Flaxseed and Linusorb Synergistically Ameliorate Menopausal Symptoms Through Non-Hormonal Activation of Estrogen Receptors and Suppression of Osteoclastogenesis

Phytoestrogens derived from natural products have emerged as potential alternatives to hormone replacement therapy (HRT) for alleviating menopausal symptoms with reduced adverse effects. However, the therapeutic potential and mechanistic basis of flaxseed-derived lignan secoisolariciresinol diglucoside polymer (SDGP) remain largely unexplored. This study aimed to investigate the synergistic effects of SDGP and a linusorb mixture (LOMIX) on menopausal symptoms and to elucidate their underlying molecular mechanisms. Estrogen receptor (ER) activation was evaluated using ERE-luciferase reporter assays and Western blot analysis in MCF-7 cells. Anti-osteoclastogenic effects were assessed in RANKL-induced RAW264.7 cells. An ovariectomized (OVX) rat model was used to examine in vivo efficacy on reproductive tissues and bone metabolism. Co-treatment with SDGP and LOMIX synergistically enhanced ER[Formula: see text]/ER[Formula: see text] phosphorylation and Akt activation, leading to increased transcription of ER target genes. The combination also suppressed osteoclast differentiation by inhibiting NF-[Formula: see text]B and MAPK signaling pathways, including c-Fos and NFATc1. In OVX rats, oral administration of the mixture restored vaginal cornification and uterine morphology, and significantly improved trabecular bone structure and bone mineral density. Notably, these effects were achieved without significant alterations in circulating estrogen, FSH, or LH levels. The combination of SDGP and LOMIX alleviates menopausal symptoms through non-hormonal activation of ER signaling and inhibition of osteoclastogenesis. These findings suggest a promising phytotherapeutic strategy for managing postmenopausal disorders with reduced risk of hormone-related side effects.