Cell Discovery最新文献

{"title":"Structural basis of human zinc-activated channel (ZAC) signaling and modulation.","authors":"Zixuan Zhou, Yonghui Long, Yulin Chao, Chuanhui Yang, Yi-Quan Tang, Yilai Shu, Hongtao Zhu, Anders A Jensen, Qianhui Qu","doi":"10.1038/s41421-026-00878-5","DOIUrl":"10.1038/s41421-026-00878-5","url":null,"abstract":"<p><p>Zinc (Zn²⁺) plays essential roles in a plethora of physiological processes, including key functions as a neuromodulator. The zinc-activated channel (ZAC) belongs to the Cys-loop receptor (CLR) superfamily of pentameric ligand-gated ion channels, which also comprises receptors for the important neurotransmitters acetylcholine, serotonin, GABA and glycine. In contrast to these classical CLRs, which have been extensively explored over decades, ZAC remains poorly characterized despite its potential significance in mammals. Here, we present several cryo-EM structures of human ZAC, including the ligand-free resting state, the Zn²⁺-bound state, and several antagonist-bound states. In the Zn²⁺-bound structure, Zn²⁺ ions bind to the subunit interfaces of the extracellular domain, corresponding to the canonical agonist-binding sites in the classical CLRs, and are primarily coordinated through cation‒π interactions with two aromatic residues. While the antagonist TTFB inhibits ZAC by insertion between the transmembrane M2 helices of adjacent subunits, d-tubocurarine acts in a dual manner by blocking the channel and interfering with agonist binding. Combined with mutagenesis and electrophysiological analysis, these evaluations highlight the distinctive structural and functional features of this atypical CLR.</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/PMC13036004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580799","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":"Highly regional generation and heterogeneous differentiation of basal cells in mouse trachea.","authors":"Xiuxiu Liu, Wendong Weng, Zhen He, Kuo Liu, Maoying Han, Wenjuan Pu, Bin Zhou","doi":"10.1038/s41421-026-00887-4","DOIUrl":"10.1038/s41421-026-00887-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13035939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580750","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":"Sheep blastocyst-like structure models derived from stem cells.","authors":"Jing Cao, Jie Li, Miaohan Jin, Wenwen Shen, Jie Li, Saizheng Han, Jiqiang Fu, Shengjiao Song, Shenshen Shang, Fei Gao, Bo Liu, Xi Cao, Xiaoyu Niu, Zhen Liu, Xiaolong Wang","doi":"10.1038/s41421-026-00872-x","DOIUrl":"10.1038/s41421-026-00872-x","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13013973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509705","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":"Bilirubin directly activates RIPK3 to induce non-classical necroptosis.","authors":"Qian Xue, Xi Ma, Ziyuan Chen, Feifei Ge, Jiawen Wu, Wenhao Bao, Li Zhou, Wei Yi, Min Wu, Siyan Liao, Wenwen Xu, Rongrong He, Jingcheng Feng, Yameng Hu, Xi Chen, Xintian Wu, Ding Yan, Daolin Tang, Xin Chen, Jinbao Liu","doi":"10.1038/s41421-026-00876-7","DOIUrl":"10.1038/s41421-026-00876-7","url":null,"abstract":"<p><p>Bilirubin, a byproduct of heme metabolism, is traditionally recognized for its antioxidant properties. However, its accumulation under pathological conditions can result in severe clinical manifestations, including neurotoxicity. Here, we report that bilirubin acts as an activator of receptor-interacting protein kinase 3 (RIPK3), inducing necroptosis and contributing to neurotoxic effects. Unlike the canonical pathway, in which RIPK3-mediated necroptosis is dependent on RIPK1, bilirubin directly binds to the D161 and S102 residues within the kinase domain of RIPK3. This binding facilitates RIPK3 oligomerization and autophosphorylation, leading to the activation of MLKL, the primary effector of necroptosis. Notably, bilirubin-induced necroptosis does not require the RHIM domain of RIPK3 or other RHIM-containing proteins, such as ZBP1 and TRIF. Functionally, the depletion of Ripk3 reduces bilirubin-induced neurotoxicity in murine models. These findings reveal a previously unrecognized mechanism of RIPK3-mediated non-canonical necroptosis, establishing it as a key mediator of bilirubin-induced neurotoxicity.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13013812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509745","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":"Rapid production of precisely edited cattle and mice via a single AAV delivered miniature IscB^#/ωRNA<sup />.","authors":"Lishuang Song, Xuefei Liu, Anqi Di, Di Wu, Chunling Bai, Lige Bu, Dongchao Pei, Jiaru Lei, Zhenting Hao, Guanghua Su, Yuefang Zhao, Zhuying Wei, Shaorong Gao, Guangpeng Li, Lei Yang","doi":"10.1038/s41421-026-00871-y","DOIUrl":"10.1038/s41421-026-00871-y","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12996356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472418","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":"Inosine promotes erythrocyte metabolic reprogramming and restores oxygen release for rejuvenation via 2,3-BPG-PNP axis.","authors":"Wuping Liu, Zhaoyu Yang, Changhan Chen, Fang Yu, Mengzhi Wu, Zhouzhou Yao, Yuhua Fan, Tingting Xie, Linlin Wan, Tiansheng Chou, Xianjing Feng, Hao Qi, Yuyu Chou, Juan Zhao, Juan Liu, Zhiyu Yang, Yujin Zhang, Rodney E Kellems, Yang Xia","doi":"10.1038/s41421-026-00877-6","DOIUrl":"10.1038/s41421-026-00877-6","url":null,"abstract":"<p><p>Aging-related diseases are aggravated by tissue hypoxia; however, the underlying mechanism remains unknown. Here, we report that the oxygen (O₂) release capacity of red blood cells (RBCs) gradually decreases with age and is closely associated with aging-related tissue dysfunction. Metabolomic profiling of human and mouse RBCs and genetic studies in mice revealed that the reduction in 2,3-bisphosphoglyceric acid (2,3-BPG) content mediated by a decrease in bisphosphoglycerate mutase (BPGM) activity is a metabolic checkpoint underlying decreased RBC O₂ release capability and dysfunction with advancing age. When glucose metabolism is impaired, erythroid inosine, transported by equilibrative nucleoside transporter 1 and converted to ribose 1-phosphate by increased purine nucleoside phosphorylase (PNP) activity, is an important compensatory fuel for RBCs during aging. In a preclinical study, inosine supplementation successfully alleviated the age-dependent reduction in BPGM activity that mediates glucose metabolic impairment, decreased O₂ delivery, and tissue dysfunction. Finally, we unexpectedly discovered that 2,3-BPG acts as an inhibitor of PNP in RBCs by competing with the phosphate (Pi)-binding domain and interacting with residues serine 33 and alanine 116. Our studies revealed that impaired glucose metabolic reprogramming resulting from decreased BPGM activity underlies RBC bioenergetic decline and is a novel hallmark of aging. As 2,3-BPG levels decrease during aging, its inhibitory effect on PNP is reduced, resulting in increased PNP activity and inosine catabolism as an alternative fuel, suggesting that inosine is a potential rejuvenating therapy.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12996605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472237","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 mitochondrial translocation of phosphorylated EZH2 promotes PARP inhibitor resistance in BRCA1-deficient epithelial ovarian cancer.","authors":"Ling Hu, Xiaolu Ma, Xushan Cai, Tianqing Yan, Kaixia Zhou, Chen Shan, Ning Guo, Hui Zheng, Yanchun Wang, Ying Tong, Suhong Xie, Heng Zhang, Cuncun Chen, Zhiyun Gong, Lin Guo, Renquan Lu","doi":"10.1038/s41421-026-00880-x","DOIUrl":"10.1038/s41421-026-00880-x","url":null,"abstract":"<p><p>BRCA1-deficient epithelial ovarian cancer (EOC) is reported to respond to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis); however, acquired resistance frequently emerges, limiting the long-term clinical efficacy of PARPis. The mechanisms driving acquired PARPi resistance in these patients remain poorly understood. In this study, we performed a systemic screen of epigenetic inhibitors in patient-derived organoids (PDOs) and identified enhancer of zeste homolog 2 (EZH2) as the key driver of PARPi resistance in BRCA1-deficient EOC. We found that in PARPi-resistant cells, intracellular EZH2 translocated from the nucleus to the mitochondria, where it promoted mitochondrial fusion and subsequently prevented PARPi-mediated apoptosis. Mechanistically, we determined that PARPi treatment activated YES1 to phosphorylate EZH2 at the Y728 residue, which promoted the mitochondrial translocation of EZH2 in a TOM20-dependent manner. Using mass spectrometry, we identified MYO19 as a main substrate of EZH2 in mitochondria and found that EZH2 trimethylated MYO19 at the K928 residue to trigger mitochondrial fusion. Moreover, Y728 phosphorylation also increased EZH2 protein stability by hindering TRIM4 binding, thus blocking TRIM4-mediated ubiquitination and subsequent proteasomal degradation. Notably, the efficacy of targeting YES1 or EZH2 to resensitize tumors to PARPis was validated in PDOs, xenograft models and EOC cell lines. Here, our findings reveal a YES1-EZH2-MYO19 post-translational modification cascade, whereby PARPi-induced phosphorylation of EZH2 triggered mitochondrial fusion, and targeting phosphorylated EZH2 rebalanced mitochondrial dynamics and resensitized BRCA1-deficient EOC to PARPis, suggesting a promising therapeutic strategy.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12982769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442842","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":"Integrative spatial profiling pipeline for determining TME architectures in archival clinical specimens using CmTSA superplex technology.","authors":"Chaoxin Xiao, Ruihan Zhou, Qin Chen, Wanting Hou, Yulin Wang, Lu Liu, Huanhuan Wang, Xiaohong Yao, Rui Zhu, Zirui Wang, Leyi Yao, Ouying Yan, Xiaoying Li, Tongtong Xu, Fujun Cao, Banglei Yin, Na Xiao, Lili Jiang, Wei Wang, Dan Cao, Chengjian Zhao","doi":"10.1038/s41421-026-00874-9","DOIUrl":"10.1038/s41421-026-00874-9","url":null,"abstract":"<p><p>The tumor microenvironment (TME) comprises diverse cellular components that spatially interact to form distinct functional niches (FNs). Profiling these TME spatial features has proven to be a critical approach for correlating tumor progression and therapeutic response. However, RNA stability limitations constrain the broad clinical implementation of spatial transcriptomics, while high background noise and low signal resolution compromise the accuracy of direct labeling-based spatial proteomic approaches in clinical specimens. To overcome these constraints in archival samples, we developed hybrid optochemical fluorescence depletion (HOC-FD) technology that integrates autofluorescence quenching with cyclic multiplex tyramide signal amplification (CmTSA) for formalin-fixed paraffin-embedded (FFPE) tissues. This unified platform enables the concurrent labeling of 30-60 biomarkers with ultrahigh signal-to-noise ratios while maintaining cost efficiency and compatibility with high-throughput processing of archival FFPE specimens. While superplex imaging captures multidimensional TME data, extracting spatial features from raw pixel-level outputs remains technically challenging. To resolve this problem, we implemented a computer vision pipeline beginning with deep learning-based cellular segmentation and phenotype classification under predefined biomarker annotation rules. Using single-cell spatial mapping of human colon and cervical cancer specimens, we systematically evaluated and selected radius-constrained neighborhood network (RNN) analysis to define functional niches, validating their accuracy and reliability in generating spatially coherent FNs with biological and prognostic relevance. In summary, the CmTSA platform combined with RNN-based spatial profiling provides an integrated framework for visualizing and quantifying multicellular functional states within architectures of the TME, potentially enhancing tumor immunology investigations and precision immunotherapies.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12976111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430446","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":"Lysine β-hydroxybutyrylation as a drought-responsive epigenetic mark in rice.","authors":"XueLu Wei, Zhengting Chen, Yuan Liu, Guiyu Xiao, Shengjun Guo, JiaDa Huang, Wen Ren, Xuan Ma, Xiaoyang Chen, Jisen Zhang, Qiutao Xu","doi":"10.1038/s41421-026-00868-7","DOIUrl":"10.1038/s41421-026-00868-7","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343530","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":"Hallmarks of the pre-disease state: prevention and control of the pre-disease state, a tipping point between health and disease.","authors":"Pei Chen, Xiaoping Liu, Rui Liu, Luonan Chen","doi":"10.1038/s41421-026-00879-4","DOIUrl":"10.1038/s41421-026-00879-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"12 1","pages":""},"PeriodicalIF":16.9,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343441","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}