Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to cope with sequestration of surplus ROS, oxidative stress results, in which excess ROS damage biomolecules. Oxidized phosphatidylserine (PS), a proapoptotic ‘eat me’ signal, is produced in response to elevated ROS, yet little is known regarding its chemical composition and metabolism. Here, we report a small molecule that generates ROS in different mammalian cells. We used this molecule to detect, characterize and study oxidized PS in mammalian cells. We developed a chemical–genetic screen to identify enzymes that regulate oxidized PS in mammalian cells and found that the lipase ABHD12 hydrolyzes oxidized PS. We validated these findings in different physiological settings including primary peritoneal macrophages and brains from Abhd12^–/– mice under inflammatory stress, and in the process, we functionally annotated an enzyme regulating oxidized PS in vivo.

活性氧（ROS）是氧代谢过程中产生的短暂的、高活性的中间体或副产物。然而，当先天机制无法应对过剩 ROS 的隔离时，就会产生氧化应激，过量的 ROS 会损害生物分子。氧化磷脂酰丝氨酸 (PS) 是一种促凋亡“吃我”信号，是响应升高的 ROS 而产生的，但对其化学成分和代谢知之甚少。在这里，我们报道了一种在不同哺乳动物细胞中产生 ROS 的小分子。我们使用该分子来检测、表征和研究哺乳动物细胞中的氧化 PS。我们开发了一种化学遗传筛选来鉴定调节哺乳动物细胞中氧化 PS 的酶，并发现脂肪酶 ABHD12 可以水解氧化 PS。我们在不同的生理环境中验证了这些发现，包括原代腹膜巨噬细胞和炎症应激下Abhd12 ^–/–小鼠的大脑，在此过程中，我们对体内调节氧化 PS 的酶进行了功能注释。