Cell Discovery最新文献

{"title":"A negative survival pressure selection system enables GPCR antagonist screening.","authors":"Tao Xu, Qinxin Sun, Shuhao Zhang, Tingzhu Liu, Xiaoou Sun, Xusheng Wang, Bin Lin, Zhongjie Liu, Juan Wang, Guodong He, Xiangyu Liu","doi":"10.1038/s41421-026-00892-7","DOIUrl":"10.1038/s41421-026-00892-7","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13172303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the role of chromatin context in the off-target effects of CRISPR gene editing with EGOLD.","authors":"Hu Feng, Jitan Zheng, Nana Li, Long Xie, Erwei Zuo","doi":"10.1038/s41421-026-00889-2","DOIUrl":"10.1038/s41421-026-00889-2","url":null,"abstract":"<p><p>Despite the power of CRISPR in genome editing, its clinical application is limited by off-target effects; these effects are currently difficult to evaluate at the genome level but are likely to involve chromatin context. Here, we developed the Endogenous Genome-wide Off-target Library Detection (EGOLD) method for high-throughput detection of off-target effects and identification of chromatin context bias in gene editor evaluation. Applying EGOLD to define the off-target characteristics of 17 base-editing tools revealed 2,145,592 total off-targets, with 1236-618,774 events detected per tool. The frequency of off-targets of CRISPR/Cas9 and derivative base editors ranged from 40% to 80% and were strongly influenced by the chromatin context. Using a large-scale endogenous off-target dataset with strict target site conditions to exclude the influence of sequence context, we found that off-target effects occurred in open chromatin genomic regions at a significantly greater frequency than in closed chromatin regions. The incorporation of EGOLD-Seq off-target chromatin context data to train machine learning-based models of gene editor activity substantially improved off-target prediction accuracy. These findings and the accompanying toolkit can guide mechanistic research and the development of safe and precise CRISPR-based tools.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13172344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASB7 promotes osteosarcoma lung metastasis through ubiquitin-mediated degradation of ATF2.","authors":"Yezi Zou, Jianliang Zhong, Lanqing Huo, Jiali Chen, Xinhao Yu, Jingxuan Wang, Zhenxuan Chen, Lifeng Yin, Cuiling Zeng, Xia Zhang, Shan Han, Ruhua Zhang, Xing-Ding Zhang, Tiebang Kang, Liwen Zhou","doi":"10.1038/s41421-026-00890-9","DOIUrl":"10.1038/s41421-026-00890-9","url":null,"abstract":"<p><p>Osteosarcoma is a highly heterogeneous and aggressive malignancy with a strong propensity for metastasis, highlighting the need to define its molecular drivers. Here, we report that ASB7 promotes tumor cell protrusion formation, invasion, migration, and lung metastasis. High expression of ASB7 is correlated with a poor prognosis. ASB7 forms an E3 ubiquitin ligase complex with CUL5 to ubiquitinate ATF2 at K383 and promote its proteasomal degradation. ATF2 reduction impairs HDAC6 recruitment to the ITGB2 promoter, thereby alleviating the transcriptional repression of ITGB2. Elevated ITGB2 expression subsequently promotes tumor lung metastasis. Our findings reveal that the ASB7-ATF2/HDAC6-ITGB2 axis regulates osteosarcoma metastasis and suggest potential treatment targets.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGM2-mediated serotonylation of GPX4 confers ferroptosis resistance to promote gastric tumorigenesis.","authors":"Junping Bai, Dandan Geng, Xinwen Chen, Wanting Li, Xiaowei Wang, Luyang Tian, Yi Han, Zhao Jin, Meihang Du, Yang Tang, Weisheng Hu, Chunxiao Zhu, Shan Zhang, Zhangting Zhao, Run Zhang, Xinru Zhang, Wei Kang, KaFai To, Sachiyo Nomura, Fenghua Guo, Shi Jiao, Yixuan Xie, Zhaocai Zhou, Chao Dong, Hui Li, Liwei An","doi":"10.1038/s41421-026-00885-6","DOIUrl":"10.1038/s41421-026-00885-6","url":null,"abstract":"<p><p>Protein monoaminylation represents a new layer of neural-cancer regulation, but its role in gastric tumorigenesis is not understood. Using untargeted plasma metabolomics, we revealed that the level of serotonin (5-HT) is significantly elevated in gastric cancer (GC) patients. Functionally, 5-HT treatment dramatically promoted GC cell proliferation and tumor growth in a dose-dependent manner. Importantly, this oncogenic effect was abrogated by the inhibition of transglutaminase 2 (TGM2), indicating a crucial role for protein serotonylation via a receptor-independent mechanism. Using a 5-HT-based chemoproteomic probe, we identified a broad spectrum of serotonylation targets, including key ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4). Specifically, we found that GPX4 is serotonylated by TGM2 at residues Gln55 and Gln77, which increases GPX4 protein stability by attenuating its ubiquitin-mediated degradation, thereby conferring resistance to ferroptosis and facilitating tumor growth. Clinically, TGM2 levels were positively correlated with tumoral GPX4 expression in GC patient specimens. Collectively, our results establish TGM2-mediated GPX4 serotonylation as a key mechanism driving GC progression through ferroptosis resistance, highlighting its potential as both a diagnostic biomarker and a therapeutic target within the neural-tumor axis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The landscape of human transposable element insertions in Chinese population.","authors":"Jiali Wang, Chong Chu, Shengqing Wan, Jun Xiang, Zheng Gong, Shengnan Liu, Cheng Wang, Jiaojiao Pang, Feng Xu, Chang Pan, Juying Qian, Hongbing Shen, Guang Ning, Yanan Cao, Yuguo Chen","doi":"10.1038/s41421-026-00886-5","DOIUrl":"10.1038/s41421-026-00886-5","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASO-based PKM splice-switching therapy increases anti-CTLA-4 antibody efficacy in pancreatic ductal adenocarcinoma.","authors":"Lijie Han, Lina Gan, Balázs Schäfer, Dillon M Voss, Mathias Danielsen, Ondrej Kostov, Jia Liu, Ting Wang, Marvin H Caruthers, Hao Chen, Adrian R Krainer","doi":"10.1038/s41421-026-00882-9","DOIUrl":"10.1038/s41421-026-00882-9","url":null,"abstract":"<p><p>The alternative splice isoform of pyruvate kinase M (PKM), PKM2, plays a pivotal role in regulating aerobic glycolysis in tumor cells. Systemic delivery of antisense oligonucleotides (ASOs) that shift PKM splicing from the PKM2 isoform to the PKM1 isoform inhibits tumor progression and reprograms intratumoral metabolism. However, the cellular populations within the tumor microenvironment (TME) are also highly dependent on PKM2 and might likewise be affected by ASO treatment. In this study, we demonstrate that PKM2 is upregulated and PKM1 is downregulated in both human and murine pancreatic ductal adenocarcinoma (PDAC) cells. PKM1 and PKM2 are mutually exclusive and expressed in a cell type-specific manner in various cell types and stages of PDAC tumors. We report that basal-like PDAC cells and their surrounding activated regulatory T cells (T_regs) rely on PKM2 to sustain glycolysis. Although PKM-ASO monotherapy had a limited effect in an immunodeficient mouse model of PDAC, synergy between PKM-ASO and anti-CTLA-4 immune checkpoint blockade (ICB), which targets T_regs, restricted tumor growth in an immunocompetent mouse model. Our findings provide preclinical support for combined antisense therapy and ICB for PDAC patients, highlighting the critical role of PKM2 in the TME and its potential as a therapeutic target.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural insights into the gating mechanism of the fission yeast phosphate exporter SpXpr1.","authors":"Hui Yang, Yuechan Wang, Chenxi Yue, Xinran Li, Yifei Wang, Ye Yu, Huaizong Shen","doi":"10.1038/s41421-026-00883-8","DOIUrl":"10.1038/s41421-026-00883-8","url":null,"abstract":"<p><p>Phosphate homeostasis is essential for fundamental cellular processes, including energy metabolism, signal transduction, and nucleic acid synthesis. Although XPR1 family proteins are conserved phosphate exporters throughout eukaryotes, their structural mechanisms in organisms other than mammals and plants remain largely unexplored. Here, we presented high-resolution cryo-electron microscopy (cryo-EM) structures of Schizosaccharomyces pombe Xpr1 (SpXpr1) in both the apo and inositol hexakisphosphate (InsP6)-bound states. While SpXpr1 shares conserved phosphate coordination sites with its human and plant orthologs, SpXpr1 employs a unique dual gating mechanism: (1) an intracellular gate formed by the N-loop of the SPX domain, stabilized by a preceding N-helix and an extended TM10 helix and (2) an extracellular ECL_plug occluding the exit. We further showed that InsP6 binding induces allosteric destabilization of the N-loop gate, facilitating phosphate release. Functional validation through phosphate efflux assays in Homo sapiens XPR1 (HsXPR1)-knockout cells and whole-cell patch-clamp recordings confirmed the structural observations. Our findings elucidated a unique gating mechanism of SpXpr1 and offer evolutionary perspectives on phosphate regulation across eukaryotes.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13083964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis of glucosinolate recognition and transport by plant GTR1.","authors":"Rui Yan, Junping Fan, Cheng Chi, Bowen Zhang, Di Wu, Huiwen Chen, Jianke Gong, Xiaoguang Lei, Daohua Jiang","doi":"10.1038/s41421-026-00884-7","DOIUrl":"10.1038/s41421-026-00884-7","url":null,"abstract":"<p><p>Glucosinolates (GLSs) play crucial roles in plant defense against herbivores. GTR1 facilitates the high-affinity transport of GLSs through a proton-dependent process. However, the molecular mechanism underlying GLS recognition and transport by GTR1 remains largely unknown. Here, we present four cryo-EM structures of Arabidopsis GTR1 in distinct states, namely, the outward-apo, inward-apo, 4MTB-bound and 3IMG-bound forms, revealing the structural basis for GLS and proton cotransport by GTR1. GTR1 consists of an MFS-like transmembrane domain and an intracellular domain (ICD). The ICD plays an essential role in GTR1 function by interacting with the gating helix, transmembrane helix 7. GLSs are recognized by the central cavity residues and directly interact with the conserved E₁X₁X₂E₂K motif. Our structural and functional analyses demonstrated that the E₁X₁X₂E₂K motif and Glu513 determine the proton coupling of GTR1. This study provides mechanistic insights into how GTR1 transports GLSs, which could aid in improving crop quality and enhancing resistance to herbivory.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13056971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss-of-function variants in ODAD1 disrupt ODA docking and induce actin cytoskeletal remodeling in primary ciliary dyskinesia.","authors":"Chunxiao Huo, Ting Luo, Shuo Yang, Yuan Jiang, Mengzhe Guo, Feng Yang, Zhangqi Xu, Junhua Xia, Lei Wu, Weize Xu, Miao Gui, Tianhua Zhou, Shanshan Xie","doi":"10.1038/s41421-026-00875-8","DOIUrl":"10.1038/s41421-026-00875-8","url":null,"abstract":"<p><p>Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by defective mucociliary clearance due to impaired motile cilia function. Outer dynein arm docking complex subunit 1 (ODAD1) encodes a structural component of the outer dynein arm docking complex (ODA-DC), which is crucial for effective ciliary beating. However, the full spectrum of ODAD1-associated pathogenesis remains incompletely defined. Here, we identified one novel homozygous loss-of-function ODAD1 variant, c.705_706insGCAG, and a recurrent homozygous splicing variant, c.-41-2A > C, in seven unrelated patients. These patients exhibited hallmark PCD symptoms with reduced nasal nitric oxide levels and situs inversus. Patient-derived nasal epithelial cells and air‒liquid interface (ALI) cultures exhibited a markedly reduced ciliary beating frequency and severe motility defects. Transmission electron microscopy and cryo-electron microscopy showed a complete loss of outer dynein arms and docking complexes, with variant-specific ultrastructural abnormalities. Unexpectedly, ODAD1 deficiency also led to reduced multiciliated cells (MCCs) abundance, misoriented basal bodies, and impaired multiciliogenesis. Proteomic profiling and immunostaining revealed prominent actin cytoskeletal remodeling, including aberrant F-actin bundling throughout the epithelial layers. Pharmacological inhibition of actin polymerization using cytochalasin B partially rescued the abundance of MCCs and multiciliogenesis, indicating that actin dysregulation is a modifiable consequence of ODAD1 loss. Finally, lentiviral re-expression of wild-type ODAD1 in patient-derived organoids restored ODA assembly and rescued coordinated ciliary beating, confirming the pathogenicity of the identified variants. Our data reveal a dual role for ODAD1 in regulating both axonemal structure and epithelial cytoskeletal integrity and identify actin dysregulation as a previously unrecognized, targetable pathological mechanism of ODAD1-associated PCD.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13039848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement 5a receptor 2 attenuates diabetic kidney disease by promoting mitochondria-associated endoplasmic reticulum membrane formation mediated by PSS-MFN2 interaction.","authors":"Yi-Yang Zhao, Yi-Hui Wang, Zi-Han Li, Dong-Yuan Chang, Lin Nie, Ming-Hui Zhao, Sydney Chi Wai Tang, Min Chen","doi":"10.1038/s41421-026-00873-w","DOIUrl":"10.1038/s41421-026-00873-w","url":null,"abstract":"<p><p>Complement-mediated metabolic disorders are considered important contributors to the pathogenesis of diabetic kidney disease (DKD). This study investigated the non-canonical roles of complement 5a receptor 2 (C5aR2) in metabolism and its underlying molecular mechanisms in DKD. In patients with DKD, we found that C5aR2 expression was upregulated in the tubulointerstitium and correlated with both disease severity and adverse renal outcomes. C5aR2 deficiency in diabetic mice exacerbated the DKD phenotype, including pronounced lipid accumulation, mitochondrial and endoplasmic reticulum (ER) dysfunction, and reduced phosphatidylserine (PS) levels in the kidney. Mechanistically, C5aR2 activated cellular Fos proto-oncogene (c-FOS) nuclear translocation, upregulated phosphatidylserine synthase (PSS) expression, and promoted the interaction between PSS and mitochondrial fusion protein 2 (MFN2), which facilitated mitochondria-associated ER membrane (MAM) formation and PS biosynthesis, improving mitochondrial and ER function. Treatment with the C5aR2-specific agonist P59 ameliorated the DKD phenotype, improved PS homeostasis and MAM formation, and thereby reversed lipid accumulation, ER stress, and mitochondrial dysfunction in db/db mice. Single-cell RNA sequencing (scRNA-seq) analysis revealed that P59 restored Pss expression in injured proximal tubular cells. These results highlight C5aR2 activation as a promising strategy for DKD treatment.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13040050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}