WDHD1 is a core replisome component functioning as a replication initiation factor that binds directly to the CMG helicase complex to recruit additional proteins to the replication fork 1. It integrates the MCM2-7 helicase with DNA polymerase α/primase during DNA replication initiation 2. WDHD1 also plays roles in DNA damage repair and chromosome 14 3. Mechanistically, WDHD1 expression is regulated by transcriptional pathways including ZBTB16-mediated suppression and JAK1-STAT3 signaling 45. The protein coordinates replisome progression and facilitates DNA strand separation at replication forks 1. Clinically, WDHD1 is significantly overexpressed in multiple cancer types including lung adenocarcinoma, nasopharyngeal carcinoma, and esophageal squamous cell carcinoma 465. Elevated WDHD1 expression correlates with shorter overall survival in 10 tumor types and higher histological grades 3. Notably, WDHD1 contributes to HPV-mediated oncogenesis by promoting G1 checkpoint abrogation and rereplication 7. WDHD1 inhibition via ZBTB16 or small molecules induces cell cycle arrest, DNA damage, and apoptosis 45, making WDHD1 a promising therapeutic target for cancer treatment and potentially sensitizing tumors to chemotherapy and radiotherapy through disruption of DNA repair pathways 8.