Natural products as selective estrogen receptor modulators in depression-related disorders: Balancing antidepressant efficacy and safety.

Depression-related disorders remain major clinical challenges, and increasing evidence suggests that estrogen receptor (ER) signaling is involved in processes relevant to depression, including neuroinflammation, synaptic plasticity, neurotransmission, and stress regulation. Natural products and Traditional Chinese Medicine (TCM) formulas have attracted growing attention because of their multi-target regulatory effects on ER-related pathways. This narrative review summarizes ER-related pharmacological evidence of natural products and TCM preparations in depression-related disorders, with emphasis on flavonoids, stilbenes, lignans, and terpenoids. Evidence was interpreted according to depression relevance and the directness of ER involvement. Current findings suggest that ERα, ERβ, and G protein-coupled estrogen receptor (GPER) are implicated in depression-related regulation through partially overlapping and context-dependent mechanisms, with their relative roles varying according to brain region, cell type, endocrine state, ligand properties, and exposure. Some natural products have been reported to exhibit SERM-like or context-dependent estrogenic activity; however, receptor-subtype selectivity and tissue-selective safety remain incompletely established. Across separate experimental studies, TCM formulas have been associated with ER-related signaling alterations together with modulation of 5-HT, BDNF, NLRP3, and neuroendocrine pathways, supporting mechanistic convergence rather than experimentally demonstrated synergy. Collectively, subtype- and context-dependent ER modulation represents a hypothesis-generating framework for evaluating natural product-based candidates in depression-related disorders, while currently available evidence does not establish selective ER modulation or clinically validated tissue-specific safety advantages.