# USP46 enzyme drives sevoflurane neurotoxicity in neonatal mice via p53-dependent ferroptosis

- Published: 2026-11-13 08:49 UTC
- Section: Life & Health › Neurotechnology
- Tags: sevoflurane neurotoxicity, USP46 deubiquitinase, neuronal ferroptosis, p53 stabilization, SLC7A11/GPX4, neonatal mice hippocampus, HT22 cells, pediatric anesthesia, lipid peroxidation, Cell Biology and Toxicology
- URL: https://realtech.media/news/rt-589a53829718b33e76a804f5_usp46_enzyme_drives/

**In neonatal mice, repeated sevoflurane exposure raised USP46 in the hippocampus; neuron-specific knockdown reduced ferroptosis and neurotoxicity. Authors describe a USP46–p53 axis as a possible target.**

![USP46 enzyme drives sevoflurane neurotoxicity in neonatal mice via p53-dependent ferroptosis](https://realtech.media/media/2026/11/62f6b68f83b6232b.jpg)
*Rama, Wikimedia Commons, CC BY-SA 2.0 fr*

The deubiquitinating enzyme USP46 promotes developmental neurotoxicity of the anesthetic sevoflurane in neonatal mice by driving neuronal ferroptosis, according to a study in Cell Biology and Toxicology by Sun, Wu, Huang and colleagues, published in 2026 [1]. Sevoflurane is an inhalational anesthetic commonly used in neonatal and pediatric patients. The work was done in mice and in HT22 neuronal cells.

## Why apoptosis does not explain the damage

The mechanisms of sevoflurane-induced developmental neurotoxicity (SIDN) remain incompletely elucidated. Earlier studies focused mainly on caspase-dependent apoptosis, which, as the authors note, does not adequately account for the pronounced neuroinflammatory responses seen in SIDN [1].

Recent evidence points to ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation. The authors state that the developing brain consumes a lot of oxygen and has an immature antioxidant defense system, which makes it highly susceptible to ferroptosis [1].

## The USP46–p53 axis

RNA sequencing of the hippocampus of neonatal mice after repeated sevoflurane exposure showed significant upregulation of USP46 [1]. Neuron-specific knockdown of USP46 alleviated neuronal ferroptosis and neurotoxicity caused by repeated sevoflurane exposure in these animals [1].

The team identified the tumor suppressor protein p53 as a substrate of USP46 in neurons. USP46 stabilizes p53 by deubiquitination, which prevents its degradation. According to the authors, stabilized p53 represses the SLC7A11/GPX4 signaling axis, which triggers lipid peroxidation and promotes neuronal ferroptosis [1].

In HT22 cells, the neuroprotective effect of USP46 inhibition was reversed by p53 overexpression. The authors regard this as further confirmation of the functional role of the USP46–p53 axis [1].

The authors conclude that USP46 promotes SIDN by orchestrating p53-mediated ferroptosis. They suggest that targeting the USP46–p53 axis may be a promising therapeutic strategy for mitigating sevoflurane-induced developmental neurotoxicity. The results were obtained in neonatal mice and cultured cells; the material reports no data from patients [1].

## Sources

1. [Cell Biology and Toxicology](https://doi.org/10.1007/s10565-026-10302-z)
2. [bioengineer.org](https://bioengineer.org/enzyme-usp46-drives-sevoflurane-induced-brain-toxicity-in-neonatal-mice-through-ferroptosis)

---

Source: RealTech, realtech.media — https://realtech.media/news/rt-589a53829718b33e76a804f5_usp46_enzyme_drives/