NHERF4 (also called IKEPP) is an epithelial PDZ domain scaffolding protein that functions as a negative regulator of intestinal fluid secretion and calcium absorption through multiple signaling pathways. Its primary function involves binding to and inhibiting guanylate cyclase 2C (GCC) activity 1. The PDZ1 domain of NHERF4 contains two catalytic region mimetics that interfere with GCC oligomerization and suppress cGMP production, thereby reducing enterotoxin-induced intestinal fluid secretion 1. Additionally, NHERF4 stimulates sodium-hydrogen exchanger 3 (NHE3) activity in response to elevated intracellular calcium through direct binding to NHE3's C-terminal domain 2. NHERF4 also negatively regulates the anion exchanger SLC26A3 through phosphorylation-dependent mechanisms, promoting its internalization from the plasma membrane 3. In renal cancer, NHERF4 is downregulated and acts as a suppressor of clear cell renal cell carcinoma invasiveness by inhibiting Mas receptor-mediated AKT/PLC signaling 4. Circadian regulation of NHERF4 protein abundance by the ubiquitin-specific protease USP2-45 controls calcium absorption in the small intestine 5. These findings establish NHERF4 as a multifunctional regulator of epithelial transport and a potential biomarker for ccRCC prognosis.