ArticleProceedings of the National Academy of Sciences of the United States of America2023
Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 57 citations in OpenAlex.
- Transcriptomic and Metagenomic Biomarkers in Peri-Implantitis: A Systematic Review, Diagnostic Meta-Analysis, and Functional Meta-Synthesis.Medical sciences (Basel, Switzerland) · 2025Pooled it
- Article
- The gasdermin family: from pyroptosis mechanisms to therapeutic targets.Signal transduction and targeted therapy · 2026Review
- Disulfiram Attenuates Adenine-Induced Renal Fibrosis by Modulating Inflammatory and Immunometabolic Responses.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Aldehyde dehydrogenase 1 A1 regulates the transcription of PD-L1 and its targeting with disulfiram together with PD-L1 immunotherapy synergistically delays cyst growth in ADPKD.Kidney international · 2026Article
- Disulfiram attenuates immobilization-induced knee joint contracture by suppressing Caspase-1/GSDMD-mediated pyroptosis.Scientific reports · 2026Article
- Exploring the therapeutic potential of disulfiram in endometriosis: mechanisms targeting inflammation, oxidative stress, pyroptosis, and angiogenesis.Archives of gynecology and obstetrics · 2026Review
- Integrated Analysis of Single-Cell and Transcriptome Data Reveals the Role and Regulatory Mechanisms of Neuroinflammation in Parkinson's Disease.Inflammation · 2025Article
- Disulfiram as an anti-inflammatory agent: mechanisms, nano-delivery strategies, and applications in non-oncologic diseases.RSC advances · 2025Review
- Pyroptosis in Respiratory Virus Infections: A Narrative Review of Mechanisms, Pathophysiology, and Potential Therapeutic Interventions.Microorganisms · 2025Review
- Unraveling the Mechanisms of Madecassoside Derivatives in Wound Healing: Network Pharmacology and Experimental Validation.Pharmaceuticals (Basel, Switzerland) · 2025Article
- ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cell death signaling and immune regulation: new perspectives on targeted therapy for sepsis.Cellular & molecular biology letters · 2025Review
- Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury.Cellular and molecular life sciences : CMLS · 2025Article
- An examination of the LPS-TLR4 immune response through the analysis of molecular structures and protein-protein interactions.Cell communication and signaling : CCS · 2025Review
- Repurposing alcohol-abuse drug disulfiram for the treatment of KSHV-infected primary effusion lymphoma by activating antiviral innate immunity.PLoS pathogens · 2025Article
- Astragaloside IV- loaded biomimetic nanoparticles target IκBα to regulate neutrophil extracellular trap formation for sepsis therapy.Journal of nanobiotechnology · 2025Article
- The Effect of Disulfiram and N-Acetylcysteine, Potential Compensators for Sulfur Disorders, on Lipopolysaccharide-Induced Neuroinflammation Leading to Memory Impairment and the Metabolism of L-Cysteine Disturbance.Molecules (Basel, Switzerland) · 2025Article
- Xuanqing Hefa formula relieves sepsis-triggered acute lung injury by targeting the NLRP3/Caspase-1 pyroptosis mechanism.Frontiers in immunology · 2025Article
- The intratumor microbiota and thyroid cancer: a review.Frontiers in endocrinology · 2025Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
Abstract
Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
Indexed as
Identifiers
What OpenQuestion holds
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.