Identification of a small molecule of nitric oxide donor-aurovertin hybrids as a GPX4 inhibitor inducing ferroptosis and apoptosis in acute T lymphocytic leukemia cells.

T-cell acute lymphoblastic leukemia is a malignant cancer with high morbidity and mortality in children. However, due to its abnormal proliferation and lack of effective therapeutic drugs, clinical treatment faces significant challenges. A series of nitric oxide donor-aurovertin B hybrids were synthesized and used to test the antiproliferative activity against triple-negative breast cancer. Particularly, the structure of the preferred compound was optimized to synthesize a new compound, 4D, which was formed by coupling a nitric oxide donor with aurovertin B hybrids. In this study, we investigated the effect of compound 4D in acute T-cell lymphoblastic leukemia cells. The results demonstrated that 4D effectively suppressed T-cell acute lymphoblastic leukemia cell proliferation while concurrently inducing apoptosis via the caspase pathway and ferroptosis through lipid peroxidation. Notably, as a ferroptosis inducer, 4D inhibited GPX4 by covalently binding, thereby suppressing both enzymatic activity and gene transcription levels. SIGNIFICANCE STATEMENT: The implications of this study are that a small molecule of furazan nitrogen oxide of nitric oxide donor coupled with aurovertin B hybrids, 4D, inhibited GPX4 through covalently binding to GPX4 to induce ferroptosis in acute T lymphocytic leukemia cells. This study identified a promising drug candidate for the development of an anti-T-cell acute lymphoblastic leukemia agent in the future.