RPRM (reprimo) is a p53-dependent tumor suppressor gene that functions through both intrinsic and extrinsic apoptotic mechanisms. Intrinsically, RPRM induces G2/M cell cycle arrest by inhibiting CDK1 activity and nuclear translocation of the CDC2-cyclin B1 complex 1. More recently, RPRM has been identified as a secreted protein that extrinsically induces apoptosis in recipient cells through a novel p53-Reprimo-Hippo-YAP/TAZ-p73 axis, wherein Reprimo binds protocadherin family receptors (FAT1, FAT4, CELSR1-3) to activate downstream pro-apoptotic genes 23. Promotional silencing through hypermethylation is a primary mechanism of RPRM inactivation across multiple cancers 45. In gastric cancer, pediatric acute myeloid leukemia, pituitary tumors, and pancreatic cancer, RPRM downregulation correlates with increased proliferation, reduced apoptosis, and poor survival outcomes 647. RPRM protein levels are tightly regulated through ubiquitin-proteasomal degradation, with stabilization during cellular stress 6. Clinically, methylated RPRM cell-free DNA serves as a non-invasive biomarker for gastric cancer detection and treatment response monitoring, demonstrating 70% sensitivity and 80.2% specificity 5. Additionally, RPRM participates in DNA damage repair and radiation response 8, suggesting therapeutic potential in cancer prevention and management of radiation-induced complications.