Trifluoperazine induces ferroptosis in acute myeloid leukemia by suppressing the Nrf2/SLC7A11/GPX4 axis.

Acute myeloid leukemia (AML) remains a therapeutic challenge due to high relapse rates and limited treatment options. Drug repurposing offers a promising strategy to accelerate clinical translation. In this study, we investigated the anti-AML potential of the FDA-approved antipsychotic drug trifluoperazine (TFP) and explored its underlying mechanisms. We found that TFP markedly inhibits AML cell proliferation by inducing cell cycle arrest and apoptosis, while exhibiting minimal toxicity to normal human umbilical vein endothelial cells and bone marrow stromal cells. Mechanistically, TFP triggers impairments in mitochondrial activity and promotes the accumulation of reactive oxygen species (ROS), and induces ferroptosis, a form of iron-dependent cell death characterized by iron overload, glutathione depletion, and lipid peroxidation. The ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively rescued TFP-induced cell death. Moreover, TFP synergized with the ferroptosis inducer erastin to enhance ferroptotic cell death. At the molecular level, TFP suppressed the Nrf2/SLC7A11/GPX4 antioxidant axis, an effect that was reversible by the Nrf2 activator ML334. In an AML xenograft model, TFP monotherapy significantly inhibited tumor growth and alleviated hepatosplenomegaly. Importantly, TFP synergized with venetoclax, a standard AML therapy, to enhance antileukemic efficacy both in vitro and in vivo. Collectively, our findings identify TFP as a potent ferroptosis inducer in AML and suggest its potential as a repurposed therapeutic agent, either as monotherapy or in combination with venetoclax.