<p>The novel selective serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor and partial agonist of the 5-HT_1A receptor, JZ-1201, shows promise in the treatment of depression. This study aimed to investigate the molecular mechanisms underlying the modulation of depressive-like behaviors by JZ-1201. SWATH‑based quantitative proteomic analysis was performed on the prefrontal cortex (PFC) and hippocampus (Hip) of male Wistar rats in the vehicle, chronic unpredictable mild stress (CUMS), and stress + JZ‑1201 groups. Catalase (CAT), identified as a commonly differentially expressed gene (DEG) across these comparisons, was further validated through real‑time quantitative PCR (RT-qPCR) and Western blotting. Subsequently, in the CUMS model, co-administration of CAT inhibitor 3-amino-1,2,4-triazole (3-AT) and JZ-1201 were used to assess the importance of CAT in regulating depressive-like behaviors by JZ-1201. Following JZ‑1201 treatment, the mRNA and protein levels of CAT were significantly increased in the PFC and Hip of CUMS rats. The expression levels of SOD2 and GPx4, two other antioxidant enzymes related to oxidative stress (OS), were also significantly elevated after JZ‑1201 administration. Similar effects were also observed for SIRT1 and PGC-1α, key regulators of antioxidant enzyme activity. Gene ontology (GO) analysis revealed significant enrichment of immune system-related pathways, and JZ-1201 enhanced levels of the immune-related transcription factor Nuclear factor (NF)-κB in CUMS rats. Moreover, the inhibition of CAT using 3-AT significantly attenuated the antidepressant effects of JZ-1201 on depressive-like behaviors. These results indicate that JZ-1201 regulates the expression of multiple antioxidant enzymes and their upstream regulators. Furthermore, CAT plays a critical role in mediating the antidepressant-like effects of JZ-1201.</p>