Unraveling the impact of ZZZ3 on the mTOR/ribosome pathway in human embryonic stem cells homeostasis

Embryonic stem cells (ESCs) are defined as stem cells with self-renewing and differentiation capabilities. These unique properties are tightly regulated and controlled by complex genetic and molecular mechanisms, whose understanding is essential for both basic and translational research. A large number of studies have mostly focused on understanding the molecular mechanisms governing pluripotency and differentiation of ESCs, while the regulation of proliferation has received comparably less attention. Here, we investigate the role of ZZZ3 (zinc finger ZZ-type containing 3) in human ESCs homeostasis. We found that knockdown of ZZZ3 negatively impacts ribosome biogenesis, translation, and mTOR signaling, leading to a significant reduction in cell proliferation. This process occurs without affecting pluripotency, suggesting that ZZZ3-depleted ESCs enter a “dormant-like” state and that proliferation and pluripotency can be uncoupled also in human ESCs. •ZZZ3 plays a key role in hESC homeostasis•ZZZ3 knockdown adversely affects ribosome biogenesis, translation, and mTOR signaling•ZZZ3 depletion does not impact pluripotency but reduces cell proliferation•ZZZ3-depleted ESCs enter a “dormant-like” state In this study, Parrotta, Cuda, and colleagues elucidated the impact of silencing the zinc finger ZZ-type containing 3 (ZZZ3) gene on the proliferation of ESCs, highlighting its modulation of the mTOR and ribosome biogenesis pathways. Notably, despite the deceleration of the cell cycle induced by ZZZ3 silencing, pluripotency is preserved, indicating that ESCs have the capacity to enter a quiescent state characterized by attenuated biosynthetic processes.