RPL21 is a structural component of the large ribosomal subunit (60S) that functions as a nucleolar-matrix protein with nucleic-acid binding properties 1. As part of the ribosomal complex, RPL21 participates in cellular protein synthesis 1. Beyond its canonical ribosomal role, RPL21 exhibits context-dependent functions: it regulates cell differentiation initiation in spermatogonial stem cells 2 and contains 5' terminal oligopyrimidine (TOP) motifs that control mTORC1-dependent translational efficiency in cancer cells, with 5'TOP-containing RPL21 isoforms correlating with survival in head and neck squamous cell carcinoma 3. Disease associations include its dysregulation in multiple pathologies: RPL21 was identified as a prognostic marker in ovarian cancer omental metastasis 4, as a potential biomarker in Alzheimer's disease diagnosis where it appears in immune infiltration-related signatures 5, in atherosclerosis pathogenesis across different arterial beds 6, and in Alzheimer's disease ceRNA networks 7. Additionally, RPL21 participates in ANGPTL4-related signaling in cholangiocarcinoma progression through AKT1-MTOR pathways 8. Clinically, RPL21 dysregulation offers diagnostic and prognostic value across cancer and neurodegenerative diseases, suggesting its utility as a therapeutic target.