PYGO1 is a chr15 reader and Wnt/β-catenin pathway co-activator that functions as a histone H3K4me3 reader 1 and forms dimeric PHD finger structures essential for association with BCL9 and Wnt transcriptional regulation 2. Mechanistically, PYGO1 interacts with histone modifications to activate β-catenin/TCF4 complexes and downstream Wnt target genes, driving cellular proliferation and differentiation programs 345. Clinically, PYGO1 dysregulation associates with multiple pathologies. Elevated PYGO1 expression promotes gastric cancer progression via the ITGB1/CD47 axis 1 and non-small-cell lung cancer proliferation and invasion 3. A GWAS identified PYGO1 variants (rs62021874) with close-to-genome-wide significance for hepatic steatosis in non-alcoholic fatty liver disease, suggesting Wnt pathway involvement in NAFLD pathogenesis 6. Conversely, PYGO1 overexpression in cardiac tissue drives pathological hypertrophy through canonical Wnt signaling, while PYGO1 inhibition ameliorates cardiac dysfunction 4. PYGO1 also shows dysregulated expression in congenital bladder disorders 7. The compound pentagalloylglucose inhibits PYGO1-H3K4me2/3 interactions, suppressing cancer progression 1. These findings establish PYGO1 as a tissue-context-dependent Wnt effector with potential therapeutic targeting applications.