Pharmacological targeting of the NLRP3 LRR domain with isothiazolinones overcomes CRID3-resistant inflammation
The NLRP3 inflammasome is a key driver in inflammatory, infectious, metabolic, and neurodegenerative diseases. Although the NLRP3 inhibitor CRID3 (also known as MCC950) exhibits potent activity, it cannot inhibit several hyperactive NLRP3 mutations associated with autoinflammatory syndromes and has not progressed clinically, underscoring the need for the development of new NLRP3 inhibitors. Through a high-throughput screening, we identified LOC14, an isothiazolinone-containing small molecule, as a selective NLRP3 inhibitor. Distinct from CRID3, which targets the NACHT domain, LOC14 binds to or near the LRR domain of NLRP3 and inhibits both CRID3-responsive and CRID3-non-responsive hyperactive or gain-of-function NLRP3 variants. Furthermore, we identified that the carbonyl oxygen of the isothiazol-3(2H)-one moiety is critical for inhibitory activity. In vivo, LOC14 exerted anti-inflammatory activity in mouse models of colitis, sepsis, and psoriasis, demonstrating broad physiological and therapeutic relevance. Our findings highlight isothiazolinone-containing compounds as selective NLRP3 inhibitors and provide a promising foundation for developing therapies targeting NLRP3-driven inflammatory diseases.
Authors
- Chirag Patel (ORCID: https://orcid.org/0000-0003-0777-7720)
- Bénédicte F. Py (ORCID: https://orcid.org/0000-0001-6716-7807)
- Si Ming Man (ORCID: https://orcid.org/0000-0002-5079-2857)
- Wonyoung Kim (ORCID: https://orcid.org/0000-0002-2897-9842)
- Chinh Ngo (ORCID: https://orcid.org/0000-0003-0757-8369)
- Hawon Woo
- Raghvendra Mall (ORCID: https://orcid.org/0000-0003-1779-3150)
- Simon Jiang (ORCID: https://orcid.org/0000-0002-3973-5114)
- Rajendra Karki (ORCID: https://orcid.org/0000-0003-4436-9128)
- Melan Kurera (ORCID: https://orcid.org/0009-0004-6901-8505)
- Min Zheng (ORCID: https://orcid.org/0009-0003-9811-4937)
- Yeonseo Jang
- Asia Nicotra
- Fenfen Zhang
- Soyeon Kim (ORCID: https://orcid.org/0009-0001-9046-6175)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Australian National University (AU)
- Centre National de la Recherche Scientifique (FR)
- Seoul National University (KR)
- Inserm (FR)
- Shenzhen Bay Laboratory (CN)
- National University College (PR)
- Institute of Molecular Biology (AM)
- National Institute on Aging (US)
- Hamad bin Khalifa University (QA)
- Centre International de Recherche en Infectiologie (FR)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-04-17
- DOI
- https://doi.org/10.1038/s44321-026-00425-5
- Citations
- 1
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 12.65
Funders
- Australian National University
- National Research Foundation
- Institut National de la Santé et de la Recherche Médicale
- Seoul National University
- National Research Foundation of Korea
- Ministry of Education, Science and Technology
- Centre National de la Recherche Scientifique
- Université Claude Bernard Lyon 1
- Ministry of Science and ICT, South Korea
- École Normale Supérieure de Lyon
- CSL Limited
- National Key Research and Development Program of China