Our study showed that CUMS caused the significant upregulation of C3aR-STAT3 signaling and proinflammatory cytokines, including IL-1β, IL-6 and TNF-α in the prefrontal cortex, confirming the regulatory property of the C3aR-STAT3 signaling pathway on proinflammatory cytokines and its involvement in the pathophysiology of depression. This evidence concerns the gene STAT3 and major depressive disorder.