Abstract

Ferroptosis is an iron dependent cell death, triggered by Fe2+ mediated oxidation of polyunsaturated fatty acids (PUFAs). Dysregulation of ferroptosis is associated with several human diseases, such as neurodegenerative diseases, multi-organ ischemia-reperfusion injuries and cancers. Hence modulating ferroptosis would provide beneficial effect in these related diseases and identification drugs especially clinically proved drugs that have anti-ferroptotic effect would provide new treatment options for ferroptosis related diseases. The effect of Olanzapine on ferroptotic inducers RAS-selective-lethal-3(RSL3) and imidazole ketone erastin (IKE) was measured by Cell Counting Kit 8(CCK8) and Hoest33342 staining. Level of lipid peroxidation and Fe2+ after Olanzapine treatment with or without RSL3 or IKE were determined by microscopy and flow cytometry assays. Influences of Olanzapine on the major anti-ferroptotic pathways were assayed by western blots. The anti-oxidant activity of Olanzapine in vitro was measured by DPPH assay. According cell viability assays, Olanzapine strongly inhibits RSL3 and IKE induced ferroptosis, but not other types of cell death induced by many chemotherapy drugs. Olanzapine showed anti-oxidant activity by DPPH assay. In this study, we have identified clinically used antipsychotic drug Olanzapine as a potent and specific inhibitor of ferroptosis. It suppresses ferroptosis in multiple cell lines, suggesting it is a general ferroptosis inhibitor.