Artesunate induces ferroptosis by inhibiting the nuclear localization of SREBP2 in myeloma cells

Abstract

Objective: Multiple myeloma (MM) is an incurable haematological cancer characterized by abnormal proliferation of plasma cells. The promising therapeutic effect of selective inhibitors of nuclear export in MM reveals the broad therapeutic prospects of nuclear localization intervention. Sterol regulatory element binding protein 2 (SREBP2) is a lipid regulatory molecule that has been implicated in the effect of drug therapy for MM. SREBP2 has been reported to be regulated by the antimalarial drug artesunate (ART) through alteration of its nuclear localization and has been shown to inhibit ferroptosis in other tumours. However, the mechanism through which this might occur has not been clarified in MM. Our study aimed to explore whether ART can induce ferroptosis in MM through nuclear localization of SREBP2. Methods: To evaluate whether ferroptosis is induced by treatment with ART in myeloma, we used two types of myeloma cell lines. We first used a series of molecular approaches and other techniques to investigate the impact of ART on cell growth, production of reactive oxygen species (ROS), Fe²⁺ levels, lipid peroxidation and expression of genes related to ferroptosis. Then, we further explored the mechanism through which ferroptosis may occur in these cells and the relationship between ferroptosis and the nuclear localization of SREBP2. Results: Upregulation of ROS, Fe²⁺, and lipid peroxidation as well as inhibition of cell growth were observed in myeloma cells after treatment with ART. Expression of acyl CoA synthase long chain family member 4 (ACSL4) was increased, while glutathione peroxidase 4 (GPX4) expression was reduced in cells treated with ART. ART-induced cell death could be reversed by ferropstatin-1 (Fer-1) and deferoxamine mesylate (DFO). Nuclear localization of SREBP2 in myeloma cells was inhibited, accompanied by downregulation of isopentenyl pyrophosphate (IPP) and GPX4, after treatment with ART. Conclusion: In conclusion, our study demonstrated that the antimalarial drug ART can inhibit nuclear localization of SREBP2, downregulate IPP and GPX4, and eventually trigger ferroptosis in myeloma cells. Through this study, we hope to establish a correlation between nuclear localization pathways and mediation of ferroptosis in myeloma cells and provide an innovative direction for exploration-related therapy.

Keywords: SREBP2; artesunate; ferroptosis; multiple myeloma; nuclear localization.