2. Academic Validation
  3. Targeting the NLRP3 inflammasome for inflammatory disease therapy

Targeting the NLRP3 inflammasome for inflammatory disease therapy

  • Trends Pharmacol Sci. 2025 Jun;46(6):503-519. doi: 10.1016/j.tips.2025.04.007.
Julia Elise Cabral 1,  Anna Wu 1,  Haitian Zhou 1,  Minh Anh Pham 1,  Sophia Lin 1,  Reginald McNulty 2
Affiliations

Affiliations

  • 1 Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
  • 2 Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA. Electronic address: rmcnulty@uci.edu.
PMID: 40374417 DOI: 10.1016/j.tips.2025.04.007
Abstract

The NOD-like Receptor pyrin domain-containing 3 (NLRP3) inflammasome is a megadalton complex implicated in numerous inflammation-driven diseases including COVID-19, Alzheimer's disease, and gout. Although past efforts have focused on inhibiting IL-1β downstream of NLRP3 activation using drugs such as canakinumab, no FDA-approved NLRP3-targeted inhibitors are currently available. MCC950, a direct NLRP3 Inhibitor, showed promise but exhibited off-target effects. Recent research has focused on optimizing the sulfonylurea-based MCC950 scaffold by leveraging recent structural and medicinal chemistry insights into the NLRP3 nucleotide-binding and oligomerization (NACHT) domain to improve solubility and clinical efficacy. In addition, oxidized DNA (oxDNA) has emerged as a key inflammasome trigger, and molecules targeting the pyrin domain have shown promise in inhibiting NLRP3 activation. This review discusses the role of NLRP3 in inflammation-related diseases, the status of ongoing clinical trials, and emerging small-molecule therapeutics targeting NLRP3.

Keywords

NLRP3 inflammasome; ROS; SU0268; TH5487; mtDNA.

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