RPS21 (ribosomal protein S21) is a component of the small ribosomal subunit (40S) essential for protein synthesis 1. In yeast, RPS21 functions in maturation of the 3' end of 18S rRNA and formation of active 40S ribosomal subunits, with overlapping roles alongside RPS0 proteins 2. In Drosophila, RPS21 acts as a translation initiation factor rather than a core ribosomal protein, interacting with the peripheral ribosomal protein P40 to regulate cell proliferation 3. Reduced RPS21 expression causes embryonic lethality in mice via p53 pathway activation 4. Clinically, RPS21 shows dysregulation across multiple malignancies. In prostate cancer, RPS21 is overexpressed in tumor tissues compared to normal prostate, correlating with higher Gleason grades (AUC=0.768), and promotes cancer cell proliferation, migration, invasion, and inhibits apoptosis 5. RPS21 is also differentially expressed in hepatocellular carcinoma associated with HBV/HCV infection 6 and functions as a potential regulatory target in Kaposi's sarcoma development, where its downregulation promotes endothelial cell proliferation and angiogenesis 7. RPS21 appears dysregulated in autoimmune diseases including type 1 diabetes and multiple sclerosis 8. These findings suggest RPS21 serves as both a diagnostic/prognostic biomarker and potential therapeutic target across multiple disease contexts.