ArticleScience advances2024
NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation.
Article in Science advances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 53 citations in OpenAlex.
- The role of protein palmitoylation in disease pathogenesis and therapeutic innovation.Annals of medicine · 2026Review
- The gasdermin family: from pyroptosis mechanisms to therapeutic targets.Signal transduction and targeted therapy · 2026Review
- Pyroptosis in chronic obstructive pulmonary disease: Beyond the canonical NLRP3/Caspase-1/GSDMD pathway.Immunologic research · 2026Review
- Gasdermin D in Neurodegenerative Diseases: Pathogenic Roles and Therapeutic Perspectives.Molecular neurobiology · 2026Review
- Review
- Ciclopirox Olamine Inhibits the NLRP3 Inflammasome to Alleviate Inflammatory Diseases.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Recipient-derived macrophages mediate acute cardiac allograft rejection via GSDMD-induced pyroptosis mechanism.Clinical and translational medicine · 2026Article
- Dual targeting of NCF1 and NLRP3 by roburic acid orchestrates redox homeostasis and inhibits macrophage death in septic lung injury.Redox biology · 2026Article
- ProteinJournal of pharmaceutical analysis · 2026Review
- Pyroptosis in cerebral ischemia‑reperfusion injury: Molecular mechanisms and therapeutic implications (Review).Molecular medicine reports · 2026Review
- From lipid modification to cell death: the diverse roles of S-palmitoylation in cell fate decisions.Cell communication and signaling : CCS · 2026Review
- Palmitoylation-dependent regulation of innate and adaptive immunity: molecular insights and translational opportunities.Cellular & molecular biology letters · 2026Review
- Gasdermins against intracellular bacterial pathogens.Nature microbiology · 2026Review
- Covalent modification of Keap1 Cys489 by NU6300 activates Nrf2 signaling and suppresses NLRP3 inflammasome-mediated pyroptosis.Journal of pharmaceutical analysis · 2026Article
- Epithelial MST1 deficiency promotes pyroptosis and aggravates inflammatory bowel disease via the YAP/p73 signaling pathway.Cell death and differentiation · 2026Article
- De novo discovery of bicyclic cysteine-rich peptides targeting gasdermin D.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- CD73 overexpression in ADSCs accelerates bladder repair by regulating the NFκB/NLRP3/caspase-1 signaling axis in neurogenic bladder rats.NPJ Regenerative medicine · 2026Article
- Emestrin-Type Epidithiodiketopiperazines Inhibited Gasdermin D-Mediated Pyroptosis via Caspase-3/7 Activation.MedComm · 2026Article
- Delaying cardiac aging: potential mechanisms centered on PANoptosis and targeted intervention strategies.Frontiers in cardiovascular medicine · 2026Review
- Gasdermin D-driven pyroptosis in sepsis: mechanisms, therapeutic strategies, and clinical translation.Frontiers in immunology · 2026Review
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate-induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.