RFC5 is a subunit of the replication factor C (RFC) complex essential for ATP-dependent loading of proliferating cell nuclear antigen (PCNA) onto primed DNA during replication by DNA polymerases delta and epsilon 1. It functions as a DNA clamp loader involved in DNA replication, repair, and checkpoint signaling 2. RFC5 is significantly upregulated across multiple cancer types. In colorectal cancer, elevated RFC5 promotes cell proliferation, migration, and invasion while inhibiting apoptosis through the VEGFa/VEGFR2/ERK pathway, regulated by the circ_0038985/miR-3614-5p axis 3. In nasopharyngeal carcinoma, RFC5 enhances DNA damage repair and immune evasion by suppressing cGAS-STING signaling, reducing CD8+ T cell infiltration and promoting T cell exhaustion 4. Similarly, in lung cancer, high RFC5 expression associates with aggressive features, advanced metastasis, and poor overall survival, correlating with cell cycle and DNA damage pathways 5. In acute myeloid leukemia, RFC5 serves as an independent prognostic factor for poor survival and correlates with M2 macrophage infiltration 6. In glioma, FoxM1 transcriptionally activates RFC5 to promote temozolomide resistance independent of MGMT status 7. Additionally, RFC5 knockout zebrafish exhibit Williams syndrome-like phenotypes including craniofacial defects and vascular problems 2, suggesting developmental significance. RFC5 emerges as a promising prognostic biomarker and therapeutic target across multiple malignancies.