Inhibition of ferroptosis alleviates chronic unpredictable mild stress-induced depression in mice via tsRNA-3029b

Depression is a common mental illness. Ferroptosis is a form of cell death that may be responsible for neurological disease, but the role of ferroptosis in depression remains unclear. tRNA-derived small RNA (tsRNA) is an emerging non-coding small RNA, making it an important medium for studying neurological diseases. Chronic unpredictable mild stress (CUMS) was used to construct the depression model in mice, which was treated with ferrostatin-1 (Fer-1). Classical behavioral test, immunofluorescence and small RNA sequencing were used to detect depression-like behaviors, neuronal proliferation and the expression profile of tsRNAs in mice, respectively. The primary neuronal cell damage model was constructed by corticosterone (CORT), and the function of key tsRNA was investigated by quantitative real-time PCR, western blot and CCK-8 assays. Here, Fer-1 reduced the depression-like behavior of CUMS-induced mice and promoted neuronal growth. In addition, CUMS caused the disorder of tsRNA expression profile in hippocampal tissues of mice, and Fer-1 alleviated the abnormal tsRNA expression, among which tsRNA-3029b was an effective target. In vitro experiments manifested that ROS accumulation and decreased expression of SLC7A11 and GPX4 were found in CORT-induced depression-like cell model, suggesting that ferroptosis was involved in neuronal injury. However, inhibition of tsRNA-3029b suppressed neuronal cell ferroptosis and facilitated neuronal regeneration. In conclusion, Fer-1 showed an antidepressant effect in CUMS-induced mice and alleviated the abnormal expression profile of tsRNA. tsRNA-3029b was a key target in depression, and silencing of tsRNA-3029b reduced the occurrence of ferroptosis and protected neurons from injury, which may provide novel target for the treatment of depression.