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.

中文翻译：

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溶血磷脂酰丝氨酸脂肪酶ABHD12的阻滞增强了癌细胞中的肥大症。

Ferroptosis是由脂质氢过氧化物的致病性积累引起的一种细胞死亡。诱导肥大症的药理机制可能提供一种杀死对其他形式的细胞死亡（如细胞凋亡）具有抵抗力的癌细胞的方法。但是，调节癌细胞中促铁作用的蛋白质仍未完全了解。在这里，我们筛选了一组丝氨酸水解酶抑制剂（一种对调节脂质代谢至关重要的酶类），用于增强HT1080纤维肉瘤细胞中的肥大症。我们发现DO264是溶血素和氧代磷脂酰丝氨酸（PS）脂肪酶ABHD12的选择性抑制剂，可增强由脂质过氧化物酶GPX4抑制剂RSL3引起的肥大性死亡。RSHD3引起的肥大病也可通过ABHD12的基因破坏得到加强。代谢组学实验表明，