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Updated: Jun 5, 2026
Revealing the Ferroptotic Phenotype of Medulloblastoma
Published on: March 15, 2024
DDIT4 silencing attenuates sevoflurane-induced ferroptosis via the mTOR pathway in neuronal cells
Shijian Yu1, Minxuan Xi1, Jiawei Chen1,2
1Department of Anesthesiology, Jing'an District Centre Hospital of Shanghai, Fudan University, No. 259 Xikang Road, Shanghai, 200040, China.
Abstract:
DNA damage-inducible transcript 4 (DDIT4) participates in neuronal cell ferroptosis and can be upregulated by sevoflurane (Sev). This study aimed to explore whether silent DDIT4 can improve Sev-induced neuronal cell ferroptosis and its potential mechanism. HT22 and SH‑SY5Y cells were transfected with siDDIT4 and exposed to Sev with or without the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In both HT22 and SH-SY5Y cells, Sev exposure increased DDIT4, promoted ferroptosis, and inhibited the mTOR pathway (all P < 0.05). DDIT4 knockdown improved HT22 and SH-SY5Y cell viability (both P < 0.05), reduced reactive oxygen species (ROS) (both P < 0.05), malondialdehyde (MDA) (both P < 0.05), and Fe2+ accumulation (both P < 0.01), while increasing glutathione peroxidase 4 (GPX4) (both P < 0.05). DDIT4 knockdown also elevated solute carrier family 7-member 11 (SLC7A11) expression in HT22 cells (P < 0.05). Additionally, DDIT4 knockdown activated the mTOR pathway in HT22 and SH-SY5Y cells (both P < 0.05). Notably, the addition of rapamycin abolished the protective effect of DDIT4 knockdown on Sev-induced ferroptosis in HT22 and SH-SY5Y cells (all P < 0.05). DDIT4 knockdown alleviates Sev-induced ferroptosis in neuronal cells by activating the mTOR pathway. The findings of this study support the possibility of DDIT4 as a therapeutic target for Sev-related neurotoxicity.
Insights
Silencing DNA damage-inducible transcript 4 (DDIT4) protects against sevoflurane-induced neuronal ferroptosis by activating the mTOR pathway. This suggests DDIT4 is a potential therapeutic target for sevoflurane neurotoxicity.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Sevoflurane (Sev) exposure can upregulate DNA damage-inducible transcript 4 (DDIT4), a factor involved in neuronal ferroptosis.
- Understanding DDIT4's role in Sev-induced neuronal cell death is crucial for developing neuroprotective strategies.
Purpose of the Study:
- To investigate the protective effects of DDIT4 knockdown against Sev-induced neuronal ferroptosis.
- To elucidate the underlying mechanism involving the mammalian target of rapamycin (mTOR) pathway.
Main Methods:
- Neuronal cell lines (HT22 and SH-SY5Y) were transfected with siDDIT4 and exposed to Sev.
- Cells were treated with or without the mTOR inhibitor rapamycin.
- Key markers of ferroptosis, oxidative stress, and the mTOR pathway were assessed.
Main Results:
- Sev exposure increased DDIT4, promoted ferroptosis, and inhibited the mTOR pathway.
- DDIT4 knockdown enhanced cell viability, reduced oxidative stress (ROS, MDA), Fe2+ accumulation, and increased GPX4 and SLC7A11 expression.
- DDIT4 knockdown activated the mTOR pathway, and this effect was reversed by rapamycin, which also abolished the protective benefits.
Conclusions:
- DDIT4 knockdown alleviates Sev-induced ferroptosis in neuronal cells through mTOR pathway activation.
- DDIT4 represents a potential therapeutic target for mitigating sevoflurane-related neurotoxicity.
