, Junhong Jiang, Mingzhou Ye.
      Chronic lung graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains difficult to treat, and broad immunosuppression increases infection risk. Single-cell profiling of bronchoalveolar lavage from bronchiolitis obliterans lesions revealed collapse of an epithelial nicotinamide adenine dinucleotide (NAD+) metabolic axis with pathogenic immune-epithelial remodeling, nominating NAD+ restoration as an entry point. Because free NAD+ is poorly cell-permeable and rapidly consumed, we engineered CaNAD+-PGB-LiP (CNAPL), a high-payload NAD+ nanomedicine enabling direct intracellular replenishment. In murine allo-HSCT GVHD, CNAPL improved clinical scores and survival, reduced vascular and epithelial injury, and curtailed hyperinflammation and effector overactivation across GVHD target organs. Unlike immunosuppression, CNAPL preserved phagocytosis, NK/NKT cell (natural killer/natural killer T cell) cytotoxicity, and T cell memory. In posttransplant influenza or Klebsiella infection, CNAPL maintained pathogen control without rekindling GVHD, decoupling inflammation control from infection susceptibility. This metabolism-centered, host-directed strategy restores immune-tissue homeostasis and provides a practical translational path for durable lung GVHD control with preserved antimicrobial defense.
    DOI:  https://doi.org/10.1126/sciadv.aef3338
  39. Sci Adv. 2026 Oct 23. 12(43): eadz0039
    An in situ forming immunomodulatory hydrogel reinvigorates exhausted CD8+ T cells via preserving their mitochondrial fitness.
    Yiming Qi, Jing Li, Ziyan Chen, Chenming Zou, Haichao Zhu, Alice Shen Yi Shan, Yuli Fu, Jingwen Hou, Chaozhu Zheng, Qiongzhe Ren, Yu Qiao, Zhu Jin, Feihu Wang, Shengrong Guo.
      CD8+ T cell exhaustion driven by mitochondrial dysfunction remains a major barrier to effective cancer immunotherapy. Here, we report an in situ forming d-α-tocopheryl polyethylene glycol succinate (TPGS)-based hydrogel [multifunctional thermosensitive composite gel (MTC Gel)] that reinvigorates exhausted CD8+ T cells by preserving mitochondrial fitness through a two-pronged strategy. After intratumoral injection, MTC Gel rapidly undergoes gelation at physiological temperature and dissociates to generate a high local concentration of TPGS, which targets cancer cell mitochondria to trigger prodeath mitophagy. This process induces robust immunogenic cell death (ICD) and blocks tunneling nanotube-mediated mitochondrial hijacking. Meanwhile, NLG919-loaded hybrid nanoparticles released from MTC Gel synergistically restore mitochondrial biogenesis in CD8+ T cells suppressed by indoleamine 2,3-dioxygenase 1. Across multiple murine tumor models, MTC Gel reprograms T cell immunity by reducing CD8+ T cells exhaustion while enhancing effector and cytotoxic functions, thereby eliciting potent tumoricidal activity. These findings highlight this rationally designed hydrogel system as a clinically translatable platform for next-generation ICD-based cancer immunotherapies.
    DOI:  https://doi.org/10.1126/sciadv.adz0039
  40. Mol Biomed. 2026 Oct 19. pii: 216. [Epub ahead of print]7(1):
    Macrophage interferon regulatory factor 7 aggravates the progression of metabolic dysfunction-associated steatohepatitis.
    Xuhao Ni, Qingfa Bu, Yuan Liang, Bozhou Pan, Jian Wang, Qingxiang Xu, Lei Liu, Qi Wang.
      Metabolic dysfunction-associated steatohepatitis (MASH) represents a growing clinical burden with increasing prevalence and lacking approved pharmacological therapies. Interferon regulatory factor 7 (IRF7) is a central mediator of type I interferon-dependent immune responses, yet the precise mechanisms by which macrophage-expressed IRF7 shapes inflammatory and metabolic events during MASH pathogenesis remain incompletely defined. This study aimed to dissect the functional role of IRF7 in MASH development. We assessed IRF7 expression in human and mouse liver specimens, and utilized myeloid-specific Irf7-deficient mice fed with high-fat high-cholesterol diet (HFHCD) or methionine-choline-deficient diet (MCD) to recapitulate MASH pathology. IRF7 was significantly elevated in MASH-affected livers, and myeloid-specific Irf7 deletion markedly mitigated MASH progression. Mechanistically, loss of IRF7 blunted IFN-α and IFN-β production, suppressing macrophage-derived type I interferon-dependent immune cascades. IRF7 directly bound to the promoters of pro-inflammatory Tnfa and Il1b to boost their transcription, and interacted with SMAD3 to activate Tgfb1 transcription. The E3 ubiquitin ligase HUWE1 mediated IRF7 monoubiquitination to enhance its nuclear translocation, driving transcription of pro-inflammatory and pro-fibrotic genes. This molecular cascade aggravated hepatic steatosis and triggered hepatic stellate cell (HSC) activation, accelerating MASH deterioration. Pharmacological IRF7 inhibition effectively counteracted these pathological alterations. Collectively, myeloid IRF7 fuels MASH progression by amplifying macrophage-mediated liver inflammation, suggesting IRF7 as a promising therapeutic target against MASH.
    Keywords:  IRF7; Inflammation; Macrophages; Metabolic dysfunction-associated steatohepatitis
    DOI:  https://doi.org/10.1186/s43556-026-00601-6
  41. PLoS Pathog. 2026 Oct 21. 22(10): e1014692
    Wolbachia outcompetes mosquito-borne viruses by reprogramming host ATPSβ1-driven ATP metabolism toward symbiotic proliferation.
    Hao Yuan, Yalan Zhang, Yaqi Zhao, Chaojun Wang, Yuanyuan Zhou, Qian Ni, Xiaodan Li, Bo Zhang, Yong Wang, Liang Cai, Hong Liu, Jinglin Wang, Juntao Gong, Meichun Zhang, Zhiyong Xi, Xiaoling Pan.
      Wolbachia endosymbionts confer broad-spectrum resistance to mosquito-borne viruses. While the antiviral metabolites in Wolbachia-Aedes have been identified during viral replication, the core metabolic gene underlying this defense across the entire viral infection cycle remains undefined. Here, we demonstrated for the first time that Wolbachia strongly suppressed the emerging alphavirus Venezuelan equine encephalitis virus, extending its known antiviral spectrum. Transcriptomic and functional analyses revealed ATP synthase beta subunit 1 (ATPSβ1) as a key metabolic hub hijacked by both MBV and the symbiont. Without Wolbachia symbiosis, dengue virus and VEEV induced ATPSβ1 to promote viral binding via the viral envelope protein and increased intracellular ATP production for viral replication. Conversely, Wolbachia overrode ATPSβ1-mediated viral binding and redirected ATPSβ1-driven ATP synthesis to fuel its proliferation, strengthening antiviral activity. Pharmacologically, adenosine increased Wolbachia wAlbB density and potently suppressed viral infection in Ae. aegypti and Ae. albopictus cells. Oligomycin reduced intracellular ATP and inhibited viral infection in Wolbachia-free Ae. aegypti cells. Collectively, Wolbachia repurposes dual-functional ATPSβ1, which governs MBV binding and replication, into a potent antiviral effector through a metabolic tug-of-war over host ATP during symbiont-virus competition. Moreover, we highlight interventions targeting the ATPSβ1-driven metabolism as promising strategies to curb MBV transmission.
    DOI:  https://doi.org/10.1371/journal.ppat.1014692
  42. Hlife. 2025 Nov;3(11): 551-564
    Prophylactic and therapeutic itaconate treatment alleviates COVID-19-associated lung injury.
    Yao Jiang, Peida Yang, Bo Yao, Liang Zhang, Man Yang, Yiyi Chen, Lunzhi Yuan, Junyu Chen, Jinhang He, Xing Lei, Feng Chen, Mingxi Yue, Siping Yan, Tong Cheng, Yixin Chen, Quan Yuan, Jun Zhang, Shuhai Lin, Tianying Zhang, Ningshao Xia.
      Itaconate (ITA), an immunomodulatory metabolite with known anti-inflammatory properties, has underexplored therapeutic or prophylactic potential against coronavirus disease 2019 (COVID-19). Using an interanimal transmission golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced acute lung injury, we first assessed ITA changes in dNS1-RBD-vaccinated hamsters via metabolomic profiling. Then, we evaluated prophylactic intranasal (20 mg/kg at 9, 6, and 3 days before SARS-CoV-2 infection) and therapeutic intraperitoneal (100 mg/kg at 6, 24, and 48 hours post-infection) ITA administration, assessed by histopathology, transcriptomic, and metabolomic profiling, followed by multi-omics integration, including gene expression clustering, pathway enrichment, and cytokine/chemokine-metabolites correlation analyses. Public bronchoalveolar lavage fluid (BALF) single-cell RNA-sequencing (scRNA-seq) datasets from COVID-19 patients were re-analyzed to explore macrophage heterogeneity. Intranasal dNS1-RBD vaccine upregulated ITA levels, prompting further exploration of its immunomodulatory role. Both prophylactic and therapeutic ITA treatments significantly mitigated weight loss and improved lung pathology. Correlation analyses implied a potential regulatory crosstalk between fatty acid β-oxidation (FAO) and reduced inflammatory response. Re-analysis of BALF scRNA-seq dataset highlighted transcriptional networks involving PPARG, RARA, BHLHE41, TCF7L2, and ESRRA-genes linked to macrophage self-renewal and metabolic homeostasis, which appeared to be preserved in ITA-treated hamsters. These findings underscore ITA's role in modulating immunometabolic responses, particularly through FAO-driven macrophage reprogramming, to attenuate SARS-CoV-2-induced lung damage. Together, this study provides insights into host-directed therapies targeting metabolic reprogramming to mitigate COVID-19 severity.
    Keywords:  acute lung injury (ALI); coronavirus disease 2019 (COVID-19); itaconate (ITA); macrophage; multiomics
    DOI:  https://doi.org/10.1016/j.hlife.2025.06.006
  43. Cell. 2026 Oct 23. pii: S0092-8674(26)01208-0. [Epub ahead of print]
    Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
    Hannah N Bell, Kavya Nair, Kole Tison, Peng Liao, Hongwei Lei, Marwa O El-Derany, Ayijiang Yisimayi, Haiwei Zhang, Ryan Rebernick, Weichao Wang, Yoshitaka Adachi, Cristina Castillo, Nupur K Das, Jinsu An, Vivien R Sutton, Xun Lin, Heng Lin, Xinghao Wang, Yunfei Li, Linda Vatan, Amr Aboud, Shuang Wei, Miguel Gijon, Samantha Goodwin, Yatrik M Shah, Ilona Kryczek, Joseph A Trapani, Margarida Barroso, Judy Lieberman, Weiping Zou.
      Cytotoxic CD8+ T cells and natural killer cells are critical effectors of anti-tumor immunity. Cytotoxic lymphocytes eliminate tumor cells by releasing perforin (Prf1), a pore-forming protein that enables granzymes (Gzms) to enter target cells and trigger both caspase-dependent and -independent cell death. Here, we uncover a previously unrecognized, Gzm-independent function of Prf1. We find that Prf1 directly induces tumoral ferroptosis, an iron- and lipid-dependent form of cell death. Mechanistically, Prf1-mediated pore formation drives endocytosis of the transferrin receptor, which increases cellular iron uptake. Prf1 promotes the formation of endosomal-mitochondrial contacts, which leads to mitochondrial iron accumulation, mitochondrial dysfunction, and tumor cell ferroptosis. Dietary iron supplementation suppresses tumor progression in murine tumor models in a Prf1-dependent manner. Higher Prf1 expression correlates with improved survival and enhanced response to immune checkpoint blockade in patients with cancer. These findings define a Gzm-independent function of Prf1 as a direct executioner of cancer cell death through ferroptosis.
    Keywords:  NK cell; T cell; ferroptosis; granzyme; immune checkpoint blockade; iron; mitochondria; perforin
    DOI:  https://doi.org/10.1016/j.cell.2026.09.062
  44. MedComm (2020). 2026 Nov;7(11): e71080
    The PIEZO1/CISD1/IP3R Mechanotransduction Axis Drives Macrophage Mitochondrial Dysfunction and Inflammatory Activation in Pulmonary Fibrosis.
    Yungeng Wei, Chao Xie, Xiangsheng Yang, Xiao Xiao Tang.
      Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and elevated tissue stiffness. While aberrant mechanotransduction is increasingly recognized as a key driver of fibrotic progression, the mechanisms by which mechanical cues orchestrate macrophage dysfunction remain poorly elucidated. Here, we identify the mechanosensitive ion channel PIEZO1 as a key mediator coupling matrix stiffening to macrophage inflammatory activation in pulmonary fibrosis. We demonstrate that PIEZO1 is substantially upregulated in fibrotic lungs, and that its activation drives intracellular calcium overload via the CISD1/IP3R signaling axis. This process elicits aberrant opening of the mitochondrial permeability transition pore (MPTP), causing mitochondrial dysfunction and augmented pro-inflammatory macrophage polarization. Conversely, PIEZO1 inhibition suppresses the CISD1/IP3R signaling cascade, alleviates calcium dysregulation, prevents mitochondrial damage, and attenuates inflammatory activation. In vitro CISD1 inhibition ameliorates PIEZO1-driven mitochondrial abnormalities and pro-inflammatory signaling in macrophages. Furthermore, genetic knockdown of CISD1 mitigates mitochondrial abnormalities and attenuates bleomycin (BLM)-induced lung fibrosis in mice. Collectively, these findings identify a previously unrecognized PIEZO1/CISD1/IP3R mechanotransduction axis coupling tissue stiffening to macrophage-mediated inflammation and fibrosis. This study offers mechanistic insights into fibrosis-associated immune dysregulation, highlighting PIEZO1 and CISD1 as promising therapeutic targets for pulmonary fibrosis.
    Keywords:  CISD1; PIEZO1; idiopathic pulmonary fibrosis; macrophage; mitochondria
    DOI:  https://doi.org/10.1002/mco2.71080
  45. Hlife. 2025 Mar;3(3): 121-131
    Neutrophils: Key players in the metabolic syndrome puzzle.
    Hui Ping Yaw, Sapna Devi, Lai Guan Ng.
      Metabolic syndrome (MetS) is a group of metabolic abnormalities associated with an increased risk of getting type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). For many years, MetS has been viewed solely as a metabolic disease. In recent decades, MetS development has been associated with chronic inflammation related to nutrient excess, especially in the adipose tissues (AT). Metabolic stress, arising from the significant metabolic changes in MetS, is known to impact the balance of immune homeostasis. Although multiple immune cells have been investigated in this context, neutrophils, the first responder to inflammation, have only gained increased attention in recent years. Hence, this review aims to summarize the current evidence for the effects of MetS-induced systemic and AT-specific metabolic changes on neutrophils and their functions. We first provide an overview of the metabolic pathways used by neutrophils, with a specific focus on their recently discovered metabolic plasticity. This is followed by a discussion on the impact of MetS-induced alterations on the systemic metabolism and in the AT environment, how these changes may affect neutrophil effector functions, and the main mechanisms involved. Finally, we will examine the roles of neutrophils and their functions in T2DM and CVD that develop due to MetS. We will also provide perspectives on how a deeper understanding of the effects of systemic and site-specific metabolic changes in neutrophils and their effector functions could unlock the therapeutic potential of targeting neutrophils, as the arbiters of innate immunity in the context of MetS.
    Keywords:  adipose tissues; inflammation; metabolic syndrome; neutrophils; tissue reprogramming
    DOI:  https://doi.org/10.1016/j.hlife.2025.01.003
  46. Cell. 2026 Oct 19. pii: S0092-8674(26)01117-7. [Epub ahead of print]
    The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion.
    Eric I Elliott, Tomomi M Yoshida, Susana C B R Nakandakari, Scott Pope, Cuiling Zhang, Timothy Nottoli, Jae Jin Chae, Daniel L Kastner, Richard A Flavell, Vishwa Deep Dixit, Vijay A Rathinam, Fayyaz S Sutterwala, Andrew Wang.
      Red-meat-containing diets are epidemiologically associated with diseases of chronic inflammation, while diets that restrict red meat improve health. Yet, it is uncertain how red meat incites inflammation. Here, we discover that ʟ-carnitine, an amino acid highly concentrated in skeletal muscle myocytes, drives inflammasome activation in lipopolysaccharide (LPS)-challenged mice and LPS-primed murine and human macrophages. We find that extracellular ʟ-carnitine represses mevalonate synthesis, thereby triggering activation of the pyrin inflammasome, downstream of cellular import by the high-affinity ʟ-carnitine transporter OCTN2. We find that the inflammatory response to skeletal muscle injury also requires pyrin and OCTN2. Thus, in summary, we identify macrophages as sentinels of exogenous and endogenous extracellular ʟ-carnitine that serve as a proxy for skeletal myocyte damage, and we open the field to examine the mechanistic basis for how excess dietary intake of carnitine-rich food drives inflammatory disease.
    Keywords:  ASC; MEFV; OCTN2; SLC22A5; caspase-1; inflammasome; interleukin-17a; interleukin-1β; pyrin; rhabdomyolysis; sepsis; ʟ-carnitine
    DOI:  https://doi.org/10.1016/j.cell.2026.09.015
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