ORAI3 is a pore-forming subunit of calcium-selective channels at the plasma membrane, functioning as a mammalian-specific homolog that evolved from ORAI1 1. It assembles with ORAI1 and ORAI2 to form hexameric store-operated calcium (CRAC) channels that mediate calcium influx upon endoplasmic reticulum depletion, activated by the sensor protein STIM1 2. Notably, ORAI3 and ORAI2 generate oscillatory calcium patterns, contrasting with ORAI1's role in sustained calcium plateaus [UniProt]. ORAI3 uniquely forms arachidonate-regulated calcium (ARC) and leukotriene C4-regulated calcium (LRC) channels with ORAI1, enabling store-independent calcium influx in response to inflammatory metabolites 3. Structurally, ORAI3 adopts a dimer-to-tetramer transition during activation, distinct from ORAI1's tetrameric state 4. Pathologically, ORAI3 is overexpressed in multiple cancers including breast, lung, colorectal, and pancreatic adenocarcinoma, where it promotes cell proliferation, migration, and apoptosis resistance through calcium signaling 35. ORAI3 also participates in neuro-immune crosstalk within the tumor microenvironment 6 and contributes to vascular smooth muscle remodeling following injury 7. These findings position ORAI3 as a therapeutic target in cancer management.