PPFIBP2 (PPFIB scaffold protein 2) is a focal adhesion-associated protein with emerging roles in cancer progression and vascular biology. The protein may regulate focal adhesion disassembly [UniProt] and localizes to the cytosol and presynaptic active zones [GO annotations]. Functionally, PPFIBP2 appears to suppress epithelial-mesenchymal transition (EMT) and tumor invasiveness; YAP1-mediated suppression of PPFIBP2 expression enhances EMT and promotes invasion and migration in head and neck squamous cell carcinoma (HNSCC), with pharmacological YAP1 inhibition reducing these effects 1. Clinically, germline loss-of-function mutations in PPFIBP2 are strongly associated with lethal prostate cancer risk (OR=13.8 in Europeans) and predict shorter survival after diagnosis 2, while common genetic variants at the PPFIBP2 locus (rs12791447) are associated with prostate cancer susceptibility across Asian populations 3. Additionally, PPFIBP2 variants appear as candidates in other malignancies including carotid paragangliomas 4 and endocervical adenocarcinoma 5. However, PPFIBP2 variants show no significant association with interstitial lung disease in rheumatoid arthritis 6. These findings suggest PPFIBP2 functions as a tumor suppressor with therapeutic potential as a target for blocking metastatic progression.