PDZK1IP1 is an auxiliary protein essential for the function of the sodium-glucose cotransporter SGLT2 (SLC5A2), which mediates renal glucose reabsorption 1. The protein interacts with transmembrane domain 13 of SGLT2 and is required for transporter activity, though it is not essential for the related transporter SGLT1. PDZK1IP1 also suppresses transforming growth factor-β signaling by binding Smad4 and preventing R-Smad/Smad4 complex formation, thereby inhibiting downstream TGF-β target gene expression 2. Clinically, PDZK1IP1 expression is dysregulated in multiple carcinomas. The protein is normally expressed only in the brush border of renal proximal tubular epithelial cells but is diffusely overexpressed in renal cell carcinoma, colorectal, breast, and lung carcinomas 3. In papillary thyroid cancer, high PDZK1IP1 expression correlates with poor progression-free survival, extrathyroidal extension, and lymph node metastasis; experimental overexpression promotes proliferation and inhibits apoptosis, while knockdown suppresses tumor growth 4. In oral squamous cell carcinoma, the microRNA miR-455-5p suppresses PDZK1IP1 to promote epithelial-to-mesenchymal transition and metastasis; low PDZK1IP1 expression predicts higher recurrence rates 5. In esophageal cancer, the RNA-binding protein FXR1 degrades PDZK1IP1 mRNA to promote tumorigenesis, and PDZK1IP1 restoration inhibits FXR1-mediated tumor growth 6.