Title: Small molecule activators of the NLRP1 inflammasome

The innate immune system uses germline-encoded receptors to detect molecular patterns associated with infection. Six of these receptors, including NLRP1, sense particularly “dangerous” signals, assemble into complexes called inflammasomes, and trigger a pro-inflammatory form of cell death called pyroptosis. Despite decades of research, however, the danger signal that activates the NLRP1 inflammasome has not been identified. We recently discovered and characterized several small molecules that specifically activate the NLRP1 inflammasome. We found that these compounds interfere with a previously unknown pathway that maintains redox homeostasis, suggesting that NLRP1 detects a conserved pathogen activity that alters the cellular oxidation state. Here, we will discuss our latest insights into the molecular details and therapeutic potential of this pathway.