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Unexpectedly, neither deletion of the NLRP3-activated pyroptotic effector GSDMD nor combined deletion of the inflammasome-activated cytokines interleukin-1\u03b2 (IL-1\u03b2) and IL-18 conferred strong protection from sHLH. Instead, co-deletion of GSDMD and caspase-8\u2013activated GSDME limited sHLH-driven lethality, demonstrating redundancy in the pyroptotic machinery required to induce sHLH. We also found that bromodomain and extraterminal domain (BET) inhibitors prevent NLRP3-driven pyroptosis, which acted by blocking inflammasome priming. BET inhibitors prevented increased NLRP3 levels in diseased tissue, limited the production of sHLH-associated IL-1\u03b2, interferon-\u03b3, and tumor necrosis factor, and protected from sHLH pathogenesis. These findings suggest that targeting NLRP3 could limit sHLH and identify clinically relevant bromodomain-selective BET inhibitors capable of eliminating NLRP3-driven pyroptosis and the sHLH cytokine storm.<\/jats:p>","DOI":"10.1126\/sciadv.adv0079","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T17:58:57Z","timestamp":1752083937000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["NLRP3 inflammasome\u2013driven hemophagocytic lymphohistiocytosis occurs independent of IL-1\u03b2 and IL-18 and is targetable by BET inhibitors"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1194-7550","authenticated-orcid":true,"given":"Farzaneh","family":"Shojaee","sequence":"first","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia."},{"name":"Department of Medical Biology, University of Melbourne, 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