Nherf1, also known as Na⁺/H⁺ exchanger regulating factor 1 or ezrin-radixin-moesin (ERM) binding phosphoprotein of 50 kDa (EBP50), is a PDZ domain-containing protein. It localizes at the plasma membrane and functions as a linker between membrane proteins and the cytoskeleton network. Nherf1 is involved in pathways such as the regulation of renal phosphate absorption, and in cancer-related signaling pathways like the PI3K/PTEN/AKT pathway [1,2,3,5]. It plays a crucial role in many biological processes including cell growth regulation and has significance in understanding disease mechanisms [1,3,5,7].

In cancer, depending on its subcellular distribution, Nherf1 can act as either a tumor suppressor when at the plasma membrane or an oncogenic protein when in the cytoplasm or nucleus. For example, in breast cancer, it inhibits the PI3K/Akt pathway via interaction with PTEN, and its cytoplasmic expression is associated with aggressive clinical parameters. In clear cell renal cell carcinoma, it shows nuclear and membranous expression, while in papillary RCC, it has membranous staining. In cervical cancer, down-regulation of Nherf1 is associated with cisplatin resistance, and overexpression enhances cisplatin sensitivity by inhibiting AKT and ERK signaling pathways. In liver cancer, repressing Nherf1 inhibits cancer progression by promoting ROS production, cell cycle arrest, and apoptosis [1,3,4,6,8].

In conclusion, Nherf1 is a key protein in regulating cellular functions and its role in diseases, especially cancer, is significant. Its subcellular distribution-dependent role in cancer, as well as its influence on drug sensitivity and cancer progression, as revealed through various in vivo-like studies, provides valuable insights into disease mechanisms and potential therapeutic targets.