Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.001
Raffaella De Pace , Saikat Ghosh , Chad D. Williamson , Juan S. Bonifacino
Endolysosomes are dynamic organelles that undergo movement along the cytoskeleton, fusion, fission, and tubulation during their lifetime. These processes are regulated by complex molecular machineries, including the structurally related hetero-octameric complexes BLOC-1 and BORC. BLOC-1 associates with early endosomes to mediate the biogenesis of lysosome-related organelles (LROs), such as melanosomes and platelet dense bodies. Accordingly, mutations in BLOC-1 subunits cause Hermansky-Pudlak syndrome (HPS), a disorder characterized by pigmentation defects and bleeding abnormalities. In contrast, BORC associates with lysosomes, late endosomes, and synaptic vesicle precursors, promoting their transport along microtubules. BORC also regulates endolysosome fusion with other endolysosomes, as well as with phagosomes and autophagosomes. Mutations in BORC subunits cause a severe neurodevelopmental disorder in humans. In this article, we review recent progress in the elucidation of the structure, evolution, physiological roles, and regulation of BLOC-1 and BORC, highlighting their critical contributions to maintaining endolysosomal organization and function.
{"title":"BLOC-1 and BORC: Complex regulators of endolysosomal dynamics","authors":"Raffaella De Pace , Saikat Ghosh , Chad D. Williamson , Juan S. Bonifacino","doi":"10.1016/j.chembiol.2025.08.001","DOIUrl":"10.1016/j.chembiol.2025.08.001","url":null,"abstract":"<div><div>Endolysosomes are dynamic organelles that undergo movement along the cytoskeleton, fusion, fission, and tubulation during their lifetime. These processes are regulated by complex molecular machineries, including the structurally related hetero-octameric complexes BLOC-1 and BORC. BLOC-1 associates with early endosomes to mediate the biogenesis of lysosome-related organelles (LROs), such as melanosomes and platelet dense bodies. Accordingly, mutations in BLOC-1 subunits cause Hermansky-Pudlak syndrome (HPS), a disorder characterized by pigmentation defects and bleeding abnormalities. In contrast, BORC associates with lysosomes, late endosomes, and synaptic vesicle precursors, promoting their transport along microtubules. BORC also regulates endolysosome fusion with other endolysosomes, as well as with phagosomes and autophagosomes. Mutations in BORC subunits cause a severe neurodevelopmental disorder in humans. In this article, we review recent progress in the elucidation of the structure, evolution, physiological roles, and regulation of BLOC-1 and BORC, highlighting their critical contributions to maintaining endolysosomal organization and function.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1106-1124"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901103","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.2025.08.002
Ariana S. Bratt , Susan Kilgas , Maria I. Tarazona Guzman , Robert S. Magin , Isabella Jaen Maisonet , Cara A. Starnbach , Wei Pin Teh , Anthony C. Varca , Bin Hu , Esteban Tarazona Guzman , Hyuk-Soo Seo , Sirano Dhe-Paganon , Nicholas M. Girardi , Guillaume Adelmant , Jarrod A. Marto , Dipanjan Chowdhury , Sara J. Buhrlage
Deubiquitinating enzymes (DUBs) are crucial regulators of ubiquitin signaling and protein degradation that remain incompletely understood in part due to the lack of high-quality chemical probes. To address this challenge, we developed CAS-010, a low nanomolar, ubiquitin-competitive inhibitor of USP28 that demonstrates preferential activity against USP28 over other DUBs, while also exhibiting some activity against the closely related USP25. We rationalized our SAR trends and observed selectivity using a crystal structure of USP28 in complex with an inhibitor. We validated on-target effects of CAS-010 on the negative regulation of p53 transactivation in the wild-type setting. We demonstrated that CAS-010 disrupts the 53BP1-USP28 interaction, and more broadly showed that USP28 catalytic activity contributes to this key interaction. Taken together, CAS-010 and the accompanying negative control compound WPT-086 and inhibitor-resistant mutant provide well-validated tools for further characterizing the role of USP28 in p53-mediated effect on cell cycle control and cell fate.
{"title":"Pharmacologic interrogation of USP28 cellular function in p53 signaling","authors":"Ariana S. Bratt , Susan Kilgas , Maria I. Tarazona Guzman , Robert S. Magin , Isabella Jaen Maisonet , Cara A. Starnbach , Wei Pin Teh , Anthony C. Varca , Bin Hu , Esteban Tarazona Guzman , Hyuk-Soo Seo , Sirano Dhe-Paganon , Nicholas M. Girardi , Guillaume Adelmant , Jarrod A. Marto , Dipanjan Chowdhury , Sara J. Buhrlage","doi":"10.1016/j.chembiol.2025.08.002","DOIUrl":"10.1016/j.chembiol.2025.08.002","url":null,"abstract":"<div><div>Deubiquitinating enzymes (DUBs) are crucial regulators of ubiquitin signaling and protein degradation that remain incompletely understood in part due to the lack of high-quality chemical probes. To address this challenge, we developed <strong>CAS-010</strong>, a low nanomolar, ubiquitin-competitive inhibitor of USP28 that demonstrates preferential activity against USP28 over other DUBs, while also exhibiting some activity against the closely related USP25. We rationalized our SAR trends and observed selectivity using a crystal structure of USP28 in complex with an inhibitor. We validated on-target effects of <strong>CAS-010</strong> on the negative regulation of p53 transactivation in the wild-type setting. We demonstrated that <strong>CAS-010</strong> disrupts the 53BP1-USP28 interaction, and more broadly showed that USP28 catalytic activity contributes to this key interaction. Taken together, <strong>CAS-010</strong> and the accompanying negative control compound <strong>WPT-086</strong> and inhibitor-resistant mutant provide well-validated tools for further characterizing the role of USP28 in p53-mediated effect on cell cycle control and cell fate.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1166-1182.e27"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928376","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.2025.08.009
Canyong Guo, Kurt Wüthrich
In an interview with Dr. Mishtu Dey, Editor-in-Chief of Cell Chemical Biology, the authors of the article entitled “Structural basis of Adenosine 2A Receptor balanced signaling activation relies on allosterically mediated structural dynamics” share their thoughts on technological advances in structural biology and how applications of genetic labeling techniques made it possible to probe into the core of a GPCR.
{"title":"Meet the authors: Canyong Guo and Kurt Wüthrich","authors":"Canyong Guo, Kurt Wüthrich","doi":"10.1016/j.chembiol.2025.08.009","DOIUrl":"10.1016/j.chembiol.2025.08.009","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 article entitled “Structural basis of Adenosine 2A Receptor balanced signaling activation relies on allosterically mediated structural dynamics” share their thoughts on technological advances in structural biology and how applications of genetic labeling techniques made it possible to probe into the core of a GPCR.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1089-1090"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078422","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.2025.08.004
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
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.
{"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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.010
Raffaella De Pace, Chad D. Williamson, Juan S. Bonifacino
In an interview with Dr. Mishtu Dey, Editor-in-Chief of Cell Chemical Biology, 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.
{"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}
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}
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