Abstract
Hematologic malignancies depend on deregulated oncogenic translation for survival and therapy resistance, making the eIF4F cap-dependent translation complex a compelling therapeutic target. Rocaglates, such as zotatifin, inhibit eIF4A1 (the helicase core of this complex), disrupting translation and impairing oncogenic protein synthesis. Beyond inhibition, rocaglates reprogram the translatome, driving distinct cellular adaptations. Among these, we identified SLC3A2, a ferroptosis-protective protein, suggesting a link between translation inhibition and ferroptosis. This study explores that connection and its therapeutic implications in blood cancers.
We show that by suppressing NRF2 translation, rocaglates impair antioxidant defenses, sensitizing lymphoma cells to ferroptosis inducers such as IFNγ, a key cytokine in CAR T cell therapy. As a result, zotatifin enhances CAR T-mediated lymphoma cell killing, establishing translation inhibition as a strategy to potentiate ferroptosis and immunotherapy in aggressive lymphomas.
Beyond cytosolic translation, we identified mitochondrial translation as a complementary vulnerability. Elatol, originally described as an eIF4A1 inhibitor, functions instead as a Complex V inhibitor, depleting ATP, inhibiting mitochondrial translation, and triggering the integrated stress response (ISR). This results in potent antileukemic activity through OXPHOS disruption and ferroptosis enhancement.
These findings uncover new therapeutic strategies that target both cytosolic and mitochondrial translation to overcome resistance in hematologic malignancies.