bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–11–02
24 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Acute hypoxia drives long-term dysfunctional neutrophil immunity.
  2. Multi-omic profiling reveals age-related immune dynamics in healthy adults.
  3. Microbiota reprogramming of macrophages.
  4. Adjusting to retirement.
  5. Stage-specific roles of clonally expanded CD8+ T cells in regulating amyloid pathology in Alzheimer's disease models.
  6. ILC2s in the nerves.
  7. Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes.
  8. Data navigation on the ENCODE portal.
  9. Secretory kinase FAM20C triggers adipocyte dysfunction inciting insulin resistance and inflammation in obesity.
  10. Longer walks beat shorter strolls for heart health.
  11. Nicheformer: a foundation model for single-cell and spatial omics.
  12. Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer's pathogenesis.
  13. Ten essential tips for robust statistics in cell biology.
  14. Low cholesterol levels and cardiovascular risk in obesity due to MC4R deficiency.
  15. Phagocytosis: a process that shapes immune responses to engulfed meals.
  16. AI can supercharge inequality - unless the public learns to control it.
  17. Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria.
  18. Improved reconstruction of single-cell developmental potential with CytoTRACE 2.
  19. Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity.
  20. UNICORN: Towards universal cellular expression prediction with a multi-task learning framework.
  21. This whale lives for centuries: its secret could help extend human lifespan.
  22. Duration of Continuous Glucose Monitoring and Glycemic Outcomes in Type 2 Diabetes.
  23. SARM1 senses dsDNA to promote NAD+ degradation and cell death.
  24. Pharmacological targeting of RIG-I can selectively activate the integrated stress response.
  1. Nat Immunol. 2025 Nov;26(11): 1861-1862
    Acute hypoxia drives long-term dysfunctional neutrophil immunity.
      
    DOI:  https://doi.org/10.1038/s41590-025-02335-z
  2. Nature. 2025 Oct 29.
    Multi-omic profiling reveals age-related immune dynamics in healthy adults.
    Qiuyu Gong, Mehul Sharma, Marla C Glass, Emma L Kuan, Aishwarya Chander, Mansi Singh, Lucas T Graybuck, Zachary J Thomson, Christian M LaFrance, Samir Rachid Zaim, Tao Peng, Lauren Y Okada, Palak C Genge, Katherine E Henderson, Elisabeth M Dornisch, Erik D Layton, Peter J Wittig, Alexander T Heubeck, Nelson M Mukuka, Julian Reading, Garrett Strawn, Teminijesu Titus-Adewunmi, Kathleen Abadie, Charles R Roll, Veronica Hernandez, Vaishnavi Parthasarathy, Tyanna J Stuckey, Blessing Musgrove, Elliott Swanson, Cara Lord, Morgan D A Weiss, Cole G Phalen, Regina R Mettey, Kevin J Lee, John B Johanneson, Erin K Kawelo, Jessica Garber, Upaasana Krishnan, Megan Smithmyer, E John Wherry, Laura A Vella, Sarah E Henrickson, Mackenzie S Kopp, Adam K Savage, Lynne A Becker, Paul Meijer, Ernest M Coffey, Jorg J Goronzy, Mikael Sigvardsson, Cate Speake, Thomas F Bumol, Ananda W Goldrath, Troy R Torgerson, Xiao-Jun Li, Peter J Skene, Jane H Buckner, Claire E Gustafson.
      The generation and maintenance of immunity is a dynamic process that is dependent on age1-3. Here, to better understand its progression, we profiled peripheral immunity in more than 300 healthy adults (25 to 90 years of age) using single-cell RNA sequencing, proteomics and flow cytometry, following 96 adults longitudinally across 2 years with seasonal influenza vaccination. The resulting resource generated a single-cell RNA-sequencing dataset of more than 16 million peripheral blood mononuclear cells with 71 immune cell subsets from our Human Immune Health Atlas and enabled us to interrogate how immune cell composition and states shift with age, chronic viral infection and vaccination. From these data, we demonstrate robust, non-linear transcriptional reprogramming in T cell subsets with age that is not driven by systemic inflammation or chronic cytomegalovirus infection. This age-related reprogramming led to a functional T helper 2 (TH2) cell bias in memory T cells that is linked to dysregulated B cell responses against highly boosted antigens in influenza vaccines. Collectively, this study reveals unique features of the immune ageing process that occur prior to advanced age and provides novel targets for age-related immune modulation. We provide interactive tools for exploring this extensive human immune health resource at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ .
    DOI:  https://doi.org/10.1038/s41586-025-09686-5
  3. Nat Immunol. 2025 Nov;26(11): 1839
    Microbiota reprogramming of macrophages.
    Paula Jáuregui.
      
    DOI:  https://doi.org/10.1038/s41590-025-02338-w
  4. Science. 2025 Oct 30. 390(6772): 534
    Adjusting to retirement.
    Tod F Stuessy.
      
    DOI:  https://doi.org/10.1126/science.aed3663
  5. Nat Commun. 2025 Oct 27. 16(1): 9458
    Stage-specific roles of clonally expanded CD8+ T cells in regulating amyloid pathology in Alzheimer's disease models.
    Masaki Ohyagi, Minako Ito, Mana Iizuka-Koga, Setsuko Mise-Omata, Akihiko Yoshimura.
      Clonally expanded CD8+ T cells may contribute to Alzheimer's disease (AD) pathology through interactions with brain-resident cells. However, the functional impact of AD-specific T cell receptor (TCR) clonotypes remains unclear. Here, we demonstrate that CD8+ T cells undergo clonal expansion in early-stage AD mouse models, AppNL-G-F and 5xFAD, and that their depletion reduces amyloid plaque accumulation. Expanded TCR-expressing CD8+ T cells preferentially infiltrate the brain, exacerbating plaque deposition. Moreover, brain-infiltrating CD8+ T cells impair microglial transition into disease-associated states, suppressing amyloid clearance via CCL5-CCR5 signaling. Pharmacological blockade of CCL5 attenuates amyloid deposition, whereas CCL5 administration aggravates pathology. Notably, T cell depletion at later disease stages exacerbates amyloid pathology, suggesting a temporal shift in their function. Early-stage CD8+ T cells exhibit cytotoxic and effector profiles, whereas late-stage cells acquire tissue-resident and exhausted phenotypes. This temporal switch-from pathogenic to protective roles-highlights the stage-specific contribution of CD8+ T cells to AD and their potential as therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-025-64503-x
  6. Nat Immunol. 2025 Nov;26(11): 1839
    ILC2s in the nerves.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-025-02340-2
  7. Nat Commun. 2025 Oct 27. 16(1): 9475
    Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes.
    J A Martínez-López, A Lindqvist, A Lopez-Pascual, A Harder, P Chen, M Ngara, L Shcherbina, S Siffo, E Cowan, S M Baira, D Kryvokhyzha, A Karagiannopoulos, S Chriett, N G Skene, R B Prasad, M Lancien, P F Johnson, P Eliasson, L Eliasson, C Louvet, P Spégel, A B Muñoz-Manchado, R Sandberg, J Hjerling-Leffler, N Wierup.
      Perturbed secretion of insulin and other pancreatic islet hormones is the main cause of type 2 diabetes (T2D). The islets harbor five cell types that are potentially altered differently by T2D. Whole-islet transcriptomics and single-cell RNA-sequencing (scRNAseq) studies have revealed differentially expressed genes without reaching consensus. Here, we demonstrate that further insights into T2D disease mechanisms can be obtained by network-based analysis of scRNAseq data from individual cell types. We developed differential gene coordination network analysis (dGCNA) and analyzed islet SmartSeq2 scRNAseq data from 16 T2D and 16 non-T2D individuals. dGCNA reveals T2D-induced cell type-specific networks of dysregulated genes with remarkable ontological specificity, thus allowing for a comprehensive and unbiased functional classification of genes involved in T2D. In beta cells eleven networks of genes are detected, revealing that mitochondrial electron transport chain, glycolysis, cytoskeleton organization, cell proliferation, unfolded protein response and three networks of beta cell transcription factors are perturbed, whereas exocytosis, lysosomal regulation and insulin translation programs are instead enhanced in T2D. Furthermore, we validated the ability of dGCNA to reveal disease mechanisms and predict the functional context of genes by showing that TMEM176A/B regulates beta cell microfilament organization and that CEPBG is an important regulator of the unfolded protein response. In addition, when comparing beta- and alpha cells, we found substantial differences, reproduced across independent datasets, confirming cell type-specific alterations in T2D. We conclude that analysis of networks of differentially coordinated genes provides detailed insight into cell type-specific gene function and T2D pathophysiology.
    DOI:  https://doi.org/10.1038/s41467-025-65060-z
  8. Nat Commun. 2025 Oct 30. 16(1): 9592
    Data navigation on the ENCODE portal.
    Meenakshi S Kagda, Bonita Lam, Casey Litton, Corinn Small, Cricket A Sloan, Emma Spragins, Forrest Tanaka, Ian Whaling, Idan Gabdank, Ingrid Youngworth, J Seth Strattan, Jason Hilton, Jennifer Jou, Jessica Au, Jin-Wook Lee, Kalina Andreeva, Keenan Graham, Khine Lin, Matt Simison, Otto Jolanki, Paul Sud, Pedro Assis, Philip Adenekan, Stuart Miyasato, Weiwei Zhong, Yunhai Luo, Zachary Myers, J Michael Cherry, Benjamin C Hitz.
      Spanning two decades, the collaborative ENCODE project aims to identify all the functional elements within human and mouse genomes. To best serve the scientific community, the comprehensive ENCODE data including results from 23,000+ functional genomics experiments, 800+ functional elements characterization experiments and 60,000+ results from integrative computational analyses are available on an open-access data-portal ( https://www.encodeproject.org/ ). The final phase of the project includes data from several novel assays aimed at characterization and validation of genomic elements. In addition to developing and maintaining the data portal, the Data Coordination Center (DCC) implemented and utilised uniform processing pipelines to generate uniformly processed data. Here we report recent updates to the data portal including a redesigned home page, an improved search interface, new custom-designed pages highlighting biologically related datasets and an enhanced cart interface for data visualisation plus user-friendly data download options. A summary of data generated using uniform processing pipelines is also provided.
    DOI:  https://doi.org/10.1038/s41467-025-64343-9
  9. J Clin Invest. 2025 Oct 28. pii: e191075. [Epub ahead of print]
    Secretory kinase FAM20C triggers adipocyte dysfunction inciting insulin resistance and inflammation in obesity.
    Ankit Gilani, Benjamin D Stein, Anne Hoffmann, Renan Pereira de Lima, Elizabeth E Ha, Edwin A Homan, Lunkun Ma, Alfonso Rubio-Navarro, Tint Tha Ra Wun, Gabriel Jose Ayala Carrascal, Bhavneet Bhinder, Adhideb Ghosh, Falko J Noé, Olivier Elemento, Christian Wolfrum, Matthias Blüher, James C Lo.
      Obesity is a major driver of type 2 diabetes (T2D) and related metabolic disorders, characterized by chronic inflammation and adipocyte dysfunction. However, the molecular triggers initiating these processes remain poorly understood. We identify FAM20C, a serine/threonine kinase, as an early obesity-induced mediator of adipocyte dysfunction. Fam20c expression is substantially upregulated in adipocytes in response to obesity, correlating with a proinflammatory transcriptional signature. Forced expression of Fam20c in adipocytes promotes robust upregulation of proinflammatory cytokines and induces insulin resistance that is dependent on its kinase activity. Conversely, deletion of adipocyte Fam20c after established obesity and hyperglycemia improves glucose tolerance, augments insulin sensitivity, and reduces visceral adiposity, without altering body weight. Phosphoproteomic studies reveal that FAM20C regulates phosphorylation of intracellular and secreted proteins, modulating pathways critical to inflammation, metabolism, and extracellular matrix remodeling. We identify FAM20C-dependent substrates, such as CNPY4, whose phosphorylation contributes to proinflammatory adipocyte signaling. Of translational relevance, we show that in humans visceral adipose FAM20C expression positively correlates with insulin resistance. Our findings establish FAM20C as an early regulator of obesity-induced adipocyte dysfunction and systemic metabolic impairment. Our studies provide proof of concept that inhibition of FAM20C may serve as a potential therapy for T2D by restoring adipocyte health.
    Keywords:  Adipose tissue; Cell biology; Diabetes; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI191075
  10. Nature. 2025 Oct 31.
    Longer walks beat shorter strolls for heart health.
      
    Keywords:  Epidemiology
    DOI:  https://doi.org/10.1038/d41586-025-03513-7
  11. Nat Methods. 2025 Oct 30.
    Nicheformer: a foundation model for single-cell and spatial omics.
    Alejandro Tejada-Lapuerta, Anna C Schaar, Robert Gutgesell, Giovanni Palla, Lennard Halle, Mariia Minaeva, Larsen Vornholz, Leander Dony, Francesca Drummer, Till Richter, Mojtaba Bahrami, Fabian J Theis.
      Tissue makeup depends on the local cellular microenvironment. Spatial single-cell genomics enables scalable and unbiased interrogation of these interactions. Here we introduce Nicheformer, a transformer-based foundation model trained on both human and mouse dissociated single-cell and targeted spatial transcriptomics data. Pretrained on SpatialCorpus-110M, a curated collection of over 57 million dissociated and 53 million spatially resolved cells across 73 tissues on cellular reconstruction, Nicheformer learns cell representations that capture spatial context. It excels in linear-probing and fine-tuning scenarios for a newly designed set of downstream tasks, in particular spatial composition prediction and spatial label prediction. Critically, we show that models trained only on dissociated data fail to recover the complexity of spatial microenvironments, underscoring the need for multiscale integration. Nicheformer enables the prediction of the spatial context of dissociated cells, allowing the transfer of rich spatial information to scRNA-seq datasets. Overall, Nicheformer sets the stage for the next generation of machine-learning models in spatial single-cell analysis.
    DOI:  https://doi.org/10.1038/s41592-025-02814-z
  12. Nat Aging. 2025 Oct 29.
    Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer's pathogenesis.
    Min Gao, Jing Bai, Fangzhou Lou, Yang Sun, Zhikai Wang, Xiaojie Cai, Yan Li, Fengjiao Zhang, Jihuan Liang, Xiangxiao Li, Yue Wu, Ziyang Zhang, Li Fan, Xinping Jin, Honglin Wang.
      Dysregulated lipid metabolism promotes persistent microglial activation and neuroinflammation in Alzheimer's disease (AD), but the underlying pathogenic mechanisms remain to be elucidated, and druggable targets remain to be identified. Here we found that multifunctional enzyme type 2 (MFE-2), the key enzyme regulating fatty acid β-oxidation in the peroxisome, was downregulated in the microglia of humans with AD and AD model mice. Microglia-specific ablation of MFE-2 drove microglial abnormalities, neuroinflammation and Aβ deposition in AD models. Mechanistically, MFE-2 deficiency facilitated lipid accumulation, resulting in excessive arachidonic acid, mitochondrial reactive oxygen species and proinflammatory cytokine production by microglia. The compound 3-O-cyclohexane carbonyl-11-keto-β-boswellic acid (CKBA) bound to MFE-2 and restored MFE-2 levels, ameliorating AD pathology by inhibiting microglial overactivation. Collectively, our data revealed a pathogenic role of microglia with impaired lipid metabolism in AD and identified MFE-2 as a druggable target of CKBA, which restores its expression and has therapeutic potential for treating AD.
    DOI:  https://doi.org/10.1038/s43587-025-00976-1
  13. Nat Cell Biol. 2025 Oct 31.
    Ten essential tips for robust statistics in cell biology.
    Eliana Ibrahimi, Brooke N Wolford.
      
    DOI:  https://doi.org/10.1038/s41556-025-01801-y
  14. Nat Med. 2025 Oct 28.
    Low cholesterol levels and cardiovascular risk in obesity due to MC4R deficiency.
      
    DOI:  https://doi.org/10.1038/s41591-025-04039-1
  15. Nat Rev Immunol. 2025 Oct 31.
    Phagocytosis: a process that shapes immune responses to engulfed meals.
    Kai Li, David M Underhill.
      The process of phagocytosis creates intracellular compartments (organelles known as phagosomes) that are central hubs for innate immune sensing of potentially dangerous microorganisms, cells, cellular debris and foreign objects. Receptors, enzymes and signalling molecules are specifically enriched in these compartments, wherein they learn everything they can about the phagocytosed material and signal for the cell to mount appropriate responses. The phagosome organelle is also a compartment that facilitates nutrient and metabolite harvesting from internalized materials. This Review explores recent developments in our understanding of phagocytosis as a specific mechanism of innate immune sensing. We discuss efforts to identify the catalogue of proteins that are enriched in different types of phagosomes to learn how these molecules work together to tailor inflammatory and antimicrobial immune responses.
    DOI:  https://doi.org/10.1038/s41577-025-01231-9
  16. Nature. 2025 Oct;646(8087): 1048-1049
    AI can supercharge inequality - unless the public learns to control it.
    Cathy O'Neil.
      
    Keywords:  Computer science; Economics; Machine learning; Policy; Society
    DOI:  https://doi.org/10.1038/d41586-025-03475-w
  17. Sci Signal. 2025 Oct 28. 18(910): eadt3549
    Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria.
    Madelyn M Jackstadt, Ronald Fowle-Grider, Mun-Gu Song, Matthew H Ward, Madison Barr, Kevin Cho, Hector H Palacios, Samuel Klein, Leah P Shriver, Gary J Patti.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to a shift in the composition of the gut microbiome. Here, we found that depletion of the gut microbiome in adult zebrafish led to the development of steatotic liver disease in animals on standard diets. Using metabolomics and isotope tracing, we found that dietary glucose was converted to sorbitol by host intestinal cells. Although bacteria degraded sorbitol in control animals, sorbitol was transferred to the livers of fish when the gut microbiome had been depleted. Within the liver, sorbitol was converted into fructose 1-phosphate, which subsequently activated glucokinase and increased glycolytic flux, leading to increased hepatic glycogen and fat content. Inhibition of sorbitol production in microbiome-depleted animals was sufficient to prevent the development of steatotic liver, and colonizing the intestines of microbiome-depleted fish with sorbitol-degrading Aeromonas bacterial strains rescued the steatotic liver phenotype. Conversely, exogenous administration of high concentrations of sorbitol phenocopied gut microbiota depletion and induced hepatic steatosis. Together, these findings show that sorbitol-degrading bacteria in the gut protect against steatotic liver disease and suggest that excessive intake of dietary sorbitol may pose a risk for the development of MASLD.
    DOI:  https://doi.org/10.1126/scisignal.adt3549
  18. Nat Methods. 2025 Oct 27.
    Improved reconstruction of single-cell developmental potential with CytoTRACE 2.
    Minji Kang, Gunsagar S Gulati, Erin L Brown, Zhen Qi, Susanna Avagyan, Jose Juan Almagro Armenteros, Rachel Gleyzer, Wubing Zhang, Chloé B Steen, Jeremy Philip D'Silva, Janella Schwab, Michael F Clarke, Aadel A Chaudhuri, Aaron M Newman.
      While single-cell RNA sequencing has advanced our understanding of cell fate, identifying molecular hallmarks of potency-a cell's ability to differentiate into other cell types-remains a challenge. Here we introduce CytoTRACE 2, an interpretable deep learning framework for predicting absolute developmental potential from single-cell RNA sequencing data. Across diverse platforms and tissues, CytoTRACE 2 outperformed previous methods in predicting developmental hierarchies, enabling detailed mapping of single-cell differentiation landscapes and expanding insights into cell potency.
    DOI:  https://doi.org/10.1038/s41592-025-02857-2
  19. Nat Immunol. 2025 Nov;26(11): 1903-1915
    Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity.
    PHOSP-COVID Study Collaborative Group
      The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3-6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.
    DOI:  https://doi.org/10.1038/s41590-025-02301-9
  20. Nat Commun. 2025 Oct 27. 16(1): 9455
    UNICORN: Towards universal cellular expression prediction with a multi-task learning framework.
    Tianyu Liu, Tinglin Huang, Lijun Wang, Yingxin Lin, Rex Ying, Hongyu Zhao.
      Sequence-to-function analysis is a challenging task in human genetics, especially in predicting cell-type-specific multi-omic phenotypes from biological sequences such as individualized gene expression. Here, we present UNICORN, a computational method with improved prediction performances than the existing methods. UNICORN takes the embeddings from biological sequences as well as external knowledge from pre-trained foundation models as inputs and optimizes the predictor with carefully-designed loss functions. We demonstrate that UNICORN outperforms the existing methods in both gene expression prediction and multi-omic phenotype prediction at the cellular level and the cell-type level, and it can also generate uncertainty scores of the predictions. Moreover, UNICORN is able to link personalized gene expression profiles with corresponding genome information. Finally, we show that UNICORN is capable of characterizing complex biological systems for different disease states or perturbations. Overall, embeddings from foundation models can facilitate the understanding of the role of biological sequences in the prediction task, and incorporating multi-omic information can enhance prediction performances.
    DOI:  https://doi.org/10.1038/s41467-025-64506-8
  21. Nature. 2025 Oct 29.
    This whale lives for centuries: its secret could help extend human lifespan.
    Heidi Ledford.
      
    Keywords:  Ageing; Molecular biology; Zoology
    DOI:  https://doi.org/10.1038/d41586-025-03511-9
  22. JAMA Netw Open. 2025 Oct 01. 8(10): e2539286
    Duration of Continuous Glucose Monitoring and Glycemic Outcomes in Type 2 Diabetes.
    Peter Lommer Kristensen.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.39286
  23. Cell. 2025 Oct 24. pii: S0092-8674(25)01126-2. [Epub ahead of print]
    SARM1 senses dsDNA to promote NAD+ degradation and cell death.
    Lina Wang, Qiaoling Liu, Siru Li, Na Wang, Yan Chen, Junren Chen, Li Wang, Yuelin Huang, Zhen Sun, Ling Dong, Shao Li, Quentin Liu, Song Gao, Xiaochi Ma, Chengli Song, Qingkai Yang.
      Detection of DNA is a fundamental strategy for life to recognize non-self or abnormal-self to subsequently trigger the downstream responses. However, the mechanism underlying DNA sensing is incompletely understood. Here, we show that a key neural executioner, sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), senses double-stranded DNA (dsDNA) to promote cell death. dsDNA-bound and -activated SARM1 to degrade nicotinamide adenine dinucleotide (NAD+) in a sequence-independent manner. SARM1 bound dsDNA via the TIR domain, and lysine residues in the TIR domain contributed to dsDNA binding. In the cellular context, cytosolic dsDNA from dsDNA transfection or chemotherapy treatment was colocalized with SARM1 and activated SARM1 to elicit NAD+ degradation and cell death, which was abrogated by SARM1 knockout or DNA-binding residue mutation. Consistently, SARM1 knockout blocked chemotherapy-induced neuropathy (CIN) in mice. Our results reveal SARM1 as a DNA sensor, which might be targetable for therapeutic interventions.
    Keywords:  CIN; DNA sensor; NAD; SARM1; TIR domain; axon degeneration; cancer; cell death; chemotherapy-induced neuropathy; metabolism
    DOI:  https://doi.org/10.1016/j.cell.2025.09.026
  24. Sci Adv. 2025 Oct 31. 11(44): eadt3014
    Pharmacological targeting of RIG-I can selectively activate the integrated stress response.
    Caroline A Cuoco, Wen Ren, Kelsey R Baron, Sakina Gologo, Valerie Perea, Prakhyat Mathur, Prerona Bora, Amina Ta, Alan Chu, Rama Aldakhlallah, Derek Rhoades, Christian M Cole, Ee Phie Tan, William C Hou, Leonard Yoon, Xiaoyan Guo, Jessica D Rosarda, Phil S Baran, Martin Kampmann, Lakeisha Tillery, Kristen A Johnson, Evan T Powers, R Luke Wiseman, Jeffery W Kelly.
      The integrated stress response (ISR) is a eukaryotic stress-responsive signaling pathway that attenuates global protein synthesis while allowing selective translation of specific mRNAs, which together can reestablish homeostasis following acute stress. Diverse pathologic insults activate one or more of the four ISR kinases, which selectively phosphorylate eIF2α to mediate ISR functions. Recent results suggest that enhancing ISR kinase activity could ameliorate pathologies linked to numerous diseases, including many neurodegenerative disorders. However, few pharmacological strategies exist to selectively activate ISR kinases and downstream adaptive signaling. Here, we report that compound A8 can preferentially activate the ISR through the binding of the cytosolic pattern recognition receptor RIG-I, which subsequently activates the heme-regulated inhibitor (HRI) ISR kinase independent of an interferon response. The establishment of A8 and its active metabolite CC81 provides opportunities to probe the biological and therapeutic relationship between innate immune signaling and ISR activation in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.adt3014
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