Major　depressive　disorder　(MDD)　is　a　leading　cause　of　disability　worldwide.　A　comprehensive　understanding　of　the　molecular　mechanisms　of　this　disorder　is　critical　for　the　therapy　of　MDD.　In　this　study,　it　is　observed　that　deubiquitinase　Mysm1　is　induced　in　the　brain　tissues　from　patients　with　major　depression　and　from　mice　with　depressive　behaviors.　The　genetic　silencing　of　astrocytic　Mysm1　induced　an　antidepressant-like　effect　and　alleviated　the　osteoporosis　of　depressive　mice.　Furthermore,　it　is　found　that　Mysm1　knockdown　led　to　increased　ATP　production　and　the　activation　of　p53　and　AMP-activated　protein　kinase　(AMPK).　Pifithrin　alpha　(PFT　alpha)　and　Compound　C,　antagonists　of　p53　and　AMPK,　respectively,　repressed　ATP　production　and　reversed　the　antidepressant　effect　of　Mysm1　knockdown.　Moreover,　the　pharmacological　inhibition　of　astrocytic　Mysm1　by　aspirin　relieved　depressive-like　behaviors　in　mice.　The　study　reveals,　for　the　first　time,　the　important　function　of　Mysm1　in　the　brain,　highlighting　astrocytic　Mysm1　as　a　potential　risk　factor　for　depression　and　as　a　valuable　target　for　drug　discovery　to　treat　depression.