胎盘的营养感知和适应对于妊娠活力和胎儿的正常生长至关重要。我们最近的研究表明，胎盘通过雷帕霉素（mTOR）抑制介导的滋养层向合体滋养层（STB）的机械靶点分化来适应营养不足，合体滋养层是一种高度专业化的多核滋养层亚型，介导广泛的母胎相互作用。然而，潜在的机制仍然难以捉摸。在这里，我们揭示了 mTORC1 下游转录因子 TFEB 在体外和体内 STB 形成中不可或缺的作用。 TFEB 缺乏显着损害人类滋养层和胎盘类器官中的 STB 分化。一致地，Tfeb 的系统性或滋养层特异性缺失会损害 STB 的形成和胎盘血管的构建，导致严重的胚胎致死。从机制上讲，TFEB 赋予人类滋养细胞中融合剂 ERVFRD-1 的直接转录激活，从而促进 STB 形成，独立于其作为自噬-溶酶体途径的主要调节因子的典型功能。此外，我们证明 TFEB 指导由 mTOR 复合物 1 (mTORC1) 信号驱动的滋养层合胞化反应。在人类胎儿生长受限的胎盘中，TFEB 表达与增强的滋养层合胞化呈正相关，表现出 mTORC1 活性受到抑制。我们的研究结果证实，TFEB-融合轴确保胎盘发育期间和营养应激下适当的 STB 形成，揭示了 TFEB 作为营养感应机制和滋养层分化之间的机制联系。

Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent study demonstrated that the placenta adapts to nutrient insufficiency through mechanistic target of rapamycin (mTOR) inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype mediating extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. TFEB deficiency significantly impaired STB differentiation in human trophoblasts and placenta organoids. Consistently, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Mechanistically, TFEB conferred direct transcriptional activation of the fusogen ERVFRD-1 in human trophoblasts and thereby promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. Moreover, we demonstrated that TFEB directed the trophoblast syncytialization response driven by mTOR complex 1 (mTORC1) signaling. TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth-restricted placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.