DLG5 is a membrane-associated guanylate kinase (MAGUK) scaffold protein that functions as a dual regulator of the Hippo signaling pathway, with opposing roles depending on its binding partners 12. It negatively regulates Hippo signaling by mediating MARK3-STK3/4 interactions to promote STK3 inactivation, while positively regulating the pathway through SCRIB-STK4/LATS1 interactions 1. DLG5 maintains epithelial cell polarity through its multi-PDZ, SH3, and GUK domains, similar to other MAGUK family members, and regulates cell proliferation, migration, adhesion, and epithelial-mesenchymal transition 34. Beyond polarity maintenance, DLG5 enhances dendritic spine formation and synaptogenesis by promoting N-cadherin cell surface localization, and acts as a positive regulator of hedgehog signaling at the ciliary base 2. Clinically, DLG5 displays context-dependent roles in cancer: it is overexpressed in pancreatic adenocarcinoma but reduced in lung, liver, breast, prostate, and bladder cancers 4. DLG5 gene polymorphisms associate with inflammatory bowel disease susceptibility in an ethnicity-specific manner, particularly the R30Q and P1371Q variants 5. Recent studies demonstrate that DLG5 upregulation suppresses osteosarcoma progression through AKT-dependent autophagy induction and Girdin-mediated migration inhibition 6.