RPS27L (ribosomal protein S27 like) is a p53-regulated ribosomal protein with dual roles in cellular homeostasis and cancer. As a direct p53 transcriptional target, RPS27L is induced following DNA damage and plays a crucial role in determining cell fate 1. The protein functions by modulating the p53-MDM2 axis through direct binding to MDM2's central acidic domain, competing with p53 for MDM2 interaction and thereby stabilizing p53 by extending its half-life 2. RPS27L promotes cell cycle arrest over apoptosis by upregulating p21 expression and facilitating DNA repair processes 3. The protein undergoes post-translational regulation through neddylation by MDM2, which stabilizes RPS27L and confers cancer cell survival 4. Paradoxically, RPS27L disruption can both activate p53 through ribosomal stress and promote genomic instability, leading to enhanced lymphomagenesis in p53+/- mice 5. Additionally, RPS27L regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis, with its silencing inducing autophagy as a survival mechanism in breast cancer cells 6. Clinically, elevated RPS27L expression correlates with better prognosis in colorectal cancer patients 7 and serves as a prognostic marker in thyroid cancer 8.