bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–11–30
thirty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mitochondrial NAD+ drives liver regeneration.
  2. Human plasma proteomic profile of clonal hematopoiesis.
  3. Motif-based models accurately predict cell type-specific distal regulatory elements.
  4. Mechanical confinement induces ferroptosis through mitochondrial dysfunction.
  5. A metabolic atlas of mouse aging.
  6. Epigenetic and transcriptional programming of murine eosinophils in the esophagus.
  7. Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice.
  8. Stabilizing iTreg cells.
  9. Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
  10. Audio long read: Faulty mitochondria cause deadly diseases - fixing them is about to get a lot easier.
  11. Estrogen dominance drives distinct patterns of brain plasticity.
  12. Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance.
  13. iHALT unlocks liver functionality as a surrogate secondary lymphoid organ.
  14. Local Treg cell loss reprogrammes systemic antitumour immunity without breaking tolerance.
  15. Scalable spatial single-cell transcriptomics and translatomics in 3D thick tissue blocks.
  16. The luminal domain region of Seipin/Fld1 is dispensable for establishing functional ER sites for lipid droplet biogenesis.
  17. Defining the role of β-cell IRE1α/XBP1 pathway and its gene regulatory network components in non-obese diabetic mice.
  18. ER exit sites mediated by the COPII adaptor sec24D selectively recruit lipid raft-preferring proteins for rapid ER export.
  19. SPACEc: a streamlined, interactive Python workflow for multiplexed image processing and analysis.
  20. Compressed sensing expands the multiplexity of imaging mass cytometry.
  21. Deciphering age- and sex-specific patterns of coronary artery atherosclerosis from a large Chinese cohort.
  22. Fructose intake driven glycolysis-ROS-EGFR axis specifically promotes the generation and pathogenicity of Th17 cells.
  23. Substrate recognition diversity and transport dynamics of ABCC1.
  24. A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes.
  25. Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2.
  26. Very long-chain fatty acids drive 1-deoxySphingolipid toxicity.
  27. A noncanonical polyamine from bacteria antagonizes host mitochondrial function.
  28. Multi-omic analysis reveals lipid dysregulation associated with mitochondrial dysfunction in parkinson's disease brain.
  29. Bridging the variant-to-function gap in type 2 diabetes: advances and challenges.
  30. The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia.
  31. Does continuous glucose monitoring deliver in gestational diabetes?
  1. Nat Metab. 2025 Nov 24.
    Mitochondrial NAD+ drives liver regeneration.
      
    DOI:  https://doi.org/10.1038/s42255-025-01414-7
  2. Nat Commun. 2025 Nov 27.
    Human plasma proteomic profile of clonal hematopoiesis.
    NHLBI Trans-Omics for Precision Medicine
      Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations show substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangle causal proteomic perturbations from TET2 CHIP. Lastly, we identify plasma proteins shared between CHIP and CAD.
    DOI:  https://doi.org/10.1038/s41467-025-66755-z
  3. Nat Commun. 2025 Nov 24. 16(1): 10370
    Motif-based models accurately predict cell type-specific distal regulatory elements.
    Paola Cornejo-Páramo, Xuan Zhang, Lithin Louis, Zelun Li, Yihua Yang, Emily S Wong.
      Deciphering how DNA sequence specifies cell-type-specific regulatory activity is a central challenge in gene regulation. We present Bag-of-Motifs (BOM), a computational framework that represents distal cis-regulatory elements as unordered counts of transcription factor (TF) motifs. This minimalist representation, combined with gradient-boosted trees, enables the accurate prediction of cell-type-specific enhancers across mouse, human, zebrafish, and Arabidopsis datasets. Despite its simplicity, BOM outperforms more complex deep-learning models while using fewer parameters. We validate BOM's predictions experimentally by constructing synthetic enhancers from the most predictive motifs, demonstrating that these motif sets drive cell-type-specific expression. By providing direct interpretability and broad applicability, BOM reveals a highly predictive sequence code at distal regulatory regions and offers a scalable framework for dissecting cis-regulatory grammar across diverse species and conditions.
    DOI:  https://doi.org/10.1038/s41467-025-65362-2
  4. Nat Commun. 2025 Nov 28.
    Mechanical confinement induces ferroptosis through mitochondrial dysfunction.
    Fang Zhou, Robert J Ju, Chenlu Kang, Jiayi Li, Ao Yang, Alexandre Libert, Yujie Sun, Ling Liang, Youwei Ai, Xiaoqing Hu, Samantha J Stehbens, Congying Wu.
      Cells in highly crowded environments are exposed to fluctuating mechanical forces. While cells can activate the cortical migration machinery to escape from undesirable compressive stress, the consequence to less motile cells and of prolonged extensive confinement is yet to be uncovered. Here, we demonstrate that nuclear deformation generated by axial confinement triggers a specific form of regulated cell death - ferroptosis. We show that axial confinement is sensed by the nucleus and results in Drp1-dependent mitochondrial fragmentation and mitochondrial ROS accumulation. Meanwhile, we detect cPLA2 translocation to mitochondria. These mitochondrial ROS accumulation and arachidonic acid production concertedly lead to lipid peroxidation and evoke ferroptosis. Interestingly, we find in osteoarthritis, a disease intimately associated with mechanical overloading and inflammation, characteristics of confinement-induced ferroptosis including mitochondrial localization of cPLA2 and high ROS. Together, our findings unveil a pivotal role of cell nucleus and mitochondria in linking mechanical confinement with cell death, highlighting the orchestration of Drp1 and cPLA2 in confinement-induced ferroptosis.
    DOI:  https://doi.org/10.1038/s41467-025-66353-z
  5. Cell Metab. 2025 Nov 25. pii: S1550-4131(25)00476-0. [Epub ahead of print]
    A metabolic atlas of mouse aging.
    Steven E Pilley, Dominik Awad, Djakim Latumalea, Connie New, Edgar Esparza, Shuo Wang, Xuanyi Shi, Li Zhang, Maximilian Unfried, Jasinda H Lee, Ernst Schmid, Ipsita Mohanty, Jenna L E Blum, Shivaanishaa Raventhiran, Esther Wong, Preeti R Iyengar, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Damien Sutton, Harrison K A Wong, Yaqi Gao, George Wang, Aeowynn J Coakley, Gilberto Garcia, Ryo Higuchi-Sanabria, Anja Karlstaedt, Timothy L Frankel, Marina Pasca di Magliano, Whitaker Cohn, Sophia Liu, Bingfei Yu, Pieter C Dorrestein, Ernest Fraenkel, Shawn M Davidson, William B Tu, Brian K Kennedy, Costas A Lyssiotis, Peter J Mullen.
      Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.
    Keywords:  LC-MS/MS; MALDI-MSI; aging; aging clocks; healthspan; human tissue; hydroxyproline; metabolism; scRNA-seq; sex
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.016
  6. Nat Commun. 2025 Nov 25. 16(1): 10454
    Epigenetic and transcriptional programming of murine eosinophils in the esophagus.
    Jennifer M Felton, Lee E Edsall, Ty D Troutman, Lydia Mack, Michael Kotliar, Netali Ben-Baruch Morgenstern, Annalise M Psaila, Mark Rochman, Andrea M Klingler, Garrett A Osswald, Simin Zhang, Julia L M Dunn, Ben Wronowski, Tetsuo Shoda, Julie M Caldwell, Rana Herro, Artem Barski, Kate G R Quinlan, Matthew T Weirauch, Marc E Rothenberg.
      Eosinophils accumulate in different tissues in allergies, cancer, and infectious diseases, adopting distinct properties. Herein, we profiled murine esophageal eosinophils during allergic inflammation using single-cell sequencing, epigenomic mapping, and flow cytometry. Esophageal eosinophils displayed an altered chromatin accessibility profile compared to bone marrow eosinophils, with 761 epi-transcriptionally regulated genes enriched in inflammation, immunoregulation, bacterial sensing, angiogenesis, migration, and apoptosis. The local environment entrains the unique esophageal eosinophil immunophenotype, as suggested by eosinophil-esophageal epithelial co-cultures, esophageal eosinophil transcriptional similarities regardless of the upstream cytokines driving their esophageal localization, and transcription factor gene editing altering esophageal eosinophilia and the associated eosinophil and global esophageal transcriptomes. Finally, the epigenomic and transcriptomic properties of murine esophageal eosinophils are largely conserved in humans. Thus, our data indicate that tissue specialization of esophageal eosinophils is entrained by local environmental cues that induce genome-wide epigenetic reprogramming and regulated by discrete transcription factors and provide a public, epigenetic database of murine tissue eosinophils.
    DOI:  https://doi.org/10.1038/s41467-025-65440-5
  7. Nat Commun. 2025 Nov 25. 16(1): 10447
    Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice.
    Xiaoyue Pan, Cyrus Mowdawalla, Samantha Bagnato, Jeffrey Pessin, Volker Vallon, M Mahmood Hussain.
      The kidneys contribute to glucose homeostasis by gluconeogenesis and glucose reabsorption. Herein, we identified previously unknown fasting-induced, glucagon-mediated inhibitory effect of the circadian clock gene basic helix-loop-helix ARNT like 1 (Bmal1) on the expression of the main proximal tubule glucose transporter solute carrier family 5 member 2 (Sglt2) in mice. During fasting, glucagon induces Bmal1, which increases expression of nuclear receptor subfamily 1, group D, member 1 (Rev-erbα). Rev-erbα represses nuclear respiratory factor 1, a transcriptional activator of Sglt2, and diminishes Sglt2 expression and thereby kidney glucose reabsorption capacity. During refeeding (lower glucagon) this process is attenuated, thereby inducing glucose reabsorption. The physiological role of this mechanism appears to ensure optimal temporal retrieval of filtered glucose during fasting/refeeding. Thus, this study demonstrates that during fasting and refeeding, glucagon regulates renal glucose reabsorption by utilizing the local cellular circadian machinery.
    DOI:  https://doi.org/10.1038/s41467-025-65402-x
  8. Nat Immunol. 2025 Dec;26(12): 2117
    Stabilizing iTreg cells.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-025-02361-x
  9. Nat Commun. 2025 Nov 28. 16(1): 10761
    Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
    Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.
      Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.
    DOI:  https://doi.org/10.1038/s41467-025-65798-6
  10. Nature. 2025 Nov 28.
    Audio long read: Faulty mitochondria cause deadly diseases - fixing them is about to get a lot easier.
    Gemma Conroy, Benjamin Thompson.
      
    DOI:  https://doi.org/10.1038/d41586-025-03797-9
  11. Nat Neurosci. 2025 Nov 25.
    Estrogen dominance drives distinct patterns of brain plasticity.
      
    DOI:  https://doi.org/10.1038/s41593-025-02086-y
  12. Nat Commun. 2025 Nov 24.
    Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance.
    Rongya Tao, Oliver Stöhr, Ozlem Tok, Ana Andres-Hernando, Wei Qiu, Baiyu He, Caixia Wang, Lars Grøntved, Charles Burant, Sheng Hui, Miguel A Lanaspa, Norbert Stefan, Kyle D Copps, Morris F White.
      MASLD (metabolic-associated steatotic liver disease) and MASH (steatohepatitis) are closely associated with hepatic IR (insulin resistance) and T2D. Regardless, insulin-stimulated hepatic lipogenesis is considered essential for MASLD development, as mouse models of complete hepatic IR become diabetic without MASLD when fed high-fat diets. Challenging this notion, we found that male LDKO mice lacking hepatic insulin receptor substrates acutely developed MASLD if fed a fructose-enriched "MASH diet" (GAN) or high-fructose diet. Fructose potentiated hepatic re-esterification of abundant circulating fatty acids in LDKO mice, evidenced by excess 13C incorporation into the glycerol backbone-but not fatty acid chains-of hepatic triacylglyceride after gavage with [U13C]fructose. Suppressing adipose lipolysis in LDKO mice by inactivating hepatic Fst (Follistatin) prevented acute MASLD, whereas over-expressing Fst in wild-type mouse liver accelerated GAN-promoted MASLD/MASH. Compatibly, higher serum FST levels among Tübingen Diabetes Family Study participants clustered with increased adipose IR and greater hepatic triacylglyceride accumulation.
    DOI:  https://doi.org/10.1038/s41467-025-66296-5
  13. Nature. 2025 Nov 26.
    iHALT unlocks liver functionality as a surrogate secondary lymphoid organ.
    John Gridley, David Pak, Anuradha Kumari, Jacob Shupak, Brantley Holland, Yifeng Shi, Sheetal Trivedi, Yongtao Wang, Sudhir Pai Kasturi, Amit Kapoor, Raymond T Chung, Arash Grakoui.
      Upon viral infection, the current paradigm of humoral immunity posits that germinal centre reactions occurring within secondary lymphoid organs (SLOs) yield effector plasma cells that subsequently traffic to infected organs or the bone marrow1-3. However, it is not well understood how viral tissue tropism may govern the spatiotemporal dynamics of such responses. Here we demonstrate that infection with a prototypical systemic virus indeed induces liver-trafficking plasma cells generated in SLOs, whereas strictly hepatotropic hepaciviral infection elicits locally primed, virus-specific plasma cells in the liver independently of SLO contribution. Such locally derived progenies emerged from inducible hepatic-associated lymphoid tissue (iHALT) structures containing generative foci of T follicular helper cells, myeloid cells and germinal centre-like B cells, often arising from single founder clones unique to individual periportal structures and locally supporting somatic hypermutation. Critically, the cellular composition, cell-cell contact partners and microarchitecture of such iHALT structures in mice were closely mirrored upon hepaciviral infection in humans. Functionally dependent upon CD40L signalling and cognate B cell receptor specificity, emerging CXCR4+VLA-4+LFA-1+CD44+CD138+ plasma cells were immediately retained along CXCL12+fibronectin+ICAM2+osteopontin+type I collagen+ periportal fibroblast tracts, acting as cognate anchoring pairs that were critical to their maintenance therein. In summary, we characterize humoral immunity exclusively generated and maintained within its extralymphoid site of viral infection in the liver amidst SLO dormancy, in which functional iHALT successfully compensates for strictly hepatotropic virus-induced SLO-evasion strategies to prevent persistent infection.
    DOI:  https://doi.org/10.1038/s41586-025-09803-4
  14. Nat Rev Immunol. 2025 Nov 26.
    Local Treg cell loss reprogrammes systemic antitumour immunity without breaking tolerance.
    Mehdi Chaib, James P Allison.
      
    DOI:  https://doi.org/10.1038/s41577-025-01253-3
  15. Nat Methods. 2025 Nov 24.
    Scalable spatial single-cell transcriptomics and translatomics in 3D thick tissue blocks.
    Xin Sui, Jennifer A Lo, Shuchen Luo, Yichun He, Zefang Tang, Zuwan Lin, Dániel L Barabási, Yiming Zhou, Wendy Xueyi Wang, Jia Liu, Xiao Wang.
      Characterizing the transcriptional and translational gene expression patterns at the single-cell level within their three-dimensional (3D) tissue context is essential for revealing how genes shape tissue structure and function in health and disease. However, most existing spatial profiling techniques are limited to 5-20 µm thin tissue sections. Here, we developed Deep-STARmap and Deep-RIBOmap, which enable 3D in situ quantification of thousands of gene transcripts and their corresponding translation activities, respectively, within 60-200-µm thick tissue blocks. This is achieved through scalable probe synthesis, hydrogel embedding with efficient probe anchoring and robust cDNA crosslinking. We first utilized Deep-STARmap in combination with multicolor fluorescent protein imaging for simultaneous molecular cell typing and 3D neuron morphology tracing in the mouse brain. We also demonstrate that 3D spatial profiling facilitates comprehensive and quantitative analysis of tumor-immune interactions in human skin cancer.
    DOI:  https://doi.org/10.1038/s41592-025-02867-0
  16. Nat Commun. 2025 Nov 27. 16(1): 10642
    The luminal domain region of Seipin/Fld1 is dispensable for establishing functional ER sites for lipid droplet biogenesis.
    Amit Khatri, Ritika Chaudhary, R Mankamna Kumari, Vineet Choudhary.
      Lipid droplet (LD) biogenesis occurs in the endoplasmic reticulum (ER), the mechanisms of which is not completely known. Seipin (Fld1 in yeast) is a crucial ER membrane protein that defines LD biogenesis sites. Here, we show that truncated seipin, Fld1-∆LR in yeast, and the human equivalent hSeipin-∆LR, mutants lacking the conserved luminal domain region (LR), functionally complement the LD biogenesis defect of fld1∆ mutants. Fld1-∆LR foci colocalize with factors: Nem1, Ldb16, Pex30 and Yft2, which are important for LD biogenesis and these sites become enriched in diacylglycerol upon stimulation of LD formation. Fld1-∆LR forms a homo-oligomeric complex facilitated by protein-protein interactions. We show that mutating the 31st proline abrogates the functioning of Fld1-∆LR. We demonstrate the critical regulatory role of LR of seipin in partitioning triacylglycerol into LDs. We conclude that LR of seipin is dispensable for establishing functional ER sites to recruit proteins for LD biogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-65645-8
  17. Nat Commun. 2025 Nov 26. 16(1): 10574
    Defining the role of β-cell IRE1α/XBP1 pathway and its gene regulatory network components in non-obese diabetic mice.
    Hugo Lee, Khagani Eynullazada, Qiaodan Ou, Junha Shin, Sushmita Roy, Feyza Engin.
      The unfolded protein response sensor, IRE1α, acts through its regulated IRE1α-dependent decay (RIDD) activity or transcription factor XBP1 to determine cell fate and survival. While blunting RIDD activity prevents diabetes in type 1 diabetes preclinical model non-obese diabetic mice, β-cell-specific function of XBP1 at different stages of disease remains unknown. Here we show that deletion of Xbp1 in β-cells (Xbp1β-/-) of non-obese diabetic mice before insulitis is protective against diabetes. Histological and transcriptomic analyses indicate that following a transient loss of maturity, β-cells of Xbp1β-/- mice exhibit reduced insulitis, apoptosis, and antigenicity phenocopying Ire1αβ-/- mice with no changes in RIDD activity. Comparative transcriptome and regulatory network analyses reveal a largely shared component between the Ire1αβ-/- and Xbp1β-/- mice as well as network components unique to Xbp1β-/-, indicative of IRE1α-independent roles of XBP1. Our findings define the role of β-cell IRE1α/XBP1 and identify previously unrecognized regulatory networks and nodes of this pathway.
    DOI:  https://doi.org/10.1038/s41467-025-65635-w
  18. Nat Commun. 2025 Nov 27. 16(1): 10694
    ER exit sites mediated by the COPII adaptor sec24D selectively recruit lipid raft-preferring proteins for rapid ER export.
    Ivan Castello-Serrano, Shikha Dagar, Rossana Ippolito, Kandice R Levental, Ilya Levental.
      The determinants of sub-cellular trafficking for many membrane proteins are poorly understood. Lipid-driven membrane nanodomains known as lipid rafts have been widely implicated in post-Golgi traffic, but their involvement in protein sorting in the endoplasmic reticulum has not been widely considered. To assess the role of membrane domains in the early secretory pathway, we use the Retention Using Selective Hooks system to synchronize and quantitatively assess trafficking rates and destinations of model proteins with tunable raft affinities. We find that raft-preferring constructs exit the ER faster than raft-excluded and have distinct preferences for ER exit sites marked by specific isoforms of sec24 cargo adaptors. Namely, raft-excluded cargo localizes to sec24A-positive sites while raft-preferring cargo localizes to sec24D ERES, dependent on p24-family cargo adapters TMED2/10. Finally, sec24D, but not sec24A, ERES accumulate a fluorescent cholesterol analog. These observations suggest that association with raft-like domains affects protein export from the ER.
    DOI:  https://doi.org/10.1038/s41467-025-65726-8
  19. Nat Commun. 2025 Nov 27. 16(1): 10652
    SPACEc: a streamlined, interactive Python workflow for multiplexed image processing and analysis.
    Yuqi Tan, Tim N Kempchen, Martin Becker, Maximilian Haist, Dorien Feyaerts, Jiaqi Liu, Marieta Toma, Yang Xiao, Graham Su, Andrew J Rech, Michael Hölzel, Rong Fan, John W Hickey, Garry P Nolan.
      Multiplexed imaging has transformed our ability to study tissue organization by capturing thousands of cells and molecules in their native context. However, these datasets are enormous, often comprising tens of gigabytes per image, and require complex workflows that limit their broader use. Current tools are often fragmented, inefficient, and difficult to adopt across disciplines. Here we show that SPACEc, a scalable Python platform, streamlines spatial imaging analysis from start to finish. The platform integrates image processing, cell segmentation, and data preprocessing into a single workflow, while improving computational performance through parallelization and GPU acceleration. We introduce innovative methods, including patch proximity analysis, to more accurately map local cellular neighborhoods and interactions. SPACEc also simplifies advanced approaches such as deep-learning annotation, making them accessible through an intuitive interface. By combining efficiency, accuracy, and usability, this platform enables researchers from diverse backgrounds to gain deeper insights into tissue architecture and cellular microenvironments.
    DOI:  https://doi.org/10.1038/s41467-025-65658-3
  20. Nat Commun. 2025 Nov 27.
    Compressed sensing expands the multiplexity of imaging mass cytometry.
    Tsuyoshi Hosogane, Leonor Schubert Santana, Nils Eling, Holger Moch, Bernd Bodenmiller.
      The multiplexity of current antibody-based imaging is limited by the number of reporters that can be detected simultaneously. Compressed sensing can be used to reconstruct high-dimensional information from low-dimensional measurements. Previously, compressed sensing using composite in situ imaging (CISI) of transcriptomic data leveraged gene co-regulation structure to recover spatial expression of 37 RNA species from images of 11 composite channels. Here, we extend the CISI framework to protein expression data measured by imaging mass cytometry (IMC). CISI-IMC accurately recovers spatial expression of 16 immune and stromal marker proteins from images of 8 composite channels with an average Pearson's correlation of 0.8 across protein. Training the CISI-IMC framework using data collected on multiple human tissues enables universal decompression of composite data from a wide range of tumor and healthy tissue types. The expression dictionary and barcoding matrix described here are immediately implementable for general immune and stromal cell type classification, but CISI-IMC can in principle be applied to other markers or other antibody-based imaging methods. Our work lays the foundation for much higher plex protein imaging.
    DOI:  https://doi.org/10.1038/s41467-025-66629-4
  21. Nat Commun. 2025 Nov 22. 16(1): 10616
    Deciphering age- and sex-specific patterns of coronary artery atherosclerosis from a large Chinese cohort.
    Xinnian Yang, Jiayin Zhang, Yanli Song, Dengqiang Jia, Qingqi Hong, Yiqiang Zhan, Xiang Sean Zhou, Yining Dong, Yining Wang, Dijia Wu, Dinggang Shen.
      Coronary artery disease poses a significant public health threat, and coronary computed tomography angiography is the preferred imaging modality for diagnosis and risk assessment of coronary artery disease through plaque evaluation. However, understandings of how atherosclerotic characteristics vary by age and sex remains limited due to challenges in manual quantitative plaque assessment. Here, we conducted a retrospective, consecutive, multi-center Chinese cohort study of 16,300 patients undergoing clinically indicated coronary computed tomography angiography that revealed multi-level quantitative patterns of atherosclerosis stratified by age and sex. We found that females experienced a delayed atherosclerosis onset by approximately 20 years compared to males, with plaque burden increasing nonlinearly with age and accelerating more evidently after menopause. The built coronary atlas identified plaque clusters, primarily within proximal segments of major coronary arteries, slightly upstream side branch bifurcations. Our findings provide deeper insights into coronary atherosclerosis in the Chinese population, supporting more tailored prevention strategies.
    DOI:  https://doi.org/10.1038/s41467-025-64940-8
  22. Nat Commun. 2025 Nov 23.
    Fructose intake driven glycolysis-ROS-EGFR axis specifically promotes the generation and pathogenicity of Th17 cells.
    Xiaoyu Liu, Wenhao Hu, Jie Sun, Bing Wu.
      Th17 cells are quite heterogeneous. Treating Th17-related inflammatory disorders requires understanding the functionally diverse subtypes in the context of tissue homeostasis, which is shaped by nutrient availability among other factors. Here, we show that increased consumption of fructose exacerbates colitis and experimental autoimmune encephalomyelitis (EAE), via pathogenic Th17 cells. Fructose selectively enhances the differentiation and function of this pathogenic subtype of Th17 cells, which are induced by a combination of IL1β, IL-6 and IL-23 (pTh17). In contrast, TGFβ1and IL-6-induced homeostatic, non-pathogenic Th17 cells remain unaffected. Notably, fructose enhances metabolic activity in pTh17 cells, leading to increased ROS production and subsequently promoting pathogenic-Th17 cell differentiation. N-acetyl cysteine (NAC), a ROS scavenger, specifically impaired pathogenic-Th17 cell immunity and mitigated high-fructose regulated colitis and EAE disease. Mechanistically, ROS accumulation results in elevated EGFR expression and phosphorylation, which leads to increased nuclear translocation. Nuclear EGFR binds to STAT3, enhancing its transcriptional activity at the CNS6 and CNS9 regions of Rorc. In summary, our work describes here a mechanism through which high fructose intake specifically exacerbates pathogenic Th17-cell-related pathologies and provides potential therapeutic targets for pTh17-mediated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-66064-5
  23. Nat Commun. 2025 Nov 25. 16(1): 10499
    Substrate recognition diversity and transport dynamics of ABCC1.
    Panpan Sun, Kexin Liu, Linnan Zhang, Qixiang Zhang, Yina Gao, Zhaolong Li, Yalan Zhu, Songqing Liu, Liguo Zhang, Ang Gao, Pu Gao.
      ABCC1 is an ATP-binding cassette (ABC) transporter that exports diverse endogenous and exogenous substrates, conferring resistance to many anticancer drugs and mediating various physiological functions. Here, we present ten cryo-EM structures of ABCC1 in different functional states, providing systematic insights into its substrate recognition diversity and transport dynamics. ABCC1 utilizes a plastic bipartite substrate-binding pocket and a substrate-induced conformational flexibility to accommodate molecules with diverse properties, including bimolecular glutathione (GSH)-substrate pairs, GSH conjugates, and GSH-independent cyclic dinucleotides. A herein characterized substrate-releasing intermediate state reveals ATP-mediated overall conformational transitions and detailed pocket reorganization during substrate loading, pre-release, and post-release. Unexpectedly, we identify a sequential nucleotide release mechanism where the hydrolysis product ADP, rather than unhydrolyzed ATP, releases first, priming the transporter for turnover and resetting. Complemented by mutagenesis and functional assays, these findings provide a complete framework for understanding ABCC1's molecular basis and offer a foundation for developing next-generation modulators.
    DOI:  https://doi.org/10.1038/s41467-025-65501-9
  24. Nat Immunol. 2025 Nov 28.
    A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes.
    Neetu Srivastava, Anthony N Vomund, Rongzhen Yu, Orion J Peterson, Yuqing Yang, David P Turicek, Omar Abousaway, Tiandao Li, Lisa Kain, Pamela Stone, Aisha Ansar, Cristina C Clement, Siddhartha Sharma, Rima Melhem, Bo Zhang, Chang Liu, Alok V Joglekar, Hao Hu, Chyi-Song Hsieh, Laura Campisi, Laura Santambrogio, Luc Teyton, Emil R Unanue, Ana Maria Arbelaez, Cheryl F Lichti, Xiaoxiao Wan.
      The antigenic landscape of autoimmune diabetes reflects a failure to preserve self-tolerance, yet how novel neoantigens emerge in humans remains incompletely understood. Here we designed an immunopeptidomics-based approach to probe HLA-II-bound, islet-derived neoepitopes in patients with type 1 diabetes. We uncovered a Cys→Ser transformation, conserved between mice and humans, that reshapes autoreactivity to insulin at the single-residue level. This transformation, which we call C19S, arises from oxidative remodeling of insulin in stressed pancreatic islets and also occurs in cytokine-activated antigen-presenting cells, contributing to a feed-forward loop of neoepitope formation and presentation. Despite involving just one amino acid, C19S is recognized by HLA-DQ8-restricted, register-specific CD4+ T cells that expand at diabetes onset. These neoepitope-specific CD4+ T cells lack regulatory potential but acquire a poised central memory phenotype that persists throughout disease progression. These findings reveal a distinct, microenvironment-driven route of neoantigen formation that fuels sustained autoreactivity in diabetes.
    DOI:  https://doi.org/10.1038/s41590-025-02343-z
  25. Science. 2025 Nov 27. eadv7111
    Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2.
    Martin S Taylor, Maggie Chen, Matthew Hancock, Maximilian Wranik, Bryant D Miller, Timothy R O'Meara, Brad A Palanski, Scott B Ficarro, Brian J Groendyke, Yufei Xiang, Kazuma T Kondo, Karen Y Linde-Garelli, Michelle J Lee, Dibyendu Mondal, Daniel Freund, Samantha Congreve, Kaay Matas, Maximiliaan Hennink, Kera Xibinaku, Max L Valenstein, Trevor van Eeuwen, Jarrod A Marto, Andrej Sali, Yi Shi, Nathanael S Gray, David M Sabatini, Nam Chu, Kacper B Rogala, Philip A Cole.
      The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2-Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved amongst at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.
    DOI:  https://doi.org/10.1126/science.adv7111
  26. Nat Commun. 2025 Nov 26.
    Very long-chain fatty acids drive 1-deoxySphingolipid toxicity.
    Adam Majcher, Gergely Karsai, Elkhan Yusifov, Martina Schaettin, Ermanno Malagola, Peter Horvath, Jinmei Li, Sofía Rodriguez-Gallardo, Kuniyoshi Shimizu, Gai Zhibo, Raghvendra Dubey, Tim Peterson, Takeshi Harayama, Thorsten Hornemann.
      1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids formed when serine palmitoyltransferase incorporates L-alanine instead of L-serine. Elevated 1-deoxySLs are associated with hereditary sensory neuropathy type 1 and diabetic neuropathy, but the molecular basis of their toxicity remains unclear. Here we show that toxicity is mediated by very long-chain (VLC) 1-deoxy-dihydroceramides (1-deoxyDHCer), particularly nervonyl-1-deoxyDHCer (m18:0/24:1) and lignoceryl-1-deoxyDHCer (m18:0/24:0). Using a CRISPR interference screen, we identify ELOVL1 and CERS2 as essential enzymes driving the formation of these toxic species. Genetic modulation or pharmacological inhibition of ELOVL1 prevents VLC 1-deoxyDHCer accumulation, rescuing the toxicity in cellular and neuronal models. Mechanistic studies reveal that m18:0/24:1 disrupts mitochondrial integrity and induces the mitochondrial permeability transition pore formation and BAX activation, leading to cell death. These findings establish a direct link between 1-deoxySL chemical structure and cytotoxicity and highlight ELOVL1 inhibition as a potential therapeutic strategy for 1-deoxySL-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-66687-8
  27. Nat Commun. 2025 Nov 26.
    A noncanonical polyamine from bacteria antagonizes host mitochondrial function.
    Kelsie M Nauta, Darrick R Gates, Matthew Weiland, Marco E Mechan-Llontop, Xiao Wang, Christine Isaguirre, Megan R Gendjar, Jason Cooper, Sawyer F Barton, Kim P Nguyen, Ryan D Sheldon, Connie M Krawczyk, Nicholas O Burton.
      Interactions between gut bacterial polyamines and intestinal cells have been proposed to contribute to inflammatory bowel diseases, but the underlying molecular mechanisms are often unclear. Here, we use a derivatization-based LC-MS approach and the model animal Caenorhabditis elegans to study microbiome-derived polyamine bioactivity. We show that aberrant polyamine metabolism in two diverse bacterial species (Escherichia coli K12 and Bacillus subtilis 168) can result in the accumulation of a noncanonical polyamine intermediate, N1-aminopropylagmatine (N1-APA). N1-APA is produced via spermidine synthase (SpeE) and is bioactive in C. elegans intestinal cells and mouse bone marrow macrophages. Specifically, bacterial N1-APA can be transported into intestinal cells via the polyamine transporter CATP-5, where it antagonizes C. elegans development and activates the mitochondrial unfolded protein response. N1-APA functions analogously to the deoxyhypusine synthase inhibitor GC7 in C. elegans and, like GC7, it antagonizes eIF5A hypusination and inhibits the alternative activation of mouse macrophages in vitro. Our results indicate that bacterial N1-APA is a bioactive metabolite that functions similarly to deoxyhypusine synthase inhibitors but has other unidentified targets that likely play roles in mitochondrial stress responses. We hypothesize that N1-APA production by the gut microbiome, caused by either high dietary agmatine or loss of agmatinase activity, might contribute to inflammatory bowel diseases.
    DOI:  https://doi.org/10.1038/s41467-025-66499-w
  28. Nat Commun. 2025 Nov 25. 16(1): 10490
    Multi-omic analysis reveals lipid dysregulation associated with mitochondrial dysfunction in parkinson's disease brain.
    Jenny Hällqvist, Christina E Toomey, Rui Pinto, Tomas Baldwin, Ivan Doykov, Anna Wernick, Mesfer Al Shahrani, James R Evans, Joanne Lachica, Simon Pope, Simon Heales, Simon Eaton, Kevin Mills, Sonia Gandhi, Wendy E Heywood.
      Parkinson's disease (PD) is an increasingly prevalent neurodegenerative disorder, largely sporadic in origin, with limited understanding of age- and region-specific lipid alterations in the human brain. Dysregulation of glycosphingolipid catabolism has been implicated in PD, yet comprehensive spatiotemporal profiling remains sparse. Here, we performed targeted lipidomics across eight anatomically distinct brain regions in post-mortem controls, mid-stage, and late-stage PD cases using high-precision tissue dissection. Each region displayed distinct lipid signatures, with several age-associated alterations-most notably in hexosylceramides, including glucosylceramide. In PD, glycosphingolipids were reduced in subcortical regions but elevated in cortical regions, particularly gangliosides, HexCer, and Hex2Cer, accompanied by increased sphingolipids and decreased phospholipids. The most pronounced mid-stage changes occurred in the putamen, where very long chain ceramide species and plasmalogen PE decreased, then normalising in late-stage disease. Lyso-phosphatidylcholine increased progressively throughout PD progression. Integrating proteomic data, we observed sphingomyelin levels associated with PD-related proteins, while dysregulated mitochondrial function correlated with antioxidant plasmalogens, long-chain ceramides, lyso-phosphatidylcholine, and HexCer in the putamen. These findings highlight region- and stage-specific lipid alterations in PD and their potential convergence with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-025-65489-2
  29. Diabetologia. 2025 Nov 22.
    Bridging the variant-to-function gap in type 2 diabetes: advances and challenges.
    Adam G Maynard, Raghav Bhardwaj, Thouis R Jones, Melina Claussnitzer.
      Type 2 diabetes is a polygenic, heterogeneous disease affecting over 530 million individuals worldwide, a number projected to rise to 1.3 billion by 2050. Genome-wide association studies have identified over 1200 loci associated with type 2 diabetes, yet only a modest proportion of disease heritability has been explained, and most risk variants lie in non-coding regions, complicating biological interpretation. This review synthesises how recent advances in variant-to-function (V2F) strategies, including fine-mapping, chromatin profiling, single-cell multi-omics, scalable CRISPR-based perturbation strategies and machine learning tools, have begun to link non-coding variants to effector genes, tissues and molecular mechanisms. We highlight examples of V2F resolution across key type 2 diabetes tissues, including the roles of TCF7L2 in pancreatic beta cell development, SLC16A11 and PNPLA3 in hepatocyte lipid metabolism, and GLUT4 trafficking pathways in adipocytes and muscle. We provide a summary table of genetically anchored, experimentally supported V2F discoveries in type 2 diabetes, and describe emerging tools and frameworks to address disease heterogeneity and context dependence. Together, these developments are on the cusp of closing the genetic association and mechanism gap while laying the foundation for future precision medicine approaches in type 2 diabetes.
    Keywords:  CRISPR; GWAS; Genetics; Multi-omics; Precision medicine; Review; Type 2 diabetes; Variant-to-function
    DOI:  https://doi.org/10.1007/s00125-025-06600-6
  30. Nat Neurosci. 2025 Nov 24.
    The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia.
    Giulia Albertini, Magdalena Zielonka, Marie-Lynn Cuypers, An Snellinx, Ciana Xu, Suresh Poovathingal, Marta Wojno, Kristofer Davie, Veerle van Lieshout, Katleen Craessaerts, Leen Wolfs, Emanuela Pasciuto, Tom Jaspers, Katrien Horré, Lurgarde Serneels, Mark Fiers, Maarten Dewilde, Bart De Strooper.
      Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41593-025-02125-8
  31. Lancet Diabetes Endocrinol. 2025 Nov 24. pii: S2213-8587(25)00297-9. [Epub ahead of print]
    Does continuous glucose monitoring deliver in gestational diabetes?
    Lene Ringholm.
      
    DOI:  https://doi.org/10.1016/S2213-8587(25)00297-9
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