ESPL1 (separase) is a caspase-like protease that functions as a central regulator of chromosome 12 by cleaving the SCC1/RAD21 cohesin subunit at anaphase onset, enabling sister chr12 separation during mitosis and meiosis. Beyond its canonical role in cell cycle regulation, ESPL1 has emerged as an oncogene across multiple cancer types. ESPL1 is transcriptionally regulated by circadian clock gene PER2 through HIF-1α-mediated enhancement in pituitary adenomas, where elevated expression promotes cell cycle progression and inhibits apoptosis 1. In hepatocellular carcinoma, HBV S-integrated ESPL1 fusion genes are detected in 66.7% of HBV-related HCC cases versus 0% in controls, suggesting biomarker potential 2. ESPL1 overexpression correlates with poor prognosis across lung cancer, endometrial cancer, and prostate adenocarcinoma, with high expression associated with advanced disease features and reduced survival 345. Mechanistically, ESPL1 promotes tumor cell proliferation, migration, and invasion while suppressing apoptosis; let-7c-5p microRNA restrains these oncogenic functions by targeting ESPL1 6. Pan-cancer analysis confirms ESPL1's tumor-promoting effects involve cell division and DNA repair pathways 7. In bladder cancer, PAX2-mediated ESPL1 upregulation activates JAK2/STAT3 signaling to confer cisplatin resistance 8. These findings identify ESPL1 as a prognostic biomarker and therapeutic target across human malignancies.