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It regulates replication fork stability, homologous recombination repair, and cell cycle checkpoints through K63-linked ubiquitination of critical DDR effectors, thereby safeguarding genomic integrity. Germline RFWD3 dysfunction disrupts genomic homeostasis, leading to hereditary non-neoplastic disorders, including Fanconi anemia and premature ovarian insufficiency, while somatic aberrations drive tumorigenesis across multiple organ systems. This narrative review summarizes the molecular mechanisms underlying RFWD3 function in the DDR network, then examines its roles in non-neoplastic disorders and tumorigenesis, and finally integrates recent advances from molecular genetics to translational medicine. 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