FXYD2 is a small transmembrane regulatory protein that modulates Na,K-ATPase function across multiple physiological systems. As the gamma subunit of Na,K-ATPase, FXYD2 regulates ion transport by altering the enzyme's affinity for sodium and potassium ions while stabilizing the pump through interactions with phosphatidylserum and cholesterol 1. FXYD2 expression is particularly abundant in tissues with high active transport demands, including kidney, choroid plexus, placenta, and pancreatic tissue 2. Mechanistically, FXYD2 serves as an intermediary linking hormonal signaling to Na,K-ATPase regulation through phosphorylation by hormone-activated kinases 3. In pancreatic β cells, FXYD2 interacts with SRC kinase to regulate the FXYD2-SRC-TEAD1 signaling pathway, controlling genes necessary for glucose-stimulated insulin secretion and β cell maturation 4. FXYD2 dysfunction is associated with several disease states. Mutations in FXYD2 (G41R) cause autosomal dominant renal hypomagnesemia with hypocalciuria, where impaired FXYD2-Na,K-ATPase interaction leads to renal magnesium wasting 15. In neuropathic pain, FXYD2 loss efficiently alleviates mechanical hypersensitivity by modulating Aδ- and C-fiber mechanosensitivity 6. Elevated FXYD2 expression in cholangiocytes marks dysplasia risk in primary sclerosing cholangitis patients 7. These findings highlight FXYD2's critical role in controlling cellular ion homeostasis and its therapeutic potential in metabolic, renal, and pain disorders.