FXYD3 (FXYD domain containing ion transport regulator 3) is a regulatory subunit of the Na+/K+-ATPase pump that modulates ion transport across cell membranes. Two human isoforms exist with differential expression patterns during cell differentiation, both associating specifically with Na+/K+-ATPase isozymes 1. The protein functions by decreasing apparent K+ affinity and increasing Na+ affinity of the pump, with isoform-specific effects on membrane potential sensitivity 1. FXYD3 facilitates sodium and liquid absorption in airway epithelia, localizing to basolateral membranes of all airway epithelial cells 2. In cancer, FXYD3 exhibits tissue-specific roles: it is downregulated in lung cancers where loss correlates with cytoskeletal disruption and cancer progression 3, yet upregulated in breast cancer stem cells with drug-tolerant persister characteristics 4. In psoriasis, FXYD3 enhances IL-17A signaling by competitively binding TRAF3, promoting inflammatory pathways 5. The protein also drives intrahepatic cholangiocarcinoma progression through IRF7 binding and JAK2/STAT5 activation 6. FXYD3's dual roles as both tumor suppressor in lung cancer and oncogene in other malignancies highlight its context-dependent functions in maintaining cellular homeostasis and disease pathogenesis.