{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:40:51Z","timestamp":1782751251808,"version":"3.54.5"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Pyroptosis is an important inflammatory form of cell death and <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>M.tb<\/jats:italic>) chronic infection triggers excessive inflammatory pyroptosis of macrophages. Our previous research has confirmed that a small compound pyrvinium pamoate (PP) could inhibit inflammatory pathological changes and mycobacterial burden in <jats:italic>M.tb<\/jats:italic>-infected mice, but the potential mechanism of PP for inhibiting <jats:italic>M.tb<\/jats:italic>-induced inflammation remains unexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of PP on the NLRP3-ASC-Casp1 inflammasome assembly and activation, gasdermin D (GSDMD) mediated pyroptosis and inflammatory cytokines expression were assessed in human THP-1-derived macrophages after <jats:italic>M.tb<\/jats:italic> H37Rv\/H37Ra\/ <jats:italic>Salmonella typhimurium<\/jats:italic> (<jats:italic>S. typhimurium<\/jats:italic>) infection or LPS treatment by Transcriptome sequencing, RT-qPCR, Co-immunoprecipitation and Western Blot (WB) analysis. The lactate dehydrogenase (LDH) release assay was used to evaluate the CC50 of PP in <jats:italic>M.tb<\/jats:italic>-infected THP-1 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that <jats:italic>M.tb<\/jats:italic>\/<jats:italic>S. typhimurium<\/jats:italic> infection and LPS treatment significantly activate NLRP3-ASC-Casp1 inflammasome activation, GSDMD-mediated pyroptosis and inflammatory cytokines (IL-1\u03b2 and IL-18) expression in macrophages, whereas PP could suppress these inflammatory effects in a dose dependent manner. Regarding the PP-inhibition mechanism, we further found that this inhibitory activity is mediated through the PP-targeting casein kinase 1A1 (CK1\u03b1)\u2013\u03b2-catenin\u2013NF-\u03baB pathway and CK1\u03b1\u2013NRF2\u2013mitochondrial oxidative phosphorylation (OXPHOS) pathway. In addition, a CK1\u03b1 specific inhibitor D4476 or CK1\u03b1 siRNA could reverse these inhibitory effects of PP on bacteria-induced inflammatory responses in macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study reveals a previously unreported mechanism that pyrvinium can inhibit NLRP3 inflammasome and GSDMD\u2013IL-1\u03b2 inflammatory pyroptosis via targeting suppressing CK1\u03b1\u2013\u03b2-catenin\u2013NF-\u03baB and CK1\u03b1\u2013NRF2\u2013mitochondrial OXPHOS pathways, suggesting that pyrvinium pamoate holds great promise as a host directed therapy (HDT) drug for mycobacterial-induced excessive inflammatory response.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1553093","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T07:27:01Z","timestamp":1740727621000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Suppression of NLRP3 inflammasome by a small molecule targeting CK1\u03b1\u2013\u03b2-catenin\u2013NF-\u03baB and CK1\u03b1\u2013NRF2\u2013mitochondrial OXPHOS pathways during mycobacterial 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