The functions of FXYD family members in human health and disease

The FXYD family (FXYD domain-containing ion transport regulators) proteins consist of short, single-pass transmembrane proteins that primarily regulate the Na⁺/K⁺-ATPase (NKA) pump, a key player in maintaining cellular ion homeostasis. Ranging from 60 to 160 amino acids in length, FXYD proteins display tissue-specific expression patterns and influence not only NKA activity but also the function of other ion channels, including potassium, sodium, and chloride channels. These proteins interact with NKA in diverse ways, modulating its activity to meet the specific needs of different tissues. In addition to their physiological roles, FXYD proteins are implicated in the development and progression of various diseases, such as cancer, cardiovascular disorders, renal diseases, and neurological conditions. This review offers an overview of the structures, biological functions, and molecular mechanisms through which FXYD proteins regulate ion transport. Furthermore, we explore their emerging roles in disease pathogenesis and discuss potential therapeutic strategies for targeting FXYD proteins in disease management.