Matrine enhances RLS3-induced ferroptosis at non-toxic doses in acute myeloid leukemia cells with MLL rearrangement

Leukemia with MLL rearrangement (MLL-r) always exhibited a poor prognosis. Targeting ferroptosis was believed to be a novel strategy for the treatment of leukemia. However, the ferroptosis inducer, RSL3 (GPX4 inhibitor), was not clinically available due to its potential off-target effects and toxicity. This study aimed to explore whether the additional matrine (MAT) could yield superior therapeutic outcomes with ferroptosis inducer. Herein, we explored that MAT can synergistically induce ferroptosis with non-toxic dosage of RSL3 in MOLM-13 and MV4-11 cells. The underlying mechanism was investigated via western blot, quantitative RT-PCR (qRT-PCR) analysis, enzyme-linked immunosorbent assay (ELISA) and Flow cytometry. We found that the combination of MAT and non-toxic-dose RSL3 significantly increased levels of intracellular ferrous ion (IFI) and lipid ROS, decreased mitochondrial membrane potential and glutathione (GSH) levels, as well as down-regulated the expression of SLC7A11 and GPX4. Systematic bioinformatic analysis results have indicated that MAT may potentiate the efficacy of RSL3 through modulation of the p53 signaling pathway. Further experiments showed that knocking down p53 reduced the synergistic effect of MAT and RSL3 in inducing ferroptosis. In addition, the combination of MAT and RSL3 can dramatically reduce the population of bone marrow CD45+ cells in AML xenograft mouse. In conclusion, MAT can synergistically promote non-toxic-dose RSL3 induced ferroptosis by modulating the p53 pathway in AML with MLL translocation, which may potentially enable the clinical application of ferroptosis inducers in further.