CHFR is an E3 ubiquitin-protein ligase functioning as a mitotic checkpoint regulator that delays mitotic entry in response to microtubule stress 1. It mediates Lys-48-linked ubiquitination of substrates like AURKA and PLK1, promoting their proteasomal degradation, while also forming Lys-63-linked chains involved in stress signaling 2. CHFR is ubiquitously expressed in normal tissues but frequently inactivated in cancers through promoter hypermethylation, occurring in 34-67% of gastric cancers 34. Despite its canonical tumor suppressor role, emerging evidence reveals context-dependent pro-tumorigenic functions: CHFR overexpression paradoxically promotes gastric cancer metastasis by suppressing ROS generation and activating AKT/ERK through the NRF2 axis 5. Additionally, circular CHFR (circ-CHFR) contributes to atherosclerosis progression via miR-214-3p-dependent regulation of PAPPA and Wnt3/β-catenin signaling 67. Clinically, CHFR methylation status predicts docetaxel sensitivity in gastric cancer patients, with unmethylated CHFR associating with chemotherapy resistance and shorter survival 8, positioning CHFR methylation as a potential biomarker for personalized cancer treatment strategies.