Introduction: As a ubiquitous environmental pollutant, methylmercury (MeHg) induces toxic effects in the nervous system. However, the exact mechanism of its neurotoxicity has not been fully elucidated. Ferroptosis may be related to methylmercury toxicity and methylmercury-induced ferroptosis may be attenuated by vitamin K.

Methods: PC12 cells with neuron-like characteristics were selected and treated with different concentrations of MeHg (0, 1, 2.5, 5, and 10 μM) for 6 h. CCK8 was used to detect cell viability; a FerroOrange fluorescent probe was used to detect the level of free ferrous ions in cells; the microplate method was used to detect the level of reduced GSH in cells; FSP1, SLC7A11, and GPX4 protein expressions were detected by Western blotting; and the changes in lipid ROS content in cells were detected by flow cytometry. In the vitamin K intervention experiment, the MeHg group was treated with 5 μM MeHg for 6 h, the vitamin K + MeHg group was pretreated with vitamin K (0, 10, 20, 40, 80, and 100 μM) for 1 h and then co-treated with 5 μM MeHg for 6 h, and the changes in intracellular lipid ROS content were detected by flow cytometry.

Results: MeHg decreased the viability of PC12 cells in a dose-dependent manner. Meanwhile, the level of free ferrous ions in cells was significantly increased; the content of lipid ROS in cells was also significantly increased; the expressions of FSP1, SLC7A11, and GPX4 decreased; and the level of GSH in cells was significantly reduced. After vitamin K intervention, cell viability increased in a dose-dependent manner compared to the MeHg group, and intracellular lipid ROS content was significantly reduced after treatment with 80 μM vitamin K.

Conclusion: MeHg can induce ferroptosis in neuron-like cells, and vitamin K intervention can alleviate MeHg-induced cytotoxicity and ferroptosis; thus, its exact mechanism is worthy of further investigation.