bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–10–04
nineteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Single-cell profiling identifies obesity-disrupted brain glucose sensing.
  2. ALKBH5-mediated microglia-neuron crosstalk inhibits sympathetic innervation and adipocyte browning in male mice.
  3. Leptin-sensitive hypothalamic Lepr+/Glp1r+ neurons limit hyperphagia and weight gain in diet-induced obesity.
  4. Dynamic neuro-immune regulation of psychiatric risk loci in human neurons.
  5. Helios is critical for Treg effector differentiation in adipose autoimmunity.
  6. Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism.
  7. Old hearts age backwards: transplanted organs adjust to host's biological age.
  8. Mitochondria before we knew them.
  9. Population-scale immune multiome atlas reveals regulatory disease mechanisms.
  10. Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
  11. Comparative analysis of mitochondrial proteomes across the tree of life.
  12. A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition.
  13. X and Y chromosomes as determinants of aging and disease.
  14. Clonal blood reshapes its home.
  15. Defining pathogenic macrophages in the fibrotic niche of human chronic liver disease.
  16. Single-Cell Mapping Identifies Aging-Associated Neutrophil Remodeling Across Multiple Organs.
  17. Addressing Cognitive Decline Among Aging Physicians.
  18. Drugging the immune system: principles of immunopharmacology.
  19. FBXW7 mitigates hepatic fibrosis by degrading NOTCH1 to transcriptionally silence SEMA3G in liver sinusoidal endothelial cells.
  1. Nat Commun. 2026 08 31. pii: 10342. [Epub ahead of print]17(1):
    Single-cell profiling identifies obesity-disrupted brain glucose sensing.
    Jenny M Brown, Marie A Bentsen, Anja Moltke Jørgensen, Thomas Svava Nielsen, Dylan M Belmont-Rausch, Din Selmanovic, Oksana Dmytriyeva, Charlotte Høy Kruse, Nadia N Aalling, Dana C Schwalbe, Oliver Knights Møller, John N Campbell, Anna Secher, Michael W Schwartz, Tune H Pers.
      Neuronal nutrient sensing in the hypothalamus and brainstem is thought to regulate energy and glucose homeostasis, yet how these brain regions respond to elevated adiposity or blood glucose remains unclear. We performed single-nucleus RNA-sequencing on 75,787 cells from the arcuate nucleus, ventromedial hypothalamus, and dorsal vagal complex of control diet- and high-fat diet (HFD)-fed male mice following intravenous glucose or saline infusion. HFD broadly altered gene expression across cell types, including Th/Slc6a3, Agrp, Ghrh, and Trh/Cxcl12 neurons. In control diet-fed mice, hyperglycemia triggered transcriptional responses conserved across brain regions in astrocytes and oligodendrocytes, and a response in Ghrh neurons, consistent with reduced neuronal activity. The transcriptional responses to hyperglycemia were largely absent or reversed after HFD. Genes enriched in both mouse and human GHRH neurons were located in loci genetically linked to human glycemic traits. These findings point to the brain's intrinsic capacity to sense hyperglycemia and suggest that this detection system is profoundly impaired in obesity.
    DOI:  https://doi.org/10.1038/s41467-026-77116-9
  2. Nat Commun. 2026 Aug 27. pii: 10297. [Epub ahead of print]17(1):
    ALKBH5-mediated microglia-neuron crosstalk inhibits sympathetic innervation and adipocyte browning in male mice.
    Yong-Feng Yang, Yan Li, Mei-Hua Chen, Xi-De Hu, Yi-Jie Hua, Xiao-Dong Shi, Dong-Hua Hu, Ting Meng, Cheng-Yu Sheng, Tao Zhuang, Cheng-Chao Ruan, Xiang-Rong Zuo, Yu Lei, Ruo-Gu Li.
      Interactions between nervous system and adipose tissue are involved in the regulation of adipocyte browning. However, whether microglial activation participates in the regulation of cold exposure-induced sympathetic innervation and adipocyte browning is unclear. Here, we demonstrate that RNA m6A demethylase ALKBH5 in the microglia nucleus of hypothalamus (PVH) region inhibits cold exposure-induced adipocyte browning in the subcutaneous white adipose tissue (sWAT) of male mice. The single nuclear-RNA sequencing, brain slice electrophysiological assay and pathological analyses show that microglia-specific ALKBH5 knockout (MCKO) enhances sympathetic activation and adipocyte browning in the sWAT during cold exposure. Mechanistically, MCKO enhances m6A methylation of Ntf5 mRNA and upregulates Ntf5 expression in the microglia. Ntf5 then activates PVH-TrkB neurons and downstream sympathetic innervation in the sWAT. During aging, MCKO prevents brown adipocyte decline in the sWAT, and promotes metabolic activity. These findings fill a gap in the research of microglia in neuron-mediated adipocyte browning, and suggest that microglia may be a potential therapeutic target for the treatment of individuals with metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-026-77050-w
  3. EMBO J. 2026 Oct 02.
    Leptin-sensitive hypothalamic Lepr+/Glp1r+ neurons limit hyperphagia and weight gain in diet-induced obesity.
    Dylan M Belmont-Rausch, Benedicte Schultz Kapel, Abigail J Tomlinson, Chao Ding, Allison M Duensing, Bernd Coester, Cecilie Vad Mathiesen, Leonie Cabot, Jenny M Brown, Charlotte Høy Kruse, Shad Hassan, Elizabeth Heaton, Christoffer Clemmensen, Michael W Schwartz, Henning Fenselau, Martin G Myers, Tune H Pers.
      Despite loss of responsiveness to exogenous leptin in obesity, endogenous leptin continues to restrain feeding, although the neural substrates that remain sensitive and mediate this effect remain unknown. Combining spatial transcriptomics with single-nucleus RNA sequencing in mice with diet-induced obesity (DIO), we here show that while most hypothalamic leptin receptor (Lepr)-positive neurons minimally respond to elevated leptin, a single subpopulation defined by glucagon-like peptide-1 receptor (Glp1r) co-expression retains robust leptin sensitivity. These Lepr+/Glp1r+ neurons project onto and inhibit orexigenic Agrp neurons. Lepr deletion from Lepr+/Glp1r+ neurons blocks the anorectic effect of exogenous leptin, reinstates hyperphagic responses normally suppressed in DIO, amplifies the obesogenic response to palatable diet, and unexpectedly attenuates hypothalamic microglial activation - a hallmark of DIO previously attributed to diet rather than leptin signaling. Hence, preserved leptin responses by a single neuronal population in the hypothalamus limit hyperphagia and weight gain, among other responses, during obesity.
    DOI:  https://doi.org/10.1038/s44318-026-00914-w
  4. Nat Commun. 2026 Aug 27. pii: 10252. [Epub ahead of print]17(1):
    Dynamic neuro-immune regulation of psychiatric risk loci in human neurons.
    Kayla G Retallick-Townsley, Seoyeon Lee, Sarah E Williams, Sam Cartwright, Sophie Cohen, Annabel Sen, Meng Jia, Hannah Young, Lee Dobbyn, Michael Deans, Meilin Fernandez-Garcia, Laura M Huckins, Kristen J Brennand.
      The immune environment influences neurodevelopment and subsequent clinical trajectories for psychiatric outcomes in childhood and adolescence. Yet it remains unclear if the impact of maternal and fetal immune activation varies with distinct polygenic risk profiles. Therefore, here we catalog genotype and environment (GxE) interactions, contrasting allele-specific regulatory activity between inflammatory cues. We report a cue-specific neuronal massively parallel reporter assay (MPRA) of 152 loci from genome-wide association studies (GWAS) of ten brain traits/disorders, empirically dissecting the impact of interleukin-6 (IL-6) and interferon-alpha (IFNα) on transcriptional activity. In human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons, 1,156 active candidate regulatory risk sequences (MPRA-active CRSs) are resolved, including 267 with variant-specific effects (MPRA-emVars) and 61 with variant-by-cytokine interaction effects (interaction MPRA-emVars). Broadly, neuronal immune-mediated regulatory activity is associated with differences in transcription factor binding and chromatin accessibility, the gene targets of which show pleiotropic enrichments for brain, metabolic, and immune disorders. Dynamic genetic regulation mediates neuroimmune effects, informing our understanding of the genomics of psychiatric and neurological traits, mechanisms governing pleiotropy across disorders, and how immune mechanisms mediate genetic risk.
    DOI:  https://doi.org/10.1038/s41467-026-77114-x
  5. J Exp Med. 2026 Nov 02. pii: e20260870. [Epub ahead of print]223(11):
    Helios is critical for Treg effector differentiation in adipose autoimmunity.
    Angela M Thornton, Xi Chen, Wenjia Cao, Tovah E Markowitz, Kimmo Virtaneva, Paul A Beare, Vinay Penna, Oksana Gavrilova, Jihyun Kim, Craig A Martens, Jinfang Zhu, Ethan M Shevach.
      The deletion of the transcription factor Helios in regulatory T cells (Tregs) in mice leads to systemic Th1 immune activation, decreased T follicular regulatory cells, and enhanced germinal center formation. We report here these mice also exhibit acquired lipodystrophy, hepatic steatosis, and insulin resistance. Adipose tissue exhibited lymphocytic infiltration followed by CD8+ T cell-mediated destruction of adipocytes. Helios-deficient Tregs were more frequent in adipose tissue and showed an enhanced effector Treg (eTreg) phenotype (CD62Llo Tcf1lo). The Helios-deficient eTregs in adipose tissue, but not spleen, failed to develop into terminally differentiated eTregs, which express ST2+, CXCR3+, IRF4, or Klrg1+. ChIP-seq studies demonstrated that Helios bound to regulatory elements in multiple genes (Tcf7, Lef1, Bach2, and Id3) known to restrict eTreg generation. Thus, Helios not only directly restricts eTreg generation but also indirectly enforces functional eTreg differentiation. In the absence of Helios, the process of eTreg differentiation proceeds unchecked, resulting in enhanced but dysfunctional eTregs, which fail to control adipose tissue homeostasis.
    DOI:  https://doi.org/10.1084/jem.20260870
  6. Nat Metab. 2026 Sep 29.
    Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism.
    Nikola Makdissi, Maria Francesca Viola, Lisa Maria Steinheuer, Nelli Blank-Stein, Ronja Kardinal, Fabrizio Musacchio, Eliana Franco Taveras, Virginia Aliprandi, Katharina Sieckmann, Akram Abdulkadyrov, Marina L Mayer, Marie-Louise Diefenbach-Wilke, Diana Fink, Hannes Beckert, Stefan Böhmdorfer, Quentin Deveuve, Frederike J Graelmann, Katharina Mauel, Nele Kronau, Jake Thomas, David Bejarano, Andreas Schlitzer, Sandra Högler, Mohamed H Yaghmour, Joerg Heeren, Christoph Thiele, Lukas Kenner, Felix Meissner, Falk Nimmerjahn, Martin Fuhrmann, Dagmar Wachten, Kevin Thurley, Elvira Mass.
      Plastic pollution is an emerging yet understudied environmental risk to the immune system. Once ingested, microplastic and nanoplastic particles (MNPs) can translocate from the gut to internal organs1-3, with macrophages serving as primary targets4. Kupffer cells (KCs), the liver-resident macrophages, have a central role in immune surveillance and metabolism5, yet their response to MNPs remains unclear. Here we identify KCs as the primary hepatic reservoir for MNPs in young male mice. Chronic plastic exposure over 12 weeks alters their transcriptional profile, impairs phagocytic function and is associated with metabolic dysregulation of hepatocytes. Microplastics, but not nanoplastics, reduce KC-mediated clearance of circulating cells. Under diet-induced obesity, microplastics exacerbate hepatic lipid accumulation, while nanoplastics alter systemic glucose metabolism and energy expenditure. These findings demonstrate that chronic MNP exposure disrupts macrophage function in a size-dependent manner, with subsequent distinct consequences for liver and systemic metabolism.
    DOI:  https://doi.org/10.1038/s42255-026-01615-8
  7. Nature. 2026 Sep 28.
    Old hearts age backwards: transplanted organs adjust to host's biological age.
    Chris Simms.
      
    Keywords:  Ageing; Medical research; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-03043-w
  8. Cell. 2026 Oct 01. pii: S0092-8674(26)01072-X. [Epub ahead of print]189(20): 6214-6216
    Mitochondria before we knew them.
    Courtney W Stairs, Ryan M R Gawryluk.
      In this issue of Cell, Chen et al. chart mitochondrial proteome diversity across eukaryotes, revealing an unexpectedly complex ancestral proteome alongside extensive lineage-specific innovation. Their broad phylogenetic reconstruction provides new insights into the mitochondrial proteome of the last eukaryotic common ancestor while unearthing a wealth of unexplored mitochondrial biology outside of traditional model systems.
    DOI:  https://doi.org/10.1016/j.cell.2026.09.003
  9. Nature. 2026 Sep 30.
    Population-scale immune multiome atlas reveals regulatory disease mechanisms.
    BioBank Japan Project
      Most disease-associated genetic variants lie in non-coding regions1,2, yet mechanistic insights are limited by the lack of an empirical framework for characterizing the molecular consequences of regulatory variation. Single-cell molecular quantitative trait locus (QTL) mapping3,4 connects variants to gene regulation but lacks the power and simultaneous measurements to trace mechanisms from chromatin to expression5. Here we show that population-scale simultaneous profiling of chromatin accessibility and gene expression across immune cells reveals regulatory architectures connecting variants to disease. From paired single-nucleus assay for transposase-accessible chromatin-sequencing (snATAC-seq) and single-nucleus RNA-sequencing (snRNA-seq) analysis of 10 million peripheral blood mononuclear cells in 1,108 Finnish individuals6, we identify 51,083 cis-expression QTLs for 20,829 genes, 338,100 cis-chromatin accessibility QTLs for 210,584 peaks, 119,094 putative causal variants and 593,765 peak-gene links. Variants completing chromatin-to-expression cascades show twice the disease colocalization of chromatin-only effects, with massively parallel reporter assays7 validating 10,428 fine-mapped molecular QTLs. At evolutionarily constrained genes, we identify multilayered regulatory buffering, in which chromatin accessibility changes occur with normal effect sizes, but transmission to expression is attenuated through weaker, more numerous enhancer-gene links. This reconciles why disease variants preferentially target constrained genes despite apparent expression QTL depletion8-11. Analysis using a massively parallel reporter assay7 confirms that this buffering acts downstream of the regulatory element, with constraint operating at the chromatin-to-expression interface rather than on intrinsic cis-regulatory activity. Our atlas provides testable hypotheses for over half of immune disease associations, illustrated by cascades at autoimmune loci (TICAM1 and RHOH) and Finnish-enriched variants (TNRC18 and IL21R).
    DOI:  https://doi.org/10.1038/s41586-026-11078-2
  10. Nat Commun. 2026 08 31. pii: 10359. [Epub ahead of print]17(1):
    Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
    Krystle C Kalafut, Yann Cormerais, Madi Y Cissé, Samuel C Lapp, Karen E Inouye, Gökhan S Hotamışlıgil, Brendan D Manning.
      The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, and aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well-defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, studies employing a liver-specific genetic mouse model demonstrate that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, postprandial activation of hepatic mTORC1 requires dietary protein, which dictates the insulin-responsiveness of the pathway. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity, despite overt impairments in insulin and glucose homeostasis, and blocking hepatic AKT-TSC-mTORC1 signaling did not affect these metabolic phenotypes. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.
    DOI:  https://doi.org/10.1038/s41467-026-77216-6
  11. Cell. 2026 Oct 01. pii: S0092-8674(26)01002-0. [Epub ahead of print]189(20): 6285-6306.e13
    Comparative analysis of mitochondrial proteomes across the tree of life.
    MitoCarta Tree of Life Consortium
      Mitochondria arose from the endosymbiosis of a bacterium with an archaea-related host cell about 2 billion years ago. To understand their origins and evolution, we compared experimentally defined mitoproteomes from the MitoCarta Tree of Life project. Across eight organisms, we identified 8,619 distinct mitochondrial proteins within 3,199 families, of which 43% lack Pfam domains. We report 33 protein families conserved in eukaryotic pathogens yet absent in humans, representing promising candidate targets for protozoan infectious diseases. Leveraging our experimentally defined mitoproteomes, we retrained a classifier based on a protein language model to predict mitoproteomes of ∼200 eukaryotes. From this expanded set, we detail the evolutionary trajectories of mitochondria, ranging from clade-specific gene family expansions to extreme mitoproteome reductions seemingly en route to complete organelle loss. Finally, we reconstruct the last eukaryotic common ancestor (LECA) mitoproteome, revealing that LECA possessed a complex mitochondrion capable of both aerobic and anaerobic metabolism.
    Keywords:  calcium; eukaryogenesis; evolution; last eukaryotic common ancestor; mitochondria; mitoproteome; oxygen; parasite; pathogen; phylogenetics
    DOI:  https://doi.org/10.1016/j.cell.2026.08.029
  12. Nat Cardiovasc Res. 2026 Sep 28.
    A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition.
    Yi Fan, Dakota J Nuttall, Yi Zhao, Dina Abbasian, Clarissa Shoffler, Christopher Petucci, Wyatt G Paltzer, Yu-Ling Chang, James Marchant, Diana Presas-Ramos, Kai P Atlass, Stephen A Nemr, Jiyoung Bae, Sanjeev S Ranade, Alexandre R Colas, Xiao Li, James F Martin, Ahmed I Mahmoud.
      Cardiac regeneration is limited in the adult mammalian heart because of restricted cardiomyocyte proliferation and persistent fibrosis. We previously demonstrated that transient pharmacological inhibition of succinate dehydrogenase (SDH) with malonate promotes regeneration after myocardial infarction. Here, we integrate single-nucleus RNA sequencing and ATAC-seq to reveal multicellular transcriptional and epigenetic reprogramming underlying this response. Cell-specific Sdhb deletion dissected contributions of SDH inhibition; cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-myocardial infarction function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function. SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3-marked and H3K27me3-marked chromatin states in cardiomyocytes and fibroblasts. Integration of CUT&RUN, chromatin accessibility and transcriptional profiling identified regulatory targets linking metabolic and epigenetic remodeling to regenerative responses. Together, these findings establish SDH as a multicellular regulator of cardiac regeneration and define distinct cell-specific mechanisms contributing to the regenerative effects of transient pharmacological SDH inhibition.
    DOI:  https://doi.org/10.1038/s44161-026-00881-9
  13. Science. 2026 Oct;394(6819): 53-59
    X and Y chromosomes as determinants of aging and disease.
    Dena B Dubal, Fabrisia Ambrosio, Michael B Stout, Dan Theodorescu.
      Sex differences have traditionally been attributed to gonadal hormones, but accumulating evidence shows that sex chromosomes exert distinct, cell-autonomous effects on health, aging, and disease. XX and XY complements alter gene dosage, epigenetic programming, immune signaling, metabolism, and cellular stress responses, which shape aging and disease trajectories in women and men. This Review integrates mechanistic advances in sex chromosome biology-including escape from X chromosome inactivation, X reactivation, parent-of-X-origin, X-skew, X- and Y-linked gene functions, and Y loss-with aging, neurologic disease, immunity, cancer, and cardiometabolic disease. We highlight insights from mouse models, human studies, and emerging technologies that disentangle hormone-driven effects from chromosome-mediated effects and discuss translational implications for diagnostics, biomarkers, therapeutics, and clinical trial design, emphasizing the integration of sex chromosome biology into precision medicine.
    DOI:  https://doi.org/10.1126/science.aeh0145
  14. Nat Immunol. 2026 Sep 30.
    Clonal blood reshapes its home.
    Xuan Zhang, Bailee N Kain, H Leighton Grimes.
      
    DOI:  https://doi.org/10.1038/s41590-026-02673-6
  15. Nat Genet. 2026 Sep 29.
    Defining pathogenic macrophages in the fibrotic niche of human chronic liver disease.
      
    DOI:  https://doi.org/10.1038/s41588-026-02778-6
  16. Aging Cell. 2026 Oct;25(10): e70735
    Single-Cell Mapping Identifies Aging-Associated Neutrophil Remodeling Across Multiple Organs.
    Yuman Wang, Teding Chang, Yangguang Fu, Guangyu Liang, Huicheng Liu, Le Zhang, Jinhua Yan, Man Liu, Anding Liu, Cuntai Zhang.
      Aging is accompanied by progressive immune remodeling and functional decline across multiple organs. However, the role of neutrophils and their heterogeneous states in these processes remains incompletely understood. Here we integrated single-cell RNA sequencing datasets from multiple organs of young and aged mice to characterize aging-associated neutrophil remodeling. We identified organ-dependent changes in neutrophil abundance and state composition, together with neutrophil subsets enriched for inflammatory, oxidative stress, complement, and IL-6-related transcriptional programs. In vitro, exposure to conditioned media from neutrophils isolated from aged mice or IL-6-stimulated neutrophil-like cells increased inflammatory and senescence-associated responses in vascular smooth muscle and hepatocyte-derived cells. Bone marrow single-cell analysis further revealed aging-associated shifts in progenitor composition and transcriptional states, including an old-enriched HPC11 population characterized by enhanced myeloid priming. Silico perturbation analysis nominated FGF didate regulators of HPC subtype-specific transcriptional programs. Together, our study provides a multi-organ single-cell resource for defining neutrophil remodeling during aging and highlights candidate neutrophil states and potential signaling axes associated with age-related inflammatory tissue environments.
    Keywords:  aging; bone marrow remodeling; inflammation; multi‐organ atlas; neutrophils
    DOI:  https://doi.org/10.1111/acel.70735
  17. JAMA. 2026 Oct 02.
    Addressing Cognitive Decline Among Aging Physicians.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.20011
  18. Nat Rev Immunol. 2026 Sep 28.
    Drugging the immune system: principles of immunopharmacology.
    E John Wherry.
      
    DOI:  https://doi.org/10.1038/s41577-026-01361-8
  19. Nat Commun. 2026 09 01. pii: 10420. [Epub ahead of print]17(1):
    FBXW7 mitigates hepatic fibrosis by degrading NOTCH1 to transcriptionally silence SEMA3G in liver sinusoidal endothelial cells.
    Chengrong Yan, Jinling Dong, Yihong Sun, Xin Min, Junhui Liu, Shaozhou Ma, Shan He, Yuru Luo, Wenyang Hao, Yuan Fang, Hongyu Su, Weihao Xue, Rui Zhou, Baochang Lai, Sasa Liu, Jianyu He, Donghong Zhang, Xiaohong Zheng, Enqi Liu, John Y-J Shyy, Fanpu Ji, Hua Han, Yue Wu, Zuyi Yuan, Xu-Feng Zhang, Yidong Wang.
      Overactivation of Notch signaling in liver sinusoidal endothelial cells (LSECs) is an established driver of hepatic fibrosis, yet its precise upstream regulators and downstream effectors remain poorly defined, limiting therapeutic translation. Here, we demonstrate that FBXW7, the primary E3 ubiquitin ligase responsible for NOTCH1 degradation, serves as a critical suppressor of liver fibrosis. Using endothelial-specific Fbxw7 knockout mice subjected to three distinct fibrosis models, we show that FBXW7 loss exacerbates liver fibrosis, promotes LSEC capillarization, and enhances hepatic stellate cell activation. Transcriptomic analysis identified Sema3g as the top upregulated gene in FBXW7‑deficient LSECs, and conditioned medium from these cells stimulated HSC activation through SEMA3G‑dependent paracrine signaling. Moreover, nanoparticle-mediated delivery of Sema3g-targeting siRNA specifically to LSECs substantially ameliorated injury-induced liver fibrosis in Fbxw7 knockout mice. Mechanistically, FBXW7 loss stabilizes NOTCH1, leading to enhanced Sema3g transcription. Consistent with these findings, human cirrhotic samples and murine fibrotic livers exhibit reduced FBXW7 expression alongside elevated active NOTCH1 and SEMA3G in LSECs. Collectively, our results demonstrate that FBXW7 mitigates liver fibrosis by degrading NOTCH1 to transcriptionally silence SEMA3G, and suggest that targeting the FBXW7/NOTCH1/SEMA3G axis represents a promising therapeutic strategy for fibrotic liver disease.
    DOI:  https://doi.org/10.1038/s41467-026-77298-2
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