<h4>Aims</h4>To explore the role and mechanism of X-linked USP11 in mitochondrial dysfunction associated with depression.<h4>Methods</h4>USP11 knockout mice and USP11 overexpression mice in the prefrontal cortex were constructed, and the role of USP11 in mitochondrial dysfunction in depression was evaluated by behavioral tests and quantitative analysis of mitochondrial function changes in the prefrontal cortex. Here, USP11 is linked to major depressive disorder.