Sestrin2 (SESN2) is a stress-inducible protein and acts as a neuroprotective regulator. The present study aimed to explore the antidepressant activity of SESN2 and its relevant mechanism. Depression mouse model was established by chronic unpredictable mild stress (CUMS) for a successive 5 weeks. Behaviors tests were conducted to examine depressive-like behaviors including sugar preference test, tail suspension test and open field test. The expression of SESN2 and ferroptosis-related proteins was examined by western blot. The production of cytokines was measured by ELISA. Iron deposition was assessed using Prussian blue staining and Fe 2+ content was measured using commercial kits. Lipid peroxidation was evaluated by thiobarbituric acid reactive substances assay. BV-2 cells were treated with LPS to induce microglial activation, which was evaluated by the iba-1 level adopting immunofluorescence assay. The ferroptosis inducer Erastin was adopted for the pretreatment in BV-2 cells to conduct a rescue experiment. SESN2 was downregulated in CUMS-induced mice, and SESN2 overexpression dramatically ameliorated CUMS-induced depression-like behaviors. Meanwhile, SESN2 reduced the production of pro-inflammatory cytokines and iba-1 level in hippocampus of CUMS mice, as well as reducing iron deposition and lipid peroxidation, demonstrating that SESN2 reduced microglial activation, neuroinflammation and ferroptosis in CUMS mice. Similarly, SESN2 also restricted iba-1 level, pro-inflammatory cytokines production, and ferroptosis in LPS-induced BV-2 cells, which was partly reversed by additional treatment of Erastin. These findings suggest that SESN2 possesses potent antidepressant property through inhibiting ferroptosis and neuroinflammation.
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