Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.012
Fan Yu , Lingyu Jiang , Quan Chen
A recent study published in Nature Cell Biology by Zhang et al. has uncovered a critical role for O-GlcNAcylation in sensing and regulating ferroptosis.1 Ferroptosis-induced ROS promotes OGT-mediated FOXK2 O-GlcNAcylation, driving its nuclear translocation to upregulate SLC7A11 and suppress cell death. This axis fuels HCC progression and therapy resistance, highlighting its therapeutic potential.
Zhang等人最近发表在Nature Cell Biology上的一项研究揭示了o - glcnac酰化在感知和调节铁凋亡中的关键作用铁凋亡诱导的ROS促进ogt介导的FOXK2 o - glcn酰化，驱动其核易位上调SLC7A11并抑制细胞死亡。这条轴促进HCC的进展和治疗抵抗，突出了其治疗潜力。
{"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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.005
Canyong Guo , Lingyun Yang , Junlin Liu , Dongsheng Liu , Kurt Wüthrich
Balanced or biased G protein and arrestin transmembrane signaling by the adenosine 2A receptor (A2AAR) is related to ligand-induced allosterically triggered variation of structural dynamics in the intracellular half of the transmembrane domain (TMD). 19F-nuclear magnetic resonance (NMR) of a network of genetically introduced meta-trifluoromethyl-L-phenylalanine (mtfF) 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.
{"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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.007
Marina Andrade Tomaz , Lisa B. Frankel
In a recent study in Science, Li et al.1 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.
{"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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.008
Caroline Tawk , Till Strowig
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.1 and Kumar et al.2 identified non-antibiotic drugs that affect the microbiome’s natural defense against enteropathogen colonization and subsequent host infection.
{"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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.006
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
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. In vivo, 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.
{"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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.003
Zhiyong He , Yuyang Xie , Honglin Huang , Zhaoyu Zhang , Shenjiong Feng , Runda Xu , Xuancheng Chen , Fei Gao , Pan Li , Ming Zhu , Sen Wu , Xuguang Du
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 in situ 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.
{"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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.011
Vsevolod V. Gurevich , Eugenia V. Gurevich
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 Cell Chemical Biology, Guo et al.1 demonstrate that agonist-induced disorder on the cytoplasmic side enables this versatile coupling, revealing the molecular basis for GPCR activation mechanisms.
{"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}
Pub Date : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.002
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
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.
{"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}
Pub Date : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.001
Yusheng Liu , Jiadiao Zhou , Yueji Wang , Daniel Nguyen , Dhyanesh Baskaran , Yuan Liu , Hua Wang
Metabolic glycoengineering of unnatural sugars provides a powerful tool to introduce unique chemical tags onto cell membrane for subsequent conjugation of cargos. However, the metabolic glycan labeling efficiency of antigen-presenting cells (APCs), the key mediators of adaptive immunity, is often low. Here, we report that APCs upregulate GlcNAc 2-epimerase (RENBP) and that RENBP inhibition leads to improved labeling efficiency of tetraacetyl-N-azidoacetylmannosamine (AAM) in APCs, including dendritic cells (1.2-fold), macrophages (1.3-fold), and B cells (1.4-fold) in vitro. RENBP inhibition can preferentially enhance AAM labeling efficiency in APCs than in non-APCs and selectively enhance the labeling efficiency of AAM over azido-galactosamine. We further demonstrate that RENBP inhibitors can improve AAM-mediated labeling of B cells and other APCs in vivo, with the largest enhancement for B cells (>3-fold) for 7 days. Our study uncovers a facile approach to improving metabolic glycan labeling of APCs, enabling the development of APC-targeted immunotherapies.
非天然糖的代谢糖工程为在细胞膜上引入独特的化学标签以进行后续的偶联提供了有力的工具。然而，作为适应性免疫的关键介质，抗原呈递细胞（antigen-presenting cells, APCs）的代谢聚糖标记效率往往较低。在这里，我们报道了apc上调GlcNAc 2- epimase (RENBP)，并且RENBP抑制导致apc(包括树突状细胞（1.2倍）、巨噬细胞（1.3倍）和B细胞（1.4倍）中四乙酰基- n -叠氮乙酰甘油三胺（AAM）的标记效率提高。RENBP抑制可以优先提高AAM在APCs中的标记效率，并选择性地提高AAM对叠氮半乳糖胺的标记效率。我们进一步证明，RENBP抑制剂可以在体内改善aam介导的B细胞和其他apc的标记，对B细胞的增强效果最大（3倍），持续7天。我们的研究揭示了一种简单的方法来改善apc的代谢聚糖标记，使apc靶向免疫疗法的发展成为可能。
{"title":"RENBP inhibition amplifies metabolic glycan labeling efficiency of antigen-presenting cells in vitro and in vivo","authors":"Yusheng Liu , Jiadiao Zhou , Yueji Wang , Daniel Nguyen , Dhyanesh Baskaran , Yuan Liu , Hua Wang","doi":"10.1016/j.chembiol.2025.07.001","DOIUrl":"10.1016/j.chembiol.2025.07.001","url":null,"abstract":"<div><div>Metabolic glycoengineering of unnatural sugars provides a powerful tool to introduce unique chemical tags onto cell membrane for subsequent conjugation of cargos. However, the metabolic glycan labeling efficiency of antigen-presenting cells (APCs), the key mediators of adaptive immunity, is often low. Here, we report that APCs upregulate GlcNAc 2-epimerase (RENBP) and that RENBP inhibition leads to improved labeling efficiency of tetraacetyl-<em>N</em>-azidoacetylmannosamine (AAM) in APCs, including dendritic cells (1.2-fold), macrophages (1.3-fold), and B cells (1.4-fold) <em>in vitro</em>. RENBP inhibition can preferentially enhance AAM labeling efficiency in APCs than in non-APCs and selectively enhance the labeling efficiency of AAM over azido-galactosamine. We further demonstrate that RENBP inhibitors can improve AAM-mediated labeling of B cells and other APCs <em>in vivo</em>, with the largest enhancement for B cells (>3-fold) for 7 days. Our study uncovers a facile approach to improving metabolic glycan labeling of APCs, enabling the development of APC-targeted immunotherapies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 983-993.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792345","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}
Pub Date : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.005
Yayoi Natsume-Kitatani , Kouji Kobiyama , Yoshinobu Igarashi , Taiki Aoshi , Noriyuki Nakatsu , Lokesh P. Tripathi , Junichi Ito , Johan Nyström-Persson , Yuji Kosugi , Rodolfo S. Allendes Osorio , Chioko Nagao , Burcu Temizoz , Etsushi Kuroda , Daron M. Standley , Hiroshi Kiyono , Kenji Nakanishi , Satoshi Uematsu , Isao Hamaguchi , Yasuhiro Yasutomi , Jun Kunisawa , Ken J. Ishii
Adjuvants are immunostimulators used to enhance vaccine efficacy against infectious diseases. However, current methods for evaluating their efficacy and safety are limited, hindering large-scale screening. To address this, we developed a prototype Adjuvant Database (ADB) containing transcriptome data, generated using the same protocols as the widely used Open TG-GATEs (OTG) toxicogenomics database, covering 25 adjuvants across multiple species, organs, time points, and doses. This enabled cross-database integration of ADB and OTG. Transcriptomic patterns successfully distinguished each adjuvant regardless of organs or species. Using both databases, we built machine learning models to predict adjuvanticity and hepatotoxicity. Notably, we identified colchicine’s adjuvant activity and FK565’s liver toxicity through data-driven analysis. Overall, ADB combined with OTG offers a framework for transcriptomics-based, data-driven screening of adjuvant candidates.
{"title":"An adjuvant database for preclinical evaluation of vaccines and immunotherapeutics","authors":"Yayoi Natsume-Kitatani , Kouji Kobiyama , Yoshinobu Igarashi , Taiki Aoshi , Noriyuki Nakatsu , Lokesh P. Tripathi , Junichi Ito , Johan Nyström-Persson , Yuji Kosugi , Rodolfo S. Allendes Osorio , Chioko Nagao , Burcu Temizoz , Etsushi Kuroda , Daron M. Standley , Hiroshi Kiyono , Kenji Nakanishi , Satoshi Uematsu , Isao Hamaguchi , Yasuhiro Yasutomi , Jun Kunisawa , Ken J. Ishii","doi":"10.1016/j.chembiol.2025.07.005","DOIUrl":"10.1016/j.chembiol.2025.07.005","url":null,"abstract":"<div><div>Adjuvants are immunostimulators used to enhance vaccine efficacy against infectious diseases. However, current methods for evaluating their efficacy and safety are limited, hindering large-scale screening. To address this, we developed a prototype Adjuvant Database (ADB) containing transcriptome data, generated using the same protocols as the widely used Open TG-GATEs (OTG) toxicogenomics database, covering 25 adjuvants across multiple species, organs, time points, and doses. This enabled cross-database integration of ADB and OTG. Transcriptomic patterns successfully distinguished each adjuvant regardless of organs or species. Using both databases, we built machine learning models to predict adjuvanticity and hepatotoxicity. Notably, we identified colchicine’s adjuvant activity and FK565’s liver toxicity through data-driven analysis. Overall, ADB combined with OTG offers a framework for transcriptomics-based, data-driven screening of adjuvant candidates.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1075-1088.e3"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813235","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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