MiR-378a-3p/ SLC7A11 regulate ferroptosis in nerve injury induced by lead exposure

An increasing number of studies have clarified that ferroptosis plays a vital role in neurodegenerative diseases, which is characterized by the accumulation of Fe²⁺, lipid peroxidation, and alteration of mitochondrial structure. However, whether ferroptosis is involved in nerve injury caused by lead exposure remains unclear. In this study, HT22 cells and mice were treated with lead acetate to investigate the role of ferroptosis in lead neurotoxicity. The results showed that lead exposure resulted in an accumulation of Fe²⁺, an increase in malondialdehyde (MDA) levels, and a decrease in glutathione (GSH) levels in vivo and in vitro. An increase in the levels of lipid reactive oxygen species (ROS) and the expression of 4HNE, as well as the change in mitochondrial morphology, were also observed in HT22 cells treated with lead acetate. In addition, deferoxamine (DFO; an iron chelator) attenuated the accumulation of Fe²⁺ and significantly enhanced the viability of HT22 cells exposed to lead. Fer-1 (an anti-ferroptosis agent) reduced the level of lipid ROS and expression of 4HNE in lead-treated HT22 cells. Furthermore, lead exposure sharply downregulated the expression of SLC7A11 in HT22 cells. Overexpression of SLC7A11 reversed the changes in MDA and GSH levels and cell viability induced by lead exposure. In contrast, lower expression of SLC7A11 accelerated the changes in these parameters. Consequently, we screened miRNAs that regulate SLC7A11 using TargetScan. We found that miR-378a-3p showed the highest expression among the target miRNAs regulating SLC7A11 expression. Inhibition of miR-378a-3p expression reversed the reduction in GSH and the increase in lipid ROS levels induced by lead exposure. Taken together, these findings indicate that lead exposure can cause ferroptosis and that miR-378a-3p exerted an important effect by regulating SLC7A11 expression. Our findings provide new insights into the mechanisms underlying the effects of lead exposure.