NLRP3 inflammasome-driven hemophagocytic lymphohistiocytosis occurs independent of IL-1β and IL-18 and is targetable by BET inhibitors

  • Sci Adv. 2025 Jul 11;11(28):eadv0079. doi: 10.1126/sciadv.adv0079.
Farzaneh Shojaee  1  2 ,  Esmaeel Azadian  1  2 ,  Min Xian Wong  1  2  3 ,  Xiuquan Ma  1  2 ,  James Rickard  4 ,  Jiyi Pang  1  2 ,  Catherine Hall  1  2 ,  Andrew J Kueh  1  2  5  6 ,  Seth L Masters  1  2  7  8 ,  Inmaculada Rioja  9 ,  Rab K Prinjha  10 ,  Marcel Doerflinger  1  2 ,  Kate E Lawlor  1  2  7  8 ,  Maryam Rashidi  1  2 ,  James E Vince  1  2
Affiliations
  • 1. The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
  • 2. Department of Medical Biology, University of Melbourne, Parkville 3010, Australia.
  • 3. Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore.
  • 4. Dorevitch Pathology, Heidelberg 3084, Australia.
  • 5. Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg 3084, Australia.
  • 6. School of Cancer Medicine, La Trobe University, Heidelberg 3084, Australia.
  • 7. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton 3168, Australia.
  • 8. Department of Molecular and Translational Science, Monash University, Clayton 3168, Australia.
  • 9. BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, UK.
  • 10. Curve Therapeutics, Delta House, Enterprise Road, Southampton Science Park, Southampton SO16 7NS, UK.
PMID: 40632844 DOI: 10.1126/sciadv.adv0079
Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal cytokine storm syndrome. Its high mortality rate reflects limited therapeutic options and a poor understanding of disease-causing signaling. We show that the NLRP3 inflammasome is responsible for increased mortality in a model of secondary HLH (sHLH). Unexpectedly, neither deletion of the NLRP3-activated pyroptotic effector GSDMD nor combined deletion of the inflammasome-activated cytokines interleukin-1β (IL-1β) and IL-18 conferred strong protection from sHLH. Instead, co-deletion of GSDMD and caspase-8-activated 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-1β, interferon-γ, 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.

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