ArticleProceedings of the National Academy of Sciences of the United States of America2018
OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 343 papers, 1 of them a synthesis that pooled it.
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Who cites it
343 citing papers in PubMed, 1 synthesis or guideline pooled it, 533 citations in OpenAlex.
- From mechanisms to therapeutics: a narrative review on pyroptosis and autophagy in osteoporosis.Annals of medicine · 2025Pooled it
- First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor.Clinical and translational science · 2024Trial
- Tubulointerstitial inflammation in glomerular diseases: mechanistic pathways, prognostic value, and translational therapeutic targets.Renal failure · 2026Review
- Trained immunity in chronic, relapsing and low-grade joint inflammation.Nature reviews. Rheumatology · 2026Review
- Innate immune sensors of inflammasomes and PANoptosomes: structural-mechanistic insights and therapeutic implications.Cell research · 2026Review
- Management of Musculoskeletal Injuries with an Inflammatory Damage-Associated Molecular Pattern (DAMP) Etiology.Pain and therapy · 2026Review
- Exercise-Induced Exerkines: Multi-Nodal Suppression of the NLRP3 Inflammasome and Translational Potential.Medicinal research reviews · 2026Review
- Inflammaging and cytokine-driven cardiovascular senescence in age-related myocardial infarction: mechanisms, biomarkers, and precision immunotherapy strategies.Biogerontology · 2026Review
- Gut microbiota-atrium axis: Microbiota metabolite-mediated regulation of the NLRP3 inflammasome in atrial fibrillation-pathophysiological roles and therapeutic perspectives.Heart rhythm O2 · 2026Review
- Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives.Immune network · 2026Review
- [Advances in innate immune-mediated neuroinflammatory mechanisms of migraine].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2026Review
- Computational evaluation of NOD-like receptor pyrin domain-containing 3 inflammasome inhibitors for endodontic inflammation: A molecular docking analysis of synthetic and phytochemical compounds.Journal of conservative dentistry and endodontics · 2026Article
- Targeted Treatment for Hyperuricemia: The Drug Pipeline.Drugs & aging · 2026Review
- Unlocking the potential of circadian biology for cardiovascular health.Physiological reviews · 2026Review
- Role of NLRP3 Inflammasome Inhibitors in Endothelial Dysfunction and Vascular Repair.Antioxidants (Basel, Switzerland) · 2026Review
- Targeting NLRP3 inflammasome to mitigate chemotherapy-induced cardiotoxicity: advances in selective inhibitors and natural modulators.Molecular biology reports · 2026Review
- The challenge of cell death switching in inflammasome-targeted therapies for bacterial and viral infections.Communications biology · 2026Review
- OLT1177 (Dapansutrile) inhibits Gasdermin D-dependent IL-1β Release and Pyroptotic Cell Death in Bone Marrow-derived Macrophages.bioRxiv : the preprint server for biology · 2026Article
- Muscone Promotes PINK1/Parkin-Associated Mitophagy to Suppress NLRP3 Inflammasome Activation: Implications for Endotoxemia Therapy.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Neuronal inflammasomes: balancing immunity, neuroinflammation, and homeostasis.Trends in immunology · 2026Review
283 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 11 institutions in 4 countries.
Funding
Abstract
Activation of the NLRP3 inflammasome induces maturation of IL-1β and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active β-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1β and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1β levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1β release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1β release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1β precursor. Steady-state levels of phosphorylated NF-κB and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1β content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000 mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.
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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.