{"title":"Galectin-13 reduces membrane localization of SLC7A11 for ferroptosis propagation","authors":"Hai-Liang Zhang, Yi-Qing Guo, Shan Liu, Zhi-Peng Ye, Li-Chao Li, Bing-Xin Hu, Zhi-Ling Li, Yu-Hong Chen, Gong-Kan Feng, Hui-Qi Shen, Rong Deng, Xiao-Feng Zhu","doi":"10.1038/s41589-025-01888-2","DOIUrl":"https://doi.org/10.1038/s41589-025-01888-2","url":null,"abstract":"<p>The mechanism of ferroptosis propagation is still unclear. Here our results indicate that the cells undergoing ferroptosis secrete Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation. FOXK1 was phosphorylated by PKCβII and then facilitated the expression and secretion of Galectin-13 during ferroptotic cell death. Correlation analysis and functional analysis revealed that ferroptosis propagation ability was a previously unrecognized determinant of ferroptosis sensitivity in human cancer cells. A synthetic Galectin-13 mimetic peptide was shown to strongly enhance the sensitivity of tumors to the imidazole ketone erastin, radiotherapy and immunotherapy by boosting ferroptosis. In particular, cancer stem cells were vulnerable to the combination of Galectin-13 mimetic peptide and ferroptosis inducers. Our study provides new insights into ferroptosis propagation and highlights novel strategies for targeting ferroptosis to treat tumors.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"6 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841661","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":"Trimming the fat from Dishevelled","authors":"Cory Nadel, Felipe de Sousa e Melo","doi":"10.1038/s41589-025-01862-y","DOIUrl":"https://doi.org/10.1038/s41589-025-01862-y","url":null,"abstract":"Wnt signaling is a major driver of colorectal cancers, but compounds targeting Wnt pathways are poorly tolerated. Chemical inhibition of Dishevelled–cholesterol binding selectively restricts colorectal tumor growth while sparing the normal intestinal epithelium, opening new doors for therapy.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"7 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837214","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":"Tuning the clock with BMAL1 ligand","authors":"Vajravijayan Senthilvadivel, Tsuyoshi Hirota","doi":"10.1038/s41589-025-01890-8","DOIUrl":"https://doi.org/10.1038/s41589-025-01890-8","url":null,"abstract":"The identification of a small molecule selectively targeting the core circadian clock protein BMAL1 provides deeper insights into the molecular mechanisms that govern biological rhythms and enables control of immune pathways.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"2 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837213","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}
Ashutosh Sharma, Julian Zalejski, Shruti Vijay Bendre, Simona Kavrokova, Hale Siir Hasdemir, Defne Gorgun Ozgulbas, Jiachen Sun, Koralege C. Pathmasiri, Ruicheng Shi, Ahmed Aloulou, Kyli Berkley, Charles F. Delisle, Young Wang, Erin Weisser, Pawanthi Buweneka, Dominick Pierre-Jacques, Sayandeb Mukherjee, Diana A. Abbasi, Daesung Lee, Bo Wang, Vladimir Gevorgyan, Stephanie M. Cologna, Emad Tajkhorshid, Erik R. Nelson, Wonhwa Cho
{"title":"Cholesterol-targeting Wnt–β-catenin signaling inhibitors for colorectal cancer","authors":"Ashutosh Sharma, Julian Zalejski, Shruti Vijay Bendre, Simona Kavrokova, Hale Siir Hasdemir, Defne Gorgun Ozgulbas, Jiachen Sun, Koralege C. Pathmasiri, Ruicheng Shi, Ahmed Aloulou, Kyli Berkley, Charles F. Delisle, Young Wang, Erin Weisser, Pawanthi Buweneka, Dominick Pierre-Jacques, Sayandeb Mukherjee, Diana A. Abbasi, Daesung Lee, Bo Wang, Vladimir Gevorgyan, Stephanie M. Cologna, Emad Tajkhorshid, Erik R. Nelson, Wonhwa Cho","doi":"10.1038/s41589-025-01870-y","DOIUrl":"https://doi.org/10.1038/s41589-025-01870-y","url":null,"abstract":"<p>Most persons with colorectal cancer (CRC) carry adenomatous polyposis coli (APC) truncation leading to aberrant Wnt–β-catenin signaling; however, effective targeted therapy for them is lacking as the mechanism by which APC truncation drives CRC remains elusive. Here, we report that the cholesterol level in the inner leaflet of the plasma membrane (IPM) is elevated in all tested APC-truncated CRC cells, driving Wnt-independent formation of Wnt signalosomes through Dishevelled (Dvl)–cholesterol interaction. Cholesterol–Dvl interaction inhibitors potently blocked β-catenin signaling in APC-truncated CRC cells and suppressed their viability. Because of low IPM cholesterol level and low Dvl expression and dependence, normal cells including primary colon epithelial cells were not sensitive to these inhibitors. In vivo testing with a xenograft mouse model showed that our inhibitors effectively suppressed truncated APC-driven tumors without causing intestinal toxicity. Collectively, these results suggest that the most common type of CRC could be effectively and safely treated by blocking the cholesterol–Dvl–β-catenin signaling axis.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"15 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837216","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}
Sen Yang, Yuan Wang, Sisi Huang, Tong Zhang, Pinglong Xu, Chao Jiang, Cunqi Ye
{"title":"Temporal oscillation of phospholipids promotes metabolic efficiency","authors":"Sen Yang, Yuan Wang, Sisi Huang, Tong Zhang, Pinglong Xu, Chao Jiang, Cunqi Ye","doi":"10.1038/s41589-025-01885-5","DOIUrl":"https://doi.org/10.1038/s41589-025-01885-5","url":null,"abstract":"<p>Biological timing is a fundamental aspect of life, facilitating efficient resource use and adaptation to environmental changes. In this study, we unveil robust temporal oscillations in phospholipid abundance as a function of the yeast metabolic cycle (YMC). These fluctuations, occurring throughout the cell division cycle, demonstrate a systematic segregation of various phospholipid species over time. Such segregation corresponds logically with their physical properties, generating entropic forces for membrane dynamics and biogenesis. Within the YMC, the temporal oscillations in phosphatidylethanolamine and phosphatidylcholine levels require biosynthesis from triacylglycerol as a crucial lipid reservoir, with phosphatidylinositol and phosphatidylserine synthesized primarily de novo. The orchestrated regulation of gene expression in biosynthesis pathways ensures precise temporal control of phospholipid dynamics, ultimately promoting metabolic efficiency.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"303 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827515","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}
Fabio P. Gomes, Kenneth R. Durbin, Kevin Schauer, Jerome C. Nwachukwu, Robin R. Kobylski, Jacqline W. Njeri, Ciaran P. Seath, Anthony J. Saviola, Daniel B. McClatchy, Jolene K. Diedrich, Patrick T. Garrett, Alexandra B. Papa, Ianis Ciolacu, Neil L. Kelleher, Kendall W. Nettles, John R. Yates
{"title":"Native top-down proteomics enables discovery in endocrine-resistant breast cancer","authors":"Fabio P. Gomes, Kenneth R. Durbin, Kevin Schauer, Jerome C. Nwachukwu, Robin R. Kobylski, Jacqline W. Njeri, Ciaran P. Seath, Anthony J. Saviola, Daniel B. McClatchy, Jolene K. Diedrich, Patrick T. Garrett, Alexandra B. Papa, Ianis Ciolacu, Neil L. Kelleher, Kendall W. Nettles, John R. Yates","doi":"10.1038/s41589-025-01866-8","DOIUrl":"https://doi.org/10.1038/s41589-025-01866-8","url":null,"abstract":"<p>Oligomerization of proteoforms produces functional protein complexes. Characterization of these assemblies within cells is critical to understanding the molecular mechanisms involved in disease and to designing effective drugs. Here we present a native top-down proteomics (nTDP) strategy to identify protein assemblies (≤70 kDa) in breast cancer cells and in cells that overexpress epidermal growth factor receptor (EGFR), which serves as a resistance model of estrogen receptor-alpha (ER)-targeted therapies. This nTDP approach identified ~104 complexoforms from 17 protein complexes, which revealed several molecular features of the breast cancer proteome, including EGFR-induced dissociation of nuclear transport factor 2 (NUTF2) assemblies that modulate ER activity. We found that the K4 and K55 post-translational modification sites discovered with nTDP differentially impact the effects of NUTF2 on the inhibition of the ER signaling pathway. The characterization of endogenous proteoform–proteoform/ligand interactions revealed the molecular diversity of complexoforms and their role in breast cancer growth.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"32 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775636","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}
Min Duan, Pan Gao, Yi-Zhou Zhang, Yu-Long Hu, Lei Zhou, Zhong-Chen Xu, Hou-Yuan Qiu, Xiao-Han Tong, Rui-Jin Ji, Xin-Lin Lei, Hao Yin, Cun-Lan Guo, Ying Zhang
{"title":"TOPO-seq reveals DNA topology-induced off-target activity by Cas9 and base editors","authors":"Min Duan, Pan Gao, Yi-Zhou Zhang, Yu-Long Hu, Lei Zhou, Zhong-Chen Xu, Hou-Yuan Qiu, Xiao-Han Tong, Rui-Jin Ji, Xin-Lin Lei, Hao Yin, Cun-Lan Guo, Ying Zhang","doi":"10.1038/s41589-025-01867-7","DOIUrl":"https://doi.org/10.1038/s41589-025-01867-7","url":null,"abstract":"<p>With the increasing use of CRISPR–Cas9, detecting off-target events is essential for safety. Current methods primarily focus on guide RNA (gRNA) sequence mismatches, often overlooking the impact of DNA topology in regulating off-target activity. Here we present TOPO-seq, a high-throughput and sensitive method that identifies genome-wide off-target effects of Cas9 and base editors while accounting for DNA topology. TOPO-seq revealed that topology-induced off-target sites frequently harbor higher mismatches than the relaxed DNA sequence, with over 50% of off-target sites containing six mismatches, which are usually overlooked using previous methods. Applying TOPO-seq to three therapeutic gRNAs in hematopoietic stem cells identified 47 bona fide off-target loci, six of which are specifically induced by DNA topology. These findings highlight DNA topology as a regulator of off-target editing rates, establish TOPO-seq as a robust method for capturing DNA topology-induced off-target events and underscore its importance in off-target detection for developing safe genome-editing therapies.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"106 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758450","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}
Yaqing Zhang, Yuan Jiang, David Kuster, Qiwei Ye, Wenhao Huang, Simon Fürbacher, Jingye Zhang, Pia Doll, Wenjun Lin, Siwei Dong, Hui Wang, Zhipeng Tang, David Ibberson, Klemens Wild, Irmgard Sinning, Anthony A. Hyman, Andres Jäschke
{"title":"Single-step discovery of high-affinity RNA ligands by UltraSelex","authors":"Yaqing Zhang, Yuan Jiang, David Kuster, Qiwei Ye, Wenhao Huang, Simon Fürbacher, Jingye Zhang, Pia Doll, Wenjun Lin, Siwei Dong, Hui Wang, Zhipeng Tang, David Ibberson, Klemens Wild, Irmgard Sinning, Anthony A. Hyman, Andres Jäschke","doi":"10.1038/s41589-025-01868-6","DOIUrl":"https://doi.org/10.1038/s41589-025-01868-6","url":null,"abstract":"<p>Aptamers, nucleic acid ligands targeting specific molecules, have emerged as drug candidates, sensors, imaging tools and nanotechnology building blocks. The predominant method for their discovery, systematic evolution of ligands by exponential enrichment, while successful, is laborious, time-consuming and often results in candidates enriched for unintended criteria. Here we present UltraSelex, a noniterative method that combines biochemical partitioning, high-throughput sequencing and computational signal-to-background rank modeling for discovering RNA aptamers in about 1 day. UltraSelex identified high-affinity RNA aptamers capable of binding a fluorogenic silicon rhodamine dye and two protein targets, the SARS-CoV-2 RNA-dependent RNA polymerase and HIV reverse transcriptase, enabling live-cell RNA imaging and efficient enzyme inhibition, respectively. From the ranked sequences, minimal aptamer motifs could be easily inferred. UltraSelex provides a rapid route to reveal new drug candidates and diagnostic tools.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"1 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736722","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}
Fangting Zuo, Li Jiang, Ni Su, Yaqiang Zhang, Bingkun Bao, Limei Wang, Yajie Shi, Huimin Yang, Xinyi Huang, Ruilong Li, Qingmei Zeng, Zhengda Chen, Qiuning Lin, Yingping Zhuang, Yuzheng Zhao, Xianjun Chen, Linyong Zhu, Yi Yang
{"title":"Author Correction: Imaging the dynamics of messenger RNA with a bright and stable green fluorescent RNA","authors":"Fangting Zuo, Li Jiang, Ni Su, Yaqiang Zhang, Bingkun Bao, Limei Wang, Yajie Shi, Huimin Yang, Xinyi Huang, Ruilong Li, Qingmei Zeng, Zhengda Chen, Qiuning Lin, Yingping Zhuang, Yuzheng Zhao, Xianjun Chen, Linyong Zhu, Yi Yang","doi":"10.1038/s41589-025-01892-6","DOIUrl":"https://doi.org/10.1038/s41589-025-01892-6","url":null,"abstract":"<p>Correction to: <i>Nature Chemical Biology</i> https://doi.org/10.1038/s41589-024-01629-x, published online 23 May 2024.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"59 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733936","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}
Xiaowei Zhang, Luis S. Mille-Fragoso, K. Eerik Kaseniit, Arden P. Lee, Meng Zhang, Connor C. Call, Yixin Hu, Yunxin Xie, Xiaojing J. Gao
{"title":"Post-transcriptional modular synthetic receptors","authors":"Xiaowei Zhang, Luis S. Mille-Fragoso, K. Eerik Kaseniit, Arden P. Lee, Meng Zhang, Connor C. Call, Yixin Hu, Yunxin Xie, Xiaojing J. Gao","doi":"10.1038/s41589-025-01872-w","DOIUrl":"https://doi.org/10.1038/s41589-025-01872-w","url":null,"abstract":"<p>Inspired by the power of transcriptional synthetic receptors and hoping to complement them to expand the toolbox for cell engineering, we establish LIDAR (Ligand-Induced Dimerization-Activating RNA editing), a modular post-transcriptional synthetic receptor platform that harnesses RNA editing by adenosine deaminases acting on RNA. LIDAR is compatible with various receptor architectures in different cellular contexts and enables the sensing of diverse ligands and the production of functional outputs. Furthermore, LIDAR can sense orthogonal signals in the same cell and produce synthetic spatial patterns, potentially enabling the programming of complex multicellular behaviors. Lastly, LIDAR is compatible with compact encoding and can be delivered as synthetic mRNA. Thus, LIDAR expands the family of synthetic receptors, holding the promise to empower basic research and therapeutic applications.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"15 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723133","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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