Blockade of the Lysophosphatidylserine Lipase ABHD12 Potentiates Ferroptosis in Cancer Cells

Ferroptosis is a type of cell death caused by the pathogenic accumulation of lipid hydroperoxides. Pharmacological mechanisms to induce ferroptosis may provide a way to kill cancer cells that are resistant to other forms of cell death like apoptosis. Nonetheless, the proteins that regulate ferroptotic sensitivity in cancer cells remain incompletely understood. Here, we screened a panel of inhibitors of serine hydrolases-an enzyme class important for regulating lipid metabolism-for potentiation of ferroptosis in HT1080 fibrosarcoma cells. We found that DO264, a selective inhibitor of the lyso- and ox-phosphatidylserine (PS) lipase ABHD12, enhances ferroptotic death caused by RSL3, an inhibitor of the lipid peroxidase GPX4. RSL3-induced ferroptosis was also potentiated by genetic disruption of ABHD12. Metabolomic experiments revealed that, in addition to elevated lyso-PS, ABHD12-inactivated cells show higher quantities of arachidonate (C20:4)-containing PS and 2-arachidonoyl glycerol, pointing to potential oxidation-sensitive lipid mediators of ferroptosis regulated by ABHD12.