Natural products as selective estrogen receptor modulators in depression-related disorders: Balancing antidepressant efficacy and safety - 07/11/26
, Jie Luo a, c, 1
, Kexin He a, b
, Dongmei Yang b, ⁎
, Hongqing Zhao a, d, ⁎ 
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | ER evidence is classified by receptor directness and causal dependence. |
• | Depression relevance is distinguished from adjacent mechanistic evidence. |
• | ER-related effects depend on brain region, sex, cell type, and endocrine context. |
• | Natural products and TCM formulas exhibit context-dependent ER-associated effects. |
• | CNS exposure and reproductive safety remain key translational challenges. |
Abbreviations : 5-HT, Aβ, ACTH, AI, AKT, APP/PS1, Bad, BBB, Bcl-2, BDNF, CAMP, Caspase-3, CeA, CORT, CREB, CRF, CRS, CSS, CUMS, DRN, E2, EPM, ERα, ERβ, ERE, ERK1/2, ERs, EXD, FDA, FSH, FST, GABA, GluR2, GLUT1, GPER, GPR30, GRAS, HDIs, HIF-1α, HPA, HPC, HPO, HRT, ICR, IGF-1, IL-1β, IL-6, INOS, K-3-G, KM, LD₅₀, LPS, MAPK, MCAO, MDCK, MTORC1, MWM, NF-κB, NLRP3, NMDAR1, NR2B, NSF, OFT, OVX, P app , PET1, PFC, PGC-1α, PI3K, PKA, PMAT, PMD, PSD-95, QEP, SAMP8, SD, SDG, SERMs, SERT, SiRNA, SPT, SSRIs, STAT3, TNF-α, TPH, TrkA, TrkB, TST, VEGF, WHI, XCHT, XYS
Keywords : Depression, Estrogen receptors, Natural products, Phytoestrogens, Herbal formulas, Estrogen receptor modulation
Plan
Vol 204
Article 119937- novembre 2026 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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