{"title":"PTPRS mediates invasion of tetanus neurotoxin into the central nervous system","authors":"Pengsheng Chen,Huan Wang,John Manion,Jonas Zähringer,Junjie Liang,Aisha Mohammed,Leo Zhao,Jie Zhang,Yuankai Wang,Kang Wang,Pyung-Gang Lee,Geoffrey Masuyer,Karla J.F. Satchell,Joseph S. Brunzelle,Taekjip Ha,Pål Stenmark,Min Dong","doi":"10.1016/j.cell.2026.09.026","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.026","url":null,"abstract":"Tetanus neurotoxin (TeNT) invades the central nervous system (CNS) via retrograde transport through motoneurons. Whether a host factor is needed to mediate TeNT trafficking has remained unknown. Here, using pull-down and mass spectrometry analysis, and by developing a luciferase-based in vivo transport assay, we identify receptor protein tyrosine phosphatase sigma (PTPRS; PTPσ) as the retrograde transport receptor for TeNT. Global or motoneuron-specific PTPRS knockout (KO) abolishes TeNT entry into the CNS in mouse models. PTPRS-TeNT interactions occur in endosomes, prevent toxin translocation, and direct TeNT trafficking in neurons. Structural studies establish that the TeNT light chain and belt region bind to the immunoglobulin domain of PTPRS. Disrupting TeNT-PTPRS interactions blocks TeNT trafficking into the spinal cord; consistently, a PTPRS-binding-deficient TeNT mutant induces botulism-like flaccid paralysis. Thus, PTPRS is the host factor mediating TeNT trafficking into the CNS, revealing a targetable pathway for post-entry intervention and drug delivery into the CNS.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"33 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Rare k-mers reveal centromere haplogroups underlying human diversity and cancer translocations","authors":"Yuichi Shiraishi,Yotaro Ochi,Masahiro Sugawa,Yoshitaka Sakamoto,Keisuke Kimura,Taro Tsujimura,Ai Okada,Rurika Okuda,Shinichi Namba,Tetsuya Hori,Yoshihisa Kobayashi,Tsubasa Miyauchi,Raúl N. Mateos,Hajime Suzuki,Kenichi Chiba,Yu Ito,Wataru Nakamura,Fumiharu Ohka,Kazuya Motomura,Takuya Yamamoto,Yosuke Kawai,Yukinori Okada,Hiromichi Suzuki,Tatsuo Fukagawa,Motohiro Kato,Ryuta Saito,Erik Garrison,Glennis A. Logsdon,Seishi Ogawa","doi":"10.1016/j.cell.2026.08.053","DOIUrl":"https://doi.org/10.1016/j.cell.2026.08.053","url":null,"abstract":"Human centromeres are highly variable but remain among the least characterized regions of the genome because their repetitive structure has hindered conventional analysis of population diversity and disease relevance. Here, we show that rare k-mers in centromeric regions capture lineage-specific variation, defining discrete haplogroups with distinct structural features. We developed ascairn to infer these haplogroups from short-read whole-genome sequencing (WGS) data. Applying this framework to >3,300 genomes reveals extensive global diversity in centromere haplogroups and signatures of population history. Analyzing short-read WGS data from 142 oligodendroglioma cases with 1p/19q co-deletion, we mapped breakpoints to the centromere regions of chromosomes 1 and 19, revealing a clear positional relationship to kinetochore attachment sites and a link between centromere haplotype structure and rearrangement susceptibility. Rare k-mers thus open centromeres to population-scale analysis, linking centromere structural diversity to human evolutionary history and disease-associated genomic instability.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"13 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mechanisms of transcription control by distal enhancers from single-gene nanoscopy","authors":"Lingling Cheng,Chayan De,Jieru Li,Rose Korff,Alexandros Pertsinidis","doi":"10.1016/j.cell.2026.09.028","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.028","url":null,"abstract":"Distal enhancers activate genes over vast genomic distances, but how this communication occurs and what signals are transmitted are poorly understood. Using real-time single-gene nanoscopy and targeted perturbations, we define physical parameters and mechanisms of enhancer-promoter communication. We find that productive interactions are dynamic, occur at a proximity of ≲100 nm, and are coordinated with transcriptional bursts. Enhancers and promoters find one another not only through passive diffusion; we often directly observe them being actively brought together by cohesin-mediated loop extrusion, which is a key determinant of transcriptional burst frequency. We also discover that specific general transcription factors (GTFs) of RNA polymerase II machinery are key to initiating transcriptional bursts, and enhancer-promoter interactions activate bursting by embedding the promoter within GTF clusters that form at the enhancers. Our results resolve the molecular and biochemical signals involved in long-range gene activation and elucidate the biophysical mechanisms for their transmission from the enhancer to the promoter.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"17 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2026-10-09DOI: 10.1016/j.cell.2026.09.017
Isabella N Grabski, Junsuk Lee, John D Blair, Carol Dalgarno, Isabella Mascio, Alexandra Bradu, David A Knowles, Rahul Satija
{"title":"Mapping transcriptional responses to cellular perturbations with RNA fingerprinting.","authors":"Isabella N Grabski, Junsuk Lee, John D Blair, Carol Dalgarno, Isabella Mascio, Alexandra Bradu, David A Knowles, Rahul Satija","doi":"10.1016/j.cell.2026.09.017","DOIUrl":"10.1016/j.cell.2026.09.017","url":null,"abstract":"<p><p>Single-cell perturbation dictionaries measure how cells respond to genetic and chemical perturbations, creating the opportunity to assign causal interpretations to observational data. We introduce RNA fingerprinting, a statistical framework that maps transcriptional responses from new experiments onto reference perturbation dictionaries. RNA fingerprinting learns perturbation representations, or \"fingerprints,\" from single-cell data, then probabilistically assigns query cells to one or more candidate perturbations. We benchmark on ground-truth datasets, demonstrating accurate assignments at single-cell resolution, scalability to genome-wide screens, and the ability to resolve combinatorial perturbations. We demonstrate broad utility across diverse biological settings: identifying context-specific regulators of p53 under ribosomal stress, characterizing dose-dependent drug mechanisms of action, and uncovering cytokine-driven B cell heterogeneity during secondary influenza infection in vivo. Together, these results establish RNA fingerprinting as a versatile framework for interpreting single-cell datasets by linking cellular states to their underlying perturbations.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":45.1,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2026-10-08DOI: 10.1016/j.cell.2026.09.057
Samuel G. Regalado,Chengxiang Qiu,Sanjay Kottapalli,Chau Huynh,Riza M. Daza,Aidan Keith,Jihye Park,Beth K. Martin,Wei Chen,Hanna Liao,Haedong Kim,Xiaoyi Li,Jean-Benoît Lalanne,Nobuhiko Hamazaki,Silvia Domcke,Junhong Choi,Jay Shendure
{"title":"A fluctuation test for gastruloid heterogeneity","authors":"Samuel G. Regalado,Chengxiang Qiu,Sanjay Kottapalli,Chau Huynh,Riza M. Daza,Aidan Keith,Jihye Park,Beth K. Martin,Wei Chen,Hanna Liao,Haedong Kim,Xiaoyi Li,Jean-Benoît Lalanne,Nobuhiko Hamazaki,Silvia Domcke,Junhong Choi,Jay Shendure","doi":"10.1016/j.cell.2026.09.057","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.057","url":null,"abstract":"Stem cells self-organize into models of early development, but even under carefully controlled conditions, the resulting organoids exhibit substantial “inter-individual” heterogeneity. To explore its origins, we generated monoclonal gastruloids, each derived from a single mouse embryonic stem cell (mESC). Molecular profiling revealed extensive heterogeneity: some gastruloids failed to develop, others were biased toward mesodermal or neural fates, and yet others contained cell types atypical of conventional polyclonal gastruloids. Applying DNA Typewriter, a cell lineage recorder, we identified heritable fate biases arising prior to gastruloid induction and found that more closely related founder mESCs give rise to more phenotypically similar gastruloids. Linking mESC subclones to their descendants’ fates revealed cryptic, fate-predictive differences in gene expression and chromatin accessibility, including at imprinted, methylation-sensitive loci linked to developmental potency. Intrinsic, heritable fluctuations in mESC state are therefore an important source of organoid heterogeneity, and DNA Typewriter enables high-resolution lineage trees in stem cell models.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"22 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2026-10-08DOI: 10.1016/j.cell.2026.09.032
Chen Xiang,Kaja Arusha,Danielle Springer,Sachiko Nakamori,Jing Cui,Ping Du Jiang,Zhi-Hong Yang,Yu Zhang,Huie Jing,Ann Y. Park,Maria H. Zhu,Sarah E. Weber,Deniz Cagdas,Hassan Abolhassani,Nasrin Behniafard,Margery G. Smelkinson,Qihui Liang,Elif Everest,Julia F. Kun,Alyssa Grogan,Bernd J. Wranik,Ngoc Vu,Bryan King,Jennifer D. Treat,Nancy Asomaning,Shijinqiu Gao,Bryson D. Bennett,Swee Lay Thein,Christa S. Zerbe,Steven M. Holland,Renu Virmani,Alan T. Remaley,Helen C. Su,Lixin Zheng,Michael J. Lenardo
{"title":"Immunoregulatory gene GIMAP6 suppresses lethal atherosclerotic vasculopathy and ischemic heart failure","authors":"Chen Xiang,Kaja Arusha,Danielle Springer,Sachiko Nakamori,Jing Cui,Ping Du Jiang,Zhi-Hong Yang,Yu Zhang,Huie Jing,Ann Y. Park,Maria H. Zhu,Sarah E. Weber,Deniz Cagdas,Hassan Abolhassani,Nasrin Behniafard,Margery G. Smelkinson,Qihui Liang,Elif Everest,Julia F. Kun,Alyssa Grogan,Bernd J. Wranik,Ngoc Vu,Bryan King,Jennifer D. Treat,Nancy Asomaning,Shijinqiu Gao,Bryson D. Bennett,Swee Lay Thein,Christa S. Zerbe,Steven M. Holland,Renu Virmani,Alan T. Remaley,Helen C. Su,Lixin Zheng,Michael J. Lenardo","doi":"10.1016/j.cell.2026.09.032","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.032","url":null,"abstract":"Controlling hyperlipidemia has reduced but not eliminated atherosclerotic cardiovascular disease (ASCVD) as a major cause of human mortality. Here, we report that loss of the immunoregulatory gene GTPase of immunity-associated protein 6 (Gimap6) in mice causes an inflammatory vasculopathy and accelerated atherosclerosis in the absence of hyperlipidemia. These vascular abnormalities cause progressive cardiac ischemia, myocardial infarction, and heart failure, culminating in early death. GIMAP6 loss precipitates early endothelial barrier failure and a mitochondrial reactive oxygen species (ROS)-PPARγ-CD36 lipid-influx cascade that lowers the threshold for foam-cell formation and induces IL-6/MCP-1/TNF-mediated inflammation. Human hypomorphic GIMAP6 variants, including the African-ancestry-enriched V65I allele, are associated with altered monocyte redox balance, increased CD36-mediated lipid uptake, and early ASCVD. Thus, GIMAP6 is a crucial safeguard for vascular integrity that restrains endothelial dysfunction, macrophage foam cell generation, and inflammation that can cause lethal ASCVD independently of systemic hyperlipidemia.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"197 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2026-10-08DOI: 10.1016/j.cell.2026.09.050
William N. Colgan,Luke W. Koblan,JoAnne Villagrana,Tien-Chi Jason Hou,Minming Wang,Gokul Gowri,Whitney Chandler,Leonardo A. Sepúlveda,Didar Ciftci,Karina Smolyar,Kathryn E. Yost,Alicia Young,Lars Wittler,Styliani Markoulaki,Kyle M. Loh,Xiaowei Zhuang,Nir Yosef,Zachary D. Smith,Jonathan S. Weissman
{"title":"Comprehensive lineage tracing maps the landscape of cell fate decisions in mouse embryogenesis","authors":"William N. Colgan,Luke W. Koblan,JoAnne Villagrana,Tien-Chi Jason Hou,Minming Wang,Gokul Gowri,Whitney Chandler,Leonardo A. Sepúlveda,Didar Ciftci,Karina Smolyar,Kathryn E. Yost,Alicia Young,Lars Wittler,Styliani Markoulaki,Kyle M. Loh,Xiaowei Zhuang,Nir Yosef,Zachary D. Smith,Jonathan S. Weissman","doi":"10.1016/j.cell.2026.09.050","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.050","url":null,"abstract":"A comprehensive cell fate map of mammalian embryogenesis has remained out of reach given the scale, cellular diversity, and non-deterministic nature of development in utero. Here, we use PEtracer to continuously install heritable genetic marks as development progresses, reconstructing lineage trees that resolve ∼75% of cell divisions across >1.4 million cells from 16 replicate embryos. We pair these trees with deep transcriptional profiling to resolve cell fate biases, restriction timing, progenitor pool sizes, and lineage relationships throughout embryogenesis. Using this quantitative reference, we uncover strikingly reproducible lineage architecture between replicate embryos and chart the lineage dynamics driving fate specification across diverse tissues. Specific biological insights include the progressive restriction of neural crest fate, the relative contributions of distinct mesodermal origins to endothelium, and the dynamics of axial elongation. This work provides a foundation for a quantitative and predictive understanding of mammalian development.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"54 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2026-10-08DOI: 10.1016/j.cell.2026.09.030
Milena Malisic,Charles Copeland,Anton Amrhein,Pengfan Zhang,Masayoshi Hashimoto,Christopher J. Harbort,Tak Lee,Yudelsy A. Tandron Moya,Lara Van Dijck,Niklas Kiel,Stanislav Kopriva,Sabine Metzger,Ruben Garrido-Oter,Ricardo F.H. Giehl,Paul Schulze-Lefert
{"title":"Arabidopsis uses distinct coumarins and bacterial pathways for pH-adaptive iron acquisition","authors":"Milena Malisic,Charles Copeland,Anton Amrhein,Pengfan Zhang,Masayoshi Hashimoto,Christopher J. Harbort,Tak Lee,Yudelsy A. Tandron Moya,Lara Van Dijck,Niklas Kiel,Stanislav Kopriva,Sabine Metzger,Ruben Garrido-Oter,Ricardo F.H. Giehl,Paul Schulze-Lefert","doi":"10.1016/j.cell.2026.09.030","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.030","url":null,"abstract":"Iron (Fe) limitation restricts plant growth in diverse soils, and root-associated microbes can alleviate plant Fe starvation. Whether plants integrate the edaphic environment and microbial activities into their Fe uptake strategies remains unclear. We show that bacterium-mediated alleviation of Fe deficiency in Arabidopsis functions at varying environmental pH and is taxonomically widespread among root microbiota isolates from soils with different edaphic profiles. This process is regulated by host-controlled and pH-adapted root exudation of different coumarin chemotypes. These exometabolites interact with root-associated bacteria to mobilize Fe either via bacterial siderophore-mediated chelation at circumneutral pH or redox-sensing-controlled, reduction-based pathways at acidic pH. The corresponding bacterial genes are prevalent in the root microbiota, and they likely evolved before the emergence of land plants. Our findings suggest that Fe malnutrition-induced exudation of redox-active metabolites by non-graminaceous plant species is a widespread adaptation for Fe mobilization from soil, mediated by the co-option of ancient microbial processes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"32 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.","authors":"Huanpeng Chen, Chao Li, Yujing Ke, Zilong Wu, Ziwei Ou, Nanqi Huang, Zhenyu Lin, Huixin Gao, Xuehu Xu, Lijuan Lu, Zhaofeng Huang, Yingjie Bian","doi":"10.1016/j.cell.2026.09.020","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.020","url":null,"abstract":"<p><p>Metabolic competition between tumors and T cells drives immune evasion, but the transporters and mechanisms remain largely elusive. Here, we establish the CareSLCs platform and identify that SLC52A3-mediated vitamin B2 (VB2) uptake is indispensable for T cell antitumor immunity. Mechanistically, VB2 deficiency impairs mitochondrial respiration and glutathione regeneration, leading to mitophagy, labile iron accumulation, and lipid peroxidation that trigger T cell ferroptosis. Unexpectedly, tumors preferentially employ SLC52A2, not SLC52A3, to scavenge VB2 and outcompete T cells. Tumor SLC52A2 ablation enhances T cell function in immunocompetent hosts without appreciably affecting intrinsic tumor growth. Clinically, high tumoral SLC52A2 correlates with T cell dysfunction and poor survival, whereas dietary VB2 intake is associated with reduced cancer risks. Thus, VB2 supplementation or SLC52A3 overexpression augments CAR-T cell antitumor efficacy. Our results suggest that tumoral VB2 competition establishes a metabolic checkpoint driving T cell ferroptosis and that enhancing VB2 uptake reinvigorates T cells to improve cancer immunotherapy.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":45.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2026-10-06DOI: 10.1016/j.cell.2026.09.024
Jing Han, Yu-Dan Zhang, Shuo Liu, Li Yang, Shuang-Li Sun, Ben Zhang, Ao-Kun Liu, Ling-Fan Zhu, Rong Wang, Dan-Dan Song, Xiao Zhuang, Yi-Jia Gao, Jing-Xin Li, Wen-Fei Li, Rong-Rong He, Heng-Xing Zhou, Lu Yu, Shi-Qing Feng, Ren-Jie Chai, Bo Chu
{"title":"A non-canonical function of glutathione to suppress ferroptosis via FSP1.","authors":"Jing Han, Yu-Dan Zhang, Shuo Liu, Li Yang, Shuang-Li Sun, Ben Zhang, Ao-Kun Liu, Ling-Fan Zhu, Rong Wang, Dan-Dan Song, Xiao Zhuang, Yi-Jia Gao, Jing-Xin Li, Wen-Fei Li, Rong-Rong He, Heng-Xing Zhou, Lu Yu, Shi-Qing Feng, Ren-Jie Chai, Bo Chu","doi":"10.1016/j.cell.2026.09.024","DOIUrl":"https://doi.org/10.1016/j.cell.2026.09.024","url":null,"abstract":"<p><p>It is well established that glutathione (GSH) is mainly utilized by glutathione peroxidase 4 (GPX4) to diminish peroxidized phospholipids and defend against ferroptosis. However, we found that GSH robustly protects a variety of GPX4 knockout (KO) cells from ferroptosis, thus indicating that there is an alternative pathway for GSH to suppress ferroptosis. By carrying out genome-wide CRISPR-Cas9 screening, we identified that ferroptosis suppressor protein 1 (FSP1) is the key factor mediating the GPX4-independent protective effect of GSH. Mechanistically, FSP1 uses GSH to generate reduced ubiquinone, which scavenges oxidized lipids and suppresses ferroptosis. Inhibition of FSP1 abolishes this GSH-dependent ferroptosis protection both in vitro and in vivo. Distinct from NAD(P)H-mediated ubiquinone reduction, GSH-stimulated generation of reduced ubiquinone via FSP1 is independent of flavin adenine dinucleotide (FAD). Together, our work clarifies a new mechanism of GSH-mediated ferroptosis suppression, thus highlighting the potential that targeting GSH metabolism should be beneficial for ferroptosis-related diseases whether or not it is related to GPX4.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":45.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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