Science Advances最新文献

{"title":"PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy","authors":"Diogo Gonçalves,&nbsp;Emma Guilbaud,&nbsp;Léa Di Mascio,&nbsp;Camille Guerrier,&nbsp;Linda Mejri,&nbsp;Sonia Núñez-Vázquez,&nbsp;Lucie Levasseur,&nbsp;Rachel Paul,&nbsp;Corinne Menigot,&nbsp;Christophe Bontoux,&nbsp;Guylène Rignol,&nbsp;Véronique Hofman,&nbsp;Paul Hofman,&nbsp;Marin Truchi,&nbsp;Bernard Mari,&nbsp;Laurent Yvan-Charvet,&nbsp;Johanna Chiche,&nbsp;Sandrine Marchetti,&nbsp;Jean-Ehrland Ricci","doi":"10.1126/sciadv.aef8820","DOIUrl":"10.1126/sciadv.aef8820","url":null,"abstract":"<div >Mitophagy, the selective degradation of mitochondria by lysosomes, is a major mitochondrial quality-control pathway, yet its role in lung cancer initiation and therapeutic response remains poorly understood. We investigated PINK1-dependent mitophagy in human lung adenocarcinoma and directly monitored mitophagy in vivo using mito-QC reporter mice during lung tumor development. We found that PINK1 activity and mitophagy are increased in human tumors and are activated from the earliest stages of tumorigenesis. Genetic inhibition of PINK1 impaired oncogenic transformation but had little impact once tumor cells were established, identifying mitophagy as a critical early adaptation during lung cancer initiation. PINK1 deficiency markedly enhanced the efficacy of <i>KRAS</i>-targeted therapy in vitro and in vivo. Together, our findings identify PINK1-dependent mitophagy as an early vulnerability in <i>KRAS</i>-driven lung cancer and provide a rationale for targeting mitophagy to improve the efficacy of <i>KRAS</i>-targeted therapies.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aef8820","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of titration-based control of DNA replication in Escherichia coli","authors":"Belén Adiego-Pérez,&nbsp;Christina Ludwig,&nbsp;Demian Fluit,&nbsp;Mareike Berger,&nbsp;Alejandra Alonso Santirso,&nbsp;Johannes Hohlbein,&nbsp;Raymond H. J. Staals,&nbsp;Pieter Rein ten Wolde,&nbsp;John van der Oost,&nbsp;Nico J. Claassens,&nbsp;Lorenzo Olivi","doi":"10.1126/sciadv.aei9788","DOIUrl":"10.1126/sciadv.aei9788","url":null,"abstract":"<div ><i>Escherichia coli</i> couples the initiation of DNA replication with cell size by modulating the activity of the replication initiator protein DnaA. The activity of DnaA is regulated both by its interconversion between an active and inactive form and by its titration on chromosomal binding sites. Whereas its interconversion has been thoroughly studied, the extent to which DnaA titration can control replication initiation is poorly understood. Here, we describe the control of <i>E. coli</i> DNA replication via titration by modulating the expression of a constitutively active DnaA variant in four growth conditions. While we obtained stable cell cycles during slow growth, faster growth associated with overlapping replication forks led to initiation instability and replicative stress. Overall, our results provide insights into the limits of titration-based systems in the control of genome replication and their potential role in the evolutionary trajectory of <i>E. coli</i>. Last, this study provides design principles for a simplified, titration-only regulatory mechanism for DNA replication in synthetic cells.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aei9788","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemogenetic ubiquitin E1 inhibitor TAK-243 CRISPR screen uncovers HAPSTR1/HUWE1 axis in chromatin proteostasis and cell cycle control","authors":"Nila K. van Overbeek,&nbsp;Linda Clijsters,&nbsp;Martina Wirth,&nbsp;Ilona J. de Graaf,&nbsp;Klaas de Lint,&nbsp;Sidrit Uruci,&nbsp;Amina F. A. S. Teunisse,&nbsp;Vyacheslav Akimov,&nbsp;Arnoud H. de Ru,&nbsp;Maja Vukic,&nbsp;Idil Kirdök,&nbsp;Lucia Daxinger,&nbsp;Peter A. van Veelen,&nbsp;Blagoy Blagoev,&nbsp;Martijn S. Luijsterburg,&nbsp;Rob M. F. Wolthuis,&nbsp;Ilana Berlin,&nbsp;Alfred C. O. Vertegaal","doi":"10.1126/sciadv.aea3388","DOIUrl":"10.1126/sciadv.aea3388","url":null,"abstract":"<div >In this study, we sought to comprehensively map ubiquitin signaling networks at the crossroads of cellular proliferation and proteostasis, both crucial in cancer. Genome-wide CRISPR knockout screening in the presence of the ubiquitin E1 inhibitor TAK-243 identified 239 genes whose ablation sensitizes cells to ubiquitination blockade. Follow-up studies reveal a role for the nuclear protein, C16orf72/HECT, UBA, and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1)–Associated Protein modifying Stress Responses (HAPSTR1), in chromatin proteostasis and DNA replication. We show that HAPSTR1 recruits the E3 ligase HUWE1 to the chromatin, keeping the chromatin-associated proteome in check, and is itself turned over by HUWE1 during cell cycle progression. Structural modeling of the HAPSTR1/HUWE1 complex, supported by mutational analysis, demonstrates that loss of HUWE1 binding renders HAPSTR1 unable to support cellular proliferation when ubiquitin signaling is suppressed. Consequently, HAPSTR1 ablation impairs clearance of chromatin-associated proteins, triggering global transcriptional and proteostatic adaptations. Under diminished ubiquitin signaling, these adaptive mechanisms give way to replication stress and premature S phase entry, culminating in cell cycle collapse and DNA damage. Our findings uncover protein networks exhibiting synthetic lethality with ubiquitin signaling blockade and highlight vulnerabilities of actively proliferating cells to proteostatic imbalance at the chromatin.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aea3388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Latent effector capacity governs reversible T cell exhaustion: A theoretical mathematical model of PD-1 blockade response","authors":"Aubrey Y. Liew,&nbsp;Ying Li,&nbsp;Haidong Dong","doi":"10.1126/sciadv.aei0840","DOIUrl":"10.1126/sciadv.aei0840","url":null,"abstract":"<div >T cell exhaustion is often viewed as a terminal state marked by irreversible loss of function during chronic infection and cancer. However, the rapid recovery of antitumor activity in clinical responders after PD-1 blockade suggests that some exhausted T cells retain hidden functional potential. To explain this paradox, we present a theoretical framework that separates latent effector capacity from active effector function. Latent effector capacity represents a history-dependent state reflecting preserved epigenetic accessibility and regulatory readiness, distinct from ongoing gene expression. In this model, PD-1 signaling acts as a reversible mask that suppresses effector function without eliminating the underlying effector capacity. The framework explains preserved chromatin accessibility, rapid reinvigoration after checkpoint blockade, and variable therapeutic responses. By incorporating nonlinear maintenance and erosion of latent effector capacity, the model predicts a bistable system with a point of no return beyond which exhaustion becomes irreversible. These principles may guide development of mechanistically informed biomarkers and artificial intelligence models predicting response to PD-1 therapy.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aei0840","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional control of meiotic recombination by DREAM complex components","authors":"Hasibe Tunçay,&nbsp;Xing Ma,&nbsp;Katja Müller,&nbsp;Yuxuan Guo,&nbsp;Valerio Filippo Toccaceli,&nbsp;Huiqi Fu,&nbsp;Franziska Böwer,&nbsp;Lucas Lang,&nbsp;David Latrasse,&nbsp;Yingxiang Wang,&nbsp;Moussa Benhamed,&nbsp;Arp Schnittger","doi":"10.1126/sciadv.aef2922","DOIUrl":"10.1126/sciadv.aef2922","url":null,"abstract":"<div >Meiotic chromosome segregation and recombination, essential for sexual reproduction and evolution, require a specialized gene set. Despite its importance, the transcriptional regulators that directly orchestrate meiotic gene expression remain unidentified in plants. We identify the MuvB core components known from the DREAM complex as key transcriptional regulators of meiotic recombination in <i>Arabidopsis</i>. Loss of DREAM components TCX5/6 and ALY1/2 leads to impaired recombination and fertility defects. Meiocyte-specific transcriptome profiling and genome-wide binding analyses reveal that core recombination genes, including the crossover-promoting helicase MER3, are direct targets. Consistently, <i>MER3</i> overexpression partially rescues recombination defects in DREAM-compromised plants. These findings establish the DREAM complex components as important regulators of the meiotic program in plants. Given that DREAM dysfunction causes reproductive defects in animals, this regulatory role may be conserved across multicellular eukaryotes.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aef2922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CellDiffusion: Enhancing scRNA-seq data integration with accurate inference of cell-cell association","authors":"Yu-Chen Liu,&nbsp;Ziying Huang,&nbsp;Simon Liang Lu,&nbsp;Lei Jiang,&nbsp;Zedong Lin,&nbsp;Jou-Hsuan Lee,&nbsp;Vijaya B. Kolachalama,&nbsp;Rong Li,&nbsp;Dong Xu,&nbsp;Juexin Wang,&nbsp;Heng Pan,&nbsp;Chao Zhang","doi":"10.1126/sciadv.aed4155","DOIUrl":"10.1126/sciadv.aed4155","url":null,"abstract":"<div >Integrating single-cell transcriptomic datasets across laboratories, conditions, and technologies remains challenging because of cell type–specific batch effects and heterogeneous biological compositions. Current methods often fail to separate genuine biological variation from technical noise, misaligning distinct cell populations or leaving batch effects uncorrected. To address these challenges, we present CellDiffusion, an unsupervised graph-based model that propagates cellular features through a diffusion process to strengthen meaningful cell-cell associations in data integration. By learning a cell-cell attention network, CellDiffusion adaptively identifies corresponding populations across batches. Our approach applies cell-specific correction in data integration, generating cell embeddings that align cells across batches while preserving intrinsic cell types and developmental trajectories. We validate CellDiffusion across various datasets, including the human endometrium, one of the most dynamic and complex tissues featuring extensive cellular and molecular changes with the menstrual cycle. This framework also improves other essential analyses such as label transfer, clustering, and trajectory inference. CellDiffusion represents a powerful paradigm for accurate single-cell transcriptomic integrative analysis.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aed4155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic-scale CAR-NK microrobots with programmable swarm navigation for targeted solid tumor therapy","authors":"Zhiguang Wu,&nbsp;Yalin Wang,&nbsp;Hongyue Zhang,&nbsp;Xinjian Fan,&nbsp;Mingtong Li,&nbsp;Zesheng Li,&nbsp;Gongzi Zhang,&nbsp;Jialin Wang,&nbsp;Yumeng Lu,&nbsp;Hongda Wang,&nbsp;Yuxin Jia,&nbsp;Hongri Gu,&nbsp;He Tan,&nbsp;Jiawei Tian,&nbsp;Ximing Sun,&nbsp;Hui Xie,&nbsp;Lihai Zhang,&nbsp;Metin Sitti,&nbsp;Jie Zhao","doi":"10.1126/sciadv.aef9412","DOIUrl":"10.1126/sciadv.aef9412","url":null,"abstract":"<div >An urgent requirement in chimeric antigen receptor (CAR) immune cell therapy [e.g., CAR–natural killer (NK) cells] for solid tumors is to engineer the cells for precise tumor targeting. Meanwhile, medical microrobots can be navigated toward specific target sites using external magnetic fields. Here, by bridging these approaches, we turn CAR-NK cells into magnetic biohybrid microrobots (CAR-NK microrobots) that achieve controllable long-distance targeted navigation at therapeutic doses (∼10⁶ cells) in both murine and nonhuman primate animal models in vivo. CAR-NK microrobots are developed through genetic engineering with CAR structures and loading with magnetic nanoparticles for field-based navigation. Different magnetic field inputs reconfigure their swarms between vortex and ribbon modes, allowing dense aggregation for targeted navigation and further broad dispersion for large-area coverage. Using programmable magnetic fields, in vivo CAR-NK microrobot–based therapy is demonstrated for metastatic leptomeningeal carcinomatosis in brain’s cerebrospinal fluid space. After intrathecal injection, the microrobots are magnetically guided long distance through the spinal canal toward the brain in vortex mode and subsequently spread over the target site in ribbon mode, as visualized by real-time angiographic imaging in a nonhuman primate model, providing a proof-of-feasibility demonstration in a nonhuman primate anatomical setting.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aef9412","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magneto-mechano-electrochemical fiber for deformation-resilient and smart electronic textiles","authors":"Xiao Xiao,&nbsp;Chang Liu,&nbsp;Zimo Wang,&nbsp;Xiao Xiao,&nbsp;He Wang,&nbsp;Chengyue Lu,&nbsp;Xinru Wu,&nbsp;Junyi Yin,&nbsp;Xiao Li,&nbsp;Wei Zhang,&nbsp;Gang Ge,&nbsp;Wenbo Ding,&nbsp;Guangmin Zhou,&nbsp;Patrick Chia,&nbsp;Lei Shen,&nbsp;Chun Zhang,&nbsp;Zhiqun Lin,&nbsp;Yiliang Lin,&nbsp;Benjamin C. K. Tee,&nbsp;John S. Ho,&nbsp;Zhuangjian Liu,&nbsp;Ghim Wei Ho,&nbsp;Changsheng Wu","doi":"10.1126/sciadv.aef4338","DOIUrl":"10.1126/sciadv.aef4338","url":null,"abstract":"<div >Electronic textiles represent a transformative platform for integrating technology into daily wear, yet their development has been undermined by a fundamental challenge: the conflicting requirements between mechanical deformation for functionality and structural stability for performance. This challenge is particularly acute in cylindrical fiber electrodes, where inherent nonuniform electric field distribution leads to dendrite formation and poor active material utilization—problems that are further exacerbated by mechanical deformation. Here, we present a magneto-mechano-electrochemical architecture that addresses this challenge. Through magnetoelectrochemistry, magneto-mechano-electrochemical fiber promotes uniform electrochemical reactions, extending the battery lifespan by (374 ± 79)% and enhancing the capacity by (61 ± 20)% at a current density of 1.0 ampere per gram in the undeformed state. The magnetic field remains effective in regulating ion transport and stabilizing electrode structure under deformation. This deformation-resilient platform simultaneously enables energy harvesting from body motion and physiological monitoring through electromagnetic induction and magnetoelastic sensing, thereby transforming conventional textiles into deformation-resilient and smart health monitoring systems.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aef4338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors","authors":"Feng-xia Ma,&nbsp;Min Wang,&nbsp;Shuo-yan Fang,&nbsp;Xiao-xin Wang,&nbsp;Shen-han Xu,&nbsp;Xin-xin Zhao,&nbsp;Yu-xiao Liu,&nbsp;Cong Wang,&nbsp;Chen Qiao,&nbsp;Qiu-ling Wang,&nbsp;Lei Cao","doi":"10.1126/sciadv.aed8795","DOIUrl":"10.1126/sciadv.aed8795","url":null,"abstract":"<div >Astrocyte pathology is increasingly recognized as a key factor in the pathogenesis of major depressive disorder (MDD), where disrupted glutamate clearance and impaired neuron-glia interactions contribute to synaptic dysfunction. However, the molecular mechanisms leading to astrocyte loss remain largely undefined. Mitochondrial dysfunction is a hallmark of MDD, yet most studies have focused on neuronal mitochondria, leaving astrocytic mitochondrial dynamics insufficiently investigated. Here, we identify mitofusin-2 (MFN2)–associated astrocyte dysfunction in depression. SMART-seq profiling of hippocampal astrocytes from chronic social defeat stress (CSDS) mice revealed <i>Mfn2</i> up-regulation, accompanied by excessive mitochondrial fusion, impaired mitophagy, and astrocyte loss. Elevated <i>MFN2</i> expression was detected in plasma, postmortem brain tissue, and iPSC-derived astrocytes from patients with MDD. Astrocyte-specific knockdown of <i>Mfn2</i> restored mitochondrial morphology and mitophagy, thereby preserving astrocyte viability and alleviating depressive-like behaviors. Using mass spectrometry–based label-free proteomics, in vivo calcium imaging, and functional assays, we demonstrated that β-arrestin2 deficiency reduced STAT1 stability, releasing its transcriptional repression on <i>Mfn2</i>. Normalization of MFN2 expression through astrocytic <i>Mfn2</i> knockdown or <i>Stat1</i> overexpression reduced extracellular glutamate accumulation and prevented neuronal hyperexcitability in CSDS mice. Collectively, our findings define astrocytic MFN2-associated astrocyte dysfunction as a central pathological event in depressive behaviors, with the β-arrestin2–STAT1 pathway acting as an upstream regulatory mechanism. This work reveals an astrocytic pathway in depression and highlights a potential therapeutic target that directly addresses astrocyte pathology, beyond the neuron-centered focus of current antidepressant treatments.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aed8795","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscle stem cells produce a protective Fibrillin-1 matrix to prevent precocious activation","authors":"Eleni Chrysostomou,&nbsp;Oussama Smail,&nbsp;Artemis Vlachopoulou,&nbsp;Takuto Hayashi,&nbsp;Nicolas Tcheng,&nbsp;Nicol Voermans,&nbsp;Dieter P. Reinhardt,&nbsp;Frederic Relaix,&nbsp;Philippos Mourikis","doi":"10.1126/sciadv.aeb8190","DOIUrl":"10.1126/sciadv.aeb8190","url":null,"abstract":"<div >Diverse biological mechanisms regulate muscle stem cell quiescence, including inhibition of differentiation, adhesion, and translational control. Here, we identify the matrix glycoprotein Fibrillin-1 (FBN1) as a Notch-regulated, cell-autonomous effector, essential for maintaining quiescence. Known for its causal role in Marfan syndrome (MFS), our work positions FBN1 as a critical niche component that protects muscle stem cells from aberrant growth factor signaling. Targeted deletion of <i>Fbn1</i> in muscle stem cells leads to dose-dependent quiescence defects, characterized by loss of cellular projections, depletion of the stem cell pool, and progressive decline in muscle function. Consistently, human MFS muscle biopsies show abnormally activated satellite cells, implicating stem cell imbalance in the development of MFS-associated myopathy. Mechanistically, the loss of FBN1 up-regulates transforming growth factor–β (TGFβ) signaling, and pharmacological blockade of TGFβ signaling rescues the cellular and physiological defects of FBN1-deficient muscle. These findings reveal a new quiescence-preserving mechanism through extracellular matrix–mediated shielding from mitogenic signals and position stem cell dysfunction as a driver of MFS myopathy.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 42","pages":""},"PeriodicalIF":13.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.aeb8190","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}