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

Overview

1. Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; (Y.F.); (W.A.); (A.N.); (W.M.)
2. Department of Bioscience and Laboratory Medicine, Hirosaki University Graduate School of Health Science, Hirosaki 036-8564, Japan
3. School of Medicine, Gunma University, Maebashi 371-8511, Japan
4. Ota College of Medical Technology, Ota 373-0812, Japan

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• rcsb.org/pdb/home, at PDB; found in the text, “4.7. In Silico Ligand–Receptor Binding Analysis”

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 3 keywords, 13 MeSH terms, 1 funder, 24 references.

Cite

This paper

Fujiwara, Y., Ariyani, W., Ninomiya, A., Miyazaki, W., Ota, R., Amano, I., & Koibuchi, N. (2026). S-equol Modulates T3-Induced Transcription and Neurite Outgrowth in Neuronal Cells. International journal of molecular sciences, 27(7), 3253. https://doi.org/10.3390/ijms27073253

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