FXYD4 (also called CHIF, corticosteroid hormone-induced factor) is a small single-transmembrane domain protein that functions as a tissue-specific regulatory subunit of the sodium/potassium-ATPase (Na,K-ATPase) 1. FXYD4 associates with Na,K-ATPase as an auxiliary subunit and modulates its transport properties by altering the apparent affinity for sodium ions 2. Unlike FXYD1 which increases Na+ affinity, FXYD4 modulates Na+ affinity in an opposite manner, suited to physiological demands of different renal tubule segments 2. Mechanistically, FXYD4 stabilizes Na,K-ATPase by protecting against thermal and detergent-mediated inactivation through amplification of phosphatidylserum-protein interactions 3. FXYD4 is predominantly expressed in kidney and plays critical roles in renal sodium reabsorption and proper tissue-specific ion handling 1. Clinically, FXYD4 downregulation has been identified in clear cell renal cell carcinoma tissues 4, and altered FXYD4 expression serves as an independent prognostic factor for recurrence in colon cancer 5. Dysregulation of FXYD proteins' control of Na,K-ATPase may be implicated in pathophysiological states 6.