bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–08–03
twenty-six papers selected by
Fawaz Alzaïd, Sorbonne Université



  1. Nature. 2025 Jul 25.
      
    Keywords:  Ageing; Medical research; Proteomics
    DOI:  https://doi.org/10.1038/d41586-025-02333-z
  2. Nat Commun. 2025 Jul 31. 16(1): 7017
      Gene editing technologies have revolutionized therapies for numerous genetic diseases. However, in vivo gene editing hinges on identifying efficient delivery vehicles for editing in targeted cell types, a significant hurdle in fully realizing its therapeutic potential. A model system to rapidly evaluate systemic gene editing would advance the field. Here, we develop the GFP-on reporter mouse, which harbors a nonsense mutation in a genomic EGFP sequence correctable by adenine base editor (ABE) among other genome editors. The GFP-on system was validated using single and dual adeno-associated virus (AAV9) encoding ABE8e and sgRNA. Intravenous administration of AAV9-ABE8e-sgRNA into adult GFP-on mice results in EGFP expression consistent with the tropism of AAV9. Intrahepatic delivery of AAV9-ABE8e-sgRNA into GFP-on fetal mice restores EGFP expression in AAV9-targeted organs lasting at least six months post-treatment. The GFP-on model provides an ideal platform for high-throughput evaluation of emerging gene editing tools and delivery modalities.
    DOI:  https://doi.org/10.1038/s41467-025-61449-y
  3. Cell Metab. 2025 Jul 23. pii: S1550-4131(25)00328-6. [Epub ahead of print]
      L-lactate participates in metabolism, including the Cori cycle, but less is known about D-lactate. We found that circulating D-lactate was higher in humans and mice with obesity. D-lactate increased hepatic glycogen, triglycerides, and blood glucose more than equimolar L-lactate in mice. Stable isotope analyses showed that D-lactate is metabolized in mice and in hepatocytes to pyruvate, TCA intermediates, lipids, and glucose. The gut microbiota is the main source of blood D-lactate. Colonization of mice with a bacterial strain that produced D-lactate elevated blood glucose more than an L-lactate producer. Oral delivery of a biocompatible polymer that traps gut D-lactate, forcing fecal excretion, lowered blood glucose and insulin resistance in obese mice in a polymer length- and dose-dependent manner. This D-lactate trap lowered hepatic inflammation and fibrosis in mice with metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH). Therefore, microbial-derived D-lactate contributes to host glucose and lipid metabolism and can be trapped to improve metabolic disease during obesity.
    Keywords:  diabetes; fibrosis; gut; inflammation; liver; metabolic dysfunction-associated steatotic liver disease; microbiome; obesity; polymer; postbiotics
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.001
  4. Nat Commun. 2025 Jul 31. 16(1): 7035
      Immune checkpoint blockade (ICB) therapies for solid tumors often fail due to resistance, necessitating new strategies. While efforts target IFNγ signaling or antigen presentation, other immune evasion mechanisms are unclear. Here, we identify Monoacylglycerol O-Acyltransferase 1 (Mogat1) as a critical modulator of tumor immune evasion using an in vivo transcriptomic screen in progressing tumors. We find that tumors exploit Mogat1 to sequester fatty acids into triglycerides, a metabolic adaptation that fuels growth and fosters an immunosuppressive microenvironment, enabling immune escape. Genetic inhibition of Mogat1 suppresses tumor growth by promoting T-cell infiltration and enhancing their tumor-killing ability. Importantly, Mogat1 loss sensitizes tumors to PD-1 blockade, overcoming resistance and suggesting reduced reliance on conventional antigen presentation. Our findings reveal a lipid metabolism-centered immune evasion mechanism and highlight Mogat1 as a potential target to improve cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-62134-w
  5. Nature. 2025 Aug 01.
      
    Keywords:  HIV infections; Infection; Vaccines
    DOI:  https://doi.org/10.1038/d41586-025-02439-4
  6. Nat Metab. 2025 Jul 25.
      Obesity increases the risk of many cancers and impairs the anti-tumour immune response. However, little is known about whether the source or composition of dietary fat affects tumour growth or anti-tumour immunity in obesity. Here, we show that high-fat diets (HFDs) derived from lard, beef tallow or butter accelerate tumour growth in a syngeneic model of melanoma, but HFDs based on coconut oil, palm oil or olive oil do not, despite equivalent obesity. Using butter-based and palm oil-based HFDs as examples, we find that these dietary fat sources differentially regulate natural killer and CD8 T cell infiltration and function within the tumour microenvironment, governed by distinct effects on the plasma metabolome and intracellular metabolism. We identify diet-related lipid intermediates, namely long-chain acylcarnitine species, as immunosuppressive metabolites enriched in mice fed butter compared to palm oil HFD. Together, these results highlight the significance of diet in maintaining a healthy immune system and suggest that modifying dietary fat may improve cancer outcomes in obesity.
    DOI:  https://doi.org/10.1038/s42255-025-01330-w
  7. Nature. 2025 Jul 29.
      
    Keywords:  Cell biology; Microscopy
    DOI:  https://doi.org/10.1038/d41586-025-02376-2
  8. Immunity. 2025 Jul 22. pii: S1074-7613(25)00313-9. [Epub ahead of print]
      Free-living mammals carry complex microbiota that co-evolved with their hosts over eons of years. The transfer of such microbiota from wild mice to genetically tractable laboratory mice has been shown to enhance modeling of human immune responses in preclinical studies. Here, we assessed the long-term stability of microbiota and immune phenotype of the first C57BL/6 mouse colony with natural microbiota (wildling mice). The bacterial gut microbiota of wildling mice maintained its increased α-diversity and richness over 5 years, with significantly greater stability than the gut microbiota of laboratory mice. Wildling mice had increased myeloid cell numbers across organs and increased activation and function of natural killer, B, and T cells, which was transferable to laboratory mice via co-housing. Immunological readouts in two preclinical models remained stable throughout the follow-up. These results demonstrate the feasibility of maintaining mouse colonies with natural, wild-derived microbiota as a sharable resource for basic and preclinical research.
    Keywords:  adaptive; dirty mice; fungus; immune; innate; microbiome; mite; myeloid; virus; wildling
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.004
  9. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2421106122
      Neonates and infants are distinct in their clinical and cellular responses to viral infections, with neonatal CD8+ T cells displaying innate-like characteristics and a low threshold for T cell receptor activation. However, specific molecular programs that drive these unique responses are incompletely understood, particularly in humans, and targetable pathways to modulate viral illness in this vulnerable population remain to be elucidated. Early-life immune responses may be developmentally programmed to prioritize avoidance of tissue immunopathology, especially while maternal immunoglobulin provides passive immunity. We set out to define the unique response characteristics and transcription factor landscape of neonatal human CD8+ T cells. Here, we report evidence that naïve neonatal human CD8+ T cells are poised for an accelerated effector switch, with elevations of killer cell lectin-like receptor G1 (KLRG1), killer cell lectin-like receptor B1 (KLRB1/CD161), Fc epsilon receptor I-gamma (FCER1G), DNAX accessory molecule-1 (DNAM1/CD226), granzymes, tumor necrosis factor alpha (TNFα), interleukin 2 (IL-2), and glycolysis compared to naïve adult CD8+ T cells. Further, rapid proliferation and cell death occur upon activation of neonatal CD8+ T cells, with cell viability largely rescued by IL-2 or IL-7. These features are coupled with a unique transcription factor landscape, including high expression of thymocyte selection associated high mobility group box (TOX) and HELIOS (IKZF2), and these signatures continue in postnatal life until at least 2 mo of age. We conclude that early-life human CD8+ T cells maintain a unique transcriptional state associated with an accelerated effector switch and short-lived effector program, revealing key nodes of regulation relevant for the unique immunobiology of neonatal humans.
    Keywords:  CD8+ T cell; differentiation; effector; neonate; transcription factor
    DOI:  https://doi.org/10.1073/pnas.2421106122
  10. Nat Commun. 2025 Jul 25. 16(1): 6854
      Porin, or the voltage-dependent anion channel (VDAC), is a primary β-barrel channel in the mitochondrial outer membrane. It transports small metabolites and ions through its β-barrel pore and plays key roles in apoptosis and inflammatory response. Here we report the cryo-electron microscopy structure of yeast porin (Por1) in its hexameric form at 3.2 Å resolution. This structure allows us to introduce various mutations at the protomer interfaces, uncovering three critical functions of Por1 assembly beyond transport. Por1 binds unassembled Tom22, a subunit of the mitochondrial protein import gate (the TOM complex), to facilitate protein import into the intermembrane space, maintains proper mitochondrial lipid composition in the outer membrane through lipid scramblase activity, and contributes to the retention and regulated loss of mitochondrial DNA, in cooperation with nucleases identified through screening enabled by the obtained Por1 mutant.
    DOI:  https://doi.org/10.1038/s41467-025-62021-4
  11. Sci Immunol. 2025 Jul 25. 10(109): eads0478
      Whereas visceral adipose tissue (VAT) primarily stores excess energy, brown adipose tissue (BAT) dissipates it in a process termed nonshivering thermogenesis. Several key VAT features, particularly murine epidydimal VAT, are regulated by a distinct population of regulatory T (Treg) cells, raising the question of whether BAT hosts an analogous population. Although Treg cells have been observed in BAT, their properties and mechanisms of action require elucidation. We found BAT Treg cells to be heterogeneous in subtissular localization and subtype composition. Punctual depletion of Treg cells unleashed interferon-γ (IFN-γ)-producing lymphocytes in BAT, but not in subcutaneous or visceral fat depots, leading to IFN-γ-dependent mitochondrial dysfunction and metabolic dysregulation, thereby impeding nonshivering thermogenesis. Cold challenge selectively expanded the IL-18R1+ Treg subtype in BAT; stripping this receptor specifically from Treg cells unleashed IFN-γ-producing lymphocytes and compromised temperature control. Thus, control of local IFN-γ production is a core feature of Treg cell control of tissue homeostasis.
    DOI:  https://doi.org/10.1126/sciimmunol.ads0478
  12. Cell. 2025 Jul 23. pii: S0092-8674(25)00791-3. [Epub ahead of print]
      Bacteria and archaea deploy diverse antiviral defense systems, many of which remain mechanistically uncharacterized. Here, we characterize Kiwa, a widespread two-component system composed of the transmembrane sensor KwaA and the DNA-binding effector KwaB. Cryogenic electron microscopy (cryo-EM) analysis reveals that KwaA and KwaB assemble into a large, membrane-associated supercomplex. Upon phage binding, KwaA senses infection at the membrane, leading to KwaB binding of ejected phage DNA and inhibition of replication and late transcription, without inducing host cell death. Although KwaB can bind DNA independently, its antiviral activity requires association with KwaA, suggesting spatial or conformational regulation. We show that the phage-encoded DNA-mimic protein Gam directly binds and inhibits KwaB but that co-expression with the Gam-targeted RecBCD system restores protection by Kiwa. Our findings support a model in which Kiwa coordinates membrane-associated detection of phage infection with downstream DNA binding by its effector, forming a spatially coordinated antiviral mechanism.
    Keywords:  DNA binding; DNA mimic; Kiwa; RecBCD; late transcription; phage defense; transmembrane KwaAB supercomplex
    DOI:  https://doi.org/10.1016/j.cell.2025.07.002
  13. Cell. 2025 Jul 23. pii: S0092-8674(25)00794-9. [Epub ahead of print]
      Fermentation products released by the gut microbiota provide energy and regulatory functions to the host. Yet, little is known about the magnitude of this metabolic flux and its quantitative dependence on diet and microbiome composition. Here, we establish orthogonal approaches to consistently quantify this flux, integrating data on bacterial metabolism, digestive physiology, and metagenomics. From the nutrients fueling microbiota growth, most carbon ends up in fermentation products and is absorbed by the host. This harvest varies strongly with the amount of complex dietary carbohydrates and is largely independent of bacterial mucin and protein utilization. It covers 2%-5% of human energy demand for Western diets and up to 10% for non-Western diets. Microbiota composition has little impact on the total harvest but determines the amount of specific fermentation products. This consistent quantification of metabolic fluxes by our analysis framework is crucial to elucidate the gut microbiota's mechanistic functions in health and disease.
    Keywords:  fermentation; gastrointestinal physiology; host-microbe interactions; human energy homeostasis; human gut microbiome; human nutrition and diet; microbial metabolism; quantitative biology
    DOI:  https://doi.org/10.1016/j.cell.2025.07.005
  14. Mol Cell. 2025 Jul 22. pii: S1097-2765(25)00545-3. [Epub ahead of print]
      Transcription in human mitochondria is driven by a core apparatus consisting of a Pol A family RNA polymerase (mtRNAP), the initiation factors TFAM and TFB2M, and the elongation factor TEFM. While earlier structures of initiation and elongation complexes provided valuable snapshots, they represent isolated stages of a highly dynamic and multistep process. Critical aspects of mitochondrial transcription-such as DNA recognition and melting, promoter escape, and the release of initiation factors-remain poorly understood. Here, we present a series of cryoelectron microscopy (cryo-EM) structures that capture the transcription complex as it transitions from the initial open promoter complex to the processive elongation complex through intermediate stages. Our data reveal new, previously unidentified determinants of promoter specificity: the sequential disengagement of mtRNAP from TFAM and the promoter, the release of TFB2M, and the recruitment of TEFM. Together, these findings provide a detailed molecular mechanism underlying transcription in human mitochondria.
    Keywords:  POLRMT; RNA polymerase; TEFM; TFAM; TFB2M; mitochondrial transcription; mtRNAP; promoter; transcription-replication switch
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.016
  15. Mol Cell. 2025 Jul 15. pii: S1097-2765(25)00580-5. [Epub ahead of print]
      Ferroptosis, a metabolic cell death process driven by iron-dependent phospholipid peroxidation, is implicated in various pathologies, including cancer. While metabolic factors such as glucose, lipids, and multiple amino acids have all been demonstrated to modulate ferroptosis, the role of oxygen, another fundamental metabolic component, in ferroptosis is not fully understood. Here, we show that cells acclimated to a low oxygen environment develop marked resistance to ferroptosis, and this resistance is independent of canonical oxygen-sensing pathway mediated by prolyl hydroxylases (PHDs) and HIF transcription factors. Instead, hypoxia suppresses ferroptosis by inhibiting KDM6A, a tumor suppressor and oxygen-dependent histone demethylase, leading to reduced expression of its transcriptional targets, including lipid metabolic enzymes ACSL4 and ETNK1, thus rewiring cellular phospholipid profile to a ferroptosis-resistant state. Relevant to cancer, pharmacological inhibition of the oncogenic histone methyltransferase EZH2, which opposes KDM6A activity, restored ferroptosis sensitivity of xenograft bladder tumor tissues harboring KDM6A mutation.
    Keywords:  ACSL4; ETNK1; KDM6A; KMT2D; bladder cancer; cancer therapy; ferroptosis; hypoxia; lipid metabolism; oxygen sensing
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.001
  16. Commun Biol. 2025 Jul 29. 8(1): 1122
      The mitochondria-associated degradation pathway (MAD) mediates removal and elimination of damaged, unfolded mitochondrial proteins by the ubiquitin-proteasome system (UPS). Previous studies revealed that MAD is critical for mitochondrial protein quality control and that MAD function extends beyond mitochondrial outer membrane (MOM) to proteins within the organelle. Here, we reconstitute retrotranslocation of MAD substrates from the mitochondrial matrix across mitochondrial inner and outer membranes in cell-free systems. This retrotranslocation is ATP-dependent but membrane potential-independent. We also identify a role for the TOM complex, the protein import channel in the MOM, in this process. Inhibition of protein translocation across the Tom40p channel reduces the retrotranslocation of MAD substrates. Our studies support the model that the TOM complex is a bidirectional protein channel in the MOM: it mediates retrotranslocation of damaged mitochondrial proteins across the MOM in the MAD pathway for mitochondrial protein quality control in addition to its function in import of proteins into the organelle.
    DOI:  https://doi.org/10.1038/s42003-025-08549-z
  17. Nat Commun. 2025 Aug 01. 16(1): 7073
      Insulin deficiency from β-cell dysfunction underpins both type 1 and type 2 diabetes. However, the regulatory pathways underlying β-cell function remain incompletely understood. Here, we identify that March5 and Trim28 as key modulators of β-cell function. March5 is downregulated and Trim28 upregulated in islets from human or mouse with impaired glucose tolerance. Loss of March5 in β-cells impairs insulin production and glucose tolerance, while its overexpression improves both. Mechanistically, March5 inhibits Trim28 by targeting it for ubiquitination, thereby preventing Trim28-mediated Kindlin-2 degradation, which elevates MafA and insulin expression in male mice. Trim28 deletion in β-cells rescues glucose intolerance in March5-deficient male mice, highlighting their joint regulatory pathway. Furthermore, March5 and Kindlin-2 double haploinsufficiency significantly impair insulin production and glucose tolerance, underscoring their shared pathway. Importantly, islet transplantation with March5-overexpressing or Trim28-deficient β-cells effectively ameliorates glucose intolerance in streptozotocin-induced diabetic male mice. In conclusion, our results suggest that targeting the March5/Trim28/Kindlin-2/MafA pathway may offer a promising therapeutic strategy to restore β-cell function in diabetes.
    DOI:  https://doi.org/10.1038/s41467-025-62587-z
  18. Nat Microbiol. 2025 Aug;10(8): 1918-1939
      The human gut microbiota has the potential to synthesize proteins that may influence host metabolism. Here we report two polypeptides, RUMTOR-derived peptide (RORDEP) 1 and RORDEP2, circulating in human blood and synthesized by specific strains of gut commensal Ruminococcus torques that correlate inversely with adiposity in humans. Oral gavage with RORDEP-expressing strains improved glucose tolerance, increased bone density and reduced fat mass with an enhanced expression of genes and proteins involved in thermogenesis and lipolysis in lean mice on a high-fat diet and diet-induced obese mice. Recombinant RORDEP1 given to rats intraperitoneally decreased plasma gastric inhibitory polypeptide but increased glucagon-like peptide 1, peptide YY and insulin. Intestinal delivery of recombinant RORDEP1 to rats potentiated insulin-mediated inhibition of hepatic glucose production by downregulating genes and proteins controlling liver gluconeogenesis, glycogenolysis and lipogenesis but upregulating those involved in insulin signalling, glycogenesis and glycolysis. These preclinical findings warrant the exploration of RORDEPs for the prevention and treatment of human metabolic disorders.
    DOI:  https://doi.org/10.1038/s41564-025-02064-x
  19. Nat Commun. 2025 Jul 28. 16(1): 6946
      Cellular and molecular heterogeneity contributes to the insufficient immunogenicity of glioblastoma multiforme (GBM), a lethal malignancy characterized by post-resection relapse, ultimately leading to limited immune cell infiltration. Here, we report a strategy to boost tumor immunity by activating the endogenous cGAS-STING signaling pathway through in-situ manipulation of the mitochondrial electron transport chain (ETC), thereby augmenting the immune responsiveness of GBM. Under white light irradiation, the synthetic butterfly-shaped photosensitizer B-TTPy disrupts the mitochondrial ETC by producing excessive reactive oxygen species. Synergistically, inhibition of checkpoint kinase 1 amplifies ETC dysfunction, thus enhancing the cytotoxicity of B-TTPy against tumor cells. Our results demonstrate that the in-house-customized Mitochondrial Electron Alteration Nanoparticles in Glioblastoma (MEANING) efficiently activate innate and adaptive immune response by recruiting antigen-presenting cells and cytotoxic T cells to the surgical margin. Moreover, biodegradable hydrogel-medicated surgical cavity treatment with MEANING can reshape the immunosuppressive tumor microenvironment and eliminate residual GBM cells. In sum, our findings establish a local immune activation approach for GBM, to prevent postoperative tumor recurrence and identify ETC blockade as a promising therapeutic strategy for low-immunogenic tumors.
    DOI:  https://doi.org/10.1038/s41467-025-62244-5