DDIT4 silencing attenuates sevoflurane-induced ferroptosis via the mTOR pathway in neuronal cells.

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.