Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association.

Mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from nutrients, growth factors, and cellular stress to regulate biosynthesis and maintain homeostasis. Dysregulated mTORC1 disrupts stem cell homeostasis and impairs cell fate transitions in vivo and in vitro. Previous studies have shown that mTORC1 hyperactivation promotes nuclear translocation of TFE3, blocking pluripotency exit in both mouse and human naïve embryonic stem cells. Similarly, our earlier work has demonstrated that sustained mTORC1 activation impedes somatic cell reprogramming via the transcriptional coactivator PGC1α. This raises the question of how mTORC1 coordinates gene transcription across distinct transitions in pluripotent cells. Here, we show that TFE3 mediates the transcriptional blockade induced by mTORC1 hyperactivation during reprogramming. Notably, during both pluripotency exit and reprogramming, TFE3 recruits the NuRD corepressor complex to repress genes essential for cell fate transitions. These findings uncover a shared mechanism by which mTORC1 and TFE3 regulate stem cell identity, highlighting the dual regulatory role of TFE3 and its potential implications in development, aging, and tumorigenesis.