Sevoflurane exposure triggers ferroptosis of neuronal cells initiated by the activation of ATM/p53 in the neonatal mouse brain via JNK/p38 MAPK-mediated oxidative DNA damage.

Neuronal death has long been regarded as a pivotal pathological factor in the developmental neurotoxicity caused by the volatile anesthetic sevoflurane in the neonatal brain, but the detailed mechanism remains controversial. Ferroptosis is a novel type of regulated cell death driven by excess lipid peroxidation secondary to intracellular iron overload, and it is implicated in the pathogenesis of various neurological disorders. Acting as a death messenger, p53 is primarily activated by ATM during DNA damage and mediates various forms of cell death, including apoptosis, autophagy, and ferroptosis. JNK/p38 MAPK are important stress-responsive pathways that can exacerbate intracellular ROS production, thereby linking DNA damage to many pathological conditions such as neurodegeneration and ischemic injury. In our present study, we demonstrated that sevoflurane exposure-induced neuronal death was correlated with intracellular iron overload and lipid peroxidation in HT22 cells, primary hippocampal neurons, and the hippocampi of neonatal mice, consistent with the hallmarks of ferroptosis. Furthermore, we found that sevoflurane-induced neuronal ferroptosis was associated with ATM/p53 activation in response to DNA damage. Additionally, sevoflurane exposure caused JNK/p38 MAPK activation followed by intracellular ROS accumulation, ultimately leading to DNA damage. Mechanistically, ATM/p53 contributed to ferroptosis caused by sevoflurane via two pathways: (1) enhancing iron uptake (upregulating TFR and downregulating FPN) and (2) promoting lipid peroxidation through NOX4, ALOX12, ALOX15 activation and SLC7A11 suppression. Collectively, these findings demonstrated that sevoflurane exposure induced ferroptosis of neuronal cells in the neonatal brain, triggered by ATM/p53 activation via JNK/p38 MAPK-mediated ROS accumulation and subsequent DNA damage.