biostudies-literatureBai YShanghai Municipal Science and Technology Major ProjectKey Research Program of the Chinese Academy of SciencesNational Key R&D Program of ChinaHHS | NIH | National Cancer InstituteNIAID NIH HHSHHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious DiseasesStrategic Priority Research Program of Chinese Academy of SciencesShanghai Pilot Program for Basic Research-Chinese Academy of Sciences, Shanghai BranchNational Natural Science Foundation of ChinaNCI NIH HHSInnovative research team of high-level local universities in Shanghaie2306399120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10401014biostudies-literatureUnknown120(31)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 Proceedings of the National Academy of Sciences of the United States of AmericaDisulfiram blocks inflammatory TLR4 signaling by targeting MD-2.PMC10401014CA240955ZDBS-LY-SM008JCYJ-SHFY-2021-00932100716R01 CA240955SHSMU-ZDCX20211002XDB2903030031972897 32122034AI399142019SHZDZX02 HS2021SHZX0012020YFA0509600 2022YFC2304700Zheng ZChen PPan YMiao RMei SMin RBai YDeng FZhang PLiu XWu ZJiang CLieberman JfalseDisulfiram blocks inflammatory TLR4 signaling by targeting MD-2.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 2023-01-01T00:00:00Z2023 Aug2025-04-05T09:33:42.236Z2025-04-05T09:33:42.236ZS-EPMC104010143748707010.1073/pnas.2306399120