POLE2 encodes an accessory subunit of the DNA polymerase epsilon complex that participates in chr14 DNA replication and DNA repair 1. The protein functions as a central hub through NPF motif recognition, enabling interactions with diverse nuclear proteins involved in replication, DNA repair, and transcription regulation 2. POLE2 expression is regulated by E2F-mediated mechanisms through Sp1 and NF-1 binding sites in its promoter region, linking its expression to cell cycle control 1. The gene plays significant roles in cancer biology, with overexpression observed in multiple malignancies including oral squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, and bladder cancer 3456. POLE2 promotes cancer cell proliferation and survival by activating PI3K/AKT signaling pathways and inhibiting apoptosis 376. Additionally, it suppresses ferroptosis in cancer cells through activation of the NRF2/GPX4 pathway 45. Germline variants in POLE2 have been identified in patients with multiple primary cancers, suggesting potential roles in cancer predisposition 8. These findings establish POLE2 as both a critical component of DNA replication machinery and a potential therapeutic target in cancer treatment.