Dual inhibition of thioredoxin 1/ glutathione induces ferroptosis in chronic myeloid leukemia cells

Abstract Ferroptosis is an iron-dependent cell death induced by the oxidation of polyunsaturated fatty acids. In recent years, ferroptosis has garnered tremendous potential in cancer therapy. However, the significance pathways of ferroptosis in chronic myeloid leukemia (CML) therapy are still poorly understood. Here, we investigated the role of a critical antioxidant protein, thioredoxin 1 (Trx1), in regulating ferroptosis in CML cells. First, we showed that Trx1 expression was higher in patients with CML than in healthy controls. Specifically, Trx1 knockdown suppressed cell growth and slowed tumor progression in xenograft models. Pharmacological inhibitors of Trx1 also attenuated cell growth, reduced colony formation, and caused CML cell death. Second, we showed that decreased Trx1 expression enhanced the cytotoxicity of the glutathione (GSH) biosynthesis inhibitor buthionine sulfoximine. Mechanistically, the combined inhibition of Trx1 and GSH synthesis disrupted the homeostasis of cellular reactive oxygen species as evidenced by increased ROS and malondialdehyde; and decreased GSH. Importantly, inhibition of Trx1 significantly resentisized GSH-depletion induced ferroptosis in CML cells. Finally, targeting Trx1 and GSH synthesis with small-molecule inhibitors caused a synergic effect on CML cells both in vitro and in vivo.Together, these results highlight an critical role of Trx1 in GSH-depletion induced ferroptosis and provide clues for dual inhibition of the Trx1 and GSH system as a combinatorial strategy for CML therapy.