RPS15 (ribosomal protein S15) is a structural component of the small ribosomal subunit (40S) essential for protein synthesis 1. Beyond canonical ribosomal functions, RPS15 participates in ribosome biogenesis, including nucleolar assembly and cytoplasmic pre-40S maturation, where its C-terminal tail is critical for quality control 2. RPS15 also functions as an RNA-binding protein: it interacts with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to enhance translation of p38 MAPK pathway proteins in an m6A-dependent manner 3, and its translation is regulated by transfer-RNA-derived small RNAs to fine-tune ribosome biogenesis 4. Clinically, RPS15 mutations are recurrent in chr19 lymphocytic leukaemia (CLL) 5, where defects in cytoplasmic pre-40S maturation may contribute to disease pathogenesis 2. RPS15 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma, promoting metastasis and proliferation through the p38 MAPK pathway; folic acid targeting RPS15 shows therapeutic potential 3. Additionally, RPS15 facilitates homologous recombination repair by promoting DNA end resection and recruiting CtIP to double-strand breaks, conferring resistance to genotoxic treatments in breast cancer 6. RPS15 emerges as a multifunctional gene with both housekeeping roles and cancer-associated functions.