Targeting NLRP3 inhibits AML progression by inducing PERK/eIF2-mediated apoptosis

Hyperactivation of the NLRP3 inflammasome has been linked to disease progression in acute myeloid leukemia (AML). However, the precise mechanisms behind this pathology remain elusive. Here, we highlight not only a significant correlation between elevated NLRP3 expression and diminished overall survival in AML patients, but also a potential pathomechanism. We show that genetic deletion and pharmacological inhibition of NLRP3 leads to a reduction in AML cell survival by triggering apoptosis. Additionally, our proteomic analyses revealed NLRP3-dependent alterations in protein translation, substantiated by increased eIF2α phosphorylation in NLRP3-deficient AML cells. Furthermore, we show that inhibition of the eIF2α kinase PERK mitigates eIF2α phosphorylation and decreases apoptosis by reducing the expression of pro-apoptotic Bcl-2 family members to levels comparable to those of wild-type cells. Substantiating these observations, we found that deleting NLRP3 in engrafted AML cells led to reduced splenomegaly and AML cell infiltration into organs in mice. Taken together, our findings demonstrate that blocking NLRP3 induces apoptosis via PERK/eIF2, revealing a promising avenue for therapeutic intervention in AML.