Blocking NRF2 Translation by Inhibition of Cap-Dependent Initiation Sensitizes Lymphoma Cells to Ferroptosis and CAR T-cell Immunotherapy.

ABSTRACT: Cancers co-opt stress response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these pathways also provide protection from ferroptosis, an iron-dependent oxidative cell death pathway triggered by clinically available drugs including chemotherapies, rheumatologic agents, and novel ferroptosis inducers under evaluation in clinical trials. Here, we found that disrupting cap-dependent translation initiation in diffuse large B-cell lymphoma (DLBCL) sensitizes cells to ferroptosis. Specifically, the eIF4A1 inhibitor zotatifin synergized with pharmacologic ferroptosis inducers primarily through suppression of glutathione production, which protects polyunsaturated fatty acids from ferroptotic oxidation. Loss of NRF2 translation, a master regulat

SUBMITTER: Manara P 

PROVIDER: S-EPMC12363560 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature