ATP1B3 encodes the β3 regulatory subunit of the Na+/K+-ATPase, a non-catalytic component essential for assembling the active pump complex with the catalytic α-subunit 1. The Na+/K+-ATPase hydrolyzes ATP to exchange Na+ and K+ ions across the plasma membrane, maintaining cellular homeostasis and membrane potential 1. ATP1B3 interacts with CASPR1 in brain microvascular endothelial cells to facilitate proper plasma membrane localization and glycosylation of the complete pump complex, supporting Na+/K+-ATPase activity required for glutamate transport 2. ATP1B3 exhibits context-specific disease relevance. In acute myeloid leukemia, ATP1B3 represents a selective paralog dependency: when its paralog ATP1B1 is epigenetically silenced, ATP1B3 elimination destabilizes the Na+/K+-ATPase pump, inducing AML cell death both in vitro and in vivo 1. In hepatocellular carcinoma, ATP1B3 is upregulated and functions as an independent prognostic factor correlating with poor overall survival and immune infiltration; silencing ATP1B3 represses HCC cell proliferation and migration while promoting apoptosis 34. ATP1B3 also restricts hepatitis B and HIV-1 replication through NF-κB pathway activation and cooperation with antiviral factor BST-2, increasing interferon-α and interleukin-6 production 56. Novel ATP1B3 fusion genes have been identified in oropharyngeal carcinoma 7. These findings position ATP1B3 as both a potential therapeutic target in hematologic malignancies and an oncogenic driver in solid tumors.