Abstract
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.
Highlights
Active cell death is a fundamental biological event, and it plays a major role in various pathophysiological processes[1,2]
Ceramide accumulates during the process of ferroptosis Ceramide is a central molecule in the sphingolipid metabolic pathway that facilitates a variety of tumor-suppressive programs such as apoptosis, autophagy, and necroptosis[21]
acid sphingomyelinase (ASM)-mediated redox amplification contributes to the autophagic degradation of glutathione peroxidase 4 (GPX4), leading to lipid peroxidation (LPO) and ferroptosis
Summary
Active cell death is a fundamental biological event, and it plays a major role in various pathophysiological processes[1,2]. Studies over the past several decades have explored and elucidated several of the key cell death (basically apoptotic and non-apoptotic) pathways. Ferroptosis has recently been identified as a non-apoptotic cell death pathway driven by ironmediated production of reactive oxygen species (ROS) and subsequent lipid peroxidation (LPO)[3]. Official journal of the Cell Death Differentiation Association. Ferroptosis has been implicated in the pathological cell death associated with neurodegenerative diseases (i.e., Alzheimer’s, Huntington’s, and Parkinson’s diseases), stroke, intracerebral hemorrhage, traumatic brain injury, ischemiareperfusion injury, myocardial infarction, and kidney degeneration[4,5,6]. An improved understanding of key players in ferroptosis will provide new opportunities for diagnosis and therapeutic intervention in alleviating human diseases including cancer, neurodegeneration, and ischemic diseases[4,5]
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