Exocarpium Citri Grandis oil relieves depressive-like behaviors via neurotransmitter and inflammatory pathway modulation.

Depression remains a global mental health challenge, with current treatments often limited by therapeutic instability, side effects, and patient adherence. This study investigated Exocarpium Citri Grandis essential oil (ECG oil) as a natural antidepressant. Extraction was optimized using Plackett-Burman Design-Response Surface Methodology (PBD-RSM), achieving a 15.224% yield. Gas chromatography-mass spectrometry (GC-MS) analysis identified D-limonene, α/β-pinene, and γ-terpinene as major active components. In vivo, both oral and nebulized ECG oil significantly alleviated depressive-like behaviors in a zebrafish larval model and chronic unpredictable mild stress (CUMS) mice (evidenced by tail suspension, open field, forced swim, and sucrose preference tests). Biochemically, ECG oil enhanced neurotransmitter activity and reduced monoamine oxidase A (MAOA) levels. Furthermore, network pharmacology coupled with molecular docking and experimental validation (qRT-PCR and Western blot) revealed that ECG oil exerts its efficacy by modulating key targets, including OXT, ESR1, PTGS2, and LEP. Conclusively, ECG oil represents a promising natural therapeutic for depression by regulating neurotransmitter and neuroinflammatory pathways.