Untargeted Metabolomics Reveals That Quercetin Alleviates Depressive-Like Symptoms in Perimenopausal Depression Rat Model by Regulating Metabolic Disorders and Inhibiting Ferroptosis in the Prefrontal Cortex

Perimenopausal depression is a subtype of depression whose pathogenesis remains unclear. Prefrontal cortex (PFC) is an advanced center for cognitive and emotional integration, which plays a critical role in the development of perimenopausal depression. This study aimed to explore the impact of quercetin on metabolic disorders in the PFC of perimenopausal depression rat models and its potential role in inhibiting ferroptosis using untargeted metabolomics technology. Female Wistar rats were randomly divided into four groups: sham group (C), model group (D), model + 17β-estradiol (E 2 ) group (E: 0.27 mg/kg.bw), and model + quercetin group (Q: 50 mg/kg.bw). The perimenopausal depression rat model was established by ovariectomy combined with chronic unpredictable mild stress. After the experiment, the PFC was collected for metabolomic analysis and related index detection. A total of 13 differential metabolites were identified in the model group. Spearman's rank correlation analysis revealed a significant correlation between differential metabolites and behavioral outcomes ( p < 0.01). Pathway enrichment analysis of differential metabolites indicated that the metabolic disorders in the PFC of the model group primarily involved lipid metabolism, amino acid metabolism, and carnitine synthesis, which were related to ferroptosis, characterized by the generation of lipid peroxides and the imbalance between oxidation and antioxidation systems. It is worth noting that quercetin can regulate metabolic disorders and inhibit ferroptosis in the PFC of rat models with perimenopausal depression by exerting anti-inflammatory, neuroprotective, and antioxidant effects, providing a new strategy for quercetin in the prevention and treatment of perimenopausal depression.