Network Pharmacology-Guided Evaluation of Ginger and Cornelian Cherry Extracts Against Depression and Metabolic Dysfunction in Estrogen-Deficient Chronic Stressed Rats

This study investigated the therapeutic effects of water extracts from <i>Zingiber officinale</i> Roscoe (ginger) and <i>Cornus officinalis</i> Siebold and Zucc. fruits (COF) water extracts on depression-like behavior and metabolic dysfunction in estrogen-deficient rats exposed to chronic mild stress (CMS). Network pharmacology analysis identified three bioactive compounds in ginger and four in COF, with 11 overlapping targets linked to both depression and metabolic pathways, primarily involving <i>NR3C1</i>, <i>HTR2A</i>, <i>MAOA</i>, and <i>SLC6A4</i> genes associated with hypothalamic-pituitary-adrenal (HPA) axis regulation and neurotransmitter modulation. Ovariectomized rats received 200 mg/kg/day of ginger or COF extracts for 7 weeks, with a 4-week CMS protocol initiated at week 3. Both extracts significantly improved depression-like behaviors, memory performance, glucose tolerance, lipid profiles, and bone mineral density, normalized HPA axis markers (corticosterone and ACTH), and increased hippocampal serotonin and dopamine levels. Ginger demonstrated greater efficacy in improving memory and metabolic outcomes compared to COF. Molecular docking further validated these findings, revealing strong and stable interactions between key phytochemicals-such as hydroxygenkwanin and telocinobufagin-and target proteins MAOA, HTR2A, and NR3C1, supporting their mechanistic role in stress and mood regulation. These results support supplementing ginger and COF extracts as promising botanical interventions for estrogen-deficiency-related mood and metabolic disorders, with potential clinical application at a human-equivalent dose of 1.5 g/day.