RPS3 (ribosomal protein S3) is a multifunctional protein that serves as a component of the cytosolic small ribosomal subunit while possessing diverse extra-ribosomal functions 1. Beyond its canonical role in protein synthesis, RPS3 acts as a critical regulator of the NF-κB signaling pathway by interacting with the P65 subunit, enhancing DNA binding and promoting transcription of target genes 1. This NF-κB interaction has significant implications for cancer progression, as RPS3 is elevated in various malignancies including colorectal cancer and clear cell renal cell carcinoma 23. RPS3 undergoes complex post-translational regulation through ubiquitination at the K214 residue, which can be mediated by different E3 ligase complexes including UBE2J1-TRIM25 and CENPU-TRIM5α 24. Importantly, RPS3 plays a crucial role in drug resistance mechanisms. In glioblastoma, CENPU-mediated degradation of RPS3 activates the ERK1/2 pathway and promotes DNA repair through E2F1 and RAD51 upregulation, contributing to temozolomide resistance 4. Additionally, RPS3 can be rescued from degradation by the G3BP1-family-USP10 deubiquitinase complex during ribosome-associated quality control, highlighting its importance in ribosomal homeostasis 5.