Ferroptosis is a type of regulated cell death characterized by ROS accumulation and devastating lipid peroxidation (LPO). The role of acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, in the induction of apoptosis has been studied; however, to date its role in ferroptosis is unclear. In this study, we report that ASM plays a hitherto unanticipated role in promoting ferroptosis. Mechanistically, Erastin (Era) treatment results in the activation of ASM and generation of ceramide, which are required for the Era-induced reactive oxygen species (ROS) generation and LPO. Inhibition of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) or removal of intracellular ROS, significantly reduced Era-induced ASM activation, suggesting that NADPH oxidase-derived ROS regulated ASM-initiated redox signaling in a positive feedback manner. Moreover, ASM-mediated activation of autophagy plays a critical role in ferroptosis inducers (FINs)-induced glutathione peroxidase 4 (GPX4) degradation and ferroptosis activation. Genetic or pharmacological inhibition of ASM diminishes Era-induced features of autophagy, GPX4 degradation, LPO, and subsequent ferroptosis. Importantly, genetic activation of ASM increases ferroptosis in cancer cells induced by various FINs. Collectively, these findings reveal that ASM plays a novel role in ferroptosis that could be exploited to improve pathological conditions that link to ferroptosis.

铁死亡是一种受调节的细胞死亡，其特征是 ROS 积累和破坏性脂质过氧化 (LPO)。酸性鞘磷脂酶（ASM）是鞘脂代谢中的关键酶，其在诱导细胞凋亡中的作用已被研究；然而，迄今为止，其在铁死亡中的作用尚不清楚。在这项研究中，我们报告 ASM 在促进铁死亡方面发挥着迄今为止意想不到的作用。从机制上讲，Erastin (Era) 治疗会导致 ASM 激活并生成神经酰胺，这是 Era 诱导的活性氧 (ROS) 生成和 LPO 所必需的。抑制烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NADPH氧化酶）或去除细胞内ROS，显着减少Era诱导的ASM激活，表明NADPH氧化酶衍生的ROS以正反馈方式调节ASM启动的氧化还原信号传导。此外，ASM 介导的自噬激活在铁死亡诱导剂 (FIN) 诱导的谷胱甘肽过氧化物酶 4 (GPX4) 降解和铁死亡激活中发挥着关键作用。 ASM 的遗传或药理学抑制可减少 Era 诱导的自噬、GPX4 降解、LPO 和随后的铁死亡的特征。重要的是，ASM 的基因激活会增加由各种 FIN 诱导的癌细胞中的铁死亡。总的来说，这些发现表明 ASM 在铁死亡中发挥着新的作用，可用于改善与铁死亡相关的病理状况。