Deubiquitinase USP46 promotes sevoflurane-induced developmental neurotoxicity by regulating neuronal ferroptosis through deubiquitinating and stabilizing p53

Sevoflurane, a commonly used inhalational anesthetic for neonatal and pediatric patients, can induce developmental neurotoxicity (SIDN), yet the underlying mechanisms remain incompletely elucidated. Traditional studies have primarily focused on caspase-dependent apoptosis, which fails to adequately account for the pronounced neuroinflammatory responses observed in SIDN. Recent evidence indicates that ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, may play a pivotal role in this process, particularly given that the developing brain exhibits high oxygen consumption and an immature antioxidant defense system, rendering it highly susceptible to ferroptosis. Here, we identify the deubiquitinating enzyme USP46 as a critical driver of neuronal ferroptosis in SIDN. RNA sequencing analysis revealed significant upregulation of USP46 in the hippocampus of neonatal mice following repeated sevoflurane exposure. Neuron-specific knockdown of USP46 alleviates neuronal ferroptosis and neurotoxicity induced by repeated sevoflurane exposure in neonatal mice. Mechanistically, we identified the tumor suppressor protein p53 as a substrate of USP46 in neurons. USP46 stabilizes p53 through deubiquitination, thereby repressing the SLC7A11/GPX4 signaling axis, triggering lipid peroxidation, and promoting neuronal ferroptosis. Notably, in HT22 cells, the neuroprotective effect conferred by USP46 inhibition was reversed by p53 overexpression, further validating the functional significance of the USP46-p53 signaling axis. Collectively, our findings demonstrate that USP46 promotes SIDN by orchestrating p53-mediated ferroptosis, suggesting that targeting the USP46-p53 signaling axis may represent a promising therapeutic strategy for mitigating sevoflurane-induced developmental neurotoxicity.