T3–THR Signaling Governed by DIO2 Contributes to Endometrial Receptivity by Regulating Epithelial Cell Membrane Fluidity

Abstract Maintaining normal thyroid function is crucial in pregnancy, and the thyroid hormone signaling pathway is involved in embryo implantation. However, the regulation of iodothyronine deiodinase 2 (DIO2), which is the central hub controlling thyroid hormone signaling, and the intracellular pathway activated by triiodothyronine (T3) binding to the thyroid hormone receptor (THR) in endometrial cells, remains unclear. Here, we demonstrate that DIO2 expression increases in endometrium during the establishment of endometrial receptivity and is involved in this process. Iopanoic acid inhibition of DIO2 in vivo can cause a delayed receptive state. In vitro adhesion models have consistently confirmed that knocking down DIO2 in epithelial cells inhibited receptivity establishment. Membrane lipidomics was performed to explore how DIO2 regulates the morphological transformation of endometrial epithelial cells. We found that the deletion of Dio2 inhibited the increase in the degree of lipid unsaturation, which subsequently decreased membrane fluidity. Transcriptomics analysis was employed to explore the downstream target gene of T3–THR signaling mediated by Dio2-mediated T3–THR signaling, and Scd1 is confirmed as the direct target gene of THR in endometrial epithelial cells. These data reveal that DIO2 could regulate lipid metabolism by targeting Scd1 through the T3–THR signaling pathway, thereby modifying membrane fluidity of endometrial epithelial cells and promoting cell morphological transformation to establish endometrial receptivity. These findings contribute to filling the gap in downstream pathways activated by T3–THR signaling in endometrial cells and provide insights into the new therapeutics, prediagnosis, and preventive strategies for the derailment of endometrial receptivity and subsequently adverse “ripple effect” including infertility.