ATP2A3 encodes SERCA3, a magnesium-dependent calcium pump that transports Ca2+ from the cytosol into the endoplasmic reticulum lumen, maintaining intracellular calcium homeostasis essential for cellular processes including muscle contraction and cell growth regulation 1. Mechanistically, ATP2A3 functions through ATP hydrolysis-coupled calcium transport and regulates calcium-dependent signaling pathways. In immune cells, linoleic acid promotes ATP2a3-mediated mitochondria-associated ER membrane formation, facilitating ER-to-mitochondria Ca2+ transfer and store-operated calcium entry, which elevates cytosolic Ca2+ to increase CTLA-4 surface trafficking on regulatory T cells 2. ATP2A3 also interacts with STING1 to regulate innate immune responses and selective autophagy of ER components 3. In cancer biology, ATP2A3 expression is typically downregulated in gastric, colon, and hepatocellular carcinomas, with epigenetic silencing through promoter methylation and repressive histone marks 4. Restoration of ATP2A3 expression through histone deacetylase inhibitors or resveratrol treatment increases apoptosis and reduces cell viability, with high ATP2A3 expression serving as a favorable prognostic marker 56. In primary aldosteronism, ATP2A3 upregulation drives aldosterone production through CYP11B2 expression regulation in response to angiotensin II and sodium restriction 7. ATP2A3 also emerges as a prognostic biomarker in nonspecific orbital inflammation, correlating with immune microenvironment changes including increased regulatory T cells and M2 macrophages 8.