PDZK1IP1 (PDZK1 interacting protein 1) functions as an auxiliary protein for electrogenic Na+-coupled glucose transporters, being essential for SLC5A2/SGLT2 activity but not SLC5A1/SGLT1 1. The protein plays diverse regulatory roles across multiple biological pathways. In TGF-β signaling, PDZK1IP1 acts as a negative regulator by interacting with Smad4, preventing R-Smad/Smad4 complex formation and retaining Smad4 in the cytoplasm, thereby suppressing both TGF-β and BMP pathways 2. PDZK1IP1 demonstrates oncogenic properties in papillary thyroid cancer, where overexpression promotes cell proliferation and inhibits apoptosis, while knockdown has opposite effects 3. The protein also contributes to immune cell stemness programs, being part of a core stemness signature in exhausted CD8+ T cells that is suppressed by BCOR and ZC3H12A 4. In disease contexts, PDZK1IP1 shows elevated expression in alcoholic liver disease and serves as a potential biomarker in ulcerative colitis and Crohn's disease, where lower expression may predict positive treatment responses to ustekinumab 567. These findings highlight PDZK1IP1's multifaceted roles in glucose transport, cellular signaling, cancer progression, and immune regulation.