PCDHB3 (protocadherin beta 3) is a calcium-dependent cell-adhesion molecule involved in establishing and maintaining neuronal connections and regulating cell-cell adhesion through cadherin-based mechanisms 12. The protein functions as a tumor suppressor in colorectal cancer, where it is frequently inactivated through mutations (5.19% of cases), copy number losses, and CpG island hypermethylation, with decreased expression observed in 81.6% of CRC tissues 1. Mechanistically, PCDHB3 suppresses cancer cell proliferation, migration, and epithelial-mesenchymal transition by inhibiting NF-κB transcriptional activity through K63 deubiquitination of p50, which competitively blocks p65 dimer-mediated transcription of pro-tumorigenic genes 1. PCDHB3 expression is also elevated in aggressive Stem-A ovarian cancer subgroup, suggesting context-dependent roles in cancer biology and involvement in non-canonical Wnt/PCP signaling pathways 2. In neurobiological contexts, PCDHB3 participates in cell adhesion pathways critical for normal development, with dosage-sensitive contributions to hippocampal function and spatial learning 3. Low PCDHB3 expression and cytoplasmic localization predict poor prognosis in advanced CRC, indicating potential clinical utility as a prognostic biomarker 1.