bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–09–07
twenty-one papers selected by
Dylan Ryan, University of Cambridge



  1. J Neurochem. 2025 Sep;169(9): e70219
      Polar metabolic profiling, as well as bioenergetic assays, were used to characterize microglial responses to lipopolysaccharide, which induces a pro-inflammatory state, and interleukin-4, which is associated with an anti-inflammatory phenotype. BV2 microglial cells and primary microglia were used for these investigations. Results revealed that lipopolysaccharide-treated microglia exhibited an increased aerobic glycolytic activity measured by extracellular flux analysis, accompanied by increased levels of endogenous itaconate, a metabolite produced by the IRG1 enzyme. Increased itaconate levels observed by LC-HRMS were found to be associated with a stabilization of the NF2L2/NRF2 transcription factor. Attenuation of the Acod1 gene leads to increased pro-inflammatory cytokine production, as measured by ELISA, while having no effect on LPS-induced oxidative stress or neurotoxicity, an effect only observed upon silencing Nfe2l2. This suggests that an IRG1/itaconate/NRF2 axis functions as a feedback mechanism. The study underscores the dual role of metabolic reprogramming in microglial activation, balancing inflammation and neuroprotection, and suggests potential therapeutic targets for neuroinflammatory diseases by modulating itaconate and NF2L2/NRF2-related pathways. This work highlights the complexity and therapeutic potential of targeting microglial metabolism in CNS disorders.
    Keywords:  IRG1/ACOD1; NF2L2/NRF2; central nervous system; immune activation; itaconate; metabolic reprogramming; microglia; neuroinflammation
    DOI:  https://doi.org/10.1111/jnc.70219
  2. Cell Metab. 2025 Aug 22. pii: S1550-4131(25)00357-2. [Epub ahead of print]
      Inflammation and its metabolic-network interactions generate novel regulatory molecules with translational implications. Here, we identify the immunometabolic crosstalk that generates homocysitaconate, a metabolite formed by homocysteine and itaconate adduction catalyzed by S-adenosyl-L-homocysteine hydrolase (AHCY). Homocysitaconate increases 152-fold during inflammation and exhibits anti-inflammatory effects. Mechanistically, homocysitaconate binds to the D312 residue of the pro-inflammatory protein methionyl-tRNA synthetase (MARS), inhibiting its function and reshaping methionine metabolism to feedback-brake the early activation of the N-homocysteinylation pathway. This metabolic switch facilitates NLR family pyrin domain-containing 3 (NLRP3) ubiquitination to control inflammation. Homocysitaconate demonstrates therapeutic effects in sepsis, high-fat-diet-induced inflammation, and colitis models. Boosting endogenous homocysitaconate synthesis through nicotinamide adenine dinucleotide (NAD+)-dependent AHCY activation (using nicotinamide riboside and pyruvate) also inhibits inflammation by targeting the MARS/NLRP3-N-homocysteinylation cascade. This study establishes homocysitaconate as an anti-inflammatory metabolite that serves as a homeostatic governor by reprogramming protein modification switches, introducing both metabolic timing regulation and clinical strategies to manage inflammatory complications.
    Keywords:  AHCY; Hci; Hcy; MARS1; N-Hcy; N-homocysteinylation; NAD+; NLR family pyrin domain-containing 3; NLRP3; S-adenosyl-L-homocysteine hydrolase; homocysitaconate; homocysteine; itaconate; methionyl-tRNA synthetase; nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.1016/j.cmet.2025.08.001
  3. Eur J Immunol. 2025 Jul;55(7): e51260
      Regulatory FOXP3+ T cells (Tregs) have been characterized with unique metabolic demands, preferentially relying on fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). Several studies have indicated that Treg mitochondrial fitness is crucial for maintaining their stability and suppressive activity with an emphasis on complex-III of the electron transport chain (ETC). Dysfunctional Tregs isolated from patients with autoimmunity like multiple sclerosis (MS) show diminished mitochondrial respiration and the induction of a T helper (Th)1-like phenotype, characterized by increased production of interferon (IFN)-γ. Teriflunomide reduces the proliferation of activated T and B lymphocytes by inhibition of de novo pyrimidine synthesis, providing therapy for patients with autoimmune diseases. Recent data demonstrated that teriflunomide further inhibited complex-III activity in line with hampered mitochondrial respiration in T cells. Considering the essential role of OXPHOS and complex-III activity for Tregs, we therefore thought to investigate with this study the effects of teriflunomide on immunometabolism and function in human Tregs. Interestingly, teriflunomide impaired the mitochondrial function of human Tregs and further induced a Th1-like phenotype in line with defective suppressive activity. Our findings suggest that teriflunomide may potentially exert distinct effects on pro- versus anti-inflammatory T cell subsets, indicating the need for further detailed evaluation.
    Keywords:  autoimmunity; immunometabolism; multiple sclerosis; regulatory T cells; teriflunomide
    DOI:  https://doi.org/10.1002/eji.202451260
  4. J Vis Exp. 2025 Aug 15.
      Upon antigen stimulation, naïve T cells undergo rapid proliferation and expansion to effector T cells. Metabolism plays an important role in the generation of biomass needed for these rapidly proliferating cells and for the generation of molecules required for effector T cell differentiation and function, which influence the outcome of the adaptive immune response in infection or cancers. Naïve T cells reprogram their metabolism upon antigenic stimulation to increase the generation of ATP, which is required to support their growth, biosynthesis, and effector functions. ATP can be generated in a cell either by the mitochondrial-oxidative phosphorylation (OXPHOS) pathway or by the glycolytic pathway. Because most of the ATP generated in a dividing, growing cell is used up for the synthesis of proteins, protein synthesis has been used as a surrogate for ATP levels. Protein synthesis can be measured by the incorporation of puromycin, which mimics the 3' adenosine of a tRNA charged with a modified tyrosine and leads to spontaneous termination of protein translation. Metabolic inhibitors like 2-deoxyglucose (2DG), which blocks the glycolytic pathway, and Oligomycin (O), which blocks complex 5 of the electron transport chain (ETC), can be used to study the dependencies of cellular ATP generation on these two pathways in conjunction with evaluation of protein synthesis in a method called SCENITH. We describe here a variation of this method that detects puromycin incorporation by flow cytometry using chemistry. This method of studying metabolism is relatively easy and can be used for evaluating rare cell populations, as well as patient samples, by flow cytometry.
    DOI:  https://doi.org/10.3791/67377
  5. J Cell Sci. 2025 Sep 01. pii: jcs.264376. [Epub ahead of print]
      Histone deacetylase 7 (HDAC7) drives several immunometabolism-related processes in macrophages including lipopolysaccharide (LPS)-inducible glycolysis and inflammatory mediator production. Using an advanced biotin ligase TurboID system in human macrophages, we report 104 candidate HDAC7 interaction partners that may contribute to its immunometabolic functions. One such protein is the mitochondrial fission-promoting GTPase dynamin-related protein 1 (DRP1), which associates with HDAC7 in cells. Using gain- and loss-of-function genetic approaches, we show that HDAC7 promotes LPS-inducible mitochondrial fission in macrophages, as well as DRP1-dependent metabolic and inflammatory responses. HDAC7 enzymatic activity was dispensable for LPS-inducible fission, as previously reported for LPS-inducible glycolysis. However, a pharmacological inhibitor of HDAC7 attenuated fission in primary human and mouse macrophages, implicating its acetyl-lysine docking function in this response. HDAC7 thus drives inducible mitochondrial fission in macrophages. Small molecules targeting the acetyl-lysine docking function of HDAC7 may have applications in preventing pathological processes driven by dysregulated mitochondrial fission.
    Keywords:  Dynamin-related protein 1; Glycolysis; Histone deacetylase; Immunometabolism; Lysine deacetylase; Macrophages; Mitochondrial dynamics; Mitochondrial fission; Post-translational modification; Toll-like receptor
    DOI:  https://doi.org/10.1242/jcs.264376
  6. J Biol Chem. 2025 Aug 30. pii: S0021-9258(25)02510-4. [Epub ahead of print] 110658
      Dysregulation of macrophage-mediated inflammatory responses is central to sepsis pathogenesis, making its modulation crucial for reducing organ damage and mortality. This study reveals that the key serine synthesis enzyme phosphoglycerate dehydrogenase (PHGDH), known for regulating tumor and immune cell functions, is significantly downregulated in mouse macrophages following LPS stimulation, as well as in patients with systemic inflammatory response syndrome (SIRS) or sepsis. PHGDH knockdown enhances inflammatory responses to LPS and E. coli in vitro, while myeloid PHGDH knockout exacerbates inflammation and organ damage in septic mouse models. In contrast, deficiency in serine and its derivative glycine inhibits LPS-induced macrophage inflammation both in vitro and in vivo. Mechanistically, PHGDH interacts with TAK1, inhibiting TAK1 binding to TAB1, thereby suppressing the TAK1-NF-κB/MAPK signaling pathway. Furthermore, AAV-mediated PHGDH overexpression in lung macrophages reduces sepsis-related inflammation and damage, highlighting PHGDH's non-metabolic role in regulating macrophage-mediated inflammation and suggesting new therapeutic strategies for sepsis treatment.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110658
  7. Virulence. 2025 Dec;16(1): 2554302
      Viral particles and proteins released during infection profoundly reshape the cellular microenvironment by disrupting host signaling, triggering inflammation, and modulating immune responses. Glucose metabolism, a critical hub for energy production and biosynthesis, is highly susceptible to viral reprogramming. This review summarizes recent findings showing that diverse viruses, including influenza virus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and enteroviruses, manipulate glucose metabolic pathways to promote replication and evade immune surveillance. Specifically, viruses modulate glycolytic flux, alter the activity of key metabolic enzymes such as hexokinase (HK) and pyruvate kinase, and interfere with signaling networks like PI3K/Akt/mTOR and AMPK. These metabolic alterations further impact the immune landscape by regulating cytokine production, immune cell activation, and antiviral responses. Our analysis highlights a bidirectional interaction: while viruses hijack host glucose metabolism to favor their survival, metabolic changes also generate host-derived antiviral responses. This review highlights the bidirectional crosstalk between metabolic remodeling and microenvironmental changes during viral infection, underscoring the potential of metabolism-based antiviral strategies. A deeper understanding of these mechanisms may inform the development of more effective and targeted interventions against viral diseases.
    Keywords:  Glucose metabolism; cellular microenvironment; immune response; metabolic reprogramming; viral infection
    DOI:  https://doi.org/10.1080/21505594.2025.2554302
  8. Sci Adv. 2025 Aug 29. 11(35): eadu6271
      Dendritic cells (DCs) hijacked by intracellular bacteria contribute to pathogen dissemination and immunopathology. How bacteria achieve DC subversion remains largely unknown. Here, we describe the mechanism used by tularemia agent Francisella tularensis exploiting host mitochondrial anaplerosis. Shortly after internalization, Francisella associates with DC mitochondria, which leads to the rapid repurposing of their oxidative metabolism for production of mitochondrial reactive oxygen species (mtROS). Mitochondrial metabolic rewiring is orchestrated by the intramitochondrial signaling mediated by protein acetylation and involves switching to glutamate as the primary substrate for DC tricarboxylic acid cycle. Rather than killing the bacterium, glutamate-fueled mtROS production activates p38-dependent proinflammatory gene expression. Blocking of glutamate utilization prevents DC activation and bacterial dissemination and alleviates inflammation in vivo. Our findings underscore the importance of metabolic plasticity in antibacterial DC response and open up potential avenues for therapies targeting host metabolism.
    DOI:  https://doi.org/10.1126/sciadv.adu6271
  9. Eur Heart J Open. 2025 Jul;5(4): oeaf068
       Aims: Calcific aortic valve disease is the most common valvular heart disease characterized by an inflammatory response in the leaflets followed by fibro-calcific remodelling of valvular interstitial cells (VICs). Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for CAVD, however the role of metabolism in driving Lp(a)-induced inflammation remains largely elusive. Therefore, we aim to investigate the role of Lp(a) in driving inflammatory and metabolic changes in VICs and examine how alterations in cellular metabolism can alter their inflammatory phenotype.
    Methods and results: Inflammatory activity in the aortic valve of patients with mild to severe aortic stenosis with elevated Lp(a) levels (>50 mg/dL) is increased, as reflected by increased 18F-FDG uptake in the aortic valve, compared with those with low Lp(a) levels (<50 mg/dL) with a maximal TBR of 1.60 ± 0.20 vs. 1.43 ± 0.16 (P < 0.002). RNA-seq analysis of VICs stimulated with a physiological relevant concentration Lp(a) revealed that Lp(a)-induced inflammation in vitro initially occurs in an NF-κB-dependent manner, but switches to glycolysis driven inflammation after long-term exposure. Glucose uptake, lactate secretion and maximal glycolytic capacity were increased by Lp(a) via the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), while inhibition of PFKFB3 results in a 50% reduction of Lp(a)-induced cytokine gene expression and secretion.
    Conclusion: Lipoprotein(a)-induced PFKFB3-mediated glycolysis in VICs sustains NF-κB-dependent inflammatory response. These insights into the inflammation-metabolic axis may offer a more refined approach to decrease valvular inflammation.
    Keywords:  CAVD; Glycolysis; Inflammation; Lp(a); PFKFB3
    DOI:  https://doi.org/10.1093/ehjopen/oeaf068
  10. J Transl Autoimmun. 2025 Dec;11 100310
       Objective: In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) alter their metabolism to support their activation. We aimed to analyse the full spectrum of metabolic alterations associated with RA by performing untargeted metabolomics in RA FLS vs. non-inflamed (NI) FLS.
    Methods: Untargeted annotated metabolomics was performed using mass spectrometry on ten primary RA and seven NI FLS culture extracts and 220 serum samples from participants with early RA from the randomised controlled NORD-STAR trial. Carnitine-related proteins were measured with Western blot. FLS bioenergetic profile was assessed with a Seahorse flux analyser.
    Results: Metabolomics analysis based on 138 annotated metabolites revealed a distinct metabolic fingerprint between RA and NI FLS. Of the 12 metabolites enriched in RA FLS, 11 were acylcarnitines. Pro-inflammatory stimulation of NI FLS also led to acylcarnitine accumulation. RA FLS exhibited lower levels of CD36, a fatty acid transporter, but similar levels of L-carnitine transporter, and carnitine palmitoyltransferase 1 A and 2 compared to NI FLS. Seahorse analyses showed no difference in fatty acid oxidation between RA and NI FLS; however, RA FLS displayed mitochondrial dysfunction and energetic impairment. Serum acylcarnitine content decreased after 24 weeks of treatment with methotrexate combined with abatacept or tocilizumab in patients with early RA achieving remission.
    Conclusion: Acylcarnitine accumulation is a characteristic of RA FLS metabolic fingerprint and could be linked to mitochondrial dysfunction. In patients with early RA, acylcarnitine content in serum decreases after successful anti-rheumatic treatment. These results indicate a dysregulation in acylcarnitine metabolism in RA at the joint level and systemically.
    Keywords:  Acylcarnitines; Fibroblast-like synoviocytes; Metabolomics; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.jtauto.2025.100310
  11. mBio. 2025 Sep 03. e0168025
      Sepsis, caused by an unbalanced host response to infection, remains a global health burden. The dysregulation between pro-inflammatory and anti-inflammatory responses is a primary driver of immune imbalance. As a central player in adaptive immunity, CD4+ T cells are crucial for maintaining this balance during sepsis by differentiating into various effector T cell subsets. Thus, elucidating the underlying mechanisms within the inflammatory and anti-inflammatory imbalance in CD4+ T cell subsets during sepsis is of great value. We first identified the proviral integration site for Moloney murine leukemia virus 1 (PIM1) as a significantly upregulated gene in CD4+ T cells from sepsis patients by conducting a comprehensive transcriptome meta-analysis. The expression of PIM1 was significantly elevated on CD4+ T cells from sepsis patients and was correlated with both SOFA and APACHE II scores. Moreover, we found that PIM1 promoted the differentiation of CD4+IFN-γ+ Th1 and CD4+IL-17A+ Th17 subsets while inhibiting the differentiation of CD25+FoxP3+ Tregs. Additionally, upon inhibiting PIM1 kinase activity in CD4+ T cells, RNA sequencing analysis revealed that the cholesterol metabolism gene, ATP-binding cassette transporter G1 (ABCG1), exhibited significant upregulation. More importantly, we found that the intracellular cholesterol content was decreased in CD4+ T cells after inhibiting the PIM1 kinase activity or knocking down PIM1. The portion of CD4+IFN-γ+ Th1 and CD4+IL-17A+ Th17 cells was recovered, and the CD4+CD25+FoxP3+ Tregs decreased after cholesterol supplementation to CD4+ T cells. These findings indicated that PIM1 may regulate the balance of Th1, Th17, and Treg subsets in a cholesterol-dependent manner in sepsis.IMPORTANCEThis study aims to elucidate the mechanism of the inflammatory and anti-inflammatory imbalance of CD4+ T cell subsets during sepsis. Our study provides evidence that PIM1 serves as a crucial regulator of sepsis-induced inflammation and elucidates that PIM1 participates in regulating the imbalance of Th1, Th17, and Treg subsets, further promoting inflammatory and anti-inflammatory imbalance in sepsis. Additionally, the cholesterol metabolism, potentially mediated by ABCG1, is implicated in PIM1's regulatory effect on the Th1, Th17, and Treg imbalance. Our study provides novel insights into the inflammatory imbalance during sepsis, which could facilitate the development of therapeutic strategies aimed at modulating the immune-inflammatory cascade in this condition.
    Keywords:  CD4+ T cell; PIM1; cholesterol metabolism; inflammation; sepsis
    DOI:  https://doi.org/10.1128/mbio.01680-25
  12. Endocrinology. 2025 Aug 28. pii: bqaf131. [Epub ahead of print]
      The importance of immunometabolism in the development of metabolic diseases is clear. Yet, how certain metabolic disorders, such as insulin deficiency (ID), influence immune cell function, and vice versa, is poorly understood. Also, therapeutic strategies to harness the interplay between immune cells and metabolism are lacking. Here, we observe that ID rearranges the immune landscape of the liver, causing a decrease of T cells and an increase of the Kupffer cells, accompanied by a shift in the transcriptional signature and polarization of the latter. Treating ID mice with the protein S100A9 rescues the polarization and lipid-related changes caused by ID in the Kupffer cells, and, through them, rescues hypertriglyceridemia and hyperketonemia in a TLR4-dependent manner. Additionally, S100A9 acts on other immune niches to increase glucose uptake in skeletal muscle, improving hyperglycemia. In summary, our findings pinpoint the S100A9-TLR4 axis as a new tool to harness immune cells for improving ID-related metabolic dysfunction.
    Keywords:  Diabetes; Immunometabolism; Kupffer cell; S100A9; Skeletal Muscle; TLR4
    DOI:  https://doi.org/10.1210/endocr/bqaf131
  13. Mol Metab. 2025 Aug 29. pii: S2212-8778(25)00148-6. [Epub ahead of print] 102241
      Some individuals exhibit metabolically healthy obesity, characterized by the expansion of white adipose tissue (WAT) without associated complications. The monoacylglycerol (MAG) hydrolase α/β-hydrolase domain-containing 6 (ABHD6) has been implicated in energy metabolism, with its global deletion conferring protection against obesity. However, the immunometabolic roles of adipocyte ABHD6 in WAT remodeling in response to nutri-stress and obesity are not known. Here, we demonstrate that in insulin resistant women, ABHD6 mRNA expression is elevated in visceral fat and positively correlates with obesity and metabolic dysregulation. ABHD6 expression is also elevated in the WATs of diet-induced obese and db/db mice. Although adipocyte-specific ABHD6 knockout (AA-KO) mice become obese under high-fat diet, they show higher plasma adiponectin, reduced circulating insulin and inflammatory markers, improved insulin sensitivity, and lower plasma and liver triglycerides. They also show enhanced insulin action in various tissues, but normal glucose tolerance. In addition, AA-KO mice display healthier and less inflamed expansion of visceral fat, with smaller adipocytes and higher stimulated lipolysis and fatty acid oxidation levels. Similar but less prominent phenotype was found in the subcutaneous and brown fat depots. Thus, adipocyte ABHD6 suppression prevents most of the metabolic and inflammatory complications of obesity, but not obesity per se. Mechanistically, this beneficial process involves a rise in MAG levels in mature adipocytes, and their secretion, resulting in a crosstalk among adipocytes, preadipocytes and macrophages in the adipose microenvironment. Elevated intracellular MAG causes PPARs activation in adipocytes, and MAG secreted from adipocytes curtails the inflammatory polarization of macrophages and promotes preadipocyte differentiation. Hence, adipocyte ABHD6 and MAG hydrolysis contribute to unhealthy WAT remodeling and expansion in obesity, and its suppression represents a candidate strategy to uncouple obesity from many of its immunometabolic complications.
    Keywords:  Adipose tissue; Inflammation; Insulin signaling; Macrophages; Monoacylglycerol; Obesity; PPARs; α/β-hydrolase domain-containing 6
    DOI:  https://doi.org/10.1016/j.molmet.2025.102241
  14. EMBO Rep. 2025 Aug 29.
      Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.
    Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing
    DOI:  https://doi.org/10.1038/s44319-025-00536-z
  15. Sci Immunol. 2025 Sep 05. 10(111): eadv4810
      RNA modifications regulate phenotype and function of macrophages by regulating RNA translation, splicing, and stability. However, the role of N7-methylguanosine (m7G) modification in macrophages and inflammation remains unexplored. In this study, we observed elevated levels of the methyltransferase METTL1 and m7G modifications in macrophages from mouse and human tissues during acute kidney injury (AKI). METTL1 deficiency in myeloid cells mitigated multiorgan inflammation induced by cecal ligation and puncture and renal ischemia/reperfusion. Genetic deletion of METTL1 inhibited macrophage proinflammatory responses. We identified internal Sarm1 messenger RNA (mRNA) as a target of m7G modification that controls macrophage metabolic reprogramming. METTL1 deficiency in macrophages inhibited metabolic reprogramming, which was reversed by SARM1 overexpression that induced NAD+ decline. Pharmacologically, SA91-0178, a specific METTL1 inhibitor, effectively alleviated tissue injury during septic inflammation. Collectively, our findings suggest that m7G modification enhances the stability of Sarm1 mRNA, thereby resulting in NAD+ imbalance in macrophages, indicating that METTL1 may serve as a potential therapeutic target for systemic inflammation.
    DOI:  https://doi.org/10.1126/sciimmunol.adv4810
  16. J Infect Dis. 2025 Aug 30. pii: jiaf456. [Epub ahead of print]
      Mycobacterium tuberculosis (MTB) remains a major cause of global mortality, yet natural immunity prevents disease in more than 90% of exposed individuals. Interferon gamma (IFN-γ) is a critical regulator of innate immunity and enhances macrophage antimicrobial responses. In this study, we investigated how IFN-γ timing influences macrophage control of MTB. We found that pre-infection IFN-γ exposure primes macrophages for enhanced bacterial control by activating key antimicrobial pathways, whereas post-infection exposure fails to confer this benefit. Using unbiased in vitro systems approaches, we identified c-Myc signaling as a central determinant of macrophage antimycobacterial function. To manipulate c-Myc in primary cells, we developed a tetracycline-inducible lentiviral system for c-Myc inhibition and overexpression. c-Myc inhibition via Omomyc enhanced macrophage bacterial control through mTORC1-dependent metabolic reprogramming and nitric oxide production. In vivo analyses, including murine models and human clinical histopathology, revealed strong associations between c-Myc expression, MTB persistence, and active tuberculosis, implicating c-Myc as a mediator of immune privilege in MTB infection and a promising target for host-directed therapies to enhance macrophage function.
    Keywords:  IFN-γ; Mycobacterium tuberculosis; Omomyc; c-Myc; granuloma; macrophage activation; metabolic reprogramming; tuberculosis
    DOI:  https://doi.org/10.1093/infdis/jiaf456
  17. Nat Commun. 2025 Aug 30. 16(1): 8123
      Microautophagy is an intracellular degradation process in which degradatory organelles, such as the lysosome, directly take up substrates by invagination and/or protrusion of their membranes. Here, we provide evidence that Rab32-positive, lysosome-related organelles in macrophages incorporate various other organelles, including endosomes and mitochondria. Our data indicates that, upon exposure to a mitochondria-damaging reagent, mitochondria can be directly engulfed by the lysosome-like organelles independently of macroautophagy or ESCRT machinery. Rab32 GTPase, phosphatidylinositol 3,5-bisphosphates, ubiquitination, and p62/SQSTM1 are crucial for this degradation. Furthermore, the degree of M1 polarization of macrophages, which is facilitated by metabolic reprogramming into increased glycolysis via mitochondrial elimination, is significantly reduced in Rab32/38 double-knockout macrophages. Thus, microautophagy plays a role in the physiological regulation of macrophages.
    DOI:  https://doi.org/10.1038/s41467-025-63531-x
  18. Biochem J. 2025 Aug 28. pii: BCJ20253132. [Epub ahead of print]482(17):
      Pseudomonas aeruginosa PA01 is one of the major causes of disease persistence and mortality in patients with lung pathologies, relying on various host metabolites as carbon and energy sources for growth. The ict-ich-ccl operon (pa0878, pa0882 and pa0883) in PAO1 is required for growth on the host molecule itaconate, a C5-dicarboxylate. However, it is not known how itaconate is taken up into P. aeruginosa. Here, we demonstrate that a genetically linked tripartite ATP-independent periplasmic (TRAP) transporter (pa0884-pa0886), which is homologous to the known C4-dicarboxylate-binding TRAP system, is essential for growth on itaconate, but not for the closely related C4-dicarboxylate succinate. Using tryptophan fluorescence spectroscopy, we demonstrate that the substrate-binding protein (SBP), IctP (PA0884), binds itaconate but still retains higher affinity for the related C4-dicarboxylates. The structures of IctP bound to itaconate (1.80 Å) and succinate (1.75 Å) revealed an enclosed ligand-binding pocket with ion pairing interactions with the ligand carboxylates. The C2 methylene group that is the distinguishing feature of itaconate compared with succinate is accommodated by a unique change in the IctP-binding site from a Leu to Val, which distinguishes it from closely related C4-dicarboxylate-binding SBPs. Together, these data suggest that this transporter, which we name IctPQM, has duplicated from a canonical C4-dicarboxylate transporter, and its evolution towards itaconate specificity enables this pathogen to now access a key metabolite for persistence in the host.
    Keywords:   Pseudomonas aeruginosa ; Gram-negative bacteria; protein structure; structural biology; transport
    DOI:  https://doi.org/10.1042/BCJ20253132
  19. J Trauma Acute Care Surg. 2025 Aug 28.
       BACKGROUND: The destruction of mitochondrial function during sepsis-induced acute lung injury can lead to tissue cell damage and organ dysfunction. Citrate synthase (CS) may maintain cellular energy metabolism by enhancing the mitochondrial tricarboxylic acid (TCA) in pulmonary macrophages.
    METHODS: Seventy-six healthy donors and 89 sepsis patients were included. The levels of CS were determined using Enzyme-Linked Immunosorbnent Assay. We established a cecal ligation and puncture (CLP) model of sepsis to evaluate the effects of CS on lung injury by pulmonary macrophages-specific CS knockdown or CS inhibitors. Isolated mouse pulmonary macrophages were stimulated with LPS to observe the impact of CS overexpression and knockdown on TCA cycle.
    RESULTS: In sepsis patients, CS was expressed at low levels and positively correlates with lung function parameters. In sepsis mice, siCS or inhibiting its expression exacerbated lung injury and oxidative stress. In pulmonary macrophages, inhibiting CS expression affected TCA cycle and worsened cell apoptosis, while overexpressing CS promoted TCA cycle, alleviating cell apoptosis and reducing oxidative stress levels. The supplementation of citric acid (a downstream metabolite of CS) helped alleviate mitochondrial damage and promotes the TCA cycle.
    CONCLUSION: These results suggested that targeting CS may be a promising therapeutic approach for treating sepsis.
    LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.
    Keywords:  Citrate synthase; macrophages; mitochondrion; sepsis; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1097/TA.0000000000004771
  20. Angew Chem Int Ed Engl. 2025 Sep 01. e202507476
      The therapeutic efficacy of adoptive cell therapy is highly dependent on the status and function of the infused cells. However, insufficient nutrient availability within the immunosuppressive tumor microenvironment (TME) often impedes these cells from fully exerting their cytotoxic potential against solid tumors. Here, we present a strategy of integrating adoptively transferred macrophages with intracellular nutrient depots composed of L-arginine-based nanomicelles to provide a sustainable supply of essential metabolite and optimize the cellular activity in the nutrient-deprived TME. Also, the nanomicelles were coated with bacterial outer membrane vesicles to endow them with immunomodulatory capability, which could activate macrophages toward anti-tumor phenotypes and resist immune suppression. We showed that our approach significantly strengthened the tumor-killing potential of macrophages, induced robust immune responses, and effectively inhibited solid tumor growth compared to the administration of an equal dose of macrophages without immunometabolic modulation. This work provides a method for orchestrating the behavior of transferred cells in vivo, offering a promising strategy to better unleash the potential of adoptive cell therapies against solid tumors.
    Keywords:  Immunotherapy; L‐arginine; Macrophages; Metabolism; Nanomicelles
    DOI:  https://doi.org/10.1002/anie.202507476
  21. Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2512385122
      Glucose metabolism impacts the innate immune response against viral infection. However, the key enzymes or the natural products and mechanisms involved are not well elucidated. Here, we found that arrestin domain containing 4 (ARRDC4), a critical regulator of glucose metabolism, senses influenza A virus (IAV) infection by interacting with viral PA protein. Upregulated ARRDC4 increases the enzymatic activity of phosphofructokinase, muscle type (PFKM) via binding its His298 site to promote the production of the metabolite fructose-1,6-bisphosphate (FBP). Consequently, FBP inhibits the K48-linked ubiquitination degradation of HSP90β, subsequently enhances its interaction with IKKβ and IKKε, and enhances NF-κB- and IRF7-mediated antiviral innate immunity, respectively. Importantly, FBP supplementation enhanced IFN-β-mediated antiviral innate immunity in vitro and in vivo. Our findings highlight a unique immunometabolic regulatory mechanism in which ARRDC4 senses IAV infection and regulates antiviral innate immunity through the PFKM-FBP metabolic axis and provide a strategy for manipulating FBP-related metabolism to treat viral infection.
    Keywords:  ARRDC4; fructose-1,6-bisphosphate; influenza; innate immunity; viral replication
    DOI:  https://doi.org/10.1073/pnas.2512385122