Tin-Yan Koo , Jason Ying Ki Li , Nga-Sze Lee , Jintian Chen , Hillary Yui-Yan Yip , Ianto Bosheng Huang , Kai-Yu Ng , Helen H.N. Yan , Suet Yi Leung , Stephanie Ma , Jingying Zhou , Clive Yik-Sham Chung
{"title":"A covalent inhibitor targeting Cys16 on RhoA in colorectal cancer","authors":"Tin-Yan Koo , Jason Ying Ki Li , Nga-Sze Lee , Jintian Chen , Hillary Yui-Yan Yip , Ianto Bosheng Huang , Kai-Yu Ng , Helen H.N. Yan , Suet Yi Leung , Stephanie Ma , Jingying Zhou , Clive Yik-Sham Chung","doi":"10.1016/j.chembiol.2025.08.004","DOIUrl":"10.1016/j.chembiol.2025.08.004","url":null,"abstract":"<div><div>RhoA is a key cancer driver and potential colorectal cancer (CRC) therapy target but remains undrugged clinically. Using activity-based protein profiling (ABPP) and mass spectrometry (MS), we identified CL16, a covalent inhibitor targeting the unique Cys16 on RhoA subfamily, which confers high specificity over other Rho family proteins. Cys16 is adjacent to the nucleotide-binding pocket and switch regions, which are critical for RhoA function. The binding by CL16 effectively disrupts GTP binding and inhibits RhoA activity in CRC cells, leading to cytotoxic killing of CRC cells through cell-cycle arrest and apoptosis. In mouse CRC models, CL16 exhibits strong antitumor and antimetastatic effects, promotes T cell infiltration into the tumor microenvironment, and shows no observable toxicity. Our findings suggest that covalent targeting of the druggable Cys16 on RhoA offers a promising strategy for CRC treatment, providing a foundation for developing specific RhoA inhibitors for clinical application.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1150-1165.e9"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996040","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}
Raffaella De Pace, Chad D. Williamson, Juan S. Bonifacino
{"title":"Meet the authors: Raffaella De Pace, Chad Williamson, and Juan Bonifacino","authors":"Raffaella De Pace, Chad D. Williamson, Juan S. Bonifacino","doi":"10.1016/j.chembiol.2025.08.010","DOIUrl":"10.1016/j.chembiol.2025.08.010","url":null,"abstract":"<div><div>In an interview with Dr. Mishtu Dey, Editor-in-Chief of <em>Cell Chemical Biology</em>, the authors of the review article entitled “BLOC-1 and BORC: Complex regulators of endolysosomal dynamics” share their perspectives on how technological innovation and chemical biology approaches are advancing cell biology and neurobiology research, discuss their career paths, and share their thoughts on life as scientists.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1091-1093"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078545","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":"Sweet signaling for ferroptosis","authors":"Fan Yu , Lingyu Jiang , Quan Chen","doi":"10.1016/j.chembiol.2025.08.012","DOIUrl":"10.1016/j.chembiol.2025.08.012","url":null,"abstract":"<div><div>A recent study published in <em>Nature Cell Biology</em> by Zhang et al. has uncovered a critical role for <em>O</em>-GlcNAcylation in sensing and regulating ferroptosis.<span><span><sup>1</sup></span></span> Ferroptosis-induced ROS promotes OGT-mediated FOXK2 <em>O</em>-GlcNAcylation, driving its nuclear translocation to upregulate SLC7A11 and suppress cell death. This axis fuels HCC progression and therapy resistance, highlighting its therapeutic potential.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1097-1098"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078427","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}
Canyong Guo , Lingyun Yang , Junlin Liu , Dongsheng Liu , Kurt Wüthrich
{"title":"Structural basis of adenosine 2A receptor-balanced signaling activation relies on allosterically mediated structural dynamics","authors":"Canyong Guo , Lingyun Yang , Junlin Liu , Dongsheng Liu , Kurt Wüthrich","doi":"10.1016/j.chembiol.2025.08.005","DOIUrl":"10.1016/j.chembiol.2025.08.005","url":null,"abstract":"<div><div>Balanced or biased G protein and arrestin transmembrane signaling by the adenosine 2A receptor (A<sub>2A</sub>AR) is related to ligand-induced allosterically triggered variation of structural dynamics in the intracellular half of the transmembrane domain (TMD). <sup>19</sup>F-nuclear magnetic resonance (NMR) of a network of genetically introduced <em>meta</em>-trifluoromethyl-L-phenylalanine (<em>mtfF</em>) probes in the core of the TMD revealed signaling-related structure rearrangements leading from the extracellular orthosteric drug-binding site to the G protein and arrestin contacts on the intracellular surface. The key element in this structural basis of signal transfer is dynamic loss of structural order in the intracellular half of the TMD, as manifested by local polymorphisms and associated rate processes within the molecular architecture determined previously by X-ray crystallography. This visualization of the structural basis of G protein-coupled receptor (GPCR) activation presents an alternative paradigm for optimizing biased signaling in drug design.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1140-1149.e3"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009489","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":"tRNA-derived RNA promotes autophagy for kidney protection","authors":"Marina Andrade Tomaz , Lisa B. Frankel","doi":"10.1016/j.chembiol.2025.08.007","DOIUrl":"10.1016/j.chembiol.2025.08.007","url":null,"abstract":"<div><div>In a recent study in <em>Science</em>, Li et al.<span><span><sup>1</sup></span></span> uncover a hypoxia-induced tRNA-derived fragment that promotes autophagy and supports renal protection. Dissecting its role in stress adaptation, the study advances understanding of RNA-based regulation, highlights the value of advanced RNA profiling, and points toward new therapeutic strategies for autophagy-related diseases.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1099-1101"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078425","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":"Disruption to the gut microbiome by non-antibiotics is linked to infection risk","authors":"Caroline Tawk , Till Strowig","doi":"10.1016/j.chembiol.2025.08.008","DOIUrl":"10.1016/j.chembiol.2025.08.008","url":null,"abstract":"<div><div>Human-targeted drugs alter the composition and function of the gut microbiome, but their effect on the risk of gastrointestinal infection has received little attention. In two studies, Grieβhammer et al.<span><span><sup>1</sup></span></span> and Kumar et al.<span><span><sup>2</sup></span></span> identified non-antibiotic drugs that affect the microbiome’s natural defense against enteropathogen colonization and subsequent host infection.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1102-1105"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078426","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}
Wonyoung Kim , Soyeon Kim , Hawon Woo , Renuka Anil Jojare , Raghvendra Mall , Asia Nicotra , Benedicte F. Py , Chinh Ngo , Si Ming Man , Chirag N. Patel , Rajendra Karki
{"title":"A potent NLRP3 inhibitor effective against both MCC950-sensitive and -resistant inflammation","authors":"Wonyoung Kim , Soyeon Kim , Hawon Woo , Renuka Anil Jojare , Raghvendra Mall , Asia Nicotra , Benedicte F. Py , Chinh Ngo , Si Ming Man , Chirag N. Patel , Rajendra Karki","doi":"10.1016/j.chembiol.2025.08.006","DOIUrl":"10.1016/j.chembiol.2025.08.006","url":null,"abstract":"<div><div>The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome detects a broad spectrum of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammatory responses through caspase-1 activation and interleukin (IL)-1β/IL-18 release. Dysregulated NLRP3 activation is implicated in a range of diseases, including infectious diseases, autoinflammatory disorders, metabolic disorders, and cancer, making it an attractive therapeutic target. Here, we identify ZAP-180013 as a potent and selective small-molecule inhibitor of NLRP3 through high-throughput chemical screening. Molecular docking predicted that ZAP-180013 interacts with histidine 698 (H698) in NLRP3; this was validated by H698A substitution, which abolished binding and inhibitory activity. ZAP-180013 effectively inhibited inflammasome activation in human myeloid cells, including those carrying MCC950-resistant NLRP3 mutations. <em>In vivo</em>, systemic administration of ZAP-180013 ameliorated psoriasiform skin inflammation and protected against lipopolysaccharide (LPS)-induced cytokine responses in mice. These findings establish ZAP-180013 as a potent and selective NLRP3 inhibitor with translational potential in both MCC950-sensitive and -resistant inflammatory disease settings.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1125-1139.e7"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018007","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}
Zhiyong He , Yuyang Xie , Honglin Huang , Zhaoyu Zhang , Shenjiong Feng , Runda Xu , Xuancheng Chen , Fei Gao , Pan Li , Ming Zhu , Sen Wu , Xuguang Du
{"title":"A base editor facilitates simultaneous purine and pyrimidine substitutions for ex vivo and in vivo mutagenesis screens","authors":"Zhiyong He , Yuyang Xie , Honglin Huang , Zhaoyu Zhang , Shenjiong Feng , Runda Xu , Xuancheng Chen , Fei Gao , Pan Li , Ming Zhu , Sen Wu , Xuguang Du","doi":"10.1016/j.chembiol.2025.08.003","DOIUrl":"10.1016/j.chembiol.2025.08.003","url":null,"abstract":"<div><div>Genetic mutations are closely linked to human diseases, yet the relationship between many mutations and their corresponding phenotypes remains poorly understood. Furthermore, tools to study the connection between nucleotide variations and phenotypes are limited. To address this issue, we developed ACGBEmax by fusing the dual-functional deaminase, engineered N-methylpurine DNA glycosylase, and evolved SOS response associated peptidase domain with nCas9(D10A). ACGBEmax enables the precise conversion of A, C, and G to other bases in mammalian cells, thereby generating an extensive range of base mutations types. We used ACGBEmax to generate HPRT variants, identifying mutations conferring resistance to 6-thioguanine. Additionally, we performed <em>in situ</em> mutagenesis of Ctnnb1 in mouse liver, identifying both known and potential oncogenic mutations. Our results prove that ACGBEmax is a powerful tool for generating a wide spectrum of mutation types at specific gene loci, highlighting its significant potential for applications in functional screening and the directed evolution of protein variants.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1183-1196.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987806","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":"Activation primes GPCRs for versatile coupling","authors":"Vsevolod V. Gurevich , Eugenia V. Gurevich","doi":"10.1016/j.chembiol.2025.08.011","DOIUrl":"10.1016/j.chembiol.2025.08.011","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) regulate numerous physiological processes, and their activation promotes receptor interaction with G proteins, GPCR kinases, and arrestins. In this issue of <em>Cell Chemical Biology</em>, Guo et al.<span><span><sup>1</sup></span></span> demonstrate that agonist-induced disorder on the cytoplasmic side enables this versatile coupling, revealing the molecular basis for GPCR activation mechanisms.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1094-1096"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078424","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}
Hannah C. Lloyd , Yuli Li , N. Connor Payne , Zhenguang Zhao , Wenqing Xu , Alena Kroupova , David Zollman , Tengfang Long , Farah Kabir , Mei Chen , Rebecca Freeman , Ethan Yang Feng , Sarah Y. Xi , Ya-Chieh Hsu , Alessio Ciulli , Ralph Mazitschek , Christina M. Woo
{"title":"A method for the detection and enrichment of endogenous cereblon substrates","authors":"Hannah C. Lloyd , Yuli Li , N. Connor Payne , Zhenguang Zhao , Wenqing Xu , Alena Kroupova , David Zollman , Tengfang Long , Farah Kabir , Mei Chen , Rebecca Freeman , Ethan Yang Feng , Sarah Y. Xi , Ya-Chieh Hsu , Alessio Ciulli , Ralph Mazitschek , Christina M. Woo","doi":"10.1016/j.chembiol.2025.07.002","DOIUrl":"10.1016/j.chembiol.2025.07.002","url":null,"abstract":"<div><div>C-terminal cyclic imides are posttranslational modifications (PTMs) on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modifications across the proteome by mass spectrometry-based proteomics, an orthogonal and generalizable method to visualize the C-terminal cyclic imide would enhance detection, sensitivity, and throughput of endogenous CRBN substrate characterization. Here, we develop an antibody-like reagent, termed “cerebody,” for visualizing and enriching C-terminal cyclic imide-modified proteins. We describe the engineering of CRBN derivatives to produce cerebody and use it to identify CRBN substrates by western blot and enrichment from whole-cell and tissue lysates. CRBN substrates identified by cerebody enrichment are mapped, validated, and further characterized for dependence on the C-terminal cyclic imide modification. These methods will accelerate the characterization of endogenous CRBN substrates and their regulation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1028-1041.e13"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797385","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}