Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia.

Caspase-1 (CASP1) is best known for regulating IL-1β processing and pyroptosis; however, its role in leukemia has not been clearly defined. Here, we show that loss of CASP1 impairs leukemic cell growth, drives differentiation, and reduces leukemic burden in vivo, independent of its CASP1 protease activity. Instead, CASP1 functions as a scaffolding hub, controlling nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling via its interaction with raptor (RPTOR), a component of mTORC1. Deletion of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell function. We further developed a proteolysis-targeting chimera (PROTAC) degrader that selectively depletes Pro-CASP1 and suppresses leukemic cells. These findings reveal CASP1 as a regulator of mTORC1-NF-κB signaling in leukemia and highlight its scaffolding activity as a therapeutic vulnerability.