TAZ, as a crucial effector of Hippo pathway, is required for spermatogenesis and fertilization, but little is known regarding its physiological function in uterine decidualization. In this study, we showed that TAZ was localized in the decidua, where it promoted stromal cell proliferation followed by accelerated G1/S phase transition via Ccnd3 and Cdk4 and induced the expression or activity of stromal differentiation markers Prl8a2, Prl3c1 and ALP, indicating the importance of TAZ in decidualization. Knockdown of TAZ impeded HB-EGF induction of stromal cell proliferation and differentiation. Under oxidative stress, TAZ protected stromal differentiation against oxidative damage by reducing intracellular ROS and enhancing cellular antioxidant capacity dependent on the Nrf2/ARE/Foxo1 pathway. TAZ strengthened the transcriptional activity of Nrf2 which directly bound to the antioxidant response element (ARE) of Foxo1 promoter region. Additionally, silencing TAZ caused accumulation of intracellular ROS through heightening NOX activity whose blockade by APO reversed the disruption in stromal differentiation. Further analysis revealed that TAZ might restore mitochondrial function, as indicated by the increase in ATP level, mtDNA copy number and mitochondrial membrane potential with the reduction in mitochondrial superoxide. Additionally, TAZ modulated the activities of mitochondrial respiratory chain complexes I and III whose suppression by ROT and AA resulted in the inability of TAZ to defend against oxidative damage to stromal differentiation. Moreover, TAZ prevented stromal cell apoptosis by upregulating Bcl2 expression and inhibiting Casp3 activity and Bax expression. In summary, TAZ might mediate HB-EGF function in uterine decidualization through Ccnd3 and ameliorate oxidative damage to stromal cell differentiation via Nrf2/ARE/Foxo1 pathway.

TAZ 作为 Hippo 通路的关键效应物，是精子发生和受精所必需的，但对其在子宫蜕膜化中的生理功能知之甚少。在本研究中，我们发现 TAZ 定位于蜕膜，促进基质细胞增殖，随后通过 Ccnd3 和 Cdk4 加速 G1/S 期转变，并诱导基质分化标志物 Prl8a2、Prl3c1 和 ALP 的表达或活性，表明TAZ 在蜕膜化中的重要性。TAZ 的敲低阻碍了 HB-EGF 对基质细胞增殖和分化的诱导。在氧化应激下，TAZ 通过减少细胞内 ROS 和增强依赖于 Nrf2/ARE/Foxo1 途径的细胞抗氧化能力来保护基质分化免受氧化损伤。TAZ 增强了直接与 Foxo1 启动子区域的抗氧化反应元件 (ARE) 结合的 Nrf2 的转录活性。此外，沉默 TAZ 通过提高 NOX 活性导致细胞内 ROS 的积累，NOX 活性被 APO 阻断逆转了基质分化的破坏。进一步的分析表明，TAZ 可能会恢复线粒体功能，这表明 ATP 水平、mtDNA 拷贝数和线粒体膜电位随着线粒体超氧化物的减少而增加。此外，TAZ 调节线粒体呼吸链复合物 I 和 III 的活性，其被 ROT 和 AA 抑制导致 TAZ 无法防御对基质分化的氧化损伤。而且，TAZ 通过上调 Bcl2 表达和抑制 Casp3 活性和 Bax 表达来防止基质细胞凋亡。总之，TAZ可能通过Ccnd3介导HB-EGF在子宫蜕膜化中的功能，并通过Nrf2/ARE/Foxo1通路改善基质细胞分化的氧化损伤。