Sevoflurane, a widely utilized inhalation anesthetic, has raised concerns regarding its neurotoxic effects, particularly during critical periods of brain development (Apai et al., 2021; Wang et al., 2022a). Emerging evidence highlights microRNAs (miRNAs) as key regulators of neuronal homeostasis, with miR-497-5p recently implicated in neuroprotection against ischemic and degenerative insults (Chen et al., 2022; Sun and Yuan, 2022). However, its role in anesthetic-induced neurotoxicity remains unexplored.

Here, we investigate whether miR-497-5p serves as a neuroprotective agent against sevoflurane toxicity by targeting SMURF2, an E3 ubiquitin ligase known to destabilize NOTCH1-a critical mediator of neuronal survival and synaptic plasticity (Gao et al., 2023). MiRNAs play a critical role in gene expression regulation by binding to the 3′ untranslated region of target mRNAs, leading to mRNA degradation or inhibition of translation. They are pivotal regulators in gene expression networks and are implicated in various diseases, making them valuable targets for therapeutic interventions.

The ubiquitin-proteasome system (UPS) is essential for maintaining neuronal protein homeostasis, and its dysregulation has been linked to neurodevelopmental disorders (Ebstein et al., 2021; Magnati et al., 2024). SMURF2, a HECT-domain E3 ligase, promotes degradation of NOTCH1, a signaling protein vital for neurogenesis and synaptic function (Chen et al., 2023; Zhang et al., 2024). Our findings indicate that mechanistically, miR-497-5p exerts its neuroprotective effect by directly targeting SMURF2 and inhibiting its expression. This suppression reduces SMURF2-mediated ubiquitination and subsequent degradation of NOTCH1, thereby preserving the activity of the NOTCH1 signaling pathway, which is critical for neuronal survival. This study elucidates a novel miR-497-5p/SMURF2/NOTCH1 axis, offering mechanistic insights into sevoflurane neurotoxicity and potential therapeutic avenues. Our findings reveal that sevoflurane disrupts normal neuronal function by modulating the miR-497/Smurf2/Notch1 axis, resulting in increased neurotoxicity in hippocampal neurons.