FAM53B (family with sequence similarity 53 member B) is a nuclear protein that functions as a positive regulator of canonical Wnt signaling pathway. Its primary mechanism involves regulating β-catenin nuclear localization; FAM53B contains both a nuclear localization signal and a β-catenin interaction domain that are essential for facilitating β-catenin translocation into the nucleus, where it activates Wnt-responsive gene transcription 1. The protein colocalizes with β-catenin-dependent gene expression in mouse intestinal crypts, and mammalian FAM53B mediates β-catenin transcriptional activity in a dose-dependent manner 1. Disease relevance: FAM53B variants are associated with cocaine dependence, with genome-wide significant association identified at rs2629540 in both African- and European-American populations 2. In the brain, FAM53B represents a trans-eQTL candidate linking to cocaine intravenous self-administration behaviors in mice 3. Paternal preconception smoking, particularly during puberty, associates with FAM53B promoter hypermethylation in offspring, correlating with increased weight and BMI 4. Additionally, circular RNA derived from FAM53B (circ_FAM53B) shows altered expression in papillary thyroid carcinoma and ovarian cancer, functioning as a competing endogenous RNA to regulate oncogenic pathways 56. FAM53B methylation also shows smoking-dependent regulation in the human nucleus accumbens 78.