S-equol Modulates T3-Induced Transcription and Neurite Outgrowth in Neuronal Cells

Thyroid hormones (THs) and estrogen (E2) play essential roles in neuronal differentiation and plasticity during brain development. S-equol, a plant-derived isoflavone metabolite, is a selective E2 receptor (ER) ligand that exhibits neurotrophic effects; however, its interaction with TH receptor (TR) signaling remains unclear. In this study, we investigated the effects of S-equol on TRβ-associated transcriptional activity and neuronal morphogenesis in mouse neuroblastoma-derived Neuro-2a cells or rat C6 glioma cells. Luciferase reporter assays demonstrated that S-equol significantly enhanced T3-induced TRβ transcriptional activity in a concentration- and time-dependent manner. Additionally, exposure to S-equol or T3 alone promoted neurite outgrowth and wound closure, whereas co-exposure to both compounds resulted in a more significant enhancement of these processes. Furthermore, mRNA expression levels of synapse-related genes (Dlg4, Syn1, Syp, Camk2b, and Bdnf) were significantly increased by S-equol co-exposure in the presence of T3. In silico docking analysis revealed that S-equol exhibited moderate to high binding affinity for TRβ (-8.7 kcal/mol), ERα, and ERβ, suggesting a structural basis for TR-ER crosstalk. Collectively, these findings indicate that S-equol functions as a dual-acting modulator that may modulate T3 signaling involving TR-ER interaction. Although S-equol may exert beneficial effects on neurodevelopment, it may also act as an endogenous endocrine modulator that alters the fine regulation of TH action during development, warranting careful evaluation from physiological and toxicological perspectives.