FLYWCH1 (FLYWCH-type zinc finger 1) is a transcription cofactor that functions as a negative regulator of Wnt/β-catenin signaling and chr16 architecture. It directly binds nuclear β-catenin and competes with TCF4 for β-catenin interaction, thereby suppressing transcriptional activation of Wnt target genes 1. FLYWCH1 localizes to peri-centromeric chr16 and interacts with H3K9me3-marked regions, facilitating gene silencing and heterochromatin maintenance 2. It plays a critical role in regulating transcriptional plasticity and DNA damage responses 3. In colorectal cancer, FLYWCH1 antagonizes β-catenin/TCF4 signaling to selectively suppress migration-associated genes (ZEB1, EPHA4) while increasing E-cadherin expression, reducing cell motility 1. Similarly, in acute myeloid leukemia, elevated FLYWCH1 expression negatively correlates with Wnt target genes and promotes cell cycle arrest 4. Loss of FLYWCH1 promotes platinum resistance in epithelial ovarian cancer through derepression of repetitive elements and altered H3K9me3 patterning 3, establishing it as a biomarker for chemotherapy response. Additionally, FLYWCH1 emerges as a master regulatory gene in coronary artery disease pathogenesis through expression quantitative trait loci analysis 5. Rare variants in FLYWCH1 have been implicated in recurrent spontaneous abortion and mitral valve prolapse, though pathogenic segregation remains inconclusive 67.