Novel Methyltransferase G9a Inhibitor Induces Ferroptosis in Multiple Myeloma Through Nrf2/HO-1 Pathway

Abstract

Abstract Multiple myeloma (MM) is a common malignant hematologic neoplasm, and the involvement of epigenetic modifications in its development and drug resistance has received widespread attention. Ferroptosis, a new ferroptosis-dependent programmed death mode, is closely associated with the development of MM. The effects of DCG066 on the viability of MM cell lines ARH-77 and RPMI-8226 cells were detected by MTT assay and Calcein-AM/PI live/dead Cell Assay Kit; intracellular level of Reactive Oxygen Species (ROS) was detected by flow cytometry; and intracellular level of iron was detected by Iron Assay Kit. The malondialdehyde (MDA) and glutathione (GSH) levels in cells were detected by Malondialdehyde Content Assay Kit and Reduced Glutathione Content Assay Kit; the levels of Solute Carrier Family 7 member 11 (SLC7A11), Glutathione Peroxidase 4 (GPX4), Transcription Factor Nuclear Factor Red Factor 2-related Factor 2 (Nrf2), and Heme Oxygenase-1 (HO-1) were detected by Western Blot. The results showed that DCG066 (5µM) inhibited the proliferation and induced ferroptosis in MM cells; the intracellular levels of ROS, iron, and MDA were significantly elevated, and the level of GSH was reduced after the treatment of DCG066; The protein expression levels of SLC7A11, GPX4, Nrf2 and HO-1 were significantly reduced, and these phenomena could be reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ). In conclusion, this study confirmed that DCG066 inhibits MM proliferation and induces ferroptosis via the Nrf2/HO-1 pathway.