bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–07–06
33 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Train your histones.
  2. Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice.
  3. Neurons protect against fibrosis.
  4. Primate retroelement exonization and sexually dimorphic IL13RA1 transcription tune type 2 immune responses.
  5. Fatty liver disease induced by maternal obesity is driven by metabolic rewiring of Kupffer cells.
  6. The Somatic Mosaicism across Human Tissues Network.
  7. Reduction of neuronal activity mediated by blood-vessel regression in the adult brain.
  8. Mice with a diverse human T cell receptor repertoire selected on multiple HLA class I molecules.
  9. Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
  10. Triglycerides are an important fuel reserve for synapse function in the brain.
  11. Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function.
  12. Modeling heterogeneous signaling dynamics of macrophages reveals principles of information transmission in stimulus responses.
  13. Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
  14. Defining and benchmarking open problems in single-cell analysis.
  15. A constricted mitochondrial morphology formed during respiration.
  16. FOXP3 dependence.
  17. CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming.
  18. GAUDI: interpretable multi-omics integration with UMAP embeddings and density-based clustering.
  19. WSTF nuclear autophagy regulates chronic but not acute inflammation.
  20. A derivative of the ancient drug salicylate for obesity treatment.
  21. Deficits in mitochondrial dynamics and iron balance result in templated insertions.
  22. Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
  23. Facilitate integrated analysis of single cell multiomic data by binarizing gene expression values.
  24. A genome-wide association study in 10,000 individuals links plasma N-glycome to liver disease and anti-inflammatory proteins.
  25. Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells.
  26. Immunocompetent cell targeting by food-additive titanium dioxide.
  27. Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype.
  28. Tumour cells mimic erythroblasts to hijack iron from bone marrow macrophages.
  29. How chemotherapy shapes hematopoietic stem cells.
  30. Transcripts with high distal heritability mediate genetic effects on complex metabolic traits.
  31. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  32. Ageing is linked to inflammation - but only in the industrialized world.
  33. Dimerization and substrate recognition of human taurine transporter.
  1. Nat Immunol. 2025 Jul;26(7): 983
    Train your histones.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-025-02214-7
  2. Nat Commun. 2025 Jul 01. 16(1): 5708
    Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice.
    Jidong Liu, Fang Xiao, Abhinav Choubey, Udhaya Kumar S, Yanxiang Wang, Sungguan Hong, Tingting Yang, Husniye Gul Otlu, Ege Sanem Oturmaz, Emanuele Loro, Yuxiang Sun, Pradip Saha, Tejvir S Khurana, Li Chen, Xinguo Hou, Zheng Sun.
      The best time of the day for chronic exercise training and the mechanism underlying the timing effects is unclear. Here, we show that low-intensity, low-volume treadmill training in mice before sleep yields greater benefits than after waking for muscle contractile performance and systemic glucose tolerance. Baseline muscle performance also exhibits diurnal variations, with higher strength but lower endurance before sleep than after waking. Muscle-specific knockout of circadian clock genes Rev-erbα/β (Rev-MKO) in male mice eradicates the diurnal variations in both training and baseline conditions without affecting muscle mass, mitochondrial content, food intake, or spontaneous activities. Multi-omics and metabolic measurements reveal that Rev-erb suppresses fatty acid oxidation and promotes carbohydrate metabolism before sleep. Thus, the muscle-autonomous clock, not feeding or locomotor behaviors, dictates diurnal variations of muscle functions and time-dependent adaptations to training, which has broad implications in metabolic disorders and sports medicine as Rev-erb agonists are exercise mimetics or enhancers.
    DOI:  https://doi.org/10.1038/s41467-025-60520-y
  3. Nat Immunol. 2025 Jul;26(7): 983
    Neurons protect against fibrosis.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-025-02216-5
  4. Sci Immunol. 2025 Jul 04. 10(109): eadr1105
    Primate retroelement exonization and sexually dimorphic IL13RA1 transcription tune type 2 immune responses.
    Tobias Plowman, Tom Hofland, Callum Hall, Rachael Thompson, Judith Pape, Kevin W Ng, Laura Doglio, George Kassiotis.
      Type 2 immunity is orchestrated by IL-4 and IL-13 signaling, initiated by binding to receptors that are specific to each cytokine or to the shared heterodimeric receptor comprising the IL-4Rα and IL-13Rα1 subunits. Here, we report that sexually dimorphic IL13RA1 transcription is regulated by estrogen and characterize an IL-13Rα1 isoform (referred to here as IL-13Rα1-LOR1a) created through facultative splicing to an alternative terminal exon composed of primate-specific retrotransposable elements (RTEs). At the mRNA level, RTE exonization replaces regulatory sequences in the canonical 3' untranslated region (3'UTR) implicated in IL13RA1 mRNA stability. Moreover, alternative splicing removes critical domains in the cytoplasmic tail, rendering the IL-13Rα1-LOR1a isoform partially signaling defective at the protein level. When coexpressed, the IL-13Rα1-LOR1a isoform antagonizes the function of the canonical receptor, reducing cellular responsiveness to IL-4 and IL-13. Thus, the balance of the two IL13RA1 isoforms appears to fine-tune type 2 cytokine signaling and downstream immune responses.
    DOI:  https://doi.org/10.1126/sciimmunol.adr1105
  5. Nat Rev Immunol. 2025 Jun 30.
    Fatty liver disease induced by maternal obesity is driven by metabolic rewiring of Kupffer cells.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01205-x
  6. Nature. 2025 Jul;643(8070): 47-59
    The Somatic Mosaicism across Human Tissues Network.
    Somatic Mosaicism across Human Tissues Network
      From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions. This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09096-7
  7. Nat Commun. 2025 Jul 01. 16(1): 5840
    Reduction of neuronal activity mediated by blood-vessel regression in the adult brain.
    Xiaofei Gao, Xing-Jun Chen, Meng Ye, Jun-Liszt Li, Nannan Lu, Di Yao, Bo Ci, Fei Chen, Lijun Zheng, Yating Yi, Shiwen Zhang, Zhanying Bi, Xinwei Gao, Yuanlei Yue, Tingbo Li, Jiafu Lin, Ying-Chao Shi, Kaibin Shi, Nicholas E Propson, Yubin Huang, Katherine Poinsatte, Zhaohuan Zhang, Dale B Bosco, Shi-Bing Yang, Ralf H Adams, Volkhard Lindner, Fen Huang, Long-Jun Wu, Hui Zheng, Simon Hippenmeyer, Ann M Stowe, Bo Peng, Marta Margeta, Qingchun Guo, Xiaoqun Wang, Qiang Liu, Jakob Körbelin, Martin Trepel, Hui Lu, Guoen Cai, Bo O Zhou, Bo Shen, Ying-Mei Lu, Wenzhi Sun, Jie-Min Jia, Feng Han, Hu Zhao, Robert M Bachoo, Woo-Ping Ge.
      The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we report that a substantial proportion of blood vessels in the adult mouse brain sporadically occlude and regress. Their regression proceeds through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels are found to be widespread in mouse, monkey and human brains. We further reveal that blood vessel regression cause a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.
    DOI:  https://doi.org/10.1038/s41467-025-60308-0
  8. Nat Commun. 2025 Jul 01. 16(1): 5432
    Mice with a diverse human T cell receptor repertoire selected on multiple HLA class I molecules.
    Arunraj Dhamodaran, Xiaojing Chen, Niklas Fellmer, Deepti Agrawal, Eric Danner, Ralf Kühn, Thomas Blankenstein.
      T cell receptor (TCR) gene therapy is an effective cancer treatment. Ideally, the TCR should be of human origin and have optimal avidity, e.g., isolated from a tumor antigen-non-tolerant host. Previously, we developed ABab-A2 mice which carry human TCRα and TCRβ gene loci and the human leukocyte antigen class I gene HLA-A*02:01 and are deficient for the corresponding mouse genes. Into these mice, we here introduce by PiggyBac transposon HLA-A*03:01, -A*11:01, -B*07:02, -B*15:01, -C*04:01, and -C*07:02 genes. These mice, termed ABab-I, exhibit increased peripheral CD8+ T cell counts and a higher CD8/CD4 ratio compared to ABab-A2 mice. ABab-I mice display a broader TCR repertoire with more unique V(D)J-TCRß clonotypes than ABab-A2 mice. Multi-HLA-I expression selected, on average, TCR with longer complementary determining region 3 (CDR3) compared to expression of a single HLA-I. ABab-I mice mount robust immune responses against viral, tumor-associated, and tumor-specific antigens. ABab-I mice allow simultaneous epitope and TCR discovery with broad HLA coverage, which could increase the number of cancer patients amenable to TCR-T treatments.
    DOI:  https://doi.org/10.1038/s41467-025-61306-y
  9. Nat Commun. 2025 Jul 01. 16(1): 5435
    Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
    Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.
      Mutations in mitochondrial DNA (mtDNA) accumulate during aging and contribute to age-related conditions. High mtDNA copy number masks newly emerged recessive mutations; however, phenotypes develop when cellular levels of a mutant mtDNA rise above a critical threshold. The process driving this increase is unknown. Single-cell DNA sequencing of mouse and human hepatocytes detected increases in abundance of mutant alleles in sequences governing mtDNA replication. These alleles provided a replication advantage (drive) leading to accumulation of the affected genome along with a wide variety of associated passenger mutations, some of which are detrimental. The most prevalent human mtDNA disease variant, the 3243A>G allele, behaved as a driver, suggesting that drive underlies prevalence. We conclude that replicative drive amplifies linked mtDNA mutations to a threshold at which phenotypes are seen thereby promoting age-associated erosion of the mtDNA and influencing the transmission and progression of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60477-y
  10. Nat Metab. 2025 Jul 01.
    Triglycerides are an important fuel reserve for synapse function in the brain.
    Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.
      Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01321-x
  11. Nat Aging. 2025 Jun 30.
    Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function.
    Ninghe Sun, Chun-Hsin Lin, Michelle Y Li, Yuting Wang, Danyang Chen, Xiangle Ren, Feng Zhang, Yi Zhang.
      Aged hematopoietic stem cells (HSCs) exhibit diminished self-renewal and myeloid-biased differentiation with a decline in hematopoiesis and adaptive immune function. However, the molecular regulation of this impaired function remains largely unknown. Here, through an in vivo CRISPR-Cas9-based screen, we uncovered clusterin (Clu) as a driver of biased differentiation. Clu is upregulated in aged HSCs, and its knockout diminishes biased differentiation. Clu promotes mitochondrial hyperfusion by interacting with Mfn2 in aged HSCs, and its ablation attenuates oxidative phosphorylation, improves mitophagy, and reverses myeloid-biased differentiation via the OXPHOS-p38-Cebpb axis. Transplantation of Clu-depleted aged HSCs into middle-aged mice results in balanced hematopoiesis and improved physical functions. Together, our data identify Clu as a critical regulator of aging-associated myeloid bias and reveal an Mfn2-OXPHOS-p38-Cebpb axis as the mechanism underlying how Clu upregulation in aged HSCs leads to myeloid-biased differentiation, providing a target for rejuvenation of aged hematopoietic and immune systems.
    DOI:  https://doi.org/10.1038/s43587-025-00908-z
  12. Nat Commun. 2025 Jul 01. 16(1): 5986
    Modeling heterogeneous signaling dynamics of macrophages reveals principles of information transmission in stimulus responses.
    Xiaolu Guo, Adewunmi Adelaja, Apeksha Singh, Roy Wollman, Alexander Hoffmann.
      Macrophages initiate pathogen-appropriate immune responses with the activation dynamics of transcription factor NFκB mediating specificity. Live-cell imaging revealed the stimulus-response specificity of NFκB dynamics among populations of heterogeneous cells. To study stimulus-response specificity beyond what is experimentally accessible, we develop mathematical model simulations that capture the heterogeneity of stimulus-responsive NFκB dynamics and the stimulus-response specificity performance of the population. Complementing experimental data, extended-dose response simulations improved channel capacity estimates. By collapsing parameter distributions, we locate information loss to receptor modules, while the negative-feedback-containing core module shows remarkable signaling fidelity. Further, constructing virtual single-cell networks reveals the stimulus-response specificity of single cells. We find that despite stimulus-response specificity limitations at the population level, the majority of single cells are capable of responding specifically to immune threats, and that the few instances of stimulus-pair confusion are highly uncorrelated. The diversity of blindspots enable small consortia of macrophages to achieve perfect stimulus distinction.
    DOI:  https://doi.org/10.1038/s41467-025-60901-3
  13. Nat Commun. 2025 Jul 01. 16(1): 5850
    Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
    Aliyah Habashy, Christopher Acree, Keun-Young Kim, Ali Zahraei, Martin Dufresne, Sebastien Phan, Melanie Cutler, Emilee Patterson, Alexandra G Mulligan, Kristopher Burkewitz, Charles Robert Flynn, Louise Lantier, Thomas Deerinck, Owen P McGuinness, Jeffrey M Spraggins, Mark H Ellisman, Rafael Arrojo E Drigo.
      Metabolic homeostasis requires engagement of catabolic and anabolic pathways consuming nutrients that generate and consume energy and biomass. Our current understanding of cell homeostasis and metabolism, including how cells utilize nutrients, comes largely from tissue and cell models analyzed after fractionation, and that fail to reveal the spatial characteristics of cell metabolism, and how these aspects relate to the location of cells and organelles within tissue microenvironments. Here we show the application of multi-scale microscopy, machine learning-based image segmentation, and spatial analysis tools to quantitatively map the fate of nutrient-derived 13C atoms across spatiotemporal scales. This approach reveals the cellular and organellar features underlying the spatial pattern of glucose 13C flux in hepatocytes in situ, including the timeline of mitochondria-ER contact dynamics in response to changes in blood glucose levels, and the discovery of the ultrastructural relationship between glycogenesis and lipid droplets.
    DOI:  https://doi.org/10.1038/s41467-025-60994-w
  14. Nat Biotechnol. 2025 Jul 01.
    Defining and benchmarking open problems in single-cell analysis.
    Open Problems Jamboree Members
      
    DOI:  https://doi.org/10.1038/s41587-025-02694-w
  15. Nat Commun. 2025 Jul 01. 16(1): 5314
    A constricted mitochondrial morphology formed during respiration.
    Manish K Singh, Laetitia Cavellini, Maria Angeles Morcillo-Parra, Christina Kunz, Mickaël Lelek, Perrine Bomme, Aurélia Barascu, Cynthia Alsayyah, Maria Teresa Teixeira, Naïma Belgareh-Touzé, Adeline Mallet, Lea Dietrich, Christophe Zimmer, Mickael M Cohen.
      Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.
    DOI:  https://doi.org/10.1038/s41467-025-60658-9
  16. Nat Immunol. 2025 Jul;26(7): 983
    FOXP3 dependence.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-025-02213-8
  17. Nat Immunol. 2025 Jun 30.
    CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming.
    Valentina Venzin, Cristian G Beccaria, Chiara Perucchini, Pietro Delfino, Elisa B Bono, Leonardo Giustini, Federica Moalli, Marta Grillo, Valeria Fumagalli, Chiara Laura, Pietro Di Lucia, Katharina Reinhard, Jutta Petschenka, Tana Annmarie Omokoko, Anna Celant, Sabrina Ottolini, Keigo Kawashima, Micol Ravà, Marco De Giovanni, Donato Inverso, Mirela Kuka, Patrick T F Kennedy, Martin Guilliams, Giulia Casorati, Federica Pedica, Maurilio Ponzoni, Uğur Şahin, Nina Le Bert, Antonio Bertoletti, Fulvia Vascotto, Luca G Guidotti, Matteo Iannacone.
      Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8+ T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4+ T cell receptor transgenic mice to show that CD4+ effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8+ T cell function and suppresses viral replication. CD4+ T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4+ T cells license Kupffer cells via CD40-CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4+ T cell pool, while IL-27 is essential for CD8+ T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8+ T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.
    DOI:  https://doi.org/10.1038/s41590-025-02199-3
  18. Nat Commun. 2025 Jul 01. 16(1): 5771
    GAUDI: interpretable multi-omics integration with UMAP embeddings and density-based clustering.
    Pol Castellano-Escuder, Derek K Zachman, Kevin Han, Matthey D Hirschey.
      Integrating high-dimensional cellular multi-omics data is crucial for understanding various layers of biological control. Single 'omic methods provide important insights, but often fall short in handling the complex relationships between genes, proteins, metabolites and beyond. Here, we present a novel, non-linear, and unsupervised method called GAUDI (Group Aggregation via UMAP Data Integration) that leverages independent UMAP embeddings for the concurrent analysis of multiple data types. GAUDI uncovers non-linear relationships among different omics data better than several state-of-the-art methods. This approach not only clusters samples by their multi-omic profiles but also identifies latent factors across each omics dataset, thereby enabling interpretation of the underlying features contributing to each cluster. Consequently, GAUDI facilitates more intuitive, interpretable visualizations to identify novel insights and potential biomarkers from a wide range of experimental designs.
    DOI:  https://doi.org/10.1038/s41467-025-60822-1
  19. Nature. 2025 Jul 02.
    WSTF nuclear autophagy regulates chronic but not acute inflammation.
    Yu Wang, Vinay V Eapen, Yaosi Liang, Athanasios Kournoutis, Marc Samuel Sherman, Yanxin Xu, Angelique Onorati, Xianting Li, Xiaoting Zhou, Kathleen E Corey, Kuo Du, Ana Maria Cabral Burkard, Chia-Kang Ho, Jing Xie, Hui Zhang, Raquel Maeso-Díaz, Xinyi Ma, Ulrike Rieprecht, Tara O'Brien, Murat Cetinbas, Lu Wang, Jihe Liu, Corey Bretz, Aaron P Havas, Zhuo Zhou, Shannan J Ho Sui, Srinivas Vinod Saladi, Ruslan I Sadreyev, Peter D Adams, Robert E Kingston, Anna Mae Diehl, Benjamin Alman, Wolfram Goessling, Zhenyu Yue, Xiao-Fan Wang, Terje Johansen, Zhixun Dou.
      Acute inflammation is an essential response that our bodies use to combat infections1. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09234-1
  20. Nat Metab. 2025 Jun 30.
    A derivative of the ancient drug salicylate for obesity treatment.
      
    DOI:  https://doi.org/10.1038/s42255-025-01312-y
  21. Nat Commun. 2025 Jul 01. 16(1): 5454
    Deficits in mitochondrial dynamics and iron balance result in templated insertions.
    Jordan Fox, Yang Yu, Yang Yu, Pilendra Thakre, Chloe Fox, Qian Li, Yunxia Wang, Adam Hughes, Xin Wang, Kaifu Chen, Grzegorz Ira.
      Mitochondrial membrane dynamics control the shape, number, and distribution of mitochondria and regulate energy production and cell health. In a screen for yeast mutants with increased levels of templated insertions (~10-1000 bp) in the nuclear genome, we identified mitochondrial fusion deficient mutants (mgm1Δ, ugo1Δ, fzo1Δ). We found that fusion mutants activate the iron regulon, have decreased iron-sulfur clusters (ISCs), and increased DNA damage, suggesting a role of iron homeostasis in preventing insertions. Consistently, a secondary screen found mutants affecting iron-sulfur cluster production (yfh1Δ, grx5Δ), vacuolar iron storage (ccc1Δ) or general iron homeostasis (aft1Δ) to exhibit high insertion levels. Treatment with iron chelators or hydrogen peroxide also increased insertions. We propose that iron dysregulation leading to oxidative DNA damage and compromised DNA repair drives insertions. These studies suggest that severe iron imbalance, associated with many human diseases and pharmacological treatments, can trigger genome instability in the form of templated insertions.
    DOI:  https://doi.org/10.1038/s41467-025-60546-2
  22. Nat Commun. 2025 Jul 02. 16(1): 6083
    Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
    Iman Man Hu, Marte Molenaars, Yorrick R J Jaspers, Bauke V Schomakers, Michel van Weeghel, Amber Bakker, Melanie Modder, Joseph P Dewulf, Guido T Bommer, Arwen W Gao, Georges E Janssens, Riekelt H Houtkooper.
      Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Using multi-omics and functional in vivo screening, we identify the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as an essential factor for longevity induced by mitochondrial translation inhibition. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition, while mitochondrial unfolded protein response activation remains unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Mechanistically, sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the "immuno-metabolic stress responses" in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.
    DOI:  https://doi.org/10.1038/s41467-025-61433-6
  23. Nat Commun. 2025 Jul 01. 16(1): 5763
    Facilitate integrated analysis of single cell multiomic data by binarizing gene expression values.
    Rohan Misra, Alexander Ferrena, Deyou Zheng.
      A cell type's identity can be revealed by its transcriptome and epigenome profiles, both of which can be in flux temporally and spatially, leading to distinct cell states or subtypes. The popular and standard workflow for single cell RNA-seq (scRNA-seq) data analysis applies feature selection, dimensional reduction, and clustering on the gene expression values quantified by read counts, but alternative approaches using a simple classification of a gene to "on" and "off" (i.e., binarization of the gene expression) have been proposed for clustering cells and other downstream analyses. Here, we demonstrate that a direct concatenation of the binarized scRNA-seq data and the standard single cell ATAC-seq data is sufficient and effective for vertical integrated clustering analysis, after applying term-frequency-inverse document frequency (TF-IDF) and single value decomposition (also called latent semantic indexing, LSI) algorithms to the combined data, when the two data modalities are collected using a paired multiomic technology. This proposed approach avoids the need for converting scATAC-seq data to gene activity scores for combined analysis. Furthermore it enables a direct investigation into the contribution of each data type for resolving cell type or subtype identity.
    DOI:  https://doi.org/10.1038/s41467-025-60899-8
  24. Nat Commun. 2025 Jul 01. 16(1): 5525
    A genome-wide association study in 10,000 individuals links plasma N-glycome to liver disease and anti-inflammatory proteins.
    Sodbo Sharapov, Anna Timoshchuk, Olga Zaytseva, Denis E Maslov, Anna Soplenkova, Elizaveta E Elgaeva, Evgeny S Tiys, Massimo Mangino, Clemens Wittenbecher, Lennart Karssen, Maria Timofeeva, Arina Nostaeva, Frano Vuckovic, Irena Trbojević-Akmačić, Tamara Štambuk, Sofya Feoktistova, Nadezhda A Potapova, Viktoria Voroshilova, Frances Williams, Dragan Primorac, Jan Van Zundert, Michel Georges, Karsten Suhre, Massimo Allegri, Nishi Chaturvedi, Malcolm Dunlop, Matthias B Schulze, Tim Spector, Yakov A Tsepilov, Gordan Lauc, Yurii S Aulchenko.
      More than a half of plasma proteins are N-glycosylated. Most of them are synthesized, glycosylated, and secreted to the bloodstream by liver and lymphoid tissues. While associations with N-glycosylation are implicated in the rising number of liver, cardiometabolic, and immune diseases, little is known about the genetic regulation of this process. Here, we performed the largest genome-wide association study of N-glycosylation of the blood plasma proteome in 10,000 individuals. We doubled the number of genetic loci known to be associated with blood N-glycosylation by identifying 16 novel loci and prioritizing 13 novel genes contributing to N-glycosylation. Among these were the GCKR, TRIB1, HP, SERPINA1 and CFH genes. These genes are predominantly expressed in the liver and show a previously unknown genetic link between plasma protein N-glycosylation, metabolic and liver diseases, and inflammatory response. By integrating glycomics, proteomics, transcriptomics, and genomics, we provide a resource that facilitates deeper exploration of disease pathogenesis and supports the discovery of glycan-based biomarkers.
    DOI:  https://doi.org/10.1038/s41467-025-60431-y
  25. Nat Commun. 2025 Jul 01. 16(1): 5546
    Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells.
    Keungmo Yang, Kyurae Kim, Tom Ryu, Young-Ri Shim, Hee-Hoon Kim, Sung Eun Choi, Min Jeong Kim, Katherine Po Sin Chung, Eunmi Lee, Kwang Woo Lee, Jehwi Jeon, Pilhan Kim, Young Seo Kim, Taeyun Ku, Haengdueng Jeong, Ki Taek Nam, Gyumin Lim, Dong Wook Choi, Seok-Hwan Kim, Hyuk Soo Eun, Won Kim, Won-Il Jeong.
      Glutamate, a crucial player in hepatic amino acid metabolism, has been relatively unexplored in immune cell activation. We show in a study with male mice that hepatic glutamate accumulates in vesicles of perivenous hepatocytes through vesicular glutamate transporter 3 (VGLUT3), regulated by the aryl hydrocarbon receptor upon chronic alcohol intake. Additional binge drinking triggers the exocytosis of glutamate by altering the intracellular Ca2+ level, stimulating metabotropic glutamate receptor 5 (mGluR5) and subsequent NADPH oxidase 2 (NOX2)-mediated ROS production in Kupffer cells (KCs). This interaction between hepatocytes and KCs is facilitated by pseudosynapse formation, arising from alcohol-induced ballooning of perivenous hepatocytes. Genetic or pharmacological interference of mGluR5 or NOX2 in KCs alleviates alcohol-related steatohepatitis (ASH). Analysis of patient samples confirmed some of the findings from mice, showing that plasma glutamate concentration and VGLUT3 levels correlate with ASH development. Conclusively, our findings highlight glutamate storage and release in mediating ASH, particularly through the pseudosynapse between hepatocytes and KCs.
    DOI:  https://doi.org/10.1038/s41467-025-60820-3
  26. Nat Commun. 2025 Jul 04. 16(1): 6067
    Immunocompetent cell targeting by food-additive titanium dioxide.
    John W Wills, Alicja Dabrowska, Jack Robertson, Michelle Miniter, Sebastian Riedle, Huw D Summers, Rachel E Hewitt, Adeeba Fathima, Alessandra Barreto da Silva, Carlos A P Bastos, Stuart Micklethwaite, Åsa V Keita, Johan D Söderholm, Nicole C Roy, Don Otter, Ravin Jugdaohsingh, Pietro Mastroeni, Andy P Brown, Paul Rees, Jonathan J Powell.
      Food-grade titanium dioxide (fgTiO2) is a bio-persistent particle under intense regulatory scrutiny. Yet paradoxically, the only known cell reservoirs for fgTiO2 are graveyard intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify immunocompetent cell targets of fgTiO2 in humans, most notably in the subepithelial dome region of intestinal Peyer's patches. Using multimodal microscopies with single-particle detection and per-cell / vesicle image analysis we achieve correlative dosimetry, quantitatively recapitulating human cellular exposures in the ileum of mice fed a fgTiO2-containing diet. Epithelial microfold cells selectively funnel fgTiO2 into LysoMac and LysoDC cells with ensuing accumulation. Notwithstanding, proximity extension analyses for 92 protein targets reveal no measureable perturbation of cell signalling pathways. When chased with oral ΔaroA-Salmonella, pro-inflammatory signalling is confirmed, but no augmentation by fgTiO2 is revealed despite marked same-cell loading. Interestingly, Salmonella causes the fgTiO2-recipient cells to migrate within the patch and, sporadically, to be identified in the lamina propria, thereby fully recreating the intestinal tissue distribution of fgTiO2 in humans. Immunocompetent cells that accumulate fgTiO2 in vivo are now identified and we demonstrate a mouse model that finally enables human-relevant risk assessments of ingested, bio-persistent (nano)particles.
    DOI:  https://doi.org/10.1038/s41467-025-60248-9
  27. Nat Commun. 2025 Jul 04. 16(1): 6169
    Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype.
    Song Lou, Rachisan DJiake Tihagam, Urszula N Wasko, Zaffar Equbal, Sanjay Venkatesan, Klaudia Braczyk, Piotr Przanowski, Bon Il Koo, Ilyas Saltani, Arjun Tushir Singh, Shibi Likhite, Samantha Powers, George M P R Souza, Robert A Maxwell, Jun Yu, Lihua J Zhu, Mark Beenhakker, Stephen B G Abbott, Zhipeng Lu, Michael R Green, Kathrin C Meyer, Jogender Tushir-Singh, Sanchita Bhatnagar.
      X chromosome inactivation (XCI) is induced by Xist long non-coding RNA and protein-coding genes. However, the role of small non-coding RNA function in XCI remains unidentified. Our genome-wide, loss-of-function CRISPR/Cas9 screen in female fibroblasts identified microRNAs (miRNAs) as regulators of XCI. A striking finding is the identification of miR106a among the top candidates from the screen. Loss of miR106a is accompanied by altered Xist interactome, leading to dissociation and destabilization of Xist. XCI interference via miR106a inhibition has therapeutic implications for Rett syndrome (RTT) girls with a defective X-linked MECP2 gene. Here, we discovered that the inhibition of miR106a significantly improves several facets of RTT pathology: it increases the life span, enhances locomotor activity and exploratory behavior, and diminishes breathing variabilities. Our results suggest that miR106a targeting offers a feasible therapeutic strategy for RTT and other monogenic X-linked neurodevelopmental disorders.
    DOI:  https://doi.org/10.1038/s41467-025-61092-7
  28. Nat Rev Immunol. 2025 Jul 01.
    Tumour cells mimic erythroblasts to hijack iron from bone marrow macrophages.
    Mehdi Chaib, James P Allison.
      
    DOI:  https://doi.org/10.1038/s41577-025-01204-y
  29. Nat Genet. 2025 Jul 01.
    How chemotherapy shapes hematopoietic stem cells.
    Terrence N Wong, Daniel C Link.
      
    DOI:  https://doi.org/10.1038/s41588-025-02231-0
  30. Nat Commun. 2025 Jul 01. 16(1): 5507
    Transcripts with high distal heritability mediate genetic effects on complex metabolic traits.
    Anna L Tyler, J Matthew Mahoney, Mark P Keller, Candice N Baker, Margaret Gaca, Anuj Srivastava, Isabela Gerdes Gyuricza, Madeleine J Braun, Nadia A Rosenthal, Alan D Attie, Gary A Churchill, Gregory W Carter.
      Although many genes are subject to local regulation, recent evidence suggests that complex distal regulation may be more important in mediating phenotypic variability. To assess the role of distal gene regulation in complex traits, we combine multi-tissue transcriptomes with physiological outcomes to model diet-induced obesity and metabolic disease in a population of Diversity Outbred mice. Using a novel high-dimensional mediation analysis, we identify a composite transcriptome signature that summarizes genetic effects on gene expression and explains 30% of the variation across all metabolic traits. The signature is heritable, interpretable in biological terms, and predicts obesity status from gene expression in an independently derived mouse cohort and multiple human studies. Transcripts contributing most strongly to this composite mediator frequently have complex, distal regulation distributed throughout the genome. These results suggest that trait-relevant variation in transcription is largely distally regulated, but is nonetheless identifiable, interpretable, and translatable across species.
    DOI:  https://doi.org/10.1038/s41467-025-61228-9
  31. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
  32. Nature. 2025 Jun 30.
    Ageing is linked to inflammation - but only in the industrialized world.
    Miryam Naddaf.
      
    Keywords:  Ageing; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-02085-w
  33. Nat Commun. 2025 Jul 04. 16(1): 6163
    Dimerization and substrate recognition of human taurine transporter.
    Yimin Zhang, Jiahui Chen, Nanhao Chen, Haolin Xiong, Zhengjiang Zhu, Dongxue Yang, Jingpeng Ge, Jie Yu.
      Taurine is a conditionally essential nutrient and one of the most abundant amino acids in humans, with diverse physiological functions. The cellular uptake of taurine is primarily mediated by the taurine transporter (TauT), and its dysfunction leads to retinal regeneration, cardiomyopathy, neurological and aging-associated disorders. Here we determine structures of TauT in two states: the apo inward-facing open state and the occluded state bound with substrate taurine or γ-aminobutyric acid (GABA). In addition to monomer, the structures also reveal a TauT dimer, where two cholesterol molecules act as "molecular glue", and close contacts of two TM5 from each protomer mediate the dimer interface. In combination with functional characterizations, our results elucidate the detailed mechanisms of substrate recognition, specificity and transport by TauT, providing a structural framework for understanding TauT function and exploring potential therapeutic strategies for taurine-deficiency-related disorders.
    DOI:  https://doi.org/10.1038/s41467-025-60967-z
This page is being maintained by Thomas Krichel. It was last updated on 2025‒07‒13 at 15:15.